PROBLEM DRUGS
Item
- Title
- PROBLEM DRUGS
- extracted text
-
Contents
. 1
.9
15
21
1A
IB
1C
ID
Introduction..............................
2A
2B
2C
2D
2E
Antidiarrhoeals............................................ 4/
3A
Antibiotics................................ .. 51
4A
4B
4C
Analgesics
Drugs and children..............
Women and drugs................
Drugs and the elderly..........
Antidiarrhoeals containing antibiotics ... 35
Hydroxyquinolines.............. .................. 41
Diphenoxylate.......................... '.... .... 45
Loperamide.................... ............ X .... 49
Dipyrone..........
NSAIDs............
.... 69
. . . .81
.... 87
Cough and cold preparations............... 97
5A
6A
6B
6C
Growth stimulants (Appetite stimulants
and anabolic steroids) .. •
.......... 105
Brain tonics.................. ........................ Ill
Vitamins............................
........ 119
125
137
143
7A
7B
7C
Drugs in pregnancy
8A
8B
8C
8D
8E
Contraceptives............................................ 14/
9A
Hormone replacement therapy............ 177
IDA
Psychotropics.............................................. 183
DES........................
EP drugs................
The pill.................................................. 157
IUDs...................................................... 163
Injectables............................................ 169
Implants................................................ 173
ndex............................................................... 197
0
Jseful Addresses............................................ 205
Acknowledgements.......................................... 207
Survey Form
3 Andrew Chetley and Health Action International (HAI-Europe), 1993
Researched and written by: Andrew Chetley
^over and text design: Publish. Amsterdam
’rinted by: Atlas BV
See acknowledgements for a list of those
vho helped in the preparation of this publication.)
-IP-gegevens Koninklijke Bibliotheek, Den Haag:
Chetley, Andrew
Problem drugs/ Andrew Chetley [researched and written;
?d. Barbara Mintzes]. - Amsterdam;
Health Action International (HAI Europe). - III. + folders
Viet index, lit. opg.
SBN 90-74006-06-X losbl.
MUGI 746,731
Frefw.: geneesmiddelen.
Problem Drugs is available from:
HAI-Europe
Jacob van Lennepkade 334T
1053 NJ Amsterdam. The Netherlands
price: DfI 30 + Dfl 5 to cover handling costs
Payments are to be made only in Dutch guilders please, using
Eurocheques. Postal Orders or credit card (VISA. Mastercard or American
Express). For credit card payments, please include your card number.
expiry date and a signature with your order.
Reduced rates available lor groups in developing countries and for
members ol HAI-Europe. Please write for details.
How to use this pack
you can use the information in this pack to do four
things:
• inform yourself
• inform others
. conduct local research
• campaign for change.
i.
Inform yourself about the problems related to
Abbrevratfons
AAMI
ADDH
ADR
AIDS
AMA
APMA
ARI
ATH
pharmaceuticals.
2. Inform others, such as local organisations, health
workers, the media and government officials, by
using the pack as the basis for news releases,
articles, talks, exhibitions, meetings and
discussions.
Conduct local research by selecting one or more of
the categories of problem drugs and examining the
situation in your community or country. Identify
local health workers, pharmacists and/or
pharmacologists who are willing to help with
technical information. You could:
a) obtain a list of all the products on the market
in one of the categories and compare them to
the medicines described in the pack to see if
they are appropriate;
b) use your local public library or a university or
medical school library to check medical journals
for promotion of inappropriate medicines
similar to those described in this pack;
c) visit pharmacies and health care facilities to
collect packages, package inserts and other
information on drugs mentioned in this pack,
and compare the information supplied. You '
could also conduct simple surveys on which
drugs are recommended for common
illnesses, such as diarrhoea or cough and
BGA
BMA
BNF
COC
CPMP
3.
DDD
DES
DMPA
DNA
DSM-III
EC
EFPIA
EP
FDA
HAI
HCG
Hib
HIV
HMG
HMO
HRT
IAAAS
4- Use the results of your research and the
IDRC
CanoTa10" ‘n thiS PaCk t0 Campaisn for cha"g*
Call on government authorities, companies and
ealth worker organisations to take action to
use ofarugs,„Xr:a.
IFPMA
important notice
Problem Drugs is not intended act x
If you have any questions ahn,,t treatment guide.
taking as a result of reading thi/ m®d'Clne you are
father information from a doc 0^ P'6aSe Seek
drug information service
pharmacist or
IKS
IOCU
ISIS-2
IU
IUD
MaLAM
MAOI
age associated memory impairment
attention deficit disorder with hyperactivity
adverse drug reaction
acquired immunodeficiency syndrome
American Medical Association
Australian Pharmaceutical Manufacturers
Association
acute respiratory infections
Programme for Appropriate Health Care
Technology (of the World Health
Organization)
German drug regulatory authority
British Medical Association
British National Formulary
combined oral contraceptive
Committee for Proprietary Medicinal
Products (of the European Community)
defined daily dose
diethylstilboestrol
depot medroxyprogesterone acetate (DepoProvera - contraceptive)
deoxyribonucleic acid
Diagnostic and Statistical Manual of Mental
Disorders
European Community
European Federation of Pharmaceutical
Industry Associations
oestrogen-progesterone (drug)
Food and Drug Administration (of the USA)
Health Action International
human chorionic gonadotrophin
Haemophilus influenzae type b
human immunodeficiency virus
human menopausal gonadotrophin
health maintenance organisation
hormone replacement therapy
International Agranulocytosis and Aplastic
Anemia Study
International Development Research
Centre (Canada)
International Federation of Pharmaceutical
Manufacturers Associations
Swiss drug regulatory authority
International Organization of Consumers
Unions
Second International Study of Infarct
Survival
international units (of vitamins)
intrauterine device (contraceptive)
Medical Lobby for Appropriate Marketing
monoamine oxidase inhibitor
minimal brain dysfunction
Market Intelligence Research Company
methicillin-resistant Staphylococci aureus
MRSA
Merck Sharp and Dohme
MSD
National Consumer Council (UK)
NCC
new chemical entities
NCEs
NEFARMA Association of Dutch Pharmaceutical
Industries
norethisterone oenanthate (contraceptive)
NET-OEN
National Institutes of Health (USA)
NIH
non-steroidal anti-inflammatory drugs
NSAIDs
oral rehydration solution
ORS
oral rehydration therapy
ORT
over-the-counter (drug)
OTC
Pan American Health Organization
PAHO
pelvic inflammatory disease
PID
premenstrual tension
PMT
progestogen-only pill (contraceptive)
POP
research and development
R&D
recommended daily allowance (of vitamins)
RDA
Swedish International Development
SIDA
Authority
x
subacute myelo-optic neuropathy
SMON
sexually transmitted disease
STD
United Nations Children's Fund
UNICEF
United Nations Educational, Scientific and
UNESCO
Cultural Organization
UNFPA
United Nations Population Fund
United States Agency for International
USAID
Development
Voluntary Health Association of India
VHAI
Working Group on Health and Development
WEMOS
Issues (Netherlands)
WHA
World Health Assembly
WHO
World Health Organization
MBD
MIRC
Terminology
*
antibiotics technically, antibiotics are only those
''
substances produced by microbes. Thus,
antibacterials or antimicrobials such as the
sulphonamides, the quinolones, and
trimethoprim are not strictly antibiotics.
However, in this pack, the term antibiotic
refers generally to all antibacterial and
antimicrobial drugs.
billion
one thousand million (1,000,000,000)
dollar or $ US dollar
PUT THE PEOPLE OF YOUR CONSTITUENCY ABOVE
PROFIT OR PRESSURE!
Fact Sheet for Policy Makers
•
•
•
•
•
India is one of the cheapest countries for drugs. For e.g. Ranitidine costs Rs. 6 for 10
tablets in India but costs Rs. 74 in Pakistan and Rs. 864 in the USA!
This was primarily because of the stance that India took of not allowing product patent,
thereby creating a vibrant pharmaceutical industry in India
In India there are 33 million diabetics, 20 million asthmatics, 4.5 million who suffer from
tuberculosis, 2 million from malaria and 5.1 million HIV AIDS patients
Low cost drugs are absolutely essential in a country like India where social/medical
insurance is not available
80 Countries are depending on India for their life saving Medicines!
Impacts of the Proposed Patent Amendment Bill: -
•
We have to adopt product patent as part of out TRIPS obligations, but we do not have
•
to adopt any measures beyond the TRIPS agreement
The proposed amendment goes beyond the TRIPS agreement
•
Given that Product patents will have serious public health impacts, we need to be careful
about the final amendment
•
Government would soon spend 10 times that of the current expenses meeting
public health and employee's drug needs if the present Amendment bill is passed
Note for instance the impact on
1.
Drug Prices
•
With Product patents, there is an absolute monopoly that is given to the owners of the
patent, which also means the absolute ability to control the price of the drug
o Patients suffering from Chronic Myeloid Leukemia (CML), a life threatening form of
cancer use an effective drug called Gleevec (sold by Novartis AG), is costing Rs.
1,20,000 while the generic versions are available at Rs. 9,000-12,000 per month.
However, the EMR granted to Gleevec is threatening the supply of generic drug.
o 4 years back HIV / AIDS drugs costed Rs. 4,50,000 per year but because of Indian
patent laws the same is now available at Rs. 7,500 per year! But these drugs could
go back to Rs. 4,50,000 once the Amendment is passed.
o
2.
A court case was won in South Africa to allow cheaper HIV / AIDS drugs
from India. But our government does not want to listen to this.
Argument of multinational Pharmaceutical companies
•
The larger Pharmaceutical companies claim that they need strong patent protection
because of the high costs involved in developing a new drug. But let the facts
speak for themselves
i.
ii.
iii.
•
•
Majority of Pharmaceutical spending is on marketing (35 %)
compared to R & D (14%)
Of the 14 % spent on R & D, the bulk is on non essential drugs like
Viagra etc
Much of R &D efforts are for new uses of old drugs rather than new
drugs
Finally very little is spent on R 8< D for new, essential drugs.
SO THE BILL SUBSIDISES THE MARKETING AND OTHER PROFIT MAKING COSTS
OF PHARMA COMPANIES WHEN THERE IS A GREATER OBLIGATION TO PROTECT
PEOPLE'S HEALTH
THE PRESENT GOVERNMENT PLANS A PRESIDENTIAL ORDINANCE ON SUCH AN
IMPORTANT ISSUE OF PUBLIC HEALTH INSTEAD OF A DEBATE IN THE PARLIAMENT!!!
- Your people
PUT THE PEOPLE OF YOUR CONSTITUENCY ABOVE
PROFIT OR PRESSURE!
Fact Sheet for Policy Makers
•
•
•
•
•
India is one of the cheapest countries for drugs. For e.g. Ranitidine costs Rs. 6 for 10
tablets in India but costs Rs. 74 in Pakistan and Rs. 864 in the USA!
This was primarily because of the stance that India took of not allowing product patent,
thereby creating a vibrant pharmaceutical industry in India
In India there are 33 million diabetics, 20 million asthmatics, 4.5 million who suffer from
tuberculosis, 2 million from malaria and 5.1 million HIV AIDS patients
Low cost drugs are absolutely essential in a country like India where social/medical
insurance is not available
80 Countries are depending on India for their life saving Medicines!
Impacts of the Proposed Patent Amendment Bill: -
•
We have to adopt product patent as part of out TRIPS obligations, but we do not have
•
to adopt any measures beyond the TRIPS agreement
The proposed amendment goes beyond the TRIPS agreement
•
Given that Product patents will have serious public health impacts, we need to be careful
about the final amendment
•
Government would soon spend 10 times that of the current expenses meeting
public health and employee's drug needs if the present Amendment bill is passed
Note for instance the impact on
1.
Drug Prices
•
With Product patents, there is an absolute monopoly that is given to the owners of the
patent, which also means the absolute ability to control the price of the drug
o Patients suffering from Chronic Myeloid Leukemia (CML), a life threatening form of
cancer use an effective drug called Gleevec (sold by Novartis AG), is costing Rs.
1,20,000 while the generic versions are available at Rs. 9,000-12,000 per month.
However, the EMR granted to Gleevec is threatening the supply of generic drug.
o 4 years back HIV / AIDS drugs costed Rs. 4,50,000 per year but because of Indian
patent laws the same is now available at Rs. 7,500 per year! But these drugs could
go back to Rs. 4,50,000 once the Amendment is passed.
o
2.
A court case was won in South Africa to allow cheaper HIV I AIDS drugs
from India. But our government does not want to listen to this.
Argument of multinational Pharmaceutical companies
•
The larger Pharmaceutical companies claim that they need strong patent protection
because of the high costs involved in developing a new drug. But let the facts
speak for themselves
i.
ii.
ill.
•
•
Majority of Pharmaceutical spending is on marketing (35 %)
compared to R & D (14°/o)
Of the 14 % spent on R & D, the bulk is on non essential drugs like
Viagra etc
Much of R &D efforts are for new uses of old drugs rather than new
drugs
Finally very little is spent on R & D for new, essential drugs.
SO THE BILL SUBSIDISES THE MARKETING AND OTHER PROFIT MAKING COSTS
OF PHARMA COMPANIES WHEN THERE IS A GREATER OBLIGATION TO PROTECT
PEOPLE'S HEALTH
THE PRESENT GOVERNMENT PLANS A PRESIDENTIAL ORDINANCE ON SUCH AN
IMPORTANT ISSUE OF PUBLIC HEALTH INSTEAD OF A DEBATE IN THE PARLIAMENT!!!
- Your people
PRICES OF MEDICINES WILL SOON RISEACT NOW OR PAY LATER!!
AFFORDABLEMEDICINES AND
TREA TMENT CAMPAIGN (AMTQ
Four years ago, millions of people living with HIV/AIDS could not afford the price
of antiretroviral (ARV) drugs. The price was between US$10,000 -12,000
(Approx.Rs.4,50,000 - 5,40,000) per annum. By 2003 the prices had come down
to US$ 140 (Rs.6300) per annum. How did this miracle happen? The answer lies
in the Indian Patents Act, which provides only process patent protection to
pharmaceutical inventions. However, after 31st December 2004, one cannot
expect a repetition of this miracle because India will have to change its patent
law and most of the new medicines will become just as costly as g/eevec.
G/eevec the most effective anti-cancer drug cost Rs. 1, 20, 000 per month
while the generic version is available less than one tenth of g/eevec. An
exclusive marketing rights for gleevec threatens the supply of generic drugs in
India.
Act now to keep medicine costs low!
What is a Patent?
A patent is a limited monopoly given to individuals/corporations for a limited number of
years for technological inventions /innovations by preventing others from using the
patented technology. It is granted at the request of individuals/ corporations by the Patent
Office in respective countries. Hence, the patent right is available within the territory of
the granting countries. Nearly 97% of the world’s patents belong to developed countries.
Broadly patents can be classified into process patent and product patent. A process
patent means that the monopoly is on the process of manufacturing the product and not
on the product per se. On the other hand, the product patent gives a monopoly on the
product itself that prevents others to manufacture, sell, distribute and import the patented
product without the authorisation of the patent holder. Hence, a product patent on drugs
means that only the patent holder can produce the patented drug in the normal
circumstances. Monopoly as a rule results in high price and put the patented drug out of
reach of majority of the people in India. On the other hand computation results in low
price.
For instance, till 2001 Antiretroviral (ARV) drugs, the only effective treatment for
HIV/AIDS, used to cost US$12000 per annum. The Indian drug companies, using the
non-availability of product patent in India, could bring down the price to US$140 per
annum within three years of their entry into the market. In 2001, the mere announcement
of availability of a generic drug forced the multinational Merck to cut down the price of
its ARV to US$800 per annum. Presently the generic companies supply these drugs at
$140 per annum.
The Future Scenario
Right now, the Indian Patents Act provides only process patents for inventions in the
pharmaceutical sector. As a result, more than one person is allowed to make the same
drug provided they use different process to make their version of the product (if the
process is protected by patent). Further, till 2002, the term of patents for pharmaceutical
inventions was only seven years. These two factors enabled competition in the market by
permitting more than one producer to produce the same drug. This resulted in the
phenomenal growth of pharmaceutical industry in India and increased availability and
accessibility of drugs. As a result drugs are available in India at world’s lowest price.
However, India must amend its Patent Act by 31 December 2004 to introduce product
patent regime to comply with Trade Related Aspects of Intellectual Property Rights
(TRIPS). TRIPS is part of the Final Act of Uruguay Round, which established the World
Trade Organisation (WTO). India signed the TRIPS Agreement to become a member of
the WTO in 1994.
The TRIPS Agreement prescribes universal minimum standards for seven types of
intellectual property rights, including patents. There is a time line for implementation of
obligations under the TRIPS Agreement. India amended its Patents Act in 1999 and
2002 to incorporate changes within the Patents Act to comply with the TRIPS
Agreement. These changes include extension of patent protection to microorganisms,
extension of the term of the patent protection, introduction of exclusive marketing rights
for drugs and agro-chemicals, etc. According to the TRIPS Agreement developing
countries like India should extend product patent protection to pharmaceuticals and agro
chemicals on or before 1 January 2005. Government is hurriedly trying to introduce an
amendment bill in the winter session of the Parliament (December 2004). The present
government has adopted the same bill introduced by the previous NDA government.
After the introduction of product patent protection only the patent holder or any
authorised person through license can produce the patented drug during the lifetime of
the patent. As a result, there would be only one manufacturer producing and distributing
the patented product Introduction of product patents means that drug companies in the
normal course come out with generic will not be able to do so until the expiry of 20
years of patented life. Further, the implementation of product patents cover all drugs
patented on or after 1 January 1995. Hence, the product patent regime reduces the access
to many new drugs and compromises the right to health. The impact of product patent in
India will not be visible immediately. However, the product patent will reduce the access
to new medicines.
Is There a Way?
Yes, certain measures can be incorporated on the Patents Act to ensure accessibility and
availability of drugs. India can safeguard its interest by using the manoeuvring space
available within the TRIPS Agreement. India has used some of these measures in the last
two amendments to the Patents Act safeguard the public interest. However, measures
have not been used at the optimum level to take maximum leverage. The main issues
with the present amendment bill are:
Patentability
The first step in this direction would be to deny usage and dosage patents. Contrary to
popular perception, there are many patents on a single drug mainly on their usage and
dosage forms. Such multiple patents on a single drug will extend the monopoly beyond
the expiry of original patent. A study shows that out of 1035 new drugs approved by the
US regulatory authority during 1989-2000 only 35% contains a new chemical entity.
However, the bill proposes to provide patents to new use of known medicines.
Compulsory License
A second step would be a total revamp of the compulsory licensing system. The present
compulsory license regime in the Patents Act is loaded with cumbersome procedural
formalities with no fixed time line. Fulfilment of these formalities itself delays the
granting of compulsory licensing unreasonably and reduces the compulsory license to an
ineffective mechanism to check monopoly.
Pre-grant Opposition
The bill proposes to do away with the pre-grant opposition procedure. Pre-grant
opposition gives the public to challenge the patent application before the grant of
patents. Therefore it is absolutely necessary to block the trivial patents.
>
>
>
>
PUT RIGHT TO HEALTH ABOVE PATENTS
SAY NO TO USAGE & DOSAGE PATENTS
RETAIN PRE-GRANT OPPOSITION
SAY NO TO TRIPS PLUS PROVISIONS
Other Required Amendments
♦
♦
♦
♦
♦
♦
♦
New definition for invention
Changes in the non patentable invention
Strengthen parallel importation
No change in the pre grant opposition
Introduce non voluntary license
Introduce ceiling on royalty
Strengthen local working requirements
For more details contact:
AMTC Secretariat, C/o Lawyers Collective HIV/AIDS Unit, 7/10, 2nd Floor, Botawalla
Building, Fort, Mumbai-400023. Tel: 91-22-22676213/9, Fax: 91-22-22702563
Email: amtc_india@yahoo. co. in
Act Up-Paris Press release - Monday December 6
Act Up-Paris had an action earlier today at the Indian Embassy. Pictures are on the web site They
transmitted the sign on letter to the secretary of the Ambassador. A meeting should be schedule later in the
week.
GaL
http://www.actupparis.org/portfolio2.php?id_document= 1510
Global access to medicines is threatened
The Indian government must postpone amending its patent law
Today December 6 2004, French aids activist group Act Up-Paris
demonstrated in front of the Indian consulate in Paris to protest
against Indian Industry Minister Mr Kamal Nath, whose recent policies
are threatening global access to generic medicines. Photographs are
available on www.actupparis.org
Minister Nath has announced a revision of the Indian Patents Act aiming
at putting India in compliance with its WTO obligations. But Mr Nath,
giving in to pressure from Washington and Western pharmaceutical
companies, is proposing amendments which, if enacted, will block the
manufacture and export of cheap generic drugs to AIDS-ridden countries
in Africa and Asia .
Starting January 1st, the WTO expects India to grant patent monopolies
on medicines to international drug companies. But India plays a unique
role in global access to medicines. According to WHO, India is the
world’s chief exporter of cheap generic drugs - primarily to poor
nations in Africa and Asia that have no pharmaceutical capability of
their own.
Due to the WTO patent process, several generics have already had to be
withdrawn from Indian pharmacies, such as the generic version of
anti-cancer blockbuster Gleevec, which the patent owner is selling at
57 000 dollars. Early next year, the top-selling HIV drug Combivir is
expected to undergo patent protection too, even though UN agencies
estimates that up to 30% of African AIDS patients receiving treatment
now are using one of the Indian generics of Combivir, such as Cipla’s
Duovir or Ranbaxy’s Avocom.
In this context, the survival of millions of indigent people with HIV
rests on India’s continued ability to make and export cheap generic
versions of new, effective HIV treatments. In 2001, the WTO recognized
developing countries’s right to circumvent drug patents through a
mechanism known as « compulsory licensing ». Yet Minister Nath intends
to rig India’s compulsory licensing system with unlimited injunctive
relief appeals that the WTO doesn’t mandate, and that the drug
companies have used to stifle the issuance of any license.
The activists from Affordable Medicines Treatment Campaign in India, as
well as Health GAP in the US and Act Up in France, demand that Mr Nath
implement a strictly enforceable deadline of one to three months for
the review of a compulsory license request, as well as the withdrawal
of injunctive relief in drug company’s rights of appeal. Activists also
stress that nothing is forcing India to amend its patent law in haste :
most other developing countries have managed to exceed the deadlines
set by WTO for complying with its patent norms.
Tomorrow Tuesday December 7, Affordable Medicines Treatment Campaign
organizes a march on Parliament in Delhi to request its amendments be
passed.
OPPOSE PATENT (AMENDMENT) BILL—WHY?
1. The Bill totally ignores the flexibility available within the Agreement on Trade
Related Aspects of Intellectual Property Rights (TRIPS) and compromises
accessibility and availability of medicines, agrochemicals, seeds, pesticides, etc. If
the bill in its present form becomes law, it will seriously compromise the right to
food and health.
2. The Bill proposes to extend the scope of patentability beyond the TRIPS
requirements by amending Section 3(d) of the Patents Act to provide patents to
new use of known medicines. There is no obligation under TRIPS to provide a
patent to either new use or new dosage of known medicines. The product patent
should be given only to new chemical entities and not to either new use or dosage
forms or any other forms of known molecules. This will limit the number of
patent protected drugs.
3. The Bill proposes to do away with the pre-grant opposition procedure. Currently,
there are approximately 6000 applications pending in the mailbox protection. In
the absence of pre-grant opposition, these 6000 applications would escape public
scrutiny. Public scrutiny is crucial in light of the fact that less than 500 drugs
have been granted marketing approvals in India between 1995-2004. Hence, pre
grant opposition is absolutely essential for blocking trivial patents. It is also part
of natural justice to give an opportunity to interested parties, including civil
society, to be heard before granting a monopoly.
4. The Bill has not properly incorporated the August 30th Decision of the TRIPS
General Council, which permits the grant of compulsory licenses for export
purpose to countries with no or insufficient manufacturing capacity in the
pharmaceutical sector. The Bill proposes to permit compulsory licensing to a
country with no or insufficient manufacturing capacity in the pharmaceutical
sector if there is a corresponding patent in the importing country. This ignores the
fact that in many instances, there may not be any patent protection in the
importing country because the deadline for Least Developing Countries (LDCs) to
comply with TRIPS is 2016. In this case, the Indian drug companies would not
be able to export to LDCs in the absence of a compulsory license granted by the
LDC.
5. Lastly, the compulsory license regime within the present Patents Act contains
cumbersome procedures without any time line for the final disposal of the
application. This renders the compulsory license system ineffective to curb abuse
of patents because procedural requirements take away the deterrent element of the
compulsory license mechanism.
6. The other safeguards in the present Patent Act, e.g. parallel importation, Bolar
provision, and experimental exception, should be amended to make use of the
TRIPS flexibility in its full extent.
What is a Patent?
• A monopoly given for limited years for
inventions
Patent & Access to Medicines
Anand Grover
Lawyers Collective HIV/AIDS Unit
• Available for products and process
Available in a territory, country, economic
union,
• Prevents another party without consent
from (making), using, offering for sale,
selling, importing the product or the
process
Lewycri Collective IITV/AIDS Unit
Patent: Implications?
Patent granted by the Patent Controller
-
Only single manufacturer in the normal course
-
Monopoly
-
No competition
-
High prices
-
Compromises accessibility & availability
-
e.g : ARV Drug
No Patent granted
-
More than one manufacturer
-
Competition
-
Lower prices
-
Availability^nd^e^l^creased
Lawyer* Collective HIV/AIDS Unit
Indian Patents Act 1970
• No product patent for drugs or chemicals
• Process patents only protected
• Protection only for only seven years
• Result: No monopoly in products
• More than one manufacturer
• Enabled competition
• Drugs are available at the lowest prices in
the world
• Compulsory Licenses to facilitate
availability & accesibility
Lawyer* Collective HIV AIDS Unit
1
TRIPS Patent Regime
Trade Related Aspects of Intellectual Property
Copyright, Trademarks, Geographical Indications,
Industrial Designs, Patents, Layout designs of ICs,
Undisclosed Information, Anti-Competitive
Practices
Laws have to be enacted in each signatory country
for protection of Intellectual Property
India is a signatory
Came into force on 1st January 1995
Applicable to inventions after 1st January 1995
Time period given for sets of countries to comply
India to comply with TRIPS by 31st December
^004
Uwyct» Collective UIV/AIDS Unit
TRIPS compliance in India
India has not used the flexibility in TRIPS
Already partially complied by 1999 and 2002 amendments
Patentable: Invention of a product or process which is
new, involves an inventive step (not obvious to person
skilled in the art) and capable of industrial application;
Excludes patenting of plants and animals except
microorganisms. Special law for plant varieties
Type of Protection: Provided for Products and Processes
Period- Provided 20 years for both
Interim period 1995 to 2004. Provided for Exclusive
Marketing Rights after Dispute Panel decision
Compulsory Licenses: Reasonable requirements of the
public. Not available at reasonably affordable prices,
invention not worked in India
Compulsory Licensing procedures very cumbersome
Uwjcn Collective HIV/AIDS Unit
TRIPS Patent Regime
Lays down minimum conditions for compliance
Allows for flexibility
Patentable: Invention which is new, involve an inventive
step and capable of industrial application, Excludes
patenting of plants and animals, except microorganisms and
varieties of plants
Type of Protection- For Products and Processes
Period of Protection. Minimum 20 years for both
Interim period 1995 to 2004. Provide for Exclusive
Marketing Rights
Minimum conditions for granting of compulsory license:
Consent, Judicial Review, Limiting Period
CL. Consent not required in cases of national emergency,
extreme urgency, non-commercial public use, anti
competitive practices
LaHycrsCollectivelllV/AlDS Unit
3rd Bill: New Use
Section 3 excludes patentability of• Invention which is frivolous or obvious
• Mere discovery of scientific principle
• Discovery of a living thing or non-living substance
occurring in nature
• Mere discovery of a new property
• Discovery of (mere) new use of a known
substance
• Substance derived from a mere admixture of
existing substances
The word mere will result in endless litigation. It
needs to be deleted
from all of Section 3
Lawyeri Collective IIIV/A1DS Urut
2
Grant of Patent: Extant Procedure
Examination and Publication
• To check for patentability and exclusion
• Application is complete with specifications
• Check for anticipated publications
• Check for prior claims: Assign Priority date
• Acceptance complete specification
• Publication of complete specification
• On publication the applicant has rights of patent
holder but cannot sue for infringement
Pre-Grant Opposition: Procedure
On publication of acceptance of complete specification any
person may oppose on the ground that the invention-•
has been wrongfully obtained
•
has been published before the priority date claimed
•
claimed is in the public domain
•
does not involve an inventive step or is not patentable
•
has been anticipated by local community knowledge
There is another application with an earlier priority date
Oppositionist is entitled to be a party to the patent grant
proceedings
lj'*vtr»Collective 1IIV ALDS Uni!
Lauym Collective HIV/AIDS Unit
Pre- Grant Opposition: 3rd Bill
Compulsory Licensing: 3rd Bill
Applicant may be granted a patent by the Patent Controller
Chapter VIII
Patent can be revoked by the High Court on many more
grounds
Pre-grant limited to
•
Patentability novelty, inventive step, industrial
application
•
Non-disclosure/ wrongful information given relating to
source or geographical origin of the biological material or
anticipation of local or community knowledge
Oppositionist is not entitled to be a party to the patent
proceedings
Patent applicant has rights to patent holder on publication of
application but can sue only of grant of patent,
retrospectivelyu>,mC(-l(dlvefllv/Aro5Ullit
There is no change of CL procedure still
cumbersome
Compulsory License can be granted only if the
country to which the product is being
exported is the without or insufficient
manufacturing capacity and has granted a
compulsory license for that product
Most countries without or insufficient
manufacturing capacity are LDCs which
do not have patent regimes. Therefore they
have no law for granting of CLs
U*)tn Collective HIV'AIDS Unit
3
EMR ON GLEEVEC
25,000 cancer patients per year suffer from
Chronic Myeloid Leukemia annually
EMR ON GLEEVEC
April 1992 (Switzerland): Original patent application
claiming wide spectrum compounds including salts
July 1997 (Switzerland): Subsequent patent application
p-crystalline form of “Imatinib mesylate”
available for treatment of CML
2003: Novartis’s Branded version of Imatinib
mesylate “Gleevec” priced at: Rs 120,000 (USD
2400) per month per person.
2003: Generic versions available at Rs. 8,500
(170USD) to 12,600 (252 USD ) per month.
I
Collective 1 IIV.’AIDS Unit
(1764/97) claiming p-crystalline form of the salt.
July 1998 (Australia): Subsequent application filed
claiming priority from ’97 Swiss application
13.08.2001 (Australia): Marketing approval granted
28.02.2002(Australia): Patent granted
4.12.2001 (India): Marketing approval granted
March 2002 (India): EMR application filed using grant
of Australian patent application and marketing
approval
10 December 2003 (India): EMR granted to Novartis for
Gleevec
EMR ON GLEEVEC
Original patent is PRE-1995 (not patentable)
Subsequent application is not patentable [S.3(d)
&(e), Patents Act, 1970]
EMR granted in India on the basis of grant of
patent and marketing approval in Australia
EFFECTS:
- High Court injunction against six generic drug
manufacturers
- Suit pending against the lone generic
manufacturer presently producing generic
version of Gleevec
- Access denied
to 25,000 CML patients annuallyJ
UvvjcnCollective UTV/AIDS Unit*
4
z<
Chetley, A. Problem Drugs, Amsterdam,
=•vTY
f-?
/o'/"z ’.iBRAm
Health Action International, 1993
'
ano
S; ■
X'-'
Health Action International’s
coordinating offices:
HAI Europe
Jacob van Lennepkade 334T
, .
1053 NJ Amsterdam
The Netherlands
10A. Psychotropics
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accion para la Salud
Avda. Palermo 531
Dpto. 104
Lima 13
Peru
Tales of dependence
Tess Higham went to her doctor suffering from exhaustion
and anxiety. The doctor prescribed antidepressants and
sleeping tablets. This prescription began a dependency on
psychotropic drugs that lasted for 21 years. The last five
years of this period she was on triazolam (Halcion). She
says: “I have lost 21 years of my life by being on drugs and
the last five were the worst while I was on Halcion. I have
forgotten many things and feel that 1 have undergone
chemical lobotomy.”1
Peter Ritson was working in a hot climate for some time
and found it difficult, to sleep. He was prescribed a benzo
diazepine tranquilliser to take every night. That was the
start of a 12-year addiction to the drug, an addiction that
took him two years to recover from.2
Psychotropic drugs are powerful agents of mood
change. All carry some risk of side effects and in
many cases give rise to psychological or physiologi
cal dependence. They can also be dangerous in
overdose.
There are four main types of psychotropics:
• hypnotics, used to treat sleeping problems;
• tranquillisers or anxiolytics, used to treat anxiety;
• antidepressants, used to treat depression; and
• antipsychotics, used to treat the major psychoses.
The box on page 184 lists some of the many drugs in
each of these categories.
The global market for psychotropic drugs was worth
S4.4 billion in 1991, and is expected to reach $7.6
billion by 1996.’ Table 10A-1 gives the breakdown
of sales according to the main types of drugs. The US
market alone was estimated at $3.3 billion in 1991
and is expected to reach $6.4 billion by 1997.
Psychotropic drug prescriptions represent nearly
20% of total prescriptions in the USA.4
Table 10A-1
World Market for Psychotropic Drugs (1991)
Therapeutic type
World Sales 1991
$ Million
Hypnotics
406
Anti anxiety drugs
1,200
Antidepressants
1,500
Antipsychotics*
1,244
Total
4,350
* includes anti-epileptics and drugs to treat Parkinson's disease
Source: FIND/SVP. The Market for Psychotropic Drugs. New York.
FIND/SVP. 1992. cited in: Anon.. ‘ Psychotropic sales $7.6 bill by
1996’", Scrip, No 1720. 22 May 1992, p26
i o A .
Psychotropics
The growth of addiction:
barbiturates
The early history of drugs to treat anxiety and sleep
disorders set out a partem of addiction that continues
today. One drug after another was introduced as the
safe replacement for an addictive drug, only to prove
in time also to be addictive. First it was alcohol and
opium; then morphine, cocaine and heroin; then
chloral, bromides and barbiturates; through into ben
zodiazepines and their most recent replacements.5
Among these drugs, barbiturates were popular for
some time. Their original purpose was to sedate
heavily or induce sleep. There are many similarities
among barbiturates and they can be used interchange
ably, but they have been promoted as if they were
thoroughly different. They were also originally
thought of and often promoted as safe. Veronal, intro
duced by Bayer, exemplifies the pattern. It was the first
barbiturate, marketed in 1903, and was advertised as
“absolutely safe and without toxic effects”. Within 10
years, reports of fatal overdose emerged.6
The recognition of dependence on rhe drugs came
much later. This was partly due to the failure to
define precisely the terms addiction, habituation,
tolerance and dependence. There was much confu
sion among the four. Because barbiturates were
prescribed for long periods in individual patients,
withdrawal syndromes were rarely identified. When
withdrawal did become evident upon discontinua
tion of the drugs, this was mistaken for a recurrence
of the original condition and the patient would be
put back on therapy.
By the 1950s, the evidence was incontrovertible that
barbiturates were true drugs of addiction, but over
prescribing continued. In rhe UK, barbiturate
consumption more than doubled in the 1950s and
continued to rise into the next decade. A 1962 edi
torial in The Practitioner suggested that too many
doctors were taking the line of least resistance and
“prescribing barbiturates as a blunderbuss remedy
for all the anxieties and stresses” of life.7
Barbiturates are still on the market in most countries.
Their only dubious distinction “is that of being the
drugs of choice for suicide, for which they are
extremely effective”.8 They should not be used to
treat anxiety,9 or as sedatives.10 They have few indi
cations today, other than as anticonvulsants to
control epileptic seizures, as anaesthetics, and for a
diminishing number of elderly people who have been
using them for many years and for whom withdrawal
would be dangerous.
Barbiturates have often been combined with other
drugs such as analgesics, antispasmodics, anti
migraine and anti-asthma products. There is no
justification for these combinations.103
Types of psychotropic drugs
Hypnotics
Benzodiazepines
flunitrazepam
loprazolam
lormetazepam
nitrazepam
temazapam
triazolam
Others
chloral hydrate
chlormethiazole
chlormezanone
dichloralphenazone
methyprylone
triclofos sodium
zopiclone
Antihistamines
promethazine
Barbiturates
amylobarbitone
butobarbitone
cyclobarbitone
heptabarbitone
phenobarbitone
quinalbarbitone
Anxiolytics/Tranquillisers
Benzodiazepines
alprazolam
bromazepam
chlordiazepoxide
clobazam
clorazepate
diazepam
ketazolam
lorazepam
medazepam
oxazepam
prazepam
Others
buspirone
chlormezanone
meprobamate
Antidepressants
Tricyclics/Cyclics
amitriptyline
butriptyline
clomipramine
desipramine
dothiepin
doxepin
imipramine
iprindole
lofepramine
maprotiline
mianserin
nortriptyline
protriptyline
trazodone
trimipramine
viloxazine
Monoamine oxidase
inhibitors
iproniazid
isocarboxazid
phenelzine
tranylcypromine
Others
flupenthixol
fluvoxamine
lithium
tryptophan
Anti-psychotics
Phenothiazines
chlorpromazine
fluphenazine
methotrimeprazine
pericyazine
perphenazine
prochlorperazine
promazine
sulpiride
thioridazine
trifluoperazine
Butyrophenones
benperidol
droperidol
haloperidol
trifluperidol
Diphenybutylpiperidines
fluspirilene
pimozide
Thioxanthenes
chlorprothixene
flupenthixol
zuciopenthixol
Others
oxypertine
i o A .
Taming people:
the benzodiazepines
The benzodiazepines gradually superseded barbitu
rates as treatments for anxiety and sleep disorders
during the 1950s and 1960s. Before they were introduced, the first alternatives to the barbiturates in the
1950s were products such as meprobamate, a
barbiturate-like substance. Although drugs like this
were claimed to be much safer, they too produced
dependence. Meprobamate is less effective than ben
zodiazepines, has a higher risk of drug addiction, is
more dangerous in overdose, produces more adverse
effects, and has no advantage over the benzodi
azepines." Despite these problems, in 1984 doctors
in the UK wrote 150,000 prescriptions for one
brand of meprobamate (Equanil).12 The British
National Formulary considers it “less suitable for
prescribing’’.13
The benzodiazepines - now among the most fre
quently prescribed drugs worldwide" - owe their
existence to a chance discovery. A few hundred mil
ligrams of a chemical substance lay forgotten in the
corner of a Hoffman-La Roche laboratory after its
first synthesis by chemist Dr Leo Sternbach in 1955.
Other projects in the lab had taken priority and it
was not until a clean up two years later that the sub
stance was rediscovered and tested. The new
chemical - called chlordiazepoxide - was found to
tame aggressive animals without seeming to sedate
them. The new drug was subsequently marketed as
Librium, and the benzodiazepine era was born.15
Roche launched Librium in 1959. Almost inevitably,
the first reports of dependence of the barbiturate type
appeared in 1961.16 By 1963, Roche had cornered
the anti-anxiety market with the launch of a second
benzodiazepine, diazepam (Valium), which became
the most widely prescribed drug of this type. It also
became the benchmark for the entire class of sedative
chemicals. Safety, particularly in overdose, was a
prime selling point. However, Valium, like Librium,
was found to cause dependence. So too was Roche’s
third benzodiazepine, nitrazepam (Mogadon),
launched in 1965 as a sleeping pill.
A clear pattern was emerging with these and the later
benzodiazepines: the product, although similar to its
earlier rivals, was launched with extensive promo
tion that focused on the safety of the drug compared
to barbiturates, that failed to mention the possibility
of dependence, and that tried to define a fragile dif
ference on the basis of poorly controlled trials.
However, benzodiazepines are far from safe.
Between 15 and 44% of long-term users become
dependent on the drugs.17 Overdose is also a prob
lem. In 1988, nearly 1.4 million incidents of overdose
were identified in the USA. Benzodiazepines
accounted for the highest number of toxic exposures
Psychotropics
reported in patients older than 17 years of age, and
they increased morbidity and mortality in incidents
of mixed overdose.18
Common side effects of these drugs include: drowsi
ness, light-headedness, sedation, lack of coordination,
difficulty in walking. More rare adverse effects include
dizziness, headaches, stomach aches, skin rashes,
blurred vision, changes of libido, slurred speech, blood
disorders, and jaundice.19 The elderly are more sensi
tive to these adverse effects, many of which can be
mistaken as signs of senile dementia. The lack of coor
dination is a concern as it can lead to fails and hip
fractures.20 Diazepam, in particular, was found to
have a high association with falls, leading researchers
to suggest that it should not be used in the elderly.21
(See the box on page 194 on psychotropic drugs and
the elderly.)
Long-term use of benzodiazepines may cause
psychological impairment and brain damage.22 Even
temporary use of a benzodiazepine could provoke
long-term, sometimes permanent changes in the
brain. Neuroscientist Prof. David Grahame-Smith
says, “just as experience alters our future behaviour
so do drugs”.23
One researcher has stated that the effects of the
shorter acting benzodiazepines such as alprazolam
(Xanax by Upjohn) can induce “a fundamental
change in rhe homeostasis (tendency towards chemi
cal equilibrium! °f rhe brain”. It can take the brain
from six to 18 months to recover after use of the drug
has been stopped.2'1
Some commentators have even argued against the
use of benzodiazepines in severe anxiety and sleep
disturbance. They claim that benzodiazepines simply
do not work and do more harm than good by creat
ing anxiety and insomnia in the long run. Gavin
Andrews, Professor of Psychiatry in Australia, says
that “benzodiazepines do not cure any anxiety disor
ders - they suppress symptoms which may return
when the drug is stopped”.25 That opinion is
reinforced by Samuel Cohen, a British psychiatry
professor, who says, “the time has come to stare
clearly that there is no use for these drugs in the treat
ment of anxiety.”26
Overprescribing
At least 25 types of benzodiazepines have been mar
keted over the years.27 There is little to choose among
the benzodiazepines in terms of either safety or effi
cacy. “As far as any real distinctions between the
differently labelled pills are concerned, they are as
subtle as those between a brick and a half brick.”28
With so many brands available, encouraging a “pill
for every ill” mentality, doctors not only began to
overprescribe but also to overdiagnose - to seek a
match between complaints from a patient and the
186' 10A.
Psychotropics
Problem Drugs
descriptions of symptoms found on the advertise
ment for the latest benzodiazepine. As one
commentator puts it, “whether or not our patients
are hooked on the drugs, the doctors are certainly
hooked on the diagnoses”.25 (See the box on page
188 about some of the many reasons that people
have been prescribed benzodiazepines.)
In the right hands, at the right dosage, for the right
length of time, benzodiazepines can be useful. They
can give a person valuable breathing space and time
when an emotional crisis becomes intolerable.
However, the powerful chain of production, pro
motion and prescribing grossly distorts the
appropriate use of these drugs.
In the UK, the Committee on Safety of Medicines
(CSM) advises that benzodiazepines should only be
used for the short-term relief (two to four weeks
only) of anxiety or insomnia that is severe, disabling
or subjects the individual to extreme or unacceptable
distress. Their use for “mild” anxiety is inappropri
ate and unsuitable.30
Unfortunately, misuse through overprescribing is
common. In the UK, there is “appalling clinical prac
tice” by some prescribers who do not attempt to
make a proper diagnosis before prescribing benzo
diazepines.31 During a three-month period, as many
as 73% of general practitioners and 68% of consul
tants in one UK health authority were found to have
prescribed a psychotropic drug to a child of 17 years
or younger.32 In South Africa, one report concluded:
“it cannot be postulated that the majority of
patients who were prescribed
benzodiazepines for anxiolysis in this
hospital were experiencing severe anxiety.
The use of these compounds in this context
is therefore unwarranted."33
In France, pharmacists believe that doctors give in
too readily to patients’ demands and overprescribe
benzodiazepines for minor states of anxiety and
“poorly defined morbid symptoms and states”,
thereby “taking refuge in the prescription”.34 In
Barcelona, Spain, a 1990 study found widespread
overuse of psychotropics, two-thirds of which were
benzodiazepines.35
In Canada in the mid-1980s, about one in 10 people
used a benzodiazepine at least once a year. Of these,
again one in 10 continued their use formore than one
year.36 In the UK in 1985, more than 23% of the
population took a tranquilliser at least once during
the year. Of these, 35% (3.5 million people) took
tranquillisers for periods of four months or more, the
time after which the drugs no longer help, and far
longer than they should normally be prescribed.37 In
1987, there were about 25 million prescriptions for
benzodiazepines issued in the UK - 15 million for use
as hypnotics and 10 million to treat anxiety.38
Women and psychotropic drugs
Many studies show that women throughout Europe and
North America are prescribed tranquillisers twice as
often as men.1 It is not uncommon for women who were
prescribed a short course of tranquillisers for some
reason to still be taking the drug some 10 or 20 years
later.2 More than two-thirds of prescriptions for
antidepressants in the USA are for women.3
There are many opinions as to why women are
prescribed more psychotropic drugs. Simplistic solutions
to this question are suggested by some studies, which
show that they are more likely to suffer from psychiatric
problems than men4 and by others, which suggest that
women complain more than men.5 However, both these
explanations may hide more fundamental problems
related to women’s status in society. Women are more
likely to be engaged in low-paid jobs outside the home,
or be working in isolated situations at home. There may
be a lack of external childcare facilities, unequal
distribution of responsibilities for childcare within the
family, and a breakdown of support from the traditional
extended family. An increasing number of households in
many countries are headed by a woman who has the
sole responsibility for bringing up her children and for
earning the principal income. A large proportion of these
households face disadvantage and poverty - all
contributory factors to anxiety, stress and depression.
Doctor's attitudes can contribute to women receiving
more psychotropic drugs. Doctors will often perceive a
woman's physical complaint as inherently psychological
and thus give mood-changing drugs.4 This is not helped
by the images used in much of the promotional material
for psychotropic drugs. Women are more often
portrayed as suffering from diffuse emotional
symptoms, while men are shown suffering from anxiety
as a result of work or accompanying organic disease.6 In
the USA, Pfizer s promotional material to launch its new
antidepressant, Zoloft (sertraline), features a woman in
her thirties who is able to move “from depression... into
the mainstream" as a result of the drug.7
Frequently the woman is targeted on behalf of her
family: “Treat one... six people benefit", was how one
advertisement expressed it, while showing a picture of a
family with the focus on the mother.8
Many women find it difficult to get support in coming off
the drugs. Self-help groups that have formed in many
countries in recent years are one step in the right
direction, helping women gradually to come off
tranquillisers. More effective, however, would be efforts
to prevent misprescribing and overprescribing to
women, and to ensure that tranquillisers stop being
used as a solution for social problems.
i o A .
Psychotropics
i8;
Problem Drugs
Sandoz promotion for doctors in India in 1990 suggesting
that women be prescribed an antipsychotic, thioridazine.
instead of diazepam
Sources:
1.
Balter, A., et al, "A cross national comparison of anti
anxiety and sedative drug use”, Current Medical Research
and Opinion. Vol 8 (Suppl. 4), 1984, pp518
2.
Phillips. A , Rakusen, J. (eds) and the Boston Women's
Health Collective. The New Our Bodies, Ourselves (2nd UK
edition), London, Penguin Books, 1989, p68
3.
Breggin, P., Toxic Psychiatry, London, Fontana. 1993,
pl86
4.
Ashton. H , “Psychotropic drug prescribing lor
women". British Journal of Psychiatry, Vol 158 (Suppl. 10).
1991. pp30-5
5.
Unlenworth, E.H., et al. "Symptom checklist
syndromes in the general population", Archives of General
Psychiatry. Vol 40, 1983, ppi 167-73
6.
Prather. J E. and Fidell, L S., "Sex differences in the
content and style of medical advertisements" in: Gabe, J
and Williams, P., Tranquillisers - social, psychological and
clinical perspectives. London and New York. Tavistock,
1986. p90
7.
Critser. G , “Dealing a new antidepressant”, Harper's
Magazine. May 1993, pp54 5
8.
Prather, J.E. and Fidell. L.S., op cit
Upjohn ad for an antidepressant, fluvoxamme (Faverin), The Lancet. 12 Dec 1992
188 10A.
Psychotropics
Problem Drugs
But it is not only the doctors and patients who are
hooked. The chain of dependence leads to the drug
companies as well. Many companies that market ben
zodiazepines rely heavily on the income from their
products and invest proportionately in marketing and
sales representatives to ensure a steady flow of
income.39 When concerns were raised about the safety
of Upjohn’s triazolam product, Halcion, (see box on
page 189 for details), the drop in sales contributed to a
2% decrease in the company’s total operating profit
during the first nine months of 1992.40
Swans and teddy bears: the new generation
The pharmaceutical industry is following up the com
mercial success of benzodiazepines with a new wave
of products. One of these, buspirone (BuSpar by
Bristol-Myers), is described as being “as easy to stop
taking as it is to start”.41 This idealised picture has led
to promotion depicting an air traffic controller who
needed “anxiolytic therapy, but alertness is part of his
job” or, the image of a swan swimming serenely on
calm waters: “Anxiety therapy pure and simple”.
Advertisements claimed there was no evidence of
dependence or abuse potential. But it may simply be
too early to know. “We need much more information
about its benefits and risks over time”, is the way one
guide to drug use expresses it.42 In the USA, product
information makes it clear that “the efficacy of bus
pirone for more than three or four weeks has not
been demonstrated in controlled trials”.43
Why people have been prescribed
tranquillisers
bereavement
emotional upsets
nursing a sick wife
husband's accident
socialising
after the flu
dry eyes
hysterectomy
alcohol problem
alcoholic father
sexual abuse
stomach trouble
business problems
coping with:
active/crymg baby
handicapped child
demanding mother
shift work
bankruptcy
fear of dying
lack of confidence
homelessness
mother committed
suicide
jury service
work pressure
loss of hearing
interview nerves
dizziness
stroke
shyness
childhood insecurity
isolation
family problems
broken neck
change of job
violent husband
prison
infertility
cystitis
cooker blew up
claustrophobia
illness
postnatal depression
exam nerves
fatal illness
disc trouble
divorce
menopause
bad fall
rugby injury
rape
car crash
headaches
back pain
mastectomy
thyroid
driving test
cat died
redundancy
hay fever
vertigo
palpitations
moving home
asthma
retirement
abortion
Note: These reasons were given in inquiries to a UK organisation
(TRANX), which provided help to people addicted to tranquillisers.
Source: Jerome, J. and Bilgorri, L, The Lost Years: tranquillisers and afterme enect minor tranquillisers can have on our life and our families, LondonVirgin Books, 1991, p24
Rhone-Poulenc advertisement for zopiclone
(Zimovane), The Lancet, 17 Aug 1991
1 o A ,
Psychotropics
lem Drugs
Halcion: a scandal?
■
i
I
By the end of the 1970s, concern had grown about
the hangover effects of the longer acting
benzodiazepines. Upjohn introduced a short acting
hypnotic, triazolam, sold as Halcion or Somese. The
promotional material said that "when short-term
problems cause insomnia, triazolam lets patients
sleep on them'’.
•
While the drug did not accumulate in the body,
reports of side effects quickly accumulated. An early
Dutch report said triazolam could cause acute
psychosis, paranoia and confusion. The Dutch
government subsequently banned the drug in mid1979. It was allowed back on the market in the
Netherlands in a reduced dosage form in 1990.
,
In other countries, the controversy waxed and waned.
Reports of memory loss, confusion, bizarre and
abnormal behaviour surfaced all over the world.
Professor Ian Oswald, a specialist in sleep disorders,
said in 1982 that the combination of short half-life
and long interval between doses led to daytime
anxiety.1 Tolerance to the drug's hypnotic effects was
also identified as a problem, as was rebound anxiety
when the drug was stopped. Seven years later,
Oswald said that Upjohn had not properly
investigated these effects with long-term trials. He
claimed that triazolam "should never be sold".2 Other
critics agreed, arguing that the drug was not an
efficient hypnotic in the first place, and the evidence
of adverse effects only reinforced its undesirable
nature. “The social consequences and even criminal
potential of triazolam are frightening."3
that the use of Halcion had caused her to become
violent and kill her mother in 1988. She went on to
sue Upjohn for damages and the case was settled out
of court in 1991. Some of the evidence that emerged
indicated that errors had been made in reporting the
information from one of the early clinical trials of the
drug, errors that downplayed the possibility of serious
psychological side effects. After reviewing this
information, the UK Committee on Safety of
Medicines (CSM) asked Upjohn to withdraw the drug.
When the company refused, the CSM withdrew the
drug's licence. This triggered off a wave of
withdrawals in at least 13 other countries 4 In April
1993, the Medicines Commission in the UK, an
advisory body to the Ministry of Health,
recommended re-instating Halcion.5 However, the UK
government decided to keep the drug off the British
market because of concerns about its safety.6
In several other countries, the drug has been allowed
to remain on the market, but at reduced dosage
levels. However, there is little evidence to support
claims that triazolam has distinct advantages over
other drugs in its class. An editorial in the British
Medical Journal makes the point that memory
impairment, psychiatric disturbance and rebound
insomnia are “more common" with triazolam than
with other benzodiazepines. The editorial concludes:
“triazolam has no compelling singular benefits that
outbalance its risks".7
It was the possible link between the drug and criminal
behaviour that led to widespread publicity of some of
these concerns in 1991. Mrs llo Grundberg. accused
of murder in the USA, was acquitted after claiming
References:
1.
Morgan. K. and Oswald. I., '’Anxiety caused by a short-life
hypnotic". British Medical Journal, 27 Mar 1982. p942
2.
Oswald, I.. "Triazolam syndrome 10 years on”, Lancet. 19 Aug
1989, pp451-2
3.
van der Kroef. C. "Triazolam", Lancet, Vol 338. 6 Jul 1991, p56
4.
Anon., "Upjohn’s CNS sales down". Scrip, No 1776. 4 Dec 1992.
pH
Most textbooks have also ignored a potentially haz
ardous problem with buspirone. Unlike minor
tranquillisers, it affects the dopamine receptors,
blocking their activity. Suppression of dopamine
activity by neuroleptics or major tranquillisers such
as chlorpromazine (Largactil) is known to cause
tardive dyskinesia (repetitive movements of the
hands, wrists, lips, tongue and jaw). While
Graham Dukes, professor of Drug Policy Studies at
Groningen University, calls the Halcion affair “one of
the drug scandals of the century, one of those which
is only just coming out into the open far too late. It’s a
scandal because it undermines the entire system on
which the safety of patients with drugs is based, the
system of trust.”8
5.
Dyer. C., “Experts urge sleeping pill ban be lifted", Guardian. 15 Apr
1993
6.
Brahams. D., "Triazolam licensing in UK", Lancet. Vol 341, 19 Jun
1993, pl587
7 McGuggin, P. and O’Donovan. M., “Editorial", British Medical
Journal. 10 Apr 1993
8 Dukes, M.N.G.. interviewed on BBC's Panorama programme on
Halcion, 14 Oct 1991
buspirone’s mode of action differs from the neu
roleptics, “the impact is sufficiently similar to raise
red flags”.44
Other new drugs such as zopiclone (Zimovane by
Rhone-Poulenc) are promoted as safer than the ben
zodiazepines. “Sleep serene... awake refreshed”
proclaims an advertisement depicting a cuddly teddy
o A.
Psychotropics
lem Di
bear. On the basis of several clinical trials, the adver
tisement said that there was “no evidence of
dependence in clinical use". However, a Lancet edi
torial in 1990 attacked the promotion, arguing that
the claims made about dependence were “inaccurate
to the point of being irresponsible”.45 Only a year
after the drug was launched in the UK, the CSM
issued a report that, based upon adverse drug reac
tions received, drew attention to the risk of
dependency on long-term use of zopiclone.46 The
irresponsible inaccuracy continues: in October 1992,
in Malaysia, a Rhone-Poulenc advertisement for
Imovane (its name for zopiclone in Asia) in the lead
ing prescribing guide, DIMS, told doctors that “No
serious adverse reactions have been seen”.47
In developing countries
As that example shows, if there are problems with
psychotropic drugs in industrialised countries, the
situation in developing countries is typically much
worse. According to the World Health Organization
(WHO), the rational use of benzodiazepines and
other psychotropic drugs is made more difficult by:
• overuse of psychotropics to control troublesome
patients when staffing levels at care facilities are
inadequate;
• use of inappropriate psychotropics due to difficul
ties in diagnosis with the limited facilities
available;
• sales in the marketplace of substances from illicit
sources; and
• inappropriately low dosage or short duration of
administration due to financial constraints.48
A further complication is the general availability of
psychotropic drugs without a prescription.
Another problem is the poor quality of information
about these drugs. In late 1988, promotional claims
for benzodiazepines in Pakistan were described by one
British doctor as “misleading.... If these claims are cor
rect, then British doctors and their patients are missing
out on a therapeutic revolution.”4’ Sandoz said that
patients who rake its brand of temazepam (Restoril)
“do not experience drug dependence”, while ParkeDavis both blamed the patient for rhe problem of drug
dependence and reassured the doctor that it was not
likely to happen with its prazepam (Verstan) because
the drug “may provide an advantage in certain
patients prone by history to drug misuse”.
Also in late .1988, Roche encouraged doctors in
.Malaysia to relax about the simplicity and safety of
its midazolam (Dormicum) by describing the drug as
the “sleep starter: Switch light off... switch sleep on”.
In Peru in 1991, Multifarma was promoting its
alprazolam (Alpaz) as a treatment for virtually every
condition of daily life. It promised relief for:
• the “syndrome of the modern woman” - who suf
fers from increased worries about work, and an
increased workload, emotional worries and stress;
Roche promotes routine use of midazolam
(Dormicum) as a sleeping pill, Malaysia, DIMS,
Oct 1988
• the “syndrome of today’s man” - who worries
about the future, his increased responsibilities,
frustrations at not reaching his goals, financial
problems and stress;
• the “syndrome of the housewife” - who worries
about the children’s education, having too much
work, financial problems, fear of domestic acci
dents and a fear of the house being burgled; and
• the “syndrome of the elderly” - who fear being
lonely, worry about their health and future, have
limited finances, and lack affection.
With sales promotion like this, it is little wonder that
the market for hypnotics and tranquillisers in Peru
has reached US $5.4 million.'’0
Medicalisation of life
This “medicalisation of life” helps to sell more drugs.
One report talks of the industry’s “encouragement of
symptomatic prescribing”.51 However it is described,
this overuse of drugs also provides a convenient solu
tion for many health workers who simply have too
little time to devote to their patients. It may be that
what many people need is sympathy and someone to
10A.
The forerunners of modern psychotropic drugs were
often described as chemical straightjackets, provid
ing the means to restrain difficult patients with
methods that seemed, on the surface, more humane.
There is a lingering concern that today’s chemicals
could still be used as control mechanisms, or be used
to replace the social contact and personal care that is
often needed to deal with psychological problems.
The high use of psychotropic drugs among the
elderly and among women is a worrying indicator
(see the boxes on pages 194 and 186). Drugs can sim
ply serve to further disempower people who may
already be feeling the impact of some form of disad
vantage in society.
As one leading psychiatrist puts it: “It is understand
able that some people want to try to handle their
problems through psychiatric or recreational drugs,
but should doctors endorse this dangerous and selfdefeating avenue as a form of medical treatment? As
physicians and psychotherapists we should empower
our patients to trust themselves and their capacity to
triumph over frightening emotions. We should help
them overcome anxiety through self-understanding,
improved self-control of their minds and actions,
more courageous attitudes and more successful prin
ciples of living.”52
Consultant psychiatrist, Brian Ballinger, says: “More
emphasis should now be placed on managing sleep
disorders and anxiety without using drugs.”53
Controlling benzodiazepines
Several countries have taken initiatives to tighten the
control of benzodiazepines. For a long time, the
Norwegian government has exemplified WHO’s con
cept of focusing on essential drugs by limiting the
numbers of products licensed. For a product to
receive a licence, it has to be more effective than
those already on the market and meet a clear medical
need.54 Even so, one commentator felt that the 10
benzodiazepines and nine antidepressants on the
market could be effectively halved without causing
any limitations on therapy.55
In April 1985, the UK government introduced a lim
ited list of drugs that could be prescribed under the
National Health Service in seven major therapeutic
areas, including benzodiazepines as hypnotics. It was
an effort to save money, but also to introduce more
rational prescribing.56 The original plan was to have
doctors restrict benzodiazepine use to just three of
the 17 products then on the market in the UK.
However, following strong lobbying from rhe phar
maceutical industry, the list was expanded to include
another six benzodiazepines.57
This concept of a limited list is one that is also fre
quently used at hospital or clinic level. Many
hospitals in different countries have their own
versions of limited lists - drug formularies - which
enable rhem to select the safest, most effective and,
usually, least expensive drugs.58
A UK hospital designed a policy to ensure that no
new addicts are created while they were in hospital
and that people who were already addicted were
weaned off the drugs as safely and rapidly as pos
sible. Benzodiazepines were only used where strictly
necessary, and not at all for the elderly. Hypnotics
were not given for more than five days. No one was
discharged with a supply to last more than three
days. Alternatives to benzodiazepines were actively
encouraged.59
In the USA, some states have attempted to restrict
benzodiazepine use by law. A controversial approach
by New York State effectively placed benzodiazepines
under the same regulatory control as opiates, barbitu
rates and amphetamines. Among its aims, the policy
hoped to reduce inappropriate prescribing. During
the first year of operation, there was a 27-53%
decrease in benzodiazepine prescriptions.60 However,
critics of the scheme point to increases in the use of
other psychotropic drugs.61 The debate on the effec
tiveness of the New York scheme continues. At any
rare it serves as a reminder that no strategy can be
used that is haphazard in rationale, motive and exe
cution. Simply wiping away part of the problem
without providing workable alternatives - non-drug
therapy for anxiety, better long-term community care
policies - will not bring real change.
Antidepressants
Many forms of depression lie on a continuum that
spans from “feeling blue” to being unable to cope
with life and feeling suicidal. All too often, the whole
range of conditions are treated with drugs, whether
or not such treatment is rational.
Identifying those forms of depression that could ben
efit from drug therapy is not always easy. Social,
economic and physical factors can all play a role in
depression. Antidepressant therapy should be con
sidered only after the nature of the symptoms and
causes of depression has been determined.62 “Some
patients may need individual or group psycho
therapy, others may respond to counselling or to
drugs, some just want a new house and a cheque for
£50,000, others want a new husband or wife, all
need to be taught how to relax.”63 As well, 30% of
191
Problem Di
talk to. Where that need is not met because of iso
lation, poverty, or other causes, the doctor or health
worker is looked upon as someone who can help
untangle a complex collection of problems.
However, the doctor or health worker is often
powerless to change anything. With limited time and
an ever-increasing array of powerful drugs promising
miraculous results, is it any wonder that there is a
growing market for these products?
Psychotropics
i o A .
Psychotropics
people may respond to placebo64 and spontaneous
improvement in depression occurs in at least one
quarter of people within the first month or so, and in
one half or more over a few months.65
Nonetheless, antidepressants are popular drugs. In
the USA, they are the second most commonly pre
scribed drugs after tranquillisers, with at least 34
million prescriptions a year being written.66
There are three main types of antidepressants: tri
cyclics and other cyclics, which are the most
commonly used; monoamine oxidase inhibitors
(MAOIs); and the newer, second generation drugs
such as trazodone, fluvoxamine, fluoxetine and ser
traline.
Many antidepressants have been on the market for
three decades. These include the tricyclics
imipramine (Tofranil) and amitriptyline (Domical,
Elavil) and the MAOI, tranylcypromine (Parnate).
They took over from stimulants such as the ampheta
mines in the late 1950s. Despite manipulation of the
basic tricyclic nucleus which has resulted in many
different drugs, rhe overall range of antidepressant
efficacy has not changed.67 Or, as one doctor put it,
“since 195S, when imipramine (Tofranil) was first
reported to be effective in depression, no other anti
depressant has been widely shown to be any more
effective”.68
The pharmaceutical industry argues that the wide
choice of different but broadly similar drugs is so
that the physician can select the most appropriate
drug on the basis of individual response. One method
of selection is on the basis of side effects. However,
there is little to choose among the various drugs. All
tricyclics produce anticholinergic effects: dry mouth,
blurred vision, constipation, difficulty in passing
urine. The other side effects include sedation, pre
cipitation of epilepsy, tremor, nausea, hypomama
and confusion. Cardiovascular effects, including low
blood pressure, have also been reported.69
One psychiatrist goes further: “evidence for their
[tricyclics’] usefulness is very slim indeed.... They
have a dulling effect on the mind... have a sedative
effect... can cause withdrawal effects... are lethal in
overdose.... They are in many ways neuroleptics in
disguise.... When the individual tries to stop taking
them the cholinergic system rebounds with great
force, making it hard to get off them."70 This depen
dency syndrome in itself is sufficient reason for
caution in the use of antidepressants.
MAOIs can also produce severe side effects. “The
potential toxic effects of the MAO inhibitors are
more varied and potentially more serious than are
those of most other groups of therapeutic agents used
in the treatment of psychiatric patients.”71 They
interact dangerously with many foods and with other
drugs, causing a dramatic rise in blood pressure. - A
special diet has to be followed. Less serious side
effects include: dizziness, headache, inhibition of
ejaculation and urination, constipation, fatigue, dry
mouth, blurred vision, and skin rashes/’
Withdrawal of the drug - as with other antidepres
sants - must be gradual. Sudden withdrawal can
cause a range of symptoms including nausea, vomit
ing, loss of appetite, headache, insomnia, and
anxiety.74 Insomnia and anxiety may even occur
when the drug is withdrawn gradually.75
Although there is general acceptance that MAOIs
“do not seem to be the best agents for most psychotic
depressions”, they still find limited use in certain
patients with “atypical" symptoms.76 However, the
difficulties with both the MAOIs and the first tri
cyclics have led to research into new drugs.
The new generation:
a breakthrough or a breakdown?
In January 1988, Eli Lilly launched one of these new
drugs, fluoxetine (Prozac). Newsweek magazine sub
sequently devoted a cover story to what it called a
“breakthrough drug for depression”. Even some doc
tors took it simply because it made them feel better.77
By 1990, Prozac had global sales of $600 million,78
rising to more than $ 1 billion by 1992, moving it into
the top 15 drugs according to sales.79 An estimated
four million people have been treated with Prozac
worldwide.80 This massive use of the drug was not in
accordance with expert opinion about the drug: “the
newer agents are not more effective than the stan
dard tricyclic drugs”.81
Much of the excitement surrounding Prozac was
because the drug worked in a different way from the
first generation products. It was thought that because
it affected the neurotransmitter serotonin, this would
make its impact more selective. There is a danger in
taking this view: “There should be no comfort associ
ated with the idea that Prozac is selective for
serotonin. The brain, an integrated organ blessed
with harmonies and balances beyond our ken, is
thrown out of balance by any such biochemical intru
sion.”82
Though promoted as a safer alternative, fluoxetine
can cause severe side effects such as uncontrollable
movement, inappropriate secretion of antidiuretic
hormone, serum sickness, sexual dysfunction, stut
tering, tics, hearing loss, manic episodes, paranoid
reactions, and intense suicidal feelings. It also inter
acts dangerously with other psychotropic drugs,83
Reports of increased suicidal tendencies have focused
attention on fluoxetine.84 Though it can be argued,
and has been by Eli Lilly, that it is depression itself
that causes suicidal tendencies, not one of these
patients felt suicidal before taking the drug. More
1 o A .
In September 1991, a meeting of the US FDA’s
Psychopharmacologic Drugs Advisory Committee
found no “credible evidence” to support a conclu
sion that the use of antidepressant drugs in general
and Prozac in particular causes the emergence or
intensification of suicidal acts or other violent behav
iours.86 There were, however, some “reservations”
among members of the committee, some of whom
suggested that “further study might be needed to
identify potential high risk patients”.87
Table 10A-2
Adverse effects of some newer antidepressants
Drug
viloxazine
Comment
antidepressant effects differ little from those of
standard drugs; nausea which appears dose
related limits usefulness
maprotiline
rashes and convulsions are among the adverse
effects; careful supervision is required
mianserin
blood disorders such as aplastic anaemia and
agranulocytosis have been reported; liver disorders
have also occurred; careful supervision is required
trazodone
priapism (persistent erection of the penis) has
been reported
lluvoxamme
nausea and vomiting are common effects,
convulsion has been reported
fluoxetine
nausea and more severe adverse effects have
been reported; too new to evaluate
While many patients have been taking the drug for a
long time, the effectiveness of fluoxetine has not been
tested in controlled trials of more than four to five
weeks. Its long-term usefulness and effects of
possible withdrawal have not been sufficiently
analysed.88 Another concern is that its adverse drug
reaction profile is similar to other drugs that have
been withdrawn for safety reasons, such as Astra’s
zimeldine
(Zelmid),
Hoechst’s
nomifensine
(Merital), and tryptophan. Overuse of fluoxetine as a
result of misleading promotional material could
cause a “surfeit of serious ADRs”.89
The role of the newer generation of antidepressants is
as a second line alternative when the older drugs do
not work for patients with severe depression.
“Therefore it is difficult to put the widespread use of
fluoxetine into perspective.... The still evolving data
on the recently introduced antidepressant drugs
remind us that only a few are truly novel.”90
Generally, “in no case has the efficacy of the new
antidepressants been shown to exceed that of the tri
cyclics”.91 As well, information about adverse effects
is still evolving. Table 10A-2 summarises this infor
mation for some of the newer antidepressants.
Bur there are alternatives to drugs:
“The vast majority of people overcome
depression without resort to any mental
health services. They do so by virtue of their
own inner strength, through reading and
contemplation, friendship and love, work
and play, religion, art, travel, beloved pets,
and the passage of time - all of the infinite
ways that people have to refresh their spirits
and to transcend their losses.’92
sertraline
too new to evaluate
Sources: Feely, J. (ed ), New Drugs, London, British Medical Journal,
1991, pp303-5; BMA and the Royal Pharmaceutical Society of Great
Britain, British National Formulary, London, BMA and The
Pharmaceutical Press, No 23. Mar 1992. ppl51-2
such as schizophrenia and other severe psychiatric
disorders. These drugs have serious risks of major
side effects - including tardive dyskinesias that may
not be reversible.93 They are not “in any sense a
cure” for the conditions for which they are used;
rather they are best seen as drugs that “can shorten
the duration of an acute psychotic episode and
increase the time interval between relapses”.94
One leading pharmacology textbook points out that
knowledge about the use of drugs in mental and
behavioural disorders “is in its infancy. In relation to
drug therapy, virtually nothing is known about the
causes of mental disease or about how many drugs
may work to relieve symptoms, though many phar
macological facts are known.... In addition, there is a
dearth of well-designed therapeutic trials such as are
essential to determine what drugs can do.”95
Another important point is that the use of these
drugs alone “does not constitute optimal care of psy
chotic patients. The acute care, protection, and
support of acutely psychotic patients, as well as mas
tery of techniques employed in their long-term care
and rehabilitation, are important medical skills.”96
Antipsychotics
Many millions of people are treated both inside and
outside mental institutions with antipsychotics
(major tranquillisers or neuroleptics) for conditions
Although these drugs should be used with caution,
usage patterns among some population groups such
as the elderly suggest that these powerful drugs are
lem Di
than 70 lawsuits have been filed in the USA against
Lilly, although none have come to trial. Lilly has also
provided evidence for the prosecution in cases where
criminal defendants are claiming that the use of
Prozac led them to engage in violent behaviour. This
line of defence has been rejected in all 10 cases
tried.85
Psychotropics
l9.
10A.
Psychotropics
Problem Drugs
Psychotropics and the elderly
1
|
I
The aging process affects the ability of the body to
use drugs. Differences in the absorption, distribution
and clearance of a drug, make an elderly person
more sensitive to both its desired and undesired
effects. Often a drug will affect an elderly person in a
strikingly different way from that expected in
someone younger.1
Studies in the USA show that the elderly, who make up
one-sixth of the total population, are prescribed onethird of all tranquillisers and more than half of all
sleeping medications.2 Studies from other countries
confirm that the elderly receive a disproportionately
high amount of prescriptions for benzodiazepines.3 In
Australia, for example, hypnotics were prescribed in
"alarming quantities", particularly for the elderly.
"Sleeping and ageing have proven to be bonanzas to
the marketer. .. Notwithstanding the plain fact that
older people require and get less sleep, a sleep market
is created with programming directed to the elderly.
Salvation is offered for the sleepless: a ‘quiet, restful,
splendid sleep'. All that is required is a simple pill."4
Hypnotics or tranquillisers in “average" doses may
cause confusion and unsteadiness in an elderly
person. A benzodiazepine sleeping pill which would
be largely excreted by most younger people within
eight hours may “hang over" throughout the whole of
the next day.5 With repeated use, concentrations of
the drug can build up until toxic levels are reached.
This hangover effect was particularly noticed in the
1970s and 1980s when it was discovered that
benzodiazepines with a long half-life (those that take
a long time to be excreted) such as nitrazepam
(Mogadon) were associated with confusion,
disorientation and lack of coordination. All of these
symptoms can be misdiagnosed as progressive brain
disease or signs of dementia.
and cognitive dysfunction in the elderly. However,
“physicians are prescribing the greatest quantities of
medications to those patients who can least well
tolerate long-term hypnotic use."6
In residential nursing homes, the situation is often
alarming. “Despite growing consensus about the
serious adverse effects of psychotropic drug use in
the elderly population, studies repeatedly show that
one-fourth to one-half of all nursing home residents
[in the USA]’receive a major or minor tranquilliser."
Frequently the greatest use takes place in those
facilities where there is neither sufficient care nor
adequate training of staff to look after people
properly. “Low resource facilities are less likely to
have well-planned social and recreational facilities.
This can contribute further to chronic loneliness and
disruptiveness and. ultimately, the chronic use of
tranquillisers as a substitute for meaningful activity
and social interaction. In effect, tranquillisers serve as
a 'chemical restraint' or 'substitute' for safer, more
effective, and more humane ways of care."7
Depression affects 10% of those over the age of 65.®
However, antidepressant drugs may not be an
appropriate response. The tricyclic antidepressants
are associated with cardiovascular and anticholinergic
effects such as dry mouth and blurred vision. This
makes them “unattractive for the elderly".9 The
dangerous food and drug interactions that can occur
with monoamine oxidase inhibitors (MAOIs), already
make them second-line drugs for depression.10 They
may be particularly unsuitable for the elderly.
The search for more effective and safer
antidepressants in the elderly has resulted in some
acceptance of the newer generation of anti-serotonin
agents as the solution. The role of drugs such as
fluoxetine (Prozac) and sertraline remains to be
established.
Long-term use of benzodiazepines has been
associated with falls, hip fractures, daytime sedation
References:
1.
Greenblatt, D.J., Harmatz, J.S., et al, “Clinical pharmacokinetics of
anxiolytics and hypnotics in the elderly", Clinical Pharmacokinetics,
Vol 21. No 3. 1991, ppl65 77
2.
Wolfe, S.M., Fugate, L, et al, IVorst Pills Best Pills, Washington,
Public Citizen Health Research Group, 1988, ppl45-155
3.
Collier, J., The Health Conspiracy, London, Century Hutchinson,
1989, pl5
4.
Jackson, D.M. and Soothill, R., Is the Medicine Making You III?, North
Ryde, Australia, Angus & Robertson, 1989, pp28 9
5.
Parish. P.. Medicines: a guide tor everybody, London, Penguin (6th
edn. revised). 1989, p32
6.
Schorr, R.l , Bauwens, S F. et al, "Failure to limit quantities of
benzodiazepine hypnotic drugs for outpatients: placing the elderly at
risk". American Journal ol Medicine, Vol 89. Dec 1990, pp725-31
! Svarstad. BL. and Mount, J.K., “Nursing home resources and
tranquilliser use among the institutionalised elderly" Journal of the
American Geriatric Society, Vol 39, 1991, pp869-75
8. Cohn, C.K, et al, "Comparison ot sertraline and amitriptyline in
elderly depressed patients". Journal ol Clinical Psychiatry Vol 51
No 12 (Suppl 12), Dec 1990. p28
9. Maletta. M.D., Mattox. K.M . et al. "Guidelines lor prescribing
psychoactive drugs for the elderly: part 1", Geriatrics Vol 46 No 9
Sep 1991. p.44
10 BMA and the Royal Pharmaceutical Society of Great Britain, British
National Formulary, London, BMA and The Pharmaceutical Press
No 23, Mar 1992, p!56
veuucai Press.
i o A.
■ t>c
Psychotropics
Oo-ooo
DEPRESS
Common symptoms:
Low Mood
x\.
Hopelessness
\
Loss of motivation
Feeling inadequate
Sleep disturbance
Conscious Guilt
ujsso; Wrest’
. ■’ >
Suicidal wishes
Indecisiveness
Loss of appetite
Put your patients
—
See them respond
on MeDera-25 right awayWITHIN A WEEK
Sandoz advertises an antipsychotic (thioridazine)
to doctors in India in 1990 for treatment of
symptoms such as “feeling inadequate" and
“indecisiveness"
Recommendations for action
much overused. Schizophrenia is the most common
reason for prescribing antipsychotics. However,
schizophrenia and other psychoses are much less
common among elderly people. Nonetheless, in the
USA, for example, an estimated 750,000 people over
65 (not counting those in mental hospitals) are regu
larly using antipsychotic drugs, even though the total
number of people over 65 estimated ro have schizo
phrenia is less than one-eighth (92,000) of that
number. Well over 80% of the elderly people in the
USA who are taking antipsychotic drugs are using
them needlessly.97
Ending the cycle of dependence
The history of the use of psychotropic drugs shows
the need for regulatory control at several different
stages. At the clinical level, adequately designed trials
of new drugs are needed, particularly among popula
tions who are most at risk from these drugs - the
elderly and women. Approval procedures could con
sider the need for drugs. Better monitoring of and
more effective responses to adverse effects would
help. So too would more cautious prescribing to
avoid the use of drugs as a palliative when social
action is required. Tough measures to ensure high
quality information and strict penalties for poor
quality promotional material would also be a start.
1. Combination products containing a barbiturate
should be banned. Single ingredient barbiturates
should be removed from the general market and
their use reserved for anaesthesia, some
anticonvulsant therapy, and for limited use among
named elderly patients who have been on them
for some time.
2. Benzodiazepine tranquillisers should be
prescribed only for the relief of severe symptoms
of anxiety, or for severe sleep disorders, and then
only for the shortest possible time and in the
lowest possible dosages. Their use should be
limited in the elderly.
3. Governments should strengthen controls to
ensure that benzodiazepine tranquillisers are not
illegally sold over the counter. Special attention
should be paid to the promotion of
benzodiazepines to ensure that their overuse is
not encouraged.
4. National and local formularies and therapeutic
guidelines should be developed for the treatment
of anxiety, insomnia and depression. Where
possible, non-drug solutions should be
encouraged.
5. Governments and health worker associations
should ensure that independent information is
available for patients and prescribers about the
rational use of psychotropic drugs, including
adequate warnings about the risk of dependency
on these drugs.
ioA.
Psychotropics
Problem Drugs
References:
i.
2.
3.
4-
5.
6.
7.
8.
9.
10.
Chaudhary. V., “Experts urge sleeping pill ban be lifted", Guardian (London),
15 Apr 1993, pa
Fitzsimons, C., “Addicts to sue over ’happy pill' misery", Observer (London),
14 Feb 1988
FIND/SVP, The Market for Psychotropic Drugs, New York, FIND/SVP, 1992,
cited in: Anon., “Psychotropic sales $7.6 bill by 1996?", Scrip, No 1720,
22 May 1992, pz6
Management and Marketing Corporation, US Psychotherapeutic Agents Rx
Strategies: Trends. Strategies, Threats and Opportunities. Stamford, CT.,
Management and Marketing Corporation, 1992
Medawar, C, Power and Dependence, London, Social Audit, 1992, pp8-2$
Ibid, P58
ibid. P69
Lacey, R, The Complete Guide to Psychiatric Drugs, London, Ebury, 1991, P37
Parish, P„ Medicines: a guide for everybody, London, Penguin (6th edn,
revised). 1989, p68
Feely. J. (ed.), New Drugs, London, British Medical Journal, 1991, pp29/-8
10a. Hartog, R. Barbiturate Combinations: Risks without Benefits, Bielefeld, BUKO
Pharma-Kampagne and Health Action International, 1993
11.
Parish, op cit, p68
12 Medawar, op cit, p/3
47.
48.
Anon., “No serious adverse reactions?", Utusan Konsumer, Jan 1993, pis
Ghodse, H„ and Khan, I (eds), Psychoactive Drugs: Improving Prescribing
49.
Practices, Geneva, WHO, 1988, pis
Birley, J.L.T., “Drug advertisements in developing countries", Lancet. 28 Jan
1989, p220
50.
Lopez Linares, R. and Phang Romero, C., iPromoviendo la Salud 0 los
Negocios?, Chimbote, Acc<6n para la Salud, 1992, pn
51.
52.
53.
54.
Anon., Scrip, No 1587, op cit, P4
Breggin, op cit, P330
Feely, op cit, P300
Joldal, B. “Selecting drugs on the basis of need", World Health Forum, Vol 6,
55.
1985, pp67-9
Bruun, K., (ed.). Controlling Psychotropic Drugs - The Nordic Experience,
56.
London, Croom Helm, 1983, P255
Collier, J., The Health Conspiracy, London, Century Hutchinson, 1989, pzo
57.
58.
59.
60.
Medawar, op cit, PP176 80
Ridley, H„ Drugs of Choice, London, Social Audit, 1986, p8
Ramster, D., Barber, A.J., et al, "A policy on benzodiazepines ”, Lancet, 12 Dec
1987, P1406
Brahams, D., "Benzodiazepine overprescribing: successful initiative in New
BMA and the Royal Pharmaceutical Society of Great Britain, British National
Formulary, London, BMA and The Pharmaceutical Press, No 23. Mar 1992,
6l
York State", Lancet, Vol 336,1 Dec 1990, PP1372-3
Shader, R I., Greenblatt, D.J., et al, "Appropnate use and regulatory control of
benzodiazepines". Journal of Clinical Pharmacology, Vol 31,1991, PP781-4
P139
14. Gaudreauit, P., Guay, J., et al, "Benzodiazepine poisoning: Clinical and
pharmacological considerations and treatment", Drug Safety, Vol 6, No 4,
1991. PP247-65
15 Winger, G., Tranquillizers: The Cost of Calmness, London, Burke, 1988, P27
16.
Hollister, L.E., Mortzenbecker, F.P., et al, “Withdrawal reactions from
chlordiazepoxide (Librium), Psychopharmacologia, Vol 2,1961, pp63-8
17.
Bienkinsopp, A. and Panton, R„ Health Promotion for Pharmacists, Oxford,
Oxford University Press, 1991, P183
18.
Votey, S.R, Bosse, G.M., et al, "Flumazenil: a new benzodiazepine
antagonist”. Annals of Emergency Medicine, Vol 20, Feb 1991, ppi8i-8
19.
Parish, op cit, P65
20.
Wolfe, S.M., Fugate, L, et al, Worst Pills Best Pills, Washington, Public
Citizen Health Research Group, 1988, P149
21.
Cumming, R.G., Miller, J.P., et al, “Medications and multiple falls in elderly
people: the St Louis OASIS Study”, Age and Ageing. Vol 20,1991, PP455-61
22.
jerram, T.C., “Hypnotics and sedatives”, in: Dukes, M.N.G, and Beeley, L.,
62.
63.
64.
Feely, op cit, P301
Parish, op cit, P74
Matthews, K. and Eagles, J.M., “Which antidepressant?", British Journal of
13.
23.
24.
(eds), Side Effects of Drugs Annual 14, Amsterdam, Elsevier, 1990, P35-44
Quoted in Medawar, op cit, pzoi
Steinberg, ]., quoted in Breggin, P. Toxic Psychiatry, London, Fontana, 1993.
P3°5
Andrews, G.. “The management of anxiety”, Australian Prescriber, Vol 14,
No 1,1991, PP17-19
26.
Cohen, S.I., “Are benzodiazepines useful in anxiety?”, Lancet, 7 Nov 1978,
25.
pio8o
Winger, op cit. P27
Lacey, op cit, p22
Medawar, op cit, pii3
BMA and the Royal Pharmaceutical Society of Great Britain, op cit, P133
Anon, “Media attention for council statement on BZDs", Pharmaceutical
Journal, Vol 243,1989, P209
32.
Anon., "Psychotropic drug prescribing in children", Scrip, No 1590,
13 Feb 1991, P23
33.
Summers, R.S., Schutte, A., Summers, B„ "Benzodiazepine use in a small
community hospital", South African Medical Journal, Vol 78,15 Dec 1990,
27.
28.
29.
30.
31.
39.
40.
41.
P724
Anon., “French benzodiazepine report calls for change”, Scrip, No 1587,
1 Feb 1991, p4
Anon., “Psychotropic misprescribing in Spain", Scrip, No 1618,22 May 1991, p9
Gaudreauit, et al, op cit
Lacey, op cit, P19
Ashton, H„ “Psychotropic drug prescribing for women", British lournal of
Psychiatry, Vol 158 (Suppl. 10), 1991, PP30 5
Medawar, op cit, pii2
Anon., "Upjohn’s CNS sales down”. Scrip, No 1776, 4 Dec 1992, pn
Anon., “Buspirone and gepirone - an expanding role in psychiatry?", Scrip,
42.
43,
No 1482, 24 Jan 1990, P24
Parish, op cit, p64
Physicians' Desk Reference, Oradell, NJ, Medical Economics Company, 44th
44.
45.
edn, 1990, P1308
Breggin, op cit, P311
Anon., “Zopidone: another carriage on the tranquilliser train”, Lancet,
34.
35.
36.
37.
38.
Vol 335, 3 Mar 1990, PP507-8
46.
Anon., "Zopidone (Zimovane) and neuro-psychiatric reactions", Current
Problems, No 30, Dec 1990, pz
General Practice, Vol 41, Mar 1991, PP123 5
Breggin, op cit, P194
Ibid, pi86
Matthews and Eagles, op cit
Rand, E.H., “Choosing an antidepressant to treat depression”, American
Family Physician, Mar 1991, PP847-54
69.
Feely, op cit, P306
70.
Breggin, op cit, pi88
71.
Gilman, A.G., Rail, T.W., Nies, A.S., and Taylor, P., Goodman and Gilman’s
The Pharmacological Basis of Therapeutics, New York, Pergamon Press,
(8th edn) 1990, P416
65.
66.
67.
68.
72.
73.
74.
75.
BMA and the Royal Pharmaceutical Society of Great Britain, op cit, 0156
Gilman, et al, op cit, P416
BMA and the Royal Pharmaceutical Society of Great Britain, op cit, pis 1
Henry, J. (ed.), The British Medical Association Guide to Medicines & Drugs,
London, Dorling Kindersley, (2nd edn) 1991, p8o
76.
77.
78.
79.
80.
Feely, op cit, P307
Breggin, op cit, P199
Anon., “US group warnings on Prozac", Scrip, No 1533, 20 Jul 1990, p26
Anon., “Top 20 products in 1992", Scrip, No 1812/13, 16/20 Apr 1993, P29
Anon., "US FDA panel on Prozac - effect on litigation”, Scrip, No 1656, 2 Oct
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
1991, p2i
Potter, W.Z., Rudorfer, M.V., et al, “The pharmacological treatment of
depression", New England Journal of Medicine, Vol 325, 29 Aug 1991,
PP633-42
Breggin, op cit, pzoo
Levinson, M.L., Lipsy, R.J. and Fuller, D.K., “Adverse effects and drug
interactions associated with fluoxetine therapy", DICP, The Annals of
Pharmacotherapy, Vol 125, Jun 1991, pp6s7-61
Teicher, M.H., Glod, C, et al, "Emergence of intense suicidal preoccupation
during fluoxetine treatment", Amencan Journal of Psychiatry, Vol 147,1990,
PP206-10
Anon., “Prozac claims", Lancet, Vol 338, 3 Aug 1991, P307
Ahmad, S.R., “USA: fluoxetine ’not linked to suicide’". Lancet, Vol 338, 5 Oct
1991. PP875-6
Anon., Scrip, No 1656, op cit, p2i
Breggin, op cit, pzo8
Anon., "Dr Moebius attacks Prozac enthusiasm", Scrip, No 1517, 25 May
1990. P27
Potter, et al, op cit
Feely, op cit, P303
Breggin, op cit, pzn
ibid, PP57-83
Morton, I., Hall, J. and Halliday, J., “Tranquillizers: The comprehensive guide,
London, Bloomsbury, 1992, ppxvi-xvii
95.
Laurence, D.R. and Bennett, P.N., Clinical Pharmacology, Edinburgh, Churchill
Livingstone, (6th, edn), 1987, P362
96.
97.
Gilman, et al, op cit, P402
Wolfe, et al, op cit, pi59
Chetley, A. Problem Drugs, Amsterdam,
Health Action International’s
coordinating offices:
Health Action International, 1993
HAI Europe
Jacob van Lennepkade 334T
1053 NJ Amsterdam
the Netherlands
Index
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accion para la Salud
Avda. Palermo 531
Dpto. 104
Lima 13
Peru
Subject
abortion. 122, 135, 137, 13S, 143, 144,145,148,
153, 154,155, 164
acne, 125, 126, 128, 174
acquired immunodeficiency syndrome (AIDS), 150,
158-9, 165-6. 171
acute respiratory infections (ARI), 9,10, 11,65,
97-8,101, 102
antibiotics use in. 9,57, 98,102
ARI News, 102
liver, 109, 159, 170
arthritis, 24,78.82, 87-8,90, 94,121
ovarian, 129, 155, 159, 170
Asia, 2, 12,43,53, 77, 84, 93, 125,137
prostate, 138, 139, 141, 153
vaginal cancer, 3, 16, 133, 138
Assad, A., 56
asthma, 75, 121-2,127, 131, 159
attention deficit disorder, 112-13
Australia, 2,41,44,45,46,49,53,54, 55, 64,
79, 85, 90, 97, 100, 139, 143, 166, 178,180,
Adami, H.-O., 181
185,194
adverse drug reactions (ADRs), 2, 9, 12, 15, 21-3,
Department of Health, 95
24. 25, 32,33, 37,41-3,46,50,55,56, 63, 77-
Australian Drug Evaluation Committee, 24, 125
8,85,88, 89, 90, 92,93, 94, 108-9, 113, 121.
Australian Pharmaceutical Manufacturers'
127. 128. 134 157, 159, 164, 174, 179, 181,
1S5,189,190, 192, 193
birth defects, 16,62, 121, 125-32, 133, 135,
139,143,144, 145, 149, 154, 171
Africa, 2,3,33,53,61, 71.76, 79, 82, 84, 91,93,
97,114, 123, 125, 131,137, 165
age associated memory impairment (AAMI),
116-17
Age-Related Mental Decline and Dementias:
The Place of Hydergine, 116
Cancer and Steroid Hormone Study
(CASH-USA), 158
cardiovascular disease, 74, 78, 122, 132, 148, 153,
157-8,171, 179, 181
Caribbean, 2,33,71, 78, 79, 82, 84, 114, 123, 131
Carriere, R., 29
Centers for Disease Control (USA), 27,57
Central African Republic, 63
Association (APMA), 45, 58
cerebral palsy, 113
Code of Conduct, 45, 58-9
children and drugs, 2, 9-14, 18, 27-31,45-7,
Australian Prescribes 12
Austria, 138, 143
49-50,55,62,63,75-6, 84, 98, 100, 101, 102,
106, 108-9,111-13, 117, 120, 121, 122,
123,186
Chile, 33,36,43,78, 144, 145
Ballinger, B., 191
China, 27, 53, 62,97,154, 163, 166, 169
Bangladesh, 30, 38,44,59, 73,79, 85, 151, 175
chlamydia infections, 63, 159, 165
Banks, D., 4
cholera, 28,30,38
Barker, E, 49
Clements, S., 112
agranulocytosis, 36, 78-9, 81, 82-4, 93, 116
Baulieu, E.-E., 154
Clinic, 102
AH Indian Drug Action Network, 144
Beecher, H.K., 70
Co-trimoxazole in perspective, 59
allergy, 75, 99, 106, 166
Belgium, 18, 77-8,79, 122, 143
Cochrane Collaboration Pregnancy and Childbirth
Alvarado, E., 163
Benjamin. E, 181
Alzheimer's disease, 115-16
Berg, A., 106
Cody. P., 139
amenorrhoea, 129, 137, 141, 143, 145, 170, 174
Bhutta.TI., 33,49-50, 107
cognitive enhancers (See: brain tonics)
American Academy of Pediatrics, 11
Birley, J.L.T., 114
Cohen, S., 185
American Association for the Advancement of
Black, D., 11-12
Collier,]., 16, 126
Science, 153
American College of Physicians, 4,54
Bolivia, 33,36,43, 82
Colombia, 33,36,43,71,75, 114, 145
Boyles, D., 76
combination drugs, 18,23, 36,39,51, 65, 66, 70,
American Dietetic Association, 120
brain tonics, 3, 12-13,25,106, 111-18
American Institute of Nutrition, 120
American Journal of Obstetrics and Gynecology,
137
American .Medical Association (AMA), 3,16, 32,
37,41,59, 60, 62,72,79, 82,98, 101, 102,
107, 108, 109, 113, 115, 119,121,122, 127,
131, 132, 139, 140, 144, 154, 160, 173
Council on Scientific Affairs, 120
“smart” drugs, 111, 112,117
Brazil, 1 1,33,36,43,57, 65,71,78, 83, 98, 112,
114, 131, 145, 174-5
Brazilian Association for the Control of Hospital
Infections, 65
breastfeeding, 18-19,27,28, 30,46,49,50,76,
106, 119, 122,127,132, 145, 155, 159, 160,
171, 174
Database, 127
71-5,79,81,91, 101-3. 122, 123, 124, 129,
134,178.184,195
common cold, 10,55, 64, 97, 103, 121,127
Conner, W.C., 69
constipation. 132, 192
Contraceptive Technology Update, 175
contraceptives, 3, 16,17, 135, 139, 141,145,
147-76
Coordinating Group on Depo-Provera (UK), 170
American Psychiatric Association, 112
Breslau, N-, 181
Coram, D., 134
American Society for Clinical Nutrition, 120
British Medical Association (BMA), 72, 75, 99,
Costa Rica, 33.36,43, 84, 106
anaemia, 78, 108, 109, 127, 133, 166
107, 119, 122, 141
Costello, A., 120
analgesics, 3,6, 11, 18,24,69-96, 102,130, 140,
British Medical Journal, 11, 116, 189
cough and cold remedies, 3, 9, 10, 18.97-104,
184
anaphylactic shock, 77-8,79, 81, 82, 83
British National Formulary (BNF). 25, 36,62, 63,
72, 100, 101, 102, 107, 113, 115, 122, 123,
130,131
Cuba, 44
132, 134, 135, 141, 160, 185
Cunliffe, P., 5
Andrews, G., 185
animal studies, 113,130, 131, 138, 153, 169
British Technology Group, 76
anorexia, 12, 105-8,113, 114,121, 174, 192
Brown, P., 5
anorexia nervosa, 107
Brunei, 53
Antibiotic Guidelines, 64, 206
Bulgaria, 82
antibiotics, 1,4, 9, 11,24-5, 29, 30, 32,35-40,
Butler,]., 35
51-68, 79, 98,103, 125,131, 152, 157, 163
Cyprus, 44,78
cystic fibrosis, 62
Datasheet Compendium, 134
Dawson. W., 92
in animals, 1, 57
Delizee, R., 77-8
in pregnancy, 62,125, 127, 130, 131
Caldwell,]., 151
dementia,25, 111, 112, 113-17, 185, 194
reserve list, 65, 66
Canada, 21,55,61,65, 78,85, 134,137, 139,
Denmark, 41,44,78,79, 85, 89,91, 143
resistance to, 1,31,36, 37,51-4, 56,57, 60,
61-2,63,65,66,98
Antibiotics in the Tropics, 37, 63
177, 186
cancer, 17,69,71,78, 117, 121-2,129,131,137,
depression, 69,89, 111, 1 14, 123, 125, 131, 159,
186, 191-3, 194, 195
138, 139, 143, 158. 170-1. 178
breast, 16, 108, 139, 141, 148, 155, 158, 159,
DES (diethylstilbestrol), 3, 16, 125, 129,133,
169,170-1, 179, 181
DES Action, 139
anxiety, 131, 183-6,188, 189, 191, 192, 195
cervical, 3, 133, 138, 148,158, 170-1
diabetes, 127, 132
aplastic anaemia, 36, 82, 83, 93,109
clear cell adenocarcinoma, 16, 138
Diagnostic and Statistical Manual of Mental
Argentina, 33, 36,41,43
endometrial, 17, 159, 170,178
anridiarrhoeals, 1, 3,9, 10, 18,27-50,62
antibiotics in, 1,3. 11,31-2,35-40,56
137-42, 159
Disorders, 112
197
198: Index
Problem Drugs
diarrhoea. 9, 10, 11,27-50,56,62, 90, 105, 106.
107, 120.121,132
Gopalan, C., 120
Diehl. H.S.. 97
Gram, H.C.J., 53
DIMS, 190
Greece, 79, 85,138, 143
dipyrone, 3. 71,78-9, S1-6
Grigoleit, H.-G., 83
Dirccks, A., 139
Groll, E., 85
Djerassi, C.. 154
growth stimulants, 12,105-110
Dodds, Sir E.C., 133,137
Grundberg, 1., 189
Dominican Republic, 44,175
Guatemala, 33, 36,43
Guidelines for the Distribution and Use of Fertility
Drug Action Forum (India), 39
Drug and Therapeutics Bulletin, 115
Jones, D., 4
Journal of Clinical Endocrinology and Metabolism,
Grahame-Smith, D., 185
drug dependence, 183-95
Regulating Methods, 155
Guillebaud, j., 148, 160
Drug Evaluations, 79, 82, 113
Gussin, R., 50
150
Journal of the American Medical Association, 97,
123
Junkmann, K., 169
Kenya, 11, 30, 36, 152
kidney damage, 3,4, 22,25, 35, 55,62, 72, 73,
76-8,89, 108, 109, 121
Klijn, K., 145
Korea, South, 53, 82,151
Kuwait, 56, 138
drug interactions, 10, 16.24,95,157,192,193, 194
dnig promotion, 3-5, 10, 12,17-19,22,25, 28,38,
39,45,56,58-61.77, 79. 84. 91,92-4,103,
Hansson, O., 41, 42,44, 93
105. 107, 108. Ill, 112, 114, 116,119, 123,
Harvey, K., 55
Lacey Smith, J., 90
124, 125.160, 163, 177,178,181, 185,186,
Hauser, H.-P., 5
lactation supression, 139-41
187-91, 195
Hawkins, D.F., 133
Health Action International (HA1), 6,35,38,71,155
Laitman, C., 137
Lancet, The, 41,49,50, 83, 85, 92-3, 94, 113,
drug safety, 1,3,4,5, 16.82-5,89,125-6,135,138,
148-9,153,154,157-8, 169, 184, 185
drugs in pregnancy, 2, 3,4, 16, 23, 46, 49, 50, 62,
Hendeles, L, 99
hepatitis, 171
114, 120, 122, 129,132,149, 158,190
Latin America, 1, 2,3, 33, 36, 43, 71, 77, 84, 93,
114, 125,137, 144, 169
76, 100. 119.121, 122, 125-46,159, 164,166,
hereditary angioneurotic oedema, 109
171, 174, 175-6
Herxheimer, A., 42,44, 93
Leisinger, K., 106
Higham.T., 183
Lesotho, 28
Hindmarch, I., 112, 116,117
Lethbridge, D.. 148
Honduras, 44, 163
liver damage, 4,44, 75,76, 77, 89, 109, 121, 159
Hong Kong, 53
Lock, M., 17, 178
Dukes, M.N.G, 11,189
dysentery, 29,30,36.38,53,59,60
East African Medical Journal, 77
East Timor, 170
hormone replacement therapy (HRT), 5, 17,
177-82
ectopic pregnancy, 138, 164,166, 174
Hoshi, M., 41
Macdonald, J., 106
Ecuador, 33,36,43. 114
human immunodeficiency virus (HIV), 148, 149,
Macnaughton, Sir M., 154
Egypt, 28.78.79,85,152, 175
150,158-9, 165-6, 172
malaria, 131
Hungary, 53, 83
Malawi, 28
89,95, 100,107,111-17, 122,179-80, 184-5,
Hunt, R., 163
Malaysia, 12, 33,44, 53, 62, 63,78, 85, 113, 114,
190, 191, 193,194, 195
hydroxyquinolincs, 3, 30,32,33, 38,41-4
elderly and drugs, 2,21-6,47,49,50,55,59, 88,
145,190
endometriosis, 109
hyperactivity, 9,12, 111-113
England (See also: UK), 30,41,163
hypertension, 78, 100, 127, 130, 132,159, 164
Maranga,J., 152
EP drugs, 16,135,143-6
hypogonadism, 108
Margolis, E., 56
epilepsy, 113, 127. 132,159, 184, 192
Martindale, 33,41,79, 85,115, 122
essential drugsconcept, 109, 155, 191
Europe. 2,27.59,60,62.65,69,77, 91, 121, 125.
137, 139,166, 180, 186
Eastern, 2,91
European Community, 114, 141
Committee for Proprietary Medicinal Products
(CPMP), 78, 114-15
Evers, H., 129
Mauritius, 78
implants, 149, 150, 173-6
McGaugh, J., 116
immunisation, 13,28, 120
McLean, A., 76
India, 27, 28,29.36,39, 51, 61,71,75,78, 82,
measles, 27, 106, 120
102, 108, 113, 114,120,123, 144, 145, 150,
Medecine d'Afrique Noire, 63
Indian Council for Medical Research, 144
Medical Lobby for Appropriate iMarketing
145,151, 175, 176
175,176
Federation of Associations of Obstetricians and
Gynaecologists (India), 144
Fefer, E., 2
Ferraz, E., 65
fever, 9,11.71,97.102, 127
Fifth World Congress on Pain, 69
Fiji, 64, 85
Medawar, C., 106
151,154
Indian Academy of Paediatrics, 51
Indonesia, 17,33,39,71,83,98, 113, 114, 120,
family planning, 17, 106,150-3,160, 169,171-2,
malnutrition, 3, 15,105-6, 107, 119,120, 124, 145
Medical Letter, The, 107, 174
(MaLAM), 25, 35,39, 113, 114, 123
megaloblastic anaemia, 133
Indonesia Index of Medical Specialities, 141
Melzack, R., 69
Indonesian Fertility Research, 175
meningitis, 37, 53-4, 63
infertility, 16, 122, 123, 127,129, 138, 149,150,
menopause, 5, 16,17, 122, 139,141, 145,171,
177-81
163, 165
injectable contraceptives, 149, 150,157, 169-72
Inman, B., 5
International Agranulocytosis and Aplastic
Anaemia Study (IAAAS), 82-4
International Federation of Pharmaceutical
menstrual disturbances, 149,164,166,169, 170,174
methicillin-resistant S. aureus (MRSA), 54
Mexico, 9,27,28,29, 33,36,43, 71,79, 113, 114,
152,157
Middle East, 33,43,56, 71, 79, 82, 84,91, 93,
Finland, 78, 101, 143, 173, 175
Manufacturers Associations (IFPMA), 2, 3, 5,
Fisher, E., 45
38, 59
114, 123, 137, 145
migraine, 107,130, 159
Fortune, 3,5
Code of Pharmaceutical Marketing Practices,
MIMS Africa, 107, 141
Fourtou,J.-R,, 2
France, 4,5,44.77,78, 102,137,138,139,154, 186
Franks, S., 145
Frost & Sullivan, 59,60, 99
38, 59
International Journal of Gynaecology and
Obstetrics, 143
International Study of Infarct Survival (ISIS-2), 74
intrauterine device (IUD), 147, 148-9,150,151,
157. 158, 163-7,175
MIMS Middle East, 92, 102, 141
Minimal Brain Dysfunction (MBD), 111,112
Monthly Index of Medical Specialities (India), 102
morning sickness, 132
Mohs, E., 106
multiple sclerosis, 159
Gabriel, S., 90
Iran, 3,30
muscular dystrophy, 109
Gal,!., 143
Ireland, 79, 85, 95, 139
Myanmar (formerly Burma), 27
gallbladder disease, 159, 179
National Drugs Advisory Board, 95
Gastroenterology. 90, 95
Israel, 78,79, 83, 85
German Medical Association, 85
Italy, 21,30,36,44,55,70,78,79, 83, 85, 91,
Germany, 35,75,76,77, 78,79, 81,83, 85,99,
126, 138, 139, 143
121, 138,139, 143, 145
drug regulatory authority’ (BGA), 83-4, 114
Health Ministry, 55
Federal Health Office, 77
national drug policies, 6
Natural Resources Defense Council (USA), 57
nausea, 18, 62, 107, 117, 121, 132, 159,192
Nepal, 44, 78, 98, 120
Netherlands, The, 41,44, 77, 78,81,89, 108, 126,
gonorrhoea, 53, 59
Jain, A.K., 152
137,138,139,141, 189
Goodman and Gilman's The Pharmacological
Centre for Monitoring of Adverse Reactions to
Basis of Therapeutics, 25, 36, 73,93, 108, 113,
Japan, 41,44, 53, 62,77,78,79, 85,91, 158, 180
jaundice, 77, 159, 171, 185
115,135, 139
Jenkins, W., 85
Society for Obstetrics and Gynaecology, 129
Drugs, 77
Index
Saudi Arabia, 44, 78, 79, 85, 138, 143
Netc England Journal of Mediante, 66, 74 78 95
115,134
’
'
New Zealand Ductor, 177
New Zealand. 53.55. 78, 85, 91, 143, 166, 177
Newsweek, 74, 192
Nigeria, 56, 57, 78
non-steroidal anti-inflammatory drugs (NSAIDs),
f 3,4, 18,22,23,24,71,76,87-96, 130
Nonh America, 2, 27, 53, 137, 186
Northern Ireland (See also: UK), 58
Norway, 44, 78, 79, 85, 91, 143, 191
Nurses’ Health Study (USA), 158, 179
132, 133, 134. 137, 138, 139, 140, 141, 143,
schizophrenia, 121-2, 193, 195
153, 154, 157, 158. 160, 163, 164, 165, 166,
Schwartz, H., 2
173, 174, 175, 177, 178, 179, 180, 184, 185.
Scotland (See also: UK), 21, 122
186, 188, 189, 191,192, 193, 194,195
Scrip, 5, 54, 59
Agency for International Development (USAID),
Segal, S., 173
151,152,164
Department of Health and Human Services, 22,
self-medication, 17-18, 78, 90, 99
sexually transmitted diseases (STDs), 61,63, 147,
139
Food and Drug Administration (FDA), 3, 4, 5,
148, 149,150, 152, 158-9, 165-6
Shelton, J., 152
22,23, 63,65, 74, 76, 78,79, 84-5, 93, 101,
Side Effects of Drugs Annual, 11, 82, 83
107,112, 115-16, 117, 128, 130, 134, 138,
Silverman, M., 114
Simand, IL, 139
140, 141-2, 143-4, 154, 160, 164, 169, 193
General /Vccounting Office, 15
Singapore, 33, 53,62,63,79, 85, 113, 114, 143
National Council Against Health Fraud, 120
Siriraj Hospital Gazette, 103
National Institutes of Health (N1H), 65
oral contraceptives, 16, 17,121, 129, 135, 144,
Smith, G., 137
State Department, 154
148, 150, 151, 157-62, 163, 170., 175, 179
Smith, J., 55
oral rehydration therapy (ORT), 10, 27, 28-9,30,
Smith, O., 137
33,35,36,47, 50
smoking, 148, 157, 159, 164
VACTERL syndrome, 135
osteoarthritis, 24, 87-8, 89, 94,95
Social Audit (UK), 46,106, 107
Venezuela, 33, 36,43,44, 79, 85, 113, 1 14, 143
osteoarthrosis, 88
Soman, C.R., 29
South Africa, 28, 78, 143, 186
Vietnam, 53
Spain, 44,53,61, 75, 78, 83, 186
vitamins, 3,12-13, 18,71,75,79,103,106, 107,
osteoporosis, 108. 109, 170, 180-81
Oswald, I., 189
over-the-counter (OTC) drugs, 10, 11, 17-18,69,
72, 94, 99, 100, 121, 126, 130, 135
spina bifida, 132,133
117,119-24, 126, 132,179
Sri Lanka, 30, 111,113
and intelligence, 122,123
sterilisation, 147, 150, 157
Sternbach, L., 185
Pakistan, 27,33,39,44,49. 50,60,71, 78.79, 82,
Vessey, M., 158
deficiencies, 12. 119-23, 132
supplements, 119-22,126,132
subacute myelo-optic neuropathy (SMON), 41-2
Voluntary Health Association of India, 144
85, 91, 92, 103, 107, 111,114, 124, 143, 145,
Sudan, 30, 36, 120
Voluntary Services Overseas (UK), 152
151,177, 190
Sunday Tinies, 76
Federal Ministry of Health, 50
Surinam, 78
Pan American Health Organisation (PAHO), 2
Swan. N., 21
Papua New Guinea, 53
Sweden, 41.44,54.61,78.79,83.85, 143, 154,179
paratyphoid fever, 37
Pardo de Tavera, M., 13
Parkinson’s disease, 114-15
Parish, P., 122
Pediatrics, 11
pelvic inflammatory disease (PID), 149, 159,
drug regulatory authority, 115
Swedish International Development Authority
(SIDA), 172
Switzerland, 41, 44, 72, 78
regulatory authority (IKS), 72
Syria, 113
164-6,167
Phacharintanakul, R, 85
Pharmacology and Therapeutics, 29
Philippines, The, 12-13, 18,33, 36,39,44,46,53,
61.
62,63, 71,75, 77, 78, 79, 82, 85, 99, 107,
Development Issues), 108,155
Werner, D., 29
whooping cough, 106
Williams, P., 117
Wilson Foundation, 178
Wilson, R., 152, 178
Wolfe, S„ 93
women and drugs, 2, 5,15-20, 121, 122, 125-82,
Peru, 13. 18,29,33,36,43, 75, 79, 114, 144,
145, 169.190
WEMOS (Working Group on Health and
186-7, 190, 191
Taiwan, 151
tardive dyskinesias, 189,193
World Bank, 105, 106
World Health Organisation (WHO), 2,6, 9, 10,
Textbook of Pain, 75
12,
Thailand, 60,61,63, 78,81,85, 103, 113, 114,
46, 50, 53, 65, 89,97,98,105, 10S, 113,129,
143, 151,171, 175
13,16,27,29,30,31,32,35, 36, 38,44,
13.3, 137, 141, 144-5, 148, 150, 151, 153, 154,
113, 114, 141, 143, 144
Philippines Index of Medical Specialities, 38,39
Timmers, R., 82, 85
travellers’ diarrhoea, 32,37,41,49
Essential Drugs List, 6,46,49, 55, 62, 65, 71,
Physician’s Desk Reference, 55,126, 141
tuberculosis, 36, 62, 65,106, 131
88,101
Pike, M, 158
pneumonia. 53-4,62,63, 97,98, 101, 102, 106,
Tunisia, 138
Programme for Appropriate Health Care
Turkey, 44,73,78, 79, 151
Technology, 52
Twycross, R.G.. 6
Special Programme of Research, Development
typhoid, 37,51, 59,63
and Research Training in Human Reproduction,
120
Po, A., 75
Population Council, 151-2, 154, 173,174,175,176
151,165
Toxicology Review Panel, 169
Portugal, 78
Practitioner, The, 184
155, 158, 164, 165, 166, 169, 170, 171, 190
UK (see also England, Northern Ireland. Scotland).
premenstrual tension (PMT), 16, 121
5.12, 13, 15, 16, 17,21,23,24,44,46,49, 54,
primary health care, 106, 109, 120, 155
55,57,61,64, 69,75,76, 78, 85, 87, 89,90,
Yelhn, A,, 4
psychotropic drugs, 11-12,23-4,25,125, 130,
91,92, 93, 99, 102, 115, 116-17, 119,121,
Yemen, 30, 36, 78
131, 180, 183-95
Public Citizen Health Research Group, 93, 115, 128
122, 123, 126, 127, 128, 133, 134, 139, 141,
Yorkshire Television (UK), 49, 50
143,145,154,157, 158,160, 163,170, 178,
Young, F,, 21
ISO, 184, 185, 186, 188, 189, 190, 191
Yugoslavia, 82
Committee on Safety of Medicines, 24, 89, 160.
Yuthavong, K., 81
Q1MP, 92,102
186, 189,190
Department of Health, 2, 85, 92,189
Medicines Act, 92
Zabriskie. J., 4
rational use of drugs, 6, 13, 19, 56, 64, 66,79, 94,
Medicines Commission, 189
Zambia, 44
124,160
Rawlins, M., 39,144, 145
National Health Sendee, 12, 90, 115, 191
Zimbabwe, 44
ulcers, 75, 90, 94, 95
Reye’s Syndrome, 11,75-6
duodenal, 90
rheumatoid arthritis, 24, 87-8, 89, 94
gastric, 89, 90
Rhodes, P., 5
peptic, 24, 70, 84, 122
Ritson, P., 183
UNICEF, 29, 106
Rose, S., 117
Royal Australian College of General Practitioners, 45
United Arab Republic, 151
Royal College of General Practitioners, 157
Uruguay, 33,36,43, 56,112
Rwanda, 78
USA, 2,4, 5, 9, 11, 16, 17,21,22,23, 27, 32,41,
United Nations Population Fund (UNFPA), 151,152
44,45, 54,55, 56, 57, 58,60,61,62, 64, 65,
69,70,74, 75, 76, 78, 79, 82, 85, 87, 88, 89,
Sakiz, E„ 154
Sastrawinata, S., 175
90, 91,93,97,99, 100,107, 109, 112, 115,
117, 120,121, 122, 123-4, 125, 126, 128, 130,
Problem Drugs
neural tube defects, 133
199
|2Oi
Index
Problem Drugs
Company
Abbott, 4,31,33,114.123
May & Baker, 31
Abbott-Takeda, 4
Miles (See: Bayer)
American Home Products (sec also: Wyeth/Ayerst),
Mcdimpex, 84,145
44, 69
Astra, 193
Australian Pharmaceutical Manufacturers’
Association (APMA), 45,58
Medochemie, 49
Merck Sharp & Dohme (MSD), 3,4, 31,58,
106-7
Multifarma, 190
Bayer, 58. 61, 75, 184
Napp, 115
Beecham (See also: SmithKline Beecham), 33,54,59
Nattermann, 31
NEFARMA (Association of Dutch Pharmaceutical
Boehringer Ingelheim, 18,103
Boehringer Mannheim, 31
Industries), 108
Boots, 31
Nicholas, 76, 144
Bristol-Myers Squibb, 4,31, 74, 188
Norgine, 141
Brocades (See: Gist-Brocades)
Byk Gulden, 12
Organisation of Pharmaceutical Producers of India,
144
Carter-Wallace, 31
Organon, 108,144, 145
Ciba-Geigy, 3,5, 17,32,41-2,84,91,93, 106,
Orion, 145
112,177
Cilag. 45,46
Continental Pharma. 91
Parkc-Davis/Warner Lambert, 31, 38, 39, 62, 102,
115,190
Pfizer, 31, 91,186
Dainippon, 31
Daikon Corporation, 164
Pharmaton SA, 13
Dumex, 31
Praxis Biologies, 4
Pharmax, 123
Duphar, 134
Ranbaxy', 61
E. Merck, 84, 85, 111, 112, 113
Efroze, 145
Eli Lilly, 5,58, 91, 92, 192-3
Raw Power, 123
Reckitt and Colman, 74
Remedica, 49
Ethica, 141
Rhone-Poulenc, 2,13,190
European Federation of Pharmaceutical Industry
Robins, AH, 33,99, 164
Associations (EFP1A), 2
Roche (See: Hoffman-La Roche)
Rorer, 31, 33
Roussel (See also: Hoechst), 77-8, 92-4, 112, 115,
Farmitalia Carlo Erba, 38,63, 114
154
Fisons, 31
Sami, 145
Gentili, 49
Sandoz, 84, 103,106-7,111, 115, 116,124, 190
Gist-Brocades, 115
Schering. 18, 145,169,177
Glaxo, 31,58, 59, 60, 117
Searle, G.D., 18,31,45-6, 90,166
Glenmark, 91
Scrvier, 123
Grant Chemical Company, 137
Grunenthal, 31, 76
Seven Seas, 12, 123
SmithKline Beecham, 31, 39,58,59,123
Sterling Winthrop, 31, 74,76, 115
Syntcx, 91
High Noon Labs, 107
Hoechst (See also: Roussel), 31,60, 77, 78-9, 81-5,
92,112,115,154,193
Hoffman-La Roche, 17,59, 84, 115, 128,185,190
UCB, 13, 116-17
Unichem, 144
Upjohn, 31, 33, 35,62, 169, 185, 188, 189
ICI,5
International Federation of Pharmaceutical
Manufacturers Associations (IFPMA), 2,3,5,
38,59
Wallace Pharmaceuticals, 108, 131
Warner Lamhert/Parke-Davis
(Sec: Parke-Davis/Warner Lambert)
Wellcome, 58
Wyeth/Ayerst, 22,31,33,39,44, 91, 177
Janssen, 31,45,46,49-50, 115
Johnson & Johnson, 31,49-50,69
Larkhall Laboratories, 123
Lederle, 63
Leiras, 173
Lipha, 115
Index
Problem Drugs
Drugs
(names with a capital first tetter are brand names, the rest are generic names or therapeutic groups)
Abiadan, 103
ascorbic acid (See: vitamin C)
ceftriaxone, 52, 59
Accutane, 125, 128
aspirin, 11,24, 69, 71,72, 73,74,75-6,78, 79, 84,
cefuroxime, 52, 58,59
ACE-inhibitors, 132
acetaminophen (See: paracetamol)
85, 87,88, 90,93, 130
Aspinna, 75
cephalexin, 52,58, 59, 60
cephalothin, 52, 59
acetates, 101
Aspro, 76
ccphamandolc, 52
acetic acid, 101
atropine, 31,45-6
cephaprin, 59
acetylcysteine, 76, 101
attapulgite, 32, 38, 39,44
cephazolm, 52
acetylsalicylic acid (See: aspirin)
Augmentin, 58,59
cephradine, 52,59
activated charcoal, 32
azapropazone, 87,93
Ceporcx, 59,60
Advil, 69
azatadme, 99
chloral hydrate, 184
alclofenac, 91,94
azithromycin, 52
chloramphenicol, 29,36-7, 39, 51,52,55,56, 63,
alcohol, 73, 75,96, 125, 179,184
aztreonam, 52
Alka-Seltzer, 75
66, 98
Chloraseptic, 100
Alpaz, 190-1
chlordiazepoxide, 17,131, 184, 185
alprazolam, 184,185, 190
bacitracin, 36,38
chlormethiazoie, 184
aluminium hydroxide, 39
Bactrim, 59
chlormezanonc, 184
amidopyrine (See: dipyronc)
bamipine lactate, 99
chloroquine, 131
amikacin, 52,54,62-3
Baralgan/Baralgin, 79, 81-2, 84, 85
Chlorostrep, 39
amino acids, 108
barbiturates, 3, 71,73, 131, 157, 184,195
chlorpheniramine, 99
aminophylline, 132
Benadryl CD, 103
chlorpromazine, 184, 189
aminopyrine (See: dipyronc)
bencyclane, 114
chlorprorhixene, 184
aminopyrine-sulphonatc sodium (Sec: dipyronc)
benoxaprofen, 23, 87, 91, 92, 94
choline, 122
amitriptyline, 184, 192
benperidol, 184
Cibalgin, 84
ammonium chloride, 101
benzodiazepines, 5,17,23-4, 131,183, 184,
cilastann, 52
Amoxil, 54,59
185-91,194,195
cimetidine, 90
amoxycillin, 52, 54, 56,58, 59, 60,65,98
benzoin compounds, 101
amphetamines, 112, 117
Bepro, 131
Cipro/Ciprobay, 58,61
ampicillin, 38,52,53,56, 57,59,65,98
beta-blockers, 23
ciprofloxacin, 52,54, 58, 60-2
Amuno Gits, 94
bicarbonates, 101
citric acid, 75
amylobarbitone, 184
bioflavonoids, 122
Claforan, 60
anabolic steroids, 106,108-9
biotin, 119, 122
clarithromycin, 52
Anacin-4,69
anaesthetics, 125, 184
bismuth, 38
clavulanic acid (clavulanate), 52,58,65, 66
Boost IQ, 123
clefamide, 36, 38
analgesics, 3, 6, 11, 18, 24, 69-96,102,130, 140,
Bradilan, 115
clemastine, 99
brain tomes, 3, 12-13,25, 106, 111-18
clemizole, 99
184
analgin (See: dipyrone)
“smart” drugs, 111, 112,117
cinnarizine, 99, 113, 114, 115
clindamycin, 52,62
analginum (See: dipyronc)
bromazepam, 184
clioqumol, 3, 32,33,41-4
antacids, 132
bromhexine, 103
clobazam, 184
anti-asthmatics, 130, 132, 185
brompheniramine, 99
clobutinol, 102
anti-cancer drugs, 125
broxyquinoline, 41
clomiphenc citrate, 129
anti-emetics, 9, 18
Bufferin, 69
clomipramine, 184
anti-ulcer drugs, 90
buflomcdil, 113,114
clorazepate, 184
antibiotics, 1,4,9,11,24-5,29,30,32,35-40,51-68,
BuSpar, 188-9
cioxacillin, 52
buspirone, 184,188-90
co-amoxiclav, 52,65
79,98,103,125,131, 151,157,163
aminoglycosides, 25, 36, 52,57,62-3
Butazolidin, 93
co-dergocrine mesylate, 111, 113, 114, 115
cephalosporins, 52,57,59-60, 65,131
butazones, 87, 91, 93, 94, 95
co-tnmoxazole, 24, 38,53,52,56, 58,59,60,65,
in animals, 1,57
butobarbitonc, 184
in pregnancy, 62,125,127,130, 131
butriptyline, 184
cobalamin (See: vitamin Bl 2)
lincosamides, 52,62
butyrophenones, 184
cobalt, 134
macrolides, 52,57,62
66, 98
cocaine, 184
penicillins, 52, 59, 62, 131
codeine, 71,72, 84, 101, 103
quinolones, 52,54,57,58, 60-2,65
caffeine, 71,73,75,102, 123, 179
Cognex, 115
reserve list, 65, 66
calcium, 121,179,180
colistin, 36,38
resistance to, 1,31, 36,37,51-4,56,57,60,61-
2,63, 65,66, 98
tetracyclines, 52,57,63, 125
iodide, 131
phosphate, 75
carbamazepine, 132
anticholinergics, 103
carbmoxamine, 99
anticoagulants, 127
carbocistene, 101
anticonvulsants, 25, 125, 130,132, 157, 184
Ccclor, 58
antidepressants, 9, 17, 18,21,100,183, 184,186,
cefaclor, 52,58, 65
191-3,194
antidiarrhoeals, 1,3, 9, 10, 18,27-50,62
cefadroxil, 52,59
antibiotics in, 1,3,11,31-2,35-40,56
cefamandolc, 59
cefazolm, 59
antifungal drugs, 157
cefixime, 52,59
antihistamines, 3,10, 79, 99,103,106-7,132, 184
ccfmctazole, 59
antihypertensives, 21,23,25, 132
cefonicid, 59
antimalarials, 131
ccfoperazone, 52,59
antipsychotics, 183,184, 193-5
cefotaxime, 52,59,60
antithyroids, 125, 132
cefotetan, 59
apazone, 78
appetite stimulants, 3,9, 12, 18, 106-8, 123
cefoxitin, 52,59
Arcalion 200, 123
ccfsulodin, 52
arginine, 112
ceftazidime, 52,59,60
Arlef,91,94
Ceftin, 58
Arret, 49
ceftizoxime, 52,59
cefpirome, 52
combination products, 18, 23, 36, 39, 51, 65, 66,
70,71-5,79, 81, 91, 101-2, 122, 123, 124,129,
134, 178, 185, 195
Conova 30,160
contraceptives, 3,16, 17,135,139, 141, 145, 147-76
abortion pill, 153-4
barrier methods, 149, 157, 158-9, 172, 176
condom, 150, 151, 153, 157, 158-9, 163
diaphragm, 148, 158
female condom, 150
implants, 149, 150, 173-6
injectable, 149, 150,157, 169-72
intrauterine device (IUD), 147,148-9, 150,
151-2, 157, 158,163-7, 175
male, 153
natural, 149, 154-5
lactational amenorrhoea method (LAM), 155
ovulation, 154
rhythm, 149
withdrawal, 149
oral, 16, 17, 121, 129, 135, 144, 148
157-62, 163, 170, 175,179
ISO, 151,
202
Index
Problem Drugs
imipramme, 184, 192
contraceptives, oral, (continued),
progestogen-only pill, 157, 159, 160
sterilisation, 147, 150,157
vaccine, 153
copper, 163, 166
Corrective Mixture, 33
corticosteroids, 130,131-2
cough and cold remedies, 3, 9, 10, 18, 97-104, 130,
131
Equanil, 185
ergoloid mesylates (See: co-dergocrine)
ergotamine, 130
Eryc, 62
erythromycin, 52, 54, 62,65,98
Eskaycillin, 59
Estraderm, 17, 177
ethinyloestradiol (EE), 121, 145, 160
ethisterone, 135
creosote, 101
Cu-7, 166
ethylestrenol, 108, 109
Cumorit, 145
etodolac, 22,71,87
cyclandelate, 113, 115
etretinate, 126
cyclobarbitone, 184
eucalyptus, 101
Cyclospasmol, 115
Eugynon 40, 160
cyproheptadine, 3,106-8
expectorants, 100-1, 103
ethynodiol diacetate, 160
Imodium, 31,49-50
Imoscc, 49
Imovane, 190
indomethacin, 71,87, 88, 89, 94, 130-1
indoprofen, 71, 94
inositol, 115, 122
insulin, 130, 132
iodides, 127
iodine, 127,131
iodoquinol, 32,41, 44
ipecacuanha, 101
iprindole, 184
iproniazid, 184
iron, 73, 125-6, 127, 132-4
isocarboxazid, 184
isoniazid, 65, 131
Cyprowal, 108
Feldene, 91
isothipendyl, 99
isotretinoin, 125, 126, 128
isoxicam, 94
Dalacin C, 62
fenbufen, 71, 87
Daikon Shield, 164,166
fenclofenac, 94
danazol, 109
fenoprofen, 71, 87
dapsone, 131
feprazone, 93, 94
Deapril-ST, 115
decongestants, 9, 10,79,99-100, 103
Flamox, 91
dehydroemetine hydrochloride, 38
lleroxacin, 52
kanamycin, 52, 62
Dependal-M, 39
Flosint, 94
kaolin, 3, 30, 32,35,38, 39
Depo-Provera (DMPA), 169-72
Floxapen, 59
Kaomycin, 35
depot medroxyprogesterone acetate
flucloxacillin, 52,59
Kaopectate, 33
flufcnamic acid, 91, 94
Karlin, 33
(See: Depo-Provera)
DES (diethylstilbestrol), 3, 16,125, 129, 133,
137-42,'159
josamycin, 52
Flenac, 94
flunarizine, 113, 114-15
Keflex, 58
flunitrazepam, 184
Kemicctine, 63
fluoxetine, 192-3,194
ketazolam, 184
desipramine, 184
flupenthixol, 184
ketoprofen, 71, 87, 89
DesPlex, 137-8
fluphenazine, 184
ketorolac, 71
dextromethorphan, 101, 102, 103
flurbiprofen, 71, 87
Kiddi Pharmaton, 13
dextropropoxyphene, 71, 73, 79
fluspirilene, 184
diazepam, 24, 127, 131, 184, 185
fluvoxamine, 184, 193
dichloralphenazone, 184
folic acid (folate), 119, 123, 127,133
Largactil, 189
diclofenac, 71,87, 91
folicle stimulating hormone (FSH), 129
lecithin, 122
dicnestrol, 138
levonorgestrel, 160, 166, 173
diethylstilbestrol (See- DES)
Fortum, 60
framycetin, 36, 38, 62
diflunisal, 87
furazolidone, 36, 38,39
Limovanil, 145
digitalis, 25
Furoxone, 39
lincomycin, 52, 62
in animals, 141-2
digoxin, 23
Librium, 17, 185
lithium, 184
dihydrostreptomycin, 36
Lodine, 22
diloxanide furoate, 36,38
gemeprost, 154
dimenhydrinate, 18
gentamicin, 52,54,62-3, 98
gentian bitters, 107,123
lofcpramine, 184
diphenhydramine, 99
diphenoxylate, 3.10,18,30,31,45-8
Genmal, 115
Lomotil, 18,31,45-6
diphenylpyraline, 99
glafeninc, 71,77-8, 79
Lopemid, 49
dipyrone, 3,71,78-9,81-6
Glifanan, 77
loperamide, 3, 10, 31,33,49-50
diuretics, 23,132
gonadotrophin, 153
Lopenum, 49
Divina, 145
gossypol, 153
loprazolam, 184
Domical, 192
guaiphenesin (glyceryl guiaicolate), 101
lorazepam, 184
Donnagel, 33
Gynaecosid, 145
lormetazepam, 184
Halcion, 183, 188,189
Lyspafen, 45,46
lysuride, 18
Donnagel PG, 33
Loftyl, 114
lysine, 108
dopamine, 189
Dopergin, 18
Loestnn 20,160
Dormicum, 190
haloperidol, 184
dothiepin, 184
heparin, 132
doxepin, 184
heptabarbitonc, 184
maprotiline, 184
doxycycline, 52
heroin, 184
Maxicam, 94
doxylamine, 99,103
hexestrol, 138
mebhydrolin napadisylate, 99
Dramamine, 18
Hexopal, 115
Mebinol Complex, 38
droperidol, 184
hormone replacement therapy (HRT), 5, 17, 177-82
meclofenamate, 89
drugs in pregnancy, 2,3,4, 16,23,46, 49, 50, 62,
hormones, 17, 18, 108, 125, 129,133, 135,
medazepam, 184
137-46,148, 153, 157-62,163, 166, 169-82
Humagel, 38
medroxyprogesterone, 145
human chorionic gonadotrophin (HOG), 129,153
mefloquine, 131
76, 100, 119,121, 122, 125-46, 159, 164, 166,
171, 174, 175-6
human menopausal gonadotrophin (HMG), 129
Elavil, 192
Hyderginc, 111, 115, 116
Effico Tonic, 123
hydroxyquinolines, 3, 30,32, 33, 38,41-4
Encephabol, 111,112,113
hyoscine butylbromide, 18
enoxacin, 52
enrofloxacin, 57
hypoglycaemics, 130,132
Entero-Pnstina, 38
hypotensives, 132
hypnotics, 23, 25, 183,184, 188, 189, 191, 194
Entero-Vioform, 32,41
Entox, 44
mefenamic acid, 71, 87
Menstrogen, 145
Mentane, 115-16
menthol, 101
meprobamate, 131, 184, 185
mepyramine, 99, 103
Merital, 193
metamizol (See: dipyrone)
methadone, 84
methampyrone (See: dipyrone)
EP drugs, 16, 135, 143-6
ibuprofen, 71,75,76, 84, 87, 88, 89, 90, 94, 130
ephedrine, 100
imipenem, 52
methandienone, 108, 109
methicillin, 52,54
Index
methotrimeprazine, 184
ondansetron, 117
Methrazone, 94
opium, 184
primidone, 132
methylcysteine, 101
Opren/Oraflex, 4,23, 91, 92, 94
prochlorperazine, 23,184
methyldopa, 132
Optalidon, 84
Progcstascrt, 166
methyloestradiol, 145
oral rchydration solution, 27,29,30
methyloestrenolone, 145
orciprenaline, 102
methylphenidate, 112-3
Osmogit, 94
methyltestosterone, 135
methyprylone, 184
metronidazole, 36, 38, 39, 131
Mexaform, 41
mianserin, 184
Microgynon, 160
midazolam, 190
mifepristone (See also: RU486), 154
Minocin, 63
minocycline, 52, 63
misoprostol, 89, 90, 95
Mogadon, 185, 194
monoamine-oxidase inhibitors (MAOIs) 100 184
192,194
morphine, 70, 71, 84, 184
Mosegor, 106-7
166, 169-72,173-6, 178, 179
promazine, 184
Ota ring (IUD), 166
promethazine, 99, 184
over-rhe counter (OTC) drugs, 10, 11, 17-18, 69,
propyphenazonc, 71,78, 79, 81,82, 84
72,94, 99,100, 121, 126, 130, 135
Ovran 30, 160
prostaglandins, 69, 70, 87, 154
protriptyline, 184
Ovranerte, 160
Prozac, 192-3
oxacillin, 52
pseudoephedrine, 10, 100
oxaprozin, 71
psychotropic drugs, 11-12,23-4,25, 125,130,
oxazepam, 18, 184
131, 180, 183-95
oxomcmazine, 99
oxpentifylline (pentoxifylline), 113, 114, 115
pyridoxine (See: vitamin B6)
oxycodone, 84
pyrimethamine, 131
oxymetazoline, 99
pyritinol, 111,113,114
pyrazolone derivatives, 71,78-9, 81-5
oxymethoIone, 108,109
oxypertine, 184
oxyphenbutazone, 87, 91, 93, 94
oxytetracycline, 36,52
moxalactam, 59
xMulti-Sanostol Syrup, 12
progesterone, 137,143-6, 154, 169
progestogens, 16,17,134-5, 143, 154, 157-161,
Osmosin, 94
Mosegor-V, 107
mucolytics, 100-1
primaquine, 131
Quemiciclina, 38
quinacrine, 38
quinalbarbitone, 184
quinine, 131
Pameton, 76
Panadol, 76
multivitamins (See: vitamins)
pantothenic acid, 119,122
mupirocin, 52
paracetamol, 24,71, 72,73, 75, 76,78,79, 84, 85,
88, 89,91,94,95, 102, 104, 130
ranitidine, 90
Reasec, 45, 46
Restoril, 190
Paramcttes, 123
retinol derivatives, 125
nabumetone, 87
Parepectolin, 33
riboflavinc (Sec: vitamin B2)
naftidrofuryl, 115
Parnate, 192
Ridol, 84
nalidixic acid, 36, 38, 52,53, 60
paromomycin, 36, 36,62
rifampicin, 131
nandrolone, 108,109
pectin, 3,30,32-3,35,38, 39
Ritalin, 112
Naprosyn, 91
pcfloxacin, 52
ritodrine, 131,134
naproxen, 71, 87,91, 130
penicillamine, 125
Roaccutanc, 128
nasal decongestants (See: decongestants)
penicillin, 52, 53,57,59,61,62,63, 98, 131
Ronicol, 115
natrium (See: dipyrone)
benzylpenicillin, 52, 59, 98
roxithromycin, 52
Neocon, 160
phenoxymethylpenicillin (penicillin V), 52,59,
RU486 (See also: mifepristone), 154
neomycin, 30,35, 36,38,43,52,55,56,62,66
60
Neoston Forte, 91
procaine penicillin, 98
netilmicin, 52, 54, 62
Penorit, 145
nicergoline, 113, 114
, pentazocine, 71, 73
salicylates, 75, 87, 130
nicofuranose, 115
peppermint, 101
Periactin, 3,106-7
salicylazosulphapyridme, 36
nicotinic acid/niacin (Sec: vitamin B3)
salbutamol, 132
Saridon(e), 84
pericyazine, 184
perphenazine, 184
Septrin, 58
nifuroxazide, 36, 38
nimesulide, 87
phenacetin, 71, 77,78,79
sertraline, 186,192
nimodipine, 113
phenazone, 82
Silastic, 173
nitrazepam, 184, 185, 194
phenelzine, 184
Silomat, 103
nomifensine, 193
phenindamine, 99
Sintaverm, 84
non-steroidal anti-inflammatory drugs (NSAlDs),
pheniramine, 99, 102
sisomicin, 62
mcotinyl alcohol, 115
3,4, 18,22, 23,24,71,76,87-96, 130
phenobarbitone, 184
serotonin, 192,194
sodium benzoate, 101
nootropics, 25,113-17
phenothiazines, 184
sodium bicarbonate, 75
Nootropil, 13, 116-17
phenylbutazone, 78, 81, 82, 87,93
sodium citrate, 101
noradrenaline, 132
noramidazophenum (See: dipyrone)
phenylephrine, 100
sodium noramidopyrine methancsulphonate
noraminophenazonum (See: dipyrone)
phenyltoloxamine, 99
Somese, 189
Norbacrin-400, 61
norethisterone, 135, 145, 159, 161, 169
phenytoin, 132
Spasmo-Cibalgin, 84
pholcodine, 101
spasmolytics, 9, 81
norerhisterone oenanthate (NET-OEN), 169-70
phthalylsulphacetamidc, 36
squill, 101
norfloxacin, 52,58,61
phthalylsulphathiazole, 36,37,43
Norigest, 169
pill, the (see: contraceptives, oral)
stanozolol, 108,109
stilbenes, 141
phenylpropanolamine, 100, 103
(See: dipyrone)
Norimin, 160
pimithixine, 99
stilboestrol, 141
Noristerat, 169
pimozide, 184
Stilboestrol, 141
Noroxin, 58
piracetam, 13, 113, 114,116-17
piromidic acid, 36,38
Strepomegma, 33
streptokinase, 74
piroxicam, 71,87, 91
pirprofen, 71, 87
streptomycin, 36, 39,43,51,52, 54,56,62
pivampicillin, 58
succinylsulphathiazole, 36,37
pizotifen, 106-7
sulbactam, 52,65,66
Polymagma, 33,39
sulfadoxine, 131
polymyxin B, 36, 38, 39
sulindac, 71,87
Norplant, 173-6
nortripryline, 184
Novalgin, 79, 81-2, 84
novamidazofen (See: dipyrone)
novaminsulfonicum (See: dipyrone)
Nutrisan, 124
oestradiol, 137, 145
oestrogen, 16, 17. 133,135, 137-46, 157-62,169,
177-81
ofloxacin, 52
omeprazole, 90
Sturgeon Forte, 115
polynoxylin, 36, 38
sulphadiazine, 36
potassium iodide, 101
sulphadimidine, 36
pramiverine, 84
sulphaguanidine, 36,37,43
Praxilene, 115
prazepam, 184,190
sulphaguanole, 36
Premarin, 177
sulphasalazine, 36
sulphamethoxazole, 24,36,38, 52,65
Problem Drugs
methionine, 76. 79, 122
Index
Problem Drugs
sulphathiazolc. 36
sulphonamides, 36, 37,38,53,56, 57
Bl 2 (cobalamin), 119,123,133
B15 (pangamic acid), 121
sulpiride, 184
B17 (lactrile), 121
sulpyrine (See; dipyrone)
C (ascorbic acid), 119, 121,122
suprofen. 94
D, 119, 121,179
Suprol, 94
deficiencies, 12, 119-23,132, 133
Surgam, 92-4
E, 119, 121,122, 123
suxibuzone, 94
K, 119
multivitamins, 12-13, 107-8, 121,122, 123,
tacrine, 115
Tampovagan, 141
124,132, 133
supplements, 119-22, 126,132, 133
Voltaren, 91
Tandacote, 94
Tandem IQ, 123
Tanderil, 94
warfarin, 125
Targifor, 112
Tatum-T, 166
teicoplanin, 52
temafloxacin, 52
Xanax, 185
xylometazoline, 99
temazapam, 184, 190
tenoxicam, 87
terfenadine, 99
Yutopar, 134
testosterone, 108-9,153
tetracycline, 38,52,53, 57,65, 125
thalidomide, 16, 23, 125
Zelmid, 193
thenyldiamine, 99
Zevit, 123
thiacetazone, 65
zimeldme, 193
thiamine (Sec: vitamin Bl)
Zimovane, 189
thioridazine, 184
zinc, 123
thymoxamine, 113
Zofran, 117
tiaprofenic acid, 71, 87,92
Zoloft, 186
ticarcillin, 65
Zomax, 94
tobramycin, 52,54, 62-3
zomepirac, 94
Tofranil, 192
zopiclone, 184, 190
tolmetin, 87, 89
zuclopenthixol, 184
tolu, 101
tramadol, 71, 76-7
tranquillisers, 3,5,17, 18,21,23-4,127,
183-91, 193-5
Tranquo-Buscopan, 18
tranylcypromine, 184,192
trazodone, 184, 192
Trental, 115
Tres-orix Forte, 107
tretinoin. 126
Triaminic, 103
Triaminic-DM, 103
Triamimc-E, 103
triazolam, 183, 184,188, 189
triclofos sodium, 184
trifluoperazine, 184
trifluperidol, 184
trimeprazine, 99
trimethoprim, 24, 36, 38,52,57, 65
tnmipraminc, 184
tripelennamine. 99
triprolidine, 99
tryptophan, 184,193
Tylenol, 69
vaccines, 109
Vacontil, 49
Valium, 185
valproate, 132
vancomycin, 38,52, 57, 65
vasodilators, 3,25,113-14
velnacrine maleate, 115-16
Veronal, 184
Verstan, 190
viloxazine, 184
Vioform, 41
Vitachieve, 123
vitamins, 3, 12-13,18,71, 73, 75, 79, 103, 106,
107,117,119-24, 126, 132,179
A, 119,120,121, 123, 125, 132
and intelligence, 122, 123
Bl (thiamine, sulbutiamine), 119, 123, 124
B2 (riboflavine), 119
B3 (nicotinic acid or niacin), 113,119,123,124
B6 (pyridoxine), 113, 119, 121, 123, 124
User Survey
Health Action International would like your opion about the pack - how you think the contents
could be improved; information about the problems in your country or region with particular cate
gories of drugs; and how you have used, or plan to use, the pack.
Please fill in both sides of this sheet and return it to:
Health Action International
Jacob van Lennepkade 334-T
1053 NJ Amsterdam, the Netherlands
Your Name:
Address:
Organisation or Institution:
1. Which categories of drugs described in this pack arc a problem in your country/rcgion/community?
Antidiarrhoeals
Antibiotics
Analgesics
Cough & cold remedies
Contraceptives
Drugs in pregnancy
Growth stimulants
Hormone replacement therapy
Psychotropics
Please give specific details:
2.
Please comment on the contents of the pack:
Arc the contents:
adequately technical
not technical enough
too technical
Do you find the design:
easy to read
difficult to follow
Are they:
practical
not practical enough
Illustrations: are there:
too many
enough
too few
Do you find the language:
very easy to understand
easy
average
difficult
very difficult
How could the pack be improved?
3. Please tell us how you have used (or plan to use) the pack, which categories of drugs particularly
interest you, and whether you would like to contact others doing similar work. Are you interested in
becoming involved in HA1 activities within your region?
Additional comments:
205
Useful Addresses
Further information on the drugs and the
issues raised in this pack are available from all
the Health Action International (HAI) coordi
nating offices:
HAI-Europe
J. van Lennepkade 334-T
1053 NJ Amsterdam
THE NETHERLANDS
Tel: (31 20)683 3684
Fax: (31 20) 685 5002
HAI Clearinghouse
IOCU
PO Box 1045
10830 Penang
MALAYSIA
Tel: (60 4) 37 13 96
Fax: (60 4) 36 65 06
AIS Latin America
Accion para la Salud
Avda. Palermo 53 J Dpro. 104
Lima 13,
PERU
Tel/Fax: (5114)712 320
World Health Organization (WHO)
WHO
Avenue Appia
1211 Geneva 27
SWITZERLAND
Tel: (41 22) 791 2111
Fax: (41 22) 791 0746
The following WFIO programmes can be
reached at the address above:
• Action Programme on Essential Drugs
(DAP)
• Acute Respiratory Infections (ARI)
• Control of Diarrhoeal Diseases (CDD)
• Division of Drug Management and Policies
(DMP)
• Expanded Programme on Immunization
(EPI)
• Programme for Appropriate Health Care
Technology (ATH)
• Special Programme of Research,
Development and Research Training in
Human Reproduction (HRP)
• Special Programme for Research and
Training in Tropical Diseases (TDR)
• Maternal and Child Health and Family
Planning (MCH)
■ \
DOCUi'Ir'JTA'l’IOI'I
UN*T
■
> I
/■
^tyGALOfjk^?
Manufacturers’ organisations
International Federation of
Pharmaceutical (IFPMA)
Manufacturers Association
30, Rue de Saint-Jean
CH-1211 Geneva I8
Switzerland
Tel: (41 22)340 1200
Fax: (41 22) 340 13 80
World Federation of Proprietary Medicine
Manufacturers
Dr Jerome A Reinstein, Director General
15 Sydney House
Woodstock Road
London W4 1DP
UK
Tel: (44 81)747 8709
Fax: (44 81)747 8711
Other international organisations
Alliance for the Prudent Use of Antibiotics
Ms C. Sherman, Administrator
PO Box 1372
Boston, MA 02117-1372
USA
Christian Medical Commission,
World Council of Churches,
P.O.Box 2100,
CH-1211 Geneva 2,
Switzerland.
Tel: (4122) 7916111
Fax: (4122) 7910361
(for guidelines on drug donations)
DES Action USA
Cathedral Building
1615 Broadway #510
Oakland, CA94612
USA
Tel: (1 510) 465 4011
Fax:( l 510) 465 4815
(for international inquiries)
DES Action,
Wilhelminapark 25,
3581 NE Utrecht,
the Netherlands
Tel. (31 30)518160
Fax: (31 30)512758
(for European inquiries)
Useful
Addresses
International Network for Rational Drug Use
(INRUD)
Dr Richard Laing
c/o Management Sciences for Health
165 Allendale Road
Boston, MA 02130
USA
Tel: (1 617)524 7799
Fax: (1 617)524 2825
International Society of Drug Bulletins
103 Hertford Rd.
London N2 9BX
UK
Tel: (44 81) 883 2769
Fax: (44 71) 935 1606 (Attn Drugs &
Therapeutics Bulletin)
Medical Lobby for Appropriate Marketing
PO Box 172
Daw Park SA 5041
Australia
Tel/Fax: (61 8) 374 2245
UNICEF
Essential Drugs Programme,
UNICEF House,
3 UN Plaza,
New York, NY 10017,
U.S.A.
Tel: (1 212) 326 7000
Women & Pharmaceuticals Project
Women’s Health Action Foundation
PO Box 4263
1009 AG Amsterdam
the Netherlands
Tel: (31 20) 665 20 02
Fax: (31 20) 665 30 02
Treatment Guidelines
Analgesic Guidelines, Antibiotic Guidelines
and Psychotropic Guidelines:
Victoria Medical Association Therapeutics
Committee
“Chelsea House”, 3rd Floor
55 Flemington Rd
North Melbourne, VIC, 3051
Australia
Tel: (61 3)329 1566
Fax: (61 3) 326 5632
Drugs in pregnancy
Cochrane Collaboration Pregnancy and
Childbirth Database
Update Software Ltd
Little Milton
Oxford 0X44 7QB UK
Fax: (44 844) 278 887
British National Formulary
British Medical Association
Tavistock Square
London WC1H9JP
UK
Health Action International’s
coordinating offices:
HAI Europe
Jacob van Lennepkade 334T
1053 NJ Amsterdam
The Netherlands
HAI Clearinghouse/ARDA
</o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accion para la Salud
Avda. Palermo 531
Opto. 104
Lima 13
Peru
Acknowledgements
Many people (too many to name them all) have
contributed ideas, information and encouragement
during the preparation of this pack: people who are
involved in the HAI network around the world;
health workers at various levels of health care systems
in both developing and industrialised countries;
government officials; representatives of international
organisations; and people working in the pharmaceu
tical industry and in the media.
David Gilbert was involved at an early stage in doing
initial research that helped to shape the contents of
the pack, and contributed substantially to the writing
of one of the sections.
The following people read and commented on drafts of
sections or all of this pack: Antonio Addis (Istituto
Mario Negri, Italy); K. Balasubramaniam (HAI/IOCU
Regional office for Asia and the Pacific); Tariq Bhutta
(King Edward Medical College, Lahore, Pakistan);
Renata Bortolus (Istituto Mario Negri, Italy); Madeline
Boscoe (Coalition on Depo Provera, Canada); Simone
Buitendijk (DES Action, the Netherlands); Helena
Lutescia Coelho (Grupo de Prevenao ao Uso Indevido
de Medicamentos, Brazil); Graham Dukes (University
of Groningen, the Netherlands); Rosemary de Groot
(HAI Europe); Hilbrand Haak (Control of Diarrhoeal
Diseases, WHO, Switzerland); Amal Abd El
Hadi (Association for Health & Environmental
Development, Egypt); Anita Harden (Women’s Health
Action Foundation, the Netherlands); Ken Harvey (La
Trobe University; Australia); Elina Hemminki (HAI
Finland); Andrew Herxheimer (International Society' of
Drug Bulletins); Ellen’t Floen (HAI Europe); Catherine
Hodgkin (HAI Europe); Piero Impicciatore (Istituto
Mario Negri, Italy); Lolkje de Jong-van den Berg
(University of Groningen, the Netherlands); Oscar
Lanza (AIS [Latin American HAI network], Bolivia);
Roberto Lopez (AIS [Latin American FIAI network],
Peru); Katri Makkonen (FIAI Finland); Benoit
Marchand (Centro de Investigaciones y Estudios de la
Salud, Nicaragua); Charles Medawar (Social Audit,
UK); Barbara Mintzes (HAI Europe); Zafar Mirza
(Association for Rational Use of Medication in
Pakistan, Pakistan); Ian Munro (HAI Europe Advisors
Committee, UK); Eeva Ollila (HAI Finland); Ana Maria
Pizarro (Centro de Investigaciones y Estudios de la
Salud, Nicaragua); Sinika Sihro (FIAI Finland);
Hermann Schulte-Sasse (BUKO Pharma-Kampagne,
Germany); Michael Tan (Health Action Information
Network, The Philippines); Jose Teran (AIS [Latin
American HAI network], Ecuador); Gianni Tognoni
(Istituto Mario Negri, Italy); James Tulloch (Division of
Diarrhoeal and Acute Respiratory Disease Con
trol, WHO, Switzerland); Krisantha Weerasuriya
(University of Colombo, Sri Lanka); Nicolien Wieringa
(Women’s Health Action Foundation, the Netherlands).
Barbara Mintzes has had the task of coordinating the
extensive consultation process, of ensuring that impos
sible deadlines were met, and of coherently editing the
final manuscript. Babet Bonemeijer, Joan Young and
Rosemary de Groot helped with the administration,
receiving and sending out drafts for review. Richard
Bastiaans of Publish (Amsterdam) was responsible for
the lay-out and design.
To all of these people, I can only say thank you. This
would not have been possible without your help.
Problem Drugs is published as part of HAI-Europe’s
programme “Towards Rational Drug Use”. This pro
gramme has been funded by the Swedish, Danish and
Dutch governments and by the European Commission
DG VIII (Development Education), all of whose
generous support has made this publication possible.
207
AND
i r" ■'
0ocu^*T'°\;
Chetley, A., Problem Drugs, Amsterdam//
Health Action International, 1993
uM't
Appetite stimulants [addendum December 1993]
In November 1993, the US-based company Merck Sharp and Dohme (MSD)
announced that it will eliminate the indication of appetite stimulation from all
of its cyproheptadine formulations (usually sold under the brand name
Periactin) during 1994. It will also withdraw all combinations of
cyproheptadine and vitamins, products which the company admits are most
commonly used for appetite stimulation.
This is an important, if overdue, step. A key reason for the action was
information in this edition of Problem Drugs drawing attention to continued
promotion of MSD’s brand of cyproheptadine for appetite stimulation in
commercial prescribing guides in Africa. In press materials for the launch of
Problem Drugs, Health Action International (HAI) also highlighted promotion
of cyproheptadine as an appetite stimulant for children by Merind. Merind was
formerly MSD’s Indian subsidiary and was partially owned by MSD until
1991, but is no longer licensed to manufacture or sell MSD products.
MSD’s move follows nearly a decade of campaigning by HAI and many of its
partner organisations around the world. "Appetite stimulants are of no medical
value in treating malnutrition. You cannot solve problems caused by poverty
with pills," said Roberto Lopez, one of HAI’s three international coordinators.
HAI is calling on other companies to follow the example of MSD. It has
issued a particular challenge to the Swiss-based company Sandoz, which
manufactures another antihistamine, pizotifen, marketed as an appetite
stimulant in developing countries.
* 5k * * *
Appetite stimulants are discussed on p3 (Introduction), pl2 (Drugs and
children) and ppi06-8 (Growth stimulants) of Problem Drugs.
Health Action International's coordinating offices:
HAI Europe
J. van Lennepkade 334T
1053 NJ Amsterdam
The Netherlands
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accidn para la Salud
Avda. Palermo 531
Dpto. 104
Lima 13, Peru
Chetley, A. Problem Drugs, Amsterdam,
Health Action International, 1993
LIBRARY
Health Action International’s
coordinating offices:
HAI Europe
Jacob van Lennepkade 334T
1053 NJ Amsterdam
The Netherlands
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accion para la Salud
Avda. Palermo 531
Dpto. 104
Lima 13
Peru
Starting the habit of a lifetime
Infants and children have frequent but not usually
serious illnesses. A child’s frequent illnesses in the
early years are part of a natural process which de
velops his or her immature immune system. These
generally mild infections help to build immunity
against common diseases.
Do children need to take a wide range of drugs for
these illnesses? On balance, no. How'ever, in general,
“too many drugs are given to babies and children.”1
According to the World Health Organization
(WHO), two-thirds of all drugs used by children may
have little or no value.2
The potential dangers of inappropriate drug use are
highlighted by the more than 12% of in-patients
between 1983 and 1986 at the Hospital Infantil de
Mexico who experienced adverse effects to the med
ication they had received before hospitalisation.3 In
rhe USA, a 1988 study found that 2% of 6,546 pae
diatric admissions to hospital wards were due to
adverse drug reactions.4
One reason for the adverse reactions is that “children
are not simply small adults”.5 Their bodies deal with
drugs differently from adults. For example, the rate
of metabolism is reduced; particularly in infants, the
blood-brain barrier is more permeable and the kid
ney and liver are still developing, so the rate of
elimination of drugs is reduced.6 As a result, infants
and children need lower dosages of drugs than
adults. The calculation of appropriate dosage usually
takes account of both age and weight.7
The way children respond to a particular drug can be
determined only through research and experience.
However, most drugs do not have established doses
for infants and children.8 About three-quarters of the
drugs on the market in the USA are either contra
indicated or contain strong precautions for use in
children, and nine out of every 10 contain warnings
against use by infants and toddlers.9
Some common examples of drug misuse
in children
• antibacterials for viral upper respiratory infections
• decongestants for colds, resulting in unacceptable
adverse effects
• drugs to treat diarrhoea
• oral anti emetics for vomiting
• antipyretic agents for fever
• tricyclic antidepressants for bed-wetting
• sedatives for sleepless children or those labelled
hyperactive
• spasmolytics for abdominal pain
• appetite stimulants
Source: Rylance, G. (ed.), Drugs lor children. Copenhagen, WHO. 1987. pll
I...................
Problem Drugs
Antidiarrhoeals and
cough and cold remedies
Nonetheless, children are often targeted as suitable
candidates for drug therapy - especially for the use of
over-the-counter remedies for self-limiting condi
tions such as diarrhoea, cough and colds. Promoting
these types of drugs for children also has a longerterm purpose in helping to create a profitable market
for medicines in the next generation. Children who
grow up with rhe habit of taking unnecessary medi
cine to relieve self-limiting illnesses are likely to
spend a good deal on drugs within their lifetime.10
At least US Si billion is wasted every year on inap
propriate antidiarrhoeal drugs and cough and cold
remedies for children. According to WHO, many of
these preparations are useless and some are poten
tially dangerous.11
Four million children a year die from diarrhoeal dis
eases.12 Oral rehydration therapy plus continued
feeding can prevent at least half of those deaths, at a
cost of little more than 50 cents a child.13 “Anti
diarrhoeal agents are ineffective and can prolong the
diarrhoea. The disease is self-limiting and the real
therapeutic goal is simply: adequate fluid intake....
Drugs such as loperamide and diphenoxylate must
not be used in children under 12 years of age.”1'1
Another common problem among pre-school chil
dren is viral respiratory tract infection. “Most
childhood infections are caused by viruses and are
self-limiting - that is, the child gers better without
any treatment.”15 This is especially true for colds:
“uncomplicated head colds, even if causing fever, do
not warrant pharmacological intervention.”16
Many cold medicines for children include an antihis
tamine which can have a sedative effect. They are
advertised with a picture of a child sleeping peace
fully while a relieved parent, usually the mother,
looks on. The overt message is that the mother has
lovingly relieved her child’s suffering; the hidden
message is that the mother can have some peace and
quiet by giving her child this type of medicine.
Because the antihistamines are often long-acting,
their effects can continue for most of the following
day, causing the child to have difficulty with muscle
control, coordination and balance. Another ingredi
ent included in many popular cold remedies, the
decongestant pseudoephedrine, can cause sleep dis
turbances and nightmares, particularly among young
children.1'
[See the sections on Antidiarrhoeals, Antidiarrhoeals
containing antibiotics, Hydroxyqninolines, Loper
amide, Diphenoxylate, and Cough and cold
preparations for more information.!
Questions for parents to ask about their
children’s drugs
1.
Is this medicine really necessary? Is there a non-drug
alternative?
2. What is the name (brand and generic) of the
medicine?
3. What does it do? How long will it take for the
medicine to work? How will I know that it is effective?
What do I do if it does not seem to be working?
4. How much do I give? How often? For how long? Are
there special times to give the medicine (for example,
before or after meals)?
5. Can my child eat a normal diet? Are there any foods
that interact with this drug?
6.
Can other medicines be given at the same time?
7. Are there any common side effects? Are there any
serious but rare side effects? What do I do if any of these
occur? Do the benefits outweigh the risks?
8. If my child is allergic to some drugs, will he or she
also be allergic to this drug?
9. Do I continue the medicine even if my child gets well
before the recommended course is completed? Is there
any danger in stopping the medication before the full
course is taken? What do I do if one or more doses are
missed?
10. How much does this medicine cost? Is there a lower
cost but comparable quality generic form available?
Source: adapted from questions prepared by Dr K. Balasubramaniam,
reproduced in Drug Monitor(Philippines). Vol III. No 12, Dec 1988, pl42
NUTRITIOUS FOOD.
CLEANLINESS.
ARE THE THREE IMPORTANT
KEEP CHILDREN HEALTHY AND PROTECT
AND VACCINATIONS
BODY GUARDS' THAT
THEM AGAINST MANY SICKNESSES.
Source: Werner D.. Thuman, C. and Maxwell, J. Where There is No Doctor- a vifeee
heM care handboo* (rev.sed edn), Palo Alto, the Hesperian Foundaton3992 p295
Drugs
and
children
Problem Drugs
However, she points out that psychotropic drugs fre
quently are used for bed-wetting and insomnia,
problems often dealt with by general practitioners.
For both conditions, there are effective behavioural
and other treatments, so drugs should never be used
as a first line of treatment because of their side effects
and the danger of toxicity in overdose (either acci
dental or deliberate).”26
Similar advice is given in the Australian Prescriber:
"Poor sleeping habits and ‘hyperactivity’ are often
inappropriately treated with drug therapy. Simple
counselling, behaviour modification and common
sense are the preferred approach.”27
[See the sections on Psychotropics and Brain Tonics
for more information.]
Appetite stimulants, vitamins
and brain tonics
Many parents have unrealistic expectations about
the food requirements of their children. According to
WHO, they need explanations and reassurance; in
most cases children eat normally. However, fear of
undernutrition or concern about rhe common child
hood symptom of loss of appetite allows
considerable scope for pharmaceutical companies to
promote a range of unhelpful products. A particu
larly disturbing example is the promotion of drugs to
stimulate children’s appetite. As WHO has pointed
out: “There is no evidence that the drugs and mix
tures that are proposed as appetite stimulants have
any effect on appetite. Therefore, these preparations
should not be used.”28
Vitamins do have a legitimate role in therapeutics.
However, it is a limited role. Children who receive a
balanced diet are unlikely to suffer from vitamin defi
ciencies. Where deficiencies do occur, there is much
more need to look at ways to improve the long-term
intake of food, while sometimes providing a short
term supplement of one or two particular vitamins.
The routine use of multivitamin preparations in chil
dren is simply a waste of money. In the UK, for
example, vitamins can be prescribed to treat deficiency
conditions under the National Health Service, but not
as dietary supplements. All of the multivitamin prepa
rations are rated as “less suitable” for prescribing.29
However, children arc an obvious target for vitamin
manufacturers. In some cases, for example in Asia,
companies have gone to extraordinary lengths to
ensure that children swallow their vitamin prepara
tions.
In the Philippines in 1989, children were sent home
from one primary school with a letter from the
school doctor, a prescription for one bottle of the
multivitamin preparation, Multi-Sanostol Syrup,
Packaging for cyproheptadine, an appetite stimulant,
promoting use for children, India, 1989-90
made by Byk Gulden and a starter sample of the
syrup.30 In Malaysia, in January 1990, children at a
kindergarten in Penang were given samples of Seven
Seas multivitamin syrup. A representative of the
company producing the vitamins returned to the
kindergarten a few days later to sell the children large
bottles of the syrup. The children also received an
attractive toy as a free gift with every bottle pur
chased, while the school received a monetary
donation for allowing the promotion to take place.31
1 B .
Drugs
and
children
Problem Drugs
Antibiotics
Antibiotics are among the most frequently prescribed
drugs for children. In the USA in 1986, about 35% of
the 57.S million prescriptions for children under the
age of three were for antibiotics.18 However, they are
often used inappropriately.19 They are not useful
against viral infections. As viruses cause most child
hood diarrhoea and respiratory illness - the two
most common childhood illnesses - the use of anti
biotics for these conditions is generally unnecessary.
In practice, antibiotics are widely used for these con
ditions. In Brazil, for example, a survey of
pharmacies found that pharmacy assistants routinely
recommended antibiotics for young children with
acute respiratory infections.20 A survey of pharma
cies in Kenya found high levels of antidiarrhocals
containing antibiotics being used indiscriminately.201-
[See the sections on Antibiotics, Antidiarrboeals con
taining antibiotics and Cough and cold preparations
for more information.)
Pain killers and drugs for fever
Most paediatric pain is acute and self-limiting,
caused by infection, trauma, surgery, or exacerbation
of chronic disease. The recurrent pains of childhood
- headaches, abdominal cramps, and limb pains seldom need a medicine, unless they are caused by an
illness or condition requiring drug treatment.21
Fever in infants is “generally due to viral infection"
and does not usually warrant drug treatment. It can
be better managed with simple measures such as
undressing the infant, fanning and, if the tempera
ture is very high, tepid sponging.22
Fever has generally been regarded as injurious to
health. As a result, treating the fever, especially in
children, has become routine. However, there is no
convincing evidence that naturally occurring fevers
do harm. In contrast, studies have clearly shown that
fever helps laboratory animals to survive an infection
whereas using drugs to prevent the fever increases
their death rate. There is also considerable labora
tory evidence that a variety of human immunological
defences function better at febrile temperatures than
at normal ones.23
11
Bad advice to doctors in Peru from Bristol-Meyers
Squibb: "Doctor...for the treatment of the most
common infections of your little patient
the unforgettable antibiotic which assures you clinical
success" (advertisement for the antibiotic cefadroxil)
general, and drugs, in particular, have inher
ent potential risks that must be weighed
against their therapeutic value. In the case of
over-the-counter drugs, such as aspirin, it is
also incumbent upon physicians to convey
this appreciation to their patients.”25
[See the section on Analgesics for more information.!
Psychotropic drugs
Graham Dukes, editor of the Side Effects of Drugs
Annual, notes that with children “it is often wise and
possible to manage a mild pyrexia [fever] without
giving drugs at al]; in that respect, some developing
countries are the most enlightened of all”.2,1
Other common problems of childhood such as
behaviour and sleep difficulties arc frequently con
sidered by parents and doctors to be indications for
drug therapy. This medicalisation of aspects and
variations of normal growth, behaviour and develop
ment is a disturbing trend.
An editorial in the American Academy of Pediatrics
journal, Pediatrics, about the association of aspirin
with Reye’s syndrome offered some sound advice
generally about caring for children:
“Physicians caring for sick children need to
appreciate that therapeutic interventions, in
“Are there good indications for the use of psy
chotropic drugs in children?”, asks child psychiatrist,
Dora Black, in an editorial in the British Medical
Journal. Her response is very cautious: “psycho
tropic drugs should be prescribed sparingly and
under the supervision of specialists”.
i B .
children
Recommendations for action
1. Health workers should pause before
prescribing any drug for a child and ask
themselves whether the drug is really needed and,
if it is, whether it is the least toxic, most effective
and affordable therapy.
2. Similarly, parents should question health
workers about the need for a drug for their
children's illness (see the box on page 10 for
suggested questions to ask). Before buying an
over-the-counter preparation, they should
consider whether it is really needed or whether an
alternative non-drug solution exists.
Other substances are also promoted to improve chil
dren’s performance at school. In Peru in 1991, the
Belgian company, UCB, advertised its piracetam
product, Nootropil, as something that would help
children with “school difficulties” such as “memory
problems, difficulty learning, lack of concentration,
intellectual tiredness, poor performance, agitation
and irritability”.33 There is no evidence that pirac
etam can perform any of these miracles.
3. Governments have a responsibility to ensure
that health workers and parents have access to
independent information about the correct use of
drugs for children.
[See the sections on Growth Stimulants, Vitamins
and Brain Tonics for more information.!
4. There should be no direct promotion of
medicines to children. Governments should also
strengthen controls on promotion of medicines
aimed at paediatric conditions. They may wish to
consider total bans on advertising medicines for
children; or they may wish to look at ways in which
promotion of medicines for children can be
subject to additional restrictions to ensure that
exploitation of parental fears is not used to sell
drugs.
Long-term effects
These examples demonstrate some of the “consider
able pressure” that parents and prescribers are under
from drug companies to use their products. Far too
often the result is the selection of “less than optimal
or greater than necessary therapy”.3,1
WHO points our that the inappropriate use of drugs
for children has both immediate and long-term
consequences. For the present, the waste of resources
and the potential for unnecessary adverse reactions
are both strong arguments to encourage more care in
the prescribing of drugs for children. But the
unknown psychological and social consequences for
children of excessive and inappropriate drug use is a
worry for the future as well. “Children may tend to
grow up believing that drugs are the solution to
many of life’s problems.” ’6
and
13
Problem Di
The Philippine letter also cautiously hinted that tak
ing vitamins might improve a child’s intelligence.
Advertisements during 1989 for another multi
vitamin syrup, Kiddi Pharmaton, went even further.
The advertisements claimed the “body-building,
appetite inducing” product - produced by the Swiss
company, Pharmaton SA and distributed by RhonePoulenc - could also contribute to “better
concentration and even improve a child's IQ perfor
mance”. During 1992, in the UK, three vitamin
manufacturers were successfully prosecuted for
claiming that their vitamin products could increase
children’s intelligence.32
Dr Mita Pardo de Tavera, then Secretary of Social
Welfare and Development in the Philippines, said in
1988 that she was disturbed to see her medical col
leagues prescribing drugs for children that were
often unsafe, ineffective or inessential. “Drugs
reinforce a curative orientation; yet most childhood
health problems are easily prevented through immu
nisation programmes, proper nutrition, access to
safe water and a clean environment and all the other
inputs that boil down to one thing: economic devel
opment and upliftmenr.... There is a role for drugs,
but it must be taken in context, used appropriately
as needed, and not through the creation of artificial
demands.”35
Drugs
I
5. Governments should also review the paediatric
medicines on the market with a view to removing
those that are hazardous or ineffective.
14
Drugs
1 B .
and
children
Problem Drugs
References:
7.
Parish, P., Medicines: a guide for everybody, London, Penguin (6th edn,
revised), 19S9, P35
Rylance, G. (ed.), Drugs for children, Copenhagen, WHO, 1987, pn
Phillips, M., Kumate-Rodriguez, J., Mota-Hemandez, E, “Costs of treating
diarrhoea in a children's hospital in Mexico City", Bulletin of the World Health
Organization, Vol 67, No 3,1989, PP273-2S0
Steele, R.W. and Kearns, G.L, “Antimicrobial therapy for paediatric patients".
Pediatric Clinics of North America, Vol 36, No 5, Oct 1989, ppi32i-49
Gaukroger, P.B., “Paediatric analgesia: Which drug? Which dose?", Drugs,
Vol 41, No 1,1991, PP52-9
Laurence, D.R. and Bennett, P.N., Clinical Pharmacology, Edinburgh, Churchill
Livingstone, (6th edn), 1987, P140
Henry, J. (ed.), The British Medical Association Guide to Medicines & Drugs,
8.
9.
London, Dorting Kindersley, (2nd edn) 1991, pzo
AMA, Drug Evaluations, Philadelphia. W.B. Saunders Co., (6th edn) 1986, P23
Anon., “Paediatric products in US development", Scrip, No 1564, 7 Nov 1990,
i.
2.
3.
4.
5.
6.
P24
Jackson, D.M. and Soothill, R., Is the Medicine Making You III?, North Ryde,
Australia, Angus & Robertson, 1989, P32
11.
Anon, “$1 b wasted on useless drugs, says WHO”, Scrip, 1633,12 Jul 1991,
zoa.Yudkin, J.S., “Dispensing of inappropriate medicines for diarrhoea", Lancet,
21.
International Anesthesiology Clinics, Vol 29, No 2, May 1991, PP37-55
22.
23.
1991, P/O2
Meilis, op cit
Kramer, M.S., Naimark, L.E., et al, "Risks and benefits of paracetamol
antipyresis in young children with fever of presumed viral origin", Lancet,
24.
Vol 337, No 8741.9 Mar 1991, PP591-4
Dukes, M.N.G., (ed.), Side Effects of Drugs Annual 11, Amsterdam, Elsevier,
25.
1987. P79
Kauffman, R.E. and Roberts, R.J, “Aspirin use and Reye syndrome", Pediatrics,
Vol 79, No 6, Jun 1987, ppi049-50
26.
Black, 0., “Psychotropic drugs for problem children: need specialist
27.
28.
29.
10.
P22
12.
WHO, The rational use of drugs in the management of acute diarrhoea in
children, Geneva, WHO, 1990, pi
13.
UNICEF, The State of the World's Children 1991, Oxford and New York, Oxford
University Press, 1990, piz
14.
Meilis, CM, “Paediatric prescribing: when is medication needed?", Australian
Prescriber, Vol 13, No 2,1990, PP34-6
15.
Barry, W. and Hall, J., Medicines for Children: the comprehensive guide,
London, Bloomsbury, 1990, px
16.
Meilis, op cit
17.
Grant, R., Which? Medicine, London, Consumers Association and Hodder &
Stoughton, 1992. P46
18.
Levy, S., “Starting life resistance-free", New England Journal of Medicine,
Vol 323, No 5,2 Aug 1990, PP335-7
19.
Parish, op cit. P35
20.
Misago, C, and Fonseda, W„ “Antimicrobial drugs advised in pharmacies in
Brazil for children with acute respiratory infections”, Lancet, Vol 338,14 Sep
Vol 335. 31 Mar 1990, P803
Maunuksela, E-L. and Olkkola, K.T., “Pediatric pain management",
supervision”, British Medical Journal, Vol 302, 26 Jan 1991, ppi90-i
Meilis, op cit
Rylance, op cit, P48
BMA and the Royal Pharmaceutical Society of Great Britain, British National
Formulary, London, BMA and The Pharmaceutical Press, No 23, Mar 1992,
PP339-A4
Anon., “Children’s vitamin preparations: kidding the kids and their parents",
Drug Monitor (Philippines), Vol IV, No 8, Aug 1989, ppio9-io
31.
Zaini, J., “Pushing children’s vitamins", HAI News, No 51, Feb 1990, pi
32.
Anon., “UK vitamin manufacturer fined over IQ claims”, Scrip, No 1763,
20 Oct 1992, p9
33.
Lopez Linares, R. and Phang Romero, C, Promoviendo la Salud 0 Los
Negocios? Un analisis de la promotion farmaceutica, Chimbote, Action para
la Salud, 1992, p8
34.
Rylance, op cit, p6
35.
Pardo de Tavera, M., “Children’s Drugs in the Philippines”, Drug Monitor
(Philippines), Vol III, No 12, Dec 1988, P131-2
36.
Rylance, op cit, ppn-12
30.
Chetley, A. Problem Drugs, Amsterdam,
Health Action International’s
coordinating offices:
Health Action International, 1993
HAI Europe
Jacob van Lennepkade 334T
1053 NJ Amsterdam
The Netherlands
1C. Women an
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accion para la Salud
Avda. Palermo 531
Dpto. 104
Lima 13
Peru
Disturbing a delicate balance
Women occupy a dual position in the use and de
livery of health care. Women make more use of
health care services and take more medicine than
men.1 As individuals, women have distinct and sig
nificant health needs, related in part to reproduction.
As “agents” they are the informal providers of health
care in the family and form the majority of profes
sional health workers in the community.2
However, although women are both the major users
and major providers of health care, they are seldom
in a position to determine the priorities.3 Most health
care systems are male-dominated in terms of policy
and decision making, and effectively exclude women
from positions of power.4 Policy makers have
designed health care systems primarily for the conve
nience of doctors (who are predominantly male),
hospitals and the medical industries.5
The model of a male life cycle is all too often taken as
a norm. When this is applied to women, it is no won
der that a large number of natural and normal
processes become diagnosed as “abnormal” and, as a
result, have a barrage of drugs thrown at them.6 The
pharmaceutical industry has a vested interest in
helping to maintain this idea and uses its marketing
strategies to promote drugs as a solution for these
“health problems.”7
Effects of drugs on women
Poor information about the effects of medication on
women is another concern. Sexual prejudice helps
determine research policies and biases some research
results. For example, in a study of more than 17,000
people in the UK to determine the possible adverse
effects of drugs taken for high blood pressure, only
men were asked whether the drugs affected their
sexual desire.8
Women metabolise drugs differently from men. In
part this is due to weight differences between men
and women and in part due to hormonal differ
ences.9 Another factor can be undernutrition or
malnutrition. In developing countries, malnutrition
is far more prevalent among women than men, a gen
der difference that often starts in childhood.10
A 1992 report from the General Accounting Office in
the USA called for the inclusion of more women in
i
lem Di
I
C .
Women
and
drugs
clinical trials for drugs and more analysis of potential
gender differences in safety and efficacy of drugs.
Only 12% of 53 drugs approved in recent years in
the USA had special studies to look at hormonal
interactions or interactions with oral contraceptives.
Drug safety data were analysed by gender for only
54% of the drugs and efficacy was analysed by gen
der in only 43%."
Questions for women to ask about drugs
Drug safety
3.
What does it do? Does it cure the disease or only
treat the symptoms? How long will it take for the
drug to work? How will I know that it is effective?
What do I do if it does not seem to be working?
4.
I am pregnant, breastfeeding or planning to
become pregnant. Should I use this drug?
5.
I use oral contraceptives. Will this drug affect the
efficacy of the contraceptives or interact with
them in any other way?
6.
Can I take other drugs at the same time? Can I
drink alcohol? Are there foods I should avoid?
7.
What are the common side effects? Are there any
rare serious side effects? What should I do if I
experience side effects?
8.
Is there any information available on the long
term effects of using this drug?
9,
If I am being given this drug to help prevent a
disease I may get later on, are there other
alternatives that may make me less likely to
develop the disease?
Drug safety has been a major concern for women
over the past three decades. The tragedy of thalido
mide in the 1960s brought home the high risk of
taking drugs in pregnancy. Most of the major drug
regulatory agencies in industrialised countries were
either established or strengthened as a result.
Extensive testing is now done to identify the drugs
most likely to cause fetal defects. Even so, as the
American Medical Association has pointed out: “for
many drugs, particularly new ones, little or no infor
mation is available on use during pregnancy.”12
There have also been tragedies with older drugs that
are now rarely used in industrialised countries, but
which still pose a problem in developing countries.
Diethylstilboestrol (DES), a synthetic oestrogen, was
widely used to prevent miscarriage but was found to
be ineffective and unsafe. Prenatal DES exposure has
been linked to malformations of the reproductive
organs in both women and men, which can lead to
problems in pregnancy and infertility. A rare form of
vaginal cancer - clear-cell adenocarcinoma - occurs
in about one in every 1000 women exposed prenatally. Women who took DES during pregnancy also
have an increased risk of breast cancer. Experts now
agree that there is no indication for the use of DES or
any oestrogen in pregnancy.13
1
What is the name (brand and generic) of the
drug?
2.
Is this drug really necessary? Is there a non-drug
alternative?
10.
Is it possible to become dependent on this drug?
High-dose oestrogen and progestogen (EP) drugs have
enjoyed wide popularity in many developing countries
as a test for pregnancy. However, the World Health
Organization (WHO) points out that as a pregnancy
test, EP drugs are unreliable and there is a risk of mal
formations if they are used during pregnancy.14
Despite the lessons of the past, there is still evidence
of unnecessarily high intake of drugs by pregnant
women. Some of this can be attributed to women not
knowing the full dangers of taking drugs during
pregnancy, but in part it is also due to routine med
ical practice. Most women who go to hospital in the
UK to have a baby are given some form of sedation
the night before delivery. Clinical pharmacologist,
Joe Collier, asks: “Who are the drugs really for - the
mother-to-be, her baby, or the medical staff who
want a quiet night?”15
[See the sections on Drugs in Pregnancy, DES, and
EP Drugs, for further information.]
Medicalisation of life events
Generally, there has been an increasing tendency to
medicalise women’s lives. More and more, women
are expected to visit the doctor to deal with normal
aspects of life such as contraception, pregnancy and
clnldbirth. Indeed, the whole time from menstrua
tion to menopause “is now often discussed as though
it were a disease”.15 Drug treatments are offered for
hormonal changes related to the menstrual cycle
such as premenstrual tension. Even rhe menopause is
being i edenned as a deficiency state.
On the whole, more women face poverty, economic
dependence, or poor housing and living conditions
i C .
One of the classic advertisements that helped to
entrench the use of tranquillisers in women was by
Roche for its Librium (chlordiazepoxide). The adver
tisement shows two hands: one of a woman, the
other of a man. The man - a doctor - is taking the
woman s pulse. And the headline reads: “Whatever
the diagnosis... Librium”.18
[See the section on Psychotropics for more informa
tion.)
Hormones
In the 1960s, women were promised freedom from
unwanted pregnancies if they used hormonal oral con
traceptives. In the 1990s, many of those same women
are being promised freedom from the effects of the
menopause if they continue on a daily dose of hor
mones. Those hormones have been linked to a variety
of side effects that can cause women discomfort and
interfere with the quality of their lives. More worrying
is the possibility that hormones may cause some forms
of cancer or other long-term effects. An American
biologist describes rhe use of hormones as being little
more than an experiment. She says “the gynecologist/obstetrician is probably more of a medical
empiricist than any other specialist; that is, the gyne
cologist administers hormones as a treatment because
they work and not because there is a clearly defined
understanding of their action in the body.”19
Certainly, too little is known about the long-term
effects.
Contraceptives
Having access to safe and effective methods of con
traception is important for women. Women in a
village in Indonesia explained what they wanted in a
family planning method: “We would gladly accept
family planning provided that it doesn’t interfere with
our work, or do us any permanent harm, or be against
our religion. It also has ro be explained to us by a
woman, who will examine us if necessary and keep it
a secret. It should also cost very little money.”20 These
simple and clearly stated criteria are seldom met.
Women, particularly in developing countries, are
poorly informed about rhe pros and cons of contra
ception. Without proper information, women
become suspicious that they are being manipulated.
and
Another reason women reject the current selection of
contraceptive' methods is that it has not been
designed with their needs in mind. For example,
women may not agree that a small increase in effec
tiveness is worth the trade-off of a higher frequency
of menstrual cycle disturbances and other side
effects. Demographers and family planning workers
may also be more concerned than individual women
about avoiding methods with the potential for “user
failures”.21
|See the sections on Contraceptives, The Pill, IUDs,
Ui/cctables, and Implants, for more information.)
Menopause and hormone
replacement therapy
“Menopause is not a disease, but a life-cycle transi
tion,” says medical anthropologist, Margaret Lock.22
It is a time of change in a woman’s life and, for most
women, it is accomplished with minimal discomfort
and without the need for medical intervention.23
The pharmaceutical industry has a different opinion.
It promotes hormone replacement therapy (HRT) oestrogen (often with progestogen) - to deal with the
symptoms of the menopause. In the USA, Ciba-Geigy
ran ads in women’s magazines for its transdermal
oestrogen preparation, Estraderm, that talked about
two common perceptions of the menopause: “No
man in his right mind would be interested in a
menopausal woman” and “you’d better leave sports
to rhe youngsters”. The advertisement concluded
that by using Estraderm, “the change of life doesn’t
have to change yours”. The implication in this adver
tisement and many others directed at consumers or
doctors is that without hormones, women will expe
rience serious loss. Most of the advertisements focus
attention on a woman’s looks and emotions rather
than on the medical effects of the drugs.24
As with hormonal contraceptives, little is known
about the effects of long-term use of hormones
during and after the menopause. There is a higher
rate of endometrial cancer among women who have
used oestrogen therapy. There is also doubt about the
benefits of hormone therapy. This, coupled with the
lack of good research into alternatives, leaves both
women and doctors with little valid information to
help them decide whether therapy is needed and if so,
which type.
[See rhe section on HRT for more information.]
Promoting drugs
Because women are the “pathway” for medicines
within the family and make the decisions about what
drugs to buy,25 they are frequently the target of pro
motional campaigns for over-the-counter (OTC)
drugs
17
Problem Drugs
than men, and more women are the primary care
givers for young children and the elderly16-', leading
to a hear y overall workload and considerable stress.
Although the real solutions to these problems are
social, political and economic, it is no wonder that
the marketing of anti-anxiety drugs and anti-depres
sants is primarily targeted to women. For every
benzodiazepine tranquilliser prescription written for
men in the UK, three are written for women.17
Similar patterns exist in other countries.
Women
18
i C .
Women
and
drugs
Problem Drugs
drugs. A large proportion of OTC drugs are aimed at
children, but the promotion is meant to tug at rhe
emotions of the parents, particularly mothers.
Advertisements for vitamins, tonics, appetite stimu
lants, cough and cold remedies and antidiarrhoeals,
often show a woman in a caregiving role, doting on a
child who is making a rapid recovery because of the
drug sin? has given. Some promotional campaigns are
for products for the women themselves to use to live
up to the image of beauty, youth and vitality that is
portrayed. Vitamins, slimming aids, skin condi
tioners all promise much. But if the products fail to
meet the promises, and the women suffer from tired
ness or menstrual pain, for example, there are more
solutions: vitamins again, various tonics, and anal
gesics and NSAIDs for the pain. One classic
advertisement from the Philippines for G.D. Searle’s
Dramamine (dimenhydrinate - a drug to treat
motion sickness) featured a housewife who was
sweeping her yard when she became dizzy. In the
comic strip used to promote the drug, her neighbour
comes to the rescue and advises her to take
Dramamine: ‘’Rest and Dramamine. That’s all she
needs.” It is an extraordinary idea that an anti-nausea
drug can deal with the fatigue of housework.26
In addition to products for self-medication, there are
hormone preparations and antidepressants that doc
tors can prescribe to deal with life’s problems.
Because women are the major consumers of medi
cines, much promotion sent to doctors promotes
prescription-only drugs specifically for women.
Much of this material has been found to emphasise
negative stereotypes. These include the idea that
women can’t cope, that they are not very intelligent,
that they can be a real nuisance to others, and that
biology determines their destiny. The basic idea was
conveyed by one early advertisement for hormone
replacement therapy that had a headline:
“Something is terribly wrong”.27 In the Philippines,
Searle relied on the comic strip approach'with a car
toon ad for doctors in 1988 that promoted its
antidiarrhoeal, Lomotil (diphenoxylate). The image
in the cartoon is of a woman who could not cope, not
even on her wedding day. Instead, it was up to
Lomotil to save the day.28 A cartoon advertisement
from Belgium in 1992 shows a male doctor being
overwhelmed by his complaining female patient who
has every gastrointestinal symptom imaginable. The
solution being offered to the doctor is Boehringer
Ingleheim’s Tranquo-Buscopan - a combination
product that contains an anti-spasmotic (hyoscine
butylbromide) and a tranquilliser (oxazepam).
In Peru, in 1991, Schering promoted its ergot deriva
tive, Dopergin (lysuride), for inhibition of lactation.
The advertisement showed five slender women, and
described the product as “the most potent inhibitor of
prolactin in the clinic”. The implicit message, suggested
by the photographs of the women was that to have a
slender figure, women should stop breastfeeding - a
The woman who can’t cope, in Searle's promotion of diphenoxylate
(Lomotil) , PIMS, the Philippines, Dec 1988
y DOKTER) IK ME&PjN/SU.MM KRAHPEH
HU BM&IA '--/ 0UIHUI-C0hl5TlPfiT/E„. SUeiAMf-BMBUI..
ACM DOWER- sMsuiBMHOaiijKiSroU^Nf \
suiueu-eu- DlARREE.. oiiutui-suiMtu.
I
su- suiewt.. au/ou-aui- &•£. . . Zo VESA
|
aut wf
5LECW VERTERE/1/^ sta
m...
EU/KR/JM.. eiA.-BUMWl EW Bl*CUM..ISUMIU..
iHiuiU!
RoMHElW^ER M DEw. w..
tm... NEESEN RiWOPWMl/K DWiMEN...
\
OPRESMXENeue..
urnusu -RHiiEPyMwewau.
J
De behandeling
van een functionele colopathie
is in twee woorden samen te vatten:
Tranquo-Buscopan
“Doctor! I am in such pain...bla bla bla...cramps...bla bla bla
constipation... bla bla bla...Oh Doctor...straining...bla
bla...diarrhoea...bla bla bla bla...So much pain...bla bla bla...bad
indigestion...bla bla bla...stomach ache bla bla bla and bla bla
bla...rumbling stomach...a knot in my bowels bla bla bla bla...feel
very bloated bla bla bla stomach ache bla bla bla."
Boehringer Ingelheim ad for Tranquo-Buscopan, Artsenkrant,
Belgium, Sep 1992
i C .
and
drugs
Recommendations for action
1. More research is needed into the effects of
drugs on women, with particular attention to their
efficacy and safety.
A majority voice which needs
to be heard
2. There should be greater consultation with
women on the research needs for contraceptives
and for products specifically meant for women.
Women make up the majority of health care con
sumers and health care workers and should have the
major voice in determining health and medical care
policy. Local communities, individual health care
facilities, and national governments all need to
explore ways in which women can have a much
greater say in how health care is organised. One
important aspect is looking at ways in which a more
rational use of drugs for women can be achieved.
4. Women need better information about drugs,
particularly their effects during pregnancy and
while breastfeeding.
5. Stronger controls are needed over the way
drugs are promoted to women, particularly
promotion which contributes to unnecessary
medicalisation of women’s lives and promotion of
psychotropic drugs which targets women.
6. Controls are needed over the way in which
images of women are used to promote drugs.
References:
l
2.
Wolffers, I., Hardon, A., and janssen, J., Marketing Fertility: Women,
Menstruation and the Pharmaceutical Industry, Amsterdam, WEMOS
International Group on Women and Pharmaceuticals, 1989, P9
Baile, S.» "Women and health in developing countries", OECD Observer,
No 161, Dec 1989-Jan 1990, ppi8-2O
3.
Zi.
5.
6.
Ibid
Collier, J„ The Health Conspiracy, London, Century Hutchinson, 1989, p6-8
Phillips, A., Rakusen, J. (eds) and the Boston Women's Health Collective.
The New Our Bodies, Ourselves (2nd UK edition), London, Penguin Books,
1989, p6o8
Rochon Ford, A., “Hormones: getting out of hand", in: McDonnell, K. (ed.).
Adverse Effects: Women and the Pharmaceutical Industry, Penang. IOCU.
7.
1986, pp27-4O
Querubin. M.P. and Tan, M.L.. "Old roles, new roles: women, primary health
care, and pharmaceuticals In the Philippines", in: McDonnell, op at, ppl/5-86
8.
Collier, op cit, ppp-to
0
Grossman, W„ "Not in my image", New Scientist, 27 Mar 1993, P37
10. lacobson, |.l„ Women’s Reproductive Health: the silent emergency,
(Worldwatch Paper 102), Washington, Worldwalch Institute, 1991. PP18'20
n Anon., "GAO study on women in clinical trials", Scrip, No 1769.10 Nov 1992.
,2.
AMA, Drug Evaluations. Philadelphia, W.B. Saunders Co.. (6th edn) 1986, P42
'u
WH0Pfte Effect of Female Sex Hormones on fetal Development and Infant
Health. Technical Report Series, No 657. Geneva, 1981
15.
Collier, op cit, pis
16.
Phillips, et al, op cit. pp6i2-3
16a. Smyke, P., Women and Health, London, UN Non-Governmental Liaison Service
and Zed Books, 1991, ppzs-27
17.
Collier, op cit, p8
18.
Medawar, C, Power and Dependence. London, Social Audit, 1992, P85
19.
Biologist Ethel Sloane, quoted by Rochon Ford, op cit, pp27-$o
20.
Warren, M., “Better safe than sorry”, New Internationalist, Oct 1987, p22
21.
Ibid
22.
Lock, M., "Contested meanings of the menopause", Lancet, Vol 337. 25 May
1991, PP1270-2
National Women’s Health Network, Taking Hormones and Women’s Health:
Choices, Risks, Benefits, Washington, 1989, pp2 and 6
24.
US Congress, Office of Technology Assessment, The Menopause, Hormone
Therapy, and Women's Health, OTA-BP-BA-88, Washington, US Government
Printing Office, May 1992, P71
25.
McDonnell, op cit, P3
26.
Querubin and Tan, op cit, PP175-86
27.
Rochon Ford, A, “In poor health", Healthsharing, Winter 1986, PP13-17
28.
Searle advertisement, PIMS, Dec 1988, P237
29.
Lopez Linares, R. and Phang Romero, C., Promoviendo la Salud 0 Los
Negocios? Un anilisis de la promotion farmac&Jtica, Chimbote, Acci6n para la
Salud, 1992, pi2
23.
19
Problem Drugs
message that plays into the stereotype that breastfeed
ing can harm the figure, but that bears little regard to
reality' or to the public health benefits for mother and
child alike that can come from breastfeeding?9
Women
Chetley, A. Problem Drugs, Amsterdam,
Health Action International, 1993
LIBRARY
Health Action International’s
AND
DOCUMENTATION
coordinating offices:
J
unit
HAI Europe
Jacob >/an Lennepkade 334T
1053 NJ Amsterdam
The Netherlands
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accion para la Salud
Avda. Palermo 531
Dpto. 104
Lima 13
Peru
Too oftefflj too many, to© much
“One of my most lasting memories of medical school in
Scotland was our teaching in drug prescribing.... Again
and again, terribly sick elderly people would be admitted.
The unfortunate medical students, sent off to examine the
frail old folk, came back thoroughly puzzled, since the pat
tern of symptoms and signs didn't fit one of our textbook
diseases.... After a few days these people, who looked
dreadful when they were carried in, walked out well. All
that had happened in between was that all their drugs had
been stopped and only those which seemed absolutely nec
essary represcribed. The combined actions and
interactions of the four, six or even nine preparations
they'd been swallowing had poisoned them."
- Dr Norman Swan, producer and presenter of The Health
Report on ABC Radio in Australia1
Health problems are highly prevalent among the
elderly. Around 80% have one or more chronic dis
eases.2 As a result, the elderly consume a high
proportion of drugs. The sale of pharmaceuticals to
elderly patients for outpatient use in the USA was
worth $4.6 billion in 1988 and is expected to reach
$10.1 billion by 1995.5 In both the UK and the USA,
the elderly consume at least 30% of all prescribed
drugs.4 In the USA, the average person over 65
receives 10.7 new and refill prescriptions a year.5 In
the UK, 70% of a representative sample of people
over 65 had been prescribed drugs, and 60% of the
sample had taken one or more prescribed drugs in
the 24 hours before being interviewed. On average,
2.8 drugs had been prescribed per person. Almost
one in three of the prescriptions was considered
"pharmacologically open to question”.6 In Italy,
40% of people over 70 take between four and six
drugs daily, and 12% take more than nine.7
Adverse drug reactions
This high consumption of drugs leads to a large num
ber of adverse drug reactions (ADRs). “All the
consequences of polypharmacy - increased costs,
ADRs, and drug abuse and misuse - are more likely
to occur in rhe elderly than in any other age group.”8
A study in the UK found that ADRs were solely or
partly responsible for 10% of admissions to geriatric
units.9 In Canada, an estimated 20% of elderly
people admitted to acute care hospitals in one
province had prescription drug-related complica
tions.10 There is, however, some debate about
whether the disproportionate number of ADRs is
directly age-related. According to Frank Young,
In the USA:
1 out of every 6 people is over 60
but they consume:
1 out of every 3 tranquillisers
1 out of every 2 sleeping pills
1 out of every 3 antidepressants
2 out of every 3 antihypertensives
2 out of every 5 gastrointestinal drugs
Source: Wolfe, S.M., Fugate. L . et al, '.Vorsf Pills Best Pills, Washington,
Public Citizen Health Research Group, 1988
22
1D.
Drugs
and
the
elderly
Problem Drugs
Lodine
cTs^es3 etodolac
EFFECTIVE NSAID THERAPY
WELL-TOLERATED
IN ADULTS OF ALL AGES’
□ The first and only pyranocarboxylic acid
□ LODINE. at 600 mg to 1.000 mg per day, demon
strates efficacy comparable to other NSAIDs’
□ As well-tolerated in older as in younger
adult patients’*
i^Tgi
Kidneys
® Liver
□ Proven therapeutic success worldwide
□ Dosing adaptable to your OA patients' needs
J
NEW
I
Lodine
SPILL;-'ETODOLAC
Easy to live with in osteoarthritis
Promotion of the NSAID etodolac (Lodine) for the elderly,
Wyeth-Ayerst, American Journal of Medicine, Aug 1991
former Commissioner of rhe US Food and Drug
Administration (FDA), it is more likely to be related
to the number of drugs taken by the elderly.'1
Although drugs can play a necessary and valuable role
both for the health and rhe quality of life of the elderly,
too often the risks of adverse effects are downplayed in
promotional materials from pharmaceutical compa
nies. For example, some of the advertising that
Wyeth-Ayerst used to launch its new non-steroidal anti
inflammatory drug (NSAID), Lodine (etodolac), in the
USA in 1991 proclaimed that it was “well-tolerated in
adults of all ages”. It went on to say that “in patients 65
years and older” there were no substantial differences in
the side effects profile compared with the general popu
lation. In the small print of the advertisement, however,
was the standard comment that etodolac, like other
NSAIDs, could cause kidney failure, and that the elderly
were among those at greatest risk.1’ The “welltolerated” headline also detracts from the available
evidence that etodolac causes “the usual spectrum of
upper GI (gastrointestinal] toxicity”.13
Table 1D-1
Drugs most frequently associated
with adverse effects in the elderly
Type of drugs
% of total ADRs
antihypertensives
13.1
antiparkinson drugs
13.0
corticosteroids
12.3
psychotropics
12.1
digitalis
11.5
insulin and hypoglycaemics
As a study released by rhe US Department of Health
and Human Services in 1989 puts it, “a major factor
in the number of adverse drug reactions among the
elderly is their doctors’ over-reliance on promotional
materials provided by the drug manufacturers”.14
9.2
diuretics
admissions for8acute
8.0
Q° 3 mull,cenlre study ol geriatric hospital
Source: Denham. M.J "AdvnrCQ ...
Vol 46, No 1, 1990, pp53-62
reactl0ns' • British Medical Bulletin,
24
Drugs
and
the
elderly
Problem Di
1.5 million elderly people have been on minor tran
quillisers daily for one year or more, and more than
500,000 elderly people use sleeping pills daily for one
month or more. In both cases, there is no evidence
that they are effective for continuous, long-term use.27
The benzodiazepine tranquillisers have long been
linked with adverse effects on psychomotor tasks,
learning and memory in elderly people.28 “Sleeping
pills, sedatives or tranquillisers in ‘average’ doses
may make the elderly person confused and unsteady;
a benzodiazepine sleeping drug which would be
excreted by most patients within eight hours may
‘hang over’ the whole of the next day.”29
Psychotropic drugs have consistently been shown to
be associated with an increased risk of falls in the
elderly. Diazepam, in particular, was found to have a
high association with falls, leading researchers to
suggest that it should not be used in the elderly.30
[See the section on Psychotropics for more informa
tion.)
NSAIDs
In the UK, about 2,500 cases of bleeding or per
forated peptic ulcers caused by NSAIDs are reported
to the Committee on Safety of Medicines each year.
They are predominantly in people who are over 60
years of age. However, most of the people receiving
these drugs are not suffering from one of the inflam
matory forms of arthritis, such as rheumatoid
arthritis or gout, where NSAIDs are of some benefit.
More than three out of every four people receiving
NSAIDs are elderly, “an age when inflammatory
joint disease is relatively uncommon”.'1
Although there was initially considerable enthusiasm
for the use of NSAIDs, the adverse effects of these
drugs, sometimes with fatal consequences among the
elderly, has begun to instil some caution in their use:
“All non-steroidal anti-inflammatory drugs
(NSAIDs), particularly those with prolonged
half-lives, should be used with caution in the
elderly.”32
“Use of aspirin and other NSAIDs should be
avoided, if possible, in older patients with a
history of upper gastrointestinal haemor
rhage.”33
For osteoarthritis, which is more prevalent among
the elderly and is less of an inflammatory condition,
NSAIDs generally only provide some symptomatic
relief. They should be used “only as required to sup
plement a baseline simple analgesic such as regular
paracetamol”.34
[See the section on NSAIDs for more information.!
Prescribing for the elderly - a checklist
□ Drug history: What other drugs (including over-thecounter preparations) is he or she taking? What
other drugs or therapy have been tried for this
condition?
□ Symptoms: Could the symptom(s) he or she is
suffering from be a side effect of a drug being
taken, or the effect of corning off a drug?
□ Necessity: Is the drug really necessary? Is there a
better non drug alternative?
□ Interaction: Is there likely to be any interaction with
other drugs being taken or with food?
□ Add one/remove one: If one drug is being added to
a therapeutic regimen, is it also possible to
withdraw one, so as not to increase the number of
drugs being taken?
□ Dosage: Is the dose appropriate?
□ Formulation: What is the best formulation to make
the drug easier to use?
□ Appropriate use: Is he or she likely to take the drug
at the right time in the right amounts? Does he or
she need more information?
□ Stop the drug: When should the drug be stopped? Is
there a good follow-up plan to ensure that the drug
is effective and does not cause adverse effects?
Antibiotics
The elderly have an increased risk of infections,35 and
a higher mortality rate from those infections than
younger adults,36 leading to a more frequent use of
antibiotics. Normal age-associated decline in kidney
function means that the time it takes for rhe body to
eliminate an antibiotic (or other drug excreted
through the kidney) increases. Therefore, the elderly
usually require lower dosages. For most antibiotics,
however, dosage guidelines do not as yet incorporate
a reduction in dosage for the elderly.37 Unless
dosages are reduced, there is a risk that drugs may
accumulate in the body, reaching toxic levels. In
addition, antibiotic side effects may be more com
mon in the elderly, and interactions between
antibiotics and other drugs may be more marked due
to declining liver function.38
The Australian Drug Evaluation Committee ruled in
1990 that product information for co-trimoxazole
preparations (trimethoprim and sulphamethoxazole)
should warn of the increased risk of serious adverse
effects in the elderly and discourage the use of the
product in this age group.39
10.
Just as the tragedy of thalidomide led to more care in
the prescribing of drugs for pregnant women and
better drug testing to establish potential risks, it took
a serious event for changes to occur regarding drugs
for the elderly. The death of elderly people who used
the NSAID benoxaprofen (Opren/Oraflex) in the
early 1980s led to the drug's withdrawal. More
importantly, it led to the establishment of more pre
cise guidelines from regulatory authorities about the
need for new drugs to be evaluated in the elderly pop
ulations for which they will be prescribed rather than
only in young volunteers.16
Changes affecting drug metabolism
Taking too many drugs is only part of the problem.
Even a single drug can have a more dramatic effect
among the elderly because of several physical
changes that affect the way the elderly metabolise
drugs. These include:
0 reduced blood flow and motility in the gastroin
testinal tract, making absorption of drugs slower;
0 decreased body weight, less body water, less pro
tein in the blood, so there is a likelihood of greater
concentration of many drugs, particularly those
that are water soluble;
• increased body fat, so fat-soluble drugs have a
lower concentration;
• reduced blood flow to and enzyme activity in the
liver, allowing some drugs to pass into the blood
stream in greater concentration and to stay in the
blood stream longer;
• reduced kidney function, so that drugs are not
eliminated from the body as quickly; and
• fewer receptors and transmitters in the brain and
central nervous system, so that drugs that act on
the central nervous system can have a more pro
nounced and long-lasting effect.1'
Because there is a greater risk of drugs accumulating in
the body, the elderly need “careful tailoring” of drug
dosages to their particular needs, their state of health
and their social circumstances. Failure to provide this
personalised prescribing can lead to tragic results. A
person who becomes confused on tranquillisers may be
considered senile and admitted to a geriatric unit, where
more drugs are administered to control the confusion.
Drugs used to reduce blood pressure lower the volume
of blood reaching the heart and brain, which again can
stimulate symptoms of senility' and put the person at
risk. Diuretics lead to more frequent emptying of the
bladder and can stimulate incontinence in the elderly.18
Diuretics are frequently overprescribed in the elderly.19
and
the
In very old people, “manifestations of normal ageing
may' be mistaken for disease and lead to inappropriate
prescribing”. For example, drugs such as prochlor
perazine are commonly misprescribed for giddiness
due to age-related loss of stability. Not only is such
treatment ineffective but the user may experience seri
ous side effects such as drug-induced parkinsonism,
postural hypotension, and mental confusion.20
Ensuring appropriate use
Another factor which can lead to complications in
therapy and possibly ADRs is a person’s failure to
take medicines appropriately. This is a problem com
mon to patients of any age. In the elderly, it may be
exacerbated by poor memory, poor hearing and
vision, difficulty in opening containers, and having to
cope with complex dosage regimes.21
The pharmaceutical industry often promotes fixed
dose combination drugs as a way of achieving compli
ance among the elderly. Popular combinations include
antihypertensives with diuretics. Such products should
never be the first choice in treating high blood pressure.
If non-drug therapy' of diet, weight loss, exercise and
lower salt intake has not achieved the desired result, a
low dose of a simple diuretic is often sufficient. If a sec
ond drug is needed (usually a beta-blocker or a
calcium-channel blocker), the two drugs should be
given separately in order to adjust the doses of both
until the right balance is found, // the doses that are
needed to control blood pressure are those found in a
combination product, then this product can be used to
simplify medicine regimens.22 “Drug therapy should be
tailored to the individual patient and increased in a
stepped fashion, with a maxim of 'start low and slow’
kept in mind to reduce the incidence of side effects and
make treatment more acceptable.”23
In general, fixed combinations of drugs should be
used only when they are logical, have been well stud
ied, and they either improve tolerance or efficacy.
Few fixed combinations meet this standard.23
Deciding when to stop a drug
There is now sufficient evidence that long-term treat
ment is not necessary for many people taking
hypnotics and other psychotropics, diuretics,
digoxin, and NSAIDs. Repeat prescribing without
review is no longer an acceptable practice.25
Psychotropics
Psychotropic drugs are frequently prescribed for the
elderly. They can cause distressing side effects. In the
UK, one study found that half of the elderly patients
admitted to the medical wards of a hospital were tak
ing benzodiazepine tranquillisers that had been
prescribed by their general practitioner.26 In the USA,
elderly
23
Problem Drugs
1 he FDA has proposed that manufacturers should
provide doctors with clear information that reflects all
available knowledge about the effects of prescription
drugs in elderly people. Where such data are lacking
for a particular drug, manufacturers should indicate
clearly that such information is not available.15
Drugs
i D .
[See the section on Antibiotics for further informa
tion.]
Drugs and dementia
With more than 50 million people worldwide over
the age of 65 currently estimated to be suffering from
dementia, analysts predict that the worldwide mar
ket for “cognitive enhancers” to treat dementia will
be over US S1.5 billion by the year2000.41
A number of "cerebral” vasodilators and similar drugs
(often called nootropics) are currently in wide use for
the treatment of mental failure in the elderly.
Goodman and Gilman’s pharmacology textbook says
“the case for clinical efficacy is unimpressive” for these
products in treating dementia.42 According to the
British National Formulary (BNF), although some
improvements in performance of psychological tests
have been reported, “the drugs have not been shown
clinically to be of much benefit in senile dementia.”43
Nonetheless, products such as these are widely pro
moted, particularly in developing countries, for a
range of symptoms associated with dementia and old
age. The Medical Lobby for Appropriate Marketing
(MaLAM) has regularly challenged pharmaceutical
companies to defend rhe claims made for the various
“brain tonics” on the market. To date, the industry
has been unable to produce much evidence in its
defence.44
and
the
elderly
Principal among these is the need to check whether a
drug is really needed. “It is important to be sure in
each case that the condition being treated really jus
tifies drug treatment in that patient at that Zone.”47
Side effects of one drug should rarely (if ever) be
treated with another.48
Next is the need to limit drugs to as few as possible,
at the lowest possible dose. “The fewest possible
drugs should be given to elderly patients, and in the
minimum dosage which is effective for them, even if
this is far less than rhe ‘average’.”49
It is “a sensible policy” to prescribe from a limited
range of drugs and to be thoroughly familiar with
their effects in the elderly.50 This means being critical
of the promotional claims made by the pharmaceuti
cal industry about drugs aimed at a variety of
conditions in the elderly.
Finally, there is the question of knowing when to stop.
Elderly people need careful monitoring to ensure that
they are not being kept on drugs unnecessarily.
Recommendations for action
1. Meeting the special needs of the elderly should
be seen as an important element of developing
drug information for both prescribers and
consumers.
On the other hand, drugs themselves are often linked
with inducing dementia. Psychotropic drugs - partic
ularly sedatives and hypnotics - antihypertensives,
anticonvulsants, and digitalis are those that have
most frequently been associated with reversible
dementia.43
2. Prescribers should use considerable caution
when selecting a drug to treat a condition in the
elderly, making sure the drug is necessary, that
the lowest possible dosage is used, and that it is
well tolerated.
[See the section on Brain Tonics for further informa
3. Elderly people and/or their carers should
question carefully the need for all medicines and
encourage doctors and health workers to explore
non-drug therapies wherever possible.
tion.]
Cautious prescribing
The adverse effects resulting from the attempt “to
rectify all age-induced and disease-induced disorders
with a panoply of polypharmaceutical remedies” are
often the last straw that makes it impossible for an
elderly person to continue to lead a reasonably inde
pendent life.46
Some simple precautions in the prescribing and use
of drugs can help prevent this. The checklist in the
box on page 24 provides some ideas for prescribers
to bear in mind.
4. Governments and health authorities need to
ensure that better information is available for the
public, prescribers and pharmacists about the
risks of unnecessary drug taking among the
elderly.
5. Governments should carefully monitor claims
made about the use of drugs in the elderly.
25
Problem Drugs
Aminoglycosides are also generally used with great
care m the elderly because of the risks of kidney dam
age and hearing loss. Both are problems which are
already more common in the elderly.'10
Drugs
26
1 D
Drugs
and
the
elderly
Problem Drugs
References:
1.
Jackson, D.M. and SoothiH. R., Is the Medicine Making You III?, Nonh Ryde,
25.
2.
Australia, Angus & Robertson. 1989, px
Zazove, P.. Mehr, D.R., et al, “A criterion-based review of preventive health
26.
3
4-
5.
6.
7.
care in the elderly: Pan 2. A geriatric health maintenance program", Journal of
Family Practice, Vol 34. No 3,1992, pp320-47
Anon.. Growing Opportunities for Geriatric Pharmaceuticals, New York, MIRC,
1989
Bird, H.A., “Antirheumatic drugs in the elderly", Annals of the Rheumatic
Diseases, Vol 49,1990, PP1022-4; Lowenthal, D.T. and Nadeau, S.E., “Druginduced dementia", Southern Medical Journal. Vol 84, Suppl. 1, May 1991.
ppiS-24--iS-3i
Cummings, D.M. and Uttech, K.M., “Antibiotics for common infections in the
elderly", Primary Care, Vol 17, No 4, Dec 1990, pp883-9O3
Anon., “Elderly people- their medicines and their doctors", Drug and
Therapeutics Bulletin, Vol 28, No 20,1 Oct 1990, PP77-9
Anon., "Drug consumption in the elderly in Italy”, Scrip, No 1721/2, 27/29 May
1992. P4
Schneider, J.K., Mion, L.C, and Frengley, J.D., "Adverse drug reactions in an
elderly outpatient population", American Journal of Hospital Pharmacy,
Vol 49, Jan 1992, PP90-6
9.
Anon., “Problems of aging overestimated?", Scrip, No 1655,27 Sep 1991, pp4-5
10.
Lexchin, J.. “Adverse drug reactions", Canadian Family Physician, Vol 37,
Jan 1991, ppiO9-i8
11.
Anon., “Drugs and the elderly - US debate continues", Scrip, No 1407, 28 Apr
1989, pi8
12.
Advertisement in the American Journal ofMedicine, Vol 91, No 2, Aug 1991,
PPA30A32
13.
Dukes, M.N.G. and Beeley, L, (eds), Side Effects of Drugs Annual 14,
Amsterdam, Elsevier, 1990, p86
14.
Anon.. “Prescriptions for profit”, transcript of a television documentary
broadcast on the Frontline programme on 28 Mar 1989, Boston, WGBH
Transcripts, P29
15.
Anon., “Drug effects in the elderly", WHO Drug Information, Vol 5, No 2,1991,
8.
16.
17.
18.
p6i
Bird, op cit
Laurence, DR. and Bennett, P.N., Clinical Pharmacology, Edinburgh, Churchill
Livingstone, (6th edn), 1987, ppi40-2
Parish, P., Medicines: a guide for everybody, London, Penguin (6th edn,
revised), 1989, P32
BMA and the Royal Pharmaceutical Society of Great Britain, British National
Formulary. London, BMA and The Pharmaceutical Press, No 23, Mar 1992, 014
20.
Ibid
21.
Williamson, J., “Introduction", British Medical Bulletin. Vol 46, No 1.1990, ppi-8
22.
Wolfe, S.M., Fugate, L, et al, Worst Pills Best Pills. Washington, Public Citizen
Health Research Group, 1988, PP69-70
23.
Potter, J.F. and Haigh, RA, “Benefits of anti-hypertensive therapy in the
elderly", British Medical Bulletin, Vol 46, No 1,1990, PP77-93
24.
Laurence and Bennett, op cit, P142
19.
Swift, C.G., “Prescribing for the elderly”, in: Feely, J. (ed.), New Drugs, London,
British Medical Journal, 1991, PP65-73
Collier, J., The Health Conspiracy, London, Century Hutchinson, 1989, P15
27.
Wolfe, et al, op cit, p8
28 Hart, R.P., Colenda, C.C. and Hamer, R M., "Effects of buspirone and
alprazolam on the cognitive performance of normal elderly subjects”,
American Journal of Psychiatry, Vol 148, No 1, Jan 1991, PP73-7
Parish, op cit, P32
Cumming, R.G., Miller, J.R, et al, “Medications and multiple falls in elderly
people: the St Louis OASIS Study”, Age and Ageing, Vol 20,1991, PP455-61
31.
Nuki, G. and Pullar, T., "Non-steroidal analgesic and anti inflammatory
29.
30.
32.
33.
agents", in: Feely, op cit, PP330-44
Bird, H.A., "Drugs and the elderly”. Annals of the Rheumatic Diseases, Vol 49,
1990, ppiO2i-2
Dumas, C. and Cusack, B.J., "Salicylate intoxication in the elderly: recognition
and recommendations on how to prevent it”. Drugs & Aging, Vol 2, No 1,
1992, ppzo-34
Nuki and Pullar, op cit
Sirgo, MA and Norris, S.; “Ceftazidime in the Elderly: Appropriateness of
twice-daily dosing", DICP, The Annals of Pharmacotherapy, Vol 25, Mar 1991,
PP284-8
36.
Yoshikawa, T.T., "Antimicrobial therapy for the elderly patient", Journal of the
American Geriatric Society, Vol 38, No 12, Dec 1990, PP135372
37.
Sirgo and Norris, op cit
38.
Sanderson, P., "Antibiotics and the elderly”, The Practitioner, Vol 234,
Dec 1990, ppio64-6
39.
Anon., "Australian ADRs", Scrip, No 1500, 28 Mar 1990, P30
40.
Yoshikawa, op cit
41.
Moran, J., Alzheimer’s Disease: New Therapies and the World Market, London,
Financial Times Management Reports, 1991
42.
Gilman, A.G., Rail, T.W., Nies, A.S., and Taylor, P„ Goodman and Gilman’s The
Pharmacological Basis of Therapeutics, New York, Pergamon Press, (8th edn)
34.
35.
1990, P781
BMA and the Royal Pharmaceutical Society of Great Britain, op cit, P92
Mansfield, P.R., "Classifying improvements to drug marketing and
justifications for claims of efficacy”, International Journal of Risk & Safety in
Medicine, Vol 2,1991, ppi/i-84
45.
Lowenthal and Nadeau, op cit
46 Ibid
47.
Williamson, op cit
48.
Laurence and Bennett, op cit, P142
49.
Parish, op cit, P32
50.
BMA and the Royal Pharmaceutical Society of Great Britain, op cit, P14
43.
44.
^WITY^^^
Chetley, A. Problem Drugs, Amsterdam,
library
Health Action International, 1993
2A. Anti diarrhoea Is
AND
\
„ DOCUMENTATION
I
k.
'
UNIT
Health Action International’s
coordinating offices:
HAI Europe
Jacob van Lennepkade 334 T
1053 NJ Amsterdam
The Netherlands
G A LOREHAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accion para la Salud
Avda. Palermo 531
Opto. 104
Lima 13
Peru
Dymg for lack of a drink
A 9-nionth old infant was suffering from vomiting and
diarrhoea. His mother was advised by telephone by a hos
pital paediatrician to purchase a commercial brand of oral
rehydration solution and was given instructions on how
to use the product correctly. She was also advised to call
back if the child's symptoms worsened or if he was unable
to drink enough of the fluid. The mother went to her local
pharmacy, but did not have enough money to buy the
solution. The following day, the child's vomiting con
tinued and the diarrhoea increased. The mother continued
to feed the child with an infant formula and with solid
foods, but the child’s condition deteriorated. The next
morning, the mother took the child to the hospital emer
gency department. Despite three days of intensive care in
the hospital, the child died. This death occurred in Boston,
USA.’
Four million children a year die from diarrhoeal dis
eases.2 A simple, highly effective therapy - oral
rehydration therapy (ORT) - plus continued feeding
can prevent at least half of those deaths,3 at a cost of
little more than 50 cents a child.'1 Instead, hundreds
of millions of dollars are wasted on so-called
antidiarrhoeal medicines that are at best ineffective
and at worst dangerous. According to the World
Health Organization (WHO), “this expenditure can
not be justified”.5
Diarrhoea is one of the leading causes of illness and
death in the developing world,6 where poverty, poor
sanitation, a lack ofclean water and increased expo
sure to infections are prevalent. It is also a serious
problem in the industrialised world. Studies in
Western Europe and North America have shown that
diarrhoea is the second most common reason for
children to be hospitalised.7 In the USA, for example,
after a 10-year survey of national mortality data, the
Centers for Disease Control in Atlanta concluded in
1988 that “diarrhoeal deaths constitute an impor
tant and preventable fraction of postneonatal
mortality in American children” and represent about
10% of preventable childhood deaths.8
There are many causes of diarrhoea.9 Worldwide,
viruses account for approximately 50% of all cases of
diarrhoea and are responsible for approximately
40% of all deaths that are attributed to diarrhoea.10
The rotavirus is the most frequent cause of diarrhoea
in infants and children under two years of age." Viral
infection is particularly likely in industrialised coun
tries, whereas in developing countries there can be a
greater incidence of diarrhoea caused by bacteria such
as Shigella or Escherichia coli (E. coli) or parasites
and various amoebae.12 Nonetheless, a two-year
study of children with acute diarrhoea in five hospi
tals in China, India, Mexico, Myanmar (formerly
Burma) and Pakistan found that rotavirus was the
most frequent cause of diarrhoea during the first year
of life.13 Diarrhoea can also occur as a result of some
drug therapy; for example, nearly all antibiotics can
induce diarrhoea.,'1 The incidence of diarrhoea is
higher amongst infants who are bottle fed rather than
breastfed.1-' Stress, tension, and change of diet can
also bring about episodes of diarrhoea. Diarrhoea
Table 2A-1
Drugs which commonly cause diarrhoea
Antimicrobials (sulphonamides, tetracyclines, most
broad-spectrum antibiotics)
Cholinergic agonists and cholinesterase inhibitors
Osmotic laxatives (sorbitol, saline cathartics)
Prokinetic agents (metoclopramide, domperidone)
Prostaglandins
Stimulant laxatives
Source: Adapted from Gilman. A.G.. Rail, T.W., Nies, A.S., and Taylor, P.. Goodman
and Gilman’s The Pharmacological Basis ol Therapeutics, New York Pergamon Press
(Sth edn) 1990, p924
28
2 A .
Antidiarrhoeals
Problem Drugs
accompanies between 20 and 60% of cases of
measles, and within six months of having had
measles, 10 to 20% of children will have a diarrhoea
attack which they would otherwise not have had.16
Diarrhoea is usually described as being acute, lasting
from a few hours to a few days, or persistent, lasting
two weeks or more or involving regularly recurring
episodes. Most diarrhoea is acute and self-limiting that is, it goes away by itself. Diarrhoea is not a
disease, but a symptom.17 Put simply, diarrhoea is the
body’s way of removing foreign toxins, bacteria or
other materials which upset the gut. It is a natural
protective mechanism. The danger of diarrhoea, and
the most frequent cause of death, particularly in
infants and young children, is the accompanying
dehydration due to the loss of
ral rehydration
large amounts of water and salts
therapy (ORT):
(electrolytes).18 “A great many
“potentially the
infants suffering from diarrhoea
most important medical
do not die from the disease but
breakthrough this
from mismanagement - and the
century”.
principal cause of death is dehy
(The Lancet, 5 Aug 1978. p300)
dration.”19
O
Oral rehydration therapy (ORT)
Preventing diarrhoea from occurring in the first place
is the best long-term solution (see box on right).
However, if diarrhoea occurs, the prevention and
treatment of dehydration should be the first prior
ity.20 ORT is effective in preventing and treating
almost all cases of dehydration from acute watery
(non-bloody) diarrhoea, including cholera.21
Studies from around the world demonstrate the
remarkable ability of ORT to reduce the number of
deaths caused by diarrhoea. ORT contributed to a
50% reduction in the number of children admitted to
hospital and the number of children dying as a result
of diarrhoea-related dehydration in a major hospital
in Natal, South Africa, between 1986 and 1990.22 In
the first two years following training of paediatric
staff in the use of ORT and the establishment of an
oral rehydration unit at the Kamuzu Central Hospital
in Lilongwe, Malawi, there was a 50% decrease in the
number of children admitted to the paediatric ward
with the diagnosis of diarrhoeal diseases and a 39%
decrease in the number of paediatric deaths associ
ated with diarrhoeal diseases. Over the same period,
there was a 32% decrease in recurrent hospital costs
attributable to paediatric diarrhoeal diseases.23 In
Mexico City, the introduction of an oral rehydration
unit at one of the main children’s hospitals led to a
25% decrease in the number of children under five
years of age admitted with diarrhoea between 1983
and 1986.24 In a major hospital in the capital of
Lesotho, admissions of children suffering from
diarrhoea declined from 23% of all paediatric admis
sions to 13% after the opening of an oral rehydration
therapy unit.25 In Egypt, a national programme to
Preventing diarrhoea
Poverty and lack of basic services may make it difficult
for families to prevent diarrhoea. However, there are
effective ways of preventing diarrhoea which cost little or
no money.
The most cost-effective preventive interventions are:
promotion of exclusive breastfeeding; improved weaning
practices: use of plenty of clean water; washing hands;
use of latrines; proper disposal of excrement, particularly
that of infants and children; and measles immunisation.
• Give breast milk alone for the first four to six months
of a baby’s life. Breast milk helps protect babies
against diarrhoea and other illnesses.
• At the age of four to six months, introduce clean,
nutritious, well-mashed, semi-solid foods and continue
to breastfeed.
• Use the cleanest water available for drinking. Water
from wells, springs or rivers should be brought to the
boil before use. Keep the water in clean containers and
keep hands out of the containers. Use a clean pot or
jar to take water from the containers.
• If possible, food should be thoroughly cooked, and
prepared just before eating. It should not be left
standing, or it will collect germs. If food is to be used
more than two hours after preparation, heat it again.
• Always use latrines to dispose of human excrement,
particularly that of children (or bury children's
excrement immediately).
• Wash hands with soap and water immediately after
using the latrine, after cleaning a child, before
preparing or eating food, and before feeding a child.
• Vaccinate children against measles because measles
frequently results in severe diarrhoea. This helps to
prevent one important cause of diarrhoea, even
though a general vaccine against diarrhoea is not
available.
Sources: UNICEF, WHO and UNESCO. Facts for Life: A Communication
Challenge, New York. UNICEF, 1989, pp47 8, Feachem. R . "Preventing
diarrhoea: what are the policy options’”, Health Policy and Planning Vol 1
No 2, 1986, ppl0917
control diarrhoea, making extensive use of oral rehy
dration therapy, has contributed to a decline in infant
mortality of at least 36% between 1982 and 1987.26
The wrong kind of medicine
Despite the unprecedented effectiveness of ORT, its use
is not yet as widespread as it could be. Why? One fac
tor is unquestionably the widespread availability, the
continuing dispensing and prescription, and aggressive
promotion of a large variety of “antidiarrhoeal” drugs.
In India, for example, a survey of 15,000 doctors
found that two-thirds claimed to use ORT in their
2 A .
National studies carried out in
Peru in 1984 and 1986 found
is like a pot with a
that the use of antidiarrhoeal
large hole. Treat the
medicines was increasing. In
child by filling up the pot
1984, 49% of children under
faster than the water
one year of age with diarrhoea
and 53% of children from one
flows out Prevent
to five years of age were receiv
diarrhoea by making the
ing antidiarrhoeal products;
pot strong. Give the child
while in 1986, 62% of children
plenty of food. If the child
under the age of five with
has diarrhoea again, start
diarrhoea were receiving anti
treatment immediately.
diarrhoeal
products.
These
This will prevent
national surveys did not indicate
dehydration.
whether the use of these prod
Dr Mira Shiva and Aspi B. Mistry.
ucts was necessary. However, a
A Taste of Tears, New Delhi:
smaller scale study carried out
Voluntary Health Association of
India. 1983
in the community of Canto
Grande in Lima from 1984 to
1989 clearly indicates that a large proportion of
antidiarrhoeal use is unnecessary. The use of drugs
to treat diarrhoea in children under three years of
age increased from 19% of cases to nearly 60%
during the period of the study. While the appropri
ate use of medication (usually antibiotics for Shigella
dysentery) increased from 3% to 32% of diarrhoea
episodes, unfortunately the misuse or inappropriate
use of drugs also increased from 16% to 28% of
cases over the period (see Table 2A-2).29 In the year
from June 1988 to June 1989, sales of inappropriate
antidiarrhoeal products in Peru amounted to US
$2,156,000. To this, an estimated $290,000 could be
added to include the proportion of sales of the
antibiotic, chloramphenicol, which was used inap
propriately for diarrhoea.30
A
child with diarrhoea
In a leading children’s hospital in Mexico City, chil
dren admitted with diarrhoea were treated with at
29
Problem Di
practice; however, 37% of rhe doctors claimed that
antidiarrhoeal preparations were “absolutely essen
tial in all cases of diarrhoea, and another 55% said
they were sometimes essential”. Forty percent of the
doctors said they used antibiotics to treat diarrhoea,
although most claimed to use them only in selected
cases. Rolf Carriere of UNICEF commented that “this
use ot antidiarrhoeals by nearly all respondents
demonstrates the extent of the problem, for these
drugs generally divert attention from oral rehydration
and are also too expensive for most families.”27 A
smaller survey at one of the leading teaching hospitals
in India found that 92% of children admitted with
mild or moderate dehydration received an antidiar
rhoeal preparation, often in combination with an
antibiotic. Dr C. R. Soman, a Professor of Nutrition in
India, points out that such practices are not surprising
given that one of rhe most popular Indian textbooks,
Pharmacology and Therapeutics, devoted nearly three
pages to discussing the various drugs to be used in the
symptomatic treatment of diarrhoea, but did not men
tion oral rehydration in the chapter on diarrhoea.28
Antidiarrhoeals
Oral rehydration salts
While there is no debate about the wisdom of replacing the
fluids lost by children with diarrhoea, there is some
discussion about the best way to do this. WHO and
UNICEF have developed a packet of oral rehydration salts
(ORS) which combines salt, sugar, baking soda and
potassium and which, when mixed with water, provides a
balanced solution which helps to replace the lost fluids
and minerals and helps to prevent further losses.1
One of the difficulties with ORS packets is that they tend
to over medicalise the treatment of dehydration, create
dependence and, even though they are inexpensive, do
nonetheless cost some money to buy. Public health
specialist, David Werner, suggests that to teach mothers
to prepare appropriate drinks at home is a more
“sustainable, empowering approach” which encourages
self-reliance.2
A home-made cereal-based drink which makes use of
sorghum, rice, wheat, millet, maize or potato - staple foods
in developing countries - is one way of increasing children's
fluid intake. Research now shows that cereal-based drinks
also help to deal with the diarrhoea by reducing the stool
output, something which ORS does not do.3
Sources:
1. WHO, The treatment and prevention of acute diarrhoea. Practical
guidelines. Geneva, WHO, (2nd edn) 1989, pl8
2. Werner, D., "Egypt: another approaching storm on the desert".
Newsletter from the Sierra Madre, No 24, June 1991, p5
3.
Molla, A M., Molla, A., Nath, S.K., et al, "Food-based oral rehydration salt
solution for acute childhood diarr hoea". Lancet, 19 Aug 1989, pp429-31
Carpenter, C.C.J.. Greenough, W.B., Pierce, N.F., "Oral-rehydration
therapy - the role of polymeric substrates", New England Journal of
Medicine, Vol 319, No 20, 17 Nov 1988, ppi346-8
WHO, "Research findings support use of rice based ORS", Essential Drugs
Monitor, No 10, 1990, pl8
Sack, D.A., "Use of oral rehydration in acute watery diarrhoea: a practical
guide ', Drugs, 41:4, 1991. pp566-73
Table 2A-2
Percentage of episodes of diarrhoea in children under three
years of age treated with appropriate or inappropriate
medicines in Canto Grande, Lima, Peru (1984-1989)
1984 1985
1986 1987
1988
1989
Number of episodes
1521
2324 2424 1854 6327 5892
Total percentage treated with drugs
18.7
28.6
38.1
34.2
33.2
59.8
3.2
7.0
10.2
9.4
12.8
32.1
15.5
21.6
27.9
24.8
20.4
27.7
Percentage of episodes where drug
therapy was probably indicated
Percentage of episodes
where drug therapy was
not indicated or was not necessary
Source: Cruz, H.. Paredes, P., and Haak, H., Medicamentos Inapropiados
en Diarrea: La magnitud del problema, Lima, Peru, Pan-American Health Organization
Nov 1989. p25
2A.
Antidiarrhoeals
Problem Drugs
least one antibiotic in about half the cases in 1983
and in 1986. Researchers pointed out that this use of
antibiotics was “difficult to justify”; in 1986, for
example, there were no cholera cases and only one of
the patients had been diagnosed as infected with
Shigella dysentery. The hospital could have saved an
estimated two million pesos (US $2,000) had those
patients not received antibiotics.31
A survey in northern Iran found that 90 out of 100
children admitted to hospital with diarrhoea had pre
viously been treated unsuccessfully with a variety of
drugs, including antibiotics and anti-motility agents.32
A study of the 902 diarrhoeal cases dealt with by 58
physicians in western Sicily in a 12-month period
during 1984-85 found that although oral rehydra
tion therapy was widely known by both general
practitioners and paediatricians, 65% of all cases
were treated with antibiotics and 8% of cases were
treated with anti-motility drugs. Only 9% of cases
were treated with ORT alone.33
A survey of 75 pharmacies in Bangladesh, Sri Lanka
and the Yemen Arab Republic (25 pharmacies in
each country) during 1984 and 1985 found that only
21% advised oral rehydration or consultation with a
health worker for diarrhoea. Instead, most pharma
cies were dispensing combination antibiotics. In
Yemen, for example, over 40% of the treatments
given our contained neomycin.34
A survey of 13 pharmacies in Kenya in 1989 found
that oral rehydration was not recommended in any
of them as the first line treatment for diarrhoea for a
two-year old child. In one pharmacy, oral rehydra
tion was recommended as a second line treatment.
Seven of the pharmacies recommended products con
taining an antibiotic, including four which contained
neomycin. Ten of the products recommended con
tained kaolin and pectin and one was diphenoxylate
syrup. Only five of the pharmacies even stocked oral
rehydration solution.35
A survey of 30 pharmacies in one city in England in
1989 found a large proportion of pharmacists recom
mending inappropriate therapy. The survey took the
form of visits to 10 pharmacies chosen at random
where a female investigator entered posing as a mother
who had a child with diarrhoea, and, in 20 other phar
macies, interviews with pharmacists who were also
asked to complete a questionnaire. Half the pharma
cists interviewed and nearly three quarters in the
“staged” visits recommended the use of an antidiarrhoeal product rather than oral rehydration. Equally
disturbing was the response of the 20 pharmacists to
questions about feeding practices for children with
diarrhoea: half suggested stopping all milk and half
suggested stopping all food, while two-thirds believed
it was necessary to stop breastfeeding during diar
rhoea.36
A survey of 63 pharmacies in Khartoum, Sudan, in
1988 found that 62% of pharmacists recommended
the use of an antibiotic for the treatment of a one-year
old child with acute diarrhoea. Only three pharma
cies (5%) recommended the use of oral rehydration.
How effective are they?
WHO has no doubt about rhe role of antidiarrhoeal
products: “There are no drugs available at present that
will safely and effectively stop diarrhoea.”38 “Most
medicines for diarrhoea are either useless or harmful. 39
Many developing countries have governmental
programmes to control diarrhoeal diseases. These
programmes rely primarily on ORT for treatment
and a few antimicrobials for specific conditions (as
listed in table 2A-4). Antidiarrhoeals are not consid
ered to be useful and their availability on the market
can interfere with a programme’s success.40
The major types of drugs used (often incorrectly) in
the treatment of diarrhoea are: anti-motility drugs;
antimicrobial agents; adsorbents; bydroxyqninolines; intestinal bacteria supplements.
Table 2A-3
Antidiarrhoeals containing antimicrobials
(1986 and 1988-89)1
Country/
region
Total antidiarrhoeals
Total containing
antimicrobials
Total containing
neomycin
1986
1988-9
No.
No.
No.
%
No.
%
No.
Africa
29
22
16
55.2
3
13.6
7
24.1
Caribbean
18
18
10
55.6
5
27.8
5
Hong Kong
26
21
7
26.9
6
28.6
Indonesia2
53
62
33
62.3
32
51.6
India
63
59
51
81.0
47
79.7
Middle East
41
23
22
53.7
6
1986
1988-9
1986
1988-9
%
No.
%
27.8
2
11.1
8
15.1
8
12.9
7
11.1
4
6.8
26.1
7
17.1
5
7.2
Malaysia &
Singapore
29
19
13
44.8
Mexico1
1
5.3
72
69
6
20.7
46
63.9
44
63.8
Philippines
62
46
5
6.9
38
61.3
Pakistan
25
54.3
56
53
36
64.3
Thailand
17
32.1
57
72
6
10.7
29
50.9
38
52.8
10
17.5
11
15.3
506
464
301
59.5
224
48.3
61
12.1
30
6.5
Totals
Notes:
1 Data from Mexico are from 1987
products, including’
Anon.. "Daltar 285%bat Yang Di ari Trf Pe
Reregistered 94 antidiarrhoeal
F°r 'Urther "'“Matron. see:
;~e2d9^ t%s,t
285 drugs
-
HKIMS (Hong Kong, Aug 86 and DecSS)\lMsn C*"bbean <Nov 86 end May 89).
India (June 86 and Feb 88), MIMS Middle Em rrv,
Singapore. June 86 and Oct 88). O/ccionarin
86 !
June 86 and Oct 88)' MIMS
Aug 89)’ 0IMS (Malaysia &
1986 and 1987). PIMS (Philippines Aug 86 a
Farmaceuticas (Mexico.
and Sep88.Feb89) and n^Th^a^. J^^a'nd^y^(PakiStan' Mar Sep'86
2 A .
Antidiarrhoeals
Anti-motility drugs operate on the premise that the
symptom (diarrhoea) must be stopped. Basically,
these drugs slow down the functions of the gut.
\X HO says these products have no role in the treat
ment of diarrhoea in children41 and that they “may
be harmful, especially for children below 5 years of
age. They... delay the elimination from the body of
the organisms that cause the diarrhoea, and may pro
long the illness. They can be dangerous, and even
fatal, if used incorrectly in infants.”42
Table 2A-4
Antimicrobials recommended by WHO for the treatment
of specific causes of diarrhoea in children
Cause
Antibiotic(s) of choice1
Alternatives1
Cholera23
Tetracycline
Furazolidone
12.5 mg/kg body weight
1.25 mg/kg body weight
4 times a day x 3 days
4 times a day x 3 days
or
Trimethoprim (TMP)-
Two important products which fall into this category
are loperamide (Imodium) manufactured by Janssen
(Johnson & Johnson) and diphenoxylate (Lomotil
with atropine) manufactured by Searle.
sulfamethoxazole (SMX)4
TMP 5 mg/kg body weight
and SMX 25 mg/kg body
weight
twice a day x 3 days
|See sections on Loperamide and Diphenoxylate for
further details.]
Shigella
Trimethoprim (TMP)-
dysentery2
sulfamethoxazole (SMX)
15 mg/kg body weight
TMP 5 mg/kg body weight
4 times a day x 5 days
Antimicrobial agents
Nearly half the 464 antidiarrhoeal preparations on
sale in 11 regions of the world during 1988-9 con
tained an antimicrobial, as Table 2A-3 shows. More
than 160 companies are involved in this trade ranging from small, national ventures trading only in
their own country, up to the large transnationals
such as Abbott, Boehringer Mannheim, Boots,
Bristol-Myers, Dainippon, Dumex, Fisons, Glaxo,
Griinenthal, Hoechst, Merck Sharp & Dohme, May
& Baker, Nattermann, Parke-Davis/Warner Lam
bert, Pfizer, Rorer, Searle, SmithKline, Sterling
Winthrop, Upjohn, Carter-Wallace, and Wyeth.43
For over 20 years, antimicrobials were used as the main
treatment in diarrhoea. Now, however, authoritative
opinion is against their use in all but a few specific
infections. This is because antimicrobial drugs may:
• alter the normal bacterial content of the gut
leading to possible fungal infections and over
growth of resistant bacteria;
• prolong the period when the patient with an
infection can pass on the disease as a carrier;
• increase the risk of relapse;
• interfere with subsequent bacteriological
diagnosis.44
According to WHO, “Antibiotics are not effective
against most organisms that cause diarrhoea. They
rarely help and can make some people sicker m the
long term. Their indiscriminate use may increase the
resistance of some disease-causing organisms to
antibiotics. In addition, antibiotics are costly, so
money is wasted. Therefore, antibiotics should not
be used routinely.”45 (See Table 2A-4 for advice on
which antibiotics to use for dysentery and cholera.)
Other experts agree. “Antibiotics have a limited role in
rhe management of diarrhoea.”46 In most cases, “Less
than one-tenth of patients with acute diarrhoea can be
treated successfully with antimicrobial drugs. ’
Nalidixic acid
and SMX 25 mg/kg body
or
weight twice a day x 5 days
Ampicillin
25 mg/kg body weight
4 times a day x 5 days
Amoebiasis
Metronidazole
In very severe cases:
10 mg/kg body weight
Dehydroemetine hydrochloride
3 times a day x 5 days
by deep, intramuscular
(10 days for severe
injection, 1-1.5 mg/kg body
disease)
weight daily (maximum 90 mg)
for up to 5 days, depending on
response
Giardiasis
Metronidazole5
Quinacrine
5 mg/kg body weight
2.5 mg/kg body weight
3 times a day x 5 days
3 times a day x 5 days
Notes:
1. All doses shown are for oral administration unless otherwise indicated. If
drugs are not available in liquid form for use in young children, it may be
necessary to approximate the doses given in this table.
2. The choice of antibiotic will depend on the frequency of resistance to
antibiotics in the area.
3. Antibiotic therapy is not essential for successful treatment, but it shortens the
duration of illness and the period of excretion of organisms in severe cases.
4. Other alternatives are erythromycin and chloramphenicol.
5. Timdazole and ornidazole can also be used in accordance with the
manufacturers* recommendations.
Source: WHO, The rational use of drugs in the management of acute diarrhoea in
children, Geneva, WHO, 1990, p3
Problem Di
Anti-motility drugs
3i
32
2 A .
Antidiarrhoeals
Problem Drugs
All the antibiotics currently used in the treatment of
diarrhoea have side effects that should be carefully
monitored. The use of antibiotics prophylactically (in
an attempt to prevent diarrhoea) can contribute to the
widespread emergence and spread of antimicrobial
resistance. The costs of such an approach arc likely to
be high and there may be no long-term benefits. The
available evidence therefore suggests that such an
approach is not a cost-effective intervention for
national diarrhoeal disease control programmes.43
proof of their efficacy is lacking.... Since amoe
bae cause only a small percentage of the
diarrhoea encountered while travelling, the
indiscriminate use of such potentially toxic
agents is unjustified. Clioquinol is no longer
available for systemic use in the United States.”50
All of the hydroxyquinolines carry a high risk of
adverse effects and most experts agree that their use
should be avoided because they are both ineffective
and dangerous.51
At least S150 million a year is wasted on antidiarrhoeal drugs which contain antimicrobial agents.49
[See also the section on Hydroxyquinolines.]
Adsorbents
[See also the sections on Antidiarrhoeals containing
antibiotics and Antibiotics.]
Adsorbents are supposed to attach themselves to toxins
and various infective agents (as well as to some thera
peutic agents) and in theory help to detoxify the gut.
The main adsorbents used in antidiarrhoeal drugs are
kaolin (usually with pectin - a stabilising agent), acti
vated charcoal and attapulgite. WHO says these
products “are not useful for the treatment of acute
diarrhoea”.52
Hydroxyquinolines
Hydroxyquinolines were discovered to have some
effect in amoebic dysentery, but their use has broadened
out to include most types of diarrhoea. The best-known
drug in this category is Entero-Vioform (clioquinol)
which was formerly manufactured by Ciba-Geigy, but
was withdrawn from the world market in 1985.
The American Medical Association describes the use of
mixtures containing opiates or poorly absorbed
antibacterial agents with adsorbents such as kaolin and
pectin and antispasmodic agents as “unwarranted.” It
According to the American Medical Association,
“Clioquinol... and iodoquinol... have been used
in the prophylaxis of travellers’ diarrhoea but
Table 2A-5
Comparison of antidiarrhoeal drugs in selected prescribing guides
Source
Total no. of
anti diarrhoeal products
No. of products with ineffective contents
Ads
Flo
No. of products with high risk
Lop
Opi
Neo
Total: ineffective
and/or high risk
Oil
Nra
No
%
India (MIMS)
Jun 85:
47
21
7
10
7
6
24
39(82.9%)
Feb 88:
62
23
11
8
4
8
30
58 (93.5%)
Feb 85:
49
22
3
6
3
6
18
22
46(93.8%)
Oct 88:
62*
21
3
18
13
8
19
25
62 (100%)
1
2
7
9
8
17
33(89.1%)
6
3
6
16(76.2%)
12
25(89.2%)
3
12(75.0%)
7
18(94.7%)
2
13(92.9%)
Indonesia (UMS)
Middle East (MIMS)
Apr 85:
37
21
Dec 90:
21
4
May 85:
28
18
1
5
Jan 91:
16
4
4
2
May 85:
19
12
2
5
6
Jan 91:
14
6
5
2
2
Africa (MIMS)
1
9
7
Caribbean (MIMS)
4
Key: Ads = Adsorbents; Flo = Intestinal bacteria supplements; Lop = loperamide; Opi = other opiates; Neo = Neomycin;
Cli = clioquinol and other hydroxyquinolines; Nra = other non recommended antibacterials
Notes:
The total in the final column is less than the sum of the individual items, due to some drugs being irrational combinations of two or more chemicals.
'In October 1991, the government of Indonesia deregistered 94 antidiarrhoeal products. For further information, see: Anon., "Daftar 285 Obat Yang Ditarik Dari
Peredaran" (List of 285 drugs which are withdrawn from circulation), Suara Pembaruan, 29 Oct 1991.
2 A .
In Pakistan in 1991, Dr Tariq Bhutta, a paediatrician
at the Nishtar Hospital in Multan, said that he was
not very optimistic’ about being able to remove
some of the useless kaolin and pectin mixtures from
the market. He had been in contact with both Abbott
and Wyeth asking them to withdraw their respective
products (Karlin and Strepomegma) in the light of
the WHO recommendation. Both companies
responded that they had no intention of doing so as
the products are permitted by many governments.54
Intestinal bacteria supplements
The theory behind the use of lactobacillus and other
intestinal bacteria supplements is that the diarrhoea
causes the loss of normal intestinal bacteria, and that
replacing these “friendly” bacteria will help.
However, as the Martindale guide to medicines points
out, “evidence to support this use is limited”.55
Missing the target
The firm conclusion is that the vast majority of
antidiarrhoeal drugs on the market worldwide are at best - unnecessary and, at worst, ineffective and
sometimes dangerous. A survey in 1980 found that
85% of antidiarrhoeals listed in the MIMS prescrib
ing guide for Africa were “undesirable”; 80% in the
Caribbean; 82% in the Middle East; 73% in
Philippines; 74% in Malaysia and Singapore; and
79% in Indonesia.56 Sadly, the situation has not
improved much over the years, as Table 2A-5 indicates.
A survey carried out in 1990 in 12 countries in Latin
America - Argentina, Bolivia, Brazil, Chile,
Colombia, Costa Rica, Ecuador, Guatemala,
Mexico, Peru, Uruguay and Venezuela - found a
total of 351 antidiarrhoeal preparations marketed.
The vast majority (78%) of these were combination
products containing from two to nine active ingredi
ents, while 63% of the products contained one or
more antibiotics. Loperamide was present in 15 /o of
the products, and 12% contained clioquinol or
another hydroxyquinoiine.57
It is difficult to reconcile the fact that over 80% of the
products on the market have no efficacy in the treat
ment of acute diarrhoea with the fact that four
million children are dying each year from diarrhoea.
It is time that waste was stopped.
Problem Di
notes that rhe patient is subjected to the combined
adverse effects of the individual ingredients and the
added expense of all of these agents. Among the
preparations it cites are: Corrective Mixture
(Beecham), Donnagel and Donnagel PG (Robins),
Kaolin with Pectin (various), Kaopectate and
Kaopectate Concentrate (Upjohn), Parepectolin
(Rorer), Polymagma (Wyeth).53
Antidiarrhoeals
Recommendations for action
Governments and health workers should
develop rational management policies for the
control of diarrhoeal diseases. These should
include the provision of clear and independent
information and education for patients and
consumers about the appropriate treatment of
diarrhoea.
2. All products labelled as antidiarrhoeals and
containing antimicrobial agents should be
withdrawn from the market.
3. The use of antimicrobials in treating diarrhoea
should be limited to those drugs and specific
indications set out by WHO (see Table 2A-4).
4. All paediatric products containing an anti
motility drug should be withdrawn from the
market.
5. Antidiarrhoeal preparations with no proven
efficacy, such as adsorbents and intestinal
bacteria supplements, should be removed from
the market.
6. All antidiarrhoeal preparations should carry a
large, clear message on the package, and in all
information and advertising material, to the
effect that ORT is the mam therapy in the
management of diarrhoea.
1.
Antidiarrlioeals
2 A .
Notes and references:
Meyets, A, Siegel, B., and Vinci, R., “Economic barriers to the use of Oral
Rehydration Therapy: a case report”, journal of the American Medical
Association, Vol 265. No 13, 3 Apr 1901, P1724
2.
WHO, The rational use of drugs in the management of acute diarrhoea in
children. Genet's, WHO, 1990, pi
WHO, A manual for the treatment of diarrhoea, (WHO/CDD/SER/80.2 Rev.2
1990), Geneva. WHO, 1990, pi
3.
WHO/UNICEF, Lessons learned: management of childhood diarrhoea, paper
prepared for Joint UNICEF/WHO CDD Strategy Meeting, 15 Apr 1991, pi
4- UNICEF, The State of the World's Children 1991, Oxford and New York, Oxford
University Press, 1990, pi2
Anon., “$i b wasted on useless drugs, says WHO", Scrip, No 1633,12 Jul
1991, P22
5.
WHO, “Rational management of diarrhoea in children”. Essential Drugs
Monitor, No 11,1991, pio
6.
Snyder, J.D., “Use and misuse of oral therapy for diarrhea- comparison of US
practices with American Academy of Pediatrics recommendations”, Pediatrics,
Vol 87, No i, Jan 1991, p28
Edmundson, SA, Edmundson, W.C, "Acute diarrhoeal disease in India and
Indonesia", Social Sciences and Medicine, Vol 29, No 8,1989, PP991-7
Fujita, K., Kaku, M., Yanagase, Y, et al, “Physicochemical characteristics and
flora of diarrhoeal and recovery faeces in children with acute gastroenteritis
in Kenya”, Annals of Tropical Paediatncs, Vol 10,1990, PP339-45
Mata, L, “How harmful is diarrhoea?”. World Health, Apr 1986, PP5-7
7.
Balistren, W.F., “Oral rehydration in acute infantile diarrhea", American Journal
of Medicine, Vol 88, No 6A 20 Jun 1990, pp3oS-33S
Conlon, CP. and Peto, T.EA, “Infectious diarrhoea", International Journal of
Colorectal Disease, Vol 5,1990, pp’36-40
Carpenter, CCJ., Greenough, W.B., and Pierce, N.F., "Oral rehydration therapy
- the role of polymeric substrates”. New England Journal of Medicine,
Vol 319, No 20,17 Nov 1988, 091346-8
Fedorak, R.NM Field, M„ “Antidiarrheal therapy: prospects for new agents",
Digestive Diseases and Sciences, Vol 32, No 2, Feb 1987. PP195 205
Radetsky, M., “Laboratory evaluation of acute diarrhea", Pediatric Infectious
Disease, Vol 5, No 2, Mar 1986, PP230-8
Snyder, J.D., op cit
Glass, R I.. Lev/, J.E. Gangarosa, R.E., et al, “Estimates of morbidity and
mortality rates for diarrheal diseases in American children”, Journal of
Pediatrics, Vol 118, No 4, Apr 1991, pp27*33
Meyers, A., Siegel, B., and Vinci, R., op cit
8.
Ho, M.S., Glass, R.I., Pinsky, P.E. et al. “Diarrheal deaths in American children:
are they preventable?". Journal of the American Medical Association, Vol 260,
1988, pp328i-4
9.
AMA, Drug Evaluations, Philadelphia, W.B. Saunders Co., (6th edn) 1986, P959
10.
Soriano-Brucher, H, Avendano, P., O'Ryan, M., et al, "Bismuth subsalicylate in
the treatment of acute diarrhea in children: a clinical study”, Pediatncs,
Vol 87, No 1, Jan 1991, ppi8-27
Henry, F.J., Bartholomew. R.K., “Epidemiology and transmission of rotavirus
infections and diarrhoea, in SL Lucia, West Indies", West Indies Medical
Journal, Vol 39,1990, pp205-i2
Ansan, SA, Springthorpe, S., and Sattar, SA, “Survival and vehicular spread
of human rotaviruses: possible relation to seasonality of outbreaks", Reviews
of Infectious Diseases, 13,1991, PP448-61
11.
Maldonado, YA and Yolken, R.H., "Rotavirus", Balhere's Clinical
i.
12.
Gastroenterology, Vol 4, No 3, Sep 1990, pp6o9-25
Po, A.L.W., Non-Prescription Drugs, Oxford, Blackwell Scientific, (2nd edn)
1990, ppzio-n
Cohen, M.B., “Etiology and mechanisms of acute infectious diarrhea in infants
in the United States", Journal of Pediatrics, Vol 118, No 4, Apr 1991. PP34-39
Fujita, K., Kaku, M., Yanagase, Y, et al, op cit
Nakano, I., Binka, F.N., Afari, EA, et al, "Survey of enteropathogenic agents
in children with and without diarrhoea in Ghana", Journal of Tropical
Medicine and Hygiene, Vol 93,1990, pp4o8-i2
Gorbach, S.L., “Bacterial diarrhoea and its treatment”, Lancet, 12 Dec 1987,
13.
PP1378-1382
Huilan, S.. Lu, G.Z., Mathan, M.M., et al, "Etiology of acute diarrhoea among
children in developing countries: a multicentre study in five countries",
14.
Bulletin of the World Health Organization, Vol 69. No 5,1991, PP549’55
Gilman, AG., Rail, T.W., Nies, AS., and Taylor, P., Goodman and Gilman's The
Pharmacological Basis of Therapeutics, New York, Pergamon Press, (8th edn)
1990, P924
Schoriing, J.B., de Souza, MA, and Guerrant, R.L, "Antibiotic use among
children in an urban Brazilian slum: a risk factor for diarrhoea?”, American
Journal of Public Health, Vol 81, No 1, Jan 1991, pp99-ioo
Laurence, D.R and Bennett, P.N., Clinical Pharmacology. London, Churchill
15.
Livingstone, (6th edn), 1987, P638
AHRTAG, Preventing and Treating Diarrhoea in the Community, undated
Popkin, B.M., Adair, L, Akin, JS, et al, “Breast-feeding and diarrheal
morbidity”, Pediatncs, Vol 86, No 6, Dec 1990, pp874-82
Victora, C.G., Vaughan, J.P., Lombardi, C., et al, “Evidence for protection by
breast-feeding against infant deaths from infectious diseases in Brazil",
Lancet, 8 Aug 1987, pp3i9-22
16.
17.
Feachem, R.G., "Prevention better than cure”, World Health, Apr 1986, ppi8-i9
Rhode, J.E., “Selective Primary Health Care: Strategies for control of disease
in the developing world. XV. Acute Diarrhoea”, Reviews of Infectious
18.
Diseases, Vol 6, No 6, Nov-Dec 1984, pp840-54
UNICEF, WHO and UNESCO, Facts for Life: A Communication Challenge. New
19.
York, UNICEF, 1989, pi9
Elarabi, I.I., “Where drugs don't help", World Health, Apr 1986, ppio-n
20.
Laurence, D.R. and Bennett, P.N., op cit at note 14, P633
2t Santosham, M., Reid, R., "Diarrhoea management", World Health, Apr 1986,
p8
Claeson, M.E. and Clements, M.L., "Ridding the world of hydroxyqumobnes",
22.
23.
British Medical Journal, Vol 299, 26 Aug 1989, PP527-8
Wittenberg, D.F., Ramji, S., Broughton, M.. “Oral rehydration therapy
revisited", Lancet, Vol 337, No 8744. 3°
1991- P798-9
Heymann, D.L., Mbvundula, M., Macheso, A., et al, "Oral rehydration therapy
in Malawi: impact on the severity of disease and on hospital admissions,
treatment practices and recurrent costs", Bulletin of the World Health
24.
Organisation, Vol 68, No 2,1990, pp 193-7
Phillips, M., Kumate-Rodrfguez, J., and Mota-Hernandez, E, “Costs of treating
diarrhoea in a children’s hospital in Mexico City", Bulletin of the World Health
25.
Organization, Vol 67, No 3,1989, ppz73-280
Hatch, D.L, Vreuls, R.C. Toole, M.J., et al, “The effective case management of
childhood diarrhoea with oral rehydration therapy in the Kingdom of Lesotho",
26.
27.
28.
29.
International Journal of Epidemiology, Vol 19, No 4,1990, ppio66 71
El-Rafie, M., Hassouna, WA, Hirschhom, N„ et al, “Effect of diarrhoeal
disease control on infant and childhood mortality in Egypt: Report from the
National Control of Diarrheal Diseases Project", Lancet, 10 Feb 1990, PP334-8
Carriere, R.C, “India: ORT survey”, Dialogue on Diarrhoea, No 29, June 1987, p2
Soman, CR., “Oral rehydration and the medical profession”, Dialogue on
Diarrhoea, No 29, June 1987, p8
Cruz, H.. Paredes, P, and Haak, H„ Medicamentos Inapropiados en Diarrea: la
magnitud del problema, Lima, Peru, Pan-American Health Organisation, Nov 1989
30.
31.
32.
33.
Ibid., pp4i-2
Phillips, M., Kumate-Rodriguez, J., and Mota-Hemandez, E, op cit, PP276
Bhardv/a, R.C., “Iran: attitudes to treatment and use of antibiotics", Dialogue
on Diarrhoea, No 33, June 1988, pz
Nastasi, A., Massenti, M.E, Scarlata, G., et al, "A study on oral rehydration
therapy of diarrheal disease in western Sicily", European journal of
Epidemiology, Vol 3, No 2, June 1987, ppiji-4
Tomson, G, Sterky, G., "Self-prescribing by way of pharmacies in three Asian
developing countries”, Lancet, 13 Sep 1986, pp6zo-i
35.
Yudkin, J5., "Dispensing of inappropriate medicines for diarrhoea", Lancet,
31 Mar 1990, P803
36.
Goodbum, E., Mattosinho, S., Mongi, P., et al, “Management of childhood
diarrhoea by pharmacists and parents: Is Britain lagging behind the Third
World’”, British Medical Journal, Vol 302, 23 Feb 1991, PP44O-3
37.
Berih, AA, McIntyre, L., Lynk, A.D., "Pharmacy dispensing practices for
Sudanese children with diarrhoea”, Public Health, Vol 103,1989, PP455 8
38.
WHO, The treatment and prevention ofacute diarrhoea-. Practical Guidelines,
Geneva, WHO, (2nd edn) 1989
39.
UNICEF, WHO and UNESCO, op cit at note 18, P47
40.
UNICEF, The State of the World’s Children 1991, Oxford and New York, Oxford
University Press, 1990, pi2
41.
WHO, The rational use of.... 1990, op cit, ppi3 & 20
42.
WHO, 1989, op cit, p4
43.
Chetley, A, Antibiotics: the wrong drugs for diarrhoea, The Hague: HAI, 1987
44.
Parish, R, Medicines: a guide for everyone, London, Penguin, (6th edn,
revised), 1989, P144
45.
WHO, 1989, op cit, 03
46.
Balistreri, W.E, “Oral rehydration in acute infantile diarrhea", American Journal
of Medicine, Vol 88 (Suppl 6A), 20 June 1990, pp6A:3oS-33S
47.
Gorbach, S.L., op cit at note 12, P1381
48.
de Zoysa, I. and Feachem. R.G., “Interventions for the control of diarrhoeal
diseases among young children: chemoprophylaxis", Bulletin of the World
Health Organization, Vol 63, No 2,1985, PP295-315
49.
Based on a world market of US $438 million (a 1983-84 figure) for all
antidiarrhoeal products, derived from industry sources, and from a
calculation made by an industry representative at a 1983 workshop on
diarrhoea held in Frankfurt, that 34% of the total world market in
antidiarrhoeals was made up of antibiotics and other antimicrobial agents.
50.
AMA, 1986, op cit at note 9, P964
51.
Claeson, M.E. and Clements, M.L., op cit at note 21, PP527-8
52.
WHO, 1989, op cit, p3
53.
AMA, 1986, op cit at note 9, P971
54.
Bhutta, T.I., "Agents for diarrhoea in children”, Lancet, 337:8746,13 Apr 1991,
34,
P925
Reynolds, J.E.F. (ed.), Martindale: The Extra Pharmacopoeia, London,
The Pharmaceutical Press, (29th edn) 1989, P1582
56.
Medawar C. and Freese, B„ Drug Diplomacy, London, Social Audit, 1982, ps 1
57.
Lanza, 0. and Kerkvliet, E., Ojo con los antidiarreicos: el abuso de
antidiarreicos en America Latina, Montevideo, AIS/IOCU, 1991, PP35-40
55,
Chetley, A. Problem Drugs, Amsterdam,
Health Action International, 1993
/<£>/■ library
;
‘
z*\
A
.
and
documentation
j r Z1
UNIT
/
2B. Antidiarrhoeals
containing antibiotics
Health Action International’s
coordinating offices:
HAI Europe
Jacob van Lennepkade 334T
1053 NJ Amsterdam
The Netherlands
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accion para la Salud
Avda. Palermo 531
Dpto. 104
Lima 13
Peru
Antibiotics and diarrhoea:
a dangerous combination
In November 1990, following two hard-hitting
documentaries on British television, and a concerted inter
national pressure campaign from Health Action
International (HAI) and the Medical Lobby for Appropriate
Marketing (MaLAM), the US-based company, Upjohn,
agreed to phase out its antidiarrhoeal product, Kaomycin,
worldwide over an 1 S-month period.
Kaomycin contained the antibiotic neomycin, as well
as the adsorbents kaolin and pectin. As long ago as
19S0 the World Health Organization (WHO) said
unequivocally that neomycin '"should never be used in
the treatment of acute diarrhoea”1 (original emphasis)
because of its lack of efficacy in the treatment of acute
diarrhoea, its ability to prolong or exacerbate diar
rhoea, and its risk of side effects such as hearing
damage or kidney failure.2 Yet it took 10 years before
one of the world’s leading manufacturers of products
containing neomycin began to take the product off the
market. Even so, an Upjohn spokesman, John Butler,
says that the company has never agreed with the stance
of WHO that the use of neomycin in acute diarrhoea
could be harmful. Instead, he says that the product was
“simply eclipsed” by oral rehydration therapy. “It was
purely a marketing decision”.’ As recently as 1989,
Kaomycin was registered for use in 22 countries
(including Germany), and Upjohn was doggedly
defending it. The company said that it “would be
irresponsible” to deny physicians access to such a
product,4 and that it had faith in the product’s effec
tiveness and said that the benefits of use outweighed the
small risk.5
Over the years, “marketing decisions”, rather than
public health decisions have led to the situation
where, in many countries, a large proportion of prod
ucts aimed at treating diarrhoea contain antibiotics or
other antimicrobial drugs. A survey of antidiarrhoeal
products carried out in 1989 found that nearly half of
the 464 products listed in prescribing guides in 11
areas of the world contained an antimicrobial drug.6
(See figure 2B-1.) A survey carried out in 1990 in 12
Figure 2B-1
Percentage of antidiarrhoeal products containing
an antibiotic (1988-89)*
2 B .
Antidiarrhoeals
containing
Problem Drugs
countries in Latin America — Argentina, Bolivia,
Brazil, Chile, Colombia, Costa Rica, Ecuador,
Guatemala, Mexico, Peru, Uruguay and Venezuela —
found that out of a total of 351 antidiarrhoeal prepa
rations marketed, 63% contained one or more
antibiotics.' In the Yemen, a survey of 25 pharmacies
during 1984 and 1985 found that over 40% of the
treatments recommended for acute diarrhoea for
children contained neomycin.8 Surveys in the Sudan
in 1988,9 in Kenya in 1989,10 in Peru in 1989," in
India in 1986,12 in Mexico between 1983 and 1986,13
in Sicily during 1984 and 1985,14 and in the
Philippines in 198415 found similar high levels of
indiscriminate use of antidiarrhoeals containing
antibiotics.
The worst of a bad lot
The indiscriminate use of antimicrobial drugs
encourages the development of resistant micro
organisms and alters the normal bacterial content of
the gut, which can lead to possible fungal infections
and the overgrowth of resistant bacteria, can
increase the risk of relapse, prolong the period when
the patient with an infection can pass on the disease,
and can also interfere with subsequent bacteriologi
cal diagnosis.16
Products containing neomycin, streptomycin or
dihydrostreptomycin, chloramphenicol, and/or one
of the many sulphonamides are of particular
concern. The British National Formulary, which
includes no combination antidiarrhoeal products
containing antibiotics, points out that:
“antibiotics and sulphonamides are generally
unnecessary in simple gastroenteritis, even
where a bacterial cause is suspected, because
the complaint will usually resolve quickly
without such treatment.... The general use of
sulphonamides in treating diarrhoea of trav
ellers is inadvisable because of the risks of
rash and agranulocytosis. Poorly absorbed
drugs such as dihydrostreptomycin, neo
mycin and sulphaguanidine should be
avoided altogether in gastrointestinal infec
tion. They prolong rather than shorten the
time taken to control diarrhoea.”17
Because of their potential toxicity, aminoglycoside
antibiotics such as neomycin, streptomycin or dihy
drostreptomycin should in general only be used for
the treatment of serious infections.18 Streptomycin is
an antibiotic which still has an important role in
tuberculosis treatment. In theory, it is potentially
active against a large number of bacteria; however,
extensive use and misuse of streptomycin has been
associated with the development of widespread resis
tance to the drug by the bacteria which causes
tuberculosis.19 Because dihydrostreptomycin is more
likely than streptomycin to cause partial or complete
hearing loss, it is rarely used.20
antibiotics
Antimicrobials and sulphonamides
found in antidiarrhoeal preparations
bacitracin
chloramphenicol
clefamide
colistin
dihydrostreptomycin
diloxanide furoate
framycetin
furazolidone
metronidazole
nalidixic acid
neomycin
nifuroxazide
oxytetracycline
paromomycin
phthalylsulphacetamide
phthalylsulphathiazoie
piromidic acid
polymyxin 8
polynoxylin
salicylazosulphapyridine
streptomycin
succmylsulphathiazole
sulphadimidine
sulphadiazine
sulphaguanidine
sulphaguanole
sulphamethoxazole
sulphasalazine
sulphathiazole
trimethoprim
The World Health Organization says quite clearly, as
a result of a careful review of the most up-to-date
scientific literature, that there is no evidence that
neomycin, streptomycin or dihydrostreptomycin are
effective in the treatment of diarrhoea, no matter
what the cause of the diarrhoea might be.21 Instead,
they divert attention and resources from the more
important aspects of diarrhoea therapy: rehydration,
proper nutrition, appropriate antibiotics for the treat
ment of dysentery. As WHO puts it: “the production
and sale of these products cannot be justified.”22
Chloramphenicol is a powerful, inexpensive antibiotic
which unfortunately is perhaps best known for its abil
ity to provoke life-threatening blood disorders (aplastic
anaemia), and “should only be given when there is no
suitable alternative and never for minor infections”.23
The latest edition of Goodman and Gilman's The
Pharmacological Basis of Therapeutics points out in
large type that chloramphenicol “should never be
employed in undefined situations or in diseases readily,
38
Antidiarrhoeals
containing
Problem Drugs
varied . The overall incidence of adverse reactions is
about 5%,30 The WHO has concluded that because of
the lack of efficacy and concerns about safety,
there is no justification for the use of non
absorbable sulfonamides, or of systemically
absorbed sulfonamides other than co-trimoxazole [sulphamethoxazole and trimethoprim], to
treat diarrhoea or dysentery.”31
Combining useful antimicrobials
with ineffective ingredients
In the small proportion of diarrhoeas where an antimi
crobial is required, such as for Shigella dysentery,
amoebic dysentery', giardiasis, or possibly in severe
cholera, WHO has prepared guidelines on which drugs
to use. For severe cholera the first choice drug is
tetracycline, with furazolidone, or trimethoprim-sulfamethoxazole (co-trimoxazole) as alternatives. For
Shigella dysentery, the drug of choice is co-trimoxazole,
with nalidixic acid or ampicillin as alternatives. For
amoebic dysentery and giardiasis the drug of choice is
metronidazole, with dehydroemetine hydrochloride as
an alternative for severe amoebic dysentery, and
quinacrine an alternative for giardiasis.32
Some of these drugs are often promoted for any type
of “bacterial diarrhoea” or simply for “diarrhoea”.
Often, too, they are combined with other products
such as kaolin, pectin, hydroxyquinolines, atta
pulgite, bismuth, or with other antimicrobials. A
study of pharmacies in Asia found that in
Bangladesh, for example, well over half the pharma
cies recommended furazolidone, usually combined
with kaolin and pectin, as the treatment for an 11month old baby with non-specific diarrhoea.33
Once again, “marketing decisions” rather than pub
lic health decisions have led to this unnecessary use
of antibiotics.
Most of the other antimicrobials that are regularly
included in antidiarrhoeal preparations are of dubi
ous value:
• Bacitracin is perhaps useful in the treatment of
antibiotic-caused diarrhoea although vancomycin
is preferred.34
• Clefamide is a minor antiprotozoal drug which has
been used in the treatment of intestinal amoebiasis.35
• Colistin and polymyxin B, because of their toxic
effects on the liver, are now rarely used.36 They are
not the drugs of first choice for the treatment of
any specific infection.37
• Diloxanide furoate is the drug of choice for chronic
intestinal amoebiasis in which only cysts are pre
sent.38 However, in other forms of amoebic
dysentery, metronidazole is the most effective drug.
• Framycetin has similar actions and uses as
neomycin,39 and its use in the treatment of diar
rhoea is extremely doubtful.
antibiotics
• Nifuroxazide is a urinary tract antiseptic with a
similarity to furazolidone. Although it has been
used in the treatment of colitis and diarrhoea40,
there is little evidence of effectiveness.
• Piromidic acid and nalidixic acid have similar
action and use, but piromidic acid is less active.41
Like nalidixic acid, its primary use is for urinary
tract infections, although it might conceivably
have a very minor use in some cases of bacillary
dysentery.
• Polynoxylin is a disinfectant which has antibacter
ial and antifungal action and is used in a variety' of
preparations for the local treatment of minor
infections.42 There is no recorded information
about its value in treating diarrhoea.
• Trimethoprim is now rarely used on its own for
diarrhoeas, although it may be useful in some
cases of Shigella dysentery.43 However, it is more
common to find co-trimoxazole recommended.
• Paromomycin is used only to treat two parasitic dis
eases: tapeworm infestation and intestinal
amoebiasis,44 although it is by no means infallible in
the latter case.45 Side effects are mainly limited to gas
trointestinal upset and diarrhoea.46 Yet, in August
1986 Warner Lambert/Parke-Davis claimed in an
advertisement in the Philippines Index of Medical
Specialities that its brand of paromomycin with
kaolin and pectin (Humagel) “stops diarrhoea fast”.
The product was indicated for all “specific and non
specific infectious diarrhoea caused by pathogens
sensitive to paromomycin.”
In this instance, and with many of the other antimicro
bial drugs which have a specific, and very limited, use
in the treatment of diarrhoea, companies have
attempted to broaden the possible uses in their promo
tional materials. Such practice is far removed from the
aims contained in the code of practice drawn up by the
International Federation of Pharmaceutical Manu
facturers Associations (IFPMA) which states that the
pharmaceutical industry should provide only products
which “have full regard to the needs of public health”.
Before there can be better management of diarrhoea,
the market needs to be cleansed of the large numbers of
so-called antidiarrhoeal products that contain antibi
otics. Over the past 10 years, HAI and many of the
individual groups in the network have focused on
antidiarrhoeal products as a key area for change, with
some success.
In November 1986, the Italian pharmaceutical firm,
Farmitalia Carlo Erba, announced that it was with
drawing three of its antidiarrhoeal products from the
market worldwide, following concerted pressure
from a UK-based justice and peace group. The three
products - Quemiciclina, Mebinol Complex, and
Entero-Pristina - had one thing in common: they all
contained antimicrobials. A Carlo Erba spokesper
son conceded that the drugs were “obsolete and no
longer defensible from a medical point of view”.46
2 B .
Antidiarrhoeals
The first sulphonamide was marketed in the mid19305. Since then many sulphonamides have been
developed and they usually function by interfering
with the ability of the bacteria to grow (bacteriostatic).
Their broad spectrum of activity, however, has become
limited because of the spread of resistance and the clin
ical use of sulphonamides therefore has declined.28
Sulphonamides that are poorly absorbed from the gas
trointestinal tract — such as sulphaguanidine,
succinylsulphathiazole and phthalylsulphathiazole —
have a long history of being used for the treatment of
diarrhoea. However, evidence of their efficacy is lack
ing.29 In addition, side effects “are numerous and
antibiotics
Travellers’ diarrhoea
Acute diarrhoea, which in most cases is a mild illness
lasting less than a week, occurs in 20-50% of travellers
to developing countries.1 Several studies have
demonstrated that antibiotics can be used successfully
to prevent travellers' diarrhoea.2 Despite this, the
consensus opinion is that there is little need to use
antibiotics in this way. In the words of the American
Medical Association (AMA):
"Although effective chemoprophylactic
regimens... are available, antimicrobial agents
are not recommended for the prevention of
travelers' diarrhoea because the risks
associated with widespread administration of
these agents outweigh the benefits of
preventing an illness that usually is mild and
self-limiting. These risks include the potential
for: (1) serious adverse drug reactions; (2) the
development of superinfections; and (3) the
emergence of widespread bacterial resistance to
the antimicrobial agents being used.3"
The best therapy is to be aware of and avoid possible
sources of bacterial contamination in food and drink,
make use of oral rehydration if diarrhoea develops,
and seek early medical treatment if severe diarrhoea
occurs with serious fluid loss and/or with blood or
mucus.
Sources:
1.
Studemeister. A , “Travel medicine for the primary care physician”,
Western Journal of Medicine, Vol 154, Apr 1991, pp418-22
Anon , "Preventing travellers' diarrhoea", Lancet, 16 July 1988, pl44
2.
Wistrom, J. and Norrby, R , "Antibiotic prophylaxis of travellers'
diarrhoea”, Scandinavian Journal of Infectious Diseases, Vol 70, (Suppl),
1990, ppi 11 29
Taylor, D.N., Sanchez, J.L., Candler, W., et al, "Treatment of travelers'
diarrhea: ciprofloxacin plus loperamide compared with ciprofloxacin
alone: a placebo-controlled, randomized trial”, Annals of Internal Medicine,
Vol 114, No 9. 1 May 1991, pp731 -4
Holtz, T.H. and Nettleman, M.D., "Emporiatrics: Diarrhea in travelers”,
Infection Control and Hospital Epidemiology, Vol 11, No 11, 1990, pp606-10
Ericsson, C.D , DuPont, H.L . Mathewson, J,J , et al, “Treatment of
A FORMULATION which
traveler's diarrhea with sulfamethoxazole and trimethoprim and
loperamide", Journal of the American Medical Association, Vol 263, No 2,
12 Jan 1990, pp257-61
3.
AMA, Drug Evaluations, Philadelphia, W.B. Saunders Co., (6th edn) 1986,
P1277
but also provide
SYMPTOMATIC RELIEF
Antibacterial plus antidiarrhoeal
□ Contains not just an
antidiarrhoeal but also
an antibacterial to
eradicate infection
■ •<_ _.-.oiainn nromO
□ Active against a variety
of gram negative and
gram positive enteric
organisms, notably
Shigella, Escherichia,
□The desire to defecate
diminishes after
approximately one hour
□Costs to your patients
just 20 palse per tablet.
_ .___ DrntPUS
Advertisement for a combination product containing
furazolidone, diphenoxylate and atropine (Lomofen)
in Searle's Diarrhoea Update, India, 1991
37
Problem Drugs
safely, and effectively treatable with other antimicro
bial agents".2'1 It is generally reserved for the treatment
of typhoid and paratyphoid fever and for meningitis.25
Because it is an inexpensive drug, because it is easy to
administer, and because if used correctly for a serious
condition such as meningitis, the risk of fatal side
effects is lower than the risk of death from meningi
tis,26 chloramphenicol should be reserved for use in
severe infections, particularly in developing countries.
As a leading textbook, Antibiotics in the Tropics, says:
“chloramphenicol should not be given in trivial infec
tions which can be treated safely with less dangerous
agents”.27
containing
Antidiarrhoeals
outrageous even to consider marketing such drugs
for diarrhoea in this day and age”.4S
In 1984, the best selling antidiarrhoeal drug in the
Philippines was Parke-Davis’ Chlorostrep, a combi
nation of chloramphenicol and streptomycin.49
Similarly in India, it was a popular product.
Following campaigns by the Drug Action Forum in
India and by the Medical Lobby for Appropriate
Marketing (MaLAM), Parke-Davis announced in
1987 that “Chlorostrep would cease to exist in
1987”.50
Correspondence from MaLAM to SmithKline in 1986
and 1987 drew attention to advertising in Pakistan,
Indonesia and India which promoted the company’s
Furoxone (furazolidone, kaolin and pectin) and
Dependal-M (furazolidone, metronidazole, kaolin and
pectin) for non-specific diarrhoea. SmithKline first
reluctantly agreed to modify its advertising claims and
ultimately recognised that the formulation was irra
tional and has subsequently dropped the kaolin and
pectin.
Despite those successes, there is still much to be done.
For example, 18 of the 39 antidiarrhoeal prepara
tions listed in the Philippines Index of Medical
Specialities in January 1991 contained an antibiotic,
and 11 of those 18 were combination products.51 One
of those products, Wyeth’s Polymagma (strepto
mycin, polymyxin B, attapulgite, pectin and
antibiotics
aluminium hydroxide), was being promoted in the
Philippines as “the antidiarrhoeal for all seasons, for
all patients. Proven efficacy against acute infectious
diarrhoea”.52 Wyeth subsequently announced that it
had begun a global discontinuation programme for
antidiarrhoeals that contain antibiotics, and that it
expected that all outstanding stocks of Polymagma
would disappear by mid-1992.
With advertising such as this, for products that have
little or no regard for public health, the time is long
overdue for much stronger measures to be taken. It is
clear that nearly half the antidiarrhoeal products now
on the market could and should be withdrawn because
they contain an unnecessary antimicrobial. If the phar
maceutical industry is not prepared to withdraw those
products voluntarily, then it is up to governments and
their regulatory authorities to prohibit their sale.
Recommendation for action
Antidiarrhoeal products containing neomycin,
streptomycin/dihydrostreptomycin,
chloramphenicol, or nonabsorbable
sulphonamides, should be taken off the market
immediately.
lem Drugs
Michael Rawlins, professor of clinical pharmacology
at Newcastle University, said of the products, “it is
containing
Antidiarrhoeals
2 B .
containing
antibiotics
Problem Drugs
Notes and references:
WHO. A Manual for the Treatment ofAcute Diarrhoea, Doc No
WHO/CDD/SER/80.2, Geneva, 1980, P13
WHO, The rational use of drugs in the management of acute diarrhoea in
children, Geneva, WHO, 1990, PP31 & 33
Scanlon, C., “Unsafe drugs find buyers abroad", Detroit Free Press, 20 May
22.
23.
24.
1991. P4A
Anon., “Antidiarrhoeals again under attack", Scrip, No 1457,20 Oct 1989, P29
Anon.. “Misuse of antidiarrhoeal medicines", Lancet, 21 Oct 1989
Chetlev, A., A Healthy Business? World Health and the Pharmaceutical Industry,
London, Zed Books, 1990, P79
7.
Lanza, 0. and Kerkvliet, E., Ojo con los antidiarreicos: el abuso de
antidiarreicos en America Latina, Montevideo, A1S/10CU, 1991, PP35-40
8.
Tomson, G„ Sterky, G., “Self-prescribing by way of pharmacies in three Asian
developing countries", Lancet, 13 Sep 1986, pp62o-i
9.
Berih, AA, McIntyre, L, Lynk, A.D., “Pharmacy dispensing practices for
Sudanese children with diarrhoea", Public Health, Vol 103,1989, PP455-8
10.
Yudkin, J5., “Dispensing of inappropriate medicines for diarrhoea", Lancet,
25.
i.
2,
3.
45.
6.
31 Mar 1990, P803
it Cruz, H., Paredes, P„ and Haak, H., Medicamentos Inapropiados en Diarrea: La
magnitud del problema, Lima, Peru, Pan-American Health Organisation, Nov
19S9
12.
Carriere, R.C, “India: ORT survey", Dialogue on Diarrhoea, No 29, June 1987,
P2
Phillips, M., Kumate-Rodriguez, J., and Mota-Hernandez, E, “Costs of treating
diarrhoea in a children's hospital in Mexico City”, Bulletin of the World Health
Organization, 67:3,1989, PP276
14.
Nastasi, A., Massenti, M.F., Scarlata, G., et al, “A study on oral rehydration
therapy of diarrheal disease in western Sicily", European Journal of
Epidemiology, Vol 3, No 2, June 1987, PP151-4
15.
Quanico, U.T., “Antidiarrhoeals in the Philippines", The Drug Monitor, Vol 2.
No 6, June 1987 (117 out of 194 antidiarrhoeal products were found to contain
antibiotics); see also: Tan, M.L., Dying for Drugs, Manila, Health Action
13.
Information Network, 1988, PP85-88
Parish, P., Medicines: a guide for everybody, London, Penguin (6th edn.
revised), 1989, P144
17.
BMA and the Royal Pharmaceutical Society of Great Britain, British National
Formulary, London, BMA and The Pharmaceutical Press, No 21, March 1991, P36
18.
Reynolds, J.E.E (ed.), Martindale: The Extra Pharmacopoeia, London,
The Pharmaceutical Press, (29th edn) 1989, pios
19.
WHO, 1990, op cit, PP25-6
20.
Reynolds, J.E.E, op cit, pzi6
2L WHO, 1990, op cit, pp28 & 34
16.
Ibid.
Reynolds, J.E.E, op cit, pio6
Gilman, A.G., Rail, T.W., Nies, A.S., and Taylor, P., Goodman and Gilman's The
Pharmacological Basis of Therapeutics, New York, Pergamon Press, (8th edn)
1990, piiz8
Pratt, W.B. and Fekety, R., The Antimicrobial Drugs, Oxford, Oxford University
Press, 1986, P193
26.
Pecoul, B, Varaine, E, et al, “Long-acting chloramphenicol versus intravenous
ampicillin for treatment of bacterial meningitis”, Lancet, Vol 338, No 8771,
5 Oct 1991, pp862-6
27 Enenkel, S. and Stille, W., Antibiotics in the Tropics: antibacterial therapy with
limited resources, Berlin, Springer-Vertag, 1988, pi4
28.
Reynolds, J.E.E, op cit, pio8
29.
WHO, 1990, op cit, PP43-9
30.
Gilman, A.G., op cit, P1052
31.
WHO, 1990, op cit, P48
32.
Ibid, p3
33.
Tomson, G„ op cit
34.
Pratt, W.B., op cit, P144
35.
Reynolds, J.E.E, op cit, p66i
36.
Gilman, A.G., op cit, P1138
37.
Pratt, W.B., op cit, P255
38 BMA. op cit, P225
39.
Reynolds, J.E.E, op cit, P234
40.
Reynolds. J.E.E, op cit, p 1595
41.
Ibid., p288
42.
Ibid., P968
43.
Salam, MA and Bennish, M.L., "Antimicrobial therapy for Shigellosis", Reviews
of Infectious Diseases, Vol 12, Suppl 4, Mar-Apr 1991, PS336
44.
Pratt, W.B., op cit, P153
45.
Gilman, A.G., op cit, pioo6
46.
Ibid.
47.
O'Sullivan, J„ "Pills for profit or saving lives?", Catholic Herald, 14 Nov 1986
48.
Ibid.
49.
Quanico, U.T, “Antidiarrhoeals in the Philippines", The Drug Monitor, Vol 2,
No 6, June 1987, pio
50.
Anon, "Parke-Davis/Wamer Lambert- Oral streptomycin chloramphenicol
combination”, MaLAM Newsletter, Jun 1987
51.
Anon., “Antidiarrheals in the Philippines — How safe, how effective?", The
Drug Monitor, Vol VI, No 3, Mar 1991, P35
52.
Letter from MaLAM to Wyeth, July 1991. See: MaLAM Newsletter, Nov 1991.
A^'ty
Chetley, A. Problem Drugs, Amsterdam,
Health Action International, 1993
'5’ -'
LIBRARY
Health Action International’s
coordinating offices:
'
' \
AND
DOCUMeNTAT®;
HAI Europe
Jacob van Lennepkade 334T
1053 NJ Amsterdam
The Netherlands
2C. Hydroxyquinoliriesig
HAI Clearinghouse/ARDA
c/olOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accion para la Salud
Avda. Palermo 531
Dpto. 104
Lima 13
Peru
Worldwide withdrawal
overdue for 20 years
When 19-year-old Mieko Hosbi came down with diar
rhoea in June 1969 and doctors were having trouble
controlling it, she was eventually given a halogenated
hydroxyquinoline drug called iodochlorhydroxyquin (or
clioquinol). Shortly afterwards, she suffered from a tem
porary paralysis of her facial muscles, causing her to lose
the ability to speak for a few days. When that problem dis
appeared, she began to suffer from a growing numbness in
her legs which spread to an almost complete paralysis of
her body. In October 1969 she also lost her eyesight. By
the beginning of 1970 it was clear that Mieko was one of
the more than 11,000 victims of a disease called subacute
myelo-optic neuropathy (SMON) that swept through
Japan between 1955 and 1970.1
However, Ciba-Geigy refused to concede that the
drug was dangerous. In a 1980 press release the
company claimed “there is no conclusive scientific
evidence that clioquinol causes SMON.”4 The
press release said that agreeing to settle the claims
for damages in Japan was “not inconsistent with
the decision to continue to offer products contain
ing clioquinol. In view of the extreme rarity of
clioquinol side-effects outside Japan, Ciba-Geigy
considers that one or more additional factors
played a part in the 1955-70 SMON epidemic in
Japan.... Used as directed, products such as EnteroVioform and Mexaform are both safe and
reliable.”
It took much of this time to uncover the cause of the
disease. On 7 August 1970, Japanese scientists
reported that clioquinol was the probable cause.
Within a month, the Japanese government banned all
of the 186 halogenated hydroxyquinolines products
on the market.2
Medical opinion disagreed with Ciba-Geigy.5
Clinicians from England, Australia, Switzerland,
Sweden, Denmark, the Netherlands and the United
States have described patients who developed
neurologic symptoms while taking iodochlorhy
droxyquin, di-iodohydroxyquin or broxyquinoline.
The clinical symptoms of these patients and the
dosages and length of therapy were similar to those
noted in the histories of Japanese patients with
SMON.6 As well as an increasing amount of evi
dence to link the hydroxyquinolines with SMON,
doubt was also emerging about the efficacy of these
products in the treatment of diarrhoea. One
researcher notes the lack of experimental evidence
of efficacy for the use of hydroxyquinolines:
“In fact, these agents appear to be of no value
in any but amoebic diarrhoea, and even then
are not drugs of choice. Drug toxicity with reti
nal degeneration has proved a high risk for
such an ineffective agent.”7
Clioquinol was the active ingredient in widely-used
antidiarrhoeal drugs such as Entero-Vioform and
Mexaform, marketed by the Swiss company, CibaGeigy. Ciba first marketed clioquinol in 1900 as a
powder for wounds under the name of Vioform. In
1934, Ciba introduced it for oral use as EnteroVioform. Only one year after it was put on the
market, Ciba received a report from doctors in
Argentina describing the same side effects as the later
Japanese cases. Animal trials in the late 1930s showed
that the drug caused convulsions in cats, some of
which were fatal. In the early 1960s, Ciba-Geigy
received studies showing that dogs with diarrhoea,
when treated with Entero-Vioform, died in seizures.
In 1966, Dr Olle Hansson of Sweden, in collabora
tion with a Swedish ophthalmologist, published a
report in The Lancet on the optic atrophy and blind
ness caused by the drug. In 1972, Japanese victims
began to take legal action against Ciba-Geigy, but it
was not until six years later that the company both
apologised to them, and paid substantial damages.3
The American Medical Association states:
“Clioquinol (iodochlorhydroxyquin) and
iodoquinol (diiodohydroxyquin) have been
used in the prophylaxis of travellers’ diarrhea
but proof of their efficacy is lacking.... The
indiscriminate use of such potentially toxic
agents is unjustified.”8
42
2 C .
Hydroxyquinolines
Problem Drugs
The authoritative Martindale guide to medicines
notes, somewhat optimistically, that “most oral
preparations of halogenated hydroxyquinolines
have been withdrawn since the association between
clioquinol and subacute myelo-optic neuropathy
(SMON) was established”.9
All of the companies have been inexcusably slow in
removing these hazardous drugs. Ciba-Geigy, under
pressure since the early 1970s, finally announced in
November 1982 its intention to “phase out” the pro
duction and sale of clioquinol oral preparations over a
three to five year period. The company still maintained
the decision was not related to the drug’s toxicity, but
rather reflected new developments in diarrhoeal dis
ease control. Dr OHe Hansson said the decision came
“15 years too late” and also, once taken, should have
been effective immediately.10 In November 1984 CibaGeigy announced that it would “accelerate” its
original policy and stop rhe supply of the products “by
the end of the first quarter of 1985”.'
Dr Andrew Herxheimer, a senior clinical pharmacol
ogist in the UK, explained that because clioquinol was
such a profitable drug for decades, when it was found
to cause disastrous neurological damage, the com
pany found itself in a dilemma. “Withdrawal of the
drug would have weakened its legal position. This
was probably a major reason for the company s pol
icy of persistent denial of the drug’s hazards and
continued assertion of its value,” said Dr Herxheimer.
He added that the 1982 announcement about a
Table 2C-1
Hydroxyquinolines available in 1988-89 in selected countries
Product Brand Name (Company Name) - ingredients
Products containing clioquinol:
India:
Mexico (1987):
Aldiamycin (Alkem)- clioquinol, streptomycin, phthalylsulphathia
Di-Sulkin (Arlex) - clioquinol, pectin, dimethicone
zole, pectin
Solfurol (Solfran) - clioquinol, furazolidone, kaolin, pectin,
Dysfur Plus (Biological E)- clioquinol, furazolidone, atropine
homatropine methylbromide
Suyodil(Farmacos Cont)-clioquinol, kaolin, pectin
Indonesia:*
Bintaform (Bintang T)
Viotabdina (Carnot) - clioquinol, phthalylsulphathiazole
Yosul (Riger's)-clioquinol, papaverine, charcoal
Diarent (Kenrose) - clioquinol, phthalylsulphathiazole, papaverine,
Yosul sp (Riger's) - clioquinol, kaolin, pectin, homatropine
B vitamins, bismuth carbonate
methylbromide
Diarent sp. (Kenrose)-clioquinol, phthalylsulphathiazole, kaolin,
B vitamins, bismuth carbonate, tanin albuminate
Diastop (Conmed) - clioquinol, phthalylsulphathiazole, kaolin,
Middle East:
Entox (Wyeth)- clioquinol, dihydrostreptomycin, attapulgite
papaverine, B vitamins
Diastop syrup (Conmed) - clioquinol, phthalylsulphathiazole, kaolin,
Thailand:
pectin, B vitamins
Chlorotracin (Chew Bros.) - clioquinol, chloramphenicol,
Enterobiotic (New Interbat) - clioquinol, neomycin, furazolidone,
phthalylsulphathiazole
kaolin, pectin, papaverine
Quinoxthaline (T P Drug Lab) - clioquinol, phthalylsulphathiazole
Enterodiastop (Combiphar) - clioquinol, phthalylsulphathiazole,
Vanotorm (Vana) - clioquinol, neomycin, phthalylsulphathiazole,
papaverine, B vitamins
furazolidone, kaolin, homatropine methylbromide
Enterosept (Soho) - clioquinol
Enteroviosulfa (Kimia Farma) - clioquinol, sulphaguanidine,
papaverine, B vitamins
Himaform Sulfa (Himajaya) - clioquinol, suIphaguanidine,
belladonna, papaverine, B vitamins
Koniform (Konimex) - clioquinol, phthalylsulphathiazole, papaverine,
chlorpheniramine
Libroform (Bin. Toed/oe)- clioquinol, sulphadimidine, belladonna,
chloroquin
Nifural (Pharos Chemie) - clioquinol, nifuroxazide
Sulfa Plus (Nellco)- clioquinol, sulphaguanidine, papaverine,
B vitamins
Viostreptin (Bernofarm)- clioquinol, streptomycin, sulphaguanidine,
kaolin, B vitamins
Viosulfon (Pharos Indon.) - clioquinol, phthalylsulphathiazole,
vitamin K, papaverine, bismuth carbonate
2 C .
Of any use?
Table 2C-1 gives some indication of the large num
ber of hydroxyquinoline products still on the
market in 1988-9 as antidiarrhoeals. More than 60
were found in prescribing guides in Asia, the
Middle East, and Latin America. A survey carried
out in 1990 in 12 Latin American countries Argentina, Bolivia, Brazil, Chile, Colombia, Costa
Rica, Ecuador, Guatemala, Mexico, Peru, Uruguay
and Venezuela - found that 12% of the total of 351
antidiarrhoeal preparations marketed contained
clioquinol or another hydroxyquinoline.13 Most of
the products in both surveys also contain other
ingredients such as phthalylsulpharhiazole, strep
tomycin, neomycin, and sulphaguanidine which
should be avoided in gastrointestinal infection
because they can prolong rather than shorten the
time taken to control diarrhoea.14
Clioquinol and the other hydroxyquinolines are also
sometimes used in skin creams and ointments to treat
various types of skin rashes. Once again, their use is
Table 2C-1
Products containing other hydroxyquinolines:
India:
Stopen (Berman) -di-iodohydroxyquin, phthalylsulphathiazole,
Amidine Plus (Griffon) - di-iodohydroxyquin, oxytetracycline,
kaolin, pectin, homatropine methylbromide
chloroquin
Vioftalyl (Bigaux)-di-iodohydroxyquin, phthalylsulphathiazole, pectin
Chlorambin (AFD) - di-lodohydroxyquin, neomycin, kaolin, pectin,
Vioftalyl suspension (Bigaux) - di-iodohydroxyquin,
belladonna
phthalylsulphathiazole, pectin, scopolia extract
Chlorambin tablet(AfO)-di-iodohydroxyquin, metronidazole
Zetaquin (Kener)-di-iodohydroxyqum, phthalylsulphathiazole,
Sari/(/?affis)-di-iodohydroxyquin, streptomycin, phthalylsulphathi-
homatropine methylbromide
azole, pectin, tanin albuminate
Pakistan:
Indonesia:*
Diarex tablet (Pharmac Apex) - dI-lodohydroxyquin, streptomycin,
Di-iodohydroxyqum (Ethical)
Di-iodohydroxyquin (PVP)
bacitracin, kaolin, pectin, vitamin K
Di-iodohydroxyquin (Sibro)
Diarex suspension (Pharmac Apex) - di-iodohydroxyquin, strepto
Di-iodohydroxyquin (Unexo)
mycin, phthalylsulphathiazole, kaolin, sodium citrate, 8 vitamins
Diodoquin (Searle) - di-iodohydroxyquin
Quixahn (Squibb) - halquinol
Diodoquin suspension (Searle)- di-iodohydroxyqum
Mexico (1987):
Bontal (Farmacos Cont) - di-iodohydroxyquin, phthalylsulphathia
zole, charcoal, homatropine methylbromide
Colfur(Wallace)-di-iodohydroxyquin, colistin, furazolidone,
dicyclomine
Diarim (Rimsa) - di-iodohydroxyquin, furazolidone, pectin,
Thailand:
Cocci/a (Thai Nakorn P.) - di-iodohydroxyquin, neomycin,
phthalylsulphathiazole, furazolidone, kaolin
Dia-Fucm (Greater Phar.) - di-iodohydroxyquin, neomycin,
phthalylsulphathiazole, furazolidone, kaolin
Diolin (Chinta) - di-iodohydroxyquin, furazolidone, kaolin, pectin,
attapulgite, homatropine methylbromide
Dipec (Yauquimia)- di-iodohydroxyquin, furazolidone, kaolin,
atropine
pectin, homatropine methylbromide
sulphathiazole, furazolidone, kaolin
Disento (Nakorn Patana)- di-iodohydroxyquin, neomycin, phthalyl
Entero Diyod (Serra!) - di-lodohydroxyquin
Mediocin (Medical Sup.) - di-iodohydroxyquin,
Entero Diyod Compuesto (Serra!) - di-iodohydroxyquin,
phthalylsulphathiazole, furazolidone
succinylsulphathiazole, papaverine
Enterocarbin (Index) - di-iodohydroxyqum, succinylsulphathiazole,
Neomobin (Osoth) - di-iodohydroxyquin, neomycin,
phthalylsulphathiazole
phthalylsulphathiazole, charcoal, homatropine methylbromide
Sources: Indonesian Index of Medical Specialities (Oct 1988): MIMS India
Oxibeldina tablets (Lagesa) - di-iodohydroxyquin,
phthalylsulphathiazole, belladonna
Oxibeldina suspension (Lagesa) - di-iodohydroxyquin,
phthalylsulphathiazole, homatropine methylbromide
Prometac (Provit) - di-iodohydroxyquin, phthalylsulphathiazole,
homatropine methylbromide
43
Problem Di
phased withdrawal ‘‘may save face but at the cost of
more years of ineffective hazardous medication.
Clioquinol already holds the scandalous record of
delay - 12 years - between the occurrence of a major
drug disaster and its effective prevention. Why then
add another 3 to 5 years? For all manufacturers and
distributors of hydroxyquinolines the message is
clear: stop now.”12
Hydroxyquinolines
(Feb 1988); MIMS Middle East (Dec 1989); Diccionario de Especialidades
Farmaceuticas (Mexico, 1987); Quick Index of Medical Preparations
(Pakistan, 1988-9); Thailand Index of Medical Specialities (Nov 1988)
Notes: *ln October 1991, the government of Indonesia deregistered 94
antidiarrhoeal products, including many which contained hydroxyquinolines
For further information, see: Anon., “Daftar 285 Obat Yang Ditarik Dari
Peredaran" (List of 285 drugs which are withdrawn from circulation). Suara
Pembaruan, 29 Oct 1991.
Hydroxyquinolines
2 C .
Problem Di
doubtful. Clioquinol has been used in the treatment
of the rare childhood skin condition, acrodermatitis
enteropathica. It has been established since 1973 that
treatment with zinc salts is more effective and safer.1'
Recent animal and human studies in the USA show
that clioquinol used in skin creams for rhe treatment
of diaper rash and other skin problems is readily
absorbed into the body. In the animal studies, all
treated dogs lost weight, became lethargic and less
responsive to stimuli and four that were examined
were found to have suffered liver damage. One dog
died after 15 days of treatment and another experi
enced hind limb paralysis. The authors of the study
noted that this paralysis was identical to that reported
in a study of oral administration of clioquinol. The
authors concluded that long-term application of the
drugs to rhe skin, particularly in the treatment of
diaper rash, could lead to liver damage.16
Time to act
Japan has banned all hydroxyquinolines. Some other
governments have also taken action over these drugs.
Clioquinol is banned in Dominican Republic,
Honduras, Nepal, US, Malaysia, Pakistan, Spain,
Zimbabwe; withdrawn in Italy, Norway, the
Netherlands, Sweden; its import into Saudi Arabia is
prohibited, and is subject to restriction in Australia,
Cuba, France, UK, Switzerland and Zambia. All
hydroxyquinoline derivatives are banned in
Bangladesh and have been withdrawn in Cyprus,
Denmark, Italy, Philippines, Turkey, and subject to
restriction in Venezuela.17
clioquinol was replaced with di-iodohydroxyquin.
Company literature put out at the time said it was a
“convenient, easily swallowed tablet for most forms
of diarrhoea”.18 Subsequently, Wyeth again reformu
lated the product, and by 1990 it simply contained
attapulgite, an ineffective adsorbent.
The continuing threat to health caused by the
hydroxyquinolines demands further swift action. In
the words of Drs Hansson and Herxheimer, as long
ago as 1984,
“a worldwide withdrawal of all oral products
containing halogenated hydroxyquinolines
has been overdue for a decade.”1’
More recently, the World Health Organization was
equally hard-hitting about the hydroxyquinolines:
“The side-effects associated with hydroxy
quinolines, while not common, can be severe.
The use of these products in the treatment of
acute diarrhoea and amoebiasis cannot be jus
tified, and there is thus no rationale for their
continued production and sale.”20
[See also the sections on: Antidiarrhoeals,
Antibiotics, Diphenoxylate and Loperamide.]
Recommendations for action
1. An immediate ban of all oral products
containing halogenated hydroxyquinolines.
2. A suspension of all skin creams containing
halogenated hydroxyquinolines unless new
evidence reliably demonstrates that they are
not toxic.
The danger of not banning all the hydroxyquinolines
is evident from the example of what happened in
Pakistan. After a government ban on clioquinol
products in February 1984 forced the withdrawal of
Entox, produced by US-based Wyeth/American
Home Products, the company relaunched the drug in
August 1984 in a “clioquinol-free” formulation. The
Notes and references:
i.
Hansson, 0., Inside Ciba-Geigy, Penang, International Organization of
Consumers Unions, 1989, PP3-6 & 13
2.
3.
4.
5.
Ibid., pp6-io
Ibid., ppi4-4O
Anon., "Round the World”, Lancet, 14 lune 1980, P1293
Claeson, M.E. and Clements, M.L, “Ridding the world of hydroxyquinolines",
British Medical Journal, Vol 299, 26 Aug 1989, PP527-8
6.
7.
Hansson, 0., op cit, P44
Rohde, |. E, "Selective primary health care: strategies for control of disease in
the developing world. XV. Acute diarrhoea", Reviews of Infectious Diseases,
8.
9.
Vol 6, No 6, Nov-Dec 1984, pp84O-54
AMA, Drug Evaluations, Philadelphia, W.B. Saunders Co., (6th edn) 1986, P964
Reynolds, J.EF. (ed.), Martindale: The Extra Pharmacopoeia, London,
10.
The Pharmaceutical Press, (29th edn) 1989, P658
Anon., "Ciba-Geigy to ‘phase-out’ clioquinol”, HAI News, No 8, Dec 1982
11.
12.
Hansson, 0., op cit, P89
Herxheimer, A., “Clioquinol: A slow withdrawal is not good enough”, HAI
News, No 9, Feb 1983
13.
Lanza, 0. and Kerkvliet, E, Ojo con los antidiarreicos: el abuso de
antidiarreicos en Amenca Latina, Montevideo, AIS/IOCU, 1991, PP35’4O
14.
BMA and the Royal Pharmaceutical Society of Great Britain, British National
Formulary, London, BMA and The Pharmaceutical Press, No 21, Mar 1991, P36
Anon., Bad Information Means Bad Medicine, London, Social Audit, 1981
Greenberg, A., et al, Citizen's petition, submitted to the US Food and Drug
Administration, on behalf of the Public Citizen Health Research Group, 24 July
1985
17.
United Nations, Consolidated List of Products Whose Consumption and/or
Sale Have Been Banned, Withdrawn, Severely Restricted or Not Approved by
Governments, 2nd Issue, Doc No ST/ESA/192, New York, 1987, pp29-3o & 75
Anon., “The name of the game”. New Internationalist, Apr 1981, p6
Anon., “Ciba to withdraw clioquinol", Utusan Konsumer, Apr 1983
Anon., "Clioquinol-free reformulated Entox now available”, Pharma News
(Karachi), 15-31 Aug 1984
Anon. "Spain for rational drug use: 111 drugs banned", HAI News, No 14,
15.
16.
Dec 1983
Ahmad, S.R., Bitter Facts About Drugs. Karachi, HAI Pakistan, 1990, PP33-4
Hansson, 0. and Herxheimer, A., "Halogenated hydroxyquinolines: still no
end”, Lancet, 13 Oct 1984, P864
19.
Ibid.
20.
WHO, The rational use of drugs in the management of acute diarrhoea in
children, Geneva, WHO, 1990, P40
18.
Chetley, A. Problem Drugs, Amsterdam,
Health Action International’s
coordinating offices:
Health Action International, 1993
HAI Europe
Jacob van Lennepkade 334T
1053 NJ Amsterdam
The Netherlands
2D. Diphenoxylate
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accion para la Salud
Avda. Palermo 531
Opto. 104
Lima 13
Peru
mowcuous drug991
In February 19S8, the US-based G.D. Searle company invited
Australian doctors who were prescribers of its antidiarrboeal
product, Lomotil (diphenoxylate and atropine), to enter a
prize draw for a nine-day trip for two to the Olympics in
Seoul, South Korea. The prize, which included the flights,
accommodation and tickets to the opening ceremonies and
other events, was valued at Aus $6,000. The president of the
Royal Australian College of General Practitioners, Dr Eric
Fisher, said:
----- WHEN DIARRHEA ------STRIKES
STOP IT FAST
WITH
LOmOTIl
7
(Uphcnoxy'ala hy^OChkXCle Smg Blropmo
0 025mQ>
“Advertisements like this one do not reflect credit on the drug
company or the practitioners. The college cannot support any
advertising which bears no relation to standards of patient
care or which does little to increase the education of the pre
scriber. "
Searle was found to be in breach of the Australian
Pharmaceutical Manufacturers’ Association code of conduct
and was forced to cancel the promotion, after 6,000 doctors
had responded.2
One of the two best-selling antidiarrhoeal drugs in
the world, Lomotil was among the top 200 most pre
scribed drugs in the USA in 1988.3 Lomotil acts as a
constipating agent in a similar manner to opiates,
focusing on the symptom, not the cause of the diar
rhoea.4 Other manufacturers of products containing
diphenoxylate include Janssen (Reasec) and Cilag
(Lyspafen).
In the USA, Lomotil carries a warning that it is “not
an innocuous drug and dosage recommendations
should be strictly adhered to, especially in children.”5
The warning is given because several cases of severe
central nervous system toxicity have been reported
with normal therapeutic doses and because overdose
is common when repeated doses are taken for severe
diarrhoea. Overdosage can result in coma or death.
Even in older children there are problems.
• FAST - Tomohl has a rapid onset ol action, resuming in
early relief of diarrhea" ’
• RELIABLE—Lomobl lias more lhan 25 years ol wendocumcnledcl-mcai experience worldwide
io dcmonslrate tls ellcacy and safely
profile
LOMOTIL*.- so dependable even astronauts have
carried it in space Hights!
REFERENCE:
1. Lullman. F El A). Bril. Jour Ckn Proc Vol 41 No 2 Much 1937
fUL PRESCRIBING INFORMATION IS AVAILABLE UPON RE QUEST
SEARLE
MAMiMAcruitfoer
UNITED LABORATORIES. INC.
MM.-DAl WONO. METRO MANILA
fordo SEA/U.E(mn.S).arc
rwsruweouiEVAno
MANOAlUrONO. METRO MANILA
TEL NO. 7B E9O2.W. 77-49 «
MTO0IJI1
RS >V(R IQPKX 26 rCRIHStRMOWCnuAHN
This advertisement from the Philippines in October 1990
misinterprets data from a scientific study. It also tries to
gain respectability by associating itself with astronauts: “so
dependable even astronauts have carried it in space flights!"
The 1991 edition of The Essential Guide to Prescription
Drugs (Long, J.W., New York, HarperCollins), points out
that the use of Lomotil “is a disqualification for piloting" and
advises pilots of aircraft to consult with a designated
Aviation Medical Examiner.
45
2 0.
Diphenoxylate
Problem Drugs
Diphenoxylate is also a common source of acciden
tal poisoning in toddlers.6 A 1983 report identified
diphenoxylate as "an important cause of accidental
poisoning in children under the age of five [in the
UK], Symptoms of overdosage in children can occur
after as little as one tablet.”7
there is thus no rationale for the production
and sale of liquid and syrup formulations tor
paediatric use.”19
[See also sections on: Antidiarrhoeals, Antibiotics,
Antidiarrhoeals containing antibiotics, Hydroxy
quinolines, and Loperamide.]
As long ago as 1975, the dangers of using Lomotil for
children were clearly recognised. “It can also mask the
signs of dehydration and cause fatal toxic reactions....
Use of this combination [diphenoxylate and atropine]
for treatment of diarrhoea in children is hazardous.”8
The World Health Organization (WHO) notes that
preparations such as diphenoxylate “can be danger
ous, and even fatal, if used incorrectly in infants”.9
In 1981, after public exposure of this problem by the
UK-based public interest group, Social Audit, Searle
agreed to restrict the use of its product worldwide to
children over two years of age.10 In the UK, the prod
uct is not recommended for children under four;11
however, most authoritative opinion agrees that
Lomotil “should not be given to children”.12 For
example, in Australia, parents are told, “Do not give
this preparation to children under 12”.15
An ineffective drug?
As well as being hazardous in children, there are seri
ous doubts about the effectiveness of diphenoxylate.
Lomotil will not relieve the underlying cause of the
diarrhoea.14 For example, diphenoxylate has been
described as “the worst means of treating” infectious
diarrhoea, because it can prolong the length of rime
that toxins from the bacteria remain in the intestinal
tract.15 The toxins destroy the lining of the intestinal
tract, which in turn allows continued loss of fluids
and increased dehydration. Most of the clinical trials
that have been carried out on either adults or children
show little or no signs of the efficacy of diphenoxy
late.16 Nonetheless, Searle uses such poor evidence to
promote its product. For example, in the Philippines
in October 1990, an advertisement for Lomotil
quoted a 1987 study17 as saying “Lomotil has a rapid
onset of action, resulting in early relief of diarrhea”.
The advertisement failed to point out that although
80% of the patients who received diphenoxylate
reported that the drug “helped a lot”, so did 75% of
patients receiving a placebo. The difference between
the two groups was not statistically significant.18 In
other words, Lomotil was really no better than
placebo in dealing with the diarrhoea, making the
headline for the advertisement - “When diarrhea
strikes, stop it fast with Lomotil” - a figment of a
marketing manager’s imagination rather than a scien
tifically valid finding.
After a careful review of the most up-to-date scien
tific evidence, WHO concluded that:
“Diphenoxylate cannot be recommended for
rhe management of diarrhoea in children, and
• Generic name: Diphenoxylate hydrochloride with
atropine sulphate
• Some brand names: Lomotil (Searle); Reasec
(Janssen); Lyspafen (Cilag)
• Indications suggested by authoritative sources:
Symptomatic relief of non- infective acute diarrhoea as
a secondary measure after initiation of rehydration
therapy; non routine use for symptomatic relief of some
chronic diarrhoeas
Essential drug?: Not on WHO's Essential Drug List
Contraindications suggested by authoritative sources:
impaired liver function;20 antibiotic-induced
diarrhoea;21 sensitivity, jaundice, intestinal obstruction,
acute ulcerative colitis;22 acute infectious diarrhoea23
Use in pregnancy: safety in pregnancy has not been
established24
• Breastfeeding: the drug passes into the milk, best to
avoid it25
Infants and children: Do not give this preparation to
children under 12;26 cannot be recommended for the
management of diarrhoea in children27
Elderly: adverse reactions and side effects may be
more frequent and severe28
Warnings: Dosage recommendations should be strictly
adhered to.
Overdosage can cause severe respiratory depression
and coma, possibly leading to permanent brain
damage or death. Use only after rehydration therapy
has been started.29 Prolonged use is not advised, may
be habit forming.30
Adverse reactions. The incidence of adverse reactions
is relatively low,31 but the variety of adverse reactions
reported include: numbness of the limbs, euphoria,
depression, malaise, lethargy, confusion, sedation,
drowsiness, dizziness, restlessness, headache,
anaphylaxis, angioneurotic oedema, urticaria, swelling
e gums, pruritus, toxic megacolon, paralytic ileus,
d^Cnrer ^lVOmiting’ nausea' anorexia’ abdominal
discomfort hyperthermia, tachycardia, urinary
memh'On’
32 -T'
“ml^n
°f the Skin and mucous
megacolon is more likely to occur
y Hl or undernourished patients.33
2D.
Diphenoxylate
47
Probli
Recommendations for action
All products containing diphenoxylate should
be contraindicated in children.
2. All product information and advertising for
products containing diphenoxylate should
contain a warning that:
a) oral rehydration therapy is the first-line
treatment in most diarrhoeas;
b) the product should not be used in acute
diarrhoea;
1.
the product should not be used for pregnant
and lactating women, the elderly, those with
liver dysfunctions or jaundice, that it could be
habit forming and that all dosage recommen
dations should be carefully followed;
d) the product should not be used in the routine
treatment of inflammatory bowel disease.
3. National regulatory authorities may wish to ban
the use of this product as non-essential in the
treatment of diarrhoea.
c)
Notes and references:
l
2.
Physicians' Desk Reference, Oradell, Nj, Medical Economics Company, 44th
edn,1990, P2069
The incident is described in Chetley, A., A Healthy Business? World Health and
the Pharmaceutical Industry, London, Zed Books, 1990, pp6o-i. The
advertisements appeared in Australian Doctor (12 Feb 1988) and Medical
Observer (17 Mar 1988). Reports of the incident appeared in: Totaro, P., ‘Row
as drug firm offers doctors prize’, Daily Telegraph (Australia), 29 Apr 1988;
McDonnell, D., ‘Drug company in offer uproar’, Sun (Australia), 30 Apr 1988,
‘Doctors enticed to prescribe anti-diarrhoea pill’ (press release), Australian
Consumers’ Association, Sydney, Apr 1988; Margo, J., 'Medicine men bewitch
3.
doctors’. Sydney Morning Herald, 14 Jan 1989.
Chilnick, L.D. (ed.), The Pill Book, New York, Bantam Books, (4th edn) 1990,
45.
6.
P946-51
Ibid., P473
Physicians' Desk Reference, op cit at note 1, P2069
WHO, The rational use of drugs in the management of acute diarrhoea in
7.
children, Geneva, WHO, 1990, pi2
Drug and Therapeutics Bulletin, “Prescribing for Acute Diarrhoea", Vol 21,
8.
9.
No 26, 30 Dec 1983
Medical Letter, “Lomotil for diarrhoea in children”, No 25,1975. P104
WHO, The treatment and prevention of acute diarrhoea: Practical guidelines,
Geneva, WHO, (2nd edn) 1989, P4
10.
Medawar, C and Freese, B., Drug Diplomacy, London, Social Audit, 1982
n. ABPI, ABPI Data Sheet Compendium 1988-89, London, Datapharm
Publications, 1988. P577
. .
...
.
,
BMA and the Royal Pharmaceutical Society of Great Britain, British National
Formulary, London, BMA and The Pharmaceutical Press, No 21, March 1991,
12.
Parish, P., Medicines: a guide for everybody, London, Penguin (6th edn,
13.
revised), 1989, pi44
Jackson, D.M. and Soothill, R„ Is the Medicine Making You III?, North Ryde
(Australia), Angus & Robertson. 1989. ppi«-4
14.
15.
Chilnick. L.D., op cit. P473
,,
Lapps, M, When Antibiotics Fail, Berkeley. North Atlantic Books. 1986, piS4
16.
WHO. 1990, op cit, ppB-ll
The advertisement was in the October 1990 edition of the Philippine Index of
Medical Specialities, P25. The study was: Lustman, F., et al, “Diphenocylate
hydrochloride (Lomotil) in the treatment of acute diarrhoea", British Journal of
Clinical Practice, Vol 41, No 2, Mar 1987, P648.
18.
WHO, 1990, op cit, p8
19.
Ibid., P7
20.
Parish, P„ op cit, P144
21.
Henry, J. (ed.), The British Medical Association Guide to Medicines & Drugs,
London, Dorling Kindersley, (2nd edn) 1991, P253
17.
Chilnick, L.D., op cit, P474
Griffith, H.W., Complete Guide to Prescription & Non prescription Drugs,
Los Angeles, The Body Press, (7th edn) 1990, P365
Reynolds, J.E.F. (ed.), Martindale: The Extra Pharmacopoeia, London,
The Pharmaceutical Press, (29th edn) 1989, pio88
Physicians' Desk Reference, op cit, P2069
22.
ABPI, op cit, P577
Griffith, H.W., op cit, P365
Physicians’ Desk Reference, op cit, P2069
23.
Henry, J., op cit, P253
Lappe, M., op cit, P154
Griffith, H.W., op cit, P365
Physicians' Desk Reference, op cit, P2069
24.
ABPI, op cit at, P577
Henry, J„ op cit, P253
25.
Griffith, H.W., op cit, P365
26.
Jackson, D.M. and Soothill, R., Is the Medicine Making You III?, North Ryde
(Australia), Angus & Robertson, 1989, ppi43-4
WHO, 1990, op cit, p7
Griffith, H.W., op cit, P365
Physicians' Desk Reference, op cit, P2069
Griffith, H.W., op cit, P365
Reynolds, J.E.E, op cit, P1087
31.
AMA, Drug Evaluations, Philadelphia, W.B. Saunders Co., (6th edn) 1986, P965
32.
Physicians' Desk Reference, op cit, P2070
Reynolds, J.E.F., op cit, P1087
27.
28.
29.
30.
33.
AMA, op cit, P965
Chetley, A. Problem Drugs, Amsterdam,
Health Action International’s
coordinating offices:
Health Action International, 1993
' '
:
2E. Loperamide
,
AND
\ documentation ; ryt
\
UNIT
.<•.
HAI Europe
Jacob van Lennepkade 334T
1053 NJ Amsterdam
The Netherlands
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accion para la Salud
Avda. Palermo 531
Dpto. 104
Lima 13
Peru
Not for children
In June 1990, executives front the US-based Johnson &
Johnson company gathered tn the chairman's office in New
Jersey to watch a video tape of a documentary made by
Britain's Yorkshire Television. The atmosphere in the office
was one of “shock" and “stunnedsilence”. As Frank Barker,
the corporate vice president for public affairs, said, “ You don’t
see many programmes where you actually see a child die on
camera”.'
Janssen responded quickly. The company asked one
of the doctors, Dr T.I. Bhutta, for further information
about the deaths. A statement was also issued which
said that it would be "premature” to take any action
until all the details were clear; that all prescribing
information for Imodium clearly stated that it should
not be used in children under 12 months of age; and
that the drops were meant to be on prescription only
and used only under medical supervision.6
The shock was ail the more intense because the pro
gramme was about the death of infants in Pakistan
who had been taking Imodium (loperamide) drops as
a treatment for diarrhoea. Imodium, the world’s
leading antidiarrhoeal drug,2 is manufactured by
Janssen, a subsidiary of Johnson & Johnson.
The drug acts on the muscles of the intestine and
slows down movement of the gut contents. However,
in very young infants, loperamide can cause paralysis
of the intestinal muscle. The result, as was the case in
Pakistan, can be death.
This had been observed as long ago as 1980,3 and
standard advice was that loperamide should not be
used to treat children under two years of age. In some
countries, such as the UK, the age limit was four,
while in Australia, loperamide was contraindicated
in children under 12 years of age.4
'
However, paediatric formulations (drops or syrup) of
loperamide continued to be made by Janssen and
other manufacturers. During two months in late 1989,
the paediatric department of a teaching hospital in
Multan, Pakistan recorded 19 cases of infants who
had severe abdominal swelling and intestinal paralysis
as a result of having taken loperamide drops produced
by Janssen. Eighteen of the children were under seven
months of age; the other was two years old. Six of the
children died in hospital, four were taken home seri
ously ill, presumably to die at home, and nine
recovered. Two doctors at the hospital wrote to
Janssen asking for Imodium drops to be withdrawn
from the market. When they received no response,
they wrote to The Lancet in February 1990, in the
hopes that such action would persuade “the manufac
turers to withdraw Imodium from Pakistan before it
kills any more children”?
• Generic name; loperamide hydrochloride
• Some brand names: Imodium, Arret, Imosec
(Janssen); Loperium (Remedica); Vacontil
(Medochemie); Lopemid (Gentili)
• Indications from authoritative sources: symptomatic
relief of non-infective acute diarrhoea as a secondary
measure after initiation of rehydration therapy; non
routine use for symptomatic relief of some chronic
diarrhoeas
• Essential drug?: Not on WHO’s Essential Drug List
• Contraindications from authoritative sources: routine
use in ulcerative colitis and Crohn’s disease;7 known
hypersensitivity;8 prolonged use;9 travellers’
diarrhoea;10 bacterial or parasitic infection of the bowel
wall when significant fever or dysentery is present;11
diarrhoea caused by antibiotic treatment12
• Use in pregnancy: safety in pregnancy not established13
• Breastfeeding: should be avoided by breastfeeding
women14
• Use in children: not recommended for acute
diarrhoeas in young children;15 not recommended for
children under 12 years of age16
• Elderly: use with caution17
• Special precautions: use with caution where
constipation should be avoided and in liver disorders;18
discontinue use in acute diarrhoea if no clinical
improvement is observed after 48 hours19
• Adverse reactions: generally rare: abdominal cramps,20
rash,21 toxic megacolon,22 intestinal obstruction,23
perforation of bowel wall in acute infective diarrhoea24
49
50
2 E .
Loperamide
Problem Drugs
By March of 1990, the situation in Pakistan was con
fused. Janssen said that it “voluntarily withdrew”
Imodium drops from the market in Pakistan,35 and
worldwide;26 the Pakistan Federal Ministry' of Health
claimed that it had banned Imodium drops and
deregistered all other paediatric preparations con
taining loperamide;27 Dr Bhutta wrote again to
Janssen telling the company of more children arriving
at the hospital with Imodium poisoning and calling
for action.28 In May, the film crew from Yorkshire
Television was able to find Imodium drops on sale in
six out of 10 pharmacies visited.29
there was “no rationale for the production and sale
of liquid or syrup formulations for paediatric use”.
As with many other antidiarrhoeal products on the
market, the use of loperamide detracts attention
from appropriate management, which includes rehy
dration and feeding of the patient.
[See also sections on: Antidiarrhoeals, Antibiotics,
Antidiarrhoeals containing antibiotics, Hydroxyquinohnes and Diphenoxylate.}
Recommendations for action
By the end of June 1990, Robert Gussin, Johnson &
Johnson’s corporate vice president for science and
technology, said in a letter to The Lancet that the
company was doing its “utmost” to withdraw rhe
oral drops formulation from Pakistan. He added,
“We have also withdrawn the drops in other devel
oping countries and have halted sale worldwide. We
are also voluntarily withdrawing Imodium syrup in
countries where the World Health Organization has
a programme for control of diarrhoeal disease.”’0
All products containing loperamide should be
contraindicated in children. All paediatric formu
lations (syrups, drops, etc.) should be banned.
2. All product information and advertising for
products containing loperamide should contain
a warning that:
a) oral rehydration therapy is the first-line
treatment in most diarrhoeas;
b) the product should be avoided in acute
diarrhoea;
c) the product should be avoided in pregnant
and lactating women, in the elderly, in those
with liver dysfunctions and in patients for
whom constipation should be avoided;
d) the product should not be used as routine
treatment in inflammatory bowel disease.
3. National regulatory authorities may wish to ban
the use of this product as non-essential in the
treatment of diarrhoea. At the very least, the
production or sale of liquid or syrup formulations
for paediatric use should be banned.
1.
Robert Gussin concluded the letter by saying that
“the safety and efficacy of Imodium used properly is
not at issue”. His enthusiasm for the drug is not
shared by independent experts around the world.
Loperamide is “not generally recommended” for the
treatment of acute infectious diarrhoea “because it
may delay the expulsion of harmful substances from
the bowel”.31 A careful review by the WHO found
little evidence of usefulness of the drug in the treat
ment of acute diarrhoea in children.32 Coupled with
possible adverse effects which “may be severe when
therapy is poorly supervised”, this led the WHO to
conclude that “loperamide has no place in the rou
tine management of diarrhoea in children” and that
Notes and references:
1.
Scanlon, C, “Unsafe drugs find buyers abroad", Detroit Free Press, 20 May
1991, p4a
In Kenya in 1989, for example, Imodium was reported as being prescribed for
40% of children with diarrhoea (see: Anon., "Misuse of antidiarrhoeal
medicines", Lancet, 21 Oct 1989, P995; Anon., "Antidiarrhoeals again under
attack". Scrip, 1457, 20 Oct 1989, P29). In the UK, Janssen's two brands of
loperamide, Imodium and Arret, account for half the antidiarrhoeal market
(see: Anon., “Janssen's ORT product, Rapolyte, introduced in UK", Scrip, 1606,
10 Apr 1991, P24).
3.
See data cited in: WHO, The rational use of drugs in the management of
acute diarrhoea in children. Geneva, WHO, 1990, P19
4.
Dukes, M.N.G. and Lunde, I., “Review of restrictive actions under the
Australian drug regulatory system”, Medical Journal of Australia, 1,1982,
PP412-16 (cited in letter from MaLAM to Janssen, July 1990)
5.
Bhutta, T.l. and Tahir, K.I., “Loperamide poisoning in children", Lancet, 10 Feb
2.
1990, P363
6.
Anon., “Janssen on loperamide ADRs", Scrip, 1491, 23 Feb 1990, P29
7,
AMA, Drug Evaluations, Philadelphia, W.B. Saunders Co.. (6th edn) 1986,
P965
8.
Physicians’ Desk Reference. Oradell, NJ, Medical Economics Company, 44th
9.
10.
edn,1990, P1083
AMA, op cit, P963
Po, A.LW., Non-Prescription Drugs, Oxford, Blackwell Scientific, (2nd edn)
1990, P217
Chilnick, LD. (ed.), The Pill Book, New York, Bantam Books, (4th edn) 1990, p476
11.
12.
AMA, op cit, P966
Griffith, H.W., Complete Guide to Prescription & Non-Prescription Drugs, Los
13.
Angeles, The Body Press, (7th edn) 1990, P573
Henry, J. (ed.). The British Medical Association Guide to Medicines & Drugs,
London, Doriing Kindersley, (2nd edn) 1991, P303
14.
15.
Black, G.J. (ed.), Physician's 1990 Drug Handbook, Springhouse, PA,
Springhouse Corporation, 1990, P575
BMA and the Royal Pharmaceutical Society of Great Britain, British National
Formulary, London, BMA and The Pharmaceutical Press, No 22, Sep 1991,
P37
Chilnick, L.D., op cit, P477
The Australian Drug Evaluation Committee also contraindicates loperamide for
children under 12 years of age. See: Dukes, M.N.G. and Lunde, I., op cit at note 4.
17.
Henry,)., op cit, P303
18.
AMA, op cit, P966
19.
Physicians' Desk Reference, op cit, P1083
20.
Gilman, A.G., Rail, T.W., Nies, A.S., and Taylor, P., Goodman and Gilman's The
Pharmacological Basis of Therapeutics, New York, Pergamon Press, (8th edn)
16.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
1990, P508
BMA, op cit, P37
Reynolds, J.E.F. (ed.), Martindale; The Extra Pharmacopoeia, London,
The Pharmaceutical Press, (29th edn) 1989, P1094
Po, A.L.W., op cit, P32
AMA, op cit
Advertisement: “Clarification: Imodium Drops", Dawn (newspaper in Karachi),
9 Jun 1990
Anon., “Janssen acts on Imodium in Pakistan", Scrip, 1525, 22 Jun 1990, pro
Anon., “Health Ministry's notice", Dawn, 13 Jun 1990
Bhutta, T.I., “Anti-motility drugs for infants", Lancet, 4 Aug 1990, P314
Anon., “Loperamide poisoning in children", Lancet, 9 Jun 1990, P1394
Gussin, R.Z., "Withdrawal of loperamide drops", Lancet, 30 Jun 1990, ppi6o3-4
Henry, J., op cit, P303
WHO, 1990. op cit, p20
Chetley, A. Problem Drugs, Amsterdam,
Health Action International, 1993
Health Action International’s
coordinating offices;
O
)
(
3A. Antibiotics
UN”
*
A NGALO^j^
HAI Europe
Jacob van Lennepkade 334T
1053 NJ Amsterdam
The Netherlands
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accion para la Salud
Avda. Palermo 531
Dpto. 104
Lima 13
Peru
Th® artsbtotic crfefe
In September 19S9, more than 500 cases of typhoid were
reported from Shrirampur in Maharashtra, India. In 83 % of
the cases, the bacteria causing the typhoid were resistant to
chloramphenicol, the life-saving drug that has been the
mainstay in the treatment of typhoid in India. Almost half
the patients were children. Twelve deaths were reported,
three of these were children. At the national conference of
the Indian Academy of Paediatrics in June 1990, similar
reports from all over the country were heard. Also heard was
the reminder that, for many years, pharmaceutical compa
nies in India had been promoting chloramphenicol and
streptomycin combination products for the treatment of
acute diarrhoea. The resistance to chloramphenicol that
developed as a result of this inappropriate use of the drug
was claimed to be responsible for the typhoid deaths.1
When antibiotics were first developed, they were
seen as “magic bullets” that would radically change
the treatment of infectious disease. Now, however,
experts are worried that the golden age of antibiotics
is over.
“We may look back at the antibiotic era as
just a passing phase in the history of medi
cine, an era in which a great natural resource
was squandered and where the bugs proved
smarter than the scientist.”2
“It is not clear how long our currently avail
able agents will be useful.... in select settings
(particularly hospitals) we are left with few,
if any, alternatives.”3
“The continual introduction of new antimi
crobial agents, many of which are no more
than minor chemical modifications, has
generated confusion amongst prescribers.”4
A key reason for the baffling array of so many antibi
otics is described by one professor of medicine and
pharmacology as “the rapid development of bac
terial resistance to every compound that has reached
general use”.5
Antibiotic resistance
According to an international task force studying
antibiotic resistance, although antibiotics have saved
and improved more lives than any other class of med
icines, their use “has set in motion the biggest
intervention in population genetics seen to date on this
planet. The effects of that intervention arc seen in the
distributions of antibiotic-resistance genes throughout
the world’s bacterial populations.”6 This change,
although invisible to the naked eye, has had as pro
found an effect on human health as the antibiotics
How antibiotics work
Antibiotics are usually described as being either
bactericidal (they kill bacteria) or bacteriostatic (they
slow the growth of bacteria to allow the immune system
to destroy the bacteria). For example, the beta-lactam
antibiotics are bactericidal because they inhibit the
synthesis of bacterial cell walls. Without the cell wall, the
bacteria die. Other antibiotics interfere with the chemical
processes within the cell, which in turn leads to the
death of the bacteria.
The newest type of antibiotics, the quinolones, causes
the DNA of the bacteria to uncoil by interfering with an
enzyme within the bacteria which ensures that the long
■strands of DNA can fit inside a small bacterial cell. The
result is that the bacteria cannot divide or produce the
enzymes they need to carry out normal activities, and
they subsequently die.
52
3 A .
Antibiotics
Problem Drugs
themselves.7 One researcher notes that “resistance to
antimicrobial agents has become a global problem
with a major impact on health care in developed and
developing countries"?
Some bacteria are naturally resistant to certain
antibiotics, but often resistance is acquired. Bacteria
become resistant by incorporating a “resistance fac
tor” into their genes to render the antibiotic
ineffective. This can pass quickly to other bacteria,
carried on small pieces of genetic material called
plasmids. The resistant genes can also sometimes be
packaged in DNA units called transposons that
allow them to jump from one DNA site to another.
Multiple resistance, where bacteria are resistant to
several antibiotics, can also be transferred from one
species to another.’ The mechanisms of resistance
may include: changes occurring within the cell of the
bacteria to affect the receptivity to the antibiotic;
changes to the cell wall which make it more difficult
for the antibiotic to attack; improvement in speed
with which the antibiotic is absorbed into or dis
charged from the cell, thus limiting the time the
antibiotic has to work and its effective concentration
within the cell; or the production of an enzyme which
renders the antibiotic ineffective.10 Although initially
encountered only in urban hospitals, resistant bacte
ria are now being detected everywhere. They can
spread between neighbouring and even distant
countries; micro-organisms do nor recognise fron
tiers. “One’s bacteria arc not solely one’s own.
Rather, they are shed, excreted, and otherwise spread
into the environment, where they become part of a
common pool.”11 This rapid spread means that
increasing numbers of people no longer respond to
antibiotics that were previously effective.
Increased use of any antibiotic “inevitably” results in
an increase in resistant bacteria.12 For example, the
likelihood of finding strains of ampicillin-resistant
Haemophilus influenzae increases in children who
previously have received antibiotics.13 However,
resistance to an antibiotic can and does exist in
people without prior exposure to the antibiotic in
question.H
A study by the World Health Organization’s (WHO)
Programme for Appropriate Health Care Techno
logy (ATH) has shown a correlation between the
occurrence of multiresistant bacteria and antibiotic
consumption patterns. The study collected data on
resistance rates, national consumption, and the dis
tribution of aminoglycoside consumption between
hospital and non-hospital outlets in 12 countries. A
second study has been commissioned to look at the
use of antibiotics in the treatment of tonsillitis, which
WHO/ATH claims is inappropriate in at least 50%
of all cases. The original study concluded: “the
increased frequency and spread of resistant bacterial
strains is a consequence of the inappropriate use of
antibiotics in outpatient as well as inpatient care.
Major classes of antibiotics
Penicillins
includes drugs such as: amoxycillin, ampicillin,
ampicillin with sulbactam, benzylpenicillin, cloxacillm,
co amoxiclav (amoxycillin with clavulanic acid),
flucioxacillin, methicillin, oxacillin,
phenoxymethylpenicillm
Cephalosporins
cefaclor, cefadroxil, cefixime, cefoperazone,
cefotaxime, cefoxitin, cefpirome, cefsulodin,
ceftazidime, ceftizoxime, ceftriaxone, cefuroxime,
cephalexin, cephalothin, cephamandole, cephazolin,
cephradine
The penicillins and cephalosporins - together with
monobactam and carbapenem antibiotics - are
collectively known as beta lactam antibiotics. Other
beta-lactam antibiotics include: aztreonam, imipenem
(which is usually administered in combination with
cilastatin)
Aminoglycosides
amikacin, gentamicin, kanamycin, neomycin,
netilmicin, streptomycin, tobramycin
Macrolides
azithromycin, clarithromycin, erythromycin,
josamycm, roxithromycin
Lincosamides
clindamycin, lincomycin
Tetracyclines
doxycycline, minocycline, oxytetracycline, tetracycline
Quinolones
nalidixic acid, ciprofloxacin, enoxacin, fleroxacin,
norfloxacin, ofloxacin, pefloxacin, temafloxacin
(withdrawn in 1992)
Others
chloramphenicol, co-trimoxazole (trimethoprim and
sulfamethoxazole), mupirocin, teicoplanin,
vancomycin
Note: Technically, antibiotics are only those substances produced by
microbes. Thus, antibacterials or antimicrobials such as the
sulphonamides, the quinolones, and trimethoprim are not strictly
antibiotics. However, they are included in the discussion in this
section.
3 A .
Most bacteria consist of single cells, each with a
protective wall. They are classified and identified
according to the properties of their cell walls. This is
usually indicated by a staining process developed by
H.C.J. Gram in 1884. Gram positive bacteria are those
which readily absorb the initial dye. while gram
negative bacteria are those which do not.
Resistance costs lives and money
The inability to treat infections with the usual antibi
otic of choice (or any other drug) can be disastrous.
Gonorrhoea, dysentery, pneumonia, meningitis, and
deadly hospital infections have all been taking their
toll.
Gonorrhoea is now established as a leading world
wide public health problem. Within developing
countries, gonorrhoea caused by resistant strains of
Neisseria gonorrhoeae has become hyperendemic.19
In industrialised countries too, resistant strains are
on the increase.20
Resistance to commonly used antibiotics for the
treatment of dysentery has become more prevalent.
Generally, the majority of Shigella isolates found in
different countries are now resistant to tetracycline
and sulphonamides. Increasing resistance to both
ampicillin and co-trimoxazole has been reported in
Asia, Africa and North America and some resistance
to nalidixic acid has been reported. In communities
where nalidixic acid is commonly used, widespread
resistance is expected to develop quickly.21
Resistance of Haemophilus influenzae to common
antibiotics is particularly worrying for children’s
health. Infections caused by H. influenzae type b
(Hib) represent more than 90% of invasive diseases
in young children. These include meningitis and
Bacteria can also be classified according to their
shape. Cocci are round, bacilli are rod-shaped and
spirochaetes are coiled. If the cocci are arranged in a
straight line, they are called streptococci; if they are
found in clumps, they are called staphylococci.
Diplococci occur in pairs.
|
Another classification divides bacteria into those
which require free oxygen in the air, aerobes, and
those which do not, anaerobes. Anaerobic and aerobic
bacteria play a common role in many infections. Both
anaerobes and aerobes can be either gram-positive or
gram-negative. Anaerobes are particularly to be found
in the head and neck, the upper respiratory tract, the
lower gastrointestinal tract, the genital tract and
occasionally in skin and soft tissue. Their role in
infections is not always recognised, in part because of
the difficulty in confirming a diagnosis, due to the
need to collect and transport samples in an "air-free''
container to avoid contamination with aerobic
bacteria. Several of the very "broad spectrum"
antibiotics introduced in recent years have very poor
activity against anaerobic pathogens, an important
consideration when such agents are proposed as
monotherapy for mixed infections.
Some bacteria, particularly those that live in the
human gut, are essential for human life. For example,
some of them synthesise vitamins. Indiscriminate use
of broad-spectrum antibiotics may destroy these
useful bacteria.
Sources: Styrt. B. and Grobach. S L . "Recent developments in the
understanding of the pathogenesis and treatment of anaerobic
infections", parts one and two, New England Journal of Medicine,
Vol 321. No 4. 27 Jul 1989. pp240 6 and Vol 321. No 5. 3 Aug 1989.
PP298-3O2
,
53
Problem Di
Types of bacteria
A possible reason for the dramatic increase in
Streptococcus pneumoniae strains resistant to peni
cillin in Hungary over a 15-year period from 1975 to
1989 was “the uncontrolled, injudicious, and
frequent administration of penicillin and its deriva
tives.” Researchers who were studying this
phenomenon called for an antibiotic policy that lim
ited the use of antimicrobials as one of the more
effective ways to prevent the further spread of resis
tant strains.16
A meeting of a WHO working group in the Western
Pacific region found that bacterial resistance was a
problem in Australia, Brunei, China, Hong Kong,
Japan, Malaysia, New Zealand, Papua New Guinea,
the Philippines, South Korea, Singapore and
Vietnam. It has called for an information network in
the region to monitor the situation.18
I
.
Therefore, a concentrated and determined action for
the establishment of national and global policies on
the appropriate utilisation of antibiotics is urgently
needed.”15
Researchers examining the problems of resistance
among 5. pneumoniae strains in Spain concluded
that two essential measures seemed necessary to
improve the situation: “exhaustive surveillance of
resistance and strict control of antibiotic use”.17
Antibiotics
lem Di
pneumonia.22 In most developing countries, bacterial
meningitis is associated with a high fatality rate - up
to 70% of cases in some settings.21
Table 3A-1
Examples of reports of antibiotic resistance
Antibiotic
Staphylococcus aureus is a particular menace in hos
pitals, where it can infect and kill surgical patients
who have had skin grafts or organ tranplants, and can
also cause pneumonia, meningitis, and septicaemia,
as well as less serious infections such as boils and
abcesses. This organism has been described as “one of
the most versatile of human pathogens”24 because it
can acquire resistance to virtually all available antibi
otics. One study of 106 strains of methicillin-resistant
5. aureus (MRSA) from 21 countries found that more
than 90% were also resistant to gentamicin,
tobramycin, netilmicin, amikacin, streptomycin, and
erythromycin.
Resistance
to
the
quinolone,
ciprofloxacin, was found in 17%. This was described
as “disconcerting”, because of the antibiotic’s novel
structure and its recent entry into clinical use.25
Bacteria
%of
Year of
Location
resistance
study
of study
amikacin
Ps. aeruginosa
12
1990
Italy20
aminoglycosides
Ps. aeruginosa
0.5
n.a.
Sweden2
aminoglycosides
Ps. aeruginosa
60
n.a.
France2
amoxicillin
E. coli
60
19857
Hong Kong22
amoxicillin
H. influenzae
24
1987-9
Atlanta, USA13
ampicillin
H. influenzae
12-18
n.a.
UK9
ampicillin
H. influenzae
20-40
n.a.
USA10
ampicillin
H. influenzae
24
1987 9
Atlanta, USA13
ampicillin
H. influenzae
31
1990
Spain15
ampicillin
H. influenzae
1227
1990
Belgium15
ampicillin
H. influenzae
11 -13
1990
France15
ampicillin
H. influenzae
6
1990
Switzerland15
ampicillin
Shigella
96
1987
Sudan6
ampicillin
Shigella
43
1988
Turkey7
ampicillin
Shigella
33 100
1988
Nigeria21
ampicillin
E. coli
60
1985-7
Hong Kong22
chloramphenicol
Shigella
72
1987
Sudan6
chloramphenicol
Shigella
37
1988
Turkey7
chloramphenicol
Shigella
25-100
1988
Nigeria21
chloramphenicol
S. pneumoniae
39
1986-9
Pakistan8
chloramphenicol
typhoid
83
1989
India1
ciprofloxacin
S. aureus
91
1990
Atlanta, USA12
co-amoxiclav
E. coli
20
1985-7
Hong Kong22
co-trimoxazole
H. influenzae
12
1987 9
Boston, USA17
co-trimoxazole
Shigella
53
1988
Turkey7
co trimoxazole
Shigella
50 100
1988
Nigeria21
co-trimoxazole
S. pneumoniae
31
1986-9
Pakistan8
co-trimoxazole
E. coli
32-35
19834
Finland23
erythromycin
enterococci
90
1990
Boston, USA24
gentamicin
enterococci
13-55
1990
USA16
gentamicin
Ps. aeruginosa
31
1990
Italy20
nalidixic acid
Shigella
23
1988
Turkey7
nalidixic acid
Shigella
85
1987
Bangladesh19
netilmicin
Ps. aeruginosa
13
1990
Italy20
pefloxacin
S. aureus
6
1985
France11
Use and misuse
in industrialised countries
penicillin
N. gonorrhoeae
14
1988
Holland5
penicillin
N. gonorrhoeae
20
1986
Amsterdam5
penicillin
N. gonorrhoeae
20-30
n.a.
New York, USA4
The use of antibiotics is widespread in industrialised
countries. In Sweden, antibiotic prescribing increased
by 12% between 1987 and 1988.20 In the UK, one in
every six prescriptions is for antibiotics.21 In
Australia, antibiotics accounted for 17-20% of all
drugs prescribed,22 and in 1986, amoxycillin was the
most widely prescribed of all drugs.22 In 1988, the
most often prescribed drug in the USA was a brand of
amoxycillin, Amoxil, produced by Beecham.24 In the
USA in 1986, about 35% of the 57.8 million pre
scriptions for children under the age of three were for
anti-infective agents.25
penicillin
N. gonorrhoeae
17
1989
USA14
penicillin
S. pneumoniae
40
1988
Spain18
N. gonorrhoeae
30 40
n.a.
Asia3
One expert notes that bacterial resistance to antibi
otics is “a major obstacle to the treatment of
infectious diseases, leading not only to treatment fail
ures but also to increased costs.”26 The cost of
antibiotic resistance in rhe USA has been estimated at
more than Si00 million a year.2' There is another
cost as well: the human one. Infections caused by
resistant bacteria are more likely to cause prolonged
illness, frequent and prolonged hospitalisation and a
higher death rate.28
The pharmaceutical industry can hardly claim that it
is unaware of the problem of resistance. In 1988
alone, Scrip, a journal which reports on develop
ments in the pharmaceutical industry, published
eight articles about antibiotic resistance.29 Most arti
cles in medical journals about antibiotics at least
mention the question of resistance. Table 3A-1 sum
marises some of the findings.
Much evidence indicates that antimicrobials are often
misused.36 The Health and Public Policy Committee
of the American College of Physicians says that
penicillins &
cephalosporins
penicillins &
cephalosporins
N. gonorrhoeae
25-50
n.a.
Africa3
streptomycin
Shigella
80
1988
Turkey7
streptomycin
Shigella
84
1987
Sudan6
streptomycin
Shigella
50-100
1988
Nigeria21
sulphonamides
Shigella
90
1987
Sudan6
tetracycline
N. gonorrhoeae
17
1989
USA14
tetracycline
Shigella
92
1987
Sudan6
tetracycline
Shigella
40
1988
Turkey7
tobramycin
Ps. aeruginosa
11
1990
Italy20
trimethoprim
Shigella
77
1987
Sudan6
trimethoprim
E. coli
34-40
1983-4
Finland23
3 A .
Sources:
1.
Anon., "Who is responsible for these unnecessary typhoid
deaths7', ACASH News. Dec 1990. pl
2 Anon., WHO/ATH on the misuse of antibiotics'. Scrip. 1272/3,
8/13 Jan 1988, p26; O'Neill. P. and McIntosh. S . Bacteria resistant
to antibiotics spread concern'. New Scientist. 27 Aug 1987, pl 6
3. O'Brien, T.F., et al. "Resistance of bacteria to antibacterial agents
report of Task Force 2", Reviews of Infectious Diseases, Vol 9
(Suppl 3), May Jun 1987, ppS244 60
4 Neu, H.C., "Antimicrobial agents: the old and the new". American
Journal of Infection Control. Vol 17, No 5. Oct 1989, pp276 85
5 van Klingeren, B . Dessens-Kroon, M.. Verheuvel. M., "Increased
tetracycline resistance in gonococci in The Netherlands", Lancet.
25 Nov 1989. pl278
6.
Shears. P.. "The Khartoum floods and diarrhoeal diseases".
Lancet. 27 Aug 1988, p517
7.
Ceyhan, M.. Dilmen, U.. Korlen. V . et al. “Shigella diarrhoea and
treatment", Lancet, 2 July 1988, pp45-6
8.
Mastro, T.D.. Ghafoor, A., et al, "Antimicrobial resistance of
pneumococci in children with acute lower respiratory tract infection
m Pakistan ", Lancet, 19 Jan 1991, Vol 337. No 8734, ppl56-9
9.
Chapman, S.T. and Walsh, T H , “Which Antibiotic for Surgical
Nosocomial Infection?" British Journal of Clinical Practice, Vol 45, No 2,
Summer 1991. ppl41-4
10.
Vallejo, J G., Kaplan. S L and Mason. E.O., “Treatment of
meningitis and other infections due to ampicillin resistant
Haemophilus influenzae type b in children". Reviews of Infectious
Diseases. Vol 13, Mar Apr 1991. pp!97 200
11 Aboukasm, A.G . Buu-Hoi, A.Y . et al, “Epidemiological study of
Staphylococcus aureus resistance to new quinolones in a university
hospital', Journal of Hospital Infection, Vol 17, 1991, pp25-33
12. Blumberg. H.M . Carroll. D.J and Wachsmuth, I.K., ‘Rapid
development of ciprofloxacin resistance in methicillin susceptible
and resistant Staphylococcus aureus". Journal of Infectious Diseases.
Vol 163. Jun 1991, pp!279-85
13. Jacobs Jr., N.F and Jems, R.C.. "Haemophilus influenzae
resistance in a community hospital". Southern Medical Journal,
Vol 84, No 6. Jun 1991, pp730-2
14
Handsfield, H H , McCormack, W M , et al. ' A comparison of
single dose cefixime with ceftriaxone as treatment for uncomplicated
gonorrhea", New England Journal of Medicine. Vol 325. No 19. 7 Nov
1991. ppl337-41
15
Cullmann, W and Then. R.L., “Cefetamet: its in vitro activity and
interaction with beta lactamases and penicillin-binding proteins".
Drug Investigation. Vol 3. No 5. 1991. pp299-307
16
Boulanger, J.M . Ford Jones, E.L. and Matlow, A.G.,
“Enterococcal bacteremia in a pediatric institution: a four year
review", Reviews of Infectious Diseases, Vol 13. Sep Oct 1991,
pp847 56
17. Pelton. S.I., Teele, D.W . et al. ‘Trimethoprim/sulfamethoxazoleresistant nontypable Haemophilus influenzae". Pediatric Infectious
Disease Journal. Vol 10. No 11, Nov 1991. pp873 4
18 Munoz. R . Coffey, T.J., et al, "Intercontinental spread of a
multiresistant clone of serotype 23F Streptococcus pneumoniae",
Journal of Infectious Disease. Vol 164. Aug 1991. pp302-6
19.
Munshi. M.H . Haider. K., et al. “Plasmid-mediated resistance to
nalidixic acid in Shigella dysenteriae type 1". Lancet. 22 Aug 1987,
pp419 21
20.
Toscano, M.A . Minneci. M.. et al. “New epidemiological data on
resistance to netilmicin and other aminoglycosides". Journal of
Chemotherapy. Vol 3. No 6, 1991. pp352-6
21.
Eko. F.O. and Utsalo, S J.. “Antimicrobial resistance trends of
shigellae isolates from Calabar. Nigeria", Journal of Tropical Medicine
and Hygiene. Vol 94. 1991, pp407 10
22 French. G. and Ling. T.. “Amoxycillm/clavulanic acid resistant
Escherichia coir, Lancet. 26 Mar 1988, p704
23. Huovinen. P„ Pulkkinen, L., et al, "Emergence of trimethoprim
resistance in relation to drug consumption in a Finnish hospital from
1971 through 1984 ", Antimicrobial Agents and Chemotherapy. Vol 29.
No 1. Jan 1986. pp73 6
24. Moellenng, R.C., “Introduction: Revolutionary changes <n the
macrolide and azalide antibiotics", American Journal of Medicine.
Vol 91 (Suppl. 3A). 12 Sep 1991, p3A 2S
perhaps as many as 64% of antibiotic prescriptions in
hospitals are unnecessary or include inappropriate
dosages.37 Overall, the result of several studies con
ducted in the USA suggests that 40 to 60% of all
antibiotics are misprescribed.38 Antibiotics are often
wrongly prescribed for minor infections39 or to treat
rhe common cold,40 which is caused by a virus. A sur
vey of physicians in the USA showed that 60%
prescribed antibiotics for treating colds.41 In the UK,
about one-third of all hospital patients receive at least
one antibiotic, and in about half these cases, the
antibiotic is inappropriately prescribed.42 A Cana
dian study found that at least one-third and perhaps
as much as one half of antibiotics were inappropri
ately prescribed in hospitals.43 The vast sales of
antibiotics in Italy in 1989 (S1.2 billion) prompted
the Italian Health Ministry to comment that this
enormous consumption “unfortunately confirms the
indiscriminate and often unjustified use of antibiotic
therapy for the treatment of frequently benign infec
tions”.44 In Australia, more than Aus $3 million a
year could be saved if doctors prescribed according to
peer-consensus recommendations for the treatment of
tonsillitis and urinary tract infection. Microbiologist
Dr Ken Harvey says, “the current situation would
appear to be the result of leaving continuing educa
tion concerning therapeutics primarily in the hands of
the pharmaceutical industry”.45
Inappropriate use of restricted antibiotics was found
in 22 out of 73 cases surveyed in a recent study in
New Zealand, representing an excess cost of
NZ $3,282 (US $2,202). The most common fault was
prescribing antibiotics as prophylaxis for too long a
period. Other studies have shown that 31 to 66% of
antibiotics are used inappropriately. According to
Professor John Smith of Otago University, antibiotic
prescribing guidelines should be introduced to help
doctors cope with “the continuing avalanche” of new
and more expensive antibiotics.46
In the USA, “the need for limiting the number of
antibiotics that a physician will use in routine prac
tice” is evident from the list of 92 antibacterial drugs
in the 1990 edition of the Physician’s Desk
Reference.4 The WHO Essential Drugs List contains
16 antibiotics.48
The misuse of antibiotics also increases the dangers
of side effects. These may be specific (for example,
chloramphenicol can damage the bone marrow;
neomycin may damage the kidneys), or due to hyper
sensitivity or allergic reactions. Furthermore, a
disturbance in the balance of the body’s micro
organisms by antibiotics can lead to superinfections
or overgrowth of yeasts, fungi and bacteria. These
are usually minor but may become serious or even
fatal. They are difficult to treat and are more likely to
occur with broad-spectrum antibiotics (those effec
tive against a wide variety of bacteria), in children
under three years of age, or in the elderly.49 Most
55
Problem Di
Table 3A-1
Antibiotics
3 A ..
Antibiotics
Problem Di
classes of antibiotics may have some negative effect
on male fertility.50
In the USA, a 1988 study found that 2% of 6,546
paediatric admissions to general or specialty paedi
atric wards (excluding neonates and children with
cancer) were prompted by adverse drug reactions.
The eight drugs most commonly implicated included
three antibiotics: ampicillin, amoxycillin and corrimoxazole. A 1985 study found that the main
antibiotic-related adverse reactions among 4.244
courses of paediatric outpatient drug therapy were
gastrointestinal complaints and rashes. The study
also noted that 64% of paediatric outpatient pre
scriptions were for antibiotics.51
Table 3A-2
Antibiotics as a percentage of the total
pharmaceutical market in selected countries
Country/Region
Year
Sales of
Total sales of
antibiotics as
antibiotics
% of total market
USS million
Iran
1990
31
Middle East
1989
29
71
Indonesia
1989
25
100
Philippines
1989
23
98.9
Mexico
1990
15
300
Argentina
1990
12
177.5
Sources: Iran Scrtp. 1550, 19 Sep 1990, p21, Middle East (refers to seven
Misuse in developing countries
The threat of infection in the Third World through
poverty, malnutrition, poor sanitation and poor
housing conditions means that antibiotics have a
potentially important role to play in improving health
care. In underdeveloped countries, a large proportion
of the drug budget is spent on antibiotics and antiparasitic drugs. Frequently, more money is spent on
antibiotics than on any other class of drugs.52
However, as in industrialised countries, antibiotics
arc only effective if they are properly used. The
reality is very different. “Most use of antibiotics in
developing countries is inappropriate; medications
that are available without prescription are used for
too short a period, at too low a dose, or without
proper indication.”53
Many antidiarrhoeal preparations containing antibi
otics (neomycin, streptomycin, chloramphenicol,
sulphonamides) are on the Third World market.
According to WHO, “antibiotics are not effective
against most organisms that cause diarrhoea. They
rarely help and can make some people sicker in the long
term. Their indiscriminate use may increase the resis
tance of some disease-causing organisms to antibiotics.
In addition, antibiotics are costly, so money is wasted.
Therefore, antibiotics should not be used routinely.”54
Dr Efrain Margolis, professor of preventive and
social medicine, says that in Uruguay one of the
causes of the unnecessarily high use of antibiotics is
the influence of commercial advertising. Manufac
turers’ indications tend to exceed rhe main spectrum
of use of a particular antibiotic.55 Dr Margolis notes
the erroneous use of antibiotics in viral infections
and points to an “explosive” use of antibiotics dur
ing flu epidemics. Also there arc many combination
antibiotics in Uruguay, despite international recom
mendations that monosubstances are preferred.
Overprescribing and inappropriate prescribing of
antibiotics by physicians arc common in the Third
World. In Nigeria, for example, one study found that
countries: Saudi Arabia. Jordan, the United Arab Emirates. Bahrain,
Kuwait. Qatar and Oman): Scrip. 1499. 23 Mar 1990. p29; Indonesia:
Scrip. 1483. 26 Jan 1990. pl7; Philippines: Scrip. 1485. 2 Feb 1990. p20,
Mexico- Scrip. 1598. 13 Mar 1991. p22; Argentina Scrip, 1638. 31 Jul
1991.p23
33% of prescriptions in government and private hos
pital were inappropriate.56 In the Middle East,
overprescribing is often due to an imprecise diagno
sis and lack of confidence on the parr of a health
worker, combined with a desire to please the patient,
according to advisers to WHO’s Middle East
Regional Office.57
Dr Abdulla Assad, director of pharmaceutical ser
vices in Kuwait, says the country urgently needs a
clear policy on the rational use of antibiotics. He has
called for better research on patterns of antibiotic
resistance in Kuwait and stricter controls on antibi
otic prescribing and dispensing. He says that doctors
are currently prescribing antibiotics without know
ing whether pathogens are resistant to them and are
also prescribing larger quantities than required.58
Assuming that diagnosis reveals underlying bacterial
infection, “the most effective, least toxic, narrowest
spectrum agent available” should be used to “reduce
the problems associated with broad-spectrum ther
apy, viz. selection of resistant micro-organisms and
superinfection.”59 However, many people do not sec a
doctor or get a diagnosis. They simply buy antibiotics
without a prescription over the counter. This wide
spread self-treatment, often with the least effective
agent in an incorrect dosage, is considered a major
factor in the development of bacterial resistance in
developing countries.60 One study in Nigeria found
that all 500 members of the public surveyed and 73%
of 500 university students admitted to having used
antibiotics at least once for a variety of symptoms
before consulting a physician.61 A survey in pharma
cies serving low-income populations in Fortaleza,
3 A .
Antibiotics in animals
About half of all antibiotics produced in the USA are
administered to animals, either to prevent or treat dis
ease, or in feed stock to promote growth.63 It has long
been recognised by farmers that antibiotics can cause
healthy animals to put on weight without consuming
more food.64 The commonest growth promoters are
tetracyclines - among the most potent drugs for pro
voking rhe rise and selection of resistant organisms. In
1985, over 90% of the drugs used in animals in the
USA were used without any veterinarian involved. It
is common practice for farm workers to buy antibi
otics directly from feed stores or other suppliers;
veterinarians are called only if problems develop after
treating the animals with the antibiotics.65
Antibiotics have been extensively but unsuccessfully
used in animals to prevent infectious diarrhoea
caused by salmonella. The spread of antibiotic-resis
tant salmonella from animals to humans was noted
in 38 outbreaks investigated by the US Centers for
Disease Control between 1971 and 1983.66 The
Natural Resources Defense Council said in 1985 that
300 deaths and 270,000 cases of salmonella poison
ing each year in rhe USA could be traced to the use of
tetracycline and penicillin as growth stimulants in
animals. In the United Kingdom in 1964, there were
only 4,500 cases of salmonella food poisoning
reported; by 1983, the figure had reached 17,000.67
Veterinary drugs are sold and used without much
control in Nigeria, which may have created a popu
lation of resistant bacteria in the animals. The
presence of antibiotic residues in meat, milk and their
products poses potential human health hazards.
Allergic skin conditions, nausea, vomiting, anaphy
lactic shock and even death have resulted from the
ingestion of residues. Cooking and freezing have
minimal effect on residues. Resistance to antibiotics
has been detected in food poisoning bacteria such as
Salmonella typhimurium, Staphylococcus aureus
and Clostridium perfringens. Some epidemiological
link has been established between S. typhimurium of
calves and human food poisoning. Judicious use of
antibiotics, public education on the health risks of
the indiscriminate use of drugs in livestock produc
tion, and hygienic slaughter, will help to reduce
bacterial drug resistance in man and animals, accord
ing to a researcher at the Department of Veterinary
Medicine, University of Nigeria.68
Evidence of increasing resistance of Salmonella bac
teria in poultry to the newer quinolones used to treat
salmonellosis in humans was described by four
British researchers as “worrying". They said that
“thought needs to be given as to whether quinolones,
such as enrofloxacin, should be given to animals".6’
Clinical trials
Susceptibility of bacteria to a particular antibiotic in
the laboratory does not necessarily mean that the
antibiotic will be effective in clinical practice. For
example, in laboratory tests (in vitro), Helicobacter
pylori is sensitive to most antibiotics (penicillin,
ampicillin, cephalosporins, macrolides, quinolones,
aminoglycosides, tetracyclines, and nitroimidazoles)
except vancomycin, trimethoprim and
sulphonamides. However, the clinical experience with
various antimicrobials has been particularly
disappointing, especially when these have been
administered alone.1 Similarly, not all antimicrobials
that are active in vitro against Shigella are effective in
practice. Thus, “efficacy of an agent can only be
assessed by properly conducted clinical trials".2
In the past, efficacy as determined by controlled
clinical trials was the single factor that determined the
prescribing of antibiotics. However, efficacy is rarely
emphasised in currently published clinical trials of
new antibiotics simply because analysis of results
almost always demonstrates therapeutic equivalence
rather than superiority of new compounds as
compared to previous standard regimens.3 The
number of patients studied is usually too small to
show any difference in efficacy.4
One expert has stated that the rapidly expanding field
of beta lactam antibiotics has led to “a steadily
increasing flood of papers covering trials which are all
too often badly planned and dubiously performed”.5
Sources:
1. Glupczynski, Y.. and Burette. A.. ‘Drug therapy for Hehcobacte'
pylori infection: problems and pitfalls". American Journal of
Gastroenterology, Vol 85. No 12. 1990. ppi545-51
2.
Salam. M.A and Bennish, M.L.. ‘Antimicrobial therapy for
shigellosis". Reviews of Infectious Diseases. Vol 13. Suppl 4. Mar Apr
1991. pS332
3.
Steele. R.W. and Kearns. G.L.. "Antimicrobial therapy for pediatric
patients". Pediatric Clinics of North America. Vol 36, No 5. Oct 1939.
ppi 321-49
4.
Bergeron. M.G.. "The future of new oral antibiotics including the
quinolones". Canadian Medical Association Journal. Vol 138, 1 Jan
1988. pp35 42; Smith. G.H.. 'Oral cephalosporins m perspective".
DICP. The Annals of Pharmacotherapy. Vol 24. Jan 1990. pp45 51
5.
Midtvedt. T.. "Penicillins, cephalosporins and tetracyclines", in
Dukes. M.N.G. (ed), Side Effects of Drugs Annual 9, Amsterdam.
Elsevier. 1985. p230
57
Problem Drugs
Brazil found that counter staff routinely recom
mended antibiotics for acute respiratory infections.62
Antibiotics
3 A .
Antibiotics
Problem Drugs
An enormous market
The global antibiotics market was put ar $ 15.5 billion
in 1991,70 and estimates suggest it will increase to $22
billion by 1993,71 and a possible $40 billion by the
year 2000. 2 In the USA in 1989, more than $1.1 bil
lion was spent on just five new, expensive oral
antibiotics: ciprofloxacin (Cipro made by Miles/
Bayer), norfloxacin (Noroxin by Merck Sharp and
Dohmc), amoxycillin/clavulanate (Augmentin by
SmithKline Beecham), cefuroxime axetil (Ceftin by
Glaxo) and cefaclor (Ceclor by Eli Lilly). The total US
antibiotic market is worth some $6 billion a year.73
Figure 3A-1
Share of world antibiotics sales in 1991
(percentages)
The efforts by drug companies to get a large share of
this massive world antibiotics market is a major fac
tor behind the misuse.
“Since the drug industry is profit oriented, it
tries to increase the sales of antibiotics. This
occurs either by increasing the volume (which
leads to unnecessary’ prescribing) or increasing
the relative proportion of expensive antibiotics,
which usually are not drugs of choice. It is
therefore questionable whether optimal pre
scribing of antibiotics can be attained in this
context.”74
The connection between promotion and misuse is
clear. In Northern Ireland, for example, there was a
dramatic increase in prescribing of pivampicillin in
1987-8 after several years of declining use; the increase
corresponded with concerted local promotion by the
manufacturer.75 The largest consumer-governed
health maintenance organisation (HMO) in the USA
recently' placed the quinolone antibiotic ciprofloxacin
on its formulary with specific use criteria. The HMO’s
review group responsible for the formulary was con
cerned about the potential for inappropriate
prescribing “due to the intense marketing of this
agent, which may have led physicians to believe it was
the most appropriate drug for most infections”.76 One
commentator describes this as a typical industry
approach in its promotion: “While the boldface ad
advocates ‘blind’ use of their product, the fine print
embodies the spirit of conservative practice. This clas
sic double message, i.e., ‘use our product without
hesitation’ and ‘use our product only with great cau
tion’, is typical of many drug company circulars
containing prescribing information.”77
Between July and December 1988, nine of the 17
breaches
of
the
Australian
Pharmaceutical
Manufacturers Association (APMA) Code of
Conduct concerned antibiotics. An advertisement by
Eli Lilly for Keflex (cephalexin) ‘implied that Keflex
was the first drug of choice for tonsillitis, even though
this was negated by a warning in small print at the
bottom of the advertisement’. A Wellcome advertise
ment for Septrin (co-trimoxazole) was termed
‘misleading’ with regard to its claims about resis
tance, while a second advertisement failed to include
Figure 3A-2
World market share by antibiotic type in 1991
(percentages)
60
3 A .
Antibiotics
Problem Drugs
or third-line therapy when amoxycillin, penicillin V,
or TMP/SMX |co-trimoxazole] have either failed or
caused hypersensitivity reactions.”90
Most independent advice is that they should be used
“only for well-defined indications. Excessive use fos
ters the emergence of resistant organisms and wastes
valuable, expensive drugs.”91 Because of this, “limited
stocks of these agents, third generation cephalosporins
should be kept and their use strictly controlled by
adherence to an antibiotic policy.”92
They are widely used in surgical practice, particularly
for surgical prophylaxis.93 This is despite the advice that
“cephalosporins have little role as first-line therapy for
surgical nosocomial hospital-acquired infection”.94
They are “not necessarily the drugs of choice in any
pediatric infection”, although they provide useful
alternative therapies in many situations. For paedi
atric practice, the general rule is that “more narrow
spectrum, less expensive agents should be used”.95
The AMA echoes those words when talking about
the general use of cefotaxime, (Claforan), or other
third generation cephalosporins.96 It also makes the
point that “additional clinical studies are necessary
before specific recommendations about use can be
made”. Hoechst is less restrained, advising doctors in
Thailand to use Claforan “when you have to be right
from the start”.97 Claforan was Hoechst’s leading
drug in 1984 with sales of $223 million, about 10%
of the company’s total pharmaceutical turnover,98
and has remained the company’s best selling drug
with sales of $400 million in 1990," about 8.5% of
total pharmaceutical turnover.
been described as “spiralingempiricism” in medicine.
However, as a doctor at the Robert Wood Johnson
Medical School in New Jersey, USA points out: "The
failure to initiate prompt antibiotic therapy in a
febrile but stable immunocompetent patient without
identifiable infection is almost never a serious error,
even in the presence of occult bacterial infection.”103
Quinolones
Quinolones (or fluoroquinolones) are among the
newest antibiotics to be developed, although the first
quinolone to be developed, nalidixic acid, has been
available for many years. Nalidixic acid is used in the
treatment of some urinary tract infections and in the
treatment of Shigella dysentery despite its frequent
side effects and the ease with which resistance to it
develops.104
Quinolones accounted for about 15% of the world
antibiotics market in 1990.105 Sales in Europe were
$600 million in 1991 according to Frost &
Sullivan.106 Every day, Americans spend $700,000 on
ciprofloxacin, but much of this expenditure is inap
propriate, according to clinicians in the USA. In 1989,
ciprofloxacin was the fourth most commonly pre
scribed antibiotic in the USA, with more than five
million prescriptions filled at a total cost of S248 mil
lion. The “astonishing popularity” of ciprofloxacin is
A Glaxo advertisement for its brand of ceftazidime,
Fortum, in Pakistan in 1990 was dramatic in its
appeal: “No time for trial, little room for error. Make
no mistake in serious infections... Fortum performs
well - right from the start.” In the background of the
ad was a repeating list of 16 bacteria that the drug
was effective against; the repetition of the names,
however, created the impression that this antibiotic
had a virtually unlimited spectrum of action.100
Another Glaxo advertisement in the same publica
tion keeps up the idea of broad coverage and wide
usage of its cephalexin antibiotic, Ceporex. In this
advertisement, the hands of a baby and an old person
are shown linked together, while the headline reads:
“From early days, till autumn years, an antibiotic for
all seasons, Ceporex”.101 With promotion like this, it
is no surprise that statements like “cephalexin
undoubtedly is used excessively”102 appear in the
medical literature.
The idea these companies are trying to get across is:
don’t wait for the results of laboratory sensitivity
tests. This type of promotion encourages what has
Glaxo ad for cephalexin (Ceporex) in QIMP, Pakistan. 1988-89
3 A .
Cephalosporins according to generation
First generation
Injectable: cephalothin, cefazolin, cephapnn
Oral: cephalexin, cefadroxil, cephradine
Second generation
Injectable: cefamandole, cefonicid, cefoxitin,
cefotetan. cefuroxime. cefmetazole
Oral: cefaclor, cefuroxime axetil
I
Penicillins
Penicillins - probably the most famous antibiotics include a range of valuable antibiotics which, if used
properly, are very effective. Global sales of penicillins
in 19S8 amounted to S3 billion.79 Amoxycillin, which
is similar to ampicillin, has been gaining in popularity
in recent years. Sales of the world’s leading brand of
amoxycillin, Amoxil, rose from S404 million in 1988
to $436 million in 1990, while sales of the amoxycillin
with clavulanate combination, Augmentin, rose from
S427 million to S793 million.80
Both ampicillin and amoxycillin are widely pre
scribed for upper and lower respiratory infections,
urinary infections (such as cystitis) and other infec
tions. They are often used inappropriately - for the
wrong disorder, in the wrong dosage, and for the
wrong length of time. Frequently, they are used for
disorders which would improve faster on benzylpeni
cillin or penicillin V.81
Promotional material for SmithKiine’s ampicillin,
Eskaycillin, in Bangladesh in 1989, claimed that the
antibiotic was “highly successful” in a wide range of
infections. It cited studies which it claimed showed a
success rate of more than 90% in respiratory tract
infections; 100% in cystitis; 88% in typhoid fever;
95% in gonorrhoea; 86% in bacillary dysentery;
and 88.4% in bacterial enteritis. Unfortunately, the
studies cited were from 1963, 1964, 1964, 1963,
1963 and 1967 respectively - anywhere from 22 to
25 years old. This is some distance from the statement
in the Code of Pharmaceutical Marketing Practices of
the International Federation of Pharmaceutical
Manufacturers Associations (IFPMA) which says that
information provided by companies “should be based
on an up-to-date evaluation of all the available scien
tific evidence”.82
None of the penicillins should be taken for trivial infec
tions or by patients who have had a previous allergic
reaction. About 5 to 15% of the population are liable
to be allergic to penicillins or cephalosporins.83
Cephalosporins
The cephalosporins, related to the penicillins, are
broad spectrum antibiotics. They are loosely cate
gorised into “generations”, based on their date of
Third generation
Injectable: moxalactam, cefotaxime, ceftriaxone,
ceftizoxime, cefoperazone, ceftazidime
Oral: cefixime
introduction, and their spectrum of activity, particu
larly against gram-negative bacteria. They are similar
to each other in their actions and “there are few
absolute indications for their use.”84
Scrip put the global market for cephalosporins in
1988 at S6.8 billion.85 The value of the European
cephalosporin market was SI.2 billion in 1991,
according to a report by Frost & Sullivan.86 One
researcher makes the point that the recent con
sumption of cephalosporins “has increased so
dramatically as to parallel the initial acceptance of
penicillin. Organisms that are resistant to the
cephalosporins will no doubt continue to thrive.”87
The American Medical Association (AMA) said in
1980 that “their very active promotion and wide
therapeutic usage is out of all proportion to their
importance in anti-infective therapy”.88 Six years
later, the AMA said that although cephalosporins are
generally effective and are used widely, rhe first and
second generation drugs usually “have nor been
regarded as antibiotics of first choice for the treat
ment of most infections because of the availability of
equally effective and less expensive alternatives”. As
for the third generation cephalosporins, “additional
clinical investigation is required to demonstrate that
they are as reliable as the already proven therapeutic
agents”.89 One thorough review concluded that
“published reports of clinical trials have failed to
show superiority of the oral cephalosporins over less
expensive alternatives in the treatment of most infec
tions for which they are approved. It is recommended
that the oral cephalosporins, especially the newer
and more expensive agents, be reserved for second-
59
Problem Drugs
a caution about use in the elderly. A booklet produced
by Roche entitled Co-trirnoxazole in perspective was
‘assembled carelessly and was misleading', as was an
advertisement for Bactrim (co-trimoxazole) and an
entire advertising campaign for Bactrim was termed
'unbalanced and misleading by implication and
omission’. A Glaxo advertisement for Ceporex
(cephalexin) made unsubstantiated claims about effi
cacy. A Beecham advertisement for Augmentin
(amoxycillin) was regarded as ‘misleading’, while
another Beecham advertisement for Floxapen (flucloxacillin) used ‘unqualified superlatives’.78
Antibiotics
3 A .
Promotion of ciprofloxacin has also featured promi
nently in journals and prescribing guides in
developing countries. Not all of the advertisements
have been in the best interests of public health. When
Bayer launched its brand of ciprofloxacin, Ciprobay,
in the Philippines, it ran advertisements which
claimed that “Ciprobay is equally effective against
gram-positive and gram-negative bacteria alike”.108
However, laboratory tests had shown that
ciprofloxacin had weaker activity against gram
positive bacteria. Bayer later admitted that the ads
were inaccurate and promised to stop using them.
However, the company refused to send letters to
physicians explaining the mistake.
Over the years, the advertising has indeed changed.
For example, a 1988 two-page advertisement for
Ciprobay in Thailand said: “Unknown pathogens,
mixed infections, problem organisms... Ciprobay
penetrates to the site of infection directly.” A head
line
added
the
message:
“Outstanding
broad-spectrum bactericidal activity”, while the list
of indications read like a who’s who of epidemiol
ogy: “infections of the respiratory tract, middle ear,
sinuses, eyes, kidneys and urinary tract, genital
organs (including gonorrhoea), abdomen (e.g. bac
terial infections of gastrointestinal tract, biliary
tract, peritonitis), skin and soft tissues, bones and
joints; further, septicaemia, infections in patients
with reduced host defence, selective gut decontami
nation”.109 By 1991 the advertisements in African
journals were simplified even more with the allembracing headline: “Antibiotic management of
bacterial infections”, and the list of indications was
the same except for the inclusion, in brackets, of the
phrase “(due to sensitive organisms)” after the
word “infections”."°The promotion is working: in
1990, global sales of Ciprobay (ciprofloxacin)
reached $800 million."1
Norfloxacin has proven to be effective in urinary
tract infections, including gonococcal infections.
However, concentrations of the drug outside the
genito-urinary tract are generally far below values
necessary to treat systemic infections success
fully."2 Also, quinolones lack effectiveness against
Chlamydia trachomatis, which frequently accom
panies other sexually transmitted disease;
therefore, quinolones cannot be used as single
drug therapy for urethritis."3 The authors of one
recent review said: “we do not believe that they are
the definitive agents of choice for any specific infec
tion”."4
An advertisement for Ranbaxy’s brand of nor
floxacin, Norbactin-400, in India in 1988 included
the reassuring-but false-statement: “development
of resistance not known”."5 A professor of medicine
and pharmacology makes the point that:
“Properly used, fluoroquinolones have the
potential to be effective for many years.
Improperly used in the community, nursing
home, and hospital, it is possible to rapidly
select resistant isolates.... Resistance to one
of the new fluoroquinolones causes resis
tance to all agents of the class, including
those still in phase-I study.”"6
By 1989, penicillin-resistant strains of Neisseria gonorrhoeae which were also resistant to norfloxacin
were found in Canada. The infections were traced to
sexual contacts in the Philippines and Thailand.
Other reports between 1988 and 1990 also identified
quinolone-resistant N. gonorrboeae isolates in the
Philippines, the UK and Spain."7
At the University Hospital in Uppsala, Sweden, since
1986 all adult bone marrow transplant patients have
received oral doses of the quinolone antibiotic,
ciprofloxacin, as a prophylaxis against bacterial
Ciprobay
Knocks out the genetic code of bacteria.
eni. miirpertJ terttfrarer
ecliona.to
problemUnknown
ortaaiiwoetnt...-pmhot
theme
direelCiwiplyrobay*
e-'en
cM«l batofontabyfcciuucrfnmj
th ItmhemedibactaetnaJe bfONA.
Wah the patten: ui mud Ciprobay*
Ciprobay
the high-performance quinolone tor bacterial infections
M for ciprofloxacin (Ciprobay) in TIMS, Thailand, 1988
61
Problem Di
attributed in part to heavy marketing. In the first six
months of 1988, ciprofloxacin was the second most
advertised product in medical journals in the USA.107
Antibiotics
62
3 A .
Antibiotics
Problem Drugs
infection. Since 1987, ciprofloxacin-resistant strains
of S. aureus have been increasing. By 1989, almost
half of such patients were found to have resistant
strains, despire protective isolation measures.118
Recently, surveys in several countries have confirmed an
increasing prevalence of resistance to quinolones
among strains of S. aureus."9 During a three-month
period in 1989, researchers at a hospital in
Pennsylvania, USA found 83 separate bacterial infec
tions resistant to ciprofloxacin. They traced 77 of these
to patients from a single nursing home where there was
“extensive prescribing” of ciprofloxacin.120 At a med
ical centre in Pittsburgh, USA where ciprofloxacin was
introduced in January 1988, microbiology reports were
showing an increase in resistance during the latter half
of 1989. A six-month study which began in November
1989 concluded that prior use of a quinolone antibiotic
“was the single most significant risk” for the develop
ment of ciprofloxacin resistance.121
It is unlikely that any of the quinolones will ever be
approved for use in children because animal studies
have shown cartilage damage following the adminis
tration of these drugs. There have also been reports of
reversible bone damage in adolescents who received
ciprofloxacin during treatment for cystic fibrosis.122
The quinolones should also be avoided in pregnancy.123
Macrolides and the lincomycin groups
Macrolide antibiotics such as erythromycin are
useful in treating tissue infections caused by bacte
ria resistant to the natural penicillins, or for
infections in patients who are allergic to peni
cillins. However, bacteria quickly become resistant
to erythromycin. Heavy clinical use of eryth
romycin has resulted in the rapid emergence of
resistance in certain clinical settings (especially in
staphylococci, group A streptococci and entero
cocci). For example, in one hospital where
erythromycin was used as the sole drug to treat
penicillin-resistant S. aureus, a resistance rate of
70% was found after only five months of clinical
use. Resistance to erythromycin has increased sig
nificantly among group A streptococci in Japan,
Europe and elsewhere.12'1
Erythromycin frequently causes gastrointestinal side
effects: nausea, vomiting and diarrhoea. These are
dose-related and also commonly occur with the
enteric-coated forms of the drug.125 “There are no
adequate data in adults to indicate that any formula
tion of erythromycin produces fewer gastrointestinal
side effects.”126 When Parke-Davis launched its
enteric-coated version of erythromycin, Eryc, in
Malaysia and Singapore, one of the prominent lines
in the advertising was “reduced potential for gas
trointestinal upset”.127
Clindamycin and lincomycin, according to the
British National Formulary (BNF), “have only a
limited use because of their serious side effects.”128
Often, despite clear warnings, misuse still follows.
The AMA says lincomycin “offers no therapeutic
advantage over clindamycin. Consequently, it has
become obsolete."129 This “obsolete” drug was mar
keted by Upjohn in the Philippines in December 1988
for “mild” and "severe” infections.130 An advertise
ment for Upjohn's brand of clindamycin, Dalacin C,
promoted the drug for “the gram positive infections
you see most: tonsillitis, pharyngitis, otitis media,
sinusitis, bronchitis, pneumonia, abscesses, skin and
soft tissue infections”.131
Streptomycin and other aminoglycosides
Global sales of aminoglycosides in 1988 reached $620
million.132 Drugs in this category include gentamicin,
amikacin, framycetin, kanamycin, neomycin, netil
micin, paromomycin, sisomicin and tobramycin. They
have a broad spectrum of action, but due to resistance
and severe side effects their usefulness is limited. They
can cause deafness, harm the kidneys and cause
muscle weakness and decreased respiration, especially
when they are used in high doses or for a long time.
They should be given with caution to those past
middle age and to patients with kidney problems.
They can produce severe allergic reactions. They
should not be used in pregnancy.133 Aminoglycosideinduced hearing loss is a major cause of deafness in
China.13'1 A multicentre study in the USA found that
the average additional cost incurred for each patient
who had aminoglycoside-induced kidney damage
amounted to $2,500.135
The AMA says “data that convincingly show differ
ences in nephrotoxicity | kidney damage! are
unavailable," although it adds that some evidence
does suggest that tobramycin is probably less nephro
toxic than gentamicin.136 More recent evidence
confirms the probable ranking of gentamicin as most
potentially toxic, followed by tobramycin, amikacin,
and netilmicin.13' Recent studies also suggest that the
aminoglycosides may well be effective when adminis
tered as a single daily dose and that this method of
administration can result in lower toxicity.138
Streptomycin, according to the BNF, “is now almost
entirely reserved for tuberculosis.”139 This is its only
indication on the WHO Essential Drugs List.140
Neomycin is too toxic to be given by injection,141 or
for systemic use.142 It can be used to sterilise the bowel
before surgery. Its main use is in applications for the
skin, eyes and ears, but hypersensitivity can occur.
Streptomycin and neomycin are often included in
antidiarrhoeal preparations. However, they “should
be avoided altogether in gastrointestinal infection.
They prolong rather than shorten the time taken to
control diarrhoea by causing masked bacterial diar
rhoea, carrier states or pseudomembranous colitis.”143
Neomycin also causes diarrhoea.144
3 A .
Chloramphenicol
The “toxic effects” of chloramphenicol, “even
though uncommon, have outweighed its useful
ness”.146 The BNF states: “Chloramphenicol is a
potent, potentially toxic, broad-spectrum antibiotic
which should be reserved for the treatment of life
threatening infections.”147 It is valuable for treating
typhoid fever and a certain type of meningitis.
However, it is widely overprescribed, and its indis
criminate use has led to many unnecessary deaths
due to bone marrow damage.148
As long ago as 1973, the US Food and Drug
Administration (FDA) required chloramphenicol
advertisements and package inserts to carry a promi
nent warning about the drug’s possible severe and
fatal side effects.149 However, 10 years later, 49% of
all prescriptions for chloramphenicol were still for
conditions in which the drug was not indicated, such
as for tonsillitis and for the prevention of infection
after surgery.150 Clear warnings have failed to pre
vent misuse.
In other countries, manufacturers’ information is
often misleading and inadequate. Overpromotion
and lack of adequate information about the dangers
of chloramphenicol encourage misuse. In the
Philippines in 1988, Farmitalia Carlo Erba was pro
moting its brand of chloramphenicol, Kemicetine,
for “a wide range of therapeutic requirements”.
Among the indications given for the product were
“enteric infections... respiratory infections, infec
tions of the urinary tract”.151
deposited in bone and bone growth stops during
tetracycline treatments. Therefore, they should not
be given to children under seven (some say eight or
12) or pregnant women.155
In 1986 in Malaysia and Singapore, Lederle was
advertising its minocycline product, Minocin, “for
the world’s fastest growing sexually transmitted dis
ease”. The ad claimed that Minocin was "virtually
safe. No toxic reactions have been reported to
date.”156 However, a 1977 study found that “patients
receiving minocycline may experience vestibular tox
icity, manifested by dizziness, ataxia, nausea, and
vomiting. The symptoms occur soon after the initial
dose and generally disappear within 24 to 48 hours
after drug administration is stopped. The frequency
of this side effect is directly related to the dose and has
been noted more often in women than in men.”157 A
1988 advertisement in Thailand described the drug as
“the simple treatment of STD”, and in particular
emphasised its use in treating Chlamydia trachoma
tis.'5* The recommended use of minocycline is now
more limited because of the association of the drug
with “significant vertigo”.159 Nonetheless, a January
1990 advertisement in Medecine d’Afrique Noire in
the Central African Republic claimed that Lederle’s
minocycline was “the treatment of STD of bacterial
origin” and that it “prevents sterility”.160
The simple treatment of STD
Minocin 100 mg
Provides single-agent therapy
for mixed infections*
g Chlamydia trachomatis
u Ureaplasma ureatytcisn
■ Gcnoanea
• SypMs
Chloramphenicol is inexpensive, easy to administer
and, if used correctly for a serious condition such as
meningitis, the risk of fatal side effects is relatively
low in comparison to the risk of death from the dis
ease.152 Therefore, chloramphenicol should be
reserved for use in severe infections, particularly in
developing countries. As a leading textbook,
Antibiotics in the Tropics, says: “chloramphenicol
should not be given in trivial infections which can be
treated safely with less dangerous agents”.153
Tetracyclines
Tetracyclines are broad-spectrum antibiotics whose
usefulness has decreased as a result of increasing bac
terial resistance.154 They are used much less than
previously, at least in industrialised countries. Their
uses include the treatment of chronic bronchitis, cer
tain atypical pneumonias and acne. In young
children, tetracyclines cause tooth discoloration and
increase the risk of tooth decay. They are also
Minocycline (Minocin) ad, TIMS, Thailand. 1988
63
Problem Di
Generally, this entire group of drugs is considered
useful in the treatment of serious infections which are
resistant to penicillin. The two most useful drugs are
gentamicin and tobramycin, with amikacin reserved
for infections which are resistant to gentamicin and
tobramycin.145
Antibiotics
3 A .
Antibiotics
Improving antibiotic prescribing
In Australia, a small booklet. Antibiotic Guidelines, was
published in 1978, and has been regularly updated since.
to provide a set of peer consensus guidelines on antibiotic
use. An educational campaign in one hospital to promote
the booklet and its advice led to an increase in
"appropriate antibiotic treatments" from 52% to 70% from
1978-1982. Two further campaigns in 12 hospitals in 1985
and 1986 led to similar significant improvements in
therapy. After costs of the campaigns were taken into
account, significant savings were also achieved. The
educational campaign made use of an "academic"
representative, a mailing of promotional material that
promoted rational prescribing, posters throughout the
hospitals, lectures, and a humorous video.1
At a community health centre in Nebraska, USA, a
comprehensive antibiotic sensitivity/prescribing guide that
reflects local conditions has been developed to improve
antibiotic prescribing. The reaction of physicians has been
generally favourable, and the scheme has spread to other
hospitals in the area. Doctors have asked for both
outpatient and paediatric schemes to also be started.2
At a district general hospital in Yorkshire, UK antibiotic
prescriptions for surgical prophylaxis changed every six
months with each intake of new junior doctors. A survey
determined that only 17% of the prescriptions were
appropriate. Following the introduction of formal guidelines
appropriate prescribing improved to 60% of cases. There
were significant cost savings as well.3
In Fiji, a training programme for staff from all health
centres and nursing stations helped to reduce the
inappropriate use of antibiotics in the treatment of acute
respiratory infections by almost 50%. Before the training
courses started in 1988, antibiotics were incorrectly
prescribed for 43% of cough and cold cases. After the
training, only 24% of patients with coughs and colds
received antibiotics.'1
i
The effect of removing an antibiotic restriction policy in
operation in a 600-bed hospital in North Carolina, USA
holds some lessons for policy makers and administrators.
It was felt that the restriction policy was too time
consuming and costly to operate. Its removal, however, led
to an 158% increase in the number of courses of therapy
administered (from 413 during a six-month period of
restriction to 1,064 during a six-month period immediately
after the lifting of restrictions). Expenditure on antibiotics
increased by 103%, from $154,542 to $313,905. There
was also an increase in the inappropriate use of at least
one of the antibiotics. Researchers studying the change in
policy advised others that a plan to remove existing
restrictions on antibiotics “should be approached
cautiously, as such a step can have a major impact on
antimicrobial costs and the quality of care".5
antibiotic treatment costs.
Poster used in an Australian campaign to improve
antibiotic prescribing.
Sources:
1. Landgren, F.T . Harvey. KJ., et al. “Changing antibiotic
prescriomg by educational marketing". Medical Journal of
Australia. Vol 149. 5 19 Dec 1988. pp595 9
2. Snyder. L.L . Clyne. K.E. ano Wagner. J.C., “Antibiotic
sensitivity and the prescribing .nformation sheet: assisting the
prescribing physician", Amer.can Journal of Infection Control,
Vol 18. No 6, Dec 1990. pp399-404
3. Dobrzanski. S.. Lawley. D.I., et al. "The impact of guidelines on
pen operative antibiotic administrat.on", Journal of Clinical
Pharmacy and Tnerapeutics. Voi 16. 1991. ppl9 24
4. Anon . ' Towards a more rational use of antib.otics in acute
respiratory infections in chiidren', Essential Drugs Monitor. No 9.
1990. p5
5 Himmelberg. C J.. Pieasants. R A . et al. “Use of antimicrobial
drugs in aduits oefore and after removal of a restriction policy .
American Journal of Hospital Pnarmacy. Vol 48. Jun 1991. ppl22O
3 A .
Although co-trimoxazole is a useful product, evi
dence suggests that “trimethoprim by itself can often
be used with results equal to that of the combination
with regard to efficacy, with perhaps less toxicity”.161
However, trimethoprim resistance has become a
major problem in developing countries.162 According
to WHO, trimethoprim resistance is a particular
problem because there is no oral drug that is as effec
tive or as cheap to replace it.163 It is also a problem in
industrialised countries. In many European coun
tries, during the 1970s and 1980s, resistance to
trimethoprim among urinary tract bacteria such as
E. coli increased from less than 10% to 30-40%.164
Combinations
Antibiotics given concurrently can be useful in very
specific circumstances (for example, as part of a com
bined treatment in tuberculosis), even though the use
of two or more antibiotics at the same time increases
the risk of side effects.165 Fixed-ratio combinations of
antibiotics (other than co-trimoxazole) have few indi
cations. There are only two (co-trimoxazole and
thiacetazone with isoniazid) on the WHO Essential
Drugs List.166 In the early 1960s, combination anti
biotics abounded; however, regulatory authorities
such as the US FDA began eliminating them because
of insufficient evidence about their efficacy and safety.
More recently, some antibiotic products which seem
to have a synergistic effect have been introduced after
having been reasonably well tested.167 Principal
among these are the combinations of a beta-lactam
antibiotic with a drug which inhibits the action of the
bacterial enzymes (beta-lactamases) which render the
antibiotic ineffective. Two such beta-lactamase
inhibitors, clavulanic acid and sulbactam, are now
commonly found in fixed-ratio combinations with
amoxycillin, ticarcillin or ampicillin. However, even
the new combination products are not without their
problems of resistance.168
In many countries, inappropriate antibiotic combi
nations abound. According to Dr Edmundo Ferraz,
president of the Brazilian /Vssociation for the Control
of Flospital Infections, 390 of the 795 antibiotics on
the market in Brazil should be withdrawn because
they are “inappropriate” combinations which can
“cause severe damage to health”. In evidence sub
mitted to the Brazilian Health Minister, he says that
resistance to antibacterials in Brazil has become a
real problem due to the inappropriate use of these
drugs.169
Policies for the future
It is commonly believed that the only way to combat
growing resistance to antibiotics is to produce new,
more effective drugs. This race for a “wonder drug”
to beat the “super bug” is misleading. The real
solution is to eliminate misuse. As one study con
cluded, “rather than attempt to overcome or
pre-empt resistance by prescribing yet another agent,
the objective should be to prevent resistance by limit
ing the amount of antibiotic prescriptions”.170
Certainly, having more new drugs won’t change the
way they are being used. In fact, as one commentator
has pointed out:
“New agents should be reserved for specific
indications - eg, infections caused by organ
isms resistant to standard drugs, or
infections in which the newcomer has been
proven superior to earlier agents by compar
ative clinical trial.”171
A WFIO expert committee has suggested that in addi
tion to the Essential Drugs List which included 16
antibiotics, a “reserve list” of antibiotics should be set
up which could include some of the third-generation
cephalosporins, quinolones and vancomycin. Such
antibiotics, although effective in a wide range of
infections, are inappropriate for unrestricted use
either because of the need to reduce the risk of resis
tance to them, or because of their high cost.172
The question of cost is certainly worth considering.
In no area of medicine are differences in cost more
apparent than in the selection of antibiotics. For
example, amoxycillin, co-amoxiclav, co-trimoxa
zole, erythromycin, cefaclor and tetracycline are
common antibiotic choices for outpatient treatment
of community-acquired upper respiratory infections.
None of these antibiotics is clearly superior for initial
treatment; however, co-amoxiclav and cefaclor cost
at least three times more than the others (in the USA)
and clearly should be reserved for special situations
or resistant organisms.173 A study in Canada found
that, as a general rule, most new drugs are two to
four times more expensive than antibiotics that have
been on the market for several years.174
Without control, there are severe dangers ahead. In
response to this, in September 1984, a large confer
ence was organised by the US National Institutes of
Health (N1H) and WHO to look into the problem
more closely than ever before. This conference posed
a threat to the pharmaceutical industry. It was
"... effectively thwarted by the pharmaceutical
industry and resulted in a little more ‘than a
pathetic call for further studies’.... We should
all keep a closer eye upon the pharmaceutical
companies. If a company is marketing obso
lete antimicrobials in developing countries or
conducting policies which will promote resis
tance to the newest agents the prescribers and
regulatory agencies in other countries should
simply ask: Why? Marketing antimicrobials is
not only a matter of money; it is a matter of
ethics as well.... We have to tell our friends in
the pharmaceutical companies that we do
65
Problem Di
Co-trimoxazole
(trimethoprim and sulfamethoxazole)
Antibiotics
66
3 A .
Antibiotics
Problem Di
indeed need some of their products, but we
certainly do not always agree with their pol
icy. One may expect the wiser companies to
take a hint as to how to behave; where a com
pany does not, its products should be
removed from the market. The question of the
worldwide increase in resistance is too serious
to be hampered by concerns about freedom
and profits.”175
The industry, having helped to turn a life-saving
group of products into a group of potentially life
threatening ones, is now trying to obstruct major
efforts to rescue the situation. The resistance of rhe
drug industry to change is as dangerous as the resis
tance of bacteria to antibiotics.
A recent review in the Neu/ England Journal of
Medicine points out that:
“If current practice prevails, the trends in
antimicrobial resistance seen in the past decade
will continue into the next century. Developing
countries and hospitals will be the breeding
grounds and reservoirs for the evolution and
maintenance of resistance genes and multi
resistant strains that will impede both current
and future chemotherapy. There are two chief
areas of concern. The first is that pathogens
for the normal host will acquire a critical com
plement of resistance and virulence genes,
leading to widespread dissemination and seri
ous infections in the community. The second is
that bacteria resistant to all available
chemotherapy will become the predominant
nosocomial [hospital-acquiredl pathogens.”176
Several leading experts in the field of infection con
trol constantly reinforce the need for responsible,
rational use of antibiotics.
“The pharmaceutical chemists still remain
one jump ahead of the bacteria. How long
this can continue depends not only upon the
ingenuity of the chemists but far more impor
tantly upon a conservative approach to
antimicrobial chemotherapy by clinicians.”177
“We have never been much more than one
step ahead, and now it seems that this slender
lead is in danger of being lost. We must there
fore strain every sinew to use antibiotics in a
responsible fashion.”178
“Decreased use of antibiotics will ultimately
reduce the pool of resistance genes and...
improved hygiene will decrease the need for
antibiotics and the transmission of bacteria
through close contact. Those who prescribe
and use antibiotics need to develop a greater
respect for their long-range ecological
effects."179
“Use antibiotics appropriately: this means
using as narrow a spectrum antibiotic as pos
sible, restricting the dose and duration of
treatment to the minimum that is optimal,
being especially careful when prescribing pro
phylactic antibiotics, and formulating and
adhering to an agreed Antibiotic Policy.”180
|See also the sections on Antidiarrboeals, Antidiarrboeals containing antibiotics, Cougb and cold
preparations, and Drugs tn pregnancy.]
Recommendations for action
Antibiotics with a potential for serious risk, such
as chloramphenicol or systemic neomycin, yet
with one or two useful indications, should be
placed under severe restriction. Wherever
possible, they should be withdrawn from the
general market and be prescribed by specialists
who are familiar with their potential risks.
2. Antibiotic combinations (except those such as
co-trimoxazole or those with chemicals such as
clavulanate or sulbactum) should be banned.
3. Governments in all countries should develop
strict antibiotic policies as part of a national
drug policy. These should include:
a) a limited list of antibiotics, with some kept in
reserve for use against micro-organisms
resistant to first-line drugs;
b) a regularly revised set of therapeutic
guidelines;
c) drug utilisation studies to monitor the use of
antibiotics and, where necessary, the
introduction of education programmes to
encourage the rational use of antibiotics.
4. Product information should carry a clear
warning about the problems of resistance and
the need for careful diagnosis and selective use.
5. Governments may wish to consider introducing
bans, or other controls, on the advertising of
antibiotics, as the information contained in
manufacturers’ promotional materials has been
implicated in poor prescribing habits.
6. Health authorities should introduce regular
refresher courses and other independent
exchanges of information on antibiotics for
health workers. One of the most important
messages to communicate is that new
antibiotics should be used cautiously and often
kept in reserve for the treatment of serious
infections that prove to be resistant to other
1.
antibiotics.
3 A .
Antibiotics
Problem Di
References:
l
2.
3.
4.
5.
6.
7.
36.
31 Aug 1986
Murray, B.E , “New aspects of antimicrobial resistance and the resulting
therapeutic dilemmas", loumal of Infectious Diseases, Vol 163, Jun 1991,
Springhouse Corporation, 1990, px
38.
Wolfe. S.M., Fugate, L, et al. Worst Pills Best Pills. Washington. Public Citizen
PPI185-94
Geddes, A.M., “Antibiotic therapy - a resume". Lancet, 6 Feb 1988, PP2869
Neu, H.C, “Antimicrobial agents: the old and the new”, American loumal of
Infection Control, Vol 17, No 5, Oct 1989, PP27685
O’Brien, T.F., et al, "Resistance of bacteria to antibacterial agents: report of
Task Force 2". Reviews of Infectious Diseases, Vol 9 (Suppl. 3), May-Jun 1987,
39.
in Qin Pu, China", New England journal of Medicine, Vol 323, No 5, 2 Aug
8.
1990. P285 9
de Groot, R., Antibiotic Resistance in Haemophilus influenzae, Rotterdam.
Erasmus University, 1991, P13
Jacoby, GA and Archer, G.L., “New mechanisms of bacterial resistance to
antimicrobial agents". New England Journal of Medicine, Vol 324, No 9,
28 Feb 1991, pp6oi-i2; Halliday, J.. Antibiotics: The Comprehensive Guide,
London, Bloomsbury. 1990, pxviii; de Groot, op cit, PP247
10.
Jacoby and Archer, op cit, pp6oi-i2; Halliday, op cit, pxviii; Henry, J. (ed),
The Bntish Medical Association Guide to Medicines & Drugs, London, Dorlmg
9.
11.
Kindersley, (2nd edn) 1991, P124
Levy, S.B., “Starting life resistance-free", New England Journal of Medicine,
Vol 323. No 5, 2 Aug 1990, PP335 7
12.
O'Sullivan, N. and Wise, R.t “Macrolide, lincosamide, and streptogramin
13.
14.
antibiotics", Current Opinion in Infectious Diseases, Vol 3,1990, PP743 50;
de Groot, R., op cit, p2o
Reed, B.D., Huck, W„ and Zazove, P., “Treatment of beta-hemolytic
streptococcal pharyngitis with cefaclor or penicillin: efficacy and interaction
with beta-lactamase-producing organisms in the pharynx", Journal of Family
Practice, Vol 32, No 2,1991, PP138-44
Hamilton-Miller, J.M.T., "The emergence of antibiotic resistance, myths and
facts in clinical practice". Intensive Care Medicine, Vol 16 (Suppl. 3). 1990,
PPS206-11
15.
Anon., 'WHO/ATH on the misuse of antibiotics', Scrip, No 1272/3,8/13 Jan
1988, p26; O'Neill, P. and McIntosh, S.. 'Bacteria resistant to antibiotics
spread concern’, New Scientist, 27 Aug 1987, pi6
16.
Marton. A., Gulyas, M„ et al. “Extremely High Incidence of Antibiotic
Resistance in Clinical Isolates of Streptococcus pneumoniae in Hungary”,
17.
Journal of Infectious Diseases, 163,3, Mar 1991. 542-8
Fenoll, A. Bourgon, CM., et al, “Serotype distribution and antimicrobial
resistance of Streptococcus pneumoniae isolates causing systemic infections
in Spain, 1979-1989", Reviews of Infectious Diseases, Vol 13, No 1, Ian-Feb
1991, 56-60
Anon . 'WHO on multiresistant bacteria', Scrip, No 1290,11 Mar 1988. p20
Barnes, R.C, Holmes, K K„ “Epidemiology of gonorrhea: current
perspectives", Epidemiology Review, Vol 6,1984, ppi-30
20.
Czachor, J.S. and Gleckman, R.A., “Third-generation cephalosporins: a plea to
save them for specific Infections". Postgraduate Medicine, Vol 85, No 4.
Mar 1989, PP169176; van Klingeren, B., Dessens-Kroon. M., Verheuvel, M,
"Increased tetracycline resistance in gonococci in The Netherlands", Lancet,
18.
19.
37.
5 Oct 1991, pp862-6
24 Brumfitt, W and Hamilton-Miller, J.. “Methicillin resistant Staphylococcus
aureus?. New England Journal of Medicine, Vol 320, No 18, 4 May 1989,
25.
26.
27.
28.
29.
PP118896
Maple, PAC, Hamilton-Miller, J.M.T. and Brumfitt, W. “World wide antibiotic
resistance in methicillin-resistant Staphylococcus aureus?. Lancet, 11 Mar
p8
45.
Harvey, 1988, op cit, PP747
46 Anon.. Scrip, No 1313,1 Jun 1988. op cit, p20
47.
lones, R.N., “Role of new cephamycins in the management of obstetric and
gynecologic infections". Journal of Reproductive Medicine, Voi 35, No 11,
(suppl.) Nov 1990. PP10707
48.
WHO, The Use of Essential Drugs. (Technical Report Series No 770). Geneva,
WHO. 1988, PP33-4- (The figure excludes drugs for parasitic infections, for
leprosy and for tuberculosis.)
49.
Parish, op cit, P283
50.
Schlegel, P.N., Chang, T.S.K. and Marshall. F.F., “Antibiotics: potential hazards
to male fertility", Fertility and Sterility, Vol 55, No 2, Feb 1991, PP235-42
51 Steele. R.W. and Kearns, G.L, "Antimicrobial therapy for pediatric patients".
Pediatric Clinics of North America. Vol 36, No 5. Oct 1989. PP132149
52.
Schorling, J.B., de Souza, MA and Guerrant, R.L., “Patterns of antibiotic use
among children in an urban Brazilian slum", International Journal of
53.
54.
55.
56.
57.
58.
59.
31.
32.
63.
Chemotherapy. 1987, PP759 63
Anon., Scrip, No 1355, 26 Oct 1988, op cit. p20
Anon., Scrip, No 1335.17 Aug 1988, op cit. p2i
Antibiotic Guidelines Sub-Committee, Health Dept of Victoria; Antibiotic
Guidelines (5th edn), Toorak, Victorian Medical Postgraduate Foundation,
14 Sep 1991. P702
Pratt. W.B. and Fekety, R . The Antimicrobial Drugs, Oxford. Oxford University
Press. 1986, pi4
64.
Erlichman, J„ Gluttons for Punishment. London, Penguin, 1986. P44
65.
Spika, J.S., Blake, PA and Cohen, M L, ‘Chloramphenicol-resistant
Salmonella newport traced through hamburger to dairy farms". New England
Journal of Medicine. 3 Sep 1987, P632; Ryan. CP. and Steele, J.H..
"Chloramphenicol-resistant Salmonella newport traced through hamburger to
dairy farms". New England loumal of Medicine, 3 Sep 1987, P632
66.
67.
68.
de Groot, op cit, ppzo-i
Erlichman. op cit, PP58 and 47
Okolo, Ml “Bacterial drug resistance in meat animals: a review". Int J
69.
Zoonoses. Vol 13, No 3. Sep 1986, ppi43-52
Piddock, L.J.V., Wray, C. et al; “Quinolone resistance in Salmonella spp:
70.
71.
72.
74.
Henry, op cit, P124
Harvey, K„ ‘Antibiotic use in Australia', Australian Prescriber, Vol II No 4.1988,
Anon., Scrip, No 1276, 22 Jan 1988, op cit. p24
Obaseiki-Ebor, E.E., Akerele, J.O. and Ebea, P.O., “A survey of antibiotic
outpatient prescribing and antibiotic self-medication". Journal of Antimicrobial
1987, pn
Enenkel. S. and Stille, W., Antibiotics in the Tropics: antibacterial therapy with
limited resources. Berlin. Springer-Veriag. 1988, P34
61.
Obaseiki-Ebor, et al, op cit, PP759 63
62.
Misago, C and Fonseca, W., “Antimicrobial drugs advised in pharmacies in
Brazil for children with acute respiratory infections", Lancet, Vol 338, No 8768.
de Groot, op cit, pi9
Anon., 'Antibiotic usage in Uruguay*, Scrip, No 1276, 22 Jan 1988, P24; Anon..
•Importance of training in EDP’, Scrip, No 1355, 26 Oct 1988, pzo; Anon.,
•Kuwait’s antibiotic consumption', Scrip, No 1335,17 Aug 1988, pzi; Anon.,
‘Misuse of antibiotics In Pakistan'. Scrip, No 1339. 31 Aug 1988. p2i; Anon..
Scrip, No 1290,11 Mar 1988, op cit, pzo
30.
Anon., "Swedish antibiotic use in 1988". Scrip, No 1479,12 Jan 1990, p8
Epidemiology. Vol 19. No 4,1991, PP293-9
Salam and Bennish, op cit, PS335
WHO, The treatment and prevention of acute diarrhoea: Practical guidelines.
Geneva, WHO, (2nd edn) 1989, p3
60.
1989. PP537 4O
Levy, op cit, PP335*7
Jacoby and Archer, op cit, pp6oi-i2
'Inappropriate use of antibiotics in New Zealand', Scrip, No 1313,1 Jun 1988.
p20; Anon., 'Combination antibiotics questioned in Brazil', Scrip. No 1296,
1 Apr 1988, pi8; Anon.. Scrip, No 1272/3,8/13 Jan 1988, op cit. p26; Anon.,
Health Research Group, 1988, P343
Parish, P., Medicines: a guide for everybody, London, Penguin (6th edn,
revised). 1989, P284
Frieden, T.R. and Mangi, R.J., “Inappropriate use of oral ciprofloxacin". Journal
of the American Medical Association. Vol 264, No 11,19 Sep 1990, ppi438-4O
41.
O’Neill and McIntosh, op cit, pi6
42.
Hamilton-Miller, op cit, pp$2o6-n
43.
Lexchin, J.. "Doctors and detailers: therapeutic education or pharmaceutical
promotion?". International Journal of Health Services, Vol 19, No 4,1989, P675
44.
Anon.. “'Indiscriminate' antibiotic use in Italy”, Scrip, No 1616,15 May 1991,
Reviews of Infectious Diseases. Vol 13. Suppl. 4. Mar-Apr 1991, PS336
de Groot, op cit, PP467
Pecoul, B„ Varaine. F., et al. “Long-acting chloramphenicol versus intravenous
ampicillin for treatment of bacterial meningitis", Lancet. Vol 338, No 8771,
No 3. Mar 1985. PP388-98
Black. G.J. (ed.), Physician's 1990 Drug Handbook, Springhouse, PA
40.
25 Nov 1989, P1278
21.
Salam, MA and Bennish, M.L., “Antimicrobial therapy for shigellosis",
22.
23.
Kunin, CM., “The responsibility of the infectious disease community for the
optimal use of antimicrobial agents". Journal of Infectious Diseases, Vol 151,
Anon.. “Who is responsible for these unnecessary typhoid deaths?", ACASH
News, Dec 1990. pi
Australian microbiologist Dr Ken Harvey, quoted in: de Bruxelles, 5. and
Ferriman, A, "Deadly 'super bug' spreads through wards", Observer (London).
PPS244-60
Lester. S.C., Pla, M.dP, et al, “The carriage of Escherichia coli resistant to
antimicrobial agents by healthy children in Boston, in Caracas, Venezuela, and
veterinary pointers", Lancet, 14 Jul 1990, P125
Anon, “8% growth for anti-infective market", Scrip. No 1791. 2 Feb 1993. P25
Scrip's 1991 Antibacterial Report. London, P|B Publications. 1991 (One source
estimates that the market will be worth more than $25 billion by 1995; see:
Anon.. “Searle launches Maxaquin in Mexico". Scrip. No 1598.13 Mar 1991.
p22.)
Geddes, op cit, pp286-9; Liss, R.H. and Batchelor, F.R., “Economic evaluations
of antibiotic use and resistance - a perspective: report of Task Force 6",
Reviews of Infectious Diseases, Vol 9 (Suppl. 3). May-Jun 19S7, PPS297312
73.
Frieden and Mangi, op cit, PP1438 40; also reported in: Anon.. “Overuse of
ciprofloxacin in US?", Scrip, No 1558.17 Oct 1990. pz6
Hemminki, E., “Adverse reactions to antibiotic drugs: the present scope of the
problem in outpatient care and possibilities for improvement". International
Journal of Health Services, Vol 11, No 2,1981, PP283-301
Wyatt, T.D., Passmore, CM., et al. “Antibiotic prescribing: the need for a policy
in general practice", British Medical Journal, Vol 300,17 Feb 1990. PP44V4
76.
Carlson. )A, “Antimicrobial formulary management: meeting the challenge in
a health maintenance organization". Pharmacotherapy. Vol u. No 1 (suppl.),
75.
PP747
33- Jackson, D.M. and Soothill, R., Is the Medicine Making You III?, North Ryde.
77.
1991, PP32S-35S
LappA M., When Antibiotics Fail, Berkeley. Calif., North Atlantic Books, 1986.
Australia, Angus & Robertson, 1989, pi2
34- Chilnlck. L.D. (ed.), The Pill Book, New York, Bantam Books, (4th edn) 1990,
78.
P96
Anon.. 'Drug promotional problems', Medical Journal of Australia. Vol 150,
79.
17 Apr 1989, P463
Scrip's 1990 Antibacterial Report, London. PJB Publications. 1990
35.
P9A6
Levy, op cit, PP335 7
67
68
3 A .
Antibiotics
Problem Drugs
Anon.. “Top 20 branded products of 1988", Scrip. No 1481.19 Jan 1990, P24
(based on estimates reported in Flemings Research's Pharmaceutical Products
Worldwide); Anon., “Ten 'key' drugs to boost SB”. Scrip, No 1614/15.
S & 10 May 1991, pio
81.
Parish, op cit. p286
82 IFPMA, IFPMA Code of Pharmaceutical Marketing Practices, Geneva, IFPMA,
8o.
83.
1989, p6
Liu, H.H., “Antibiotics and infectious diseases”, Primary Care, Vol 17, No 4,
Dec 1990, PP74574
BMA and the Royal Pharmaceutical Society of Great Britain, British National
Formulary, London, BMA and The Pharmaceutical Press, No 22, Sep 1991,
P196
85.
Scrip's 1990 Antibacterial Report, op cit
86.
Anon., “European antibiotic mkt projections”, Scrip, No 1591,15 Feb 1991, p6
. (citing a 1991 Frost & Sullivan report. The European market for antibiotic
products)
87.
Gentry, L.O., “Newer concepts in antimicrobial therapy”, Clinical Orthopaedics
and Related Research, No 261, Dec 1990, pp23-6
88.
AMA, Drug Evaluations, Philadelphia. W.B. Saunders Co., (4th edn) 1980,
84.
89.
P1344
Smith, G.H., “Oral cephalosporins in perspective”, DICP, The Annals of
Pnarmacotherapy, Vol 24, Jan 1990, PP45-51
91.
Czachor and Gleckman, op cit, PP169-176
92.
Antibiotic Guidelines Sub-Committee, op cit, P15
93.
Karam, G.H., Saunders, C.V, and Aldridge, K.E., “Role of newer antimicrobial
agents in the treatment of mixed aerobic and anaerobic infections”, Surgery,
Gynecology & Obstetrics, (suppl. to vol 172) 1991, PP57-64
94.
Chapman, S.T. and Waish, T.H., “Which Antibiotic for Surgical Nosocomial
Infection?" British Journal of Clinical Practice, Vol 45, No 2, Summer 1991,
ppi4i-4
Rodriguez, W.J. and Wiedermann, B.L., “Progress in antibacterial therapy.
cephalosporins and quinolones". Advances in Pediatric Infectious Diseases,
Vol 4,1989, ppi83-2io
AMA, 19S6. op cit, P1369
Advertisement in Thailand Index of Medical Specialities, Vol 17, No 3,
Nov 1988, facing p2i2
98.
Anon., “Hoechst pharma analysed", Scrip, 25 Nov 1985, py
99.
Anon., ‘Hoechst's 1990 pharma sales up 2%", Scrip, No 1619, 24 May 1991,
pio
100.
Advertisement in Quereshi, A.H. (ed.), Quick Index of Medical Preparations,
Nos 1 & 2, Mar-Aug 1990, facing p2A
101.
Ibid, facing P93
102 Neu, op cit, DP276-85
103.
DiNubile, MJ., “Antibiotics: the antipyretics of choice?”, American Journal of
Medicine, Vol 89, Dec 1990, PP787 8
104.
Liu, op cit, pp745-74
105.
Anon.. Scrip, No 1598,13 Mar 1991, op cit, p22
106.
Anon., Scrip, No 1591,15 Feb 1991, op cit, p6
107.
Frieden and Mangi, op cit, PP1438-40; reported in: Anon., Scrip, No 1558,
17 Oct 1990. op cit, p26; and in: Anon., “Quinolones: costs and benefits",
Drug Monitor (Philippines), Vol VI, No 4, Apr 1991, P42
108.
Tan, ML, Dying for Drugs: Pill power and politics in the Philippines, Manila,
Health Action Information Network, 1988, PP142-3
109.
Advertisement in Thailand Index of Medical Specialities, op cit, facing P234
110.
Advertisement in MIMS Africa, Vol 31, No 4, Jul 1991, P73
111.
Anon., "Top 50 branded products worldwide", Scrip, Review issue 1990, pzi
(based on Barclay de Zoete Wedd's Pharmaceutical Industry Perspectives)
96.
97.
Steele and Kearns, PP1321-49
Rodriguez and Wiedermann, op cit, PP183-210
Hooper, DC. and Wolfson, J.S., "Fluoroquinolone antimicrobial agents", New
England Journal of Medicine, Vol 324. No 6, 7 Feb 1991, pp384-94
115.
Advertisement in Af/MS India, Vol 8, No 2, Feb 1988, P83
116.
Neu, op cit. PP276-85
117.
Yeung, K.H. and Dillon, J.R . “Norfloxacin resistant Neisseria gonorrhoeae in
North America”, Lancet. Vol 336, No 8717, 22 Sep 1990, P759‘. Jephcott, A.E.
and Turner, A., "Ciprofloxacin resistance in gonococci", Lancet, Vol 335,
112.
113.
114.
118.
No 8682, 20 Jan 1990, P165
Hedin, G and Hambraeus, A., “Multiply antibiotic-resistant Staphylococcus
epidermidis in patients, staff and environment - a one-week survey in a
bone marrow transplant unit", Journal of Hospital Infection, Vol 17.1991,
PP95-106
119.
Trucksis, M„ Hooper, D.C and Wolfson, J.S., “Emerging resistance to
fluoroquinolones in staphylococci: an alert", Annals of Internal Medicine,
120.
121.
Hampson, N.B., Woolf, R A. and Springmeyer. S.C, "Oral antibiotics for
127.
pneumonia", Clinics in Chest Medicine, Vol 12, No 2, lun 1991, PP395-4O7
Advertisement in Drug Index for Malaysia & Singapore, Vol 15, No 2, |un
128.
1986, facing pi6
BMA and the Royal Pharmaceutical Society of Great Britain, op cit, P205
129.
130.
Vol 114. No 5,1 Mar 1991, PP424-6
Anon., "Emerging ciprofloxacin resistance", Scrip, No 1566,14 Nov 1990, p28
Muder, R.R., Brennen, C, et al, "Association with prior fluoroquinolone
therapy of widespread ciprofloxacin resistance among gram-negative
isolates in a Veterans Affairs medical center”, Antimicrobial Agents and
122.
123.
124.
Chemotherapy, Vol 35, No 2, Feb 1991, pp256-8
Steele and Kearns, op cit, PP1321-49
Liu, op cit, PP745-74
Moellering, R.C, “Introduction: Revolutionary changes in the macrolide and
azalide antibiotics", American Journal of Medicine. Vol 91 (Suppl. 3A), 12 Sep
125.
1991, P3A-2S
Rodnick, J.E. and Gude, J.K., “Diagnosis and antibiotic treatment of
community-acquired pneumonia". Western Journal of Medicine, Vol 154,
Apr 1991, PP405-9
AMA, 1986, op cit, P1405
Advertisement and product listing in Philippine Index of Medical
Specialities, Vol 17, No 3, Dec 1988, ppzi7-i8
131.
132.
133.
134.
135.
136.
137.
138.
P1230
AMA, Drug Evaluations, Philadelphia, W.B Saunders Co., (6th edn) 1986,
90.
95.
126.
139.
Ibid, pzi6
Scrip's 1990 Antibacterial Report, op cit
Parish, op cit, PP290-1
Hu, D.-N., Qiu, W.Q., et al, "Genetic aspects of antibiotic induced deafness:
mitochondrial inheritance", Journal of Medical Genetics, Vol 28,1991,
PP79-83
Wilson, S.E., “Aminoglycosides; assessing the potential for nephrotoxicity”,
Surgery, Gynecology & Obstetrics. Vol 171 (SuppL), 1990, pp24-30
AMA, 1986, op cit, P1434
Steele and Kearns, op cit, PP1321-49
Neu, op cit, PP276-85; Bergogne-Berezin, E., "Current trends and new
perspectives in antibiotic therapy". Journal of Chemotherapy, Vol 1, No 5,
1989, pp285’92
BMA and the Royal Pharmaceutical Society of Great Britain, op cit, pzoz
140.
WHO, 1988, op cit, P35
141 BMA and the Royal Pharmaceutical Society of Great Britain, op cit, P203
142.
143.
Parish, op cit, P291
BMA and the Royal Pharmaceutical Society of Great Britain, op cit, P36
AMA, 1986, op cit, P1446
Reynolds, J.E.F. (ed.), Martindale: The Extra Pharmacopoeia, London, The
Pharmaceutical Press, (29th edn) 1989; BMA and the Royal Pharmaceutical
Society of Great Britain, op cit; AMA, 1986, op cit
146.
Cawson, R. and Spector, R„ Drugs and Medicines: a consumers' guide,
Oxford, Oxford University Press, 1990, P37
147.
BMA and the Royal Pharmaceutical Society of Great Britain, op cit, p2o6
148.
Parish, op cit, D292
149.
Dunne, M„ et al. "Indications and warnings about chloramphenicol", Lancet,
6 Oct 1973, PP781-3
150.
Wolfe, et ai, op cit, P343
151.
Advertisement and product listing in Philippine Index of Medical
Specialities, Vol 17, No 3, Dec 1988, P175
152.
Pecoul, et al, op cit, pp862-6
153 Enenkel and Stille, op cit, pi4
154.
BMA and the Royal Pharmaceutical Society of Great Britain, op cit, pzoo
155.
Parish, op cit, P290
156.
Advertisement in Drug Index for Malaysia and Singapore, Vol 15, No 2, Jun
1986, facing P189
157 A.G., Rail, T.W., Nies, A.S., and Taylor, P., Goodman and Gilman's The
Pharmacological Basis of Therapeutics, New York, Pergamon Press, (8th
edn) 1990, p 1122 (quoting a 1977 study by Fanning. W.L., et al, "Side effects
of minocycline: a double-blind study”, Antimicrobial Agents and
Chemotherapy, Vol 11,1977, PP712-17)
158.
Advertisement in Thailand Index of Medical Specialities, Vol 17, No 3, Nov
1988, facing P230
159.
Liu, op Cit, PP745-74
160.
Letter from MaLAM to Lederle Laboratories, Feb 1991
161.
Hollister, LE. (ed.). 1988 Year Book of Drug Therapy, Chicago, Year Book
144.
145.
Medical Publishers, 1988, P191
de Groot, op cit, PP35-7, 53-4
WHO, The World Drug Situation, Geneva, WHO, 1988, P19
de Groot, op cit, PP35-6
165.
Pauly, D.J., Musa, D.M., et al, “Risk of nephrotoxicity with combination
vancomycin-aminoglycoside antibiotic therapy". Pharmacotherapy, Vol 10,
No 6,1990, PP378 82
166.
WHO, 1988, op cit
167.
Steele and Kearns, op cit, PP1321-49
168.
French, G. and Ling, T., “Amoxycillin/davulanic acid resistant Escherichia
coir, Lancet, 26 Mar 1988, P704
169.
Anon., Scrip, No 1296,1 Apr 1988, op cit, pi8
170.
Wyatt, etal, opcit, pp44i-4
171.
Geddes, op cit, pp286-9
172 Anon., "WHO proposes ‘reserve antibiotics'”, Scrip, No 1493, 2 Mar 1990,
162.
163.
164.
pz8
Friedman, R.B. and Katt, J.A., "Cost-benefit issues in the practice of internal
medicine”, Archives of Internal Medicine, Vol 151, Jun 1991, ppn6s-8
174.
Bergeron, M.G., “The future of new oral antibiotics including the
quinolones”, Canadian Medical Association Journal, Vol 138,1 Jan 1988,
173.
PP35-42
Midtvedt, T., “Increasing worldwide microbial resistance: a worldwide
responsibility for all, including the pharmaceutical industry and the World
Health Organisation”, in Dukes, M.N.G. and Beeley, L. (eds), Side Effects of
Drugs Annual 12, Amsterdam, Elsevier, 1988, pp2o6-8
176.
Jacoby and Archer, op cit, pp6oi-i2
177.
Wise, R., “Antimicrobial agents: a widening choice”, Lancet, 28 Nov 1987,
175.
178.
179.
180.
ppi25i-4
Hamilton-Miller, op cit, ppS206-n
Levy, op cit, PP335-7
Hamilton-Miller, op cit, ppS2o6-n
Chetley, A. Problem Drugs, Amsterdam,
Health Action International, 1993
Health Action International’s
coordinating offices:
HAI Europe
Jacob van Lennepkade 334T
z>A. Analgesics
1053 NJ Amsterdam
The Netherlands
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accion para la Saiud
Avda. Palermo 531
Dpto. 104
Lima 13
Peru
Killing pain
True or false?: “You can’t buy a more potent pain reliever
without a prescription " - Extra Strength Tylenol. "Tylenol
provides relief without the stomach irritation you can get
from aspirin or Advil". Anacin-3 "recommended over five
million times for headaches and other kinds of pain”.
Bufferin "reaches the bloodstream twice as fast”.
According to Manhattan US District Court Judge William
C. Conner, all the claims are untrue or misleading. After a
two-year suit and countersuit between Johnson & Johnson
and American Home Products who were contesting for
supremacy in the Sl.S billion over-the-counter (OTC) pain
killer market in the USA, his 65-page decision included the
comment: "Small nations have fought for their very sur
vival with less resources and resourcefulness than these
antagonists have brought to their epic struggle for com
mercial primacy in the OTC analgesic field.
Pain is one of the most common of symptoms, and
one of the most frequent reasons why people seek
medical care.2 It is not surprising, therefore, that
analgesics (pain killers) are among the most used
categories of drugs.’ In 1981, about 9% of all drug
prescriptions in the USA were for analgesics and
associated medications.4 In the UK in 1989, sales of
analgesics accounted for 20% of the total market
for OTC drugs.5 The US market for pain manage
ment products - which includes prescription drugs,
OTC drugs, devices and alternative therapies stood at US S5 billion in 1988 and is expected to
exceed $7.8 billion by 1995, of which an estimated
$4.04 billion will be for prescription drugs, and
$3.61 billion will be spent on OTC products.6 By
1995 the European market for all types of pain
relief products is expected to reach $7 billion.7
The human body has thousands of nerve endings,
highly sensitive to pain, scattered throughout various
tissues. When tissue is damaged due to injury or
infection, chemicals called prostaglandins are
produced. These prostaglandins act on the nerve
endings so that a message is sent along the nerves to
the brain and we respond with the feeling of pain “an unpleasant sensory and emotional experience”.8
Pain is not simply a perception. It is a complex phe
nomenon or syndrome, only one component of which
is the sensation actually reported as pain. Pain has
four major components: nociception (the impact of
the local injury or trauma on the nerve endings or
nociceptors); the perception of pam which is a psy
chological state; suffering as a consequence of the
pain (which usually manifests as anxiety in the case of
acute pain and depression in the case of chronic pain);
and pain behaviour (facial expression, restlessness,
seeking isolation or company, medicine taking, and so
on).9 It is at least partially a learned response.10
Animal studies have shown that pain and stress can
inhibit immune function and enhance tumour
growth. One of the leading experts on pain, Dr
Ronald Melzack, expressed it plainly when he told
colleagues at the Fifth World Congress on Pain,
“Pain can... have a major impact on morbidity and
mortality... it can mean the difference between life
and death.”11
Pain is usually described as acute or chronic, with the
difference being based on the rime a pain lasts. For
example, chronic pain is usually defined as pain which
persists past the expected normal time of healing,12
while acute pain can be defined as an event whose end
can be predicted.13 At least among children, it has been
suggested that there should be three categories: acute
pain, cancer pain, and chronic non-malignant pain.14
Most paediatric pain is acute and self-limiting. The
recurrent pains of childhood - headaches, abdominal
cramping, and limb pains - seldom need pharmaco
logical therapy unless an organic basis exists.15
69
4 A .
Analgesics
Problem Drugs
Chronic pain is one of rhe costliest of today's health
problems in industrialised countries. It has been esti
mated to affect 25-30% of the populations in
industrialised countries.16 In the USA, the overall
cost of pain amounts to nearly $90 billion a year.1'
Table 4A-1
Sales figures and projections (in US$ millions) for
Treating pain
United States of America
pain management products in selected markets
(1988-1995)
1988
Although acute pain can often be dealt with in a rel
atively simple manner, dealing with chronic pain is a
much more complex matter, one which more and
more is coming to rely on a multidisciplinary
approach that takes into account a wide range of
therapies and support mechanisms.18
The best way to treat acute pain is to attempt to
remove the underlying cause. A pain killer should be
used only when the cause of the pain cannot be
removed.19 One of the reasons for this is that anal
gesics do not take the cause of rhe pain away, they
simply reduce the response produced by the pain.
However, the relief of pain does not necessarily
depend on the use of analgesics. Cold water applied to
a skin burn may relieve the pain; heat or massage may
relieve muscle pain; an alkali mixture may relieve the
pain of a peptic ulcer. Recently too, evidence has been
emerging from clinical studies to suggest that
acupuncture or electrical nerve stimulation across the
skin (transcutaneous) can relieve some types of
pain.20 It is also worth remembering the 1955 study
by Henry K. Beecher which found that 35% of people
suffering from a variety of painful conditions experi
enced relief when they were given a placebo.21
However, much misprescribing of pain killers seems to
occur. One study of 500 patients with headache in Italy
found that the treatments prescribed by doctors “var
ied widely, seemed not to be closely correlated with the
subtype of headache (e.g. migraine, muscle contrac
tion), and seemed not to reflect the recommendations
given in controlled studies in the scientific literature. A
very large number of drugs were used |76 different
drugs], often in combinations, and some had scant or
no rationale for use for the indication of headache.”22
One doctor points out that most of the analgesics on the
market are simply “alternatives of fashion or conve
nience. Appreciating this helps prevent ‘kangarooing’
from analgesic to analgesic in a desperate search for
some drug that will suit the patient better.”23
Total1
1989
1995
2500
3610
5000
OTC2
7800
Prescription3
4040
European Community4
Total
7000
anti-inflammatory/
antipyretic analgesics
5700
local anaesthetics
587
opioid analgesics
500
homoeopathic medicines
104
pain control devices
19
Germany
Total
OTC5
2067
306
UK
Total
OTC5
817
215
Italy
1231
Total
OTC5
131
France
1780
Total
OTC5
71
Spain
Total
Total
374
Notes and sources:
1.
These figures are the total for all pain management products, which
includes prescription drugs, OTC drugs, devices and alternative therapies.
From a report. Accelerated Growth in Pain Management Markets;
Forecasts of Pharmaceuticals, Devices and Alternative Treatments, by the
Market Intelligence Research Company (MIRC), reported in: Anon., "New
publications". Scrip, No 1483. 26 Jan 1990, p4
2.
OTC figure for 1989 is from a Euromonitor report, Analgesics - The
International Market 1991, reported in: Anon., "OTC analgesic trend
‘static"’. Scrip, No 1587, 1 Feb 1991. p27; OTC figure for 1995 is from the
MIRC report referred to above.
3.
The prescription analgesics figure is from the MIRC report referred to
above.
4.
All the 1995 figures for the European Community and its member
states are from a Frost and Sullivan report. The European Market for Pain
Management Products - Pharmaceuticals. Pain Control Devices & Alternative
Medicines, reported in: Anon., "European pain relief market set to rise",
Scrip. No 1587. 1 Feb 1991, p27.
5.
All the 1989 figures for the OTC market share by different countries is
from the Euromonitor report referred to above.
Types of analgesics
There is no internationally agreed classification of
analgesics. Some text books classify them according to
their effectiveness in treating either mild or severe
pain. Others classify them according to inhere they
work - either at the site of the pain or on the brain.
Pain relievers that work at the site of pain block the
production of prostaglandins, which in turn prevents
the stimulation of the nerve endings so no pain
405
Benelux
message is sent to the brain; those that work on the
brain block the transmission of pain signals between
brain cells and therefore interfere with the perception
of pain.24 Another approach is to talk about narcotic
or opioid analgesics (those analgesics of natural or
synthetic origin with actions like morphine) and
4 A .
Analgesics
Combination products
The narcotic analgesics are generally subject to strict
controls in most countries and are reserved for use in
cases of severe pain such as after surgery, or in termi
nal cancer patients. There are fewer restraints on
non-narcotic analgesics. In most countries, there are
dozens on the market.
As Table 4A-2 on the next page shows, a survey of
1988 prescribing guides from 13 regions of the world
found that just under 40% of analgesics were combi
nation products. By 1990, prescribing guides in
Africa, the Caribbean, the Middle East and Pakistan
indicated that one-third of the analgesics in those set
tings were combination products. This is despite
years of standard independent advice that the use of
combination analgesics offers no real advantage, can
be harmful, and is certainly more costly. As one
The WHO Essential Drugs List contains four nonopioid analgesics/antipyretics/NSAIDs. They are:
• acetylsalicylic acid (aspirin) - which has both anal
gesic and anti- inflammatory properties;
• paracetamol - an analgesic without significant
anti-inflammatory properties;
• ibuprofen - an anti-inflammatory drug that is also
effective as a pain killer; and
• indomethacin - an anti-inflammatory drug with
analgesic properties.
Ibuprofen and indomethacin are included as exam
ples of a therapeutic group, and other drugs in the
same group may be substituted depending on cost
and availability.28 Such drugs could include other
propionic acid derivatives for ibuprofen - naproxen,
fenoprofen, ketoprofen, flurbiprofen, fenbufen, pirprofen, oxaprozin, indoprofen or tiaprofenic acid and sulindac for indomethacin.
A Health Action International (HAI) survey pub
lished in 1986 found that three-quarters of the
analgesics on the market in Africa, Indonesia, India,
the Middle East and the Caribbean during 1985
should not be used - either because they contained
potentially dangerous ingredients, were irrational or
ineffective combinations, or were simply unnecessar
ily expensive when compared to equally effective
alternatives on the market.29
A survey of drugs manufactured by German companies
that were on the market in seven areas of the world in
1988 (Africa, Brazil, Central America, Colombia,
India, Mexico, Philippines) found that 77% of the 81
analgesics were “inappropriate”.30 Drugs were classi
fied as inappropriate because they were irrational
combinations, efficacy data were lacking, safer alterna
tives were available, unsuitable dosage forms were
used, or there was not enough active ingredient.
One way companies try to distinguish their pain
killers from a competitor’s brand is to add extra
ingredients and produce a combination drug.
Popular combinations include:
• aspirin and/or paracetamol with codeine
• paracetamol or aspirin with dextropropoxyphene
• aspirin and/or paracetamol with caffeine
• paracetamol with pentazocine
• aspirin or paracetamol with vitamins
• aspirin and/or paracetamol with phenacetin
• aspirin or paracetamol with a pyrazolone derivative
• aspirin or paracetamol with a barbiturate.
Common analgesics
Opioid or narcotic analgesics
morphine
codeine
dextropropoxyphene
pentazocine
tramadol
Non-narcotic analgesics/antipyretics
aspirin*
paracetamol (acetaminophen)
dipyrone (metamizol)
glafenine
phenacetin
propyphenazone
Anti-inflammatories (NSAIDs)
aspirin
ibuprofen
indomethacin
mefenamic acid
diclofenac
ketoprofen
ketorolac
etodolac
naproxen
piroxicam
tiaprofenic acid
•Note: aspirin is classified as both a non narcotic analgesic and an antiinflammatory
Problem Drugs
non-narcotic or non-opioid analgesics (such as
aspirin). Narcotic analgesics may produce drug
dependence. They are used frequently and effectively to
relieve severe pain, usually from internal organs, but
also from other parts of the body. Non-opioid
analgesics are used to relieve skin, muscle, joint, bone
or tooth pains.25 Still another classification divides pain
killers into those that simply relieve pain and fever
(antipyretics), and those that relieve pain, fever, and
help to reduce inflammation.26 The latter are usually
described as non-steroidal anti-inflammatory drugs
(NSAIDs) or, because aspirin is the prime NSAID, they
are sometimes called aspirin-like drugs.27
7i
72
4 A .
Analgesics
Problem Drugs
recommended.
Single-ingredient
preparations
should be prescribed in preference because com
pound preparations rarely have any advantage and
complicate the treatment of overdosage.”34 Thus,
for example, although the combination of aspirin
or paracetamol with an opioid such as codeine
might be considered rational in the treatment of
some types of moderate to severe pain, “it is advis
able under most circumstances... to prescribe the
two agents separately so that individual dose
adjustments can be made”.33 In 1991, the Swiss reg
ulatory authority, the IKS, announced that all
combinations of analgesics with codeine would be
made prescription-only. The IKS said that compa
nies that wished to continue marketing these
products as OTC preparations could do so by
reformulating them without the codeine and filing
an application for a modification to the product. It
promised to process these applications without any
further questions, provided no other ingredient was
included to replace the codeine.36
textbook on clinical pharmacology says, “there is
accumulating evidence that analgesic mixtures are
more likely to produce renal [kidney] damage than
single agents”.11
The American Medical Association says that
although mixtures of analgesics or of analgesics with
other classes of drugs are among the most widely used
pharmaceutical products, “relatively few wellcontrolled studies have been performed to determine
their comparative effectiveness”.32 The British
Medical Association concurs: “there is little evidence
that preparations containing more than one analgesic
are more effective than a single drug. A combined
preparation may also combine the side effects of both
classes of drug. For these reasons it is usually advis
able to use a single ingredient preparation.”33
According to the British National Formulary,
“Compound analgesic preparations of, for exam
ple, aspirin, paracetamol, and codeine are not
Table 4A-2
Comparison of analgesics on the market in selected countries (1987-1990)
Country/
Year
No & % of drugs containing:
Total no. of
analgesics
region
other pyrazolones
dipyrone
combinations
barbiturates
vitamins
No.
%
No.
%
No.
%
No.
%
No.
%
9
7
1
1
50
40
1
<1
34
13
135
52
28
41
Africa
1988
126
21
17
11
9
Brazil
19878
261
155
60
3
1
Canbbean
1988
68
12
18
0
Hong Kong
1988
80
5
6
5
6
1
1
3
India
1988
73
18
25
3
2
3
0
Indonesia
36
8
4
5
3
2
43
4
3
0
7
0
0
0
1988
176
63
Malaysia &Singapore 1988
116
0
Mexico
1987
153
92
60
5
3
27
34
48
66
24
72
41
6
28
24
13
9
68
44
4
Middle East
1988
146
24
16
12
8
9
6
4
3
57
39
Pakistan
1987
205
26
13
4
2
4
2
3
2
60
29
Philippines
1988
179
6
3
1
1
0
1
1
17
10
South Africa
1988
135
8
6
2
2
5
4
2
2
98
73
2
2
28
21
113
6
716
39
2
2
42
35
26
39
Thailand
1988
133
28
21
3
2
0
Total
1988
1851
458
25
61
3
34
2
Africa
1989
121
18
15
9
7
1
1
Caribbean
1989
66
12
18
6
9
0
Middle East
1989
143
21
15
10
7
1
1
4
3
50
35
Pakistan
1988-9
177
21
12
2
1
1
3
2
49
28
Total
1989
507
72
14
27
5
3
1
1
9
2
167
33
Africa
1990
115
18
16
9
8
1
1
2
2
41
36
Caribbean
1990
66
12
6
9
0
26
39
Middle East
1990
141
21
18
15
10
7
1
1
5
4
52
37
Pakistan
1990
186
21
11
2
1
1
1
3
2
50
27
Total
1990
508
72
14
27
5
3
1
10
2
169
33
Totals
1988-90
2866
602
21
115
4
40
1
132
5
1052
37
0
0
Sources: Africa: MIMS Africa May 1988, July 1989, July 1990; Brazil: DEF 1987-88; Caribbean- MIMS Caribbean May 1988. Nov 1989. July 1990; Hong Kong: HKIMS April
1988: India: MIMS India Feb 1988: Indonesia. UMS Feb 1988; Malaysia & Singapore: DIMS Feb 1988: Middle East: MIMS Middle East Apr 1988, Dec 1989, Jun 1990;
Mexico: DEF 1987: Pakistan: QIMP 1987. 1988-89. 1990; Philippines: PIMS April 1988: South Africa: MIMS May 1988: Thailand: TIMS March 1988
4 A .
The inclusion of caffeine in pain killers “does not
contribute to the analgesic or anti-inflammatory
effect of the preparation and may possibly aggravate
the gastric irritation caused by aspirin.”40 In most
cases, the amount of caffeine contained in such com
bination products is not sufficient to enhance the
analgesic effect of paracetamol or aspirin.41 There is
probably more caffeine in a cup of tea or coffee.42
Goodman and Gilman's The Pharmacological Basis
ofTherapentics notes that “there are few data to sub
stantiate its efficacy for this purpose”.43 One recent
(April 1991) study pointed out: “To date, to our
knowledge, no single published study has definitively
established the role of caffeine as an analgesic adju
vant”.44 The study itself offered some limited
evidence that caffeine was useful as an analgesic
adjuvant, at least for pain caused by a sore throat,
over a period of two hours. Other recent studies
found no significant difference between paracetamol
and caffeine versus paracetamol in headache,45 or
between aspirin and caffeine versus aspirin in moder
ate postoperative oral surgery pain.46 One study in
Germany has found that there are strong associa
tions of kidney disease with regular use of
paracetamol-aspirin combinations, especially when
taken jointly with caffeine.47
The combination of paracetamol with pentazocine is
irrational. When given orally, pentazocine has “rela
tively weak and unpredictable analgesic activity”. In
both acute and chronic pain, other analgesics have
been found to be equally or more effective and with
fewer adverse effects than pentazocine.48
Barbiturates today have a very limited clinical use on
their own and generally should be avoided because of
dependence problems and the possibility of serious,
often fatal, withdrawal effects.49 Their use in combi
nation with analgesics is totally unjustifiable.
Some countries have taken steps to remove combina
tion analgesics. Analgesics in combination with
alcohol, iron or vitamins have been banned in
Bangladesh. Analgesics in combination with barbitu
rates have been withdrawn in Turkey. Analgesics in
Table 4A-3
Analgesics containing dextropropoxyphene
in selected markets
Company
Brand name
Other
Countries/regions where
ingreds.
product was available
BR
Darrow
Algafan
Pa
Darrow
Algafan Comp.
De
BR
Boeh.Mann.
Algaphan
Pa
AF88;CA88.89.90: ME88.89.90
Concept
Anadex
Dp
IN
Arcana
Apa
Pa
HK
Fawns&McAllan
Capadex
Pa
HK
Roussel
Corbutyl
Pa
IN
SKF
Daprisal P
As
IN
Lilly
DarvocetN
Pa
AF88,89.90:CA88.89,90; ME88,89.90
PCW
Deprogesic
Cf.Pa
PK87,89,90
Remedica
Destirol
Pa
AF88.89,90;CA88.89, 90; ME88,89.90
Jean-Marie
Dextropropoxy.
Ld
HK
Wilson's
Diagesic
Pa
PK87.89.90
Diba
Dibagesic
As
MX
Lilly
Distalgesic
Pa
AF88,89,90;CA88: ME88,89,90;SA
Lilly
Doiogesic-32
Pa
HK.MS.PH
Pharmador
Dolorin
Cf.Co.Pa
SA
Al-Hikma
Dolostop
Pa
AF88.89.90.CA88, ME88.89.90
Al-Hikma
Dolostop Forte
Pa
AF88.89,90;CA88; ME88.89.90
Lilly
Doloxene Comp. As.Cf
Lilly
Doloxene-A
As
BR
Nordmark
Dolo-Neurotrat
Vi
MS
Synco
Dolpocetmol
Pa
HK
Covan
Doxyfene
Pa
SA
Silanes
Espasmo-Qual
Dp, De
Continentales
Fardolina Comp. Dp
Lepetit
Femidol
As.Cp.Pa.Cf AF88.89;ME88.89.90
Mer Nat.
Lentogesic
Pi,Gt
SA
Medochemie
Medonol
Pa
AF88.89.90;CA88. 89,90;ME88.89,90
DuPont
Neo-Percodan
Pa
MX
Cipla
Norgesic
Pa
IN
Pharmador
Paprox
Pa
SA
AF88,89,90;CA88,89,90;HK:
ME88.89.90;-PH;SA;TH
MX
MX
Protea
Paradex
Pa
MS
JagsonPal
Parvon/(-N)
Dz.Pa
IN
JagsonPal
Parvon-P
Pa
IN
JagsonPal
Parvon-Spas
Di,Dz.Pa
IN
Wockhardt
Proxyvon
Pa
IN
Silanes
Qual
Pa
MX
Wockhardt
Spasmo-Proxyvon De,Pa
Ranbaxy
Sudhinol
Pa
IN
Restan
Synap Forte
Cf.Dh.Pa
SA
Wallace
Walagesic
Dz.Pa
IN
Wyeth
Wygesic
Pa
IN
IN
Contents key:
As=aspirin. Cf=caffeme; Co=codeme: Cp=chlorphemramine; Oc=dicyclomme.
Dh=diphenhydramtne; Di=dipipanone; Dp=dipyrone: Dz=diazepam; Gt=glutamine;
Ld=lidocame; Pa=paracetamol: Pi=pemolme. Vi=vitamins
Country/region key and sources:
AF=AFRICA: MIMS Africa: May 1988. July 1989, July 1990; BR=BRAZIL: DEF: 1987-88:
CA=CARIBBEAN: MIMS Caribbean: May 1988. November 1989. July 1990, HK=H0NG
KONG: HKIMS: April 1988; IN=lNDIA: MIMS India: Feb 1988; MS=MALAYSIA &
SINGAPORE: DIMS: Feb 1988; ME=MIDDLE EAST: MIMS Middle East: April 1988. December
1989. June 1990; MX=MEXICO: DEF: 1987; PK=PAKISTAN: QIMP: 1937. 1988 89. 1990'
PH=PHILIPPINES: PIMS: April 1988; SA=S0UTH AFRICA: MIMS: May 1983;
TH=THAILAND: TIMS: March 1988
73
Problem Drugs
Some specific combinations are particularly depre
cated. The use of dextropropoxyphene in combination
with either aspirin or paracetamol “should not be
encouraged”.37 This is because “combinations of dex
tropropoxyphene with paracetamol and with aspirin
can be more dangerous in overdose than aspirin or
paracetamol on their own.”38 An overdose of dextro
propoxyphene can cause respiratory depression,
particularly in combination with alcohol; cardiac col
lapse and death follows rapidly.” For this reason, the
drug has tragically become a popular and effective
means of committing suicide. The widespread avail
ability of analgesics containing dextropropoxyphene,
as indicated in Table 4A-3, is a matter of some concern.
Analgesics
4 A .
Analgesics
Problem Di
Aspirin: preventing the headache of heart ache
At the end of January 1988, Reckitt and Colman shares
began to soar on the London Stock Market; across the
Atlantic ocean, a similar boom hit the shares of Sterling
and Bristol Myers. All three companies are major
manufacturers of aspirin. They were benefitting from a
surprise announcement in the New England Journal of
Medicine, that an aspirin every other day could reduce
the risk of a healthy person having a heart attack by
about 50%. The claim was based upon the preliminary
findings of a study of 22.000 male physicians in the
USA, half of whom were taking aspirin, the other half
were receiving a placebo. The researchers halted the trial
two years earlier than planned in order to release the
results "to help save lives”. Not surprisingly, the news
made headlines around the world. Newsweek, for
example, ran a cover story about the findings. Some
concern was initially expressed about the way the
information was made public without drawing clear
attention to the possibility that although heart attacks
might decrease, haemorrhagic (bleeding) strokes could
increase, due to aspirin's ability to thin the blood. (That
ability means that aspirin is valuable in the treatment of
strokes caused by blood clots, where it has been shown
to reduce the risk of recurrent stroke by about 25-30%).
The US Food and Drug Administration asked aspirin
manufacturers not to begin to claim that the drug
prevents heart attacks. The final report of the
physician's study was published by the New England
Journal of Medicine in July 1989. The overall reduction in
risk of heart attack was found to be 44%; however, the
reduction in risk was apparent only among those who
were 50 years of age and older and the study failed to
find a significant reduction in risk of death from all
cardiovascular causes. Another study, the second
International Study of Infarct Survival (ISIS-2)-which
followed 17,000 patients in 16 countries who had ,ust
had a heart attack and who were treated with either
aspirin, a blood clot dissolving drug called streptokinase,
both drugs or a placebo - found that an aspirin a day for
a month reduced the risk of death by 23%,
streptokinase alone by 25%, and both drugs by at least
34%. An observational study of nearly 88,000 female
nurses in the USA, reported in 1991, found some
evidence that regular aspirin use might be associated
with reduced risk of heart attack, but was unable to
determine whether there was a significant reduction in
the risk of cardiovascular death.
Research is continuing into the use of aspirin in the
prevention and treatment of cardiovascular disease.
Because of aspirin’s well-documented adverse effects,
the use of the drug without medical supervision in an
attempt to prevent heart attacks is foolhardy and likely
to cause complications.
Sources: Steering Committee of the Physicians’ Health Study Research Group, “Preliminary report: Findings from the aspirin component ot the ongoing Physicians’
Health Study”. New England Journal ot Medicine. Vol 318, No 4. 28 Jan 1988, pp262-4; Reiman. AS.. “Aspirin for the primary prevention ot myocardial infarction''.
New England Journal ol Medicine. Vol 318, No 4. 28 Jan 1988, pp245 6; Steering Committee of the Physicians’ Health Study Research Group, "Final report on the
aspirin component of the ongoing Physicians’ Health Study-, New England Journal ol Medicine, Vol 321, No 3. 20 Jul 1989. ppl29 35. Foster. V., Cohen, M. and
Halperin, J„ "Aspirin in the prevention of coronary disease”, New England Journal ot Medicine, Vol 321. No 3. 20 Jul 1989. pp!83 5: ISIS 2 Collaborative Group.
“Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction ISIS-2", Lancet, No 8607.
13 Aug 1988, pp349 60; Hershey. L A.. “Stroke prevention in women: role of aspirin versus ticlopidine '. American Journal of Medicine, Vol 91, No 3. Sep 1991,
pp288 92; Leppard, D., “Aspirin: a headache for science". The Sunday Times (London), 31 Jan 1988. pAlO: Clark. M., What you should know about heart attacks".
Newsweek. 8 Feb 1988, pp42 6; Kingman, S.. “Will an aspirin a day keep the doctor away?-, New Scientist. 11 Feb 1988. p26; Anon., "FDA checks aspirin claims". New
Scientist. 10 Mar 1988: Anon.. "Aspirin cuts deaths after heart attacks'. New Scientist. 7 Apr 1988, p22; Anon.. “Aspirin prevents first Ml in women?", Scrip. No 1639.
2 Aug 1991, p25; Graedon. J. and Graedon. T„ Graedon's Best Medicine, from herbal remedies to high-tech Rx breakthrough, New York, Bantam Books, 1991. p79
4 A .
Analgesics
75
Problem Drugs
combination with vitamins have been disapproved in
the Philippines as an irrational combination, and
have been prohibited for manufacture, sale and
import in India.50
Aspirin
Most expert opinion agrees that, for the treatment of
simple, intermittent pain - toothache, headache,
occasional backache - aspirin is the “analgesic of
choice”.51 The Textbook of Pain says: “In terms of
effectiveness, it is difficult to improve on aspirin. No
currently available drugs... have been shown to
be more than marginally better.”52 So popular is
aspirin that more than 40 billion aspirin tablets
a year are consumed in the USA alone.53
Aspirin does have its disadvantages.
It probably should be avoided by people
with uncontrolled high blood pressure,
or with a tendency to bleed. Also,
people with asthma, ulcers or sensitive
stomachs, or anyone with an allergy to
aspirin-like drugs should not use
aspirin.56 Aspirin is not recommended
for children under 12, because of its association
with the development of Reye’s Syndrome, a seri
ous, potentially life-threatening disease in children
with viral infections.55 The US Surgeon General
warned against the use of aspirin or related
salicylates for children suffering from chicken
pox or influenza in 1982; similar warnings were
issued in the UK in 1986, and all aspirin
formulations for children were withdrawn from
the market.56 In Peru in 1990 there were at least
five anti-flu products especially for children that
contained aspirin.57 In March 1990, the Australian
con ASHMNK
206051
38-
Analgesics and alcohol: a bad mix
In Spam, a 1991 television advertisement
shows a couple arriving home from a party.
One complains of a headache, the other of
stomach upset; both take Alka-Seltzer - an
effervescent preparation of aspirin, calcium
phosphate, sodium bicarbonate and citric acid.
Similar ads have been used in the UK, while in the
USA, Alka-Seltzer preparations are labelled as
being useful for “upset stomach with headache
from overindulgence". In Barranquilla, Colombia,
in 1991, packets of Alka-Seltzer were included in
the stock of mini-bars in a leading five-star hotel,
while a complimentary packet of two of Bayer’s
brand of effervescent aspirin, Aspirina, was left on
the pillow for hotel guests each evening. The
message on the Aspirina packet was: “sleep well
without pain... with Aspirina, which does not
irritate your stomach." ["Buenas noches sin dolor...
con Aspirina, que no irritata su estomago!"]
As Alain Po points out, “the common practice of
using aspirin to relieve ‘hangover’ headache should
be questioned". Aspirin does irritate the stomach,
causes gastric bleeding and pain and may cause
ulcers. Alcohol has a similar effect; combining the two
simply increases the risk.
Paracetamol also has risks. The British Medical
Association says that “large doses of paracetamol
may be toxic if you are a regular consumer of even
moderate amounts of alcohol”. There is also some
evidence to suggest that alcohol may increase the
likelihood of liver damage by smaller doses of
paracetamol.
Ibuprofen is also not a good drug to combine with
alcohol. Unlike aspirin, ibuprofen rarely causes
bleeding in the stomach; however, like aspirin, with
alcohol, the risk of stomach disorders with ibuprofen
increases.
Sources: Po. A.L.W.. Non-Prescription Drugs, (2nd edn). Oxford. Blackwell Scientific. 1990. pp520: Figueras. A.. Juan. J., et al. “Misuse of aspirin for abdominal
discomfort". Lancet. Vol 338. No 8765. 24 Aug 1991,pp5O6 7; Diamond. J.. "They'll never swallow that", Sunday Times Magazine. 17 May 1987. pp82-4: Henry. J.
fed.). The British Medical Association Guide to Medicines & Drugs. London. Dorling Kindersley, (2nd edn) 1991. ppl95. 286. 332
4 A .
Analgesics
Problem Drugs
company, Nicholas, promoted its brand of aspirin
tablets, Aspro, in East Africa for children as young
as one year “for headache, toothache, earache,
fever, colds and flu”.'’8
Paracetamol
If it is not advisable to use aspirin, the next best
choice is paracetamol (also known as aceta
minophen in many countries), “probably a little less
effective”, but “a very well-tolerated alternative.’"’'’
Paracetamol “is less irritant to the stomach.”60
However, regular and prolonged use of paracetamol
may cause liver and kidney damage, and an overdose
may cause serious liver damage which can be fatal.61
In the USA, in the 10-year period from 1976 to
1985, over 11,000 cases of suspected paracetamol
overdose were reported.62 Paracetamol poisoning is
estimated to constitute 5% of the total number of
drug poisonings in the USA and the UK.63 In 1986,
200 people in the UK overdosed on paracetamol.M
As little as 20-30 tablets (10-15g) of paracetamol is
enough to cause potentially fatal liver damage.65
The best advice is to use paracetamol, or any anal
gesic, sparingly. Two researchers investigating the
possible risk of kidney damage with paracetamol
concluded that “it is naive to think that this or any
drug is safe in all circumstances for all uses in all
patients. It seems prudent to discourage the unneces
sary daily use of acetaminophen.”66
A doctor at Vanderbilt University advises that “cau
tion in the use of acetaminophen in certain situations
would appear to be prudent. Its use should be
avoided in patients with any active hepatic processes
and minimised in habitual consumers of alcohol.”6
Ibuprofen
NSAIDs such as ibuprofen are generally more expen
sive than aspirin or paracetamol, and they are nor
necessarily more effective. However, a limited number
of studies have indicated that ibuprofen is ar least as
effective or more effective than aspirin. A significant
benefit of ibuprofen is that it tends to have a low inci
dence of adverse effects and is generally better tolerated
than aspirin.68 However, it is not recommended for use
by pregnant women or during breastfeeding.69 The US
FDA requires that labelling for 200mg ibuprofen
tablets carries a warning that “it is especially important
not to use ibuprofen during the last three months of
pregnancy unless specifically directed to do so by a doc
tor because it may cause problems in the unborn child
or complications during delivery”.70 It is not recom
mended for children under one year of age.71
Tramadol
Tramadol first appeared in Germany in 1977,
launched by the German company, Griinenthal. It is
an opioid analgesic which appears to have less likeli
hood of causing dependency than morphine and less
respiratory depression and sedation than some of the
A combination drug that copes with
paracetamol overdose
In 1975. Dr Andre McLean, a professor of toxicology
at University College Hospital in London, suggested
that an antidote for paracetamol overdose methionine - should be added to paracetamol tablets.
One reason for this is that unless the antidote is given
within 10-12 hours, it is not effective. The British
Technology Group and Sterling Winthrop (one of the
major manufacturers of paracetamol) jointly
developed such a product (Pameton) which was given
a product license in the UK in 1983, and went on
general sale in 1986. One drawback to Pameton is its
higher price: in 1991. a tablet containing 500mg of
paracetamol plus 250mg of methionine cost about 9
times a generic 500mg tablet of paracetamol.
However. Pameton is considerably cheaper, both in
financial and human terms, than the additional
treatment should an overdose with plain paracetamol
occur.
When the product came onto the market in 1986,
Sterling Winthrop gave it little or no publicity. A
spokesperson at the company, Dennis Boyles, agreed
that the company had been rather discreet about the
drug. He told a Sunday Times reporter, "We probably
should be giving it more publicity, and it would be a
reasonable thing to have in a house where there are
children." One UK pharmacist suggested that the
reason for the company's modesty was that
promoting the drug might convey to the public the
idea that paracetamol is unsafe, something that would
undoubtedly affect the company’s heavy selling pain
killers like Panadol which contain paracetamol.
If an overdose of paracetamol does occur, the usual
treatment (within 10-12 hours) is methionine tablets,
or within about 15-16 hours, intravenous
acetylcysteine or liquid acetylcysteine or as a tablet,
where these are available.
Sources: BMA and the Royal Pharmaceutical Society of Great Britain.
British National Formulary. London, BMA and The Pharmaceutical
Press. No 22, Sep 1991. pl8; Diamond, J.. “They’ll never swallow
that”. Sunday Times Magazine. 17 May 1987, pp82-4; Anon., “Cold
shoulder for ‘safe’ paracetamol". New Scientist. 18 Dec 1986; McLean.
A E.M , "Why do patients still die from paracetamol poisoning?", British
Medical Journal, Vol 293, 1 Nov 1986. pl 172; Gilman. A.G.. Rail. T.W..
Nies. A.S.. and Taylor, P., Goodman and Gilman's The Pharmacological
Basis of Therapeutics, New York. Pergamon Press. (8th edn) 1990,
p658: Dukes. M.N.G., (ed.). Side Effects of Drugs Annual 11,
Amsterdam. Elsevier, 1987. pp80 1
4 A .
Glafenine
Another analgesic that is prevalent in many markets
in developing countries is glafenine, also marketed
by a German company Hoechst or its French sub
sidiary, Roussel. Global sales of the drug in 1984
amounted to some S30 million, making it one of
Hoechst’s top 10 drugs. In France, it was the best sell
ing prescription analgesic in 1986.74 By 1990, sales in
France had reached some 4.2 million packs, and the
product was on the market in more than 70 countries
worldwide.75 Nonetheless, there is little information
in the international literature about the efficacy of
the drug in comparison to other analgesics.
However, it does feature in regular reports about
adverse effects. In France, glafenine is second only to
phenacetin as the commonest cause of drug-induced
kidney damage.76 Liver damage has also “repeatedly
been described in patients taking glafenine”, and the
damage is characterised by a high prevalence of jaun
dice and a high fatality rate.77 In 1980, 1981 and
1982 more adverse drug reaction (ADR) reports in
France involved glafenine than any other drug;
between 1 April 1980 and 31 October 1982, the
French authorities received 734 reports of reactions
possibly caused by glafenine.78 In the Netherlands,
glafenine has been the most frequently reported
cause of drug-induced anaphylaxis (allergic reaction
which can lead to life-threatening shock) since its
registration in 1967; in 1980-84, for example, 121
cases of anaphylaxis to glafenine were reported to
the Netherlands Centre for Monitoring of Adverse
Reactions to Drugs.79 Worldwide, 14 deaths have
been attributed to the drug.80
Table 4A-4
Analgesics containing glafenine in selected markets
Company
Brand name
Other
Countries/regions with
ingreds.
product available
Th.Mp
AF88,89,90;CA88,89,90;
Roussel
Adalgur*
Biomedis
Biofenin
Pyridam
Citofen
ID
Meprofarm
Fenal
ID
Terramedic
Flanin
PH
Unilab
Glafenine
PH
Siam B.
Glafine
TH
United Amer.
Glafme
PH
Pharos
Glaphen
ME88.89.90
ID
ID
AF88,89,90;BR:
Roussel/Hoechst Glifanan*
CA88;89.9O;1D;MS;
ME88.89, 90:PH;TH
Sarsa/Hoechst
Glifarelax’
Th
Pyridam
NeuroCitofen
Vi
Biomedis
Revalan
Biomedis
Skelan Forte
BR
ID
PH
Cs.Pk
PH
•withdrawn. May 1992
Contents key:
Cs=carisoprodol; Mp=meprobamate; Pk=phenylbutazone;
Th=thiocolchicoside; Vi=vitamins
Country/region key and sources:
AF=AFRICA: MIMS Africa' May 1988, July 1989. July 1990; 8R=BRAZIL:
DEF: 1987-88; CA=CARIBBEAN: MIMS Caribbean: May 1988, November
1989. July 1990, ID=INDONESIA: IIMS: Feb 1988; MS=MALAYSIA &
SINGAPORE: DIMS' Feb 1988; ME=MIDDLE EAST: MIMS Middle East: April
1988. December 1989. June 1990; PH=PHILIPPINES: PIMS: April 1988:
TH=THAILAND: TIMS: March 1988
Largely on the basis of the information from the
Netherlands, the German Federal Health Office
began to look closely at the drug in the early 1980s.
Before the process had gone very far, Hoechst quietly
withdrew the drug from the German market in 1983.
Hoechst’s headquarters claimed that the withdrawal
of glafenine was a pure marketing decision.81
In 1985, Hoechst/Roussel promoted its brand of
glafenine, Glifanan, as “tomorrow’s analgesic” in an
advertisement in the East African Medical Journal. It
described the drug as “the ideal pure analgesic:
potent, yet safe, and flexible”. In 1990, in the
Philippines, the company was promoting glafenine as
a drug with “outstandingly good tolerance”.82
On 1 January 1991, Roussel withdrew glafenine
from the Belgian market at the request of the Bel
gian Secretary of State for Health, Roger Delizee.
This Roussel/Hoest
advertisement from the
Phillipines in 1988
emphasises Glifanan's
“outstandingly good
tolerance’’. In 1992, the
drug was withdrawn
worldwide because of safety
concerns - concerns that
had been evident for more
than 10 years.
77
Problem Di
other opioid drugs.72 The product is on the market in
Japan, several other Asian countries and in Latin
American countries, and applications for licences arc
pending in several European countries.7’ However,
there is too little clinical data available to determine
the role of the drug in pain therapy.
Analgesics
78
4 A .
Analgesics
Problem Drugs
Mr Delizee said the reason for the withdrawal was
the drug’s adverse effects, which included two
deaths in patients in Belgium who took the drug
without medical advice.83 In early 1992, the
European Committee for Proprietary Medicinal
Products (CPMP) advised that marketing approvals
for glafenine should be withdrawn because of the
high risk of anaphylactic shock.84 It was subse
quently withdrawn or suspended in Spain, France,
the Netherlands, Italy and Portugal,85 and in May
1992, Roussel announced a global withdrawal of
the drug, although other manufacturers may still be
producing it.86
Table 4A-5
Analgesics containing phenacetin
in selected markets
Company
Brand name
A major 20-year epidemiological study of abuse of
analgesics conducted in Switzerland from 1968 to
1987 found that regular use of analgesics containing
phenacetin increased the risk of hypertension and
increased the risk of death from cardiovascular disease,
cancer, or kidney disease. The study documented 74
deaths among 623 female phenacetin users compared
to only 27 deaths in 621 matched controls, a relative
risk of 2.2. Analysis of the relative risk of death due to
kidney disease produced a figure of 16.1,8S
A less reliable case-control study of 554 adults with
newly diagnosed kidney disease in the USA found
that daily users of any analgesic (phenacetin, parac
etamol or aspirin) were about twice as likely to have
kidney disease than those who used analgesics infre
quently. The risk of kidney disease was highest in
daily users of phenacetin (odds ratio, 5.11), although
it was also a risk in daily use of paracetamol (odds
ratio, 3.21).89
An editorial in the New England Journal of
Medicine, commenting on the Swiss study, pointed
out the public health implications of leaving a prod
uct like phenacetin on the market. It said, “the
removal of phenacetin, both as a single agent and as
part of a compound, is advisable in countries that
still allow use of the drug”.90
A US FDA panel concluded as far back as 1977 that
phenacetin “is not safe for OTC use because of the
high potential for abuse, the high potential for harm to
the kidney and the lack of compensating benefits of the
drug”. The panel also suggested that it “should be
removed from analgesic compounds”.91 It was with
drawn in the USA and prohibited for export in 1983.92
Countries/regions where
ingredients
product was available
Teuto
Analgin
As.Cf.Bt
BR
PPP
Aspagm
As
PK87
Vernleigh
Codaspasol
As,Co
SA
Vernleigh
Contradol
As,Co.
SA
Pfizer
Coryban
Cf.Pb.PI
As.Cf,
PK87.89.90
Cp.Pf.Vi
Phenacetin
Phenacetin was first introduced into therapy in 1887
and is structurally very similar to paracetamol,
which is a metabolite of phenacetin. Not surpris
ingly, it has a similar analgesic affect as paracetamol,
but it is now generally considered too toxic for regu
lar use. It has been identified as a carcinogen, and its
prolonged use has been strongly correlated with a
high incidence of kidney disease and anaemia.87
Other
AFD
Maldnne
Bb.Pc
PK87
Riker
Norgesic Forte
As.Cf,Or
CA88.89.90
Vernleigh
Tricodein
As,Co
SA
Contents key:
As=aspirin; Bb=butobarbitone; Bt=butalbital butylbromide. Cf=caffeine.
Co=codeine: Cp=chlorpheniramme, Or=orphenadrme.
Pb=phenobarbnone, Pc=phenylsemicarbazide: Pf=phenylpropanolamine;
Pl=phenolphthalein; Vi=vitamins
Country/region key and sources:
BR=BRAZIL: DEF: 1987-88; CA=CARIBBEAN: MIMS Caribbean. May 1988,
November 1989. July 1990. PK=PAKISTAN. QIMP: 1987, 1988 89. 1990.
SA=S0UTH AFRICA MIMS' May 1988
Phenacetin has also been banned or withdrawn in
Canada, Chile, Cyprus, Denmark, Egypt, Finland,
Germany, India, Israel, Italy, Japan, Malaysia,
Mauritius, Nepal, The Netherlands, New Zealand,
Nigeria, Norway, The Philippines, Rwanda, Saudi
Arabia, Surinam, Sweden, Thailand, Turkey, the UK,
and Yemen.93
Despite this action, a few analgesics containing
phenacetin can still be found. As Table 4A-5 shows,
products containing phenacetin were on the market
in the Caribbean and Pakistan in 1988, 1989 and
1990; and in Brazil and South Africa in 1988.
Pyrazolones
The pyrazolones also date from the late 19th century.
Most have now disappeared off the market because
of their potential for causing agranulocytosis (a
potentially fatal condition in which the white blood
cell count is reduced, leaving the victim susceptible to
many diseases).94 A few, however, still remain;
among them, phenylbutazone, propyphenazone and
dipyrone, as well as a more recent addition, apazone.
Phenylbutazone is now usually reserved for use in
treating the pain of particular types of arthritis (see
the section on NSAIDs for more information).
Apazone is a new agent that is also being tried in some
forms of arthritis. Propyphenazone and dipyrone are
the agents that most regularly appear in analgesics,
and of these, the most popular is dipyrone.
The major manufacturer of dipyrone, the German
company Hoechst, relies heavily on the product. In
4 A .
There is little if any justification for the use of dipy
rone or any of the other pyrazolones for the
treatment of acute pain. According to the Martindale
guide to medicines, because of the risk of agranulo
cytosis the use of dipyrone “is justified only in serious
or life-threatening situations where no alternative
antipyretic is available or suitable”.97 A major text
book on clinical pharmacology notes that dipyrone is
“notorious” in causing agranulocytosis and “need
never be used, as there are adequate substitutes.”98
A further problem with dipyrone is its propensity to
cause anaphylactic shock (serious, widespread aller
gic reaction). The importance of shock has been
underestimated until recently. According to a
German textbook on clinical pharmacology, the risk
of dipyrone-induced shock is 1 to 50,000 for oral
use, and could be 1 to 5,000 for injections.99
Propyphenazone has been banned or withdrawn in
Ireland and Turkey.105
All pyrazolones have been severely restricted in
Germany, Greece, Japan and Saudi Arabia.106
[See also the sections on Dipyrone and NSA/Ds.|
Time for action
The misuse of analgesics can have serious and some
times fatal side effects. Analgesic-associated kidney
disease or kidney failure is a global problem. Where
reliable studies have been done, a significant propor
tion of patients undergoing kidney replacement or
dialysis can be linked to the use of analgesics. In
Australia in 1987, the figure was 13%; in Germany
in 1986, it was 16.8%; in Belgium in 1988, it was
18%.107 To assume that simply because a product is
available over the counter it is “safe” is a serious mis
take.
The bewildering array of analgesics on the market in
many countries, all being promoted as being more
effective, faster acting, or safer for rhe treatment of
pain, only complicates matters. For many of them, as
was noted earlier, no proof can be found for the
claims. For some of them, the evidence is clear that
the risks outweigh any supposed benefits. The time
has come to introduce a more rational approach to
treating pain.
As long ago as 1973, rhe American Medical
Association’s Drug Evaluations said that dipyrone’s
“use as a general analgesic, antiarthritic or routine
antipyretic cannot be condoned”.100 The 1977 edi
tion stated that the drug had become “obsolete in the
US”,101 and any mention of it has disappeared from
subsequent editions. The US FDA withdrew it from
the market and prohibited it for export in 1977.102
Slowly, action is being taken in other countries to
remove dipyrone and other pyrazolones from the mar
ket. Eighty analgesic preparations containing a
pyrazolone in combination with another active com
pound were withdrawn from sale in the Federal
Republic of Germany in 1982 (however some prod
ucts containing dipyrone alone and in combination
were allowed to remain); all combination products
containing dipyrone were taken off the market in
Israel in 1983; combinations of pyrazolones with anti
histamines, vasoconstrictors, decongestants, muscle
relaxants, antibiotics or vitamins are prohibited in
Mexico; several combination products containing
pyrazolones are not approved in the Philippines.103
Dipyrone is prohibited for importation into
Australia or Singapore; withdrawn or banned in
Denmark, Norway and Sweden; is severely restricted
in Bangladesh, Egypt, Germany, Greece, Israel, Italy,
Peru, the Philippines, and Venezuela; not accepted
for use in paediatric preparations in Mexico.104
Recommendations for action
1. All analgesics should be limited to single
ingredient preparations (with the exception of
buffered aspirin, or of paracetamol combinations
with a methonine antidote).
2. All analgesics containing dextropropoxyphene,
glafenine, phenacetin or pyrazolone derivatives
should be removed from the market immediately.
3. All analgesics should be clearly labelled with
the generic name of the product as well as
maximum dosage limits, particularly in the case of
paracetamol.
Problem Drugs
1987, Hoechst’s two dipyrone products - Novalgin
and Baralgin - accounted for more than 5% of the
company’s total world drug sales.95 In 1991,
Novalgin alone had global sales of some $125 mil
lion and contributed 2.3% of the company’s total
sales.96 As Table 4A-2 indicated (see page 72), in
1987-88, dipyrone featured in 25% of the analgesics
on the market in 13 areas of the world, while in
1990, in Africa, the Caribbean, the Middle East and
Pakistan, one out of every seven analgesics contained
dipyrone.
Analgesics
80
4 A .
Analgesics
Problem Drugs
Notes and references:
McLeod, D.C, “An analgesic for nonprescription pain reliever promotions". Drug
Intelligence and Qinical Pharmacy, Vol 22, Jun 19S8, P503
2.
Grichnik, K.P. and Ferrante. EM., “The difference between acute and chronic pain".
Mount Sinai Journal of Medicine, Vol 58, No 3, May 1991, pp2i7-20
3.
Holland, AJA, Jackson, S.H.D. and Turner, P„ “A survey of analgesic drug utilization
within and between clinical units in a health district", International Journal ofClinical
Pharmacology, Therapy and Toxicology, Vol 26, No 9.19S8, PP4657
4- Greenwald, H.P., “Interethnic differences in pain perception", Pain, Vol 44,1991,
PP157-63
5.
Po, ALW, Non-Prescription Drugs, Oxford, Biackwell Scientific, (2nd edn) 1990, P9
6.
According to a 1989 report, Accelerated Growth in Pain Management Markets:
Forecasts ofPharmaceuticals, Devices and Alternative Treatments, by the Market
Intelligence Research Company, reported in: Anon., “New Publications", Scrip,
i.
No 1483, 26 Jan 1990, P4
According to a 1991 Frost and Sullivan report, The European Market for Pain
Management Products - Pharmaceuticals. Pain Control Devices & Alternative
Medicines, reported in: Anon., “European pain relief market set to rise”, Scnp,
No 1587,1 Feb 1991, p27
8.
Laurence, D.R. and Bennett, P.N., Qinical Pharmacology, Edinburgh, Churchill
Livingstone, (6th edn), 1987, P301
9.
Ibid, P302
10.
Acs, G. and Drazner, E, “The incidence of postoperative pain and analgesic usage in
children", Journal of Dentistry for Children, Jan-Feb 1992, pp48-5 2
11.
Liebeskind, J.C, "Pain can kill", Pain, Vol 44,1991, PP3-4
12.
Grichnik and Ferrante, op dt, PP217-20
7.
13.
14.
Laurence and Bennett, op cit. P303
Gaukroger, P.B., “Paediatric analgesia: Which drug7 Which dose?", Drugs, Vol 41,
No 1,1991, pp52-9
15.
Maunuksela, E-L and Olkkola, K.T., “Pediatric pain management", International
Anesthesiology Clinics, Vol 29, No 2, May 1991, PP37 55 (However, pain resulting
from chronic diseases or surgery does demand sensitive and often prophylactic
therapy as children typically do not request analgesics as adults do.)
16.
Grichnik and Ferrante, op at, ppzi7-20
17.
Lebovits, AHM “Chronic pain- the multidisciplinary approach", International
Anesthesiology Oinics, Vol 29, No 1,1991, ppi-7
18.
Ibid; Turk, D.C and Rudy, T.eL “Neglected topics in the treatment of chronic pain
patients - relapse, noncompliance, and adherence enhancement”, Pain, Vol 44,
1991, PP5-28
19.
Parish, R, Medicines: A Guide for Everybody, (6th edn, revised), London, Penguin,
1989, piS7
20.
Katz, J. and Melzack, R^ “Auricular transcutaneous electrical nerve stimulation
(TENS) reduces phantom limb pain”. Journal of Pain and Symptom Management,
Vol 6, No 2, Feb 1991, PP73-83
21.
Beecher, HX, “The powerfoi placebo", Journal of the American Medical Association,
49 BMA and the Royal Pharmaceutical Society of Great Britain, op cit, pi.32
50. United Nations, Consolidated List of Products Whose Consumption and/or Sale
Have Been Banned, Withdrawn, Severely Restricted or Not Approved by
Governments, 2nd issue, Doc No ST/ESA/192, New York, 1987, ppios, 107,118
51. BMA and the Royal Pharmaceutical Society of Great Britain, P159
52 Wall and Melzack, op cit, P507
53.
Jones, M.P. and Schubert, M.L., “What do you recommend for prophylaxis in an
elderly woman with arthritis requinng NSAIDs for control7”, American Journal of
54.
Gastroenterology, Vol 86. No 3,1991, PP264-6
Graedon, J and Graedon, I, Graedon's Best Medicine: from herbal remedies to
55.
56.
high-tech Rx breakthrough, Nev/ York, Bantam Books, 1991, p79
BMA and the Royal Pharmaceutical Sodety of Great Britain, op dt, P159
Lesser, E, "Aspirin: the slow gestation of a warning". New Scientist, 19 Jun 1986,
57.
58.
59.
60.
P23
Lopez, R. and Kroeger, A (eds), Morbilidad y Medicamentos en Peru y Bolivia,
Lima/Heidelberg/Chimbote, Universidad Peruana Cayetano Heredia/Universidad de
Heidelberg/Accion para la Salud, 1990, P146
fAaLATA letter to Nicholas, March 1990
Wall and Melzack (eds), op cit, P507
BMA and the Royal Pharmaceutical Society of Great Britain, op cit, P159
Parish, op dt, P195
Nelson, S.D., "Molecular mechanisms of the hepatotoxicity caused by
acetaminophen", Seminars in Liver Disease, Vol 10, No 4,1990, PP267-78
63.
Levy, M, “Adverse reactions to over-the-counter analgesics: an epidemiological
evaluation”, Agents Actions Supplement, Vol 25,1988, PP21-31
64.
Diamond, J., “The/ll never swallow that", Sunday Times Magazine, 17 May 1987,
61.
62.
PP82-4
BMA and the Royal Pharmaceutical Society of Great Britain, op cit, pi8
Sandler, D.P. and Weinberg, C.R., "Analgesic use and chronic renal disease",
New England Journal of Medicine, Vol 321, No 16,19 Oct 1989, PP1126-7
67.
Burk, R.E, “N-acetylcysteme in the treatment of acetaminophen overdose",
65.
66.
68.
69.
70.
New England Journal of Medicine, Vol 320, No 21,25 May 1989, P1418
AMA op cit, P75
Gilman, et al, op cit, pp66s-6
Physicians' Desk Reference, Oradell, NJ, Medical Economics Company, 44th edn,
71.
1990, P2293
Anon., “Junifen suspension - ibuprofen for febrile children", Drug and Therapeutics
Bulletin, Vol 29, No 3,4 Feb 1991, ppi 1-12
Reynolds, J.E F (ed.), Martindale: The Extra Pharmacopoeia, London,
The Pharmaceutical Press, (29th edn) 1989, P1321
73.
Anon., “Grunenthal pursues tramadol", Scrip, No 1509,27 Apr 1990, P34
74.
Offerhaus, L., “Glafenine: kiespljn of kiespijn?” (Glafenine: toothache or toothache?),
72.
Nederiands Ti/dschr Geneeskd, Vol 132, No 40,1988, PP1853 57
Anon., “Glafenine withdrawn in Belgium", Scrip, No 1581,11 Jan 1991, P34. In 1991,
glafenine was marketed in 78 countries, according to an article in The Lancet
(Vol 339,8 Feb 1992, P357).
76.
Offerhaus, op cit, ppi853-57
77.
Dukes, M.N.G. and Beeley, L. (eds), Side Effects of Drugs Annual 12, Amsterdam,
Vol 27, Jun 1987. pp345-5°
23.
Laurence and Bennett, op cit, P307
Elsevier, 1988, P90
24.
Henry, J. (ed.). The British Medical Association Guide to Medicines & Drugs, London, 78.
Offerhaus, op cit, PP1853-57
Dotting Kindersley, (2nd edn) 1991, P77
79.
Stricker, B.H.Ch., de Groot, R.R.M. and Wilson, I.H.P., “Anaphylaxis to glafenine",
25.
Parish, op Gt. pi88
Lancet, Vol 336, No 8720,13 Oct 1990, PP943-4
26.
Wall, RD. and Melzack, R., (eds). Textbook of Pam, London. Churchill Livingstone,
80.
Herxheimer, A, “Belgium: Withdrawal of glafenine”, Lancet, Vol 337, No 8733,
12 January 1191, pio2
1984, P505
27.
Gilman, AG., Rail, T.W., Nies, AS., and Taylor, P. (eds), Goodman and Gilman's The
81.
BUKO Pharma-Kampagne, Hoechst: A Cause of Illness?, Bielefeld, BUKO PharmaPharmacological Basis of Therapeutics, New York, Pergamon Press, (8th edn) 1990,
Kampagne, 1987, pp21-2
82.
MaLAM letter to Roussel, June 1990
P638
28.
WHO, “WHO Model List: revised in November 1991", WHO Drug Information, Vol 5, 83.
AnonM Scrip, No 1581, op cit, P34
84.
Anon., ‘Glafenine withdrawal recommended’, Scrip, No 1685,22 Jan 1992, P23
No 4,1991, pi82
29.
Chetley, A and Gilbert, D., Problem Drugs, The Hague/Penang, Health Action
85.
Anon., “Withdrawal of glafenine", Lancet, Vol 339, No 8789,8 Feb 1992, P357
86.
Anon., “Glafenine: voluntary withdrawal", WHO Drug Information, Vol 6, No 2,1992,
International, 1986
30.
Hartog, R. and Schulte-Sasse, H., German and Swiss drug supplies to the Third
P57
World, Amsterdam/Zurich/Lausanne/Bielefeld. HAI-Europe/Berne Declaration Group/
87.
Sanberg, P. and Krema, R.M.T., Over-the-counter Drugs: harmless or hazardous?,
London, Burke Publishing, 1988, P49
BUKO Pharma-Kampagne, 1990, P32
3L Gillies, H.C, Rogers, H.J., Spector, R.G. and Trounce, J.R., A Textbook of Clinical
88.
Dubach, U.C., Rosner, B. and Sturmer, T„ "An epidemiological study of abuse of
Pharmacology, (2nd edn), London, Hodder and Stoughton, 1986, P308
analgesic drugs: effects of phenacetin and salicylate on mortality and cardiovascular
32.
MAA;Drug Evaluations, Philadelphia, VZB. Saunders Co., (6th edn) 1986, P76
morbidity (1968 to 1987)", New England Journal ofMedicine, Vol 324, No 3,17 Jan
75.
Vol 159,1955, ppi602-6
22.
Scarani, G_. Beghi, E. and Tognom, G., “Pharmacological treatment of a primary
headache- analysis of current practice from a drug utilization stud/', Headache,
33.
34.
Henry, op cit, P77
BMA and the Royal Pharmaceutical Society of Great Britain, British National
Formulary, London, BMA and The Pharmaceutical Press, No 22, Sep 1991, pi6i
35.
Analgesic Guidelines Sub-Committee, Victorian Drug Usage Advisory Committee,
Analgesic Guidelines, (1st edn), Toorak, Victorian Medical Postgraduate Foundation,
36.
37.
38.
39.
1988, p22
Anon., “New Swiss analgesic prescribing rules", Scrip, No 1607,12 Apr 1991, p9
Analgesic Guidelines Sub-Committee, op cit, pi8
Parish, op cit, P192
BMA and the Royal Pharmaceutical Society of Great Britain, op cit, pi8
40.
Ibid, pi6i
41 Laurence and Bennett, op at. P307
42. Po, op cit, P535
43. Gilman, et al P629
44- Schachtel, B.P., Fillingim, J.M., et al, “Caffeine as an analgesic adjuvant: a double
blind study comparing aspirin with caffeine to aspirin and placebo in patients with
sore throat”. Archives of Internal Medicine, Vol 151, Apr 1991, PP733-7
45. Ward, N„ Whitney, C, Avery, D. and Dunner, D., “The analgesic effects of caffeine fn
headache", Pain, Vol 44,1991, PP151-5
46. Forbes, JA, Jones, K.E, et al, “Evaluation of aspirin, caffeine, and their combination
in postoperative oral surgery pain". Pharmacotherapy, Vol 10, No 6,1990, PP38793
47- Bennett, W.M. and DeBroe, M.E, "Analgesic nephropathy - a preventable disease",
New England Journal of Medicine, Vol 320. No 19,11 May 1989, PP1269-71
48. Hoskin, P.J. and Hanks, G.W., “Opioid agonist-antagonist drugs in acute and chronic
pain states", Drugs, Vol 41, No 3,1991, PP326-44
i99h PP155-60
Sandler, D.P., Smith, J.C, et al. “Analgesic use and chronic renal disease", New
England Journal of Medicine, Vol 320, No 19,11 May 1989, ppi238-43
90.
Stolley, RD., “The risks of phenacetin use”. New England Journal ofMedicine,
Vol 324, No 3,17 Jan 1991, ppi9i*3
91.
Graedon, )., The People's Pharmacy ■ 2, New York, Avon Books, 1980, P41
92.
United Nations, op cit, P77
93,
Ibid, pp76-8; Anon., “FRG voluntary phenacetin withdrawals", Scrip, No 1081,3 Mar
1986, P3; Consumers’ Association of Penang, Drugs and the Third World:
Phenacetin risks, benefits and marketing in Malaysia, Penang, CAP, 1986, p4
94.
Gilman, et al, op cit, PP654-5
95.
Anon., "Hoechst in 1987 and 1988", Scrip, 23 Mar 1988, P14
96.
Anon., “Good growth for Hoechst Pharma”, Scrip, No 1702,20 Mar 1992, pp8-9
97.
Reynolds, op cit, pis
98.
Laurence and Bennett, op cit, pi68
99.
Fuellgraff, G. and Palm, D. (eds), Pharmakotherapie • Klinische Pharmakologie, (6th
edn), Stuttgart, Gustav Fischer Vertag, 1986, P194
100.
AMA Drug Evaluations, (2nd edn), Chicago, 1973, PP262-7
101.
AMA Drug Evaluations, (3rd edn), Chicago, 1977, P341
102.
United Nations, op cit, p6z
103.
United Nations, op dt, pus
104.
United Nations, op cit, PP62-3
105.
United Nations, op dt, P89
106.
United Nations, op cit. P90
107.
Bennett and DeBroe, op cit, PP1269-71
89.
Chetley, A. Problem Drugs, Amsterdam,
Health Action International, 1993
Health Action International’s
97" LIBRARY
coordinating offices:
AND
DOCUMENTATION
V
UNIT
J
HAI Europe
Jacob van Lennepkade 334T
1053 NJ Amsterdam
The Netherlands
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AiS Latin America
Accion para la Salud
Avda. Palermo 531
Dpto. 104
Lima 13
Peru
A drug no one needs
Dr Kitima Yuthavong, the medical adviser of Hoechst's
subsidiary in Thailand, said in 1987 that Baralgan - a
product that contains dipyrone - "kills pain very effec
tively. Patients who are crawling with pain from intestinal
colic will feel like a different person after taking the
drug.
In 1987, a young woman in Holland nearly died after
being given Baralgin (Hoechst ’s brand name for a similar
product in Europe) for vague abdominal complaints.2
Between July 1981 and July 1986, 94 people in Germany,
where Hoechst is based, did die after taking products con
taining dipyrone. Agranulocytosis (severe loss of white
blood cells, due to bone marrow damage) was the reason
for 46 of the deaths, while 39 were due to anaphylactic
shock, a severe allergic reaction2
Because of these deaths, in 1987 the German drug
regulatory authority placed all dipyrone products on
prescription and restricted their indications to
severe pain after surgery or trauma, colic, or tumour
pain. All combination drugs containing dipyrone
were withdrawn, except for combination products
containing a spasmolytic (like Baralgan/Baralgin),
which were temporarily suspended pending resolu
tion of an injunction taken out by another
manufacturer.4 Hoechst ‘‘voluntarily” withdrew
Baralgin from the German market at the beginning
of 1987.
Dipyrone is an analgesic (pain killer) with anti
inflammatory and antipyretic (fever-reducing) properties.
It is the sodium sulphonate derivative of amidopyrine or
ammopyrine and, like propyphenazone and
phenylbutazone, it is a member of the pyrazolone group
of chemicals. The drug was first introduced by the
German manufacturer, Hoechst, in 1922. Dipyrone is
known by many names: analgin, analginum. metamizol,
aminopyrine-sulphonate sodium, sodium noramidopyrine
methanesulphonate, sulpyrine, methampyrone,
novamidazofen, natrium, novaminsulfonicum,
noramidazophenum, and noraminophenazonum.
Bad health - good business
However, dipyrone continues to be a popular and
profitable pain killer in many countries. In 1987,
Hoechst’s two dipyrone products - Novalgin and
Baralgin - brought in more than US $190 million,
just over 5% of its total world drug sales? In 1991,
Novalgin alone contributed 2.3% of the company’s
total sales and was Hoechst’s sixth most popular
drug with global sales of some $125 million.6 In
1989, Novalgin and Baralgin, with sales of US $4.3
81
4 B .
Dipyrone
Problem Drugs
million, made up nearly 25% of Hoechst’s total sales
in Pakistan.7 In 1990, Baralgan was India’s sixth
most sold branded drug on the public market
(excluding sales to hospitals or government health
centres), with sales reaching $5.2 million.8 In the
Philippines in 1990, Baralgin accounted for more
than one-third of Hoechst’s total sales.9 In 1991 in
Bolivia, Novalgina was the best-known and most
commonly used analgesic. It was available without a
prescription and was even being sold in the street
markets.10
Many companies produce analgesics containing
dipyrone or other pyrazolone derivatives. As Table
4B-1 indicates, nearly one in five of the analgesics on
the market in 1990 in Africa, the Caribbean, the
Middle East and Pakistan contained dipyrone or
another pyrazolone derivative. In 1989, dipyrone
was the most commonly used analgesic in Bulgaria.11
In South Korea in 1989, 42 brands of dipyrone were
produced by 33 companies.12 In Yugoslavia in 1990,
dipyrone was the drug with the second highest vol
ume of use.13
The continued popularity of dipyrone and other
pyrazolones is hard to justify in the face of the evi
dence of the risks of agranulocytosis and
anaphylactic shock. A major textbook on clinical
pharmacology notes that dipyrone is ’’notorious” in
causing agranulocytosis and ‘'need never be used, as
there are adequate substitutes”.14 A German text
book on clinical pharmacology explains that the risk
of dipyrone-induced shock is 1:50,000 users of the
oral form, and could be 1:5,000 for injections.15
In 1980, the Side Effects of Drugs A nnual concluded:
“Since effective, less dangerous alternative drugs are
available there is no case for the continued use of
aminopyrine and dipyrone.”16 As long ago as 1973,
the American Medical Association’s Drug Evalua
tions said that the use of dipyrone “as a general
analgesic, antiarthritic or routine antipyretic cannot
be condoned.”17 In the 1977 edition, it was stated
that the drug had become “obsolete in the US”,18 and
any mention of it has disappeared from subsequent
editions.
However many companies, Hoechst included, claim
that dipyrone is a safe and effective product.
According to Dr R. Timmers, head of Hoechst’s divi
sion of Medical Affairs, dipyrone has an
“outstanding safety margin” and “has proven itself
since more than 60 years to be an effective and at the
same time outstandingly well tolerated analgesic sub
stance".19*
21
The other pyrazolones
Like dipyrone, the other pyrazolone derivatives tend to
be associated with unpredictable allergic reactions or
with life-threatening blood disorders.
amidopyrine: "The risk of agranulocytosis in patients
taking amidopyrine is sufficiently great to render this
drug unsuitable for use. Onset of agranulocytosis
may be sudden and unpredictable.”1
phenazone (antipyrine): “now used only as a marker of
hepatic drug-metabolising activity”; even with this
limited use, allergic reactions can occur.2
propyphenazone: anaphylactic shock has been reported
with this drug.3
phenylbutazone: primarily used in the treatment of
some types of arthritis (see the section on NSA/Ds
for more information); it is "poorly tolerated by a
number of patients", and a number of deaths have
occurred from aplastic anaemia and
agranulocytosis.4
Sources:
1.
Reynolds, J.E F. (ed.), Martindale: The Extra Pharmacopoeia, London,
The Pharmaceutical Press, (29th edn) 1989, p3
2 Dukes, M N.G. and Beeley, L., (eds), Side Effects of Drugs Annual 14,
Amsterdam, Elsevier, 1990, p92
3. Dukes, M.N.G. and Beeley, L , (eds), Side Effects of Drugs Annual 12,
Amsterdam, Elsevier, 1988, p83
4- Gilman, A.G , Rail, T.W , Nies, A.S., and Taylor, P. (eds), Goodman and
Gilman s The Pharmacological Basis of Therapeutics, New York, Pergamon
Press, (8th edn) 1990, p654
Table 4B-1
Number and percentage of analgesics
containing a pyrazolone (1990)
Country/
No. of
No. &%of drugs containing:
Region
analgesics
dipyrone
Africa
Caribbean
Middle East
The “Boston study”
In an effort to resolve the debate over the incidence
of dipyrone-induced agranulocytosis, an Inter
national Agranulocytosis and Aplastic Anaemia
Pakistan
other pyrazolones
_N_°-
%
No.
115
66
141
186
18
12
21
21
16
18
15
H
98
69
10
7
2
1
508
72
14
%
1990; Middle^' WMSMiddi^1 9^°i Caribbean: “MS Caribbean July
S M,ddle Easl Jun 1990; Pakistan: QIMP 1990
84
4 B .
Dipyrone
Problem Di
re-emphasised its view that mono-preparations of
dipyrone were drugs of last resort, primarily for
tumour pain.
Excessive promotion
In most parts of the world, products containing dipy
rone are being promoted not as drugs of last resort,
but for everything from headaches to period pains.
In Africa30 and the Caribbean31 in 1991 and the
Middle East32 in 1990, Hoechst’s Baralgan/Baralgin
was recommended for all types of “spasmodic and col
icky pains” and conflicting information was provided
about the use of the product in children. Injections
were not recommended for children under three
months of age and tablets were not recommended for
children under six years of age, even though dipyrone
was said to be generally contraindicated for children
under 15 years of age. Hoechst’s Novalgin was rec
ommended for rheumatic pain, “headaches and
toothache, after injuries and operations, cramp in
the gastrointestinal region, the biliary tract, kid
neys and lower urinary tract”, and for
“lowering high temperature” in diseases with
fever. Medimpex’s Ridol was promoted in rhe
**Pouk. Sin ,
Middle East in 1990 for “pain and spasm” of
the gastrointestinal or urinary tracts. In 1992,
in Costa Rica, a package insert for E. Merck’s
Sintaverin (containing dipyrone and an anti
spasmodic, pramiverine) indicated the
product for all types of “spasm and colic”,
including that caused by conditions such as
“peptic ulcer”, “cystitis” or “dysmenorrhoea” (menstrual pain).
Indications such as these were also reported in a
1986 survey33 which looked at marketing claims
from 1983 to 1985. Similar claims were also found
in Asia, Africa and Latin America between 1987
and 1989.34 With this irresponsible overpromo
tion, it is little wonder that products containing
dipyrone have become such popular medicines in
some countries, often available without prescrip
tion. Yet dipyrone has no advantage over less
hazardous analgesics currently on the market. For
simple pain, aspirin, paracetamol or ibuprofen are
as effective. Codeine is useful for moderate pain.
For severe pain, such as cancer pain or post-operative
pain, standard advice is to use a strong opioid such as
morphine, methadone or oxycodone.33
Contrary to Hoechst’s claims, the Boston study failed
to remove doubts about dipyrone’s safety. If any
thing, it merely confirmed that here was a drug that
no longer had a place in modern medicine.
SintaVerin
Sinh■^verfn
Antispasmodic
A,lalgesic
unun
■0
‘"‘n^cpai,
Refer,
—'Mrto.
rrta'^0«Mno(ohwrod0niorfinajy
Products containing propyphenazone
The other main pyrazolone derivative that is found today
in pain killers is propyphenazone. Three Swiss
companies - Ciba-Geigy, Sandoz and HoffmanLa Roche
- are the principal manufacturers. Like dipyrone,
propyphenazone products are usually promoted for a
broad range of pains, as the table below indicates.
Indications (partial)
Company
Brand name
Ciba-Geigy1
Cibalgin
headache, dental pain, fever
Ciba-Geigy1
Spasmo-Cibalgin
painful spastic conditions,
Roche2
Saridon(e)
dysmenorrhoea
pain, headache, toothache,
menstrual pain, influenza, fever
Sandoz2
Optalidon
headache, toothache,
dysmenorrhoea
The US Food and Drug Administration, which in
1977 withdrew approval of dipyrone because of its
association with agranulocytosis and because of rhe
availability of “alternative drug products and
Notes:
1. Africa and the Caribbean in 1991 and the Middle East in 1990
2. Africa in 1991 and the Middle East in 1990
Sources: Africa: MIMS Alrica, July 1991; Caribbean: MIMS Caribbean.
Jan 1991; Middle East: MIMS Middle East, June 1990
zi B .
In three of the locations - Ulm, Berlin and Barcelona
- the risk of agranulocytosis was 23.7 times higher
from using dipyrone than from not taking the drug.
However, in Israel and Budapest, the relative risk was
less than one - a variation which the authors of the
study were unable to explain. Nonetheless, they cal
culated an “excess risk” (or absolute risk) from
dipyrone on the basis of the German and Spanish
data of no more than 1.1 cases per million users per
week. As Tbe Lancet subsequently pointed out:
“The calculation underlying this estimate is
not explained. The peculiar denominator is
difficult to apply to real life. The risk for
exposure during one year could be up to 50
times higher. It would be expressed more
clearly as the number of cases per million
defined daily doses (DDD), or per 100,000
packs sold.”22
by Hoechst as “misleading”, and pointed out that by
taking into account the actual level of use of the drug,
there could be over 7,000 cases of dipyrone-induced
agranulocytosis each year.25 Given that the fatality
figures suggested by the IAAAS related to industri
alised country settings, that previous estimates of
agranulocytosis fatality rates in developing countries
have ranged as high as 73%,26 and that the major
markets for dipyrone products now lie in developing
countries due to restrictions on sales or outright bans
in industrialised countries, it is reasonable to suggest
that there could be at least 2000 deaths a year
globally from dipyrone.27
The German drug regulatory authority - the BGA also found Hoechst’s interpretation of the Boston
study difficult to accept. Ar a hearing held in
September 1986, epidemiologists invited by the
BGA challenged the statistical methods used in the
study. The hearing also noted “the relative paucity
of data on the basic pharmacology and pharmaco
kinetics of dipyrone, and the lack of knowledge
about the immunological mechanisms underlying
the adverse reactions and means of identifying
vulnerable individuals. There were no adequate
studies comparing its therapeutic efficacy with that
of alternative drugs."28 In addition to introducing
the restrictions mentioned earlier, the BGA ruled
that the use of dipyrone for other types of severe
pain, such as toothache or migraine, or for high
fever, was to be seen only as “a last resort when
other analgesics are contraindicated”.29 In
February 1990, the BGA issued an order banning
all combination products containing dipyrone and
No matter what the controversy over the risk
attached to dipyrone, the study was useful in deter
mining, without question, that dipyrone can induce
agranulocytosis; that dipyrone was responsible for
about one-quarter of the drug-induced cases of
agranulocytosis in the participating countries; and
that in some areas, patients who had taken dipyrone
in the week before the study were 20-30 times more
likely to develop agranulocytosis than those who did
nor use dipyrone.2’’ The Boston study did not look at
the other major adverse effect associated with
dipyrone - anaphylactic shock.
Misleading interpretation
Hoechst declared that as the risk of dipyroneinduced agranulocytosis was proven to be
“extremely low”, the main “problem” with dipyrone
for over 40 years was now “solved”. Hoechst’s mar
keting director, Dr Hans-Gunther Grigoleit, said “in
view of the improved risk/benefit situation of
dipyrone, there is no need to change the legal status
of dipyrone towards more restrictions”.24 The Side
Effects of Drugs Annual described this interpretation
Hoechst advertises dipyrone's “outstanding safety margin"
in Thailand in the late 1980s.
83
Problem Di
Study (1AAAS) was set up in 1978, partially funded
by Hoechst, and carried out by the Boston
University Drug Epidemiology Unit. This "Boston
study” aimed to collect all reports of patients with
agranulocytosis and aplastic anaemia that were
admitted to hospital or occurred during a stay in
hospital in eight locations: Israel, Barcelona, Ulm,
West Berlin, Milan, Budapest, Sofia and
Stockholm/Uppsala, with a total population of 22.3
million people. Attempts to collect data in Brazil and
Indonesia were abandoned because it was not pos
sible to ensure reliable data. Only five of those
locations - Israel, Barcelona, Ulm, West Berlin and
Budapest - were used for the calculations on dipy
rone-induced agranulocytosis. The results20 were
surprising, and have triggered off even more
debate.21
Dipyrone
4 B .
In 1987, William Jenkins, then a principal medical
officer at the UK Department of Health, commented
that “my personal views are the same as those
expressed in Martindale, The Extra Pharmacopoeia,
28th edition/' Although arguments continue about
the true incidence of serious and fatal adverse reac
tions to amidopyrine and dipyrone, 1 find the
frequency unacceptable.”38
In its editorial in 1986, The Lancet concluded that
the findings of the Boston study “reinforce the argu
ments for banishing dipyrone and where possible
using paracetamol or aspirin instead”.39
Trying to preserve the market
Since 1986, Hoechst and many other companies
have been trying to convince prescribers and drug
regulatory authorities, particularly in developing
countries, that dipyrone is a “safe” drug.
In Thailand,
Hoechst’s Manager,
Phornvit
Phacharintanakul, said that the company believed
that Baralgan “scientifically and technically speak
ing, will pose no problem to users”.40 To reinforce
the message, Dr R. Timmers, the head of the
Hoechst’s Medical Affairs division, visited Thailand
several times and toured medical schools giving pre
sentations on the Boston study. During his talks, he
claimed that dipyrone was as “safe as aspirin”. At
the same time, Hoechst distributed copies of the
Boston study, carefully highlighted to draw attention
to its more favourable messages.41
Similarly, Dr Erhard Groll of E. Merck said the matter
should be looked at on a country-by-country basis:
“For instance, a drug which has passed clini
cal tests and was marketed in Germany was
found to have caused a few fatalities after it
was used among tens of thousands of con
sumers. As a result, it was withdrawn from
the market. But if the same drug could save
the lives of thousands of people in a develop
ing country, then would it be morally wrong
to export the drug to that country?
However, as the indications mentioned above
demonstrate, dipyrone is not being promoted for lifethreatening illnesses. People generally do not die
from headaches or menstrual pains. This point is
reinforced by the Medicines Commission of the
German Medical Association:
“Renal or biliary colic kills no one. For this
reason, even a small risk of a life-threatemng
condition... is an unacceptable price to pay for
pain relief, especially since it cannot be main
tained that alternatives are not available .
Dipyrone has been banned or severely restricted in
Australia, Bangladesh, Canada, Denmark, Egypt,
Fiji, Germany, Greece, Ireland, Israel, Italy, Japan,
Malaysia, New Zealand, Norway, the Philippines,
Saudi Arabia, Singapore, Sweden, the UK, the USA,
and Venezuela, and combination products contain
ing dipyrone have been banned in Pakistan.44
[See also the sections on Analgesics and NSAJDs],
Recommendation for action
It is time that dipyrone and the other pyrazolone
derivatives were removed from the market
worldwide. Dipyrone is not a safe drug. It is not an
essential drug. It offers no significant therapeutic
benefit for the risk it presents. Therefore, the only
course of action is to ban dipyrone and other
pyrazolone analgesics, immediately.
85
Problem Drugs
non-pharmacoiogical therapies that would have less
potential for risk”, stated in 1988 that its position on
dipyrone “has not changed”.36
Dipyrone
86
Dipyrone
4 B .
Problem Drugs
Notes and references:
Khanthong, T.. “Hoechst asserts its drug not harmful", The Nation. 22 Oct
1987, pt9
2.
Zijimans, J.M., Class. F.H.J. and Overbosch. D., “Baralgin, pijn of -penis?", Ned
Tijdschr Geneeskd. Vol 131,1987. ppsoo-i
3.
BUKO Pharma Kampagne. Hoechst, A Cause of Illness? The Pharmabusiness in
the Thiro World. Germany, May 1986, P19
4- Anon., "Federal Health Office decides on dipyrone", Lancet, 20-27 Dec 1986,
22.
Anon., Lancet, 18 Oct 1986, op cit, pp899-900
23.
24.
del Favero, op cit, ppi
.
.
Anon., “Hoechst, dipyrone and agranulocytosis - the ISAAA stud/, bcnp.
PP1450-1; Anon., “BGA's metamizole comb suspension", Scrip, No 1208/9,
27-29 May 19S7, p6
5. Anon, “Hoechst in 1987 and 1988", Scrip, No 1293, 23 Mar 1988, piz,
6 Anon., "Good growth for Hoechst Pharma", Scrip, No 1702,20 Mar 1992, pp8-9
7.
Ahmad, S.R., Bitter Facts About Drugs, Karachi, HAI-Pakistan, 1990, P9
8.
Anon, “Indian branded drug sales", Scrip, No 1650,11 Sep 1991, P19
9.
Anon., "German and Swiss companies' drug supplies to the Third World: how
rational?". Drug Monitor, Vol V, No 11, Nov 1990, P141
10.
Persona! communication from 0. Lanza, La Paz, 1 Sep 1992
11.
Vlahov, V. and Bacracheva. N., "Agranulocytosis and dipyrone", Lancet,
27.
i.
No 8673,18 Nov 1989, P1215
Anon., “S Korean consumers highlight banned drugs”, Scrip, No 1457, 20 Oct
1989. P23
13.
Anon.. “Top drugs in Yugoslavia”, Scrip, No 1665,1 Nov 1991, p22
14.
Laurence. D.R and Bennett, PN., Clinical Pharmacology, (6th edn), Edinburgh,
Churchill Livingstone, 1987, pi68
15.
Fuellgraff, G. and Palm, D. (eds), Pharmakotherapie - Klinische
Pharmakologie, (6th edn), Stuttgart, Gustav Fischer Verlag, 1986, P194
16.
Dukes, M.N.G., (ed.). Side Effects of Drugs Annual 4, Amsterdam, Elsevier,
1980, PP63-4
17.
AMA, Drug Evaluations, (2nd edn), Chicago, 1973, PP2627
18.
AMA. Drug Evaluations, (3rd edn). Chicago. 1977. P341
19.
Letter from Hoechst to the Medical Lobby for Appropriate Marketing. 21 Sept
12.
1984
International Agranulocytosis and Aplastic Anemia Study, “Risks of
agranulocytosis and aplastic anemia: a first report of their relation to drug use
■with special reference to analgesics", Journal of the American Medical
Association. 256. 3 Oct 1986, PP1749-57
21.
See for example:
Faich, GA, "Analgesic use and pharmacoepidemiology ”, Journal of the
American Medical Association, Vol 256, No 13. 3 Oct 1986, P1788
van Dijke, C.P.H, “Analgesic use, agranulocytosis, and aplastic anemia",
Journal of the American Medical Association, Vol 257, No 19,15 May 1987,
P2590 (letter). Additional letters in the same issue and with the same
heading were from: Feldman, U., et al; Kumana, C; and a reply from Levy,
M., et al.
Anon., "Analgesics, agranulocytosis and aplastic anaemia: a major case
control study”, Lancet, 18 Oct 1986, PP899 900
Levy, M. and Shapiro, S., “Safety of dipyrone”, Lancet, 1 Nov 1986. PP1033 4
Doll, R., Lunde, P.K.M. and Moeschlin, S., “Analgesics, agranulocytosis and
aplastic anaemia", Lancet, 10 Jan 1987, pioi
del Favero, A., “Analgesic use and nsks of agranulocytosis and aplastic
anemia", in. Dukes, M.N.G. (ed.), Side Effects of Drugs Annual 11,
Amsterdam, Elsevier. 1987, PP89-91
Offerhaus, L, “Metamizol; een honderdjarige treurnis" (Dipyrone: the
sadness of a centenary), Ned Tijdschr Geneeskd, Vol 131, No 12,1987,
20.
PP479-81
Levy, M. and Shapiro, S„ reply to Offerhaus, Ned Tijdschr Geneeskd, Vol 131,
No 38,1987, pp 1680-1
Offerhaus, L, rejoinder to Levy and Shapiro, Ned Tijdschr Geneeskd, Vol 131,
No 38,1987, ppi68i-3
No 1128.13 Aug 1986. P22
25.
Dukes, 1987, op cit, P91
. „
26.
Hemheimer, A and Yudkin, J.S.. "Agranulocytosis and pyrazolone analgesics
(letter), Lancet, 31 Mar 1984. p73°
Calculated by assuming at least 50% of consumption of dipyrone is in
developing countries, and taking a 50% fatality rate results in some 1750
deaths, plus another 350 deaths in industrialised countries. If anything, that
figure is liable to be an underestimate, given the difficulty (as the IAAAS itself
demonstrated) of collecting reliable epidemiological data in developing
country settings on the incidence of dipyrone-induced agranulocytosis.
28.
Anon., "Dipyrone: Hearing by the German Drug Authority , Lancet, 27 Sep
1986, P737
29.
Anon., "Federal Health Office decides on dipyrone”, Lancet, 20/27 Dec 1986,
30.
31.
32.
33.
34.
35.
P1450
MIMS Africa, Vol 31, No 4. July 1991
MIMS Caribbean, Vol 21, No 1, Jan 1991
MIMS Middle East. Vol 21, No 3, June 1990
Chetley, A. and Gilbert, D., Problem Drugs, The Hague/Penang, HAI, 1986
BUKO, Dipyrone: a drug no one needs, 1989. Bielefeld/Amsterdam, BUKO
Pharma Campaign/HAI, ppn-12
Analgesic Guidelines Sub-Committee, Victorian Drug Usage Advisory
Committee. Analgesic Guidelines, (1st edn), Toorak, Victorian Medical
Postgraduate Foundation, 1988, PP32-3
Letter from Diane F. Walker, Consumer Safety Officer at the FDA to the Thai
Drug Study Group, 21 March 1988, reproduced in: Junkyard Thailand ■
Dumping of drugs and double standards in drug information: the case of
dipyrone, Bangkok, Drug Information for Action Centre, 1988, pp40-i
37.
Martindale stales, on page 251, that the use of dipyrone "is justified only in
serious or life-threatening situations where no alternative antipyretic is
36.
available or suitable”.
Silverman, M., Lydecker, M. and Lee, PR , Bad Medicine, Stanford, Stanford
University Press, 1992, P96, quoting a letter from Jenkins to the Chairperson
of the Thai Study Group
39.
Anon., Lancet, 18 Oct 1986, op cit
40.
Khanthong, T., “Hoechst asserts its drug not harmfur’, The Nation (Thailand),
22 Oct 1987, P19
41.
Junkyard Thailand, 1988, op cit; BUKO, Pharma-Brief, “Wie werden
Medikamente in der Dritten Wei vermarktet? Zum Beispiel: Baralgan in
Thailand”, April 1988, pp2-3
42.
Anon., “Germans prefer ‘soft-sell’ in patent protection issue”, Bangkok Post,
3 Dec 1987
43.
Rummel, W., “Metamizol: Kommentar zu Berichten liber lebensbedrohliche
Kreislauferkrankungen" (Dipyrone: commentary on reports of life-threatening
circulatory disorders), Deulschen Anteblatt, Vol 84(B), No 50,10 Dec 1987,
38.
44.
pp24o8-n
United Nations, Consolidated List of Products Whose Consumption and/or
Sale Have Been Banned, Withdrawn, Severely Restricted or Not Approved by
Governments, 2nd issue, ST/ESA/192, New York, 1987, pp62-3; Anon., Scrip,
No 1128,1986. op cit; Anon., “Fiji bans import of certain products", Scrip,
No 1529,6 July 1990, p22; Balasubramaniam, op cit, p4; Anon., "Health
ministry bans dipyrone combinations”, Lancet, 17 Oct 1987. P905
Chetley, A. Problem Drugs, Amsterdam,
Health Action International’s
coordinating offices:
Health Action International, 1993
HAI Europe
Jacob van Lennepkade 334T
1053 NJ Amsterdam
The Netherlands
4C. NSAIDs
HAI Clearinghouse/ARDA
c/o 1OCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accion para la Salud
Avda. Palermo 531
Dpto. 104
Lima 13
Peru
New sorts off asprin m
dfegufee = NSABDs1
'“NSAIDs are overvalued as symptomatic treatments, yet
they continue to be prescribed in high quantities.... Empirical
evidence suggests that a high proportion of long-term
NSAID users can be safely switched to simple analgesics
without compromising their therapy... Not only would there
be a real saving of health expenditure through the use of
cheaper drugs, but also there would be a considerable reduc
tion in mortality’ and morbidity from NSAID side-effects. ”2
osteoarthritis by the age of 65.6 In the UK, at least
45% of people over the age of 65 have symptoms of
arthritis. This leads to about one-third of all their
consultations with a doctor.7
1
Types of NSAIDs
Non-steroidal anti-inflammatory drugs (NSAIDs)
are pain killers or analgesics. They work by blocking
the production of chemicals called prostaglandins
that are released at the site of any tissue damage.
Prostaglandins stimulate nerve endings to pass the
message to the brain that is interpreted as pain. They
are also believed to be responsible for producing the
inflammation that occurs at the site of tissue damage.
So, NSAIDs can both block the sensation of pain and
reduce inflammation. They are commonly prescribed
for back pain, menstrual pain, headaches, mild pain
following surgery, gout, and pain caused by strains
or sprains. But their most common use is in the treat
ment of rheumatoid arthritis, osteoarthritis and
other rheumatic conditions.3
Arthritis can be painful and crippling. Although
there are many types, the two main categories are
rheumatoid arthritis and osteoarthritis. Rheumatoid
arthritis affects about 1% of the adult population
worldwide.4 Osteoarthritis is more common - about
15% of the world’s population is affected.5 In the
USA, 80% of the population shows some evidence of
Salicylates
aspirin
diflunisal
Propionic acid
derivatives
benoxaprofen*
fenbufen
fenoprofen
flurbiprofen
ibuprofen
ketoprofen
nabumetone
naproxen
pirprofen
tiaprofenic acid
Acetic acid derivatives
diclofenac
etodolac
indomethacin
sulindac
tolmetin
Oxicams
piroxicam
tenoxicam
Butazones
azapropazone
oxyphenbutazone
phenylbutazone
Sulphonanilides
nimesulide
Other
mefenamic acid
• withdrawn by the manufacturer for safety reasons
87
88
4 C .
NSAIDs
Problem Drugs
The symptoms of rheumatoid arthritis almost always
include inflammation. In osteoarthritis, inflamma
tion may not always be present or may be very mild.
For this reason, osteoarthritis is sometimes also
known as osteoarthrosis, to indicate disease rather
than inflammation of the joint. In either condition,
NSAlDs do not provide a cure.s
Table 4C-1
Costs of NSAIDs in the UK in 1992
Generic name
Brand name
Maximum
Cost/28 days
Daily dose
(£)
0.90
Analgesics
There are no well-designed controlled studies which
show that NSAIDs are better than a simple analgesic
such as paracetamol in the treatment of the symp
toms of osteoarthritis.9 While the efficacy of NSAIDs
is not in doubt, their superiority over pure analgesics
is “a matter of medical opinion” rather than being
based on scientific evidence. Most studies of NSAIDs
compare one with another or with a placebo. The
few good studies that compare NSAIDs to analgesics
have been able to show that NSAID treatment is only
trivially superior or equivalent to pure analgesics for
the relief of joint pain due to osteoarthritis.10
For most of this century, aspirin has been considered
the drug of choice in the treatment of the symptoms
of rheumatoid arthritis and similar conditions.
Aspirin’s major disadvantage is the need to give it
regularly in fairly high doses to achieve sufficient
anti-inflammatory action. At this dosage, aspirin
produces adverse effects such as stomach upsets, gas
tric bleeding and noises in the ear. These may be
reduced by taking aspirin after meals and/or by tak
ing a buffered aspirin.11
paracetamol
generic
4g
aspirin
generic
4g
1.64
ibuprofen
generic
2.4g
4.37
buffered aspirin
Palaprin
4g
5.60
phenylbutazone
Butacote
300mg
1.68
indomethacin
generic
200mg
3.08
aspirin
generic
8g
328
ibuprofen
generic
2.4g
7.62
ketoprofen
generic
200mg
8.09
ketoprofen
Orudis
200mg
8.09
piroxicam
generic
20mg
8.12
piroxicam
Feldene
20mg
8.87
indomethacin
Inocid
200mg
9.97
buffered aspirin
Palapnn
8g
11.20
sulindac
Clinoril
400mg
11.51
naproxen
generic
1.25g
11.55
mefenamic acid
generic
1.5g
11.59
NSAIDs
mefenamic acid
Ponstan
1.5g
11.59
azapropazone
Rheumox
900mg
14.15
tiaprofemc acid
generic
600mg
15 13
diflunisal
generic
1.5g
15.16
diclofenac
Voltarol
150mg
15.32
diclofenac
generic
150mg
15.33
Which drug to choose?
fluribprofen
Froben
300mg
15.46
The adverse effects of aspirin are particularly a prob
lem among the elderly - who are more likely to suffer
from arthritis.12 In an attempt to provide alternative
treatment with fewer side effects, a new wave of
drugs began to appear during the 1970s. There was
soon a dazzling and confusing array of these NSAIDs
on the market.
nabumetone
Reliflex
1g
15.68
tiaprofemc acid
Surgam
600mg
15.89
tenoxicam
Mobiflex
20mg
16.52
etodolac
Lodine
600mg
17.14
17.50
With so many drugs, it is difficult for physicians to
know which
is best. The World Health
Organization’s Essential Drugs List recommends
acetylsalicylic acid (aspirin), ibuprofen, and
indomethacin as the anti- inflammatory drugs to use.
Ibuprofen and indomethacin are included as exam
ples of a therapeutic group, and other drugs in the
same group may be substituted depending on cost
and availability.13 In total, therefore, about 15
NSAIDs could be considered.
Five factors can help in the decision about which
drug to use: efficacy, safety, individual response to
the drug, convenience, and cost.
Cost
Most of the newer drugs on the market cost signifi
cantly more than the older, better known drugs. The
use of an NSAID in the USA was found to be anywhere
naproxen
Naprosyn
1.25g
fenbufen
Lederfen
900mg
19.61
fenoprofen
Fenopron
3g
21.98
tolmetin
Tolectin
1.8g
44 72
Note: aspirin and ibuprofen are listed as both analgesics and NSAIDs as
they are widely used as both simple pain killers (at lower dosages) and as
anti inflammatory drugs (at higher dosages)
Source: British National Formulary. No 23, Mar 1992
4 C .
Table 4C-2
Adverse reactions during the first five years of
marketing in the UK
Drug
Serious adverse reactions
(per million prescriptions)
Total
G/l
Deaths
indomethacin
n.a.
n.a.
3.3
ibuprofen
13.2
6.6
0.7
flurbiprofen
35.8
27.4
3.3
Efficacy
ketoprofen
38.6
33.2
1.6
Experts everywhere agree that “differences in efficacy
have appeared relatively slight”.15 Reviews of 179 clin
ical trails of NSAIDs in osteoarthritis and more than
400 trials in rheumatoid arthritis have not demon
strated significant differences in efficacy, nor have they
provided any basis to rank these drugs according to
efficacy.16 In another review of 196 trials that looked at
NSAIDs in rheumatoid arthritis, more than 70 differ
ent effect variables were identified, making
comparisons virtually impossible.17 Although the num
ber of NSAIDs has increased, none of the new NSAIDs
have been proven to be more effective than aspirin.18
diclofenac
39.4
20.9
3.1
naproxen
41.1
32.8
5.6
fenoprofen
43.7
32.3
6.6
diflunisal
47.2
33.5
3.5
sulindac
54.3
23.9
5.1
fenbufen
55.3
28.4
3.6
tolmetin
66.7
41.7
0.0
Safety
piroxicam
68.1
58.7
6.2
tiaprofenic acid*
80.0
75.0
10.0
azapropazone
87.9
67.0
9.9
’data based on less than 5 years marketing
Sources: Scrip, Nos 1102 and 1252. 14 May 1986 and 28 Oct 1987, p25
and p26; Cohen. P., "Non steroidal anti inflammatory drugs and serious
gastrointestinal adverse reactions", British Medical Journal. Vol 293. 5 Jul
1986, p51
If the drugs have roughly equivalent efficacy, then
their relative safety could provide a clue to appropri
ate selection. However, once again, with a few
exceptions, there is little to choose. “There do not
seem to be significant differences among these drugs
- with the exception perhaps of ibuprofen at low
doses - in the incidence of major side-effects.”19
Tables 4C-2 and 4C-3 (on page 91) show two ways of
looking at the relative safety of NSAIDs. Adverse reac
tions to NSAIDs among patients in Denmark over 15
years provided similar findings.20 An attempt by
researchers in the USA recently to develop a “toxicity’
index” of NSAIDs resulted in the identification of
aspirin and ibuprofen as being among the least toxic,
while indomethacin, tolmetin, meclofenamate and
ketoprofen were the most toxic. However, the differ
ences were only significant between the top three and
bottom three drugs.21
As a class of drugs, “NSAIDs are one of the most
common causes of adverse reactions reported to drug
regulatory authorities”.22 In the UK, NSAIDs account
for 5% of all drugs prescribed, but are responsible for
25% of all adverse drug reactions reported to the
Committee on Safety of Medicines.23 In the UK, an
estimated 3,000 to 4,000 deaths each year are due to
NSAlD-related adverse effects.24 In the USA, NSAID
use leads to more than 70,000 hospitalisations and
7,000 deaths a year.25 The toxic effects of NSAIDs
often limit their usefulness in the elderly.26
Three major types of side effects are common with
NSAIDs: gastrointestinal problems including gastric
ulcer (see the box on the next page); kidney failure
after long-term use; and cognitive dysfunction
including forgetfulness, lack of concentration,
sleeplessness, paranoia, and depression.2 A less
frequent side effect is liver damage, in some cases
severe.28
Individual response
An important variable with these products seems to
be individual patient response. “Large variations are
possible in the response of individuals to different
aspirin-like drugs, even when they are closely allied
members of the same chemical family.”29 Therefore,
there needs to be a reasonable choice of products
available, but it need not be large. A study in the
Netherlands found that a small number of NSAIDs
suffices to meet the needs of patients suffering from
rheumatoid arthritis.30 A small selection of drugs as
advocated by WHO could easily be sufficient.
A profitable market
NSAIDs are good business. An obvious reason for
concentrating on the development of NSAIDs is the
size of the potential market for these products.
NSAIDs are the most widely prescribed group of
drugs worldwide.31 Globally, more than 30 million
89
Problem Drugs
from twice to eight times the monthly cost of using a
simple generic analgesic - like paracetamol or an anal
gesic dose of ibuprofen. If an NSAID was administered
together with misoprostol to lessen the risk of NSAIDcaused gastric ulcer, the costs were at least nine times
that of simple analgesic therapy.14 Table 4C-1 shows a
similar comparison of products in the UK. Using a sim
ple analgesic is much more cost effective; equally,
NSAID strengths of aspirin or ibuprofen or the inex
pensive NSAID, indomethacin, cost six to 14 times less
than the most expensive NSAIDs.
N S A I D s
90
4 C .
N S A I D s
Problem Drugs
NSAIDs and ulcers
Gastrointestinal adverse effects are the most
common problem with NSAIDs. NSAID users have
about a three times greater relative risk than nonNSAID users of developing serious adverse
gastrointestinal events. Patients over the age of 60
seem to be among those who are at the highest risk.1
About seven out of every 10 NSAID users are subject
to inflammation in the small intestine,2 and about one
out of every three NSAID users suffer from
indigestion (dyspepsia).3 However, the biggest
problem is highlighted by an editorial in the journal,
Gastroenterology: "Ulceration due to drugs is a major
public health risk, because the use of aspirin and
other nonsteroidal anti-inflammatory drugs (NSAIDs)
continues to increase. In part, this reflects
overprescribing by physicians.”4 At any one time,
between one in five and one in 10 NSAID users will
suffer from an ulcer.5 The cost of treating
gastrointestinal complications caused by NSAIDs in
the USA is estimated at $4 billion a year.6
gastric and duodenal ulcers.7 However, misoprostol
itself can cause adverse effects. Diarrhoea is reported
in 25 to 40% of users, depending on dosage. Dr
Sherine Gabriel of the Rheumatology Division of the
Mayo Clinic notes that ’’diarrhoea is a dreaded event
among disabled patients with arthritis with limited
abilities for self care”, which obviously impairs the
quality of life of those affected.8
Misoprostol is produced by Searle, so it is not
surprising that speakers at a Searle-sponsored press
conference in the UK in October 1991 said that
"misoprostol should be given to all NSAID patients at
high risk of ulcer complications, particularly the
elderly". It was estimated that this high risk group
would include about one-third of all NSAID users.9
Other commentators doubt the wisdom of this
approach for dealing with NSAID-induced ulcers or
“NSAID gastropathy” as it is increasingly being called.
Dr J. Lacey Smith, a gastroenterologist in the USA,
describes the term as a “cover-up”. He says it should
really be called “NSAID toxicity, or poisoning. The
terminology is not academic, because the first
principle of treatment for toxicities is removal or
reduction of the offending agent, not the application
of yet another drug on the poor poisoned patient,
especially when we don’t know if the proposed
antidote works.”10
Treatment of NSAID-related ulcers has opened up a
new market area for the world’s leading anti-ulcer
drugs - Hz-blockers such as ranitidine and cimetidine
and the new proton pump inhibitor, omeprazole. The
traditional anti-ulcer drugs have been most successful
in treating duodenal ulcers, which are less common
than gastric ulcers.6 There is some limited evidence to
suggest that the prostaglandin analogue, misoprostol,
may be effective in treating and preventing both
Sources:
1 Gabriel, S.E., Jaakkimainen, L and Bombardier. C.. 'Risk for
serious gastrointestinal complications related to use of nonsteroidal
anti inflammatory drugs a meta analysis". Annals of Internal Medicine,
Vol 115, No 10. 15 Nov 1991. pp787-96
2.
Rooney. PJ. and Bjarnason, I.. “NSAID gastropathy - not just a pain
in the gut!". Journal of Rheumatology. Vol 18, No 6, 1991. pp796 7
3.
Bush, T.M., Sholtzhauer. T.L.. and Imai, K.. “Nonsteroidal anti
inflammatory drugs: proposed guidelines for monitoring toxicity",
Western Journal of Medicine, Vol 155. Jul 1991, pp39-42
4.
Talley, N.J., “Chronic peptic ulceration and nonsteroidal anti
inflammatory drugs: more to be said about NSAIDs?",
Gastroenterology, Vol 102, No 3, Mar 1992, ppl074-7
5.
Nuki, G . “Pam control and the use of non steroidal analgesic anti
inflammatory drugs". British Medical Bulletin, Vol 46, No 1, 1990,
PP262-78
6.
Day. R., and Henry, D , “Do anti-ulcer drugs prevent
gastrointestinal damage from NSAIDs?", Australian Prescriber, Vol 14,
No 3. 1991, pp42 3
people a day take an NSAID, and 40% are over the
age of 60.32 In Australia, more than 11 million pre
scriptions for NSAIDs are written each year,-’3
accounting for 7% of all prescriptions.34 In the UK,
NSAIDs account for about 10% of the total annual
pharmaceutical costs of the National Health
Service,35 and about 23 million NSAID prescriptions
are dispensed each year.36 In the USA, one in seven
people is likely to be prescribed NSAID treatment
each year;37 while some 13 million of the country’s
37 million arthritis patients take NSAIDs as therapy
7.
Scheiman, J M.. "Pathogenesis of gastroduodenal injury due to
nonsteroidal antiinflammatory drugs implications for prevention and
therapy", Seminars in Arthritis and Rheumatism, Vol 21. No 4, Feb
1992, pp201-10; Hayliar, J., Macpherson. A. and Bjarnason, I.,
“Gastroprotection and nonsteroidal anti inflammatory drugs (NSAIDs):
rationale and clinical implications", Drug Safety, Vol 7, No 2. 1992,
pp86105
8 Gabriel, S.E.. "Is misoprostol prophylaxis indicated for NSAID
induced adverse gastrointestinal events? An epidemiologic opinion",
Journal of Rheumatology, Vol 18, No 7, 1991, pp958-61
9. Anon., “Cytotec best in NSAI ulcer prophylaxis". Scrip, No 1664,
30 Oct 1991, p26
10. Lacey Smith, J.. “What do you recommend for prophylaxis in an
elderly woman with arthritis requiring NSAIDs for control’", American
Journal of Gastroenterology. Vol 86, No 3, 1991, p266
for chronic conditions.38 NSAIDs account for more
than 4% of the total prescription market in the USA
- more than 100 million prescriptions are written
each year for NSAIDs - and these figures do not
include the aspirin and ibuprofen products available
over the counter.3’ More than 40 billion aspirin
tablets are used each year in the USA.40
The global market for products used in the treatment
of arthritis was worth more than S6.7 billion in
1991, about 4% of the total world pharmaceutical
4 C .
Several individual products are major moneyspinners for the companies producing them.
Ciba-Geigy’s diclofenac product, Voltaren, earned
nearly $ 1.2 billion in 1991,44 and Syntex’s naproxen,
Naprosyn, is predicted to reach the $1 billion mark
in 1993;45 its 1991 sales already exceeded $950 mil
lion. Pfizer’s piroxicam, Feldene, is another strong
product, with sales in 199 1 reaching $680 million.46
Problem Di
market. More than 90% of sales is for NSAIDs, mak
ing the global NSAID market worth over $6 billion.
The largest market areas are Western Europe, with
27%, the USA with 24.5%, Japan with 19%, and
Eastern Europe with 10%.41 The US prescription
market for NSAIDs is expected to reach S2.4 billion
by 1995.42 In 1989, NSAID prescription sales in the
UK were more than £219 million ($395 million).43
NSAIDs
Table 4C-3
Comparison of NSAID-related deaths
in the UK and the USA
Drug
Accumulated
Estimated deaths per
prescriptions*
million prescriptions
(x 1 million)
UK
USA
60.0
7.6
3.8
51.3
4.9
2.2
5.6
6.1
4.3
5.1
Sulindac
2.0
20.6
4.0
3.8
Naproxen
12.0
23.6
3.9
2.4
52.3
1.8
UK
USA
Phenylbutazone
58.2
Indomethacin
57.8
Piroxicam
Diclofenac
3.2
Ibuprofen
33.0
1.9
1.3
• Accumulated prescriptions since 1964 (UK), 1969 (USA), or introduction
Unnecessary risk
In a competitive rush to capture a share of this prof
itable market, some manufacturers have brought
out many drugs in a blaze of advertising, only to
have them quickly withdrawn when they were found
to have a high incidence of serious side effects. One
of the most infamous of these products was
benoxaprofen, marketed by Eli Lilly as Oraflex or
Opren. The box on the following page highlights the
story of its withdrawal. The story of the butazones,
a particularly hazardous group of NSAIDs is still
unfolding. The box on page 93 explains the need for
more action to be taken to remove the risk that these
drugs pose. Some of the other drugs that have been
withdrawn during the 1980s are listed in the box on
page 94.
However, companies have sometimes been slow to
withdraw these products in developing countries.
Wyeth had its flufenamic acid derivative, Arlef, on
the market in Africa in July 1991, although flufe
namic acid products were taken off the market in the
UK in 1984 because of safety concerns. Glenmark,
an Indian company, had a paracetamol and
oxyphenbutazone combination product, Flamox, on
the market in the Middle East in December 1990,
despite the banning of oxyphenbutazone in countries
such as Norway and the UK by the end of 1984.
Continental Pharma, a Belgian company, had a com
bination product, Neoston Forte, that included
alclofenac on the market in Pakistan in 1990.
Alclofenac was withdrawn in 1979 in the UK, Italy
and New Zealand and in 1984 in Denmark. Pakistan
ruled in 1987 that alclofenac should be deregistered
for import. However, because there was no restric
tion on the sale of the drug, the product was allowed
to remain on the market until “its stock jwas]
exhausted”.4'
In all, out of 460 NSAIDs on the market in develop
ing countries during 1990 and 1991, 165 (36%)
should be removed because of their poor safety
date
Source: Dukes, M.N.G. (ed.). Side Effects of Drugs Annual 9. Amsterdam.
Elsevier, 1985, p87
MERVAN
(alclofenac)
503 mg tablets tn boxes of 24
2 tablets tld. for one week
folio-wed by 2 tablets hid.
or 1 tablet txd.
[meruw
effective
and
safe in
spinal
cervical
lumbar
Osteoarthritis
656 mg ampoules LM.
in boxes of 6
1 inj/day ♦ 2 tablets hxd.
CONTINENTAL PHARMA
uxrta'0-W
Continental Pharma promoted alclofenac as
“effective and safe" (MIMS Middle East, Dec 1988)
in spite of prior withdrawals in the UK. Italy. New
Zealand and Denmark.
9
4 C .
NSAIDs
Problem Drugs
records, their lack of significant therapeutic advan
tage over safer preparations, and, in most cases, their
much higher cost (see Table 4C-4).
Benoxaprofen
When it was launched in 1980. Opren (benoxaprofen)
was described by Eli Lilly's Dr William Dawson as "the
most significant advance in the treatment of arthritic
conditions since aspirin", a claim that some
rheumatologists agreed with. However, the aggressive
promotion of the drug as being especially safe, and its
subsequent overprescribing meant that far too many
at-risk patients were exposed to the drug. In
advertisements, the company claimed that “the side
effects story as a whole is very impressive indeed, as
they are generally mild and transient in nature".1
After just two years on the market, Opren was
withdrawn worldwide by the company, because of the
high incidence of side effects, including deaths. In the
UK alone, at least 100 people are reported to have
died and nearly 4.000 suffered side effects - mainly
skin disorders and gastrointestinal disorders. More
than 1.400 of the victims took Lilly to court for
negligence.2 At the end of 1987, Lilly offered the
claimants a sum of £2.3 million (about £1,800 each)
to settle the case out of court.3 All but 28 of the
victims accepted the settlement, even though it was
10 to 20 times less than the offer made to victims in
the USA.4
Promoting false claims
Because it is difficult to identify a scientific difference
among the various NSAIDs, it is often left to the cre
ative talents of marketing staff in the pharmaceutical
industry to define a difference. Sometimes, however,
that can lead to difficulties as Roussel, a subsidiary of
Hoechst, found out to its cost. When Roussel
launched its tiaprofenic acid derivative, Surgam, in
the UK in April 1982, it used the slogan “potency
with protection” and claimed the product relieved
joint pain while being gentle on the stomach. There
was no evidence for the claim, and the Department of
Health took the unprecedented step of pressing crim
inal charges against the company and its medical
director for misleading promotion that contravened
the 1968 Medicines Act in the UK. In a court case
that ended in 1987, the medical director was fined
£1,000 and the company was fined £20,000 and had
to pay a proportion of the prosecution costs.48
,
However, Roussel seems to be continuing its practice
of stretching the claims for Surgam. One of the latest
claims is that Surgam has “cartilage benefits” accord
ing to an advertisement in the December 1990 issue of
MIMS Middle East, and that it “spares cartilage”
according to advertisements in the March-August
1990 issue of Q1MP in Pakistan. However, there is no
clinical evidence to demonstrate that any NSAID has a
beneficial effect on preventing cartilage damage or
regenerating cartilage. Indeed; there has been a sug
gestion that NSAIDs may actually accelerate damage
to cartilage.49 In 1991, an editorial in The Lancet drew
attention to Roussel’s data sheet for Surgam in the UK
which stated that laboratory experiments suggested “a
neutral or possibly beneficial effect of tiaprofenic acid
on joint cartilage”. The data sheet added that “the
clinical significance of these findings is not known but
Sources:
1.
Opren Action Committee. Briefing on Benoxaprofen (Opren).
July 1985
2.
Erlichman, J , “First offers to Opren victims". Guardian, 3 Jul 1987, p3
3 Lesser. F.. “Drugs companies flinch at Opren settlement". New
Scientist, 14 Jan 1988
4.
Ferriman, A.. "Drug victim Wilma's 'no' to handout", Observer,
14 Feb 1988
Table 4C-4
NSAIDs on the market in selected regions (1990-91)
Description
Country/Region
Middle East
Pakistan
No.
%
No.
%
No.
TOTAL
Caribbean
Africa
%
No.
%
No.
%
460
83
No. of products
108
On WHO Essential Drugs List
63
58.3
94
62.7
81
68.1
57
68.7
295
64.1
Butazones
17
15.7
7
4.7
4
3.4
6
7.2
34
7.4
Banned/withdrawn
2
1.9
3
2.0
2
1.7
7
1.5
45
41.7
56
37.3
38
31.9
26
31.3
165
35.9
119
150
in another region
Not recommended*
* Reasons for not recommending products are either a poor safety record, no therapeutic advantage over safer products, or higher cost.
Sources: QIMP, Mar-Aug 1990, Pakistan; MIMS Middle East, Dec 1990; MIMS Africa. Jul 1991; MIMS Caribbean, Jan 1991
4 C .
N S A I D s
Problem Drugs
Butazones: time to bury them
I
When phenylbutazone was launched in 1949, there
were few other drugs on the market that could be
used in the treatment of arthritis. Its main
manufacturer, Ciba-Geigy, also introduced a related
drug, oxyphenbutazone, in 1960. By the early 1980s,
the two drugs together contributed more than 3.5%
of Ciba-Geigy's global pharmaceutical turnover.1
Phenylbutazone and oxyphenbutazone have been
described as “toxic and dangerous” with a long list of
potential side effects.2 Aside from the usual risks that
can occur with any NSAID, the butazones are
particularly likely to cause fatal blood disorders such
as aplastic anaemia and agranulocytosis. Of the
newer butazones, feprazone is chemically closely
related to phenylbutazone, and has similar adverse
effects. Azapropazone is less closely related and
appears to be less toxic; blood disorders are less
frequent, but rashes and gastrointestinal adverse
effects are common.
In the early 1980s, a Ciba-Geigy memo revealed that
phenylbutazone was responsible for at least 777
deaths between 1952 and 1981, and
oxyphenbutazone was responsible for another 405
between 1960 and 1982.3 Dr Sidney Wolfe of the US
Public Citizen Health Research Group estimates that
it is more likely to be over 10,000 worldwide, although
the real total of deaths may never be known.4
The Ciba-Geigy memo was made public by Swedish
paediatric neurologist, Dr Olle Hansson, who had
received a copy of it from a source within the
company. The public outcry led Ciba-Geigy to
announce in April 1985 that by the end of September
1985, all its oxyphenbutazone products would be
withdrawn worldwide and indications for Butazolidin
(phenylbutazone) would be restricted to the “drug of
second choice" in the treatment of: active ankylosing
spondylitis; acute gouty arthritis; active rheumatoid
arthritis; acute attacks of osteoarthritis.
Sources:
1. Hansson, 0., Inside Ciba-Geigy, Penang, International Organization
of Consumers Unions, 1989, pl 14
2. Chilnick. L.D. (ed.), The Pill Book, New York, Bantam Books, (4th
edn) 1990. p699
3 Dukes, M.N.G (ed.), Side Effects of Drugs Annual 9. Amsterdam,
Elsevier. 1985, p87
4.
Silverman, M., Lydecker, M. and Lee, P.R., Bad Medicine: the
prescription drug industry in the Third World, Stanford, Stanford
University Press, 1992. pl6
5.
BMA and the Royal Pharmaceutical Society of Great Britain, British
National Formulary, London, BMA and The Pharmaceutical Press,
No 23, Mar 1992, p349
93
In the UK. phenylbutazone is restricted even further:
its only indication is as a second-line treatment of
ankylosing spondylitis (arthritis of the spine) by
hospital specialists.5 Goodman and Gilman’s text on
pharmacology sums up the role of phenylbutazone
succinctly: “at the present time, phenylbutazone is
not considered to be the drug of choice for any
condition”.6
Other companies and other butazones
Although Ciba-Geigy has been the market leader,
many other companies have butazone drugs on the
market. As Table 4C-4 indicates, more than 7% of the
drugs on the market in four regions of the world
contain butazones. A survey carried out in 1987-8
found 21 oxyphenbutazone products for sale in Asia,
Africa, the Middle East and Latin America.7
Aspirin and other NSAIDs are just as effective as
phenylbutazone and much safer.8 As clinical
pharmacologist Andrew Herxheimer pointed out, the
butazones have outlived their usefulness and “should
be given a decent burial”.9 That means banning them
all. Restrictions on indications are unlikely to work if
the drugs are available in general practice or through
pharmacies. Evidence from the USA shows that four
years after Ciba-Geigy deleted the indication for
osteoarthritis and thrombophlebitis for
phenylbutazone, 392,000 prescriptions (17% of total)
were issued for these indications. Dr. Sidney Wolfe
told a hearing at the US Food and Drug
Administration that: "Heavy promotion to treat
inflammation of various kinds has locked many
doctors into prescribing for this wide variety of
indications.... The record shows that past labelling
changes for these drugs has not deterred physicians
from a large amount of prescribing for unapproved
uses or for age groups or durations of therapy warned
against in the label."10
6.
Gilman, A.G.. Rail, T.W., Nies, A.S., and Taylor, P. (eds). Goodman
and Gilman's The Pharmacological Basis of Therapeutics, New York,
Pergamon Press, (8th edn) 1990, p655
7.
Silverman, et al, op cit, pl8
8.
Wolfe. S.M., Fugate, L., et al. Worst Pills Best Pills, Washington,
Public Citizen Health Research Group, 1988. p213
9.
Silverman, et al. op cit, pl8
10.
Statement of Sidney M Wolfe, Director. Public Citizen’s Health
Research Group, before the US FDA Hearing on Petit.on for Imminent
Hazard Ban of Phenylbutazone (Butazolidin) and Oxyphenbutazone
(Tanderil), 31 Jan 1984, pplO ll
4 C .
N S A I D s
is being further investigated”. The Lancet comments
that “the wording is reasonable yet nevertheless seems
designed to raise the possibility that this drug might be
more than just another NSAID.” The same comment
about reasonableness cannot be made about Roussel’s
promotional claims in developing countries. The
advice of The Lancet to its readers was that they
“would be unwise to base their choice of NSAID on
any supposed cartilage-sparing effect"'" - advice that
applies in every setting.
Time for action
As this section shows, the NSAID market is littered
with dozens of very similar drugs. They may differ
slightly chemically, but their therapeutic effects are
almost indistinguishable. Their unwanted effects are
also broadly similar. The past 20 years of research
and development have not brought any significant
breakthroughs in treatment, despite the appearance
of a large number of drugs. If anything, the only
result has been a more expensive way to inflict gas
trointestinal upsets, ulcers, irritating skin rashes and
other allergic conditions on patients already suffer
ing from crippling pain. With the rush of new
products there has also been an unnecessary linger
ing on the market of older products like the
butazones whose hazards are beyond question.
Millions have been wasted. Thousands of people have
died. Unnecessary suffering has been inflicted on an
unknown number of people. It is time to introduce a
more rational approach to the treatment of arthritis.
While analgesics are increasingly being recom
mended for use in arthritis instead of NSAIDs, many
companies are trying to encourage the use of NSAIDs
instead of analgesics in simple pain relief conditions.
There is some reason for this, particularly if opioid or
narcotic analgesics are being replaced, and if
NSAIDs are used only for a short time. The Lancet,
for example, suggests that post-operative pain relief
may be a possible indication for NSAIDs.51
Substituting NSAIDs for simple analgesics in rhe
treatment of acute pain conditions such as headaches
or menstrual pain, however, is not likely to be a wise
or cost-effective decision. “These potent drugs with
recognised dangerous side effects should be restricted
in their prescription and used with caution for trivial
and self-limiting complaints.”52 This is a particularly
important point as more and more NSAIDs begin to
come onto the market in many countries as over-thecounter drugs that do not require a prescription.53
In osteoarthritis, if a drug is needed, the first choice
should be a simple analgesic like paracetamol. With
rheumatoid arthritis, where NSAIDs may have some
additional benefit, the first drug to use should be
ibuprofen. If NSAIDs are used in osteoarthritis at all,
they should be prescribed only in short courses to
minimise the risk of serious adverse effects among
FIRST-LINE NSAID WITH CARTILAGE BENEFITS
s.v.-rj'xi-'-tt etteo yrrct an«(»cix>qapcx>a(^.i e. tuex can r«Kvn veeiau-icrawt t-xhai
CO** u." 'lUtr^a—fXi COVJUXI CCSAGC AdublOrtj fcjCmgO.jin<J..Cr>3<5OMt Cu'rrlicwtn
nut e It n« 'WHM.-J to
oauo* of Surja.-! s' rJm? or n (no c< i- ;<J 13
unit ■-(■>
tn 10m 'tU
« .»
CUI
O» redxtd to
taK« CtJf CO'ttni
AIOVS
Ar.-n xrx JCio'e-v rptrwie. tf P'ECA-T.O'.S Uw »Ui cut m pat*r.u ■nt.'i a Mlcvj o'
>.<e<»t'On w.rrr
rr'ul-r
■r'a^'C'encj afc~>rj wtUTtf >0 a»p»mM oTtr
»rtr .%'U-.««»t>rai;ant»|tt$*ln .nc^»mc«
ar^alcomjcU-wMart'aaw.T Uo.V<r.<rct o:ua;< r-j, nrrtiiar,
.-.nn^t--,
t;
and ■'•t&jljCM-x Mjerli Eater,
kZIkuici Kat net Ue<neVa'-il.-«3aM
n
w“> 3—e- KSA-t ►S-^-.xtratron ajrq
I;» And tail trartcer thduSI b» a.CxlHl StOC LIHCT5 Gain.
n'nlrul itx' neadarfta iov-etl a<xj tin rain turf xriwr.a!| t«n r»pc«t«d 0>LAD0$K>l Supfcd w and
Bjupttoutc CUrcj COWPOSKC* lur-e'e'* tod PRtStNUnO*' Suqtn M«tj Utedt Su^a-t XW rrj latMl
lix .V. a
ROUSSEL /
<x>
bon
Roussel promotes Surgam's "cartilage benefits",
MIMS Middle East, Aug 1990
NSAIDs that have been withdrawn in
industrialised countries
alclofenac
benoxaprofen (Opren/Oraflex)
fenclofenac (Flenac)
feprazone (Methrazone)
flufenamic acid (Arlef)
indomethacin (controlled release preparations: Osmosin,
Osmogit, Amuno Gits)
indoprofen (Flosint)
isoxicam (Maxicam)
oxyphenbutazone (Tandacote, Tanderil)
suprofen (Suprol)
suxibuzone
zomepirac (Zomax)
4 C .
N S A I D s
Problem Di
Questions to ask before prescribing/receiving an NSAID
Physician
1. Is the drug really required?
2.
3.
4.
Should the dose be lowered?
Is the patient at risk from drug interactions and
can the number of drugs be reduced?
Is this a high risk NSAID?
5.
Is the patient a high risk patient and does he/she
have another disease that puts him/her at risk?
6.
Will the patient take the drug prescribed and what
are the consequences if he/she does not do so?
Patient
1. Do I need this drug? Why? Is it for pain,
inflammation or both?
2. Can I take a smaller dose? Is it safe to take a larger
dose? How long do I need to take it?
3. Will this drug interact with other medicines I am
taking? With food? Alcohol?
4. What are the adverse effects of this drug? Is there
a safer drug available? Is there a non drug therapy
that would help?
5. Will this drug affect any existing illness that I have?
Is there anything that I should be extra careful
about?
6. What if I don’t like the effects of this drug: can I
stop taking it? What if I forget one or two tablets:
will it affect the treatment?
Source: doctor's questions from- Nuki. G.. "Pain control and the use of non-steroidal analgesic anti inflammatory drugs". British Medical Bulletin Vol ^6
No 1, 1990, pp262-78
the elderly, as has been recommended by the
National Drugs Advisory Board in Ireland,54 and by
the Australian Department of Health.55
An editorial in the journal Gastroenterology is clear
that “until non-toxic alternatives are discovered,
NSAIDs should be prescribed only when absolutely
necessary, and then only in the lowest effective doses.
Other agents (e.g., acetaminophen [paracetamol|)
should be substituted where possible, particularly
because NSAIDs in either analgesic or anti-inflamma
tory doses may not be superior to acetaminophen for
the short-term symptomatic relief of osteoarthritis.”56
Two doctors writing in the New England Journal of
Medicine comment that manufacturers have an ethical
responsibility “to exercise caution in marketing and to
maintain surveillance” of NSAIDs since patients may
well become daily users for long periods.57
The fashionable habit of prescribing an NSAID and
misoprostol together as a means of minimising the
most serious risk associated with NSAIDs (ulcers) is
part of a worrying trend. The initial problem is
caused by the administration of a drug; throwing a
second drug at the problem - one which has its own
troubling adverse effects - is clumsy at best and rein
forces the “pill for every ill” mentality.
Recommendations for action
1. The marketing of any new NSAID should be
restricted so that a carefully controlled number of
patients receive the drug initially and so that its
adverse reaction profile can be determined. As
well, there should be an adequate independent
system to monitor adverse drug reactions - sadly
lacking in many countries. Therefore,
governments and health authorities should take
steps to establish such systems.
2. As equally effective and safer drugs are
available, all butazones should be banned in all
markets, immediately.
3. Regulatory bodies, health ministries and
independent drug information units should
urgently review the safety profiles of all NSAIDs on
the market, with a view to limiting the number of
preparations to the 10 with the best safety record,
coupled with efficacy and low cost.
[See also the sections on Analgesics and Dipyrone.]
4. Products which have been withdrawn for safety
reasons in one country should be withdrawn in all
countries.
96
4 C .
N S A I D s
Problem Drugs
References:
1.
2.
3.
4-
5.
6.
7-
8.
Balme. H.W., "NSAIDs”, (letter to the ed.). Lancet, 4 Feb 1984
Dieppe, PA, Frankel, S.J. and Toth. B., “Is research into the treatment of
osteoarthritis with non-steroidal anti-inflammatory drugs misdirected?-*, Lancet,
Vol 341.6 Feb 1903, PP353-4
Henry; J. (ed.). The British Medical Association Guide to Medicines & Drugs,
London, Dorling Kindersley, (2nd edn) 1991, pp/7 and 112
Markenson, )A, “Worldwide trends in the socioeconomic impact and long-term
prognosis of rheumatoid arthritis*, Seminars in Arthritis and Rheumatism,
Vol 21, No 2 (Suppl. 1), Oct 1991, PP4-12
Ghosh, P and Brooks, P., “Chondroprotection - exploring the concept”, Journal
of Rheumatology. Vo! 18. No 2,1991, ppi6i-6
Bradley. J.D., Brandt, K.D.. et al, “Comparison of an antiinflammatory dose of
ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment
of patients with osteoarthritis of the knee", New England Journal of Medicine,
Vo! 325, No 2,11 Jul 1991, ppSz-91
Nuki, G., “Pain control and the use of non-steroidal anti-inflammatory drugs",
British Medical Publication, Vo! 46, No 1,1990, PP26278
Parish, P., Medicines: a guide for everybody, London, Penguin (6th edn,
revised), 1989, P197
Brandt, K.D., "The mechanism of action of nonsteroidal antiinflammatory
drugs”, Journal of Rheumatology, (Suppl. 27) Vol 18,1991, ppi20-i
Mazzuca, SA, Brandt, K.D., et al, “The therapeutic approaches of community
bajed primary care practitioners to osteoarthritis of the hip in an elderly
patient", Journal of Rheumatology, Vol 18, No 10,1991, ppi593-6oo
11.
Parish, op cit, P197
12.
Calkins, E., “Arthritis in the elderly”, Bulletin on the Rheumatic Diseases, Vol 40,
No 3,1991, ppi-9
13.
WHO, The Use of Essentia! Drugs, Fifth report of the WHO Expert Committee
(Technical Report Series No 825), Geneva, WHO. 1992, p22
Gilman, A.G., Rail, T.W., Nies, A.S., and Taylor, P. (eds), Goodman and Gilman's
The Pharmacological Basis of Therapeutics, New York, Pergamon Press,
(8th edn) 1990,9643
30.
Wijnands, M„ van Riel. P„ et al, “Longterm treatment with nonsteroidal
antiinflammatory drugs in rheumatoid arthritis: a 9rospective drug survival
29.
31,
Bulletin, Vol 28, No 7, 2 Apr 1990,9925-6
Zeidler, H„ “Epidemiology of NSAID-induced gastropathy”, Clinical
Rheumatology, Vol 10. No 4.1991. PP3&973
33.
Day, R„ and Henry, D„ “Do anti-ulcer drugs prevent gastrointestinal damage
32.
from NSAIDs?", Australian Prescriber, Vol 14, No 3,1991,9942-3
34.
35.
36.
Cham9ion, 09 cit
Anon., “UK arthritis costs estimated”, Scrip, No 1708,10 A9r 1992,95
Anon., "Miso9rostol for co-9rescription with NSAIDs”, Drug and Therapeutics
37.
38.
Bulletin, Vol 28, No 7,2 A9r 1990, pp25-6
Brooks, 1988, 09 cit
Agrawal, N„ “Risk factors for gastrointestinal ulcers caused by nonsteroidal anti
inflammatory drugs (NSAIDs)", Journal of Family Practice, Vol 32, No 6,1991,
9.
39.
10.
Mazzuca, et al, op cit
Fries, J.F., Williams, CA and Bioch, DA. “The relative toxicity of nonsteroidal
antiinflammatory drugs". Arthritis and Rheumatism, Vol 34, No 11, Nov 1991,
ppi353-6o
16.
Champion. G.D., “Therapeutic usage of the non-steroidal anti-inflammatory
drugs”. Medical Journal of Australia, Vol 149,15 Aug 1988,pp203-i3
17.
Gotzsche, P.C. "Sensitivity of effect variables in rheumatoid arthritis: a meta
analysis of 130 placebo controlled NSAID trials”, journal of Clinical
Epidemiology, Vol 43, No 12,1990. PP1313-18
18.
Dumas, C and Cusack, B.J., "Salicylate intoxication in the elderly: recognition
and recommendations on how to prevent it”, Drugs & Aging, Vol 2, No 1,1992,
14.
15.
PP20-34
Brooks, PA, “Side-effects of non-steroidal anti-inflammatory drugs”, Medical
Journal ofAustralia, Vol 148.7 Mar 1988, PP248-51
20.
Anon., “15 years of NSAls in Denmark", Scrip, No 1083, to Mar 1986. P4
21.
Fries, et al, op cit
22.
Brooks, P.M., "Clinical management of rheumatoid arthritis”, Lancet, Vol 341,
30 Jan 1993, PP286-90
23.
Anon,, "Need for NSAI guidelines". Scrip, No 1741, 5 Aug 1992. p22
24.
Hayllar,Macpherson, A. and Bjamason, I., “Gastroprotection and nonsteroidal
anti inflammatory drugs (NSAIDs): rationale and clinical implications", Drug
Safety, Vol 7, No 2,1992, pp86-tO5
25.
Scheiman. J.M., "Pathogenesis of gastroduodenal injury due to nonsteroidal
antiinflammatory drugs: implications for prevention and therapy”, Seminars in
Arthritis and Rheumatism, Vol 21, No 4, Feb 1992, pp2oi-io
26.
Calkins, op cit
27.
Ibid
28.
Gay, G.R., "Another side effect of NSAIDs”, Journal of the American Medical
Association, Vol 264, No 20,28 Nov 1990,992677-8
19.
study". Journal of Rheumatology, Vol 18, No 2.1991,99184-7
Anon., “Misoprostol for co-prescription with NSAIDs", Drug and Therapeutics
40.
99619-24
Ho9pmann, R A.. Peden, J.G., and Ober, S.K., “Central nervous system side
effects of nonsteroidal anti-inflammatory drugs: aseptic meningitis, psychosis,
and cognitive dysfunction", Archives of Internal Medicine, Vol 151, Jul 1991,
9P13O9-13
Jones, M.P. and Schubert, M.L, “What do you recommend for prophylaxis in an
elderly woman with arthritis requiring NSAIDs for control?”, American Journal of
Gastroenterology, Vol 86, No 3,1991, 99264-6
Anon., The European Market for Arthritis Treatment Products, London, Frost &
Sullivan, 1991
42.
Anon., The US Market for Prescription Anti-inflammatory Agents, New York, Frost
81 Sullivan, 1991, cited in: Anon., “LIS anti-inflammatory market $4 billion in
1995?", Scrip, No 1632,10 Jul 1991, pi8
43.
Anon., Scrip, No 1708, op cit, 95
44.
Anon., “Top 25 products in 1991", Scrip, No 1717.13 May 1992, 928 (based on
UBS Philips & Drew’s Global Pharmaceutical Revied)
45.
Anon., “$270 million US sales for Tidid?”, Scrip, No 1586, 30 Jan 1991,921
46.
Anon., Scrip, No 1717, op cit, 928
47.
Ahmad, S.R, Bitter Facts About Drugs, Karachi, HAI-Pakistan, 1990,99233-4
48.
Dyer, C, "The penalties of issuing misleading advertisements”, British Medical
Journal, Vol 294,14 Feb 1987. 99426-7
49.
Brandt, op cit; Rashad, S., Revell, P. et al, “Effect of non-steroidal anti
inflammatory drugs on the course of osteoarthritis”. Lancet, No 8662,2 Sep
41.
1989. PP519-522
Anon., “Chondroprotection", Lancet, Vol 337,30 Mar 1991, 99769-70
Anon., "Postoperative pain relief and non-opioid analgesics”, Lancet, Vol 337,
2
Mar 1991, PP524-6
52.
Gay, op cit
53.
Bennett, W.M. and DeBroe, M.E., "Analgesic nephropathy - a preventable renal
disease", New England Journal of Medicine, Vol 320, No 19,11 May 1989,
991269-71
54.
Anon., "Nonsteroidal anti-inflammatory agents; hazards of long-term use", WHO
Drug Information. Vol 5, No 1,1991, pn
55.
Anon., "NSAl restrictions on Australian PBS”, Scrip, No 1790,29 Jan 1993, pi8
56.
Talley, N.J., "Chronic peptic ulceration and nonsteroidal anti-inflammatory drugs:
more to be said about NSAIDs?”, Gastroenterology, Vol 102, No 3, Mar 1992,
50.
51.
57.
PP1074-7
Bennett and DeBroe, op cit
Chetley, A. Problem Drugs, Amsterdam,
Health Action International, 1993
Health Action International’s
J
„<
'
and
.
pocuW'/’”" /' />
5A. Cough and co
preparations
coordinating offices:
HAI Europe
Jacob van Lennepkade 334T
1053 NJ Amsterdam
The Netherlands
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accidn para la Salud
Avda. Palermo 531
Dpto. 104
Lima 13
Peru
Peddling placebos
Every year millions of people around the world come
down wirh the “common cold”. The symptoms are
well known: a sore throat, a stuffy or runny nose,
sneezes, perhaps a mild fever, some aches and pains
and sometimes even an irritating cough.
The cause is also well known: one of more than 200
different strains from six families of viruses. From 30
to 50% of colds are caused by rhinoviruses, while
coronaviruses account for some 15 to 20%.
Respiratory syncytial, influenza, parainfluenza and
adenoviruses cause most of the rest.1
Although the common cold is usually benign and
self-limiting,2 colds together with influenza and other
acute respiratory infections (ARI) accounted for
48% of all short-duration (acute) illness in the USA
in 1982? More than three million people a year suf
fer from pneumonia in the USA, 500,000 of whom
require hospitalisation? Generally, in industrialised
countries, acute respiratory diseases account for 25
to 50% of all medical consultations. About one-third
of parienrs complain of common cold, one-third have
symptoms of pharyngitis, laryngitis, or tonsillitis,
and the remainder suffer from bronchitis, pneumo
nia or influenza.5
In China in 1989, respiratory diseases accounted for
25% of all deaths in rural areas.6 In Africa, ARIs are
the leading cause of illness and the main reason for the
use of health services by children. ARIs account for an
estimated 20 to 40% of children visiting outpatient
clinics and as many as one-third of hospital admissions
in Africa.7 Globally, the World Health Organization
(WHO) estimates that at least four million children
under five years of age die each year from ARl-related
infections - mostly pneumonia. That represents
10,000 deaths every day; two-thirds of those deaths
occur in children under the age of one?
Ineffective and a waste of money
There are no means to prevent or cure the common
cold.9 However, as long ago as 1933, H.S. Diehl
wrote in the Journal of the American Medical
Association that 35% of patients with colds who
were treated with a lactose placebo reported good
results. This finding led him to write: “it is possible to
convince the public that practically any preparation
is of value for the prevention or treatment of
colds”.10 Over the years, the pharmaceutical industry
has been very successful at doing precisely that, with
the result that vast sums are spent every year trying to
treat the untreatable.
A 1985 advertisement for cold remedies aimed at
Australian pharmacists left no doubt about the com
pany’s intentions with its headline: “How to turn an
98
5a.
Cough
and
cold
preparations
Problem Drugs
The use of antibiotics in the treatment of acute respiratory infections
Upper and lower respiratory tract infections are the
primary cause of antibiotic use in general practice in
patients of all ages.1 A survey in pharmacies serving
low-income populations in Fortaleza, Brazil found that
antibiotics were routinely recommended for acute
respiratory infections.2 However, 95% of all acute
infections of the upper respiratory tract are caused by
non-bacterial organisms.3 According to the American
Medical Association (AMA), “routine administration of
antimicrobial agents to patients with colds has been
shown to be completely useless’’.4 Only if the
symptoms fail to abate within one to two weeks is
there some possibility that a secondary bacterial
infection of the sinuses, the ears, bronchial tract or
lungs may be present. In the meantime, appropriate
diagnostic studies could be carried out to determine
whether treatment with penicillin, ampicillin,
amoxycillin, co-trimoxazole or erythromycin may be
needed.
Inappropriate antibiotic treatment of ARI in developing
countries wastes the resources of health services and
can increase the occurrence of drug-resistant
bacteria.5 WHO says that in most ARI cases,
“antibiotics are not necessary’’.6 In children less than
five years old with a cough or difficult breathing, fast
breathing or chest indrawing will identify the children
who need antibiotic treatment for pneumonia. Fast
breathing is defined as a respiratory rate of more than
60/min for infants under two months, 50/min for two
months to one year, and 40/min for one year to five
years. Children who have chest indrawing, or who have
other danger signs of severe disease (not able to
drink, abnormally sleepy or difficult to wake,
convulsions, a calm child who makes a harsh noise
while inhaling [stridor], or severe malnutrition) should
be referred to hospital for treatment. If children have
a cough without these signs, signs of an acute ear
infection or of suspected streptococcal throat
infection, they have a simple cough or cold and can be
cared for at home without antibiotics or any
Sources:
1. Bergogne-Berezm, E.; "Continuous activity of significant
antibiotics", Clinical Therapeutics, Vol 13, No 1, 1991, ppl81-8
2. Misago, C and Fonseca, W., "Antimicrobial drugs advised in
pharmacies in Brazil for children with acute respiratory infections”,
Lancet. Vol 338, No 8768, 14 Sep 1991, p702
3.
Lode, H., "Respiratory tract infections: when is antibiotic therapy
indicated?”, Clinical Therapeutics, Vol 13, No 1, Jan-Feb 1991, ppl49
156
4.
AMA, Drug Evaluations, Philadelphia, W.B. Saunders Co. (6th edn)
1986, p376
5.
Sutrisna, B., Frerichs, R.R. and Reingold, A.L., "Randomised,
controlled trial of effectiveness of ampicillin in mild acute respiratory
infections in Indonesian children’’, Lancet, Vol 338, No 8765 24
1991, pp471-4
'
AugB
6.
Chetley, A.. Pedaling Placebos. An analysis of cough and cold
remedies, Amsterdam, HAI, 1990, pl
commercial drugs.7 For example, in Indonesia children
with mild ARI were treated with either ampicillin or a
placebo. Researchers found that the children who
were given ampicillin did not improve any faster.
Four simple rules have been developed to deal with
children who have a cough:8
1. Most children with a cough do not need an
antibiotic;
2. If there is coughing and fast breathing, oral cotrimoxazole or amoxycillin, or intramuscular
injections of procaine penicillin are recommended;
3. If there is coughing and chest indrawing, the child
should be referred to hospital and given
intramuscular benzylpenicillin (with gentamicin if
the child is under two months of age);
4. If there is coughing and cyanosis (bluish
discoloration of the skin due to lack of oxygen in the
blood) or the child cannot drink, the child should be
admitted to hospital and given intramuscular
injections of chloramphenicol (or benzylpenicillin
with gentamicin if the child is under two months of
age).
A study in Nepal found that even if referral facilities
were lacking, village health workers and semi-literate
parents could be trained to recognise and treat
pneumonia with two oral antibiotics: first,
cotrimoxazole and, if there was no improvement, oral
chloramphenicol. After three years, there was a 30%
reduction in death rates due to pneumonia.9 An
analysis of nine studies (including the one in Nepal)
found a reduction in infant mortality from pneumonia
of between 26 and 35%.10
According to WHO, improved understanding about
the correct use of antibiotics in the treatment of
bacterial pneumonia has led to the prevention of
children's deaths. In some countries, this has also led
to a reduction in the misuse of antibiotics for other
forms of ARI.11
7.
WHO, Acute respiratory infections in children: Case management in
small hospitals in developing countries. A manual lor doctors and other
senior health workers, (WH0/ARI/90.5), Geneva WHO 1990
a Anon , Childhood Pneumonia: strategies to meet the challenge
'“.“ T"85
A
r
‘hf F.'rS‘ lnternat'°nal Consultation on the Control of
Acute Respiratory Infections. 1991). London, AHRTAG 1992
Pandey. M.R., Oaulaire. N.M.P., et al. "Reduction in total under.five
trea ment'nNepal throush conimunity.based antimicrobial
treatment of pneumonia , Lancet, Vol 338, 19 Oct 1991 nn993 7
io. Sazawal, S . and Black. R.E., "Meta-analysis of interienfon tnals
Vol 340e T97ug79^1OppP528UT30nia
C°mmUni,y Set,”'8s"' lancet,
unhealthy customer into a healthy profit”. The rest
of the text continued: "There's nothing like a cold
winter to blow a hot profit your way. Especially
when you've stocked up on these proven money spin
ners from Robins.”11 The conflicting and often
ridiculous claims made in promotional material for
cough medicines are described in the box on page 103.
In 1990, the world market for over-the-counter
(OTC) cough and cold remedies was at least $7.3 bil
lion. By the year 2000, analysts estimate the figure
could be more than $9.5 billion.12 The US market for
cough and cold preparations was worth $5.5 billion
in 1988 (35% of which was for prescription-only
products) and is expected to reach sales of $7.8 bil
lion (40% on prescription) by 1993, according to
market analysts Frost and Sullivan.13 In the
Philippines in just six months in 1987, people in the
capital city of Manila spent an estimated $3.1 million
on cough syrups.14 In the UK, cough and cold reme
dies account for 25% of the market for OTC drugs;15
in 1991, an estimated £152 million (USS 275 mil
lion) was spent on OTC cough and cold products.16
In Germany in 1991, DM 875 million ($547 million)
was spent on self-medication with cough and cold
products.17
hay fever seasons. In a country such as the UK, this
would most likely be during June to September.
However, a year-long study of antihistamine pre
scribing in four socio-economic areas in Liverpool in
the UK found antihistamine use was at its highest in
January and at its lowest from June to September.23
With rhe large number of cough and cold products
which contain antihistamines, it is probable that sim
ilar patterns occur in other countries.
Nasal decongestants - usually sympathomimetics
(drugs which mimic the stimulation of the sympa
thetic nervous system) - are also popular ingredients
in cough and cold remedies. However, most nasal
decongestants can cause problems. Decongestant
nasal sprays, drops or inhalers may work for a short
time. However, they are liable to lead to a “rebound
effect” in that after they have been used, the conges
tion returns even more strongly. They may prolong a
cold and repeated use may damage the lining of the
nose.24 The British Medical Association (BMA) says
that “most common colds do not need to be treated
with decongestants”.25 If a decongestant is needed,
sprays, drops or inhalers containing oxymetazoline
or xylometazoline could be used for a day or two;
however, a simple salt and water solution (0.9%
Paying through the nose
One of the most ineffective ingredients in cold reme
dies is an antihistamine, usually included in the
mistaken belief that it will help to dry up a runny
nose, and therefore make it easier to breathe.
Although antihistamines are effective in dealing with
rhinitis (inflammation of the nose) caused by allergic
reactions, numerous studies of antihistamines
(including the newer so-called non-sedating antihista
mines) in the treatment of the common cold have
yielded inconclusive results.18 Dr Leslie Hendeles,
professor of pharmacy and paediatrics at the
University of Florida, points out that “since antihista
mines have the potential to cause harmful effects, the
risks associated with their use outweigh any meagre
benefit. It is my opinion that these drugs should be
removed from all non-prescription products pro
moted for the relief of cough and cold symptoms.”19
Most authoritative texts agree that there is “no evi
dence” that antihistamines “are of the slightest
value” in the treatment of rhinitis resulting from
colds.20 One pharmacology textbook points out that
although they may have a weak effect on runny
noses, “this drying effect may do more harm than
good” and their sedative effect may also be harm
ful.21 There is also evidence to suggest that the new
non-sedaring antihistamines can cause fluctuations
in heart rhythms, some of which have been fatal.22
If antihistamines were used rationally, that is, used
for the treatment of allergic rhinitis, it would be
expected that most sales would occur during peak
Antihistamines used in
cough and cold remedies
azatadine
bamipine lactate
brompheniramine
chlorpheniramine
clemastine
clemizole
cinnarizine
carbinoxamine
doxylamine
diphenhydramine
diphenylpyraline
isothipendyl
mebhydrolin napadisylate
mepyramine
oxomemazine
phenindamine
pheniramine
pimithixine
promethazine
phenyltoloxamine
terfenadine
thenyldiamine
tripelennamine
triprolidine
trimeprazine
100
5a.
Cough
and
cold
preparations
Problem Drugs
saline) is “effective, cheap and may be useful in
young children”.26
Many cold preparations now contain nasal decon
gestants in tablet or syrup form, as this is thought to
make the drugs more convenient to take. However
there is little evidence that they are effective. The
British National Formulary (BNF) says oral nasal
decongestants “are of doubtful value”.27 Moreover,
“nasal decongestants taken by mouth... produce con
striction of other blood vessels in the body and
increase the blood pressure.... They are best
avoided.”28 They may also cause adverse behav
ioural changes in young children. Two doctors in the
USA who reported two cases of such behavioural
change in 1987 said their experience caused them “to
question the routine use of over-the-counter decon
gestants in the treatment of children with upper
respiratory infections”.29
Hard to swallow
For many people, a sore throat is the first indication
that a cold has started. This irritation of the throat is
caused by the viral infection. There is “no convincing
evidence” that antiseptic lozenges and sprays or
commercial gargles are of any benefit.30 Many sprays
and lozenges contain a local anaesthetic, which may
relieve pain, but can irritate the throat; making the
pain worse when the anaesthic wears off. Nearly two
million bottles of one throat spray, Chloraseptic,
were sold in 1989 in the UK. However, it also was
linked to swelling of the throat and larynx that could
cause respiratory difficulties (including one death),
and its use in children under six was contraindicated
in 1990.3’
Some “cough” lozenges contain soothing substances
such as honey, liquorice or glycerin which may act on
the surface of the throat. They may also contain
pleasant smelling and tasting substances such as pep
permint, eucalyptus, cinnamon, lemon, clove or
aniseed. “The main effect of these preparations is
that their smell or taste may help you feel better. They
may increase the production of saliva, which is
soothing and helps to wash the inflamed surfaces of
the throat.... Cough medicines which contain the
same ingredients in liquid form are even more irra
tional since they are swallowed directly into the
stomach and only have a fraction of a second to work
locally on the throat.”32
Coughs - medicines or myths?
Cough is the single most common reason for patients
to visit a doctor in Australia, accounting for more
than 10% of all visits.33 A cough is generally a useful
reflex which serves to get rid of inhaled foreign bod
ies or to clear the air passages of sputum.34 Such a
cough is described as “productive”. A cough which is
simply dry and irritating serves no purpose and is
Oral nasal decongestants
The most commonly used oral nasal decongestants are
ephedrine, phenylephrine, phenylpropanolamine and
pseudoephedrine. Like all sympathomimetics, they
should be avoided by people with hypertensin,
hyperthyroidism, coronary heart disease, or diabetes,
and by people taking monoamine-oxidase inhibitors
(used as antidepressants).1
Ephedrine
Because of its stimulant effect, ephedrine should not
usually be given after 4pm. It is contraindicated in
women who are breastfeeding, its safety in pregnancy
has not been established, and it is not usually prescribed
to people over 60 years of age.2'3
Phenylephrine
Phenylephrine is not usually prescribed in pregnancy as
it may cause heart defects in the unborn baby, it is not
usually recommended for infants, and adverse effects
are more likely in people over 60.3
Phenylpropanolamine
Phenylpropanolamine is not recommended for children
under eight, its safety in pregnancy has not been
established, adverse effects are more likely in people
over 60, and it has been associated with serious
toxicity.3'4'5
Pseudoephedrine
Pseudoephedrine has been associated with rare
incidences of visual hallucinations in children.2
Sources:
1.
BMA and the Royal Pharmaceutical Society of Great Britain. British
National Formulary. London, BMA and the Pharmaceutical Press. No 23.
Mar 1992. pl30
2 Reynolds, J.E.F. (ed.), Martindale: The Extra Pharmacopoeia. London,
The Pharmaceutical Press, (29th edn) 1989, ppl462 and 1478
3
Henry, J. (ed .), The British Medical Association Guide to Medicines &
Drugs. London. Dorling Kindersley, (2nd edn) 1991, pp265, 340 and 341
4
Lowenstein, S.R. & Parrino, T.A.. "Management of the Common Cold",
Advances in Internal Medicine, 32, 1987, p219
5. Orson. J. & Bassow, L., "Over the Counter Cough Formulas", Clinical
Pediatrics, June 1987, p287
called “unproductive.” In most cases of acute cough
no medicine is needed, unless there is evidence of
more serious lower respiratory illness.35
However, a whole mythology has developed around
various types of cough remedies. There are basically
wlXhyPeS °f n't8? expectorants or mucolytics,
which supposedly help to expel the sputum more eas-
s on^e SUpPreSSaT ’ Which suPPosedly work to
stop the coughing reflex.
Most expectorants act by irritating the lining of the
stomach which in turn causes a reflex stimulation of
5 A .
Mucolytics - such as acetylcysteine, carbocistene and
methylcysteine - and other enzymes have been
shown to “digest” sputum in the laboratory but their
effect in real life situations has been variable. “Few
patients... have been shown to derive much benefit
from them.”40
Most experts agree that there are few occasions when
a cough suppressant should be used. According to
the BNF:
“The drawbacks of prescribing cough sup
pressants are rarely outweighed by the
benefits of treatment and only occasionally
are they useful, as for example, if sleep is dis
turbed by a dry cough. Cough suppressants
may cause sputum retention and this may be
harmful in patients with chronic bronchitis
and bronchiectasis. Though commonly used
in acute bronchitis and pneumonia, they can
be harmful; such conditions are best treated
by prompt administration of antibacterial
drugs. Cough suppressants such as codeine,
dextromethorphan, and pholcodine are sel
dom sufficiently potent to be effective and all
tend to cause constipation. The use of cough
suppressants containing codeine or similar
opioid analgesics is not generally recom
mended in children and should be avoided
altogether in those under 1 year of age.”41
A Finnish study in 1991 found that the most com
mon cause of cough is acute viral respiratory
infection. This type of cough is usually transient and
self-limiting and does not need treatment. The study
concluded that cough suppressants should not be
routinely used in rhe treatment of children with acute
viral infection.42
According to the AMA, “reports on the effectiveness
of various antitussive agents |cough suppressants]
frequently conflict because of the difficulties in
assessing their effects”. One that does work, provid
ing it is given at the appropriate dosage level, is
codeine - although it can cause constipation and
may, very rarely, produce drug dependence of the
morphine type in some patients. The AMA describes
it as “the most efficacious antitussive in the treatment
of acute and chronic cough caused by a wide variety
of disease states”,43 and it is the only cough inedicme
suggested in the WHO Essential Drugs list.
and
cold
preparations
The WHO list does indicate, however, that codeine
should be considered as an example of a therapeutic
group and that a similar drug such as dextromethor
phan could be used. The AMA describes
dextromethorphan as “the safest antitussive avail
able” and as being “as effective as codeine except for
severe acute cough”.45
Combined mayhem
One of the most irrational types of products on the
market is a combination of ingredients which are
supposed ro act as expectorants or mucolytics with
those which act to suppress coughs. The vast major
ity of products sold as cough and cold remedies are
combination products. The BNF says:46
“Compound cough preparations have no
place in the treatment of respiratory disor
ders.... Such preparations are to be deprecated
not only as irrational but also for leading to
patients receiving inappropriate drugs.”
The US Food and Drug Administration (FDA) has
concluded that “no significant target population
exists which could benefit from a combination prod
uct containing more than three pharmacologic
groups”.47 Similarly, the AMA says that if a combi
nation is to be used, it should meet the following
criteria:
1. It contains no more than three active ingredients
from different pharmacologic groups and no
more than one active ingredient from each phar
macologic group.
2. Each active ingredient is present in an effective
and safe concentration and contributes to the
treatment for which the product is used.
3. The product is used only when multiple symp
toms are present concurrently.
Ingredients used as “expectorants”
acetates
acetic acid
ammonium chloride
benzoin compounds
bicarbonates
creosote
eucalyptus
guaiphenesm (glyceryl guiaicolate)
ipecacuanha
menthol
peppermint
potassium iodide
sodium benzoate
sodium citrate
squill
tolu
101
Problem Drugs
the nerves supplying the glands in the bronchi. This is
said to result in an increased production of secretions,
thus making rhe sputum more watery and easier to
cough up. However, most of these drugs produce nau
sea and even vomiting at doses high enough to
increase the secretions.36 According to the BNF “there
is no evidence that any drug can specifically facilitate
expectoration’.” For this reason, expectorant cough
medicines have been described as “an expensive
myth”.38 There is no rationale for their use.39
Cough
102
Cough
5a.
and
cold
preparations
Problem Drugs
The product is therapeutically appropriate for the
type and severity of symptoms being treated.
5. The possible adverse reactions of the components
are taken into consideration.
The AMA then comments: “many mixtures popular
with the lay public and physicians for treatment of
lipper respiratory tract disorders do not meet these
criteria”.48
4.
The AMA’s comment is, if anything, an understate
ment. A survey of prescribing guides from 12 regions
of the world during late 1987 and 1988, found that
well over one-third of the 2,198 cough and cold
preparations listed contained more than three ingre
dients. A staggering 86% of all the products listed
contained ingredients deemed by independent
sources to be ineffective in the treatment of cough
and colds. And, to add injury to insult, 55% of the
products contained ingredients liable to cause harm
ful adverse reactions.49 The situation is not
improving. A survey of prescribing guides in four
regions during 1990 and 1991 found similar results,
as Table 5A-1 on the next page shows.
To put the scale of the problem into a little more per
spective, in most cases, the products listed in
commercial prescribing guides represent only a small
proportion of drugs likely to be on sale in any coun
try. As a researcher in India pointed out, the Monthly
Index of Medical Specialities listed only some 6% of
the estimated 30,000 brands of all drugs on the
Indian market. He commented: “the most obnoxious
and downright criminal drugs are largely, though not
entirely, eliminated” from the lists in the prescribing
guide.50
Also, these surveys do not analyse products on the
market in industrialised countries. The market in
developing countries is a more obvious indicator of
irrational therapies; however, the problem is not
limited to them. In the UK in 1992, the British
National Formulary listed 60 preparations for
coughs or for nasal decongestion. It described 50 of
them (83%) as “less suitable for prescribing”?1 A
guide to over-the-counter medicines in France pub
lished in 1992, said that of the 276 cough medicines,
“only a dozen are worthy of a place in the medicine
cabinet”.51 Even that may be an overgenerous state
ment.
An editorial in ARI News sums up the situation suc
cinctly:53
“While millions of children die each year for
lack of lifesaving therapy for severe ARI,
many more are overtreated with unnecessary,
potentially harmful drugs for mild ARI. Mild
ARI nearly always gets better without the
need for drug treatment.... A huge range of
substances are now produced and promoted
as the answer to the problems of ARI.... Not
only may they give parents a false sense of
Treating coughs and colds
Most people with a cold need no drugs at all. The illness
will run its course in anything from four to 14 days. Plenty
of rest and warm fluids in the early stages of the infection
are helpful. Paracetamol, used sparingly, can ease aches,
pain and fever (although the usually mild fever is part of
the body's defence mechanism against the infection).
When the nose is blocked (congestion), blowing the nose
or simple gentle cleaning of the nostrils is helpful.
For a sore throat, anything sucked or chewed in the
mouth helps to stimulate saliva production which in turn
eases the soreness of the throat. Similarly, warm fluids
are helpful. Gargling with warm water with a little salt
added may ease the soreness or a drink of warm water,
lemon juice and honey may soothe the throat.
If a ''productive” cough develops, cough suppressants
should be avoided. Again, warm fluids may help. With a
dry, non productive cough, the main relief is to keep the
throat lubricated. Cough suppressants should not be
used for children; in adults, if the cough is severe or is
disturbing sleep, then the use of a cough suppressant
such as dextromethorphan may occasionally help.
If there are signs present that pneumonia has developed
- fast breathing or chest indrawing - then medical
attention and the use of an appropriate antibiotic are
required (see box on page 98).
Health workers should make every attempt through
better health education to discourage the use of drugs in
the treatment of a simple cough or cold, but if a patient
insists on a cough medicine, then health workers can
recommend that parents make a safe, soothing
preparation at home or can provide such a simple
mixture for young children.
security about a sick child, they may also be
an expense families cannot afford, using up
family income that could be better spent.
The glut of ineffective medicines on the market inter
feres with appropriate therapy. An international
conference on ARI held in 1991 made the point that
“enormous government and individual expenditure
is committed to ineffective and potentially harmful
treatments, while antibiotics vital for pneumonia
treatment are unavailable”.54 On the other hand, this
conference stressed that a solution is possible: “If
parents can be persuaded by inaccurate messages
about ineffective medicines, then it should also be
possible to reach them with accurate information
and low-cost treatments which will genuinely protect
their children’s lives.”55
Cough
and
cold
preparations
lem Di
Table 5A-1
Cough and cold preparations with ineffective or potentially harmful ingredients in
selected regions (1990-1991)
Country/Region
Africa (July 1991)
Caribbean (Jan 1991)
Number of
No. with
No. with
No. with
preparations
potentially
harmful ingredients
ineffective
more than
ingredients
3 ingredients
No.
%
No.
52.6
83
85.6
27
27.8
67.6
59
86.8
20
294
No.
%
97
51
68
46
%
Middle East (Dec 1990)
155
76
Pakistan (Mar-Aug 1990)
49.0
131
84.5
41
26.5
123
88
71.5
111
90.2
69
56.1
Totals all areas:
443
261
58.9
384
86.7
157
35.4
Sources: Africa MIMS; Caribbean MIMS; Middle East MIMS; QIMP (Quick Index ol Medical Preparations) Pakistan
Conflicting claims
Companies will tell doctors almost anything to help sell
cough medicines. In some cases, as these examples
illustrate, the same company will use very different
arguments - arguments that condemn some of their
own products!
In March 1988 in Thailand, Parke-Davis ran an
advertisement in the medical journal Clinic to promote
its “new” cough medicine, Benadryl CD, highlighting
the fact that one of its ingredients, codeine, is
“among the most effective agents for suppressing
cough". In May 1987, Parke-Davis ran an
advertisement in another Thai journal, the Siriraj
Hospital Gazette, for Benadryl Expectorant (which
does not contain codeine) that claimed the product
was “as effective as codeine” but did not have the
“possible codeine complications”. The introduction of
the “new” product with codeine had little to do with
improvements in health care.
In Pakistan in 1989, Sandoz distributed leaflets to
doctors promoting its Triaminic syrup (which contains
two antihistamines - pheniramine and mepyramine and the nasal decongestant, phenylpropanolamine).
The leaflets claimed that the "balanced formula” and
"absence of unnecessary ingredients" led to an
“absence of unwanted side effects". In other places,
the leaflet claimed the product was one which
“minimizes side effects" and that it was free from
“unnecessary side effects”. At the same time, doctors
were also being circulated with leaflets promoting
Triaminic-E as "the only safe, effective and most widely
used expectorant". One of its selling points was that,
because it only contained phenylpropanolamine and
the supposed expectorant, guaifenesin, it avoided the
antihistamine side effects and it also “saves the patient
from side effects of shotgun therapies”. In 1990, an
advertisement for Tnaminic-DM (phenylpropanolamine
and dextromethorphan) in the QIMP prescribing guide
also promoted the antihistamine-free benefits,
describing the product as a "non-sedating cough
suppressant". With all three of these products, the best
way of avoiding side effects is to simply avoid the
products.
In April 1990, an advertisement for Boehringer
Ingelheim’s Silomat (clobutinol) in MIMS Middle East
made the point that, on the rare occasions when cough
suppression was needed, “a simple preparation
containing a single agent” was preferred. The ad went
on: “The problem is many antitussives today also
contain one or more additional agents like caffeine,
antihistamines, analgesics, decongestants,
anticholinergics, expectorants or even vitamins - the socalled cough cocktail. Most are either ineffective or
contain inappropriate combinations which may be
dangerous." This is good advice. Following it would
effectively eliminate most of the cough medicines on the
market-including Boehringer Ingelheim's own product,
Abiadan, listed in the same issue of the Middle East
prescribing guide. Abiadan contains orciprenaline,
bromhexine and doxylamine - a sympathomimetic
(decongestant), a mucolytic, and an antihistamine.
104
5a.
Cough
and
cold
preparations
Problem Di
Recommendations for action
Governments should institute full reviews of the
cough and cold preparations on the market both prescription-only and over-the-counter
drugs - with a view to:
• removing those products containing
potentially harmful ingredients, or those with
more than three ingredients; and
• eliminating those products which contain
ineffective ingredients.
2. Governments, health authorities, and
professional associations of doctors,
pharmacists and nurses should develop
accurate information for health workers and
the general public advising them that there is
no such thing as a cure for colds, and that the
most effective treatment for the symptoms are:
rest, plenty of warm liquids, and the occasional
paracetamol to relieve aches or pain.
1.
References:
1.
2.
3.
4.
5.
6.
Sperber, S.J. and Hayden, F.G., “Chemotherapy of Rhinovirus Colds",
Antimicrobial Agents and Chemotherapy, Vol 32, No 4, April 1988, PP409-19
AMA, Drug Evaluations, (6th edn), Philadelphia, W.B. Saunders, 1986, P376
Lowenstein, S.R. and Parrino, T A., “Management of the Common Cold",
Advances in Internal Medicine, Vol 32,1987, pp2O7-34
Hampson, N.B., Woolf, R A. and Springmeyer, S.C, "Oral antibiotics for
pneumonia", Clinics in Chest Medicine, Vol 12, No 2, Jun 1991. pp395-407
Lode, H„ “Respiratory tract infections: when is antibiotic therapy indicated?",
Clinical Therapeutics, Vol 13, No 1, Jan-Feb 1991, PP149-156
Anon., “Respiratory disease main cause of mortality in China", Scrip, No 1550,
7.
8.
19 Sep 1990. p22
von Schirnding, Y.E.R., Yach, D. and Klein, M., “Acute respiratory infections as
an important cause of childhood deaths in South Africa", South African
Medical Journal, Vol 80, 20 Jul 1991, pp79-82
Anon., Childhood Pneumonia: strategies to meet the challenge, (Proceedings
of the First International Consultation on the Control of Acute Respiratory
Infections, 1991), London, AHRTAG, 1992, pi
9.
10.
11.
AMA, op cit, P376
Sperber and Hayden, op cit, pp4io
Jackson, D.M. and Soothill, R„ Is the Medicine Making You III?, North Ryde,
Australia, Angus & Robertson, 1989, P29
12.
Anon., “30% growth for OTC market", Scrip, No 1686, 24 Jan 1992, P19 (These
figures refer to sales in the world’s 15 largest markets.)
13.
Anon., OTC & Prescription Cough & Cold Products Market in the US, New
York, Frost and Sullivan, 1989; cited in: Anon., “US growth predicted for cold
14.
products", Scrip, No 1453.6 Oct 1989, P19
Tan, M.L., Dying for Drugs, Quezon City, Health Action Information Network,
15.
1988,P89
Po, A.L.W., Non-Prescription Drugs, (2nd edn), Oxford, Blackwell Scientific,
16.
1990, P9
Anon., “UK OTC market worth £438 million in 1991", Scrip, No 1756, 25 Sep
17.
1992. P3
Anon., "Self-medication products in Germany", Scrip, No 1773, 24 Nov 1992,
P4
Berkowitz, R.R. and Tmkelman, D.G., “Evaluation of oral terfenadine for
treatment of the common cold", Annals of Allergy, Vol 67, Dec 1991, PP593-7
19.
Ahmad, S.R., “USA: Antihistamines in cold remedies", Lancet, Vol 339, 25 Apr
18.
20.
1992, p 1045
Parish, P., Medicines: A Guide for Everybody, (6th edn, revised), London,
Penguin, 1989. pioi; Sperber, op cit, P414: AMA, op cit, P317; Reynolds. J.E.F.
(ed.), Martindale: The extra pharmacopoeia, (29th edn), London, The
Pharmaceutical Press, 1989, p444
21.
Gilman, A.G., Rail, T.W., Nies, A.S., and Taylor, P. (eds), Goodman and Gilman's
The Pharmacological Basis of Therapeutics, New York, Pergamon Press, (8th
22.
23.
edn) 1990, P587
Anon., “CSM on terfenadine/astemizole ADRs", Scrip, No 1777,8 Dec 1992, p26
Chan, K. and Chan, G., “A study of prescribed Hi-antihistamine preparations
over a period of 12 months in community pharmacy", Journal of Clinical
Pharmacy and Therapeutics, Vol 12,1987, ppi-9
Parish, op cit, pioo
Henry, j. (ed.), The British Medical Association Guide to Medicines & Drugs,
London, Doriing Kindersley, (2nd edn) 1991, p89
26.
Rylance, G. (ed.), Drugs for children, Copenhagen, WHO, 1987, P59
27.
BMA and the Royal Pharmaceutical Society of Great Britain, British National
Formulary, London, BMA and the Pharmaceutical Press, No 23, Mar 1992,
24.
25.
P130
Parish, op cit, ppioo-i
Orson, J. and Bassow, L., “Over-the-counter cough formulas", Clinical
Pediatrics. Vol 26, No 6, June 1987, P287
30.
Parish, op cit, pio8; BMA and the Royal Pharmaceutical Society of Great
Britain, op cit, P385
31.
Anon., "Chloraseptic throat spray ADR warning”, Scrip, No 1524,20 Jun 1990,
28.
29.
P3i
Parish, op cit, PP104-5
Harris, M.F. and Fisher, R.R., “Management of acute lower respiratory
infections", Medical Journal of Australia, Vol 155, 21 Oct 1991, PP538-46
34.
Parish, op cit, P103
32.
33.
35.
36.
37.
38.
39.
40.
41.
42.
Phelan, P., “How the experts manage mild ARI”, ARI News, No 8, Aug 1987, p2
Parish, op cit. P103
BMA and the Royal Pharmaceutical Society of Great Britain, op cit, P129
Parish, op cit, piO4
Lowenstein and Parrino, op cit, p22i
BMA and the Royal Pharmaceutical Society of Great. Britain, op cit, P127
Ibid, pi28
Korppi, M., Laurikainen, K., et al, "Antitussives in the treatment of acute
transient cough in children", Acta Paediatrica Scandinavica, Vol 80,1991,
PP96971
AMA, op cit, PP374-5
WHO, The Use of Essential Drugs: fourth report of the WHO expert committee,
(Technical Report Series No 796), Geneva, WHO, 1990
45.
AMA, op cit, PP374-5
46.
BMA and the Royal Pharmaceutical Society of Great Britain, op cit, P129
47.
Lowenstein and Parrino, op cit, p2i8
48.
AMA, op cit, P385
49.
Chetley, A., Peddling Placebos: An analysis of cough and cold remedies,
Amsterdam, HAI, 1990, ps
50.
Sundararaman, T., “Essential Vs. Irrational Drugs", in A Decade After Hathi
Committee, (Ekbal, B„ ed.), Sivakashi, India, Kerala Sastra Sahitya Parishat,
43.
44.
51.
52.
1988, P199
BMA and the Royal Pharmaceutical Society of Great Britain, op cit, PP1128-31
Anon., “New guide to OTC medicines in France", Scrip, No 1715/16,6/8 May
53.
54.
55.
1992, p8
ARI News, No 8,1987, pi
Anon., Childhood Pneumonia..., op cit, piz
Ibid
Chetley, A. Problem Drugs, Amsterdam,
Health Action International, 1993
/,o'\ ■ LIBRARY
■7
AND
\ - < \ documentation
6A. Growth stimulated
Health Action International’s
coordinating offices:
HAI Europe
Jacob van Lennepkade 334T
1053 NJ Amsterdam
The Netherlands
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accion para la Salud
Avda. Palermo 531
Dpto. 104
Lima 13
Peru
Swatting the symptoms
of malnutottton
Malnutrition is a daily reality for as many as a billion
people - nearly one-fifth of the world’s population.
According to World Bank statistics, women and chil
dren account for 80% of malnourished people.1
Malnutrition affects more than 500 million children
in developing countries according to the World
Health Organization (WHO).2 As many as 8.5 mil
lion deaths a year of children under five can be
attributed to malnutrition. Millions more children
survive on the edge of starvation.3
If malnutrition is not checked, children who do not
die are likely to be permanently handicapped, both
physically and mentally. “Malnutrition impairs the
physical and mental development of children and the
working and earning capacity of adults; it is there
fore a cause as well as a consequence of poverty.”4
This waste of human potential begins early in life,
sometimes even before birth. Maternal malnutrition
during pregnancy and lactation is one factor linked
to children’s failure to grow (stunting).3 Poor mental
development in stunted children is at least partly
attributable to undernutrition.6 Because 80% of the
development of the human brain occurs before birth
and during the first two years after birth, malnutri
tion of the mother during (or before) pregnancy or of
the child after birth can harm the development of the
child’s brain.7
One-third of babies born in developing countries
weigh less than 2,500 grams. Preventing low birth
weight, by improving the nutritional health of
women and girls, and by ensuring more food and rest
in pregnancy, will reduce the risk of malnutrition.8
Low-birth-weight infants are less likely to grow well,
more likely to fall ill, and four times more likely to
die in the first year of life than babies of normal
weight.9
Malnutrition and disease
Malnutrition and disease work together synergically,
especially in children.10 Malnutrition lowers resis
tance to infectious disease, so that a child is more
likely to be infected and the disease is more pro
longed, more severe, and has more complications.
But also, all infections have a nutritional impact.
Infections can decrease the body’s absorption of
nutrients. They can induce rejection of food by vom
iting. They can drain away nutrients through
diarrhoea. They can induce mothers to stop feeding
while the diarrhoea lasts. And by any or all of these
methods, infections can lead to decreased rates of
child growth and impaired appetite.11
In any child, growth is the most important single
indicator of health. If a child is regularly putting on
weight every month, there is unlikely to be anything
fundamentally wrong.12
Loss of appetite is a common symptom of illness. It is
important to encourage children who are ill to take
food and drink in small amounts regularly. Even when
105
6 A .
Growth
stimulants
Problem Di
young children (under three) are well, because their
stomachs are small, they should eat small amounts of
food high in energy five or six times a day.1’
Alan Berg, the World Bank’s nutrition adviser,
stresses that “the poorest cannot wait. A direct
attack on malnutrition is needed as well, and govern
ments willing to make that effort now have effective
and affordable measures to make it happen.”19
Missing the mark
Klaus Leisinger, Head of International Relations at
Ciba-Geigy, makes the point that “there are no specific
preventive measures for illnesses that arise from
poverty”.14 However, that has not stopped the phar
maceutical industry from promoting a wide range of
products to do what has been called “symptom swat
ting” - focusing on ways of dealing with the
symptoms, rather than treating the underlying
causes.15 The symptoms of malnutrition are easy to
identify-poor growth, loss of appetite, impaired men
tal development, tiredness and fatigue. The products appetite stimulants, anabolic steroids, brain tonics,
and vitamins - are almost always inappropriate, some
times harmful, and a waste of scarce resources.
Some of the interventions that deal with the inter
linked causes and effects of poverty and malnutrition
include preventing measles, tuberculosis, and whoop
ing cough; encouraging breastfeeding; treating
pneumonia and diarrhoea at an early stage; and reduc
ing undernutrition before birth. Dr Edgar Mohs,
former Minister of Health of Costa Rica, explains
some lessons that have been learned in his country:
“In the past, we believed that the lack of
food was a major cause of illness and
malnutrition. We have now started to accept
that family spacing, breastfeeding, and the
control of infectious disease are the keys to
eradication.”20
The use of these medicines for the “treatment” of
conditions resulting from malnutrition has to be
strongly condemned. One researcher examining the
promotion of anabolic steroids said, “the promotion
of a drug which so blatantly exploits parents’ con
cern for their children - claiming it helps them to put
on weight in countries where undernutrition and/or
infection are invariably responsible for a failure to
thrive - is one of the least creditable of all the exam
ples of dangerous promotion”.16
Overall, UNICEF has found that, in several regions
of the world, child malnutrition can be cut in half at
a cost of only US $ 10 per child per year.21 Ironically,
the cost of one course of Sandoz’s appetite stimulant,
pizotifen, also comes to about $10.22
Primary health care specialist John Macdonald
makes clear the chain of events and exploitation that
lead to the ineffective use of drugs for conditions of
malnutrition:
“Poor, underfed people, suffering from
diseases of poverty and a general situation of
marginalisation, frequently believe that they
have to spend what little money they have on
drugs in an often desperate effort to keep
their families alive.... If blame is to be laid at
anyone’s door, it should not be at that of the
mother but at the door of those who exploit
her poverty for their own profit. Neither can
we pass by the door of those health workers
who are happy to leave intact and unchal
lenged the medical model of health care with
its emphasis on drugs because their interests
are served by the existing situation.”17
In the long term, the problems of malnutrition and
hunger can be solved only through improvements in
the social and economic conditions of the world’s
poor. A World Bank study concludes: “Many people
do not have enough to eat, despite there being food
enough for all. This is not a failure of food produc
tion, still less of agricultural technology. It is a failure
to provide all people with the opportunity to secure
enough food - something that is very hard to do in
low-income countries.
Appetite stimulants:
more harm than good
“I cannot clearly recall any occasion on
which I considered that an appetite stimulant
drug was indicated. Furthermore, in practice
in developing countries (where I spent
20 years) the indiscriminate use of appetite
stimulants that have powerful and
potentially dangerous pharmacological
properties in children whose failure to
thrive usually reflects lack of food and
often is caused by underlying diseases like
tuberculosis, is in my view contraindicated
and probably unethical.”
- Professor of Tropical Paediatrics23
In 1985, the UK-based organisation, Social Audit,
launched an international campaign to halt the
unethical promotion of appetite stimulants for hun
gry children in developing countries. At the time,
Social Audit’s director, Charles Medawar, described
appetite stimulants as “a complete irrelevance” and
“a waste of money”.24
Promoting the side effect
The two leading products - Mosegor (pizotifen) by
Sandoz and Periactin (cyproheptadine) by Merck
Sharp & Dohme (MSD) - have one thing in com
mon: they both tend to increase appetite and
promote weight gain in some patients, as a side
effect. Cyproheptadine is an antihistamine which can
be used to treat allergic reactions such as itchiness or
6 A .
skin rashes. Pizotifen is also an antihistamine but is
generally used in the prophylaxis and treatment of
migraine or vascular headaches.
Cyproheptadine may' initially lead to some increase in
appetite and weight gain, but the result is short-lived.
The American Medical Association (AMA) says that
■‘although the results of several studies suggest that
cyproheptadine stimulates linear growth and weight
gain in children, this effect is inconsistent, transient,
and quickly reversible after withdrawal of the drug.”25
The British Medical Association describes weight
gain as a result of appetite stimulation as “the main
disadvantage of prolonged use of pizotifen.”26
Both drugs also have undesirable side effects, the
most common being a tendency towards drowsiness,
which “may be troublesome” with pizotifen. Other
side effects of both drugs include: inability to con
centrate, dizziness, hypotension, weakness, nausea,
vomiting, diarrhoea, constipation, headache, blurred
vision, irritability, nightmares, anorexia, dryness of
the mouth, tightness of the chest, and weakness in
the hands.27
Uncertain efficacy and a wide range of possible side
effects throws into doubt the usefulness of either
drug. As a leading textbook on clinical pharmacol
ogy points out, “in general, little or nothing is gained
by stimulating appetite by drugs.”28
Finding the cause
Loss of appetite (anorexia) in a child may be tempo
rary and not require any treatment. When loss of
appetite is serious, it is important to identify and
treat the cause - that is, whatever led to the loss of
appetite. In children, this may include: malnutrition,
infections, emotional deprivation, malabsorption,
heart failure, renal/central nervous system/endocrine
disorders, chronic inflammation, genetic disorders
and malignancies. In adults and the elderly anorexia
with weight loss may be caused by any of a similarly
long list of medical conditions.
In extreme cases of malnutrition or anorexia ner
vosa, use of appetite stimulants may be dangerous.
Loss of appetite due to food shortage should be
treated by gradually increasing the amount of food.29
A professor of pharmacology concludes: “I do not
believe that there is a role for appetite stimulants of
the cyproheptadine or pizotifen type in medical prac
tice, be it in the developed world or Third World
countries.”30
Growth
stimulants
apparent delight of his attentive mother. This
advertising will probably encourage wide
spread pediatric use of cyproheptadine....
Although cyproheptadine stimulates appetite
in some children, Medical Letter consultants
believe that promotion of the drug as an
appetite stimulant will do more harm than
good.”31
In the same year, the US Food and Drug
Administration (FDA) considered the evidence for
using cyproheptadine as an appetite stimulant to be
inadequate, and MSD stopped promoting it for this
indication in the USA. It is “not recommended” as an
appetite stimulant by the British National
Formulary.31
However, in 1991, Periactin was still listed in MIMS
Africa as “an appetite stimulant where, in the opin
ion of the physician, increased food intake is
desirable and an adequate diet is available.”33 MSD
told Social Audit in 1986 that it would no longer pro
mote cyproheptadine as an appetite stimulant.
Nonetheless, the company maintained that appetite
stimulation was a “well established and medically
valid” indication for use.34
In 1985, Sandoz told Social Audit that it would with
draw all promotional material for Mosegor
(pizotifen) and have it redesigned at headquarters
level. When the new material emerged in countries
such as Pakistan in 1987, there was very little
change. The promotional material simply stressed
that “loss of appetite can be a symptom of many clin
ical and surgical conditions” and suggested pizotifen
as a means of helping to deal with it.
In 1991, in the Philippines, pizotifen was still being
advertised as an appetite stimulant.35 In 1991, in
Pakistan, appetite stimulants were the fourth largest
category of drugs. MSD and Sandoz were both sell
ing their products, as were several other companies
including High Noon Labs with its cyproheptadine
preparation, Tres-orix Forte. Following discussions
with paediatrician Prof. T.I. Bhutta, High Noon
agreed to withdraw its product. However, it had not
yet been withdrawn by the end of 1992. Sandoz
agreed to withdraw Mosegor-V (pizotifen and vita
mins) and, once again, to modify its product
information for Mosegor.36
Other ingredients
Traditional remedies for loss of appetite include
preparations containing simple and aromatic bitters
such as alkaline gentian mixture. The British National
Formulary says they “all depend on suggestion”.37
Double standards
In the USA in 1971, the Medical Letter noted that:
“multiple page advertisements of cyprohep
tadine in current medical journals picture an
attractive child devouring a large meal to the
These preparations sometimes include vitamins, as do
some brands of pizotifen and cyproheptadine. The vit
amins do not add to the usefulness of these products,
despite claims to the contrary. Similarly, many
6 A .
Growth
stimulants
multivitamin products often include as one of their
indications “loss of appetite” as well as other associ
ated conditions such as weakness, tiredness, and
physical or mental strain. However, their use for these
symptoms is not supported by any firm scientific evi
dence. Other food substances, such as amino acids, are
also sometimes included with cyproheptadine. Wallace
Pharmaceuticals advertised its Cyprowal syrup with
cyproheptadine and lysine (an amino acid) in India in
1989 as a product that “builds up appetite, adds nutri
tional value and helps children gain weight”.38
Drugs to stimulate appetite are more than just a
waste of resources. A WHO publication points out
that “these preparations should not be used.”39 They
cause harm by diverting attention away from the real
causes of poor growth and development, and replace
this with the idea that a drug is the answer.
Anabolic steroids: of no use?
Anabolic steroids are also often promoted (incor
rectly) as appetite stimulants. The Dutch company,
Organon, controls at least half the world market for
anabolic steroids - synthetic derivatives of the male
sex hormone, testosterone. The main anabolics are:
ethylestrenol, methandienone, nandrolone, oxymetholone and stanozolol.
Testosterone has both an androgenic effect - it stim
ulates the development of the male sex organs and
male secondary sexual characteristics such as beard
growth and deepening of the voice - and an anabolic
effect, stimulating protein synthesis and the growth
of body tissues such as muscles, bones and blood.
The primary use for androgens is to deal with impaired
functioning of the testes (hypogonadism). Because
androgens have significant effects on muscle mass and
on body weight when given to hypogonadal men, it
was assumed, but never proven, that they could pro
mote growth of muscle above normal levels. This
assumption was based upon the belief that anabolic
and androgenic actions are different, and a concerted
effort was made to devise pure anabolic steroids that
have no androgenic effects. However, “all anabolic
hormones tested to date are also androgenic.”40
The use of anabolic steroids in children may actually
stunt their growth.41 The AMA says that “anabolic
steroids should not be used to stimulate growth in
children” because they can cause the bones to stop
growing at an earlier age than normal.42
In 1983, the Dutch group, WEMOS (Working Croup
on Health and Development Issues) complained to
the Association of Dutch Pharmaceutical Industries
(NEFARMA) about Organon’s promotion of ana
bolic steroids in developing countries. WEMOS said
Organon was promoting its anabolic steroids to
“stimulate appetite”, “improve normal growth” and
“increase body weight” among children. One adver
tisement from India talked about offering children
who used the product “a life full of fun and frolic”.
NEFARMA ruled in January 1984 that “Organon
had not exercised sufficient care” in its marketing
practices. NEFARMA commented on the “signifi
cant differences” between product literature in the
Netherlands and that used in developing countries,
saying that “this could result in users, particularly
children, being at risk.” Organon accepted
NEFARMA’s findings, and announced that “correc
tive action has been taken”.43
Slow to change
However, Organon was slow to change. WEMOS
carried out a survey in 1987 and found evidence that
the company was still promoting anabolics for chil
dren and for a wide range of dubious indications in
adults.44 The survey found that in 23 prescribing
guides, there was an average of five indications that
lacked scientific validity (range: 2 to 14). A total of 26
package inserts from three formulations in 14 coun
tries also contained an average of five indications that
lacked scientific validity (range: 1 to 8). Organon
responded that it was doing its best to ensure that the
information in all prescribing guides and product
information conformed to its own guidelines on the
use of anabolic steroids (which themselves contained
six indications that lacked evidence of validity).
Unlikely uses
Among these unlikely uses are convalescence, osteo
porosis, breast cancer, and management of kidney
failure. Anabolic steroids have been found to be
“ineffective” at building up body protein during con
valescence after major surgery or a severe accident
and for treating patients with chronic debilitating
diseases.45 A nutritious diet high in protein is more
effective ar enabling the body’s own mechanisms to
control the required build-up of protein.46 The virilising side effects and lack of evidence of efficacy of
“anabolics” rules them out for the treatment of post
menopausal women with osteoporosis.47
Goodman and Gilman’s pharmacology textbook
notes that “androgens do not play a major role in the
management of carcinoma of the breast”, and that
they are “of little value in the management of nitro
gen accumulation in chronic renal failure; at best
they induce a transient improvement in nitrogen bal
ance that is of doubtful importance. In acute renal
failure... patients do well without androgen ther
apy.” They add that “androgens have a minor role in
treatment of the anaemia of renal failure.... Whether
the benefits of such treatment outweigh the potential
adverse effects is unclear.”48
Adverse effects
Adverse effects with anabolic steroids can be severe.
In addition to the side effects already noted - the
6 A .
Anabolic steroids are associated with “a long list of
potentially toxic effects”. In particular, they can
cause benign and malignant liver tumors, and a rare,
but dangerous condition called peliosis hepatis
which leads to blood-filled cysts in the liver that can
suddenly rupture.50 This, and other liver damage, is
particularly liable to occur with the use of the 17alpha-alkylated steroids such as ethylestrenol,
oxymetholone,
methandienone, danazol and
stanozolol. Experts now agree that the potential for
the development of these serious side effects means
that these steroids should be avoided “in almost all
circumstances with the possible exception of heredi
tary angioneurotic oedema” (a rare allergic
condition producing swelling of the skin and severe
itching), or for life-saving treatment such as aplastic
anaemia.51
Danazol is also extensively used in the treatment of
endometriosis, a condition in which the type of tissue
lining the womb is found at other sites within the
pelvic cavity. However, it may not be of any benefit to
women with mild endometriosis; endometriosis may
recur after treatment; and it is “considerably more
expensive” than therapeutically equivalent courses
of other medication.515
advise against use by athletes.56 However, in 1990
and 1991, companies were still promoting anabolic
steroids for a variety of unproven indications such as:
osteoporosis, debility, senility, kidney disease, mus
cular dystrophy, and convalescence.57 Stronger
measures could be taken. The scientific evidence sug
gests that many of the anabolic steroids currently on
the market have no use whatsoever - particularly
those liable to cause liver damage - and the remain
der have only a very limited role to play in therapy.
[See also the sections on Brain Tonics and Vitamins.]
Recommendations for action
Continuing to waste resources on ineffective and
inappropriate drugs is not the answer to problems
of malnutrition. The solutions are more likely to lie
in efforts to:
1.
concentrate available resources on
strengthening the primary health care
infrastructure, including the supply of essential
drugs and vaccines for common infections
which exacerbate malnutrition or are made
much more dangerous by existing malnutrition.
2.
eliminate wasteful expenditure on drugs which,
at best, attempt to deal only with the symptoms
of malnutrition and, at worst, are ineffective or
dangerous;
3.
introduce licensing restrictions and promotional
controls on products such as appetite
stimulants, brain tonics, anabolic steroids, and
vitamin preparations. These should include:
• a ban on all anabolic steroids with a potential
for causing serious liver damage - with the
exception of stanozolol and danazol products
which should be removed from the general
market and severely restricted to hospital
use only by specialists for indications such as
hereditary angioneurotic oedema, aplastic
anaemia, or serious cases of endometriosis;
• restricting the use of the remaining anabolic
steroids - such as nandrolone - to hospital
based specialists as an experimental drug for
the treatment of unresponsive anaemias;
• an end to all forms of promotion of appetite
stimulants and their removal from the
general market.
The effects on the liver have not been reported with
injectable testosterone esters. Thus, in ail cases where
androgen therapy is legitimately indicated, “testos
terone esters are the preferred agents.”52
Anabolics and athletic performance
A major, although generally illegal, use of anabolic
steroids is among athletes to enhance performance.
In highly competitive situations, for example among
high school students in the USA where the ability to
excel at a sport might mean winning a scholarship to
attend university, nearly 7% of male students in their
final year have used anabolics, two-thirds of them
began using them before the age of 16.53 However,
“appropriately controlled studies of the effects of
androgens on strength and performance in condi
tioned athletes have yielded inconclusive results ,5
The AMA says such use of anabolic steroids is “con
trary to the ethical principles of athletic competition
and is deplored.” It adds that not only is this “a med
ically trivial indication”, but adverse effects are likely
ro occur.55
A limited market
A survey carried out in 1988 found that many of the
“anabolics” manufacturers had begun to get the
message about the need to convey more warnings
against the use of their products in children and to
stimulants
109
Problem Drugs
problems of masculinisation in women and stunted
growth in children - anabolic steroids can also cause
feminising side effects in men. The reason for this is
poorly understood, but the effects are particularly
severe in children.4’
Growth
Growth
6 A .
stimulants
Problem Di
References:
i.
2.
Seitz, I.L.. The Politics of Development, New York, Basil Blackwell, 1988. P47
Latham, M.C., “Protein-energy malnutrition - its epidemiology and control",
JEPTO, Vol 10, No 4-5, Jul-Oct 1990, ppi68-i8o
3.
Anon., “The backdrop of poverty, disease and debt", New Scientist, 17 Feb
29.
30.
31.
1990, P4i
UNICEF, The State of the World’s Children 1990, Oxford and New York, Oxford
University Press. 19S9, P27
5.
Kusin, JA, Kardjati, S., et al, “Energy supplementation during pregnancy and
postnatal growth". Lancet, Vol 340,12 Sep 1992, pp623-6
6.
Grantham-McGregor. S.M., Powell, CA, et al, “Nutritional supplementation,
psychosocial stimulation, and mental development of stunted children; the
Jamaican study", Lancet, Vol 338,6 Jul 1991, ppi-5
7.
Seitz, op cit, P52
8.
UNICEF, The State of the World's Children 1991, Oxford and New York, Oxford
University Press, 1990, pio
9.
UNICEF, WHO and UNESCO, Facts for Life: A Communication Challenge, New
York, UNICEF, 1989, ps
10.
Macdonald, J.J., Primary Health Care: medicine in its place, London, Earthscan,
32.
4.
Medawar and Gilbert, op cit, p2
Daniel, op cit, pz
Anon., “Cyproheptadine (Periactin)”, The Medical Letter on Drugs and
Therapeutics. Vol 5, No 3, 5 Mar 1971
BMA and the Royal Pharmaceutical Society of Great Britain, British National
Formulary, London, BMA and The Pharmaceutical Press, No 23, Mar 1992,
33.
34.
pi22
MIMS Africa, Jul 1991, pio6
Anon., “Merck & Co stops promoting Periactin", Scrip, No 1101,12 May 1986,
P7
35.
Quijano, R„ "Vitamins, tonics and appetite stimulants", The Drug Monitor,
Vol VI, No 8/9, Aug/Sep 1991, PP74’7
36.
Anon., “Appetite stimulant withdrawn", HAi News, No 61, Oct 1991, p3; Anon.,
HAI International Meeting Report, Amsterdam, HAI-Europe, 1993, pn
37.
BMA and the Royal Pharmaceutical Society of Great Britain, op cit, P344
38.
39.
40.
CIMS, Sep-Dec 1989, pi2
Rylance, G. (ed.), Drugs for children, Copenhagen, WHO, 1987, P48
Gilman, AG., Rail, T.W., Nies, AS., and Taylor, P. (eds), Goodman and Gilman's
The Pharmacological Basis of Therapeutics, New York, Pergamon Press,
1993. P21
Pryer, J. and Crook, N„ Cities of Hunger: urban malnutrition in developing
(8th edn) 1990, PP1423-7
countries, Oxford, Oxfam, 1988, pn
41.
Ibid
12.
UNICEF, 1989, op cit, P31
42.
AMA, Drug Evaluations, Philadelphia, W.B. Saunders Co., (6th edn) 1986,
13.
UNICEF, WHO and UNESCO, op cit, ppz8-9
pp68o-i, 699
14.
Leisinger, K.M., Poverty, Sickness and Medicines: an unholy alliance?, Geneva, 43.
IFPMA, IFPMA Code of Pharmaceutical Marketing Practice: Status Report
IFPMA19S9, P23
March 1984, Geneva, IFPMA, Apr 1984. p3
15.
Kennedy, I., The Unmasking of Medicine, London, Paladin, 1983, P23
44.
WEMOS, Organon and anabolic steroids, Amsterdam, 1987, p6
16.
Muller, M., The Health of Nations, London, Faber & Faber, 1982, P35
45.
Gilman, et al, op cit
17.
Macdonald, op cit, P46
46.
Parish, P., Medicines: a guide for everybody, London, Penguin (6th edn,
18.
Cited in: McKeown, T., “The road to health". World Health Forum, Vol 10,
revised), 1989, p226
No 3/4,1989, PP408-16
47 AMA, 1986, op cit, pp68o-i, 699
19.
UNICEF, 1989, op cit, P29
48.
Gilman, et al, op cit
20.
UNICEF, The State of the World's Children 1989, Oxford and New York, Oxford 49.
Ibid
50.
Dukes, M.N.G. and Beeley, L, (eds), Side Effects of Drugs Annual 14,
University Press, 1988, P46
21.
UNICEF, 1990, op cit, pio
Amsterdam, Elsevier, 1990, P360
22.
Medawar, C and Gilbert, D„ Double Standards, Londonffhe Hague, Social
51.
Gilman, et al, op cit; Dukes and Beeley, op cit
Audit/IOCU, 1985
Sia.AMA, op cit., pp 741-2 and 74708.
23.
Daniel, T., Appetite Stimulants for Children In Developing Countries? Experts
52.
Gilman, et al, op cit
53.
Geddes, JA, "Anabolic steroids and the athlete", Canadian Family Physician,
say DON'T!, London, Social Audit, 1986, p2
24.
Social Audit, press release, Social Audit Calls For Withdrawal of Appetite
Vol 37. Apr 1991. PP979-83
54.
Gilman, et al, op cit
Stimulants, London, 24 June 1985
25.
AMA, Drug Evaluations, Chicago, (5th edn) 1983, P1478
55.
AMA, 1986, op cit, pp68o-i, 699
56.
Silverman, M., Lydecker, M. and Lee, P.R., Bad Medicine: the prescription drug
26.
Henry,). (ed.), The British Medical Association Guide to Medicines & Drugs,
London, Doriing Kindersley, (2nd edn) 1991, P346
industry in (he Third World, Stanford, Stanford University Press, 1992, pp3927.
Reynolds, J.E.F. (ed.), Martindale: The Extra Pharmacopoeia, London,
40, 313. 315
The Pharmaceutical Press, (29th edn) 1989, PP443.451.458-9
57.
See: MIMS Africa, Jan 1991, P140; or MIMS Middle East, Dec 1990, P140, for
28.
Laurence, D.R and Bennett, P.N„ Clinical Pharmacology, Edinburgh, Churchill
example.
Livingstone, (6th edn), 1987, P365
11.
Chetley, A. Problem Drugs, Amsterdam,
Health Action International, 1993
6B. Brain tonics
Health Action International's
coordinating offices:
-7
J i
AND
-• «•
DOCUMENTATION
HAI Europe
Jacob van Lennepkade 334T
1053 NJ Amsterdam
The Netherlands
J
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accidn para la Salud
Avda. Palermo 531
Dpto. 104
Lima 13
Peru
Drugs m search of a dfeease
**• Ercrinatovocc
&J ENCEPHABOL L,auID
Two types of people feature prominently in advertis
ing for drugs designed to deal with “brain
disorders”: children who suffer from lack of atten
tion, poor performance at school, and hyperactivity;
and the elderly who suffer from loss of memory,
dementia, depression. In both cases, the claims for
the drugs suggested for treatment stretch medical
findings far beyond acceptable limits. That has not
stopped a third group of people - students of all ages
who need to concentrate and an increasing number
of young business people - from turning to medicines
in the hope that drugs will help improve their con
centration and memory power.
Merck advertises
Encephabol in Pakistan,
May 1989
From cradle to grave
PUT LIFE BACK INTO THEIR LIFE
The German company, E. Merck, was promoting its
“brain tonic”, Encephabol (pyritinol), in Pakistan in
1989 as “The clinically proven drug for ‘Minimal
Cerebral Dysfunction’ in children, following perina
tal distress”. The illustration used on the
promotional leaflet showed a baby taking his first
steps. Similar promotion in Sri Lanka in 1991 advo
cated the use of the drug for neonates.
In 1990 in Pakistan, Swiss-based Sandoz was selling
its “brain tonic”, Hydergine (co-dergocrine mesy
late), as a product to improve “dizziness,
forgetfulness and concentration problems” among
the elderly. “Put life back into their life” proclaimed
the advertisement in a prescribing guide. The illus
tration in the ad showed a group of elderly men
obviously enjoying life.
Hydergine for the elderly:
in QIMP, Pakistan, 1990
112
6 B .
Brain
tonics
Problem Drugs
In 1991, in Uruguay, French-based Roussel (a sub
sidiary of the German company, Hoechst) ran public
advertising in a newspaper proclaiming that its
“brain tonic", Targifor (arginine aspartate), would
help students pass their exams because it “increases
concentration, increases intellectual output”.1 In
1988 in Brazil, Roussel's advertising to doctors for
Targifor also promoted the drug for “intellectual
fatigue”, but added the even more dubious claim that
it would deal with “sexual fatigue”.
These examples illustrate the broad range of poten
tial sales for companies marketing “brain tonics” or
“cognitive enhancers”. Estimates suggest that the
market in rhe USA alone will be worth more than
$20 million a year by 1994.2 There are more than
160 “cognitive enhancers” in development world
wide. Professor Ian Hindmarch, from the Human
Psychopharmacology
Research Unit at the
University of Surrey in the UK, describes the phar
maceutical industry’s efforts to put a large number of
drugs on the market for people who are growing old
as little more than a way of “printing money”.3 With
more than 50 million people worldwide over the age
of 65 currently estimated to be suffering from
dementia, analysts predict that the worldwide mar
ket for “cognitive enhancers” to treat dementia will
be over S1.5 billion by the year 2000.'1
Attention deficit disorder
with hyperactivity
But as E. Merck’s efforts to sell Encephabol demon
strate, the entry point for “cognitive enhancers” is
often with children, although the credit for the
process of creating a market for a not very well spec
ified disease condition should probably rest with
another company, Ciba-Geigy.
In 1961, Ciba-Geigy proposed that its amphetaminelike drug, Ritalin (methylphenidate), should be used
to treat functional behavioural problems in children.
Initially rejected by the US Food and Drug
Administration (FDA), it was approved for this use in
1963. In the same year, a task force was formed in the
USA to define a previously unrecognised patient: the
child with Minimal Brain Dysfunction (MBD). By
1966, the task force was able to produce a definition
that included 99 symptoms that can cause learning
difficulties, ranging from too little to too much activ
ity. The head of the task force, Dr S. Clements,
subsequently worked as a consultant for Ciba-Geigy
and produced the company’s handbook for doctors
on MBD.5 These efforts were backed with a concen
trated “push” on selling the drug and the condition.
Sales representatives were told in a 1971 sales report
that their “ingenuity” in promoting the syndrome
and the product was paying off as doctors themselves
began to talk about the behavioural disorder.6 By
1975 around one million US children were diagnosed
Neste case...
Acao cnergetJca defatigante a nivel muscular,
intelectual o sexual
Na fadiga e
Tuacdos de stress
2 comprimidos oo dia
“In this case...", Roussel makes dubious
claims for arginine aspartate (Targifor) in
Ars Curandi, Brazil, Oct 1988
as suffering from MBD. Of these, 515,000 were
treated with drugs; 265,000 were given Ritalin.7
In 1980, the Diagnostic and Statistical Manual of
Mental Disorders (DSM-1II) of the American
Psychiatric Association rejected the term minimal
brain dysfunction in favour of either “attention deficit
disorder with hyperactivity, attention deficit disorder
without hyperactivity, and attention deficit disorder,
residual type (hyperactivity is no longer present but
attention deficit and impulsiveness persist).”8 The
term that has tended to stick is attention deficit disor
der with hyperactivity (ADDH) and about 3-6% of
school age children in the USA are currently believed
to be taking medication for the disorder,9 despite
some doubt as to whether it is actually a disease, and
if so, whether drug therapy is the answer.
Although drugs such as methylphenidate may improve
short-term learning in some children initially, “no data
are available to demonstrate conclusively that they
improve learning for long periods. Follow-up studies
indicate that these children may continue to have diffi
culty in school, exhibit behavioural disorders, and
have poor self-esteem into adolescence or even into
adulthood.”10 Generally, 70-80% of children who had
ADDH continue to have significant problems in
adolescence.11 Although treatment with ampheta
mine-type drugs may produce clinical improvement, it
does not seem to affect selective attention. This sug
gests that psychostimulants alone are not sufficient.12
Because there are multiple factors that are implicated
in ADDH, “it is unlikely that a ‘cure’ or even a mode
of prevention will be found”.13
6 B .
tonics
cte&o'tcCen&
For
Provides energizer & neuroregulator action to brain
and improves the output of physical & intellectual
activities.
indications Mental strain,decreased mental output, emotional
instability, hyperexitability, boredom and apathy.
Decreased social adaptation & sleep disorders.
Behaviour problems in difficult children.
Manufactured by
No scientific evidence
If there is a dispute about whether to use
methylphenidate or other amphetamine-like drugs
for children with learning and behavioural disorders,
there should be no dispute about E. Merck’s
Encephabol (pyritinol). Pyritinol is derived from, and
has a similar chemical composition to, vitamin B6,
although in animal tests it has been shown to possess
no vitamin B6 action. According to E. Merck, pyriti
nol improves blood supply to the brain and also
alters the metabolism of the nerve cells so that oxygen consumption and glucose uptake improves.15
However, despite all the claims made by Merck, and
despite the drug having been available for some 30
years, it fails to get even a mention in authoritative
texts on pharmacology and therapeutics such as
Goodman and Gilman’s The Pharmacological Basis
of Therapeutics or the AMA’s Drug Evaluations.
WHO points out that the effectiveness of pyritinol
“has not been demonstrated”.16 In 1988, the
Medical Lobby for Appropriate Marketing
(MaLAM) was unable to find a single published clin
ical trial of the efficacy of pyritinol “for any
indication”.17
A British doctor with considerable experience in
developing countries wrote in The Lancet: “There is
no scientific evidence for this drug’s efficacy. I have
seen this drug prescribed for children with various
disabilities, including cerebral palsy, mental retarda
tion, epilepsy, and learning and behavioural
problems, in Syria, India, Sri Lanka, Malaysia,
Singapore, and Indonesia.”18 A recently published
survey of 1988 prescribing guides found Encephabol
and other pyritinol products being promoted for
children in India, Indonesia, Thailand, Malaysia,
Singapore, the Philippines, Mexico, and Venezuela.19
“Cerebral” vasodilators
Merck also promotes pyritinol as a treatment for
senile dementia, making much of the supposed benefit
of increasing the blood flow to the brain. This argu
ment is based on outdated theories that attributed the
cause of senile dementia to inadequate blood flow to
the brain. Although this explanation has been discred
ited, it gave rise to a number of “cerebral”
vasodilators and similar drugs (often called nootropics) that are still currently in wide use for the treatment
113
Problem Di
In any event, the use of methylphenidate is not rec
ommended by the World Health Organization
(WHO), at least not in general practice, "because of
the frequency and severity of its adverse effects”.
These include loss of appetite, weight loss, growth
inhibition, tearfulness, irritability, insomnia and per
sonality change such as disorientation, aggression
and paranoid psychosis.14 Some of these conditions
are those that methylphenidate is supposed to ame
liorate.
Brain
FERRER INTERNATIONAL., S.A.
Gran Via Carlos 111.94 Barcelona (Espana, Spam)
A cure for boredom and emotional instability (among other
things): Gamalate Be, in QIMP, Pakistan, 1990
of mental failure in the elderly. These include products
such as nicotinic acid derivatives, nicergoline, oxpentifylline, thymoxamine, co-dergocrine mesylate,
cyclandelate, piracetam, buflomedil, cinnarizine, flunarizine, and the calcium channel blocker,
nimodipine.
One expert notes that:
“No drug has a special effect upon the blood
vessels which supply the brain. Those that
are used are general vasodilators. Their
effectiveness in treating disorders produced
by changes in the arteries supplying the
brain, though of help in some patients, has
never been clearly evaluated because of the
complexities involved. Furthermore, there
are risks involved in the use of such drugs fall in blood pressure and redistribution of
blood supply away from areas that may
require more oxygen as the result of an
already diminished blood supply.”20
Goodman and Gilman’s pharmacology textbook says
“the case for clinical efficacy is unimpressive” for these
products in treating dementia.21 According to the
British National Formulary (BNF), “these drugs are
claimed to improve mental function. Some improve
ments in performance of psychological tests have been
reported but the drugs have not been shown clinically
to be of much benefit in senile dementia.”22
Nonetheless, products such as these are widely pro
moted, particularly in developing countries, for a
range of symptoms associated with dementia and old
114
6 B .
Brain
tonics
Probl
age. Dr J.L.T. Birley, a British doctor, wrote in The
Lancet of the shock of finding misleading advertising
for “brain tonics” when he attended a conference in
Pakistan in late 19S8. US-based Abbott claimed its
buflomedil (Loftyl) “alleviates symptoms of intellec
tual deterioration, change of personality, and loss of
memory’”, while Farmitalia Carlo Erba’s nicergoline
was indicated for “memory disorders, reduced con
centration, mood depression, unsociability, loss of
self-care, asthenia |weakness], anorexia [loss of
appetite], and dizziness”.23
Table 6B-1
Complaints made by the Medical Lobby for
Appropriate Marketing (MaLAM) about promotion of
brain tonics (1986-1991)
Company, Brand and generic names
Abbott, Loftyl, buflomedil
Claims/indications
"improved memory and
concentration, improved reasoning
ability, better sleep, improved
adaptation to environment",
MaLAM has regularly challenged pharmaceutical
companies to defend the claims made for the various
“brain tonics” on the market (see Table 6B-1). To date,
the industry has been unable to produce much evidence
in its defence. Where companies have responded to
MaLAM, the quality of the studies they have used to
justify their claims has generally been poor.24
Pakistan, late 19881
Bayer, Nimotop, mmodipine
function... such as reduced capacity
for concentration and memory,
depression, fear, lack of initiative,
lack of social contact, dizziness",
Panama, Nov 19912
Carlo Erba, Sermion, nicergoline
Milton Silverman and his colleagues documented a
vast array of similar claims for products containing
piracetam, bencyclane, buflomedil, cinnarizine,
co-dergocrine, flunarizine, oxpentifylline (pentoxi
fylline), and pyritinoi made during 1987-88 in Africa,
Brazil, Caribbean, Central America, Colombia,
Ecuador, India, Indonesia, Malaysia, Mexico, Middle
East, Peru, Philippines, Singapore, Thailand, and
Venezuela.25
“FDA approved", “changes in brain
“symptoms of chronic cerebral
insufficiency”, Indonesia June 1988;
"chronic cerebral insufficiency, senile
and pre senile dementia”,
Philippines, April 19883
Hoechst, Trental, oxpentifylline
“prevent recurrent ischaemic
attacks... improve cognitive and
mental function", Indonesia, 19901
Janssen, Sibelium, flunarizine
“lack of concentration, confusion,
memory disorder, irritability", “safe”,
Hong Kong, December 19865
Two of these products warrant additional commentflunarizine and ergoloid mesylates such as
co-dergocrine. Flunarizine illustrates the need to use
caution with drugs of this type because of their pos
sible risks, and co-dergocrine illustrates the difficulty
of proving efficacy of these drugs and the need to
take company claims with a large dose of scepticism.
Roussel, Targifor, arginine aspartate
“comprehensive treatment for
fatigue and stress... for... the
elderly... increases concentration..
increases intellectual output",
Uruguay, 19916
Sandoz, Hydergine, co-dergocrine
“impressive improvement of the
symptoms of cerebral insufficiency",
Pakistan, 1986; “symptoms of
Flunarizine
When MaLAM carried out a literature search, it failed
to turn up “any convincing evidence for using flunar
izine for any indication. Flunarizine appears to be both
useless and harmful. New evidence has shown it to be
a cause of Parkinsonism and depression.”26 Concern
about the lack of efficacy of flunarizine and its potential
for serious side effects led rhe German drug regulatory
authority (BGA) in 1991 to restrict the indications for
the product to vestibular vertigo only. The BGA said
there have been “no studies using methods appropriate
to produce adequate measurements of the effect of flu
narizine on cerebral blood flow. From the clinical
studies available there is insufficient proof of efficacy
for flunarizine in the treatment of disorders of periph
eral arterial blood flow.”27 The Committee for
Proprietary Medicinal Products (CPMP) of the
European Community also called for severe restric
tions on the indications for the drug in 1991, limiting
its use to prophylaxis of severe refractory migraine, and
functional vestibular vertigo. “All other indications
should be withdrawn,” said the CPMP. Even with these
indication, the CPMP pointed out that there was still a
mental decline (confusion, dizziness,
memory lapses)”, Philippines, 1986’
Sources: Letters from MaLAM to the companies - 1) to Abbott. Jul 1989; 2) to
Bayer. Sep 1992; 3) to Farm.taha Carlo Erba. Aug 1988: 4) to Hoechst. Nov
1990, 5) to Janssen, Sep 1987: 6) to Roussel, Mar 1991; 7) to Sandoz. Feb 1987
6 B .
Ergoloid mesylates
Ergoloid mesylates such as Deapril-ST, Hydergine,
and Gerimal have been reported to produce modest
improvement of confusion, depressed mood, dizzi
ness, unsociability, and self-care in controlled clinical
trials. The AMA notes however, that “it is difficult to
predict which patients will benefit”.29 That did not
stop Sandoz from achieving global sales of $227.6
million for Hydergine in 1987.30
Goodman and Gilman point out that “the mixture of
ergoloid mesylates has been widely employed in the
treatment of senile dementia. In a few apparently
well-controlled studies, patients... have displayed
slight improvement in some behavioural or other
psychological measures.... The mechanisms that
underlie any beneficial responses are poorly under
stood, and the subject remains controversial.”31
In the UK, the BNF notes that “some improvements
in performance of psychological tests have been
reported but the drugs have nor been shown clini
cally to be of much benefit in senile dementia.”32
Martindale reports on various trials but makes the
point that although improvements could be found on
some behavioural or psychological measures, con
clusions as to the therapeutic usefulness of
co-dergocrine mesylate were “guarded”.33
In the United States, the FDA requires Sandoz to
include the following information in its labelling and
product information:
“... nor is there conclusive evidence that the
drug particularly affects cerebral arterioscle
rosis or cerebrovascular insufficiency.
Indications-. A proportion of individuals over
60 who manifest signs and symptoms of an
idiopathic decline in mental capacity... can
experience some symptomatic relief upon
treatment with Hydergine.... The identity of
the specific rrait(s) or condition(s), if any,
which would usefully predict a response ro
Hydergine therapy is not known.... The deci
sion to use Hydergine in the treatment of an
individual with a symptomatic decline in
mental capacity of unknown etiology should
be continually reviewed since the presenting
clinical picture may subsequently evolve suf
ficiently ro allow a specific diagnosis and a
specific alternative treatment.... Precautions:
Practitioners are advised that because the
target symptoms are of unknown etiology,
careful diagnosis should be attempted before
prescribing Hydergine preparations.”3'1
In 1990, a study published in the New England
Journal of Medicine concluded that Hydergine was
“ineffective as a treatment for Alzheimer’s dis
ease”.35 This prompted the Public Citizen group in
the USA to call on the FDA to ban ergoloid mesy
lates. Public Citizen said that rhe new study served to
demonstrate the poor quality of earlier research.36
A poor research record
According to the Drug and Therapeutics Bulletin,
none of the drugs being promoted in the UK for
related conditions, such as intermittent claudication
(limping caused by an inadequate supply of blood to
the muscles), are worth using. However, they cost the
National Health Service more than £25 million (USS
37.5 million) a year. The products that were evaluated
were: inositol nicotinate (Hexopal by Winthrop),
naftidrofuryl (Praxilene by Lipha), oxpentifylline
(Trental by Hoechst), cyclandelate (Cyclospasmol by
Brocades), mcofuranose (Bradilan by Napp), cinnarizine (Sturgeon Forte by Janssen), nicotinyl alcohol
(Romcol by Roche).37 One of those products,
Hoechst’s Trental (oxpentifylline) had global sales of
$380 million in 1990,38 with 1993 sales estimated by
Nikko Securities to be $446 million.39 In 1991, the
Swedish drug regulatory authority, after 10 years of
studying the drug, rejected an application for a prod
uct licence for Trental on rhe grounds that the quality
of the clinical studies was poor.40
One industry analyst says that “the pharmaceutical
industry has an abysmal record in treating disorders
of the brain and nervous system.... For the most seri
ous problems - degenerative brain diseases such as
Alzheimer’s - there is still nothing that really
works.”41 This is confirmed by the Drug and
Therapeutics Bulletin which said in 1991 that “drugs
now available for treating Alzheimer’s disease offer
no clinically significant benefit”.42
The fear of Alzheimer’s disease, which causes about
half of all cases of senile dementia,43 has triggered off
a wave of research. Among the products to emerge is
tacrine, manufactured by Warner-Lambert as
Cognex. An early study that raised hopes was subse
quently questioned and led the US FDA to call for
further evidence of efficacy and safety. The FDA was
particularly concerned about the possibility that
tacrine could cause liver damage. In 1991, the FDA
granted an investigational licence for the drug, but
asked for further efficacy studies before full approval
could be given.44 Initial results show some improve
ments in some patients. However, this research
suggests that tacrine “is not for everyone”.45 A
similar drug, velnacrine maleate (produced by
Hoechst-Roussel as Mentane) has been found by an
FDA advisory committee to have an unacceptable
tonics
Problem Drugs
need for extensive, double-blind clinical studies “in
order to support the benefit/risk ratio” of the drug. The
CPMP also proposed that product information should
contain a “special warning” pointing out that use of
the drug “may give rise to extrapyramidal and depres
sive symptoms and reveal Parkinsonism, especially in
predisposed patients such as the elderly. Therefore, it
should be used with caution in such patients.”28
Brain
116
6B.
Brain
tonics
Problem Drugs
risk-benefit ratio. The committee was particularly
concerned about the risk of agranulocytosis that had
appeared in the early studies.'1'’
Age-associated memory impairment
The difficulty’ in identifying a suitable therapy for
Alzheimer’s is perhaps one of the reasons for the
recent emergence of a syndrome called age associated
memory impairment (AAMI). The starring point for
the syndrome is "benign forgetfulness” which are
mild memory impairments that usually do not deteri
orate. By the mid-1980s, a definition of the syndrome
began to emerge that mirrored in some ways the early
definition of MBD in children. The definition was so
broad that most people over 50 could probably be
included, in the same way that most children could
have been included in the MBD definition. One of the
factors that makes the definition so all-inclusive is
that it compares the memory power of a healthy non
demented adult over 50 to that of a young adult. It is
almost inevitable that memory performance will be
worse in older people. An editorial in the British
Medical Journal says that the syndrome is “too broad
an entity to justify drug treatment yet”.47
Clearly, however, the pharmaceutical industry is
interested in having rhe aging process defined as a
disease so that, in the words of Prof. James McGaugh
of the Center for Neurobiology of Learning and
Memory at the University of California, Irvine,
“something that normally occurs now will be called
a disease, so it can then be treated by a drug to
improve memory”. Prof. Ian Hindmarch calls AAMI
“a pseudo-disease. It’s having a drug and wanting an
illness for that drug. It’s a modern disease, when
pharmaceutical chemists can produce hundreds of
molecules and rhe industry is desperately wanting to
get these molecules on the market.”48
Sandoz is one of the companies hoping to cash in on
AAMI. It has produced a booklet promoting
Hydergine called Age-Related Mental Decline and
Dementias: The Place o/ Hydergine." The Belgian
company UCB is also hopeful. Its brand of piracetam,
Nootropil, was advertised in the Middle East in
December 1990 as a product for “memory, concentra
tion” which “activates, protects and restores
metabolism, circulation and functions of rhe brain
cortex”.50 With global sales of S 100.7 million for the
product in 1990, the company is looking for new mar
kets.51 The product was licensed in the UK in early
1993 for the treatment of cortical myoclonus, a condi
tion that results from brain damage and affects only
about 50-60 people in the UK. However, the company
hopes that additional indications will be approved in
the future. The company says it is not seeking the indi
cation of AAMI for the product in the UK “as current
data would probably not be sufficient for the UK
authorities, which are believed to take a stricter view
of this condition than many other regulatory
“Are your neurons tired? You’ll feel better with Cogitum" ■
a 'psychostimulant' for French pharmacists, in Le
Quotidien du Pharmacien, 20 Jan 1992
6 B .
Gktxo is a company which has clearly targeted
AAM1. It says early trials of ondansetron (produced
as Zotran and registered in the UK to treat nausea
caused by cancer chemotherapy) provide evidence
that it is the “first pharmaceutical agent that has been
effective in normalising a memory impairment”.53
Glaxo’s director of clinical research on the central
nervous system, Dr Paul Williams, says that the com
pany believes that at least four million people in the
United Kingdom suffer from age-associated memory
impairment, so if it is eventually made available to
them, there d be an awful lot of people very inter
ested indeed”.54
“Smart” drugs
There are another group of people who are interested
in drugs that might improve memory. The idea
appeals to students everywhere and increasingly has
been taken up by business people who want to be
able to compete more effectively. Some people in the
USA are spending as much as $600 a month55 con
suming a cocktail of “cognitive enhancers”, vitamins
and nootropics - collectively called “smart drugs” in the hope that the drugs will increase their brain
power, improve their memory, their concentration
and their ability to learn.
Those supposed effects reflect the often unfounded
claims that have been made for these products in pro
motional advertising over the years. While the
evidence is sparse to suggest that these products are
effective in disease conditions, there is absolutely no
evidence to support their efficacy among healthy
people. Professor Steven Rose, of the Brain and
Behaviour Research Group at the Open University in
the UK, says that “if a normal person takes drugs
which are developed for this purpose, then the best
that you could have is what one might call the
placebo effect - that is, that people would expect to
feel better as a result of taking them, and then maybe
they would.”56
Prof. Hindmarch describes the appeal of “smart”
drugs as being “very compelling”. He says that, “if
you believe that these drugs enhance your concentra
tion and memory”, there is a tendency “for you to take
them for life, and of course, this is why there are many
pharmaceutical companies who would wish you to
start taking them. If you can perform better in your
school by using drug X, then this means you’ve prob
ably got to take drug X for the rest of your life.”
The drawback - other than the lack of efficacy - is the
risk of side effects. This is already a high risk with
some of these products; using them in an unsupervised
wav simply increases the risk. The US FDA is con
cerned about this and is trying to crack down on the
tonics
selling of these products as “smart” drugs.58 As Prof.
Rose points out, “it can be harmful to throw chemical
spanners into the workings of the human brain”.59
[See also the sections on Vitamins, Growth
Stimulants, Children and Drugs, and Drugs and the
Elderly. ]
Recommendations for action
Because there is very little good evidence to justify
the efficacy of most of the products used for
mental and behavioural disorders, because many
of them are likely to cause serious side effects,
and because they are generally expensive and
unnecessarily divert scarce resources, their sale
and promotion need to be subject to stricter
controls.
1. Governments should review the products
currently on the market for the treatment of
cerebral dysfunction in the elderly, and products
for learning and behavioural disorders in children,
with a view to removing ineffective preparations
and introducing much stricter controls on the
indications, claims, and prescribing information
allowed for any products that remain on the
market.
2. The use of amphetamines and amphetaminelike drugs in the treatment of learning and
behavioural disorders in children should be
severely restricted. These products should be
removed from the regular market and be
permitted for use only by specialists when there is
clear evidence of a measurable brain disorder.
3. Strict controls should be introduced to prevent
the non-medical use of psychoactive drugs in the
false hope that memory, concentration or
intelligence can be improved.
4. Independent information about the treatment
of senile dementia and of behavioural and
learning disorders in children should be prepared
for health workers to remove the dependence on
misleading promotional material prepared by the
industry. There should be greater emphasis on
non-drug solutions to these problems, such as
counselling and memory training.
117
Problem Drugs
agencies.” However, UCB recognises that titere may
well be some oft label” use of Nootropil for AAMI.52
Brain
Brain
6 B .
tonics
Problem Drugs
References:
MaLAM, letter to Roussel, Mar 1991: Anon., “MaLAM questions Roussel on
arginine aspartate", Scrip, No 1609,19 Apr 1991. pij
Clayton, R. “Can a pill make you more intelligent:", Evening Standard
(London), 24 Jul 1991
3.
BBC, Food for Thought (Transcript of “Horizon" programme transmitted 10 Jun
28.
1991), London, Broadcasting Support Services, 1991, par
Moran,)., Altheimer's Disease: New Therapies and the World Market, London,
Financial Times Management Reports, 1991
5.
Melville, A. and Johnson, C, Cured to Death, London, New English Library,
1982. PP72-4
6.
Braithwaite,)., Corporate Crime in the Pharmaceutical Industry, London,
Routledge & Kegan Paul, 1984, p222
7.
Melville and Johnson, op cit, PP72-4
8.
AMA, Drug Evaluations, Philadelphia, W.B. Saunders Co., (6th edn) 1986, pi6z
9.
Brown, CS., “Treatment of attention deficit hyperactivity disorder: a critical
review", DICP, The Annals of Pharmacotherapy, Vol 25, Nov 1991, ppi207-i3
10.
AMA, op cit, P163
11.
Hechtman, L„ “Resilience and vulnerability in long term outcome of attention
deficit hyperactive disorder", Canadian journal of Psychiatry, Vol 36, No 6,
Aug 1991, PP415-21
12.
Everett, J., Thomas,)., et al, “Cognitive effects of psychostimulant medication
in hyperactive children", Child Psychiatry and Human Development, Vol 22,
No 2, Winter 1991, PP79-87
13.
Rosenberger, P.B., “Attention deficit". Pediatric Neurology, Vol 7, No 6,1991,
31.
32.
33.
Gilman, et al, P946
BMA and the Royal Pharmaceutical Society of Great Britain, op cit, P92
Reynolds, l.E.F. (ed.), Martindale The Extra Pharmacopoeia, London, The
34.
Pharmaceutical Press, (29th edn) 1989, P1051
Physicians' Desk Reference, Oradell, NJ, Medical Economics Company, 44th
i.
2.
4.
PP397-4O5
Rylance, G. (ed.), Drugs for children, Copenhagen, WHO, 1987, P89
E. Merck, Encephabol Prospectus, Darmstadt (Germany), Jan 19S6 (English
translation of the German original for the company by J. T. Lazandes)
16.
Rylance, op cit, P89
17.
MaLAM, letter to E Merck, Apr 1988
18,
Hosking, G., “Drug marketing in the Third World", Lancet, 1986 (Vol II), pi64
19.
Silverman, M., Lydecker, M. and Lee, P.R., Bad Medicine: the prescription drug
industry in the Third World, Stanford, Stanford University Press, 1992, PP35-6,
14.
15.
298-9
20.
Parish. P„ Medicines: a guide for everybody, London, Penguin (6th edn,
revised), 1989, pi74
21.
Gilman, A.G., Rail, T.W., Nies, A.S., and Taylor, P, Goodman and Gilmans The
Pharmacological Basis of Therapeutics, New York, Pergamon Press, (8th edn)
1990, P781
BMA and the Royal Pharmaceutical Society of Great Britain, British National
Formulary, London, BMA and The Pharmaceutical Press, No 23, Mar 1992, P92
23.
Birley, J.L.T, “Drug advertising in developing countries", Lancet, 28 Jan 1989,
22.
24.
25.
26.
27.
P220
Mansfield, PR., “Classifying improvements to drug marketing and
justifications for claims of efficacy", International Journal of Risk & Safety in
Medicine, Vol 2,1991. PP171-84
Silverman, et al, PP33-6 and 289-99
MaLAM Newsletter, Aug 1987
Anon., “Germans restrict flunarizine use", Scrip, No 1599,15 Mar 1991, P23
Anon,, “CPMP restricts flunarizine indications". Scrip, No 1601, 22 Mar 1991,
P22
29.
AMA, op cit, pi6z
30.
Anon,, "Monitor: R&D And Expansion To Boost Sandoz”, IMS Marketletter,
14 Nov 1988 (according to Mark Edmiston and Kah Foo of SBCI Savory Milin)
edn, 1990, P1939
35.
Thompson, T.L, Filley, CM., et al, “Lack of efficacy of Hydergine in patients
with Alzheimer’s disease", New England Journal of Medicine, Vol 323, No 7,
36.
37.
38.
16 Aug 1990, PP445-8
Anon.. “Ergoloid mesylates ban urged in US”, Scrip, No 1592, 20 Feb 1991,
P23
Anon., “Present drugs fail in claudication", Scrip, No 1487,9 Feb 1990, 027
Anon., “Top 50 branded products worldwide”. Scrip, Review issue 1990, p2i
(based on Barclay de Zoete Wedd's “Pharmaceutical Industry Perspectives")
Anon., “Hoechst's 1989 pharma sales up 13.6%", Scrip, No 1516, 23 May 1990,
39.
pu
40.
41.
42.
Anon., “Swedes reject pentoxifylline", Scrip, No 1601, 22 Mar 1991, pzi
Cookson, C„ “New era looks to mind drugs”, Financial Times, 26 Jun 1992, pi2
Anon., "Economic prescribing", Drug and Therapeutics Bulletin, Vol 29, No 2,
21 Jan 1991, p5
Anon, "Alzheimer’s: the path of forgotten memories”, Health Horizons, No 13,
May 1991, pp26-8
44.
Anon., “FDA panel urges further efficacy studies for Cognex", Scrip, No 1636,
43.
45.
46.
24 Jul 1991, PP24-5
Anon., “Tacrine’s benefits confirmed”, Scrip, No 1770,13 Nov 1992, P29
Anon., “Mentane risk-benefit unacceptable", Scrip, No 1769.10 Nov 1992,
PP22-3
O'Brien, J.T. and Levy, R., "Age associated memory impairment", British
Medical Journal, Vol 304,4 Jan 1992, PP5-6
48.
BBC, op cit, ppzo and 22
49.
Cited in: Dean, W. and Morgenthaler, J., Smart Drugs and Nutrients, Santa
Cruz, Calif., B&J Publications. 1990, pis
50.
MIMS Middle East, Dec 1990, p6?
51.
Anon., "Piracetam leads UCB's pharma sales", Scrip, No 1650,11 Sep 1991, pi4
52.
Anon., “Piracetam approved in the UK", Scrip, No 1797, 23 Feb 1993, pzi
53.
Anon., “Ondansetron in psychiatry - cautious optimism", Scrip, No 1626,
19 Jun 1991, PP24-5
54.
BBC, op cit, p22
55.
Anon., “Nootropics: steroids for stockbrokers?", Scrip, No 1626,19 Jun 1991,
47.
56.
57.
58.
59.
pz6
BBC, op cit, p9
Ibid, pp74-5
Anon, “FDA cracks down on ‘smart drugs'", Scrip, No 1713, 29 Apr 1992, pi6
Anon., “Smart Drugs", Which? Way to Health, Feb 1993, pp22-5
Chetley, A. Problem Drugs, Amsterdam,
Health Action International, 1993
Health Action International’s
coordinating offices:
Jf
I
K'10
riTiOM
J
HAI Europe
Jacob van Lennepkade 334T
10$ 3 MJ Amsterdam
The Netherlands
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Action para la Salud
Avda. Palermo 531
Dpto. 104
Lima 13
Peru
Vitamms stimulate growth...
of the pharmaceutical industry
Vitamins are organic compounds which are neces
sary for good health. Food is the best source of
vitamins and minerals. Healthy persons eating an
adequate balanced diet will not benefit from addi
tional vitamins.1
Although malnutrition and disease in developing
countries can contribute to quite severe vitamin defi
ciencies which can be corrected with large doses of
specific vitamins, in the long term the answer lies in
improving the diet. The widespread promotion of
vitamins helps to “medicalise” hunger so that the
economic and social causes of malnutrition are not
tackled. Instead, the focus is placed on “cure” and
treatment and scarce financial resources are spent on
unnecessary vitamins rather than necessary food
stuffs.2 (See the box about vitamin A supplements on
the following page.)
Lack of a vitamin caused by an inadequate diet may
lead to a specific deficiency syndrome. Deficiencies
can also occur because of malabsorption of food or
be due to an increased metabolic need, for example,
during pregnancy or lactation. In these circum
stances, it is sometimes useful to include vitamin
supplements as a part of the therapy. However,
according to the American Medical Association
(AMA), “there are few valid indications for vitamin
or mineral supplements.... Massive-dose therapy
usually is justified only in patients who cannot utilize
nutrients properly, in those with certain diseases, or
in those with inborn errors of metabolism”.3
In industrialised countries, clearly identifiable vitamin
deficiencies are rare, except in some specific sub-groups
of the population. In the UK, for example, the British
Medical Association (BMA) says that most people
“obtain sufficient quantities of vitamins in their diet,
and it is therefore unnecessary in most cases to take
Dubious claims for
multivitamins “for the
whole family", in Mims
Caribbean, Jan 1990
The 13 vitamins
Water soluble
ascorbic acid (vitamin C)
thiamine (Bl)
riboflavine (B2)
nicotinic acid or niacin (B3)
pyridoxine (B6)
cobalamin (B12)
folic acid
biotin*
pantothenic acid*
Fat soluble
vitamin A
vitamin D
vitamin E*
vitamin K
‘therapeutic value not proven and natural deficiency is extremely rare
Problem Drugs
O < LIBRARY
6 C .
Vitamins
lem Di
additional vitamins in the form of supplements”.'1 In the
USA, “clinically apparent vitamin deficiencies are rare...
and subclinical deficiencies are difficult to detect”.5 As a
result, rhe American institute of Nutrition, the
American Society for Clinical Nutrition, the American
Dietetic Association and the National Council Against
Health Fraud, together with the AMA’s Council on
Scientific Affairs issued a statement pointing out that:
“Healthy children and adults should obtain
adequate nutrient intakes from dietary
sources. Meeting nutrient needs by choosing
a variety of foods in moderation, rather than
Vitamin A supplements
An estimated 40 million children worldwide under five
years of age suffer from vitamin A deficiency. As a
result, about 400,000 die and more than 250,000
children a year become partially or completely blind.1
Vitamin A deficiency increases the severity and the
risk of the three main health threats facing children in
developing countries: diarrhoeal diseases, measles
and pneumonia. The pooled evidence from six
separate investigations in India, Indonesia and Nepal
over the past 10 years indicates that child deaths can
be reduced by about one-third by improving children’s
vitamin A intake.2
In these six investigations, the improvements have
come about after giving a high dose (200,000
international units - IU) of vitamin A every six months
or, in the case of one of the Indian studies, weekly
doses of 8,333 IU of vitamin A. This Indian study
found a reduction in childhood mortality of 54%,3 but
the other Indian study concluded that vitamin A
supplementation alone might not reduce child
mortality.4 That was also the conclusion of a study
carried out in northern Sudan.5 The authors said that
"reducing poverty, improvements in sanitation, and
access to adequate diets should remain the mam
goals to improve child survival”.
This is the crux of an important debate and one which
affects attitudes towards vitamins in general as well as
the rational use of other drugs. In the words of the
Indian researcher, C. Gopalan, “there are just no
miracle drugs, magic bullets and short-cuts in the war
against poverty and malnutrition”.6 He argues strongly
that vitamin supplements are not the solution to
deficiencies.
“The logical way to ensure vitamin A nutrition is
through dietary improvement, and fortunately the
countries afflicted with vitamin A deficiency have an
abundance of natural food resources to combat it.
These countries must be helped to harness their
food resources for this purpose; and they should
Sources:
1.
Ramalingaswami, V., •‘Challenges and opportunities-one vitamin, two
minerals", World Health Forum, Vol 13. No 2/3, 1992, pp222-31
2.
UNICEF, The State of the World's Children 1993. Oxford and New York,
Oxford University Press, 1992, pl2
3.
Anon., "Vitamin A and malnutrition/infection complex in developing
countries", Lancet, Vol 336, 1 Dec 1990, ppl349-50
4.
Vijayaraghavan, K„ Radhaiah, G., et al, “Effect of massive dose
vitamin A on morbidity and mortality in Indian children", Lancet, Vol 336,
1 Dec 1990. ppi342-5
not be misled, through exaggerated claims, into
relying perpetually on periodic medication with
massive doses of synthetic vitamin A - an approach
that was initially adopted purely as a short-term
measure.”
Other researchers are also calling for caution in the
rush to provide vitamin A supplements. A third Indian
study concluded that vitamin A alone was not enough
“to solve the problems of health and nutrition”. It
called for social and public health programmes to work
on literacy, education, employment, immunisation and
sanitation as well as "the promotion of child feeding
initiatives based on locally available, affordable,
culturally acceptable, nutritious foods, including those
high in vitamin A".7
The main point that critics of the supplementation
route make is that this type of intervention cuts across
all the social and political goals of primary health care.
As Anthony Costello of the Institute of Child Health in
London points out, vitamin A supplements should be
widely available as one of the tools for primary health
care, “but international agencies should think carefully
before supporting vertically run national vitamin A
supplementation programmes. Money might be spent
more effectively and sustainably on initiatives to
improve an integrated primary health care service
through better management and training, and the
development of an organisational culture which makes
these services more user-friendly for poor and
disadvantaged families, one of whose problems is
vitamin A deficiency."8
As an editorial in The Lancet in 1990 concluded, the
evidence seems clear that dealing with vitamin A
deficiency will have public health benefits beyond the
immediate deficiency problems. The challenge,
however, is to identify how to improve vitamin A intake
in ways “that are effective and sustainable at a
community level".3
and rhinT0
14651611 p-- et al. "Vitamin A supplementation
and chdd survival . lancet. Vol 340, 1 Aug 1992, pp267 71
Vol 3°4P0aT8^^^177.8enCyCh"dh°°d mOr,a"ly"' U"“''
infecZs*hanrt » L^nde™oodi B.A., et al, -Diarrhea, respiratory
supplement-%t.T" nOt al,6c,ed by a
'6«-dose vitamin A
India' AmeneaT M
',C<5?lr0"ed 'i6ld ,nal in Chlldr6n in 5°uth6m
8 Costello A MJ! C miCal Nutritl0n’Vd 54, 1991. pp568-77
31 Aug 1991' p568L" V‘tarnin A supplementation". Lancet. Vol 338.
6 C .
Selling a cure for tiredness...
The French company, Servier, promoted Arcalion
200 (vitamin Bl - sulbutiamine) in the Middle East in
1990, and in Africa and the Caribbean in 1991 as a
treatment for “all forms of functional asthenia
|weakness or fatigue]”, and recommends taking two
of the 200mg tablets “with breakfast” every day.40
The recommended daily allowance for vitamin Bl is
1.5mg for an adult.41 The healthy human body con
tains only about 25mg of the vitamin. Furthermore,
it has no means of storing any excess taken in the
diet. This product has the general properties of thi
amine42 and “there is no evidence that thiamine is of
value for anything other than deficiency”.43 A com
puter search carried out by the Medical Lobby for
Appropriate Marketing (MaLAM) of the medical lit
erature of the past 15 years was only able to turn up
one article on the use of sulbutiamine; however, it
was of such poor quality that it could not be used to
demonstrate proof of efficacy of the product.44
... a cure for infertility...
In April 1991, SmithKline Beecham advertised its mul
tivitamin with zinc preparation, Zevir, in the Indian
edition of the Journal of the American Medical
Association for a long list of indications that included:
“... mood alteration, loss of libido, infertility, impo
tence, lethargy, depression”. Once again, MaLAM
searched the literature: this time it was unable to find
any controlled trials of Zevit or an equivalent combi
nation that provided any evidence for the indications.45
...a way to promote children’s growth...
In the Caribbean in 1991, Abbott advertised its multi
vitamin and mineral preparation, Paramettes, as a
product that “helps promote proper growth in chil
dren, helps increase energy and vitality'”. Children need
food to grow properly and to have sufficient energy
and vitality'. Promoting vitamins as growth stimulants
is a practice that is both misleading and unethical.
Problem Drugs
The BNF also advises that there is “little place for the
use of vitamin B12 orally” and “there is no justifica
tion for prescribing multiple-ingredient vitamin
preparations containing vitamin B12 or folic acid”.39
Vitamins
again”. Primarily based on vita
mins Bl and B3, it also contained
a little caffeine (“fights tired
ness”) and some gentian bitter to
“promote appetite”.
Controlling the market
In most countries, the market is
littered with ineffective products,
with irrational combinations or
formulations, or with high-dose
vitamins posing an unnecessary
threat to health and an addi
tional financial burden. A survey
of prescribing guides from five
regions of the world in 1985 found that more than
three-quarters of the 888 vitamin preparations listed
could not be recommended.47 The situation has not
improved as Table 6C-I shows. During 1990-91 of
the 636 vitamins listed in prescribing guides in four
regions of the world, more than four out of every five
could not be recommended. In the USA, a 1991
report found that the amounts of vitamins in more
than 3,400 different preparations on the market in
1986 varied enormously. They could include any
thing from 7% of the RDA of vitamin E to 50,000%
of the RDA of vitamin B6 in single ingredient prepa
rations, and less than 0.5% of the RDA of vitamins
A, E, Bl, B3, or B6 to as much as 53,333% of the
Table 6C-1
Vitamins on sale in selected markets (1990-1991)
Description
Pakistan
No.
Total no. of vitamins
%
263
Middle East
No.
%
195
Africa
Caribbean
No. %
No.
94
84
%
Indications:
... a way to promote children’s intelligence...
For therapeutic use
94
35.7
111
56.9
60 63.8
58
69.1
In 1992, in the UK, three vitamin manufacturers Seven Seas (Boost IQ), Raw Power (Vitachieve), and
Larkhail Laboratories (Tandem IQ) - were all suc
cessfully prosecuted for claiming that their vitamin
products could increase children’s intelligence.46
Once again, the evidence to support the claims was
lacking (see the box about vitamins and intelligence
Prophylaxis/supplement 172
65.4
85
43.6
33 35.1
23
27.4
Unproven indications
109
41.4
140
71.8
67 71.3
62
73.8
Non-essential ingredient
96
36.5
99
50.8
41 43.6
34
40.5
Irrational formulation
122
46.4
125
64.1
55 58.5
54
64.3
Excessive dosage
120
45.6
95
48.7
39 41.5
32
38.1
Not Recommended
204
77.6
175
89.7
84 89.4
70
83.3
Total vitamins all areas:
636
Formulation:
on the previous page).
... a tonic to fight tiredness and boost appetite
In 1993, in a leafier available to the public in pharma
cies in the UK, Pharmax promoted its Effico Tonic as
the “pick-me-up" to “build up your appetite, restore
your vitality, and allow you to enjoy life to the full
Total not recommended: 533 (83.8%)
Sources: QIMP (Pakistan). Mar-Aug 1990: MIMS Middle East. Dec 1990 p!28 MIMS
Africa. Jul 1991, p98: MIMS Caribbean. Jan 1991
122
6 C .
Vitamins
Problem Drugs
have no beneficial effect in patients with advanced
cancer”. It also says that megadoses of vitamin C have
not been found to have any effect on atherosclerosis,
healing of wounds or schizophrenia and that there are
a variety of diseases - including asthma and male
infertility - for which there is not enough evidence to
conclude whether vitamin C is of any use.28
There is no evidence to support the efficacy of vita
min E in the numerous conditions for which it is
popularly used. “Large doses do not protect against
arteriosclerosis, cancer, pulmonary damage from air
pollution, or deterioration from aging, and vitamin E
is ineffective in inflammatory skin disorders, habitual
abortion, heart disease, menopausal syndrome,
infertility, peptic ulcer, burns, and porphyria.”29
If doses of the vitamins on their own are ineffective
for such ailments, there is little likelihood that if they
are all combined together their effectiveness will
improve. However, many of the multivitamin “ton
ics” claim to do just that. According to the BMA,
“vitamin supplements should not be used as a gen
eral tonic to improve well-being - they do not do so
- nor should they be used as a substitute for a
balanced diet”.30 A UK consumer guide to medicines
makes the point that “multivitamin tablets are
mainly of value to the manufacturers”.31
Professor Peter Parish notes that manufacturers give
the impression that the recommended daily
allowances of vitamins and minerals are to be added
to a normal diet. He advises: “do not be misled: vita
mins may be required to supplement an inadequate
diet but never to complement a diet. High-dose vita
min preparations should be avoided - do not be
attracted because they are called ‘super vitamins’ or
any other name that indicates that the dose is above
what is normally required.”32
Even for conditions where vitamin supplementation is
sometimes useful, not every patient will require them.
Usually it is assumed that all women who are pregnant
or lactating, infants and growing children, and the
elderly require vitamin pills. However, for pregnant
women, “a balanced diet is a better basis for health
than vitamin supplementation”;33 for children, vita
mins are only recommended in the rare cases of
specific deficiency states, when inadequate diet occurs
as a result of cultural traditions, or when children have
specific metabolic disorders or experience malabsorp
tion;34 and for the elderly, “the most important step
that you can take to maintain your nutritional well
being is to eat a healthy and well-balanced diet”.35
Ineffective ingredients
Some vitamin preparations, in addition to being pro
moted for the wrong use, contain ingredients that are
unnecessary or useless. The AMA advises that in
multivitamin preparations, “additional components,
such as liver, yeast, and wheat germ, do not confer
Vitamins and intelligence
Claims that vitamins can boost intelligence have been
around almost as long as vitamins. The roots of the
claims lie in the widely accepted evidence that
malnutrition can affect brain development and mental
functioning. Thus, a deficiency in vitamins could also be
linked to poor mental performance. The subsequent leap
in faith, however, that increasing the intake of vitamins
in otherwise well nourished individuals would increase
their intelligence, is unproven.
Not that there haven't been attempts. A 1988 study
carried out in Wales claimed that vitamin supplements
improved children's non-verbal intelligence.1 It was
followed up by another study in 1988 that found no
improvement in intellectual performance among children
in London given vitamin supplements,2 and a study in
Scotland in 1990 that found no improvement on
reasoning tests by children taking vitamin and mineral
supplements.3 A Belgian study in 1990 suggested that
there might be a sub-set of children who consume a poor
diet who could benefit from vitamin and mineral
supplementation.4 A study among schoolchildren in
California, published in 1991 once again suggested that
there might be some benefit from supplementation;
however, the results were uneven within each sample
group and it was a short term trial. The Lancet concluded
that "the case for vitamin and mineral supplementation
as a method of increasing a child's IQ remains
unproven”.5
Sources:
1.
Benton. D. and Roberts, G., “Effect of vitamin and mineral
supplementation on intelligence of a sample of schoolchildren", Lancet,
23 Jan 1988, ppl40-3
2.
Naismith, D.J , Nelson, M., et al, "Can children’s intelligence be increased
by vitamin and mineral supplementation? ', Lancet. 6 Aug 1988, p335
3.
Crombie. I.K., Todman, J., et al, "Effect of vitamin and mineral
supplementation on verbal and non-verbal reasoning of schoolchildren".
Lancet, Vol 335, 31 Mar 1990, pp744 7
4 Benton, D. and Buts, J-P., ” Vitamin/mineral supplementation and
intelligence", Lancet, Vol 335, 12 May 1990, ppi 158-60
5.
Anon., "Brains and vitamins", Lancet, Vol 337, 9 Mar 1991, pp587-8
any special advantage over the pure chemical ingre
dients, and inclusion of agents that have no proved
value (eg. choline, methionine, lecithin, bioflavonoids,
inositol) is unwarranted”.36 The British National
Formulary (BNF) says that “there is no evidence” of
the value of ingredients such as pantothenic acid,
biotin, choline, or inositol.37 Martindale says that pan
tothenic acid “has no accepted therapeutic use”;
biotin has “no clearly defined therapeutic uses”; “a
deficiency syndrome has not been identified in man
and daily requirements have not been established” for
choline and “its functions do not justify its classifica
tion as a vitamin”; and inositol “has an uncertain
status as a vitamin and a deficiency syndrome has not
been identified”.38
6 C .
A growing market
Vitamins provide a profitable market for the pharma
ceutical industry. A study of vitamin use among the
elderly in 12 European countries found that much of
the time the use of vitamin supplements does not
correspond to nutritional needs.' In 1988, sales of vita
min and mineral supplements in the UK were estimated
at £108 million (US $194 million).8 In 1991, Germans
spent nearly S348 million on over the counter (non
prescription) vitamin and mineral preparations.9 In rhe
USA, a 1987 survey (reported in 1990) found that
more than 51% of all adults had taken a vitamin/mineral supplement within the previous 12 months, and
23% did so daily.10 Women were more likely to use vit
amins than men.11 The US market for over the counter
vitamins and mineral preparations was worth more
than $2 billion in 1984;12 estimates predicated sales of
more than S3.5 billion a year by 199O.13
Adverse effects
Although it is generally believed that vitamins are harm
less, there are real dangers related to the use of some of
them. "Excessive use of one or more vitamins may cause
relative deficiencies of other essential micronutrients,
and large doses of a 11 minerals, fat-soluble vitamins, and
some water-soluble vitamins are toxic.”14
Large amounts of vitamin A, which is fat-soluble,
can produce loss of appetite, itching, skin disorders,
loss of weight, enlargement of the liver and spleen,
debility and painful swellings of bone and joints.15
High doses of vitamin A given to pregnant animals
have caused deformities,16 and evidence of a terato
genic effect in humans17 has led to recommendations
that the recommended daily allowance (RDA)
should not be exceeded during pregnancy. In the UK,
pregnant women are advised that they should take
care not only with vitamin A supplements, but also
refrain from consuming large dietary amounts of vit
amin A from food such as liver.
Excessive doses of vitamin D produce a rise in blood
calcium which causes debility, drowsiness, nausea,
abdominal pains, thirst, constipation, loss of appetite,
deposits of calcium in various tissues and organs, kid
ney damage and kidney stones.18 The AMA advises
that “vitamin D supplements should be avoided in
individuals, especially infants and children, who have
adequate exposure to sunlight or a normal diet”.19
Prolonged overconsumption of vitamin D in infants
can cause mental and physical retardation, kidney
failure and death. Symptoms of toxicity may occur
with doses greater than 25 micrograms (1,000 IU)
daily. In children and normal adults, amounts
exceeding 1.25 milligrams (50,000 IU), produce
abnormally high concentrations of calcium in the
blood, and prolonged use of massive doses ultimately
results in irreversible kidney failure and death. If
vitamin D is contained in any multivitamin prepara
tion, the amount should not exceed the RDA of 10
micrograms or 400 IU.20
Because Vitamin E is also fat-soluble, large doses
“should be used cautiously”. The long-term use of
doses as low as 270 to 540mg daily has been reported
to cause nausea, muscular weakness, fatigue,
headache and blurred vision in some patients.21
There is no good evidence for vitamin E deficiency or
for the need for supplementation.
The water-soluble vitamins (the B vitamins, and vita
min C) readily pass out of the body when excessive
amounts are taken, so adverse effects arc minimised.
Nonetheless, doses of vitamin C greater than one
gram per day may cause diarrhoea by irritating the
intestines. Large doses can also interfere with the
results of common blood tests. As well, a dose of one
gram per day can raise blood levels of ethinyl estra
diol. If women using oral contraceptives containing
ethinyl estradiol abruptly stop taking vitamin C, con
traceptive failure can result.22 Large doses of vitamin
B6 have caused severe nerve damage.2-1
Two “B vitamins” that should be avoided are vita
min B15 and vitamin B17. The AMA says, “the toxic
substances known as vitamin B15 (pangamic acid)
and vitamin B17 (laetrile) are neither nutrients nor
vitamins. Laetrile contains 6% cyanide by weight
and has caused chronic cyanide poisoning and death.
Pangamic acid or pangamate may be mutagenic.
Neither substance has any established nutritional or
other usefulness.”24
Fact versus fiction
Vitamins are claimed to be of value in a wide variety
of conditions such as arthritis, asthma, nephritis,
rheumatic fever, schizophrenia, and vascular disor
ders. In the USA, an important reason for taking
vitamin supplements is “the erroneous belief that
such preparations provide extra energy and make
one ‘feel better’”.25
A popular myth is that the B vitamins, in particular
B6, are useful in treating nausea and vomiting in
pregnancy and also premenstrual tension (PMT).
However, “these possible therapeutic effects need
confirmation in properly controlled clinical trials”.26
Vitamin C is popularly believed to be the cure for the
common cold and, more recently, has been suggested
as a cure for cancer. “Claims that vitamin C amelio
rates colds or promotes wound healing have not been
proved.”27 The AMA says that “there is good evi
dence that pharmacological doses of ascorbic acid
121
Problem Drugs
by supplementation, reduces the potential
risk for both nutrient deficiencies and
nutrient excesses.”6
Vitamins
Vitamins
124, 6 C .
Problem Drugs
RDA of vitamin Bl in multivitamin preparations.'18
Misuse of vitamins can do harm. For example, it can:
• distort national health priorities;
• drain limited national economic resources and
foreign exchange;
• waste limited individual and family financial
resources;
0 encourage incorrect and harmful beliefs about the
nature of health; and
• encourage ineffective and harmful practices.
Food in a capsule:
Sandoz advertises
Nutrisan in Pakistan
Access to good nutrition should be a priority for pub
lic health in all countries. Encouraging individual
and government spending on unnecessary vitamin
preparations does not contribute to public health
needs. Rather, it reinforces the misleading belief that
there is a magic pill that can fulfil those needs. The
Sandoz Nutrisan advertisement from Pakistan in the
late 1980s (pictured above) is an example of the type
of pharmaceutical marketing that has contributed to
that belief. By suggesting that the vitamin capsule can
replace the nutrients in food, it diverts efforts to solve
problems of hunger, malnutrition and vitamin imbal
ances.
SANDOZ
Recommendations for action
1. Governments should introduce strict controls
over the claims made for vitamin preparations.
2. High-dose vitamins, used for treatment of
specific deficiencies, should be clearly labelled
and differentiated from preparations used as
dietary supplements. If a deficiency does exist,
single ingredient vitamins should be used rather
than a multivitamin preparation.
3. Irrational vitamin combinations should be
removed from the market.
4. Independent information about the rational use
of vitamins should be developed for health
workers and consumers.
[See also the sections on Growth Stimulants, Brain
Tonics, and Drugs in pregnancy.]
References
1.
2.
AMA, Drug Evaluations, Philadelphia, W.8. Saunders Co., (6th edn) 1986, p8z, 1
Macdonald, J.J., Primary Health Care: medicine in its place, London, Earlhscan, 1993, P25
AMA, op cit, p8Zji
Henry,). (ed), The British Medical Association Guide to Medicines & Drugs, London,
Dorling Kindersley, (2nd edn) 1991, P145
5.
AMA, op cit, P859
6.
Griffith, H.W., The Vital Vitamin, Wellingborough, UK, Thorsons, 1988, pi
7 Amorim Cruz, JA, Moreiras-Varela, 0., et al, “Intake of vitamins and minerals", European
Journal of Clinical Nutrition, Vol 45 (Suppl. 3), 1991, ppni-38
8.
Anon., “Who needs vitamin pills?”, Which?, Feb 1990, P77
9.
Anon., “Self-medication products in Germany", Scrip, No 1773, 24 Nov 1992, p4
10.
Subar, A.F. and Block, G., "Use of vitamin and mineral supplements, demographics and
amounts of nutrients consumed", American Journal of Epidemiology, Vol 132, No 6,1990,
3.
4.
PP1091-1101
Medeiros, D.M., Bock, M.A., et al, "Long-term supplement users and dosages among adult
westerners". Journal of the American Dietetic Association, Vol 91. No 8, Aug 1991. pp98o-2
12.
Sanberg, P. and Krema, R.M.T., Over-the-counter Drugs: Harmless or Hazardous?, London,
11.
13.
14.
15.
Burke Publishing, 1988, p8i
Chemical Market Review, 8 Oct 1984
AMA, op cit. P859
Parish, P., Medicines: a guide for everybody, London, Penguin (6th edn, revised), 1989,
16.
17.
p212
AMA, op cit. P847
Martinez-Frias, M.L and Salvador,“Megadose vitamin A and teratogenicity”, Lancet,
30 Ian 1988, P236; Anon., “Vitamin A intake in pregnancy", Lancet, Vol 336, 27 Oct 1990,
P1063
18.
Parish, op cit, P214
19.
AMA, op cit, pp86o-i
20.
Ibid, pp848 and 860
21.
ibid, P849
22.
Ibid, PP850-1
23.
Grant, R., Which? Medicine, London, Consumers Association and Hodder & Stoughton,
1992. P466
AMA, op cit, P841
Gilman, A.G., Rail, T.W., Nies, A.S., and Taylor, P. (eds), Goodman and Gilman's The
Pharmacological Basis of Therapeutics, New York, Pergamon Press, (8th edn) 1990, P1528
26.
Reynolds, J.EF. (ed.), Martindale: The Extra Pharmacopoeia, London, The Pharmaceutical
Press, (29th edn) 1989, P1271
24.
25.
27.
BMA and the Royal Pharmaceutical Society of Great Britain, British National Formulary,
London, BMA and The Pharmaceutical Press, No 23, Mar 1992, P341
28.
29.
30.
31.
AMA, op cit, PP850-1
Ibid, P849
Henry, op cit, P145
Cawson, R. and Spector, R ., Drugs and Medicines: a consumers' guide, Oxford, Oxford
University Press, 1990, P105
32.
Parish, op cit, PP214-5
33.
Phillips, A., Rakusen, J. (eds) and the Boston Women’s Health Collective, The New Our
Bodies, Ourselves (2nd UK edition), London, Penguin Books, 1989, P345
34.
Rylance, G. (ed.), Drugs for children, Copenhagen, WHO, 1987, P147
35 Wolfe, S.M, Fugate, L., et al, Worst Pills Best Pills, Washington, Public Citizen Health
Research Group, 1988, P426
36.
AMA, op cit, P859
37.
BMA and the Royal Pharmaceutical Society of Great Britain, op cit, P340
38.
Reynolds, op cit, ppi257,1258,1266 and 1270
39.
BMA and the Royal Pharmaceutical Society of Great Britain, op cit, P320
40.
MIMS Middle East, Dec 1990, piz8; MIMS Africa, Jul 1991, P98; MIMS Caribbean, Jan 1991,
41.
42.
43.
44.
45.
46.
47,
48.
P55
AMA, op cit, P844
Reynolds, op cit, P1276
AMA, op cit, p85/4
MaLAM letter to Servier, Apr 1990
MaLAM letter to SmithKline Beecham, Jan 1992
Anon., “UK vitamin manufacturer fined over IQ claims", Scrip, No 1763, 20 Oct 1992, P9
Chetley, A. and Gilbert, D., Problem Drugs, The Hague. HAI, 1986, p6 of Vitamins section
Park, Y.K., Kim, I, and Yetley, E.A., “Characteristics of vitamin and mineral supplement
products in the United States", American Journal of Clinical Nutrition, Vol 54,1991, PP750-9
Chetley, A. Problem Drugs, Amsterdam,
Health Action International, 1993
Health Action International’s
coordinating offices:
HAI Europe
Jacob van Lennepkade 334T
1053 N| Amsterdam
The Netherlands
7A. Drugs in
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accion para la Salud
Avda. Palermo 531
Dpto. 104
Lima 13
Peru
Unnecessary risks
Margaret, aged 31, finally became pregnant in the USA
after she and her husband had tried for years to have a
baby. At about the same time, and before she realised that
she was pregnant, a dermatologist started her on a treat
ment for cystic acne with a new drug, Accutane
(isotretinoin). She took the drug for six weeks and her
acne improved. At 34 weeks, Margaret had a premature
delivery. Her baby girl weighed just over two kilograms,
and was found to have water on the brain and defects in
her heart. The baby, Susan, only survived for a few
weeks.1
During the first three months (first trimester) of preg
nancy, and particularly from the 18th to 60th day,
while organs are developing, the fetus is most sus
ceptible to drugs which may cause congenital
malformations.2 These teratogenic drugs may be lethal
and lead to abortion, or to the birth of a child with
defects. During the fourth to sixth month (second
trimester) of pregnancy, teratogenic drugs can still
cause disorders of growth and function, particularly in
the brain and spinal cord, but these disorders are rarely
fatal. Drugs given late in pregnancy may lead to prob
lems during childbirth or immediately after, which may
be fatal and are frequently related to drug-induced res
piratory failure. This is particularly a problem in
premature infants, whose lungs are poorly developed
at birth.
Only an estimated 3% of congenital abnormalities
are definitely due to drugs,3 but the number of drugs
that have been identified as causing abnormalities is
growing. The best known is thalidomide. In
November 1956, thalidomide was first marketed for
use in a wide range of conditions including influenza,
functional disorders of the stomach and gall bladder,
mild depression, insomnia and menstrual tension. It
was widely promoted, without sufficient evidence, as
a safe and effective drug to be used during pregnancy.
The resulting tragedy of some 10,000 severely
deformed babies is now history.4
Over the years, the list of teratogenic drugs has grown
to include thalidomide, anti-cancer drugs, hormones
(including DES), warfarin, penicillamine, antithy
roids, anticonvulsants, inhalation anaesthetics,
alcohol, some psychotropic drugs, tetracycline and
other antibiotics, and retinol derivatives.5 A terato
genic effect could exist for high doses of vitamin A.6
Table 7A-1, on the next page, describes the system
devised by the Australian Drug Evaluation Committee
to classify the risk of various drugs in pregnancy.
The use of drugs in pregnancy continues to be a con
troversial, little known area, both in terms of risks
and benefits. There are very few drugs that are cer
tainly safe in early pregnancy. One leading textbook
on pharmacology points out that “the fetus is to at
least some extent exposed to essentially all drugs
taken by the mother”.7 If drugs are necessary during
pregnancy or when pregnancy is a possibility, those
which have been extensively used and shown to be
usually safe are to be preferred to new drugs.
Overuse
The thalidomide tragedy had a profound effect on
attitudes toward drug safety and in particular to pre
scribing or using medicines during pregnancy.
However, both too many and too wide a range of
drugs are still being used in pregnancy.
A 22-country study carried out in the late 1980s, which
included women from Europe, Asia, Latin America,
and Africa, found that only 14% of women did not
take any drugs during their pregnancy. Among the
86% of women who took at least one drug, the average
number was nearly three drugs, including iron and
126
7 A .
Drugs
in
pregnancy
Problem Drugs
vitamins (range 1 to 15).s A 1986 study in the UK
showed that about 35% of women took drugs (exclud
ing iron and vitamin supplements and drugs used
during labour) at least once during pregnancy,
although only 6% took a drug during the first three
months of pregnancy - the time at which the risk of a
drug causing deformities in the fetus is at its greatest.9
A 1985 survey in the USA showed that about 45% of
pregnant women took at least one prescription drug
during pregnancy and many more used drugs bought
over the counter.10 A 1987-8 study carried out in the
Netherlands found that 86% of women took at least
one drug (including iron and vitamins) during preg
nancy. The average was just over four drugs.11
Many factors contribute to drug use in pregnancy.
The “pill for every ill” mentality extends into preg
nancy. Often, medicines are taken before the
pregnancy has been confirmed. Some of this use is
fostered by doctors and the pharmaceutical industry.
For example, the number of prescriptions written in
the USA in the late 1980s for the highly teratogenic
drug, isotretinoin, bore little relation to the number
of cases of cystic acne, its only indication. Instead the
drug was being prescribed for acne vulgaris, the com
mon, milder form of acne.12
does not mention the risk of teratogenicity, whereas
the Physicians’ Desk Reference in the USA warns
women to use the product in pregnancy only if
absolutely necessary.16
Overall, too little is known about the effects of
drugs taken in pregnancy. As the American
Table 7A-1
Australian Risk Classification System
Category
A
Description
Drugs which have been taken by a large number of preg
nant women and women of childbearing age without an
increase in the frequency of malformation or other direct
or indirect harmful effects on the fetus having been
observed.
B
Drugs which have been taken by only a limited number of
pregnant women and women of childbearing age, without
Pregnancy itself has come to be seen more as a disease
state than as a normal, healthy, condition. In such cir
cumstances, medical intervention becomes virtually
inevitable. This “medicalisation” of pregnancy means
that women lose control of decisions affecting them.
Often, they are not given information when they need
it, and they can be misled into thinking that interven
tion in pregnancy is the normal way to cope with the
problems that arise. Clinical pharmacologist Dr Joe
Collier says that most pregnant women who go to
hospital in the UK to have their babies are given some
form of sedation the night before delivery. “Who are
the drugs really for - the mother-to-be, her baby, or
the medical staff who want a quiet night?”13
an increase in the frequency of malformation or other
direct or indirect harmful effects on the human fetus
having been observed.
As experience of effects of drugs in this category in
humans is limited, results of toxicological studies to date
(including reproduction studies in animals) are indicated
by allocation to one of three subgroups:
Bl
Studies in animals have not shown evidence of an
B2
Studies in animals are inadequate and may be lack
increased occurrence of fetal damage
ing, but available data show no evidence of an
increased occurrence of fetal damage.
B3
Studies in animals have shown evidence of an
increased occurrence of fetal damage, the signifi
Health workers often lack the information they need to
prescribe a rational course of treatment during preg
nancy. The information provided by the drug industry
is often unhelpful. For example, “in most countries
where isotretinoin and etretinate are available, there
are no formal programmes which systematically edu
cate physicians and patients about the teratogenic
hazards of these agents and, at the same time, attempt
to assess the effectiveness of these interventions.”14 (See
the box on isotretinoin on page 128.) More generally,
companies include a standard protection line in drug
information that simply states that “safety for use dur
ing pregnancy has not been established”.15
cance of which is considered uncertain in humans.
C
on the human fetus or neonate without causing malforma
tions. These effects may be reversible. Accompanying
texts should be consulted for further details
D
Drugs which have caused an increased incidence of human
fetal malformations or irreversible damage These drugs
may also have adverse pharmacological effects.
Accompanying texts should be consulted for further details.
X
Usually, a lack of reliable, objective information on
drugs is the norm in developing countries. However,
even in industrialised countries, contradictory infor
mation is given about drug use. For instance, in Italy
in 1992, product information on tretinoin cream
Drugs which, owing to their pharmacological effects, have
caused or may be suspected of causing, harmful effects
Drugs that have such a high risk of causing permanent
damage to the fetus that they should not be used in preg
nancy or where there is a possibility of pregnancy.
Source: Australian Drug Evaluation Committee. Medicines in Pregnancy,
Canberra. Australian Government Publishing Service, 1989, ppl-4
7 A .
According to a UK consumer guide on medicines, “it
is probably best to try and avoid taking any nonessential drugs in pregnancy or if you are trying to
become pregnant.... We really know little more than
that some drugs may produce abnormalities (teratogenesis) and that these are more likely when the drug
is taken within the 12 weeks after conception.”18
After birth, the newborn baby is less able than the
adult to metabolise and excrete certain drugs and is
hence more susceptible to their undesirable effects.19
Some drugs can become concentrated in the mother’s
milk, such as iodine, which can then produce goitre
in the baby; some tranquillisers such as diazepam can
produce lethargy and weight loss in the baby and
oral anticoagulants can produce bleeding. There are
many other examples, and generally because there is
“insufficient information available” on the effect of
drugs in breast milk, “any drug should be taken with
caution by breastfeeding mothers”.20
A clear framework for deciding which drugs to pre
scribe or use during breastfeeding is difficult to
develop. A starting point is to be certain that the drug is
really needed by the mother. Other questions involve
whether the drug would be absorbed by the baby if it is
present in breast milk and, if so, whether it would harm
the baby. The short answer is that any drug in the milk
will be absorbed and, in therapeutic doses, would be
likely to have a harmful effect. With most drugs, thera
peutic dosage levels are unlikely to occur in breast
milk.21 However, a few drugs, such as iodides, may be
concentrated in the milk, causing toxicity.22 Table 7A-2
lists some drugs which have been identified as poten
tially hazardous while breastfeeding.
Conditions when drugs might be
used
There are four main types of conditions arising dur
ing or around the time of pregnancy when drugs are
often used. These are:
• infertility, when drugs may be used to stimulate
ovulation;
• acute conditions that arise during pregnancy (pain
and fever, infections, coughs and colds) or chronic
conditions unrelated to pregnancy (asthma,
epilepsy, diabetes);
• conditions commonly related to pregnancy (morn
ing sickness, hypertension, anaemia); and
• complications of pregnancy and labour (threat
ened miscarriage, premature labour, toxaemia,
pain in childbirth).
in
pregnancy
Table 7A-2
Drugs to avoid or use with caution* during
breastfeeding
Avoid
amantadine, anticancer drugs, bromocriptine,
chloramphenicol, ergot alkaloids, clemastine, gold salts,
iodine, lithium, phenindione, thiouracil
Caution
alcohol, aminophylline, amiodarone, aminoglycoside,
antibiotics, anthraquinones, aspirin, atropine, barbiturates,
benzodiazepines, beta blockers, calciferol, carbimazole,
chlorpromazine, cimetidine, clindamycin, corticosteroids,
diuretics, indomethacin, isoniazid, laxatives.
meprobamate, methyldopa, metronidazole, nalidixic acid.
nitrofurantoin, opioid analgesics, oral contraceptives,
penicillins, phenobarbitone, phenylbutazone, reserpine,
sex hormones, sulphonamides.
• Note: Using a drug with caution means to avoid use if possible. If the
drug is needed, seek additional information on how to minimise risks.
Some drugs should only be used at low doses or on a short term basis.
For many drugs, insufficient evidence is available to establish safety
Drugs not listed in this box are not necessarily safe; obtain more
information before prescribing or taking any drug during breastfeeding.
Sources: Lewis. P.J , and Hurden, E.L.. “Breast feeding and drug
treatment", in: Hawkins. D F. (ed.). Drugs and Pregnancy. London,
Churchill Livingstone. (2nd edn) 1987. p318; Laurence. D.R. and Bennett,
P.N., Clinical Pharmacology. Edinburgh, Churchill Livingstone. (6th edn).
1987, ppl31-2
A database on beneficial drugs
Randomised clinical trials (RCTs) that compare a drug
to an inactive treatment, or to a treatment whose
effectiveness is known, are the best source of
information for making rational decisions about
therapy. Such trials can show whether a drug is
beneficial, which people benefit, and by how much. It
is, however, time consuming and difficult to find the
reports of all the relevant RCTs that have been
performed and to review them systematically and
reliably. The field of pregnancy and childbirth is the
first for which a database of regularly updated
systematic reviews exists - the Cochrane Collaboration
Pregnancy and Childbirth Database.1 It contains nearly
600 detailed reviews on topics such as: drug treatment
of hypertension in pregnancy, routine iron
supplementation in pregnancy; periconceptional folate
in high-risk mothers; antibiotics for asymptomatic
bactenuria; and brief corticosteroid therapy before
pre term delivery (to reduce the risk of respiratory
distress syndrome in the baby). The database is
expected to be of great value to pregnant women
considering treatment options, as well as to doctors
and midwives. It is worth emphasising, however, that
the adverse effects of treatments often cannot be
reliably identified or predicted in RCTs.
Note: A paperback guide based on the database was published tn
1990: Enkin, M., Keirse. M. and Chalmers. I.. A Guide to Effective Care
in Pregnancy and Childbirth, Oxford. Oxford University Press. 1990.
The database itself is produced twice a year on computer disks. [See
the section on Useful Addresses for ordering information.)
Problem Di
Medical Association (AMA) notes, “for many
drugs, particularly new ones, little or no informa
tion is available on use during pregnancy.”17 (See
the box below about efforts to develop an effective
database on drugs used during pregnancy and
childbirth.)
Drugs
7 A .
Drugs
in
pregnancy
Isotretinoin: warning about risk
Less than a year after the introduction of isotretinoin*
in 1982 in the USA, the manufacturer, Hoffman-La
Roche, had reported seven spontaneous abortions and
five birth defects associated with use of the drug
during pregnancy.1 By 1991, 91 serious cases of birth
defects had been reported in the USA.2 Because of the
general under-reporting of adverse effects, some
estimates suggest that a more realistic number is
nearer 240.3
isotretinoin were "widely accepted’’ by physicians.4 One
estimate placed the magnitude of overuse of the drug
at some 15 to 20 times greater than the number of
women with severe recalcitrant cystic acne.5 When the
drug was first introduced, there was no demand that a
pregnancy test be performed, and the drug was heavily
promoted to doctors, "minimizing the importance of
the risks’’.6
During 1983, both Roche and the US FDA began to
take steps to alert physicians to the dangers, including
sending letters, updating information brochures, and
issuing warnings in the FDA's bulletin. However in
1988, public concern about the drug and about
continuing cases of it being used by pregnant women
led to public hearings and the introduction of an even
stronger programme of education about the drug’s
use. The programme includes an elaborate consent
form, detailed explanation to the patient about the
hazards of pregnancy, a pregnancy test, confirmation
that the woman can and will take necessary
contraceptive measures, and careful selection of
patients who meet the treatment criteria: only those
with severe, disfiguring cystic acne that is not
responsive to other therapies. Before the introduction
of the programme, other non-labelled indications for
Since the programme was introduced, there have been
two further modifications to strengthen the warnings in
1990 and 1991 and a survey of use of the drug in
women has been carried out, under contract from
Roche. Although it found that virtually all women
enrolled in the educational programme were aware of
the dangers of using the drug during pregnancy, 37%
of women did not have a pregnancy test before starting
on the drug. There was also evidence of "a large
amount of reckless and dangerous prescribing" with
nearly one-third of the women of child-bearing age
surveyed showing no sign of acne cysts. These findings
led the Public Citizen Health Research Group to repeat
its call for the drug to be restricted to specifically
registered doctors.3 In the UK, the drug is available
only through hospital pharmacies for use in hospitals
and hospital clinics and should be given by or under
the supervision of a dermatologist.7
•Note: Isotretinoin is marketed by Roche as Accutane in the USA, and
as Roaccutane in the UK and many other countries.
Sources:
1.
Mitchell, A.A., "Oral retionoids: What should the prescriber know
about their teratogenic hazards among women of child bearing
potential?”, Drug Safety, Vol 7, No 2. 1992, pp79-85
2.
Anon., “FDA cm’ttee on Accutane labelling”, Scrip. No 1623. 7 Jun
1991,p26
3.
Anon , "Roche elaborates on US Accutane warnings", Scrip,
No 1537, 3 Aug 1990, p27
4.
Stern, R.S., "When a uniquely effective drug is teratogenic: the case
of isotretinoin". New England Journal of Medicine, Vol 320, No 15,
13 Apr 1989, pp!007-9
5.
Faich, G. and Rosa, F., “When a uniquely effective drug is
teratogenic- the case of isotretinoin" (letter). New England Journal of
Medicine. Vol 321, No 11. 14 Sep 1989, pp756-7
6.
Anon., “Acne. Accutane, abortions and life threatening birth
defects", Health Letter, 12 May 1988
7.
BMA and the Royal Pharmaceutical Society of Great Britain. British
National Formulary, London. BMA and The Pharmaceutical Press.
No 23. Mar 1992, p405
7 A .
Drugs
in
pregnancy
In April 1993, The Lancet published a report on a
possible relationship between the use of fertility drugs
and the development of ovarian cancer. Dutch
researchers reported that 12 out of 5250 women who
were treated for infertility with clomiphene citrate and/or
gonadotrophins developed granulosa-cell tumours, a
form of ovarian cancer. The age of the women varied
from 25 to 38. Half the women sought fertility treatment
because they developed amenorrhoea following the use
of oral contraceptives.
Although the authors stated that they could not "prove
the existence of a causal relationship" because the
number of women studied was small for such a rare
form of cancer, they pointed out that this was a much
higher rate of ovarian cancer than would be expected in
this age group. They urged caution in prescribing ovarian
stimulants.
Serono advertises two drugs to “respond to the
challenge of infertility" without mentioning specific
indications: QIMP, Pakistan, Sept 1988-Feb 1989.
Drugs for infertility
Drugs are only useful in the treatment of female
infertility when the cause is some form of hormone
deficiency that prevents ovulation. This accounts for
a minority of cases of infertility. WHO points out
that one-third of all infertility among couples occurs
because of an abnormality in the male partner. In
women, the commonest cause of infertility is damage
to the Fallopian tubes as a result of infection.23 In
developing countries, between 50 and 80% of infer
tility in women is attributable to reproductive tract
infections.24 Even where drugs to induce ovulation
are indicated, pregnancy is likely to occur in only
approximately 30% of cases.25 If pregnancy is suc
cessful, multiple births are more likely.26
The main drugs used are clomiphene citrate, follicle
stimulating hormone (FSH), human menopausal
gonadotrophin (HMG), and human chorionic
gonadotrophin (HCG), sometimes in combination.
As with all drugs taken around the time of concep
tion, there is a theoretical possibility of causing
damage to the fetus.27 The effects of clomiphene on
early gestation, however, “are not understood” and
pregnancy should be ruled out before it is adminis
tered.28 Particular concern has been raised because of
the structural similarities between clomiphene and
diethylstilbestrol (DES). Some experimental studies
The Dutch Society for Obstetrics and Gynaecology
appears to have come to different conclusions.
Dr H. Evers, a gynaecology professor, acted as the
Society’s spokesperson after the report was released. He
commented in a local newspaper that “there is no reason
for concern”. He said that “tens of millions of women all
over the world have been treated with these hormones.
I find it a comforting thought that nobody ever noticed
the development of this type of cancer in such a large
group... these researchers apparently found a few
patients with granulosa cell tumours. They continued to
look and out of a group of 5250 they picked these 12.
Gynaecologists who possibly treated thousands of
women with hormones and who did not find granulosa
cell tumour were left out of this study. No, there is no
reason for concern."
Sources:
Willemsen. W.. Kruitwagen. R., Bastiaans, B.. Hanselaar. T.. and Rolland.
R., “Ovarian stimulation and granulosa cell tumour". Lancet. Vol 341, 17
April 1993. pp986 S
Kaashoek. P.. “Mogelijk eierstokkanker door vruchtbaarheidsmedicijn",
Eindhovens Dagblad, I May 1993
________________________________________________________________________________________ I
have shown that high doses of clomiphene can cause
changes to fetal vaginal tissues similar to those that
occur with DES. Clomiphene could have a terato
genic effect if taken just before conception because
metabolites of the drug may still be present during
early pregnancy.29 There is also some evidence of
abnormalities among children born to women who
inadvertently took clomiphene during the first six
weeks after conception.30 The risk of ovarian cancer
among women taking clomiphene or gonadotrophins
is another cause for concern (see box above).
Problem Drugs
Fertility drugs and ovarian cancer:
a cause for concern?
129
Drugs for acute or chronic
conditions
It possible, it is best ro avoid drug use for acute or
chronic conditions during pregnancy. Where it is not
possible, the choice should be those drugs that have
been in use for the longest time with no evidence of
harmful effects.
Analgesics, non-steroidal inflammatory drugs
(NSAIDs), antibiotics, cough and cold remedies, and
a variety of psychotropic drugs are among rhe prod
ucts often prescribed or used for acute conditions
during pregnancy. NSAIDs, antimicrobials, and
some psychotropic drugs might also be prescribed
for chronic conditions, along with products such as
corticosteroids and other anti-asthmatics, insulin
and hypoglycaemics, and anticonvulsants.
Table 7A-3
Safety of antibiotics during pregnancy
While all drugs, including antibiotics, should be avoided if possible during
pregnancy, the treatment of infections may be necessary for the health of
either the mother, the baby or both. In such cases, the following guideline
indicates which antibiotics are considered to be least harmful.
Antibiotic
Trimester in which
Comments
antibiotic is
considered safe
Aminoglycosides
Third
risk of damage to hearing
increases in second trimester;
gentamicin is considered safest
Cephalosporins
All
avoid cefamandole, moxalactam,
cefotetan and cefoperazone
Analgesics
Analgesics, if needed, should be taken at as low a
dose and for as short a time as possible. Simple pain
killers are preferred. Paracetamol is the drug of
choice if a pain killer is needed during pregnancy.31
Chloramphenicol
First and second
Erythromycin
All
can cause “grey baby" syndrome
avoid erythromycin estolate
which may cause maternal
hepatitis
Estimates for the use of aspirin in pregnancy in the
USA range from 10 to 45% of women, with most use
occurring in the first trimester of pregnancy.32
Although animal studies have shown that salicylates
(aspirin-like drugs) can cause birth defects, there is
no conclusive evidence that they cause malforma
tions in humans. However, if taken late in pregnancy,
aspirin can inhibit uterine contraction, lead to com
plications during delivery, and can cause neonatal
and maternal bleeding.33 It is generally recom
mended that aspirin should be avoided completely in
pregnancy.34
However, recent investigations suggest that there
may be a therapeutic role for low-dose aspirin among
a limited number of women at risk from pregnancyinduced hypertension or poor fetal growth.35
Nonetheless, even after these findings, the US Food
and Drug Administration (FDA) ruled that labels of
over-the-counter products containing aspirin should
warn women not to use aspirin during the last three
months of pregnancy unless told to do so by a doc
tor.36 As one of the studies points out, even though
there may be some justification for a restrained use of
aspirin, “massive use of aspirin by millions of preg
nant women yearly cannot be recommended”.37
Isoniazid
considered the safest of all anti
tuberculosis drugs, but
prophylaxis should be post
poned until after delivery, due to
risk of hepatitis; animal studies
have shown the drug to be
embryocidal
Penicillins
All
studies of combination forms
with clavulanic acid have not
demonstrated toxic effects
Quinolones
None
diseases of the joints have been
noted when used in immature
animals; nalidixic acid has been
used safely in second and third
trimesters but should be discon
tmued at labour
Sulphonamides
Second
possible antifolate effects in first
trimester; risk of brain damage
caused by bile pigment (biliru
bin) in third trimester
Tetracyclines
None
maternal risk of liver, pancreas
or kidney diseases; fetal risk of
teeth discoloration, abnormal
Migraine medications such as ergotamine are con
traindicated in pregnancy.38 Narcotic analgesics may
depress the brain and respiration of the baby, partic
ularly when given to relieve the pain of childbirth.3’
development of bone tissues,
retarded bone growth
Trimethoprim
Like aspirin, NSAIDs can inhibit uterine contractions
and lead to difficult labour. Drugs such as
indomethacin, ibuprofen and naproxen should be
avoided at least in the last three months of pregnancy.40
None
First and third
folate antagonism
Source: adapted from Lynch. CM.. Sinnott IV. J.T., et al. "Use of Antibiotics
During Pregnancy". American Family Physician. Vol 43. No 4. Apr 1991, p!367
7 A .
Antibiotics
A range of epidemiological studies carried out over
the past 30 years show that an antibiotic is taken by
anywhere from one out of every six to one out of
every two pregnant women.42 Most of those studies
have looked at drug use in industrialised countries.
However, the dangers of poverty-related infection
and the generally excessive misuse of antibiotics in
developing countries only serve to highlight the need
for a critical look at the consumption of antibiotics
during pregnancy.
Well-known antibiotics which have been used for
years are usually effective and more recent drugs can
be reserved for infections that do not respond.
“There is little indication to use the latest trivial
molecular modification whose side effects in preg
nancy are ill-documented.”43 The penicillins and
cephalosporins are considered the antibiotics of
choice for most infections in pregnancy. Table 7A-3
highlights the evidence on safety of antibiotics in
pregnancy.
Metronidazole is not recommended in early preg
nancy, as animal studies demonstrated a possible risk
of cancer;44 however, the animal research is contro
versial, and it is generally thought to be safe for use
in the last six months of pregnancy.45
Isoniazid is considered to be the safest anti tuberculosis
drug for use during pregnancy, but prophylactic use
should be avoided. Rifampicin should be avoided dur
ing the first three months.46
Antimalarial drugs such as pyrimethamine with
either dapsone or sulfadoxine are no longer recom
mended for use. Primaquine should be avoided
during pregnancy.47 High doses of quinine can cause
fatal congenital malformations. Chloroquine is the
drug of choice for treatment or prevention of malaria
in pregnancy, but has been associated with rare cases
of damage to the cyes.4S There is also the problem of
increasing resistance to these standard therapies for
malaria. Mefloquine has shown some promise in
treating primaquine or chloroquine resistant malaria
and may also be acceptable in pregnancy, but it has
not yet been studied sufficiently to be certain about
its effect during pregnancy.49 It should probably not
be used during the first three months.'1
Cough and cold remedies
As a large proportion of cough and cold remedies
contain ineffective ingredients, some of which are
potentially harmful, their use should be avoided gen
erally, but especially so during pregnancy. Some
in
pregnancy
proprietary cough medicines obtainable without pre
scription contain iodine. The use of iodine (or an
iodide) and medicines containing iodine is con
traindicated in pregnancy.51 In Brazil in 1988,50 out
of 315 (16%) cough and cold preparations contained
an iodide.52 In Africa and the Caribbean during
1991, Wallace was marketing Bepro cough syrup
that contained calcium iodide. The product listing in
prescribing guides gave no warning about avoiding
use in pregnancy.53
Psychotropics
Anxiety, insomnia and depression may occur during
pregnancy. However, use of drugs to control these
symptoms should be avoided if possible. “Other forms
of treatment are important and include support from
staff or self-help groups, psychological treatments
such as relaxation exercises or cognitive therapy, and
mobilisation of community resources.”54
Very little is known about the effects of psychotropic
drugs in pregnancy. While no definite evidence exists
to link the use of barbiturates or benzodiazepines to
birth defects, “there are few valid indications for
using these drugs in early pregnancy and it is possible
that their use may be associated with a small
increased risk of malformation”.55 Diazepam use, for
example, has been linked to an increased risk ofcleft
lip and palate in some studies.56 Similar reports of
malformations have been associated with the use of
barbiturates, chlordiazepoxide and meprobamate.57
In later pregnancy, when brain cells are developing,
psychotropic drugs can affect neurotransmitters and
may produce subtle changes which result in func
tional disturbance and behavioural difficulties in
later life.58
Long-term exposure to diazepam or any of the ben
zodiazepines can also cause withdrawal symptoms.
Sedation and poor feeding in the newborn can followuse of diazepam before delivery. According to the
AMA, “withdrawal symptoms and signs can be
expected in infants born to mothers who are physi
cally dependent on benzodiazepines during rhe last
trimester".59
As one textbook on the use of drugs in pregnancy
points out:
“No sedative is entirely free of effects on the
newborn and it would seem prudent to avoid
repeated doses of any of this group of drugs in
late pregnancy unless good indications exist.”60
Drugs for chronic conditions
Some drugs are given as therapy for continuing con
ditions. Corticosteroids are often used in pregnancy
for asthma patients. Although animal studies demon
strate a teratogenic effect, human experience
suggests that the risk is small and may be dose
related. Where possible, corticosteroids should be
Problem Drugs
There is, however, some indication that indomethacin
may be useful in the treatment of premature labour,
provided that the fetus is carefully monitored.41 (See
the box on page 134 about ritodrine - another drug
used for treating premature labour.)
Drugs
132
7 A .
Drugs
in
pregnancy
Problem Drugs
avoided in early pregnancy and the lowest possible
doses used ar other times.61 Drugs used to treat respi
ratory conditions should also be used with caution.
Sympathomimetics (such as noradrenaline, amino
phylline) may harm the fetus, and beta adrenoceptor
stimulants (like salbutamol) should be avoided late
in pregnancy. However, generally, in normal doses
none of the usual anti-asthma drugs harm either the
mother or fetus.62
In epilepsy, anticonvulsants (carbamazepine, pheny
toin, primidone or valproic acid) are usually needed,
although all these drugs are possible teratogens.
Valproic acid, in particular, has been linked to an
increased risk of spina bifida.6’ In general, where
anticonvulsant therapy is essential, a single drug
rather than a combination of drugs should be used to
minimise risk.64 According to Tbe Lancet, epileptic
seizures pose a greater overall risk to mother and
baby than do anti-epileptic drugs used properly.6’
Although there is no convincing evidence that oral
hypoglycaemic agents will damage the fetus, these
drugs may cause hypoglycaemia in the newborn. In the
USA, oral hypoglycaemic agents are contraindicated
during pregnancy.66 Pregnant diabetic women not con
trolled by diet alone should be treated with insulin.
All antithyroid drugs can produce goitre in a small
number of infants, so caution and careful monitoring
of newborns is recommended.67
Pregnancy-related conditions
Some drugs are given in pregnancy for relatively tran
sient problems. Drug treatment is rarely if ever needed
for those conditions commonly related to pregnancy.
Health workers and pregnant women need informa
tion about non-drug solutions instead of drugs.
Common complaints such as heartburn, indigestion
and constipation are best treated simply. Diet changes,
fresh air or sleep are the safest remedies.68 Changes in
dietary habits or simple antacid preparations are
recommended for stomach problems, while fluid or
roughage is best for constipation. Preparations which
stimulate bowel activity may also stimulate uterine
contraction and are contraindicated in pregnancy.69
Morning sickness occurs in about 50% of pregnan
cies during the first three months - a time that
coincides with the maximum risk for teratogenic
effects.70 Antihistamines are frequently prescribed or
recommended, even though there have been some
concerns expressed about teratogenic risk.71
However, according to the British National
Formulary, “nausea in the first trimester of
pregnancy does not require drug therapy”.72
Circulatory and renal changes during pregnancy can
often create hypertension. However, drug treatment is
not necessarily the best way to deal with pregnancyinduced hypertension. Bed rest and dietary measures
are often sufficient. Underlying or "essential” hyper
tension that was present before pregnancy has been
treated with a wide variety of drugs: sedatives,
hypotensives, diuretics, heparin or anticonvulsants.
The preferred drug has usually been methyldopa. ’
Women who are already suffering from hypertension
and are using an ACE-inhibitor when they become
pregnant should be switched to a different antihyper
tensive because of reports of fetal death when
ACE-inhibitors are used in later pregnancy. 4
Iron and vitamin supplements
Vitamins and minerals, particularly iron, are regu
larly prescribed or taken during pregnancy. Often
they are taken in the belief that because they are
“natural” substances, they are harmless. However,
that is not the case. For example, vitamin A and its
analogues have long been known to be teratogenic in
animals.75 An overdose of iron can be “extremely
dangerous” and can lead to dangerously lowered
blood pressure, and congestive heart failure.76 A
leading guide to women's health makes the point that
“taking large doses of vitamins is not wise in preg
nancy. Vitamins are active chemical agents and
should only be taken to make up a definite defi
ciency.” There is no evidence to suggest that the
routine administration of vitamins to generally
healthy pregnant women offers any advantage what
soever.8 As the AMA points out:
“The routine prescription of multivitamin
and mineral supplements for pregnant
and lactating women is common but
generally unnecessary. A well balanced diet
designed to meet the needs of pregnant and
lactating women minimises the need for
supplementation.”79
One controversial subject is the question of the “need”
for iron supplementation in pregnant women. Most
pregnant women have lower iron levels in the blood,
so it has been assumed that supplementation is neces
sary. However, the reduction in iron levels is a natural
process in pregnancy because the mother’s blood vol
ume is increased in order to supply the growing baby.
The human body also has large reserves of iron in the
liver and bone marrow and during pregnancy these
stores are drawn upon.
There is no evidence that prophylactic treatment
with iron in pregnancy has any significant effect on
the health of either mother or child. In fact, iron sup
plements may do more damage than good. Iron
preparations often cause gastrointestinal distur
bances. They are reported to be the commonest
causes of vomiting in pregnancy. They can also cause
either constipation or diarrhoea which frequently
lead women to stop taking them. Prophylactic oral
iron is unnecessary for the majority of healthy preg
nant women in an industrialised country. The daily
7 A .
dietary intake of iron is usually sufficient to maintain
sufficient iron stores in all but a tiny percentage - per
haps as low as 2% - of women in most industrialised
countries. It is only women who are already anaemic
or have depleted iron stores at the start of pregnancy
- perhaps due to chronic nutritional deficiency, heavy
menstrual blood loss, or repeated pregnancies - who
need routine iron supplements.80
However, the situation differs in developing coun
tries. The World Health Organization (WHO)
estimates that more than 700 million people suffer
from iron-deficiency anaemia worldwide. It sug
gests that all pregnant women in developing
countries should receive iron supplements during
the last four to five months of pregnancy.81 Iron
supplementation, however, is a curative approach.
Efforts to improve general nutrition and ensure that
people have access to an affordable supply of food
which meets all their nutritional needs are more
important.82
Folate (folic acid) deficiency - the second most
important cause of anaemia during pregnancy after
iron deficiency - is frequent in developing coun
tries. Research shows that folate supplementation is
effective in improving pregnancy outcomes in
developing countries or in populations whose
socio-economic status is low.83 Folic acid supple
mentation may benefit both mother and baby. A
deficiency of folic acid can lead to a severe form of
anaemia (megaloblastic anaemia) in women and
can cause congenital abnormalities in the fetus such
as spina bifida and other failures of the neural tube
- the tissue structure from which the brain and
spinal cord develop - to close properly. Identifying
women at risk and ensuring they begin folic acid
supplementation before pregnancy has successfully
reduced the incidence of neural tube defects.84 This
is now recommended practice in the USA and the
UK. In both countries, it is also recommended that
all women receive a small amount (0.4mg) of folic
acid supplement daily before and during the first 12
weeks of pregnancy.85
Although there may be cases where both iron and
folic acid are required, there is little justification for
using combination preparations, and certainly no
justification for iron together with multivitamins.
Goodman and Gilman’s textbook on pharmacology
points out that
“it is particularly undesirable to use [iron]
preparations that contain other compounds
with therapeutic actions of their own, such
as vitamin B12, folate, or cobalt, since the
patient’s response to the combination cannot
be easily interpreted. Despite the straight
forward nature of therapy with iron, it is
discouraging to see the frequency with which
expensive preparations with worthless
additives are prescribed.
Drugs
in
pregnancy
Prescribing in pregnancy
The editor of one leading book on drug use in
pregnancy, Dr D.F. Hawkins, a consultant obstetrician,
gynaecologist, and pharmacologist suggests four
basic rules for prescribers.
1. Review all patients with medical disorders before
they conceive, regarding every woman of
reproductive age as a potential antenatal patient,
and encouraging them to attend for counselling
before planning a pregnancy.
2. Question the real need for any drug in pregnancy,
giving due consideration to alternative methods of
treatment.
3. Review all drug regimens in pregnancy to see how
careful therapeutics and good control can
minimise risks.
4. Use medicines that have been widely employed in
pregnancy for years in preference to the latest
drugs.
Source: Hawkins, D F. (ed.). Drugs and Pregnancy. London. Churchill
Livingstone, (2nd edn) 1987
Complications in pregnancy or labour
For pregnancy complications, only drugs with
proven efficacy in improving survival rates and/or
the health of the baby or mother should be used.
During labour and delivery, the routine use of drugs
should be discouraged and interventions that
increase the need for drugs to reduce pain should be
avoided unless there is proof of effectiveness in
improving survival rates and health.
Diethylstilboestro! (DES), a synthetic oestrogen, was
first used to prevent miscarriage but was found to be
ineffective and unsafe. However, DES became widely
used with tragic results. Daughters of women who
used DES during pregnancy may develop a rare form
of vaginal and cervical cancer at a young age. This
occurs in between one in 1000 to one in 10,000
women exposed prenatally. DES has also caused mal
formations of the reproductive organs in women
and, to a lesser extent, in men exposed before birth.
Experts now agree that there is no indication for the
use of DES or any oestrogen in pregnancy.8'
Oestrogens can cause masculinisation of the female
fetus if given over a long period during pregnancy
and, rarely, feminisation of the male fetus.
Even Sir Charles Dodds, the inventor of DES, was cau
tious about the use of hormones in women because
their reproductive cycle was “far too delicate a
mechanism to bombard with exotic, powerful, foreign
chemicals”.88
134
7 A .
Drugs
in
pregnancy
Problem Di
Ritodrine: a risk to mothers?
In July 1992, a 20yearold pregnant woman,
Deborah Coram, died when a drug used to inhibit
premature labour, ritodrine (Yutopar), was
incorrectly mixed by hospital staff in Chatham. UK.
The cause of death was attributed to a chest
infection that result from the side effects of the
drug. The drug was mixed in a saline solution rather
than the dextrose solution recommended by the
manufacturer. None of the doctors questioned at a
coroner's inquest knew of the drug’s adverse
effects if it was wrongly mixed. This is not
surprising, as neither the Data Sheet Compendium
nor the British National Formulary provide a warning
against the use of a saline mix. The Data Sheet
Compendium does indeed recommend a dextrose
solution, but the manufacturer. Duphar, has now
issued new guidelines banning the use of saline
solutions with the drug.1
The US FDA’s fertility and maternal health drugs
advisory committee reviewed ritodrine in October
1992. It concluded that the injectable form is
effective in improving the course of preterm labour,
but that oral ritodrine "is not effective in maintaining
remission of preterm labour at the current
recommended doses” and "does not have a place in
obstetric medicine at its current dosage levels”.2
This is expected to have considerable impact on the
billion dollar market for the drug in the USA, where
an estimated 100,000 women a year use ritodrine.3
A paper published in July 1992 in the New England
Journal of Medicine reported on a double blind trial
of ritodrine in Canada which found that ritodrine
had "no beneficial effect on fetal or neonatal
mortality, or on the incidence of pre term delivery".
An editorial in the same issue of the Journal drew
attention to the 95 reports of fluid in the lungs
(pulmonary oedema) in the USA since ritodrine’s
approval in 1980, and the association of the drug
with unusual heart rhythms. At least 14 maternal
deaths have been recorded. Because of these
"substantial maternal risks” and the "vanishingly
small neonatal benefits”, the editorial called for a
reappraisal of ritodrine.4
Sources:
1.
Anon., “Drug mixing error is blamed for pregnant woman's
death", Guardian. 22 Dec 1992, p3 (See also: ABPI, ABPI Data Sheet
Compendium 1988-89, London, Datapharm Publications, 1988,
pp449-50; BMA and the Royal Pharmaceutical Society of Great
Britain, British National Formulary, London, BMA and The
Pharmaceutical Press, No 23, Mar 1992; pp279 and 520)
2.
Anon., “FDA committee reviews Astra’s ritodrine", Scrip,
No 1769, 10 Nov 1992, p27
3.
Anon., “Labour drug ritodrine proves ineffective", New Straits
Times (Malaysia), 4 Aug 1992, p31 (based on a New York Times
report)
4.
Anon., “Ritodrine’s nsk/benefit in preterm labour questioned".
Scrip, No 1744, 14 Aug 1992, p20
yutopar
Ritodrine (Yutopar), advertised
in Pakistan in 1988 as having
“proven efficacy and safety",
with “minor side effects"
7 A .
|See the section on DES for further information.!
Progestogens - such as ethisterone, norethisterone,
and methyltestosterone - may cause congenital
defects and have virilising effects if taken in early
pregnancy. These drugs have been used to treat
threatened or habitual abortion, but their efficacy is
doubtful, and such use is not recommended.90
Oestrogens and progestogens, when used in low
doses, as in the contraceptive pill, have been associated
with fetal damage. The VACTERL (vertebral, anal,
cardiac, tracheal, oesophageal, renal and limb malfor
mations) syndrome of defects has been reported due to
exposure to sex steroids during pregnancy. However,
it is thought that the risk is small.91
One danger of any hormone treatment is that it can
actually mask the onset of pregnancy, so that the
woman is inadvertently put at extra risk by continu
ing the treatment. Unfortunately, many high-dose
ocstrogen-progestogen (EP) drugs are still sold in
developing countries without sufficient warning of
their dangers. Too often, these products are misused
in attempts to provoke an abortion. This is particu
larly a problem where safe, low-cost legal abortion is
not available. While regulatory and educational
efforts are necessary to control availability and mis
use of ineffective abortifacients, removing the
demand by ensuring access to legal abortions is more
likely to have the greatest effect.
[See the section on EP Drugs for further informa
tion.]
Avoiding unnecessary drug use
Overall, caution with drugs during pregnancy must
be stressed. According to the .British National
Formulary:
“No drug is safe beyond all doubt in early
pregnancy.... Drugs should be prescribed in
pregnancy only if the expected benefit to the
mother is thought to be greater than the risk
to the fetus, and all drugs should be avoided
if possible during the first trimester."92
Unfortunately drug consumption in pregnancy is
often needlessly and alarmingly high, exposing the
fetus to risks of malformations or developmental
problems.
in
pregnancy
Recommendations for action
1. Health authorities should develop information
for women on drugs in common use during
pregnancy, and on non-drug solutions for
common health problems experienced during
pregnancy.
2. Similar information should be prepared for
prescribers and dispensers of drugs, along with
notices to be prominently displayed to remind
about the need for caution in pregnancy.
3. There should be international implementation
of uniform categories for labelling drugs that
clearly identify relative risks in pregnancy.
4. A clear, understandable and universally
recognised graphic symbol illustrating that the
product should not be used in pregnancy should
be developed and placed on all prescription and
over-the-counter drugs whose safety in
pregnancy has not been verified.
135
Problem Drugs
The tragedy with DES is “an example of what has
happened and can happen unless we are vigilant”.89
It also highlights the difficulty in assessing the
adverse effects of drug use during pregnancy. Babies
exposed to DES were fine and healthy at birth. The
effects only became evident after puberty. The initial
invisibility of these effects reinforces the need to
avoid the unnecessary use of drugs in pregnancy.
Drugs
7 A .
Drugs
in
pregnancy
Problem Drugs
References:
i.
2.
3.
4.
Anon., “Acne, Accutane, abortions and life-threatening birth defects”, Health
Letter, 12 May 1988
Lynch, CM., Sinnott, J.V., et al, “Use of antibiotics during pregnancy”,
American Family Physician, Vol 43, No 4, Apr 1991, 991365-8
Niebyl, J.R., “Drugs and related areas in pregnancy”, Zent.bl. Gynakol.,
Vol 113,1991. PP375-SS
Laurence, D.R. and Bennett. P.N., Clinical Pharmacology, London, Churchill
Livingstone, (6th edn). 1987, pSs
9.
AMA, Drug Evaluations, Philadelphia, W.B. Saunders Co., (6th edn) 1986,
PP41-5O
Martinez-Frias, M.L and Salvador, J., “Megadose vitamin A and
teratogenicity”. Lancet, No 8579, 30 Jan 1988, 9236
Gilman, A.G., Rail, T.W., Nies, A.S., and Taylor, P., Goodman and Gilman’s
The Pharmacological Basis of Therapeutics, New York, Pergamon Press, (8th
edn) 1990, pi3
Collaborative Group on Drug Use in Pregnancy, “Medication during
pregnancy: an intercontinental cooperative study", International loumal of
Gynecology and Obstetrics, Vol 39,1992, PP185-96
Rubin. P.C (ed.), Prescribing in Pregnancy, London, British Medical journal,
10.
1987, pi
Whittle, M.|. and Hanretty, K.P., "Identifying abnormalities”, in: Rubin, op cit,
5.
6.
7.
8.
pp8-i8
de long-van den Berg, L.T.W., van den Berg, P.B., et al, “Investigating drug
use in pregnancy: methodological problems and perspectives”,
Pharmaceutisch Weekblad Scientific Edition, Vol 13, No 1,1991, PP32 -8
12.
Fugh-Berman, A., “On the FDA’s recommendations for the use of isotretinoin",
The Drug Monitor (Philippines), Vol V, No 10, Oct 1990, ppi27-8
13.
Collier, J., The Health Conspiracy, London, Century Hutchinson, 1989, 915
14.
Mitchell, AA, “Oral retinoids: what should the prescriber know about their
teratogenic hazards among women of child-bearing potential?”, Drug Safety,
Vol 7, No 2,1992, 9979-85
15.
Ledward, R.5., “Antimicrobial drugs in pregnancy", in: Hawkins, D.F. (ed.), Drugs
and Pregnancy, London, Churchill Livingstone, (2nd edn) 1987,99148-65
16.
Camera, G. and Pregliasco, P., “Ear malformation in baby bom to mother
using tretinoin cream", Lancet, Vol 339,14 Mar 1992, 9687
17.
AMA, 09 cit, 942
18.
Parish, P., Medicines: a guide for everybody, London, Penguin (6th edn,
revised), 1989,9933-4
19.
Henry, J, (ed.), The British Medical Association Guide to Medicines & Drugs,
11.
London, Dorling Kindersley, (2nd edn) 1991, 920
Pansh, 09 cit, 934
Lewis, P.j. and Hurden, E.L, “Breast feeding and drug treatment", in:
Hawkins, D.F. (ed.), Drugs and Pregnancy, London, Churchill Livingstone, (2nd
edn) 1987,99304-32
22.
BMA and the Royal Pharmaceutical Society of Great Britain, British National
Formulary, BMA and the Pharmaceutical Press, No 23, Mar 1992,99517-21
23.
Khanna, J., van Look, P.FA, and Griffin, P.D. (eds), Reproductive Health: a Key
to a Brighter Future, Geneva, WHO, 1992, 9104
24.
Jacobson, J.L, “Improving women’s reproductive health", chapter 6 in: Brown,
L.R., Brough, H„ et al. State of The World 1992, London, Earthscan, 1992,
20.
21.
PP83-99
Adashi, E.Y., Rock J A, Sapp, K.C et al, “Gestational outcome of clomiphenerelated conceptions”, Fertility and Sterility Vol 31,1979, pp62O-626, cited In:
Jong-v.d, Berg, L.T.W., Cornel, M.C, van den Berg, P.B., et al “Ovulation
inducing drugs: a drug utilization and risk study in the Dutch population."
International journal of Risk and Safety in Medicine, Vol 3,1992, 9107
26.
Henry, J. (ed.), The British Medical Association Guide to Medicines & Drugs,
London, Dorling Kindersley, (2nd edn) 1991, 9160
27.
Phillips, et al, op cit, 9429
28.
Gilman, A.G., Rail, T.W., Nies, A.S., and Taylor, P., op cit, 91397
29.
jong-v.d. Berg et al, 1992, op cit, pioo
30.
Rowland, Rl, Living Laboratories: Women and reproductive technology,
25.
31.
London, Lime Tree/Octopus, 1992, PP50-1.
Howden, GW., “Treatment of common minor ailments" in- Rubin, op cit,
ppi9-25
Werier, M.M., Mitchell, AA and Shapiro, S., "The relation of aspirin use
during the first trimester of pregnancy to congenital cardiac defects”, New
England Journal of Medicine, Vol 321, No 24,14 Dec 1989, 991639-42
33.
Australian Drug Evaluation Committee, Medicines in Pregnancy, Canberra,
Australian Government Publishing Service, 1989, p6
32.
34.
35.
Howden, op cit, 9919-25
See for example: Eider, M.G., de Swiet, M., et al, “Low-dose aspirin in
pregnancy", Lancet, No 8582, 20 Feb 1988, 9410; Schiff, E„ Peleg, E„ et al,
“The use of aspirin to prevent pregnancy-induced hypertension and lower the
ratio of thromboxane A2 to Prostacyclin in relatively high-risk pregnancies”,
New England Journal of Medicine, Vol 321, No 6,10 Aug 1989, PP351-6;
Cunningham, EG. and Gant, N.E, “Prevention of preeclampsia - a reality?",
New England Journal of Medicine, Vol 321, No 9,31 Aug 1989, pp6o6-7;
Werier, et al, op cit, PP1639-42; Uzan, S., Beaufils, M., et al, “Prevention of
fetal growth retardation with low-dose aspirin: findings of the EPREDA trial",
Lancet, Vol 337,15 Jun 1991, 991427-31; Anon., "Aspirin beneficial in
36.
pregnancy”, Scrip, No 1637, 26 Jul 1991, 927
Anon., “US FDA tightens aspirin warning”, Scrip, No 1530,11 July 1990, pzz
37.
38.
Uzan, et al, op cit, ppiz-27-31
BMA and the Royal Pharmaceutical Society of Great Britain, op cit, P176
39.
40.
41.
Hawkins, op cit, P79
Anon., “Drug use in pregnancy", The Prescriber, No 1, Jan 1992, P7
Moise, K.J., Huhta, J.C, et al, “Indomethacin in the treatment of premature
labor”, New England Journal of Medicine, Vol 319, No 6,11 Aug 1988, 99327-31
42.
Lewis, J.H., “Drug hepatotoxicity in pregnancy", European Journal of
Gastroenterology and Hepatology, Vol 3, No 12,1991, 99883-91
43.
44.
45.
46.
47.
48.
49.
Ledward, op cit, 99148 65
Lynch, et al, op cit, 991365-8
Ledward, op cit, 9155
Lynch, et al, op cit, 991365-8
Rubin, op cit, 938
Ledward, op cit, 99148-65
Collignon, R, Heihir, J. and Mitchell. D., “Successful treatment of falciparum
malaria in pregnancy with mefloquine”, Lancet, No 8644, 29 Apr 1989,9967
50.
51.
52.
Anon., The Prescriber, op cit, p8
Hawkins, op cit, ppioo-i and 105
Chetley, A., Peddling Placebos: an analysis of cough and cold remedies,
53.
Amsterdam, HAI, 1989
MIMS Africa, Vol 31, No 4, July 1991, pm; MIMS Caribbean, Vol 21, No 1,
54.
55.
Jan 1991, 962
Loudon, J B., “Psychotropic drugs", in: Rubin, op cit, PP49’57
Palmer, P.G., “Sedatives and anticonvulsants in pregnancy", in: Hawkins,
56.
57.
58.
59.
60.
61.
62.
op cit, 99128-147
Niebyl, op cit, 99375-88
Palmer, op cit, 99128-147
Anon., The Prescriber, op cit, pio
AMA, op cit, 990
Palmer, op cit, 99128-147
Sidhu, R.K., “Corticosteroids in pregnancy” in: Hawkins, op cit, 99166-79
Anon., “Asthma, progesterone, and pregnancy". Lancet, Vol 335, 27 Jan 1990,
9204
63.
Jones, K.L., Lacro, R.V., et al, “Pattern of malformations in the children of
women treated with carbamazepine during pregnancy", New England Journal
64.
of Medicine, Vol 320, No 25, 22 June 1989, ppi66i-6
Brodie, M.J., “Management of epilepsy during pregnancy and lactation",
65.
Lancet, Vol 336,18 Aug 1990, PP426-7
Anon., "Teratogenesis with carbamazepine”. Lancet, Vol 337,1 Jun 1991,
PP1316-17
Piacquadio, K., Hollingsworth, D.R. and Murphy, H., “Effects of in-utero
exposure to oral hypoglycaemic drugs", Lancet, Vol 338,5 Oct 1991, 99866-9
67.
Hawkins, op cit, ppioo-i and 105
68.
Phillips, A., Rakusen, J. (eds) and the Boston Women's Health Collective,
The New Our Bodies, Ourselves (2nd UK edition), London, Penguin Books,
66.
1989. P347
Howden, op cit, 9919-25
Jackson, D.M. and Soothill, R„ Is the Medicine Making You III?, North Ryde,
Australia, Angus & Robertson, 1989, pioo
71.
Howden, op cit, 9919-25
72.
BMA and the Royal Pharmaceutical Society of Great Britain, op cit, 9162
69.
70.
73.
74.
Hawkins, op cit, P105
Anon., “FDA tightens warning on ACE-inhibitors", Scrip, No 1702, 20 Mar
1992, P20
75.
Weber, J.C.P., "Limitations of a voluntary reporting system", in: Hawkins, op
cit, PP37-47
76.
Henry, op cit, P409
77.
Phillips, and Rakusen, op cit, 9347
78.
Hawkins, op cit, 967
79.
AMA, op cit, 99843-4
80.
Hawkins, op cit, pp64-6
81.
Anon., “Preventing iron-deficiency anaemia”, Lancet, No 8673,18 Nov 1989,
P1231
Ramalmgaswami, V, "Challenges and opportunities - one vitamin, two
minerals", World Health Forum, Vol 13, No 2/3,1992, 99222-31
83.
Larroque, B., Kaminski, M., et al, “Folate status during pregnancy:
relationship with alcohol consumption, other maternal risk factors and
pregnancy outcome", European journal of Obstetrics and Gynecology and
Reproductive Biology, Vol 43,1991, 9919-27
84.
Hobbins, J.C, "Diagnosis and management of neural-tube defects today",
New England Journal of Medicine, Vol 324, No 10, 7 Mar 1991, 99690-1
85.
Anon., "UK folic acid supplementation", Lancet, Vol 341, 2 Jan 1993, 946
86.
Gilman, et al, op cit, P1290
87.
AMA, op cit, P701
88.
WHO, Drugs in Pregnancy and Delivery, Copenhagen, Dec 1984, 953
89.
Cody, P., “A history of the DES action movement”, in: Mintzes, B. (ed.), DES: A
Drug with Consequences for Current Health Policy, Utrecht, DES Action The
Netherlands, 1990, ppio-12
90.
Gilman, et al, op cit, 91401
91.
AMA, op cit, 9727
92.
BMA and the Royal Pharmaceutical Society of Great Britain, op cit, 9499
82.
Chetley, A. Problem Drugs, Amsterdam,
Health Action International, 1993
Health Action International’s
coordinating offices:
HAI Europe
Jacob van Lennepkade 334T
1053 NJ Amsterdam
The Netherlands
7B. DES
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accion para la Salud
Avda. Palermo 531
Dpto. 104
Lima 13
Peru
The 0m@ bomb opfodtes
“Take a brand new drug. Then, based primarily on theory,
manufacture it and prescribe it to millions of patients for
over 30 years. Stop only when it is shown beyond doubt to
cause cancer.
With those three sentences, Cynthia Laitman,2 a
mother who took the drug in question-DES (diethyl
stilbestrol) - describes a product that has been called
everything from “a medical nightmare”3 to a “toxic
time bomb”.4 The “nightmare” was the range of side
effects that have been found in daughters, sons and
mothers exposed to DES during pregnancy. The “time
bomb” refers to the long gestation period for these
effects to emerge, and the indications that the effects
may even stretch into a third generation.
DES is a synthetic oestrogen, first developed by Sir
Edward Charles Dodds in 1938. Three times more
potent than the natural oestrogen, oestradiol, DES
was soluble in water and effective when taken orally,
whereas the natural hormone had to be injected.
Because DES was never patented, in no time at all
several manufacturers had the drug on the market. In
the USA alone, 267 pharmaceutical companies were
eventually granted licences to manufacture and sell
DES.5 Table 7B-1, on page 140, gives an indication
of some of the brand names under which DES and
related oestrogens have been sold around the world.
No one was sure what DES could be used for. It was
tried in many clinical conditions including amenorrhoea (absence of menstrual bleeding), dysmenorrhoea
(painful menstruation), senile vaginitis and the sup
pression of unwanted lactation. However, a leading use
for DES soon became the prevention of miscarriage.
This use was widely accepted, not on the basis of
therapeutic evaluation, but on the strength of what the
World Health Organization (WHO) calls “an assertive
deduction”.6 The main impetus for this came from
research carried out by Drs George and Olive Smith
between 1938 and 1948. They were working on the
theory that habitual abortion was caused by a lack of
progesterone and that giving oestrogen would stimu
late the production of progesterone. On the basis of a
poorly designed trial of 632 pregnant women, the
Smiths claimed in a 1948 article in the American
Journal of Obstetrics and Gynecology that administer
ing DES could increase the chance of a successful
pregnancy in women who had had previous miscar
riages or suffered from high blood pressure, and that
the risk of premature deliveries would be reduced.7
Between 1948 and 1971, DES was given to some two
to three million pregnant women in the USA alone,
thereby exposing between two to three million of their
children to the effects of the drug.8 The Canadian
health authority estimates that some 400,000 children
could have been exposed.9 In Europe an estimated
four million women may have used DES while preg
nant.10 In the Netherlands, between 180,000 and
380,000 women were treated with DES while preg
nant. In France, an estimated 200,000 pregnant
women and their children were exposed to DES.11
Extravagant promotion of the drug helped ensure its
widespread use throughout North America, Europe,
Latin America, Africa, the Middle East and Asia. For
example, a 1957 advertisement in the American
Journal of Obstetrics and Gynecology by the GrantChemical Company claimed its DesPlex brand was
able “to prevent abortion, miscarriage and prema
ture labor” and recommended the drug “for routine
137
138 7 B .
DES
Problem Drugs
prophylaxis in ALL pregnancies" with “no gastric or
other side effects".
Ineffective and unsafe
However; DES was ineffective. A double blind, placebo
controlled study of 1,600 women published in 1953
showed clearly that DES did not reduce the incidence
of abortion, prematurity or postmaturity.12 Sadly, the
study failed to report the important point that DES
“significantly increased abortions, neonatal deaths and
premature births”13 - a conclusion that could, and
should, have been made from the data in rhe study.
Not only was DES ineffective, but it was also unsafe.
In the late 1930s and early 1940s, animal research
showed that DES and other oestrogens could cause
cancer.1'1 The link between the use of DES and the
development of cancer in humans was made in 1971.
Researchers found a rare form of vaginal and cervical
cancer (clear cell adenocarcinoma) in daughters of
women who had taken DES early in pregnancy. The
US Food and Drug Administration (FDA) quickly
withdrew approval for DES use in pregnancy.15
Other countries reacted more slowly. Austria with
drew all products containing diethylstilbestrol,
dienestrol, hexestrol and their derivatives in 1977;
Italy withdrew dierhylstilbesrrol;
and in 1980, Kuwait banned the
import of products containing
ost of us who
DES
or diethylstilbestrol diphos
are DESphate. Germany and Greece have
exposed can
restricted the indication for use of
remember exactly when
DES to the treatment of prostate
we first learned about
cancer; Saudi Arabia and Tunisia
DES. I was reading my
have prohibited the use of DES in
morning paper one April
pregnancy.16 France banned the
day in 1971 when I saw
use of DES in pregnancy in 1977.
the headline "Drug
The Netherlands made rhe deci
sion to ban use in pregnancy in
Passes Rare Cancer to
1972, although it took another
Daughters’. The minute 1
three years before the ban was put
read the story 1 was
into effect and the indication “for
clutched with fear. There
use in cases of risk of miscarriage”
was no doubt this was
disappeared off the label.17
Yes...
Lprevent
oeABORTION,
> jt.
MISCARf'AGE anil
PREMATURE LABOR
1 ded for
recommcn'
in ML M^nanC’e’-de5PUX
96 Pcr
liv. <W«O
H of 1200
’"“nd T.rens.
- bigg"
Ho gastric or
other side effects
iiher high of
with desPit*
low do»t>9e
with 25 mg.
ielhylslilbejlrof, U.S.P..
imooth and accelerate absorption and
desPlEX tablet
»’<” ullramicronlied dielhylililbcifrol i
n of this
oc"vl,V
«he lobio’ coaling "■ • . prompt help in emergencies
It oho conloin vitamin C ond certain mombeu of the
id detoxification
ond the effectua-
dcsPLEX »oble”
vitamin »
.
f°'
REFrRENCE--
GR1BT
■am «»■*
1457
abnormalities of the cervix and vagina and carci
noma in situ.20
Fortunately, clear cell adenocarci
noma is rare, occurring in only
seven months during my
one in 1,000 to one in 10,000
pregnancy.”
exposed daughters.18 But it
mainly affects women in their
•• Pat Cody, co founder of DES
Action USA
early twenties and it is not a can
cer that was previously seen in
women of this age. As a result, it has been described
as “fundamentally a new iatrogenic (medically
induced) disease”.19 The treatment involves exten
sive and mutilating surgery or radiation therapy.
At least two-thirds of DES daughters have adenosis, a
condition in which mucus-producing cells normally
found inside the cervical canal are also present on the
surface of the cervix and vagina. Adenosis can cause a
more abundant vaginal discharge. This condition is
harmless, naturally regresses over time, and does not
require any medical treatment. Structural defects of
the cervix, vagina, uterus and fallopian tubes have
been found in more than 40% of DES daughters,21
with one study putting the figure at two-thirds of
exposed daughters.22 DES daughters are more likely
to be infertile than other women. Further, DES daugh
ters have a much increased risk of a number of
adverse pregnancy outcomes. Compared with non
exposed women, DES daughters have four times the
risk of miscarriage and pre-term labour.23 Ectopic
pregnancy - which can be a life-threatening condition
- occurs in 4-8% of pregnancies in DES daughters24
In addition, DES daughters are about twice as likely
as unexposed women to develop pre-cancerous
All DES daughters need special gynaecological exami
nations annually. They should be performed by a
me; I remembered well
four times a day for
'
obit “
M
taking those little pills
"i
7 B .
In December 1990 in MIMS Middle East and July
1991 in MIMS Africa the listing for Norgine’s
Tampovagan (stilboestrol) indicates the product for
vaginal irritation including if it is caused by the
menopause, a common and minor health complaint
for which a form of DES should not be used. The
British National Formulary describes Tampovagan
as “less suitable for prescribing”.36
The use of DES or other oestrogens as a “morningafter pill has risks for the fetus if the woman is
pregnant and the pill does not work. The Physicians'
Desk Reference in the USA carries the clear message,
approved by the US FDA, that DES “should not be
used as a postcoital contraceptive”.37
Even the use of oestrogens such as DES in the pallia
tive treatment of breast and prostate cancers (the
only indications for DES in rhe UK or in the USA) is
being questioned. The British Medical Association
notes that “side effects are common with the drug,
and it is because of these potential risks that it is now
less widely used.”38
No matter what the indication for the product, in
many developing countries, products containing
DES are available without a prescription, not just
over the counter, but in street markets. The mere
availability of the product prolongs the unnecessary
risk to women and their children.
DES in animals
Another use for DES and related oestrogens has been
in animals as growth stimulants. Unlike natural
steroids, they are not readily destroyed in the liver
and residues remain in meat products. According to
WHO,
“the continuing accumulation of evidence
that diethylstilbestrol is a potential carcino
gen in man and the discovery of undesirably
high levels of diethylstilbestrol in some baby
foods within the past few years, provides
strong endorsement of the decision already
taken in many countries to ban the use of all
stilbenes as growth promoting agents.”39
DES has been banned for both human and veterinary
use in the Philippines.40 The European Community
adopted a directive in 1981 which banned the use of
DES and other stilbenes in animals.41 Originally
banned for use in animals in rhe USA in 1972, an
appeal court decision overturned the ban in 1974 and
it was not until 1979 that the US FDA again banned
Lawsuits seek compensation
More than 1,000 lawsuits have been filed in the USA
in an attempt to gain compensation for the victims of
DES. Because of the large number of manufacturers
and the time lag between taking the drug and its
effects becoming evident, it has often been difficult
for women to identify the precise brand of DES that
they or their mothers took. This meant that in many of
the early cases, the women were not able to identify
the individual manufacturer, and therefore lost. In
1980, however, the California Supreme Court ruled
that women should be able to sue the companies as a
group and that if the suit was successful, companies
should pay compensation according to the market
share each company had at the time the drug was
used. Other legal arguments have been accepted by
different courts in the USA, including alternative
liability, concert of action, enterprise liability, and risk
contribution.
The Dutch Supreme Court took a different approach
in a case brought by six DES daughters against the 10
companies known to have sold DES in the
Netherlands. The case began in 1986 and the district
court and appeal court both found against the
daughters on the grounds that they were unable to
cite the company that produced the DES pills that
their mothers had taken. The Supreme Court decided
in October 1992 that such a burden of proof was
unacceptable, and ruled that every manufacturer
should be equally and fully liable for damages,
regardless of their market share at the time. This
decision has opened the door for the case to return to
the appeal court to be judged on grounds of
negligence, foreseeability and causation.
Sources: Anon., "Diethylstilboestrol - effects of exposure in utero".
Drug and Therapeutics Bulletin, Vol 29. No 13, 24 Jun 1991, pp49-50;
Cody. P , "A history of the DES action movement", in; Mintzes. B.
(ed.)_ DES: A Drug with Consequences for Current Health Policy, Utrecht,
DES Action The Netherlands, 1990, pplO-12; Dutton, D.B., Worse than
the disease: pitfalls of medical progress, New York, Cambridge
University Press, 1988, p262-5, Spanjer, M._ "Netherlands: Liability
for diethylstilboestrol damage", Lancet, Vol 340, 21 Nov 1992, pl280
the use of the drug as a growth promoter in cattle and
sheep.42 However, as late as February 1983, 1,500
cattle were found on several farms with recent residues
of DES in their system because of illegal use.43
“Risk without benefit”
Although DES was originally prescribed with the
hope of benefitting women who might have difficult
pregnancies, as one obstetrician/ gynaecologist puts
it, “DES presented risk without benefit”.44 There can
no longer be any excuse for extending that risk.
141
Problem Drugs
The October 1988 listing for Ethica’s Stilboestrol in
the Indonesia Index of Medical Specialities includes
inhibition of lactation as one of the indications for
the drug. Another indication is “amenorrhoea”.
Pregnancy is the most common cause of amenorrhoea.
DES
7 B .
It is not only DES daughters who are affected. Effects
on sons whose mothers used DES are not as clear.
This is mainly due to a lack of studies. One relatively
large study found no excess of urogenital anomalies
in exposed sons;26 however, other studies found an
increase in epididymal and testicular abnormalities
such as undescended testes, incomplete or defective
testicular development and low sperm counts.27
Mothers who took DES have a 1.5 times increased
risk of breast cancer and there is concern that an
increased risk of breast cancer may also emerge
among their daughters.28
According to one professor of obstetrics and
gynaecology,
“This whole thing could be a time bomb. 1
hesitate to use that word, but effects keep
popping up. First it was in the female in the
cervix, then in the female in the uterus and
the male in the Wolffian ducts, and who
knows in the future what may be in store.”29
Other uses?
Goodman and Gilman’s textbook on pharmacology
leaves no doubt: “the use of estrogens in pregnancy is
not indicated". It makes the point that “pregnant
patients should not be given estrogens, particularly
during the first trimester - a time when the fetal
reproductive tract is developing and may be influ
enced by exogenous estrogens”.30 Similarly, the
American Medical Association (AMA) is crystal
clear on this point:
“The administration of any estrogen is con
traindicated during pregnancy. The use of
synthetic hormones to treat threatened abor
tion is ineffective and carries the risk of
teratogenicity.”31
However, oestrogens, including DES, remain in use
for other indications such as suppression of lactation,
menopausal problems, as a postcoital (morning-after)
pill, and as therapy for some breast and prostate can
cer. There are dangers associated with these uses.
DES, as a known carcinogen, should not be used as a
morning after pill, lactation suppressant or for
menopause. There are also better alternatives for
breast and prostate cancer.
Goodman and Gilman note that the use of oestro
gens to relieve breast engorgement or suppress
lactation after delivery “has decreased in recent
years, since the incidence of painful engorgement is
DES Action groups
In 1974 Pat Cody, an American woman who had taken
DES during pregnancy, wrote to the national
Department of Health to ask what was being done to
notify the millions of women who had taken DES.
“We’re doing a study,” the Department of Health
responded. "We don’t want to alarm women.” Harriet
Simand, a Canadian who became aware of her DES
exposure when she developed cancer, was told that
"DES wasn’t really a problem in Canada, only in the
US”, when she tried to find out what had been done to
notify DES-exposed people in Canada.
Anita Direcks from the Netherlands spoke in 1990
about the continued lack of information and resources
for DES-exposed people in Europe, "In most European
countries, the national governments, the medical
profession, and the general public seem to be hardly
aware of the DES-problem in their countries. The
national authorities have forbidden the use of DES
during pregnancy, but have not informed the medical
profession nor the public of the consequences of
exposure to DES.”
In response to the view that DES is a mistake of the
past - best forgotten - exposed women have formed
DES Action groups in the USA in 1975, Australia in
1980, the Netherlands in 1981, Canada in 1982,
France in 1987, the UK in 1989, Ireland in 1990 and a
European network in 1988. In Italy and Germany,
women’s health organisations initiated national
campaigns on DES in 1988. Networks of women with
cancer from DES exposure have also been formed in
the US, the Netherlands and in Europe.
DES Action groups raise public awareness about DES
in order to reach and inform people who are as yet
unaware of their exposure. They provide information
and counselling for DES-exposed people and
information for the medical profession on appropriate
health care. They also provide support for litigation
and act as political pressure groups to ensure that the
problem of DES exposure is taken seriously by
national authorities and the medical profession.
Source: Mintzes, B. (ed.). DES: A Drug with Consequences lor Current Health Policy. Utrecht, DES Action The Netherlands. 1990, pp8, 10 and 31
139
Problem Drugs
gynaecologist who is familiar with DES-related
problems. Being a DES daughter may have implica
tions for contraceptive choices, treatment with fertility
drugs, and pregnancy. Some doctors advise great cau
tion with the use of fertility-related drugs and
hormonal contraceptives.25
DES
7 B .
DES
Problem Drugs
low and this condition is readily controlled with
analgesics.”32 According to the AMA, oestrogens
“have been used to prevent postpartum lacta
tion.... However, there is an increased risk of
thromboembolic phenomena [blood clots], and
rebound lactation often occurs after withdrawal of
medication.” As a result, other drugs are now rec
ommended in the rare instances when it might be
necessary to suppress lactation with drug ther
apy.33 “Physical methods of lactation suppression,
like breast binding, are associated with more pain
in the first week after delivery than pharmacologi
cal methods, but they appear to be more effective
in the longer term.”34 The US FDA withdrew the
indication of suppression of lactation for oestro
gens in 1978.35
Table 7B-1
Names under which DES and related oestrogens have been sold
Acestrol
Diethylstilbestrol
Laboestrm
Acro-Estrol
Dietilstilbestrol Digestil
Linguets
Agostilben
Discorvin
Agostilgen
Distilbene
Albestrol
Amperone
Ovextrol
Stilboefral
Stilboestroform
Pabalate
Stilboestrol
Makarol
Pabestrol
Stilbofollin
Domestrol
Manostilbeen
Palestrol
Stilbol(um)
Dyestrol
Menocrin
Palmestil
Stilboral
Menosteroid
Percutacrine
Stilbostrol
Antigestil
Enboestrol
Menostilbeen
Oestrogenique
Stilcap
Benzestrol
Estilbestrol
Meprane
Isocovesco
Stilestrate
Bio-des
Estilben
Mestilbol
Phenestrol
Stilkap
Bufon
Estilbin
Mestralon
Preostrin(a)
Stilnestrin
Protectona
Stilpalmitate
Estilbin MCO
Methallenestrol
Calmovarin
Estimon
Metrokin
Carnosirol
Estril
Metysil
Ragestrol
Stilrol
Chembestrol
Estrobene
Micrest
Remrumestrol 2
Stilronate
Chlorotrianisene
Estrofix
Microest
Restrol
Stilrone
Cicloestrina
Climazin
Estromenin
Microsest
Rumestrol 1
Stils
Estromon
Mikarol
Rumestrol 2
Synestrin
Climoterine
Estrosyn
Milestrol
Rymestrol
Clinestrol
Estrovena
Monomestrol
Sedestran
Synthoerin
Comestrol
Follidien
Neo-Foliculanpomada
Serral
Synthoestrin
Cyren
Fonatol
Neo Oestranol
Sexestrol
Synthofollin
New-Estanol
Sexocretin
Syntofollin
Ginoxol
Nomestrol
Sexogen
Grafestrol
Normavagin
Sibol
Tace
DAES
Gynben
Normestrol
Sintestrol
Tampovagan
Dawe’s Destrol
Gyneben
Novostilbestrol
Stibilium
Tylandril
Deb
Delvinal
Gynestogene
Novostilboestrol NSC-
Stibrol
Tylosterone
Gynopharm
3070
Stil
Stilbal
Vagestrol
Desma
H-Bestrol
Nulabort
Oekolp
Stilbarol
Vallestril
DesPlex
Hexestrol
Oestrodienolum
Stilbenol
Destrol
Hexoestrol
Oestrogen-Holzinger
Stilbest-Oral
Diastyl
Hi-Bestrol
Oestrogenin
Stilbestrina
Stilbestrol
Clinoestrol
Cyren A
Cyren B
DES
Stilphostrol
Diathylstilbostrol Dibestil
Holzinger
Oestrogenine
Dibestrol 2 Premix
Honvol
Oestrol Vetag
Stilbestronate
Dicorvin
Hormostilboral
Oestromenin
Stilbestrone
Dienestrol
Oestromensyl
Stilbestrosan
Dienoestrol
Idroestril
Oestromon
Stilbetan C
Di-erone
Implanetten
Opoginol
Stilbetin
Diestryl
Implantin
Orestol
Stilbilium
Diethylex
Iscovesco
Ostromenin
Stilbindon
Ovendosyn
Stilbinol
Diethylstilbenediol
Synestrol
Synoestrin
Willestrol
Sources: United Nations, Consolidated List of Products Whose Consumption and/or Sale Have Been Banned, Withdrawn, Severely Restricted or Not Approved by
Governments. 2nd issue, Doc No ST/ESA/192, New York, 1987, pp312-3; Wemos/HAI International Group on Women and Pharmaceuticals, "D.E.S.”, Women and
Pharmaceuticals (pack), Amsterdam, 1987, p4; Hardon, A. (ed.), Women and Pharmaceuticals Bulletin, Amsterdam, Wemos/HAI International Group on Women
and Pharmaceuticals, Nov 1990, p6; DES Action Canada, DES. The Wonder Drug You Should Wonder About, Montreal, no date; Somers, D.C, Diethylstilboestrol au
Bresil, unpub. thesis, Universite Pierre et Marie Curie, Paris, 1993, p58
142
7 B .
DES
Problem Drugs
Recommendations for action
1. DES should be banned both as a product for
humans and for use as growth stimulants in
animals raised for human consumption.
2. Governments should research the extent of the
problem and, where possible, attempt to trace all
DES-exposed people and provide them with full,
accurate information on the problems they could
face, and make appropriate health care available.
3. Health workers should be informed on how to
recognise the signs of DES exposure and monitor
and treat associated health problems.
4. Universities and health workers should
undertake further research into the effects that
DES may have on DES mothers, their children,
and their children's children (the so-called third
generation).
Notes and references:
Laitman, C. “DES on prescription: it’s time for Europe to act". Scientific
European, Oct 1990, pp27-9
2.
Cynthia Laitman is a biologist and writer and is the author of one of the first
books on DES - DES: the complete story, New York, St Martin's Press, 198k
3.
Brackbill, Y. and Berendes, H.W., "Dangers of diethylstilboestrol: Review of a
1.
4.
5.
6.
7.
8.
1953 paper. Lancet, 2 Sept 1978
Anon., “Diethylstiiboestrol - effects of exposure in utero”, Drug and
Therapeutics Bulletin, Vol 29, No 13, 24 Jun 1991, PP49-50
Laitman, op cit
WHO, Drug Information, Doc No PDT/DI/84.4, Geneva, Oct-Dec 1984, pp8-io
Smith, O.W., “Diethylstilbestrol in the prevention and treatment of
complications of pregnancy”, American /oumal of Obstetrics and Gynecology,
Vol 56,1948, pp82i-34
Stillman, R.J., "In utero exposure to diethylstilbestrol: adverse effects on the
reproductive tract and reproductive performance in male and female
offspring", American Journal of Obstetrics and Gynecology, Vol 142, No 7,1 Apr
1982, PP9O5-21
Martin, L, “The DES issue". Protect Yourself, Sep 1983, PP42-4
Cody, P., “A history of the DES action movement”, in: Mintzes, B. (ed.), DES:
A Drug with Consequences for Current Health Policy, Utrecht, DES Action The
Netherlands, 1990, ppio-12
n. von Eickstedt, K.-W., “Sex hormones and related compounds including
hormonal contraceptives”, in: Dukes, M.N.G. and Beeley, L., (eds), Side Effects
9.
10.
12.
13.
14.
15.
of Drugs Annual 14, Amsterdam, Elsevier, 1990, pp343-64
Dickmann, W.J., Davis, M.E., et al, "Does the administration of
diethylstilbestrol during pregnancy have therapeutic value?", American Journal
of Obstetrics and Gynecology, Vol 66,1953, ppio62-8i
Brackbill and Berendes, op cit
Geschickter, CT., “Mammary carcinoma in rat with metastasis Induced by
estrogen". Science, Vol 89,1939, P35; Shimkin, M.B., Grady, H.G.,
"Carcinogenic potency of stilbestrol and estrone in strain C3H mice", Journal of
the National Cancer Institutes, Vol 1,1940, P19
’t Hoen, E., “Diethylstilbestrol, the effects on the health of users and their
children", in: Hardon, A. (ed.), Women and Pharmaceuticals Bulletin,
Amsterdam, Wemos/HAI International Group on Women and Pharmaceuticals,
Nov 1990, PP5-7
United Nations, Consolidated List of Products Whose Consumption and/or Sale
Have Been Banned, Withdrawn, Severely Restricted or Not Approved by
Governments, 2nd issue, Doc No ST/ESA/192, New York, 1987, P38
17.
Direcks, A. and't Hoen, E., “DES: the crime continues" in McDonnell, K. (ed.),
Adverse Effects: Women and the Pharmaceutical Industry, Penang, IOCU, 1986,
16.
PP41-9
18.
Anon., “Diethylstiiboestrol - effects of exposure in utero", Drug and
19.
Therapeutics Bulletin, Vol 29, No 13, 24 Jun 1991, PP49'5O
Rakusen, J., “DES", in: Phillips, A., Rakusen, J. (eds) and the Boston Women’s
Health Collective, The New Our Bodies, Ourselves (2nd UK edition), London,
Penguin Books, 1989, P520
AMA, Drug Evaluations, Philadelphia, W.B. Saunders Co., (6th edn) 1986, P701
Anon., Drug and Therapeutics Bulletin, op cit, PP49-50
AMA, op cit, P701
Senekjian, E.K., Potkul, R.K., et al, "Infertility among daughters either exposed
or not-exposed to diethylbesteroi”, American Journal of Obstetrics and
Gynecology, Vol 158,1988, PP493-8; Barnes, A.B., Colton, T„ et al, "Fertility
and outcome of pregnancy in women exposed in utero to diethylstilbestrol”,
New England Journal of Medicine, Vol 302,1980, PP609-13; Stillman, op cit
24.
Kleiverda, G., "How can we provide appropriate care for DES-exposed
women?", in: Mintzes, op cit, ppiz^-iS
25.
Ibid
26.
Leary, F.J., Resseguie, L.J., et al, “Males exposed in utero to diethylstilbestrol",
Journal of the American Medical Association, Vol 252,1984, pp2984-9
27.
Gill, W.B., Schumacher, G.F.B., et al, “Assocation with diethylstilbestrol
exposure in utero with cryptorchidism, testicularhypoplasma and semen
abnormalities", Journal of Urology, Vol 122,1979, PP36-9; Gill, W.B.,
Schumacher, G.F.B., et al, “Male genital tract changes in humans following
intrauterine exposure to diethylstilbestrol", in: Herbst, A.L and Bern, HA
(eds), Developmental Effects of Diethylstilbestrol (DES) in Pregnancy, New
York, Thieme Stratton, 1981, PP103-19
28.
Anon., Drug and Therapeutics Bulletin, op cit
29.
Anon,, “Odd-shaped uteri mark daughters of DES women", Medical Tribune,
19 July 1977
30.
Gilman, A.G., Rail, T.W., Nies, A.S., and Taylor, P„ Goodman and Gilman’s The
Pharmacological Basis of Therapeutics, New York, Pergamon Press, (8th edn)
20.
21.
22.
23.
1990, PP1390 and 1393
AMA, op cit, P7O1
Gilman, et al, op cit, P1395
AMA, op cit, P699
Enkin, M., Keirse, M. and Chalmers, I., A Guide to Effective Care in Pregnancy
and Childbirth, Oxford, Oxford University Press, 1989, P336
35.
DES Task Force, Summary Report, DHEW Pub No (NIH) 79-1688, Washington,
Dept of Health, Education and Welfare, 21 Sep 1978, pi4
36.
BMA and the Royal Pharmaceutical Society of Great Britain, British National
Formulary, London, BMA and The Pharmaceutical Press, No 23, Mar 1992,
31.
32.
33.
34.
P280
Physicians' Desk Reference, Oradell, NJ, Medical Economics Company, 44th
edn, 1990, pizn
38.
Henry, J. (ed.), The British Medical Association Guide to Medicines & Drugs,
London, Doriing Kindersley, (2nd edn) 1991, P373
37.
39.
40.
41.
42.
43.
44.
WHO, op cit
Tan, M.L., Dying for Drugs: Pill power and politics in the Philippines, Manila,
Health Action Information Network, 1988, pio6
Jopling, M., “The growth factor”, The Guardian, 29 July 1986
Anon., “FDA bans DES in animals”, The Nation's Health, Aug 1979
Schell, 0., Modem Meat, New York, Random House, 1984, PP253-4
Stillman, op cit
Chetley, A. Problem Drugs, Amsterdam,
Health Action International, 1993
Yo/"' library
<
i'"
ano
1
7C. EP drugs
\
■
DOCUMENTATION
UNIT
f'GALOV
Health Action International’s
coordinating offices:
>
’l
}
HAI Europe
Jacob van Lennepkade 334T
1053 NJ Amsterdam
The Netherlands
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accion para la Salud
Avda. Palermo 531
Dpto. 104
Lima 13
Peru
A sordid, sorry tale
Salma suspected she was pregnant again. Her husband sug
gested that she go to a nearby maternity clinic in Karachi,
Pakistan. The doctor prescribed a course of oestrogen
progesterone (EP) tablets to test pregnancy and told her to
come back after five days. When she did, he confirmed that
she was pregnant. Months later, she woke up in the middle
of the night in pain and was rushed to the maternity home.
She gave birth to a baby girl - born without eyes.1
Mercy, a Filipino woman, also suspected that she was preg
nant. She went to her doctor who gave her an injection of
Gynaecosid, an EP drug. She went back two more times,
and each time he gave another injection. After the third
visit, the doctor confirmed that Mercy was pregnant. She
later gave birth to a boy with a club foot.2
The use of high-dose EP drugs - those that contain
about 0.05 milligrams of oestrogen and 10 mil
ligrams or more of progestogen - to test for
pregnancy has been popular in many developing
countries. It is a deceptively simple procedure. Highdose EP drugs were originally introduced in the
1950s to help regulate menstrual disorders, as they
were thought to start menstruation in women whose
periods were delayed and who were not pregnant.
Thus, a woman whose period did not start after
taking EP drugs was assumed to be pregnant. The
problem is that high-dose EP drugs are both unreli
able and unsafe as pregnancy tests. A study published
in the International Journal of Gynaecology and
Obstetrics in 1976 indicated that the test result was
false positive in about one out of every five women.3
The identification of harmful effects on the fetus
came in 1967 in a study by Dr Isabel Gal and her col
leagues.4 For the next 10 years, a regular flow of
papers appeared reporting on the dangers of these
drugs.5 Abortions, stillbirths, malformed live births
and possible long-delayed effects (such as the risk of
cancer in children) are among the dangers of giving
high doses of sex hormones at an early stage of fetal
development.
These findings led some governments to ban the use
of high-dose EP drugs entirely, or prevent their use
for pregnancy testing. They were withdrawn in
Norway and Sweden in 1970; Finland in 1971;
Denmark in 1974; the USA and Australia in 1975;
the UK in 1977; Austria, Belgium and Italy in 1978;
Greece in 1980. They were banned for import into
Singapore in 1978, withdrawn in New Zealand, pro
hibited in Thailand, not approved for use or sale in
Venezuela, not allowed to be promoted for preg
nancy testing in South Africa, and are not
recommended for use in Saudi Arabia. In Germany,
high-dose EP drugs were withdrawn for the indica
tion of use as treatment in secondary amenorrhoea
(absence of menstrual periods).6
In the USA, the Food and Drug Administration said
the products had been withdrawn for use in preg
nancy testing because there was “a lack of proof of
safety for that use in view of the potential danger in
the presence of pregnancy and the availability of
accurate alternatives”.7 It took the position that
143
7 C .
EP
drugs
Problem Di
there was “no justification for using progestogen and
estrogen in threatened abortion or as a pregnancy
test".8 The American Medical Association describes
hormonal pregnancy tests as “outmoded”.9
In 1981, the World Health Organization (WHO) rec
ommended an end to the use of high-dose EP drugs
during pregnancy. WHO said that as a pregnancy
test, the products were unreliable and there was no
way of guaranteeing that they would not harm the
fetus. Besides, a safer alternative - the urine test was on the market.10
An easy abortion?
Another part of the mythology of high-dose EP drugs
is the belief that they can be used to induce abortion,
even though none of the companies have promoted
the products for this purpose. An acknowledged side
effect of high-dose EP drugs is spontaneous abortion.
As many as one in 10 women who used high-dose EP
drugs to test for pregnancy were found to have had a
spontaneous abortion." Unfortunately, many
women have been led to misuse this “side effect” to
induce abortion - with tragic results when the
method fails, which it often does. In one study of 52
mothers in Madras, India who had given birth to
babies with congenital defects, 31% had taken hor
monal preparations during early pregnancy, often
with a view to termination.12
By the early 1980s, research in countries such as
India, Peru, Chile and the Philippines was demon
strating that the use of EP drugs to cause an abortion
was a growing trend.’3 One researcher in Peru com
mented,
“One of the most alarming examples of dan
gerous drug use I encountered is that of
injections (mainly oestrogen-progesterone
combinations) in the mistaken belief that
they will terminate unwanted pregnancies.
From observations in drug stores, discus
sions with health workers and a series of
interviews conducted in some of the poorest
districts of the Peruvian city of Chimbote - I
got the impression that their use is wide
spread in poor communities in Latin
America.”14
In India, researchers claimed in 1980 that high-dose
EP drugs were being used with “the intention of
inducing abortion” - successfully in some cases.
They commented, “these hormones are easily avail
able for patients seeking abortions with no
restrictions”.15
Menstrual disorders
High-dose EP drugs are still used as a treatment for
menstrual disorders, but even this is a very doubtful
indication. WHO pointed out in 1981 that it was
Removing high-dose EP drugs in India
In June 1982, on the advice of the Indian Council for
Medical Research, the Drug Controller of India issued a
notice to ban all high-dose EP drugs, with production to
cease from the end of 1982 and sales to end from the
end of June 1983. Very quickly, three companies Unichem, Nicholas and Organon - filed suits in the
Bombay and Calcutta courts arguing for a stay order
until a legal decision was handed down. The Federation
of Associations of Obstetricians and Gynaecologists and
the Organisation of Pharmaceutical Producers of India
also raised their voices in opposition to the ban.
In January 1983. a stay order was granted against the
ban and two-year extensions of product licences were
granted by the courts. The stay order was further
extended while the Supreme Court deliberated the
matter. Finally in November 1986, the Court directed the
Drug Controller to hold public hearings on whether all
oestrogen-progesterone products, including low-dose
oral contraceptives, would remain on the market. This
extension of the discussion to products that were clearly
of use served only to complicate the issue.
Four public hearings were held - in Madras, Delhi,
Calcutta and Bombay - although the notices
announcing the hearings came late and were not widely
publicised. This made it difficult for bodies such as the
Voluntary Health Association of India and the All Indian
Drug Action Network - both of which were campaigning
strongly to have the drugs removed - to prepare for the
hearings. Nonetheless, they were able to present
considerable evidence from around the world to
demonstrate that there was no need for these drugs.
During the hearings, the main industry argument was
that unquestionably, the products should not be used
in pregnancy, but that they were of use to treat
gynaecological conditions in non pregnant women. The
industry argued that if abuse of the products occurred
- that is, if they were taken by pregnant women - the
industry could not be held responsible for that, nor
should it be penalised by not being allowed to sell a
supposedly useful product. Clinical pharmacologist
Professor Michael Rawlins, of Newcastle University in
the UK, said quite bluntly in evidence presented to the
hearings that he was “dismayed that the Indian
pharmaceutical industry should wish to seek to
maintain their market in high-dose oestrogenprogestogen products".
In the end, nearly one year after the final public hearing,
on 15 June 1988, the Drug Controller announced that
the ban on high-dose EP drugs was to go into effect.
Source: S.lverman, M , Lydecker, M. and Lee, P.R, Bad Medic,ne the
pXs'XV"^'" the ™ W°"d
Stanford University
7 C .
unwise to use these products as a treatment for
missed periods: “Women who are not pregnant will
have their menses further delayed if hormones are
administered.’’16
According to Dr Stephen Franks, a senior lecturer in
reproductive endocrinology at St Mary’s Hospital
Medical School in London, “there is no justification
for the use of these drugs in amenorrhoea, menstrual
irregularities and other gynaecological disorders”.17
Aside from pregnancy, the causes of amenorrhoea
can include menopause, breastfeeding, too little body
fat, malnutrition, dieting, heavy athletic training,
previous use of hormonal contraceptives, stress, hor
monal imbalance, congenital defects, tumours, or
disease.18 The specific cause should first be identified
and attempts made to treat that cause. It is unlikely
that hormonal therapy will be necessary; if it is, then
low-dose hormones are preferred.19 In developing
countries, undernutrition or underlying disease con
ditions are among the most likely causes of
secondary amenorrhoea.
Time for action
The dangers of high-dose EP drugs have been known
for more than 25 years. Yet, the withdrawal of these
products has been painfully slow. Virtually all the
sales of high-dose EP drugs now occur in developing
countries where the products have not been banned.
Warnings about the dangers associated with these
drugs are often inadequate or non-existent. A
Pakistani publication described the situation as “a
sordid, sorry tale of the multinational drugmakers’
quest for profit, our doctors’ ignorance and the
authorities’ apathy”.20 A six-year battle in India to
have high-dose EP drugs withdrawn further illus
trates the reluctance of companies to move quickly
(see box on page 144).
During rhe 1980s, an estimated 180,000 women a
year used high-dose EP drugs in India. In the mid1980s, one in 20 Indian women over the age of 15
used high-dose EP drugs at least once a year. In more
than three-quarters of the pharmacies in Cusco,
Peru, it was possible to buy high-dose EP drugs with
out a prescription. Malaysia, Indonesia, Colombia,
Brazil and Chile are other countries where wide
spread use of these drugs has been reported.21
In March 1987, the German company, Schering,
finally withdrew the world’s leading high-dose EP
drug, Cumorit, from the global market, following
sustained pressure from public interest groups. The
Dutch company, Organon, withdrew the oral form
of Menstrogen, the second leading product, from the
global market in January 1988, again after consider
able pressure.22 (The injectable form is still on the
market.)
EP
drugs
It is worth putting these withdrawals into some per
spective. The first clear warning about the risks of
these drugs to the unborn child emerged in 1967. It
has taken more than 20 years to get the two leading
brands removed globally. This is despite the with
drawal of Menstrogen from the UK market in March
1975, and the withdrawal of the equivalent to
Cumorit in the UK in 1978 and in Germany in 1980.
Yet there is evidence that similar products are still
being used in many countries.
In the Middle East in December 1990, Orion’s
Divina (2mg oestradiol and lOmg medroxyproges
terone) was indicated
for “amenorrhoea”,
Medimpex’s Limovanil (2.5mg oestradiol and
12.5mg progesterone) was indicated for “primary
and secondary amenorrhoea... habitual abortion”.23
Also in 1990, in Pakistan, Efroze’s Gynaecosid (5mg
methyloestrenolone and 0.3mg of methyloestradiol)
was recommended for “secondary amenorrhoea”;
Organon’s Menstrogen (0.02mg ethinylestradiol and
12.5mg progesterone) was indicated for “selected
cases of primary and secondary amenorrhoea”;
Sami’s Penorit (lOmg of norethisterone and 0.02mg
of ethinyloestradiol) was indicated for “secondary
amenorrhoea of short duration”.2,1
Parr of the problem is the reluctance of companies to
face the acknowledged risks of these drugs - risks
without any obvious benefits. In 1988, a senior
Organon manager, K. Klijn, said that his company’s
high-dose EP product, Menstrogen injection, offered
“no risk for mother or fetus; the product’s active
principles are natural hormones and no convincing
evidence of a terarological or virilizing effect
exists”.25
As long as these drugs remain on the market without
adequate warnings or controls on use, thousands of
women and their unborn children are exposed to
unnecessary danger. As M. D. Rawlins, professor of
clinical pharmacology at Newcastle University in the
UK, states: “There is no scientific or clinical justifica
tion for the continued use of these products.”26
Recommendations for action
Governments should:
1. ban all high-dose EP drugs, immediately;
2. make available and publicise the use of
alternative forms of pregnancy testing;
3. publicise the dangers of taking any drugs
during pregnancy.
4. provide access to safe, legal, low-cost abortion
to eliminate the demand for abortion through selfmedication with hazardous products.
U%| 7 C .
EP
drugs
Problem Di
References:
i.
2.
3.
4-
5.
6.
Anon., “The untold story". Herald (Pakistan), Sept 1982
Marcelis, C. and Shiva, M., “EP drugs: unsafe by any name", in: McDonnell, K.
(ed.). Adverse Effects: Women and the Pharmaceutical Industry, Penang,
IOCU, 1986, ppn-26
Salam. D.V., et al, “Estrogen-progesterone withdrawal bleeding in diagnosis of
early pregnancy". International Journal of Gynaecology and Obstetrics, Vol 14,
1976, PP348-53
Gal, I., et al. “Hormonal pregnancy tests and congenital malformations",
Nature, Vol 216,1967, P83
See, for example: Levy, E.P., Cohen. A. and Fraser, F.C, “Hormone treatment
during pregnancy and congenital heart defects". Lancet, 1973 (I), p6n;
Janerich, D.T., Piper, J.M. and Glebatis, DM., “Oral contraceptives and
congenital limb-reduction defects", New England Journal of Medicine. Vol 291,
1974. PP697700, Nora, A.H. and Nora, J.J., “A syndrome of multiple
congenital anomalies associated with teratogenic exposure", Archives of
Environmental Health, Vol 30,1975, PP17-21; Hellstrom, B., Lindsten, J., and
Nilsson, K., “Prenatal sex hormone exposure and congenital limb-reduction
defects". Lancet, 1976 (II), P373, Heinonen, O.R, Slone, D., et al.
“Cardiovascular birth defects and antenatal exposure to female sex
hormones", New England Journal of Medicine, Vol 296,1977, PP67-70;
Janerich, J.T., Dugan, J.M., et al, “Congenital heart disease and prenatal
exposure to exogenous sex hormones", British Medical Journal, 1977,
ppio58-6o; Nora, J.J., Nora, A.H., et al, “Exogenous progestogen and estrogen
implicated in birth defects", Journal of the American Medical Association,
Vol 240,1978, PP837-43
United Nations, Consolidated List of Products Whose Consumption and/or
Sale Have Been Banned, Withdrawn, Severely Restricted or Not Approved by
Governments, 2nd issue, Doc No ST/ESA/192, New York, 1987, ppm-12;
Marcelis and Shiva, op cit, ppn-26; Gal, I., Teratological Adverse Drug Effects:
Review of Evidence Implicating Hormonal Pregnancy Tests, (mimeo)
submitted to UK Department of Health and Social Services, 1978/9, p3
United Nations, op cit, ppii2
Silverman, M., Lydecker, M. and Lee, P.R., Bad Medicine: the prescription drug
industry in the Third World, Stanford, Stanford University Press, 1992, pii2
9.
AMA, Drug Evaluations, Philadelphia, W.B. Saunders Co., (6th edn) 1986, P700
10.
WHO, The Effect of Female Sex Hormones on fetal Development and Infant
7.
8.
Health. Technical Report Series, No 657, Geneva, 1981
n. Marcelis and Shiva, op cit, ppn-26
12.
Voluntary Health Association of India (VHAI), The Case Against EP Forte, New
Delhi, 1983, pi
Wolffers, I., Hardon, A., and Janssen, J., Marketing Fertility: Women,
Menstruation and the Pharmaceutical Industry, Amsterdam, WEMOS
International Group on Women and Pharmaceuticals, 1989, p28
14.
Melrose, D., Report on Research and Networking Visit to Latin America,
13.
15.
16.
17.
18.
The Hague, HAI, 1983, PP9-10
Palaniappan, B. and Poorva Devi, V, "Hormones for withdrawal bleeding",
Journal of the Indian Medical Association, Vol 74, No 4,18 Feb 1980, P69
WHO, op cit
Silverman, et al, op cit, pii7
Phillips, A., Rakusen, J. (eds) and the Boston Women's Health Collective, The
New Our Bodies, Ourselves (2nd UK edition), London, Penguin Books, 1989,
P510
19.
Wolffers, et al, op cit, P25
20.
Anon., Herald, op cit
21.
Wolffers, et al, op cit, PP45-5O
22.
Ibid, PP32 and 44
23 M/A15 Middle East, Vol 21, No 6, Dec 1990, pp8i-2
24. Qureshi, A.H. (ed.), Quick Index of Medical Preparations, Vol 22, No 1 and 2,
Mar-Aug 1990, PP71-2
25. MaLAM, Newsletter, Sep 1988, pi
26 Silverman, et al, op cit, pn8
r,',-
Chetley, A. Problem Drugs, Amsterdam,
ARY
>. °\
Health Action International’s
coordinating offices:
Health Action International, 1993
70’ ■'
ano
, .... •
HAI Europe
Jacob van Lennepkade 334T
1053 NJ Amsterdam
The Netherlands
8A. Contraceptives
HAI Clearinghouse/ARDA
c/o I0CU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Action para la Salud
Avda. Palermo 531
Dpto. 104
Lima 13
Peru
Wh©9s m control?
“The burden of ill health associated with reproduction is
divided very unequally between the two sexes, with women
bearing the brunt of it. For instance, only women face the
health hazards of pregnancy and childbirth. Most STDs
[sexually transmitted diseases! have more serious sequelae
[symptoms or conditions! in women than tn men....
Contraceptive use worldwide is three times greater among
women than men, and among all available methods, those
used by women carry more potential health hazards.
An estimated 381 million people in developing
countries use some form of contraception in order
to avoid pregnancy.*12 Female sterilisation is the most
widely used method in the world, with the
intrauterine device (IUD) being the most commonly
used reversible method? Table 8A-1 gives an indi
cation of the numbers of people using different
methods globally, while Figure 8A-1 on page 148
indicates the different patterns of usage globally
and in different regions.
Nonetheless, the lack of access to birth control is
enormous: “more than 500 million married women
now express the desire for access to birth control, but
cannot obtain methods suitable to their needs.”4
Despite the different types of contraception, for most
women there is actually a very limited choice. In the
words of a 20 year old single woman, “I wish they
could find another way.... I feel like you have prob
lems with everything and I don’t have very many
options except not being sexually active which... I’m
not willing to do right now.”5
The choice is even more limited if a health care
provider does not prescribe certain methods or does
Table 8A-1
Global estimates of the number of people using
different methods of contraception (1980s)
Method
Number of users
Sterilisation
male
42 million1
female
140 million1
Hormonal contraceptives
oral
63 million2
injectables
6 million3
implants
1.5 million4
IUD
80 million*5
Condom
40 million6
Other barrier methods
8 million7
Natural birth control
32 million7
Withdrawal
32 million7
’nearly 60 million IUD users are in the People's Republic of China.
Sources:
1. Anon., “Vasectomy: New Opportunities", Population Reports, Series D,
No 5, Vol XX, No 1. Mar 1992
2. Finger, W.R., “Using oral contraceptives correctly: progress on package
instructions", Network, Vol 12, No 2, Sep 1991, ppl4-17 and 27
3. WHO, Injectable Contraceptives, Geneva, WHO, 1990, p2
4. Mintzes, B.. Harden, A. and Hanhart, J. (eds), Norplant: Under her Skin,
Amsterdam, Women's Health Action Foundation and WEMOS, 1993
5. Farley, T.M.M , Rosenberg, M.J., et al, “Intrauterine devices and pelvic
inflammatory disease: an international perspective", Lancet, Vol 339,
No 8796, 28 Mar 1992, pp785-8
6, Bounds, W., "Male and female barrier contraceptive methods", chapter
10 in: Filshie, M. and Guillebaud, J. (eds), Contraception: Science and
Practice, London, Butterworth-Heinemann, 1989, ppi72-202
7. Diczfalusy. E., “Contraceptive prevalence, reproductive health and our
common future", Contraception, Vol 43, No 3, Mar 1991, pp201-27
147
148 8 A .
Contraceptives
Problem Drugs
not believe specific methods are appropriate for an
individual woman. Dona Lethbridge, who exam
ined women’s perceptions of contraceptive use,
reports on the experience of one woman who
wanted to change from an IUD to the diaphragm:
“When I went to get my IUD out, he (the physician)
refused and said I would just get pregnant again. So
1 had to go to another doctor and she took it out.”6
Access to safe legal abortion is an important compo
nent of birth control strategies. Ar least 50 million
abortions are induced annually throughout the
world, many of which are performed illegally.7 The
World Health Organization (WHO) estimates that
up to 200,000 maternal deaths a year in developing
countries can be attributed to unsafe abortions.8
Figure 8a-i
Percentages of different contraceptive methods
used in the 1980s.
Choice of methods
Choosing the appropriate contraceptive method
involves a number of variables, including age, health,
frequency of intercourse, and whether rhe reason for
use is to prevent or postpone pregnancy. Those vari
ables will change over time, making it necessary ro
have a wide variety of contraceptive methods on
offer at any time. The box on the next page provides
some questions that could help in choosing a contra
ceptive method.
Fundamental to the decision are questions of efficacy,
safety, cost and, increasingly, concerns about
whether rhe method provides protection against sex
ually transmitted diseases (STDs) and human
immunodeficiency virus (HIV). Table 8A-2 on the
next page indicates how various methods compare in
terms of efficacy, safety and protection against STDs.
Safety
Safety is one of the more difficult factors to assess. As
British gynaecologist Dr John Guillebaud points out,
it is important to avoid damaging health when
choosing a contraceptive method. “In trying to find a
method of birth control, the main action is to inter
fere with a normal body process and this means
taking extra-special care. The method will be used by
initially healthy women or men and should not make
them unhealthy; on the other hand, it could be used
by people who are already unhealthy and must not
do them additional harm.”9
It is worth remembering that all forms of contraception
carry some risk. Concern about the safety of the pill
(oral contraceptives) and other hormonal contracep
tives raises ethical questions about giving a powerful
hormone ro millions of healthy women. In 1977,
reports of increased risk of thrombosis in pill takers especially smokers - led some women to stop the pill.
Two reports in the 1980s that linked oral contraceptives
with increased risk of breast and cervical cancer turned
many women to the IUD, despite many reports of side
effects. The IUD may not be a reversible method for
■ industrialised
■Developing
□Global
Source:
and the'challeng^ahead”'™ Kh^na
m'!d: tV'° decades of Progress
(eds), ffeprodX Hea/tpj-a Key to a S™kLa,ncL?°k' PpFA’ and Gri,,in' P D'
« ney to a Brighter Future, Geneva, WHO, 1992, p7
8 A .
some women. Women with IUDs are two to five times
more likely to develop pelvic inflammatory' disease
(PID) than women not using a contraceptive. Risks for
users of IUDs who have never given birth may be twice
this level. Scarring and blockage of the fallopian tubes
from PID is now believed to be the major preventable
cause of female infertility.10
Longer acting injectable contraceptives can lead to
bleeding disorders described in The Lancet as “men
strual chaos”. Menstrual disturbances are also a
problem with implants and, for both methods, long
term safety has yet to be established. There are
possibilities of birth defects if a woman becomes
pregnant or is already pregnant while using these
methods.
The barrier methods of contraception are increasingly
popular and have few physical adverse effects.
However, they are not always as effective as hor
monal methods. The alternatives to hormones or
barrier methods are the “natural” methods. The most
widely used natural methods - rhythm and with
drawal - are the least effective. The thickness of the
cervical mucus and/or early morning temperature can
be monitored as indicators of ovulation. This is more
effective than rhythm or withdrawal, but requires
prior training and consistent monitoring.
Contraceptives
Choosing a method
Questions for a woman to consider before choosing a
contraceptive method.
1. Are you delaying a first child, spacing your children or
not planning to have any (more) children?
2. How would you feel and what would you do if you got
pregnant in spite of your method?
3. Will you feel comfortable using this method? Can you
talk to your partner about it? Who will use the method,
you or your partner? Does your partner feel responsible
as well?
4. How well does this method work? Can this method
harm you? How much of your body does it affect?
5.
How much does it cost?
6. How will this method affect your sexual relationship
with your partner?
7. Are there medical reasons why you should not use a
particular method?
8. How great is the risk of your getting a sexually
transmitted disease, including HIV?
Source: Adapted from: Berer, M., ‘ Contraception", chapter 15 in: Phillips,
A . Rakusen. J. (eds) and the Boston Women's Health Collective, The New
Our Bodies, Ourselves (2nd UK edition), London, Penguin Books, 1989, p277
Table 8A-2
Comparison of some methods of contraception
Method
Pregnancy rate per
Risk of
Protects against
100 women1
Adverse effects
STD/HIV?
Sterilisation
Notes:
1 Large variations in pregnancy rates for some
methods mostly reflect differences in how consistently
or well a method is used.
2. The low pregnancy rate with injectables is
dependent upon consistent use: this is more likely to
occur in clinical trials than in real life situations.
3. The pregnancy rate with implants is higher than this
in women weighing more than 70kg.
4. Breastfeeding makes a substantial contribution to
birth spacing and fertility control in many areas, and
gives a pregnancy rate of less than 2 per 100 during
the first six months providing the baby is nearly fully
breastfed, and that the mother's menstruation has not
returned.
5. Long term safety of injectables and implants is not
certain; also any adverse effects may continue for the
duration of the effectiveness of the injection or until
after the implant has been removed.
6. Injectables and implants may increase the risk of
transmission of HIV if unsterile equipment is used
7. Use of an IUD is a probable risk factor in some STDs.
8. The diaphragm and some other barrier methods
reduce the risk of transmission of some STDs, but
Male
0-0.2
low
no
Female
0-0.5
medium
no
combined pill
0.2-7
medium
no
progestogen only
0.3-5
medium
no
Injectables
less than I2
medium-high5
no6
Implants
0.3-1.43
medium-high5
no6
IUDs
0.3-9
high
no’
2-20
low
yes/no3
have no effect on HIV.
Diaphragm
Sources: Guillebaud, J., Contraception: your questions
answered, London, Churchill Livingstone, (revised edn)
1991, pp8 and 201; WHO. Injectable Contraceptives,
Geneva. WHO, 1990, p20; Anon., "Breastfeeding as a
family planning method”, Lancet, 19 Nov 1988,
ppi204-5; Henry, J. (ed ), The British Medical
Association Guide to Medicines & Drugs, London, Dorling
Kindersley, (2nd edn) 1991, pl57; Berer, M..
“Contraception”, chapter 15 in: Phillips. A., Rakusen, J.
(eds) and the Boston Women’s Health Collective, The
New Our Bodies, Ourselves (2nd UK edition), London,
Penguin Books, 1989, pp271-308
Oral contraceptives
Condom
2-20
low
yes
Sponge
9-27
low
yes/no8
Spermicide
4-30
low
yes/no8
Withdrawal
5-20
-
no
Rhythm
Ovulation monitoring
25-30
--
no
3-25
-
no
Breastfeeding
24
-
no
8 A .
Contraceptives
Problem Drugs
Sterilisation is effective but irreversible and, like all
surgery, carries a risk of infection. It is useful for
people who are certain they want no more children.
[See the sections on The Pill, IUDs, Injectables, and
Implants.]
IUVIV vz* .
Annual number of new sexually transmitted
infections worldwide
Condition
Sexually transmitted disease
The recent public health focus on AIDS, although
well-deserved, has overshadowed a widespread epi
demic of STDs. WHO describes the global spread of
an estimated 250 million new sexually transmitted
infections each year as “one of the major disappoint
ments in public health in the past two decades”11 (see
Table 8A-3).
In rural areas of developing countries, the facilities
for the diagnosis and treatment of these STDs are
often lacking. One study in two villages in India
found that 92% of the 650 women examined had
one or more gynaecological or sexual disease, with
an average of 3.6 infections per woman. Only 8% of
the women had undergone gynaecological examina
tion and treatment in the past.12 The consequences
for women include chronic genital infection, infertil
ity, chronic pain, and death. Infected pregnant
women risk higher rates of maternal and infant ill
ness and death. The genital lesions produced by some
STDs may increase the risk of contracting or trans
mitting HIV, the incidence of which is already
increasing rapidly among women.13
Number of new cases
(millions)
Trichomoniasis
Chlamydia
50
Human Papillomavirus
30
Gonorrhoea
25
Herpes
20
Syphilis
4
Chancroid
2
HIV
1
Source: Khanna. J., van look. P F.A., and Griffin. P.O. (eds), Reproductive Health:
a Key to a Brighter Future. Geneva, WHO. 1992, pl3
For millions of women, therefore, a prime considera
tion when choosing a contraceptive may be not only
its efficacy in preventing pregnancy, but also its abil
ity to prevent the spread of STDs. An editorial in the
Journal of Clinical Endocrinology and Metabolism
makes the point that:
“Barrier contraception with condoms... not
only prevents pregnancy, but also limits the
spread of sexually transmitted diseases.”14
The condom is currently the only contraceptive
which is known to effectively prevent the transmis
sion of HIV. Female condoms can also prevent HIV
transmission, but they are relatively expensive and
not yet widely available.
Birth control or population control?
No discussion of the risks versus benefits of any form of
contraception can be understood without looking at
why and how they are used; the social, economic, polit
ical and cultural background to the issue. Discussion
on the technical merits of one contraceptive over
another often ignores these questions entirely.
The development of the pill, and the reliance on the
medical profession to dispense it, led to increased
intervention in women’s fertility. This pattern has
continued as a result of research into new types of
contraceptives, many of which tend to make women
An ad for condoms in Pakistan promotes
child spacing. QIMP. 1990
dependent on health workers for their administra
tion and removal. IUDs, injectables and implants all
require specially trained health personnel for admin
istration and follow-up, while trained personnel are
also required for the removal of IUDs and implants.
These “provider-dependent” methods carry the
potential for abuse within family planning pro
grammes because a woman who no longer wishes to
use the method cannot simply stop; she has to find a
health worker to remove the device.15
That worry is exacerbated by the recognition that
“family planning programmes tend to be more con
cerned with the welfare of society as a whole than
with the well-being of an individual woman.”16
Through the 1960s and 1970s, the fear of a looming
population crisis meant that fertility control became
8 A .
The US Agency for International Development
(USAID) is the "dominant donor" in the population
field. In a 10-year period since 1981, USAID con
tributed some $2.6 billion to population activities,
approximately 45% of international population
funds. In 1991 alone, USAID spent $330 mill ion on
population activities. USAID also provides 75% of
the developing world’s donor-provided contracep
tives. Since 1968, it has supplied 1.6 billion cycles of
oral contraceptives, 7.8 billion condoms, and 50 mil
lion IUDs.19
The development and introduction of the oral con
traceptive in the 1960s was heralded in industrialised
countries as a revolution in fertility control allowing
women to have sex without the fear of pregnancy. In
the words of the United Nations Population Fund
(UNFPA) in 1985,
“women in the developed countries already
enjoy as a matter of course such basic repro
ductive freedoms as knowledge of and access
to contraception which give them some con
trol over their own fertility.”21’
In developing countries, the starting point was not
always the same. Contraceptives have been made
available in developing countries not as a means of
increasing reproductive options for women, but as
part of national population reduction strategies.2'
The reasons for such strategies seemed obvious at rhe
time: there were too many people for the available
resources. Limiting population growth would
encourage economic and social development. In
many cases, the problem had more to do with the
distribution and consumption of resources. None
theless, the idea that controlling population is the
way to tackle poverty and development has led to
severe distortions in planning and ignored important
social justice questions.
In the early 1960s, the US-based Population
Council, alarmed at the “problem of unchecked
population growth”, focused on the IUD as a means
of solving the population crisis in developing coun
tries. It convened a conference to encourage the
medical profession to look afresh at the IUD as a
viable contraceptive method. Participants were
assured that two developments made such an
approach feasible: new developments in inert plas
tics that allowed the design of IUDs that could be
easily inserted, and the introduction of antibiotics
that could cure any infections that occurred. That
infections would occur was taken for granted. One
leading gynaecologist, Robert Wilson, told the con
ference,
“If we look at this from an overall longrange view - these are things that 1 never
said out loud before and I don’t know how
it is going to sound - perhaps the individual
patient is expendable in the general scheme
of things, particularly if the infection she
acquires is sterilizing and not lethal.”22
The main goal of many population control schemes
was to “motivate” people to see the need for limiting
family size. But the rationality of the West (to prevent
food shortages or social problems) is not the same as
in rhe developing countries. In many developing
countries, people leading subsistence lives rely heav
ily on their children to augment family income and to
take on family responsibilities. John Caldwell, a
leading researcher on population studies, has pointed
out that subsistence farmers “would be irrational” if
they encouraged policies that limited the number of
children who could help our with agricultural and
household tasks.23
Many of the programmes designed to motivate
greater acceptance of contraception are aimed at
women. Yet, the root of the problem may be with
men's attitudes. A doctor at a clinic in Mexico notes
that “when a wife wants to try to limit the number of
mouths to feed in the family, the husband will
become angry and even beat her. He thinks it is unac
ceptable that she is making a decision of her own. She
is challenging his authority, his power over her - and
thus the very nature of his virility.”24
In some cases, coercion, strong persuasion, or various
inducements were used to encourage contraception. In
countries such as Bangladesh, Egypt, India, Indonesia,
Pakistan, Taiwan, Thailand, Turkey, Korea and the
United Arab Republic, either the acceptors or the pro
moters of contraception (and sometimes both) have
received payments. The payments were either cash or
goods and services such as clothing, farm animals,
preferential access to housing, or even food.2’
Where incentives are combined with targets to ster
ilise, inject, implant, or insert IUDs into a certain
number of women a day or month, the idea of a
woman having a free choice of methods quickly dis
appears. Only certain contraceptives are offered to
women, often with inadequate warnings on side
effects and given by poorly trained health workers
under pressure to deliver results. Further, lack of
screening and other medical facilities prevent “at
risk” women (for example, those with pre-cancerous
conditions or already pregnant women) from being
identified. As Anrudh K. Jain, a senior associate at
the US-based Population Council, explains,
151
Problem Di
a•I?ai°r prl0rity in rhe funding of both research and
aid. By the early 1990s, an estimated $5.3 billion a
year was being spent on family planning pro
grammes, with about two-thirds of that amount
($3.5 billion) being spent in developing countries 17
Between 1970 and 1991, the WHO Special
Programme of Research, Development and Research
Training in Human Reproduction spent about $310
million, with the annual expenditure during the early
1990s averaging about $22 million.18
Contraceptives
8 A .
Contraceptives
"With the passage of time, meeting demo
graphic objectives became the overriding
concern of organised family planning pro
grammes [that] in certain circumstances...
lost track of the underlying principle of
meeting individual needs.”26
For women to be able to make a free choice, they
need full information. However, past experience
shows that women involved in family planning pro
grammes in developing countries have not always
been told the full story about the adverse effects of
different contraceptives.2' It may be in the agencies’
best interests not to explain side effects or other
problems with contraceptive methods. James
Shelton, Chief of the Research Division of USAID's
Office of Population, said in 1991 that USAID pre
ferred not to use the term “contraindications” when
talking about contraceptives, “It is a term which may
have very negative connotations and a major
inhibitory effect, especially when transmitted down
ward through the system. A low-level health worker
needs a lot of confidence to go against even a ‘relative
contraindication’.”28
foreign concept and it is important that the
organisations concerned make it clear that it
is only through planned parenthood that our
children can be adequately provided for.”30
In recent years, there are some indications that more
informed attitudes and behaviours are occurring in
family planning programmes. Increasingly, the com
plex interaction of social, economic and cultural
factors that maintain high levels of population
growth in some parts of the world are being
addressed in a more holistic manner rather than rely
ing on the technological response of controlling
population first. According to the United Nations
Population Fund, “raising the status of women in
developing countries by giving them access to
adequate education, health care, and work at a fair
wage is an essential part of slowing population
growth and thus reducing poverty.”31
He also identified several “medical barriers” that
could hinder the effectiveness and impact of family
planning programmes, particularly those that were
involved in providing hormonal contraception.
Among the “barriers” were: “unnecessary labora
tory tests; excessive physical exams (e.g., pelvic and
breast);... excessive follow-up schedules;... conserva
tive medical thinking (e.g., taking a woman off rhe
pill for a while if she develops a headache just to play
it ‘safe’);... excessive counselling and history
taking;... categorical exclusion of clients (e.g., by
arbitrary age and parity criteria); categorical exclu
sion of methods (e.g., by not providing IUDs because
the STD rate is too high in the population)....” Many
of these tests and exclusion criteria are seen as a rou
tine part of safe provision of contraceptives in
industrialised countries.
At the root of the controversy is the difference
between the concept of population control - some
thing imposed from outside - and the concept of
birth control, birth spacing and family size decisions that ought to be made by the individuals
most concerned: women and their partners. Women,
not governing institutions, “are the rightful arbiters
of women’s birth-control requirements.”29
Jayne Maranga, a Kenyan woman who works in the
Nairobi office of the UK-based Voluntary Services
Overseas, makes the point that for women in Kenya,
“especially those who have never been to
school, there is still confusion as to the
difference between family planning and birth
control. Most of them have interpreted what
the government is saying to mean that they
should stop having children. This is seen as a
Schering advertises an oral contraceptive to doctors in the
Netherlands, The Practitioner, March 1992
8 A .
The US Agency for International Development
(USAID) is the “dominant donor” in the population
field. In a 10-year period since 1981, USAID con
tributed some $2.6 billion to population activities,
approximately 45% of international population
funds. In 1991 alone, USAID spent $330 million on
population activities. USAID also provides 75% of
the developing world’s donor-provided contracep
tives. Since 1968, it has supplied 1.6 billion cycles of
oral contraceptives, 7.8 billion condoms, and 50 mil
lion IUDs.19
The development and introduction of the oral con
traceptive in the 1960s was heralded in industrialised
countries as a revolution in fertility control allowing
women to have sex without the fear of pregnancy. In
the words of rhe United Nations Population Fund
(UNFPA) in 1985,
“women in the developed countries already
enjoy as a matter of course such basic repro
ductive freedoms as knowledge of and access
to contraception which give them some con
trol over their own fertility.”20
In developing countries, the starting point was not
always the same. Contraceptives have been made
available in developing countries not as a means of
increasing reproductive options for women, but as
part of national population reduction strategies.21
The reasons for such strategies seemed obvious at rhe
time: there were too many people for the available
resources. Limiting population growth would
encourage economic and social development. In
many cases, the problem had more to do with the
distribution and consumption of resources. None
theless, the idea that controlling population is the
way to tackle poverty and development has led to
severe distortions in planning and ignored important
social justice questions.
In the early 1960s, the US-based Population
Council, alarmed at the “problem of unchecked
population growth”, focused on the IUD as a means
of solving the population crisis in developing coun
tries. It convened a conference to encourage the
medical profession to look afresh at the IUD as a
viable contraceptive method. Participants were
assured that two developments made such an
approach feasible: new developments in inert plas
tics that allowed the design of IUDs that could be
easily inserted, and the introduction of antibiotics
that could cure any infections that occurred. That
infections would occur was taken for granted. One
leading gynaecologist, Robert Wilson, told the con
ference,
“If we look at this from an overall longrange view - these are things that I never
said out loud before and I don’t know how
it is going to sound - perhaps the individual
patient is expendable in the general scheme
of things, particularly if the infection she
acquires is sterilizing and not lethal.”22
The main goal of many population control schemes
was to “motivate” people to see the need for limiting
family size. But the rationality of the West (to prevent
food shortages or social problems) is not the same as
in the developing countries. In many developing
countries, people leading subsistence lives rely heav
ily on their children to augment family income and to
take on family responsibilities. John Caldwell, a
leading researcher on population studies, has pointed
out that subsistence farmers “would be irrational” if
they encouraged policies that limited the number of
children who could help out with agricultural and
household tasks.23
Many of the programmes designed to motivate
greater acceptance of contraception are aimed at
women. Yet, the root of the problem may be with
men’s attitudes. A doctor at a clinic in Mexico notes
that “when a wife wants to try to limit the number of
mouths to feed in the family, the husband will
become angry and even beat her. He thinks it is unac
ceptable that she is making a decision of her own. She
is challenging his authority, his power over her - and
thus the very nature of his virility.”24
In some cases, coercion, strong persuasion, or various
inducements were used to encourage contraception. In
countries such as Bangladesh, Egypt, India, Indonesia,
Pakistan, Taiwan, Thailand, Turkey, Korea and the
United Arab Republic, either the acceptors or the pro
moters of contraception (and sometimes both) have
received payments. The payments were either cash or
goods and services such as clothing, farm animals,
preferential access to housing, or even food.25
Where incentives are combined with targets to ster
ilise, inject, implant, or insert IUDs into a certain
number of women a day or month, the idea of a
woman having a free choice of methods quickly dis
appears. Only certain contraceptives are offered to
women, often with inadequate warnings on side
effects and given by poorly trained health workers
under pressure to deliver results. Further, lack of
screening and other medical facilities prevent “at
risk” women (for example, those with pre-cancerous
conditions or already pregnant women) from being
identified. As Anrudh K. Jain, a senior associate at
the US-based Population Council, explains,
151
Problem Di
a major priority in rhe funding of both research and
aid. By the early 1990s, an estimated $5.3 billion a
year was being spent on family planning pro
grammes, with about two-thirds of that amount
($3.5 billion) being spent in developing countries.17
Between 1970 and 1991, the WHO Special
Programme of Research, Development and Research
Training in Human Reproduction spent about $310
million, with the annual expenditure during the early
1990s averaging about $22 million.18
Contraceptives
8 A ,
Contraceptives
With many women dissatisfied about current contra
ceptive methods, and with the importance given to
contraception generally, it is not surprising that a
great deal of research is underway to find better
methods. However, the search for alternatives is lim
ited by the same sorts of forces that drove research
towards female hormonal contraceptives in the first
place. Research continues to focus mainly on hor
monal or provider-dependent methods to be used by
women, while alternatives are largely rejected. This
has led one gynaecologist to comment that contra
ceptive researchers
“would do better to concentrate their
resources on making the safe methods more
effective.... Concentrating on improving these
methods is surely better than the conven
tional wisdom of the scientific establishment,
which starts with current or innovative sys
temic methods which are highly effective and
convenient, and then strives diligently
towards making them risk-free. Success down
that road will be nearly as impossible to
prove as it ever will be to achieve!”32
Among the areas being looked at the moment are:
male contraceptives, a contraceptive vaccine, and an
abortion pill.
Male contraceptives
Research on male contraceptives has been slow.
Weekly injections of the male hormone testosterone
have been found to maintain “safe, stable, effective
and reversible contraception for at least 12 months”,
although the frequency of injections was a major
cause for discontinuation. Also, as with the injectable
contraceptive for women, the long-term risks are not
known, although both prostatic cancer and cardio
vascular disease are potential risks.33 Animal studies
on a combination of testosterone with a chemical to
inhibit the secretion of gonadotrophin releasing hor
mone have successfully prevented sperm production
in primates, and such a product is predicted to have a
similar effect in humans,34 although whether it will
prove to be safe and acceptable is still in doubt.35
Another chemical, gossypol, a substance found in
raw cotton seed oil, can reduce sperm production,
but has been shown to inhibit sexual desire in animal
studies.36 Human studies have also raised the possi
bility that as many as 10% of users may become
permanently sterile.37
However, a male contraceptive - other than
improving condoms and encouraging increased use
- is unlikely to emerge in the near future. Even if a
promising substance is identified, today’s ‘stringent
toxicological studies and licensing procedures com
pared with 25 years ago when the female pill was
first widely available” will slow down the developIQ
ment process/0
A contraceptive vaccine?
Optimists suggest that a birth control vaccine for
women could be in use within 15 years, with the
most likely candidate being a vaccine that targets
human chorionic gonadotrophin (hCG) - a hor
mone that is produced during pregnancy. Blocking
the action of the hormone interferes with the ability
of the embryo to implant in the womb.39
Research is also underway to find a vaccine that pre
vents fertilisation by interfering with the proteins
contained in either the sperm or the egg. One such
vaccine, developed by scientists at the University of
Virginia in the USA, is expected to go into clinical tri
als by 1994. It acts by stimulating the production in
the woman of antibodies to a particular protein that
is believed to be present in all human sperm. The
binding of the antibodies to the protein will prevent
the sperm from fertilising the egg.40
Another team is looking at a vaccine that will
develop antibodies to a protein on the surface of the
egg. The binding of the antibodies to the protein will
effectively keep out the sperm.41
The as yet unproven hypothesis is that these vaccines
are likely to be relatively side effect free. WHO also
says that they would be “easy to administer and
would be comparatively inexpensive”.42 However,
there are many safety and efficacy questions that need
to be resolved. The effect if a woman is already preg
nant or becomes pregnant while using these vaccines
is not known. Also, because of the variation in
immune responses in individual women, the actual
period of efficacy cannot be accurately predicted.43
Although a more traditional vaccine sets up an
immune response to an external toxin entering the
human system, these anti-fertility vaccines are trying
to provoke an auto-immune response - that is, they
are targeted on interfering with the normal function
ing of the human body and its immune system. With
the increased prevalence of diseases that attack the
human immune system, is it wise to develop a vaccine
that may make it easier for those attacks to take root?
As Carl Djerassi, the chemist who produced the first
orally active progestogen, norethisterone, in 1951,
has pointed out recently, “even if the medium-term
technical problems are resolved, it will take many
years of carefully controlled studies with large num
bers of women volunteers to determine how long it
takes for the effect of the antifertility vaccine to wear
off, whether all women are then able to produce nor
mal babies,“and whether there are serious side effects
after extensive use of such vaccines.”44
An abortion pill?
Some of the most controversial contraceptive
research in recent years has focused around the
development and introduction of an antiprogesto
gen called mifepristone that is sometimes better
Problem Drugs
Searching for alternatives
153
8 A .
Contraceptives
known by its drug testing identification number,
RU486. The drug, manufactured by Roussel Uclaf,
prevents the functioning of the hormone proges
terone, which is essential for a successful pregnancy.
It has been licensed in France, China, Sweden and
the UK for the medical termination of pregnancy
(abortion), provided that a prostaglandin analogue
(such as gemeprost) is administered two days later.45
It has been shown to be effective in about 95% of
cases if it is taken by the 7th week of pregnancy.
Popularly known as the “abortion pill”, mifepristone
has been both hailed and condemned, depending on
attitudes towards abortion. Carl Djerassi described
mifepristone as “the most significant research
achievement of the 1980s in new practical fertility
control”.46 Sir Malcolm Macnaughton, Professor of
Obstetrics and Gynaecology at the University of
Glasgow, said it was “an advance in reproductive
medicine of the same magnitude as the development
of the hormonal contraceptive pill”.47 Threats of a
boycott by the anti-abortion lobby led Roussel Uclaf
to announce at one point that it would suspend distri
bution of the drug in France, only to reintroduce it
two days later on the instruction of the French
Minister of Health who described it as the “moral
property of women”.48 In 1991, two anti-abortion
groups called on UK doctors to boycott products
manufactured by Roussel and its parent company,
Hoechst.49 In the USA, the pressure from the anti
abortion lobby has led to a reluctance on the parr of
Roussel to seek registration of the drug, despite calls
for clinical research on mifepristone by the American
Medical Association and the American Association
for the Advancement of Science.50 It also led to an
“import alert” from the US Food and Drug
Administration banning personal importation of
mifepristone on rhe grounds that medical supervision
was required for proper use.51
In developing countries, Roussel originally had a
distribution agreement with WHO, although
Professor Etienne-Emile Baulieu, who developed
rhe drug, has accused Roussel and WHO of block
ing the product’s marketing worldwide because of
political pressure.52 An indication of the kind of
political pressure being levelled on WHO is evident
in the request from the US State Department to
WHO to ensure that no US funds were being used
to promote the use of the drug. It also asked
whether WHO was recommending the use of the
drug in countries where medical supervision is
unlikely.53 Roussel announced in May 1993 that it
would license the drug and make it over to the
Population Council. The Population Council would
then be responsible for finding a manufacturer and
conducting the necessary clinical trials to enable
wider use of the drug. 53a
Professor Baulieu claims that mifepristone could be
most useful in developing countries, even though
there is the possibility that it could be used in less
stringent conditions than those in force in France and
the UK.54 Other commentators are more cautious,
pointing out that “in many developing countries
women with unwanted pregnancies face not only
poor access to medical care but also the illegality of
abortion unless medically indicated. In such circum
stances, it is likely that these drugs will only be
available on the black market, at a price, and proper
information on the drugs will not be available.
Edouard Sakiz, chairman of Roussel, said in 1990
that “the quickest way to sabotage the product and its
usage procedures would be to market it as it is in
Third World countries”. He said that health authori
ties in China and India had said that “it would be
impossible to control a product of that kind in their
countries.”55,1
The controversy around mifepristone is likely to
continue throughout the 1990s. It is likely to be
some time (if ever) before widespread use of a
product like mifepristone will become a reality.
Many questions must still be resolved about the use
of this type of abortifacient. A safety issue, that also
has bearing on the need for adequate health services,
is what happens in the 5% or more (with improper
use) of cases where a pregnancy is not successfully
terminated? Prostaglandins have been reported to be
teratogenic in humans, so the availability of an alter
native means of termination is essential.56 This
means that the abortion pill is not a do-it-yourself
substitute for vacuum aspiration abortions.57
Roussel’s chairman has stated clearly that using
mifepristone is much more complex than vacuum
aspiration. “It’s an appalling psychological ordeal”
for the woman.57,1 In any case, vacuum aspiration is
an effective and relatively safe method of abortion.
The problem is not the method, but lack of access to
it in developing countries. The abortion pill is not an
appropriate answer to a* series of social, cultural,
political and economic constraints that make it diffi
cult for women to have access to safe, legal
abortions.
Natural family planning and breastfeeding
The difficulties that now exist in the field of con
traceptive development have provided an
opportunity to take a fresh look at natural family
planning (NFP).58 NFP methods have been
described as “probably the methods of choice” for
developing countries because they are simple,
inexpensive (requiring only some educational
input), free of side effects, and acceptable to most
cultures and religions.59 An international study
conducted by WHO found that couples who used
the methods correctly (daily monitoring of tem
perature and cervical mucus for eight cycles) were
able to achieve a contraception rate of 97%. The
study also found that 94% of women could iden
tify the fertile phase after a training period that
covered three cycles.60
8 A .
Breastfeeding also significantly lowers the risk of
both ovarian and breast cancer. For example, the
risk of breast cancer for women who breastfeed is
half that of women who do not breastfeed.62
Including breastfeeding as part of a natural family
planning programme may be a way of ensuring con
traceptive protection while promoting infant
health, as exclusive breastfeeding provides rhe best
possible nutrition during the first four to six
months of life.
Recommendations for action
Family planning programmes will be more
effective if reproductive services incorporate the
Essential Drug and Primary Health Care concepts:
fertility regulating services should be
comprehensive, including maternal and child
health care and other health services, accessible
to everyone, irrespective of age, sex or marital
status. Paying attention to women’s overall
reproductive health may lead to safer choices of
contraception.
For this to happen, women and men should have a
free choice of methods and balanced information.
This involves meeting basic criteria such as those
set out in the WEMOS and HAI Guidelines for the
Distribution and Use of Fertility Regulating
Methods:63
1. a wide range of contraceptive methods as well
as safe abortion and sterilisation to choose from;
2. full, unbiased information about the
contraceptive options available; their risks, their
benefits, clear instructions about how they should
be used, and the possible impact they will have on
personal relationships and daily life;
3. an opportunity to decide on which method to
use free from sanctions or incentives;
4. access to a good health care system because
many methods are provider-dependent, and
require settings where the user has access to
follow-up care, and where removal on demand is
assured.
Research efforts should also be expanded to
improve the availability and convenience of
existing user-controlled methods of contraception
including barrier and natural methods.
Above all, improving the political, economic and
social status of women and involving them more
fully in the design and implementation of family
planning programmes is liable to have the most
long-lasting impact.
155
Problem Drugs
Breastfeeding, long hailed as the single most impor
tant method of birth spacing, is now often
incorporated into NFP programmes. Studies have
shown that when a baby is nearly fully breastfed for
the first six months and when menstruation has not
returned, ovulation fails to occur. This lactational
amenorrhoea method (LAM) provides at least 98%
protection against pregnancy.61
Contraceptives
156' 8 A
Contraceptives
Problem Drugs
References:
1.
2.
3.
4-
Khanna,)., van Look, P.FA, and Griffin, P.D. (eds), Reproductive Health: a Key
to a Brighter Future, Geneva, WHO, 1992, p4
Ibid, p6
DaVanzo,)., Parnell, AM., and Foege, W.H., “Health consequences of
contraceptive use and reproductive patterns: Summary of a report from the
US National Research Council", Journal of the American Medical Association,
Vol 265, No 20, 22/29 Msv 1991. PP2692-6
Jacobson, |.L, Women’s Reproductive Health: the silent emergency,
(World-.vatch Paper 102), Washington, Woridwatch Institute, 1991. P52
Lethbridge, D.J., “Choosing and using contraception: toward a theory of
women’s contraceptive self-care", Nursing Research, Vol 40, No 5, Sep-Oct
1991, pp2/6-8o
Ibid
34.
Bremner, W.J., Bagatell, C.J. and Steiner, RA, "Gonadotropin-releasing
hormone antagonist plus testosterone: a potential male contraceptive”,
Journal of Clinical Endocrinology and Metabolism, Vol 73, No 3,1991,
35.
36.
PP465-9
Winters and Marshall, op cit, PP464A-B
Taylor, G.T., Griffin, M.G. and Bardgett, M., "Search for a male contraceptive:
the effect of gossypol on sexual motivation and epididymal sperm", Journal
37.
of Medicine, Vol 22, No 1,1991, PP29-44
Jeffcoate, S.L., “Progress towards a systemic male contraceptive", chapter 17
38.
39.
in: Filshie and Guillebaud, op cit, PP3O5-9
Ibid
Grubb, G.S., “Experimental methods of contraception”, Current Opinion in
Filshie, M., "Abortion”, chapter 14 in: Filshie, M. and Guillebaud, |. (eds),
Contraception: Science and Practice, London, Buttenvorth-Heinemann, 1989,
40.
41.
Obstetrics and Gynecology, Vol 3,1991, PP491-5
Anon., “Ortho’s contraceptive vaccine", Scrip, No 1687, 29 Jan 1992, pz6
Pain, S., "Hopes grow for 'perfect' contraceptive”, New Scientist, 2 Mar 1991
PP250-74
Potts, M. and Rosenfield, A, “The fifth freedom revisited: I, background and
existing programmes", Lancet, Vol 336,17 Nov 1990, PP1227-31
9.
Guillebaud, J., The Pill, Oxford, Oxford University Press, (4th edn) 1991, P227
10.
Jacobson, op cit, PP32-3
11 Khanna, et al, op cit, P13
12.
Bang, RA, Bang, AT., et ai. “High prevalence of gynaecological diseases in
rural Indian women”. Lancet, No 8629,14 Ian 1989, pp8s-8
13.
Jacobson, op cit, p28
14.
Winters, S.J. and Marshall, G.R., “Editorial: Hormonally-based male
contraceptives: will they ever be a reality?", Journal of Clinical Endocrinology
and Metabolism, Vol 73, No 3.1991, pp464A-B
15.
Hardon, A, “Contraceptive research: women's perspectives”, in: Mintzes, B.
(ed.), A Question of Control: Women’s Perspectives on the Development and
Use of Contraceptive Technologies, Amsterdam, WEMOS Women and
Pharmaceuticals Project/HAI, 1992, P7
16.
Lethbridge, op cit, PP276-80
17.
Brown, P„ “Cash for contraception will keep family sizes faliing", New
Scientist, 18 May 1991, P15
18.
Khanna, et al, op cit, P139
19.
Spieler, J., “US Agency for International Development: Support for NFP”, in:
Queenan. J.T., Jennings, V.H., et al, Natural Family Planning: Current
Knowledge and New Strategies for the 1990s, (Proceedings of a conference
held at Georgetown University, 10-14 Dec 1990), Washington, DC, Georgetown
University, Apr 1992, p6
20.
UNFPA, 1984 Report, New York, UNFPA, 1985, p8
21.
LaCheen, C., “Population control and the pharmaceutical industry", in:
McDonnell, K. (ed.). Adverse Effects: Women and the Pharmaceutical
Industry, Penang, IOCU, 19S6, P90
22.
Pappert, A., “The rise and fall of the IUD", in: McDonnell, op cit, pi68
23.
Lappe, EM. and Schurman, R„ Taking Population Seriously, London,
Earthscan Publications, 1989, p22
24.
Ibid, ppz6-7
25.
Ibid, PP4O-2; LaCheen, op cit, ppi20-24
26.
Jacobson, op cit, P39
27.
Lappe and Schurman, op cit, P45
28.
Letter from James D. Shelton, Chief, Research Division, and Cynthia Calla,
Medical Officer, Family Planning Services Division, of the Office of Population,
USAID, Washington, DC, to Carlos Huezo, Medical Director, International
Planned Parenthood Federation, London, 21 Aug 1991
29.
Jacobson, op cit, P52
30.
Maranga, J., “A question of education", Orbit, Autumn 1988, pi4
31.
United Nations Population Fund, The State of the World Population 1992,
New York, 1992, cited in: Anon., “Women’s status and world population”,
Lancet, Vol 339, 2 May 1992, pno7
32.
Guillebaud, J., Contraception: your questions answered, London, Churchill
Livingstone, (revised edn) 1991, PP293-4
33.
WHO Task Force on Methods for the Regulation of Male Fertility,
“Contraceptive efficacy of testosterone-induced azoospermia in normal men”.
Lancet, Vol 336, 20 Oct 1990, PP955-9
42.
43.
5.
6.
7.
8.
Khanna, et al, op cit, P91
Hardon, A, “An analysis of research on new contraceptive vaccines”, Women
and Pharmaceuticals Bulletin, Nov 1990, pp22-4
44.
Djerassi, C, “The bitter pill", Science, Vol 245, July 1989, PP356-61
45.
Khanna, et al, op cit, PP98-9; Anon., "Mifepristone approved in Sweden",
46.
47.
48.
Scrip, No 1752,11 Sep 1992, P27
Djerassi, op cit, PP356-61
Anon., “UK approval for mifepristone", Lancet, Vol 338,13 Jul 1991, ppm-2
Williams, C. (ed.), The “Abortion Pill": widening the choice for women,
49.
London, Birth Control Trust, 1990, p6
Anon., “UK pro lifers boycott Roussel/Hoechst”, Scrip, No 1656,1 Nov 1991,
P7
Potts, M., “USA: Access to mifepristone”, Lancet, Vol 339,9 May 1992,
PP1161-2
51.
Charo, A., “USA: Personal importation of mifepristone”, Lancet, Vol 340,
25 Jul 1992, P229
52.
Anon., “Prof Baulieu on mifepristone", Scrip, No 1542, 22 Aug 1990, P19
53.
Anon., “New York Mayor’s mifepristone campaign", Scrip, No 1608,17 Apr
1991, pi8
53a Anon., “Mifepristone", Lancet, Vol 341,1 May 1993, p 1146
54.
Anon., Scrip, No 1542, op cit, P19
55.
Fonseca, W., Misago, C. and Kanji, N., "Misoprostol plus mifepristone",
Lancet, Vol 338, 21/28 Dec 1991, P1594
55a.Nau, J.-Y., “Drug firm defends marketing strategy on abortion pill”, Guardian
Weekly, 19 Aug 1990 (from an article in Le Monde, 1 Aug 1990)
56.
Silvestre, L., Dubois, C, et al, “Voluntary interruption of pregnancy with
mifepristone (RU 486) and a prostaglandin analogue: a large-scale French
experience". New England Journal of Medicine, Vol 322, No 10,8 Mar 1990,
50.
pp645-8
LeGrand, A, “The abortion pill: A solution for unsafe abortions in developing
countries?", Social Science and Medicine, Vol 35, No 6,1992, ppyGy-yG
57a.Nau, J.-Y., op cit
58.
Kambic, R.T., "Natural family planning use-effectiveness and continuation",
American Journal of Obstetrics and Gynecology, Suppl. to Vol 165, No 6,
Part 2, Dec 1991, pp2O46-2O48
59 Ryder, R.E.J., “Abortion”, Lancet, Vol 339, 20 Jun 1992, P1544
60.
Queenan, J J. and Moghissi, K.S., “Natural family planning: looking ahead",
American Journal of Obstetrics and Gynecology, Suppl. to Vol 165, No 6,
Part 2, Dec 1991, PP1979-80
61.
Gross, BA, “Is the lactational amenorrhea method a part of natural family
planning? Biology and policy, American Journal of Obstetrics and Gynecology,
Vol 165, No 6, Part 2, Dec 1991, PP2014-19
62.
Labbok, M. and Koniz-Booher (eds), Breastfeeding: protecting a natural
resource, Washington, Georgetown University, 1990, p8
63.
WEMOS/HAI, Guidelines for the Distribution and Use of Fertility Regulation
Methods, Amsterdam, WEMOS/HAI, 1991
57.
Chetley, A. Problem Drugs, Amsterdam,
Health Action International, 1993
Health Action International’s
coordinating offices:
/<j Z
\
8B. The pill
(
:VlO
oocO^T'
\v-’5 1
HAI Europe
Jacob van Lennepkade 334T
1053 NJ Amsterdam
The Netherlands
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accion para la Salud
Avda. Palermo 531
Dpto. 104
Lima 13
Peru
Lowering the risks
Oral contraceptives are among the most widely used
prescription drugs,1 the most widely researched,2 and,
“with an incredible profit margin", are among “the
most profitable of all pharmaceuticals”? First intro
duced in the 1960s, they are now used by more than
63 million women worldwide every day,4 46 million
of them in developing countries.5 The world market
for oral contraceptives was estimated at SI.8 billion
in 1989? In the UK in 1987, approximately 45% of
women aged 20-29 were using “the pill”. Although
only about 40% of women born in the 1930s had ever
used the pill, about 80% of those born in the 1950s
had used it.7 In the US in 1991, 28% of women
between the age of 15 and 44 were using oral contra
ceptives, the highest level since 1975? By 1995, the
US market for oral contraceptives is expected to be
worth some S1.4 billion dollars? However in
Mexico, where the pill was the most-widely used con
traceptive in the 1970s, it is now less popular than
injectable contraceptives, the intrauterine device
(IUD) and sterilisation. The reason: Mexican women
believe that the pill is more likely than other contra
ceptives to cause harmful side effects.10
Efficacy
Because the pill is taken by generally healthy women,
it is even more important that it should be extremely
safe as well as effective. Its effectiveness, when used
correctly, is not in doubt: with the combined oral
contraceptive (COC) containing two synthetic hor
mones, an oestrogen and a progestogen, pregnancy
occurs in less than one in 100 women per year.11 The
rates are similar for the newer “phased” COCs that
contain varying amounts of hormones in an attempt
to mimic the body’s own pattern of production of
hormones. Pregnancy rates for women using a
progestogen-only pill (POP) are higher, ranging from
one to three per 100 women years.12 The COC func
tions by preventing ovulation - creating a simulated
pregnancy - as well as making the cervical mucus less
penetrable by sperm and making the lining of the
uterus less receptive to implantation of a fertilised
egg. With the POP, the main effects are on the mucus
and uterus lining, although some disruption of the
ovulation cycle also occurs.
The effectiveness, of course, depends on the pills
being taken regularly. Recent research has shown
that from six to 20% of pill users may become preg
nant because of incorrect use.13 Most COCs are
taken for 21 days, followed by a seven day pill-free
time (or seven days of a placebo pill). If a pill is
omitted for more than 12 hours, alternative contra
ception, such as a condom or other barrier method,
should be used along with the pill during the next
seven days. Pills missed near the beginning or end of
the cycle are particularly likely to increase the risk of
ovulation and hence of pregnancy.133
Effectiveness can also be altered by interactions with
other drugs. In particular, drugs which may diminish
absorption by causing gastrointestinal disturbances
or inducing enzymes, such as antibiotics, antifungal
drugs, anticonvulsants or barbiturates, have been
identified as reducing the efficacy of oral contracep
tives.14 There is also some evidence that smoking - in
addition to being linked with an increased risk of car
diovascular adverse effects among pill users - could
reduce the efficacy of the pill.15
Safety
The safety profile is more controversial. In the late
1970s, it became clear that women using the pill had
an increased risk of thrombosis and other vascular
disorders-especially if they were smokers. A study by
the Royal College of General Practitioners in 1983
found a four-fold increased risk of death from arterial
diseases in COC users. The report also showed that
the pill user who smoked was not only more likely to
suffer an arterial disease event (chiefly a heart attack
157
158 8 B .
The
pill
Problem Drugs
or stroke) but was also much more likely to die as a
consequence. Deep venous thrombosis, pulmonary
embolism, myocardial infarction, thrombotic strokes,
haemorrhagic strokes and other arterial diseases have
been shown to be commoner in COC users.16
The pill and breast cancer
In 1983, another concern surfaced about the pill.
Two studies linked the pill with cancer. The first, by
Professor Malcolm Pike and his colleagues in Los
Angeles, suggested that women under 25 who took a
COC with a high progestogen content for five years
ran a four-fold risk of getting breast cancer. The sec
ond study, by Professor Martin Vessey and his
colleagues at Oxford University, suggested that
women using COCs ran a 75% greater risk of devel
oping cervical cancer than those using an IUD. Both
reports, published in the same issue of The Lancet,
stirred up controversy.17
Since then, both studies have come in for consider
able reassessment and additional research has looked
for other associations which could explain the
results. A 1989 study in the UK found that women
under 36 years of age who used an oral contraceptive
for more than eight years ran a 74% increased risk of
developing breast cancer, while the increased risk
was 43% for those who had been using the pill for
between four and eight years.18 The Nurses’ Health
Study in the USA, which has been monitoring nearly
120,000 women for more than 10 years, concluded
that “past use of oral contraceptives is not associated
with a substantial increase in breast cancer”.19 A
detailed analysis of data from the Cancer and Steroid
Hormone Study (CASH study) in the USA concluded
that “oral contraceptive use appeared to increase
slightly the risk of breast cancer for women aged 2034 years of age, did not appear to affect the risk of
breast cancer for women aged 35-44, and appeared
to confer a slightly decreased risk of breast cancer for
women aged 45-54 years”.20 It noted that caution
was needed in interpreting the findings because the
range of increase or decrease of risk was quite small.
A comprehensive epidemiological review published in
1992 concluded that “there is no consistent evidence
of an association between progestins and breast can
cer”.21 A review of case-control studies, published in
1991, used data collected principally in the 1980s by
well recognised research groups observing strict pro
tocols. This review concluded that there was a “strong
consensus that oral contraceptives have not increased
the risk of breast cancer in women over age 45, even
when they have been used for long periods”. It also
found that among younger women, the evidence for a
causal relationship between oral contraceptives and
breast cancer was insufficient.22 A second 1991 review
concluded that oral contraceptives “have caused little
or no overall increase in the risk of breast cancer in
women in developed countries”. It added that “limited
information from developing countries... suggests that
use of oral contraceptives may moderately enhance
risk in women in low risk populations”. In other
words, women who would not normally be expected
to develop breast cancer may be more at risk.-3
Despite more than three decades of use, the evidence
about the links between the pill and breast cancer is
still inconclusive. There is little information available
regarding the risk to women who start using the pill
when they are very young - often the very women for
whom the pill is the most popular form of contracep
tion.2,1 As one researcher points out, “it is possibly
too soon to know what the long-term effects of using
oral contraceptives while young on breast cancer
actually are”.25 Partly this is because of the constant
changes in dosage levels of oral contraceptives over
the last 30 years which makes accurate comparison
of effects over time difficult,26 and partly it has to do
with the difficulty' in establishing possible causes of
breast cancer generally.
Risk of cervical cancer
On the question of oral contraceptives and cervical
cancer, Vessey himself subsequently said that
“although the balance of evidence suggests quite
strongly that prolonged oral contraceptive use
slightly increases the risk of cervical cancer”, it was
“impossible to be sure that the effect is not due to
incompletely controlled confounding by sexual fac
tors.”27 Nevertheless, he considered it important for
women using an oral contraceptive to have an annual
cervical examination.
A WHO study carried out in eight developing and three
industrialised countries found a 20% increased risk of
cervical cancer among oral contraceptive users in
developing countries. However, the report also noted
that “the observed increase in risk in users may be due
to behavioural characteristics of users or their male
partners conducive to the spread of sexually trans
mitted diseases”.28 In contrast, use of barrier methods
of contraception, such as the diaphragm, led to a reduc
tion in the risk of cervical cancer by as much as 75%.29
AIDS and the pill
One barrier method of contraception - the condom is now a valuable tool in public health efforts to com
bat the spread of sexually transmitted diseases (STDs)
in general and acquired immunodeficiency syndrome
(AIDS) in particular. In the light of evidence that shows
increases in the heterosexual spread of AIDS, a new
factor needs to be considered when decisions are made
about choices of contraceptives. A major disadvantage
of the pill is that it does not provide any protection
from STDs, nor from the human immunodeficiency
virus (HIV) causing AIDS. In Japan, for example,
where 80% of married couples use the condom for
contraception, the government has consistently
8 B .
The
pill
Problem Drugs
delayed issuing a licence for low-dose contraceptive
pills. The reason is cited as being concern that avail
ability of the pill might contribute to the spread of HIV
infection in Japan.30
Several studies have suggested that hormones in the
pill can modify immune mechanisms. “The effects
are of a similar nature to, but less marked than, those
associated with pregnancy.... The prospective studies
have shown an increase in inflammations and some
disorders which are believed to have an immune
basis.”31 Taking a drug which might challenge the
human immune system itself, albeit in a minor man
ner, should not be a light decision. This is particularly
important when considering the usual group of
women who use the pill.
The pill is often prescribed for young, sexually active
women who may have multiple sexual partners (or
whose partners may be sexually involved with oth
ers). They are among the groups with the greatest
risk of STDs and AIDS, and a major consideration
should be a choice of contraceptive that protects
against more than simply pregnancy. In today’s
world, the pill may not be the prime choice.
Other adverse effects
The risk of liver cancer is increased among pill
users.32 Because liver cancer is rare, the absolute risk
is quite low, but it nonetheless exists. Pill users also
have an increased risk of gall bladder disease and of
gallstones.33
Because the COC causes a hormonal change similar
to a state of pregnancy, many of the frequent side
effects resemble those of pregnancy. The most com
monly reported adverse effects include: nausea,
vomiting, headache, tenderness of the breasts,
changes in body weight, thrombosis, loss of libido,
depression, brown pigmentation on the face
(chloasma), raised blood pressure, impaired liver
function, reduced menstrual loss, “spotting” early in
the cycle, loss of periods, and (rarely) sensitivity of
the skin to sunlight.34
A common complaint from pill users is depression. It
has been reported in both the COC and POP pills.34*
“Norethisterone particularly seems to be related to
depression of mood.”35 However, norethisterone has
one of the lowest ratings for progestogen potency, and
is therefore a frequently used progestogen in COCs.
Possible advantages
The pill has been shown to have some advantages in
addition to its effectiveness as a contraceptive. Among
these are predictable menstrual periods with less blood
loss, and less risk of fibroids and of benign breast dis
ease.36 Oral contraceptive use decreases the risk of
pelvic inflammatory disease by about 50%, although
1591
Wyeth advertises the “unsurpassed safety profile" of the oral
contraceptive Nordette in Pakistan in 1990 without any
information on risks of serious adverse effects or
comparisons to risks of other contraceptives.
some evidence suggests that the use of the pill leads to a
two to threefold increase in chlamydia infections of the
cervix.37 Ovarian cancer, which is rare, and cancer of
the endometrium (the lining of the uterus) are less com
mon among oral contraceptive users.38 Women who
use an oral contraceptive for as little as six months have
40% less risk of developing ovarian cancer for up to 15
years after use. Women who use an oral contraceptive
for at least a year have about half the risk of endome
trial cancer. In both cases, the greatest protective effect
is evident among women with few or no children those who are usually at the highest risk of these types
of cancer.39
Contraindications
The pill should not be used by women who are preg
nant, have a history of thrombosis or jaundice, have
previously been exposed to diethylstilbestrol (DES), or
who have liver disease, sickle cell anaemia, high blood
fat levels, cancer of the breast or womb, severe
migraine, undiagnosed bleeding from the vagina, his
tory of severe itching (pruritus) in pregnancy or
deteriorating otosclerosis (a condition which causes
hearing loss). The pill should not be the first choice con
traceptive for women who suffer from obesity,
diabetes, raised blood pressure, heart or kidney disease,
mild migraine, epilepsy, depression, asthma, multiple
sclerosis, who wear contact lenses, have varicose veins,
smoke, are over 35 years of age, or are breastfeeding.40
8 B .
The
pill
Selecting the right pill
Identifying who could use the pill is the first step
towards more rational use. The second is deciding
which pill to use. There is now almost universal
acceptance that low-dose pills are best.
“Safer pills are smaller pills (i.e. lower dose).
The dose of ethinyloestradiol (EE) should be
no more than 30-35 mcg combined also with
a low dose of the selected progestogen - both
hormones being capable of unwanted meta
bolic effects and their epidemiological
consequences. The dose of both the oestrogen
and the selected progestogen should be the
lowest acceptable in the individual woman.
Latest data suggest that this policy really does
reduce the risk of major side effects. Clinical
experience shows that minor side effects also
(apart from those linked with the bleeding
pattern) are less frequent and less severe.”'11
The American Medical Association (AMA) says, “as a
general rule, preparations containing the smallest
quantity of steroid consistent with efficacy and tolera
ble side effects are preferred. This means selection of a
product containing less than 50 mcg of estrogen for a
first-time user.”42 Because higher-dose oestrogen for
mulations are associated with a greater incidence of
adverse effects without greater efficacy, the US Food
and Drug Administration (FDA) has recommended
that they no longer be marketed in the United States.43
The FDA has also warned oral contraceptive manu
facturers not to use unfounded claims in their
promotional materials in an attempt to define non
existent differences among the low-dose pills.
According to the FDA, “there have been no data sub
mitted to the agency which demonstrate that the
differences being cited in the promotion of low-dose
oral contraceptives indeed exist, and if so, are clini
cally relevant.”44
The UK Committee on Safety of Medicines has
recommended that “women receiving oral contra
ceptives should be prescribed a product with the
lowest suitable content of both oestrogen and
progestogen.”45
Progestogen-only pills “are suitable for older
patients who may be at risk from oestrogen, heavy
smokers, and those in whom oestrogens cause severe
side-effects.”46 Because the POP does not interfere
with the quantity of breast milk and only very tiny
amounts of the hormone have been shown to get into
the milk, POPs are widely used by women who are
breastfeeding.47 However, because hormones might
affect the endocrine balance in the infant 47a and
long-term effects are not known, it is preferable to
use a non-hormonal form of contraception while
breastfeeding.
No matter which pill is selected, “patients require
periodic evaluation for side effects.”48 According to
the AMA, “Patients taking OCs should be monitored
regularly. Biannual [every six months] blood pres
sure measurement and annual physical examination,
including urinalysis, liver palpation, and breast and
pelvic examinations... should be performed....
Patients should be encouraged to examine their
breasts monthly.”49
Regular examinations are unlikely in many develop
ing countries. In some countries, programmes to
distribute contraceptive pills explicitly target those
who do not have access to health care. This means
that women with high-risk conditions may be more
likely to use the pill and that follow-up medical
attention may be more difficult to find in the event of
unpleasant or dangerous adverse effects.50
Sensible use in developing countries is also compli
cated by the abundance of different types of pills on
the market. Dr John Guillebaud, a gynaecologist and
expert in famdy planning, answers the question
“which COC brands are unacceptable for normal
prescribing?” by stating:
“First, the 50 mcg oestrogen brands, since
the aim of effective contraception is achiev
able with less oestrogen in most cases....
Secondly, the brands giving 250 mcg of lev
onorgestrel (Eugynon 30, Ovran 30) and
2000 mcg of ethynodiol diacetate (Conova
30) are unbalanced.... Their use should be
restricted mainly to gynaecological indica
tions.... Microgynon/Ovranette and
Neocon/Norimin alter lipids adversely
enough to be no longer first choice pills for
women starting the method.”51
Another brand which is of dubious value is Loestrin
20, described by the British National Formulary as
“less suitable for prescribing” because the amount of
oestrogen present may be too small to provide ade
quate contraception.’2
During the 1980s, there has been “a dramatic shift” to
low-dose oral contraceptives, particularly in industri
alised countries. According to IMS - an international
market research firm - by 1987 low oestrogen pills
accounted for 85% of all pharmacy purchases of
COCsin 18 industrialised countries and about 60% in
19 developing areas.53 Even so, as the table on page
161 indicates, more than 40% of the 87 oral contra
ceptives on the market in four regions of the Third
World during 1990 and 1991 could be considered as
less suitable for prescribing - usually because the level
of oestrogen was at the highest acceptable level cou
pled with a high level of progestogen potency, or
because they were unbalanced, with an excessive
progestogen content.
[See also the sections on: Contraceptives, IUDs,
Injectables, and Implants]
8 B .
-- ----------------------------- ------------------- -
Oral contraceptives on the market in selected areas (1990-1)
Brand name & company
OES
PRO
PRO
Type of
mcgs.
mgs.
POT
progestogen
Availability
First choice
Brevinor (Syntex)
35
0.50
L
Gynera (Schering AG)
norethisterone
30
008
L
Loestrin 30 (Parke-Davis)
gestodene
M
30
1.50
L
Marvelon 28 (Organon)
norethist. acet
A
30
0.15
L
desogestrel
Minulet (Wyeth)
p
30
0.08
L
Ortho Novum 1/35 (Ortho)
gestodene
A
35
1.00
L
norethisterone
Ortho Novum 7-7-7 (Ortho)
C
35
0.75
L
norethisterone
C
Ovysmen (Ortho-Cilag)
35
0.50
L
norethisterone
A, M
Synphase (Syntex)
35
0.71
L
norethisterone
C, M
Trinovum (Cilag)
35
0.75
L
norethisterone
A
Anteovm (Medimpex)
50
0.13
M
levonorgestrel
A.C, M
Logynon/ED/Triquilar(Schering)
32
0.09
M
levonorgestrel
A, C, M
Lyndiol (Organon)
50
2.50
M
lynestrenol
A
Mmovlar 21 (Schering)
50
1.00
L
norethist. acet
P
Non-Ovlon (Germed)
50
1.00
L
norethist. acet
M
Norimin (Syntex)
35
1.00
L
norethisterone
A, M
A, C, M
A, C, M
Second choice
Norinyl-1 (Syntex)
50
1.00
L
norethisterone
Ortho Novin (Ortho Cilag)
50
1.00
L
norethisterone
M
Ortho Novum 1/50 (Ortho)
50
1.00
L
norethisterone
C, M
Trinordiol (Wyeth)
32
0.09
M
levonorgestrel
A, C, M
Yerminol (Ciba)
40
2.00
n/a
lynestrenol
A, M
Femulen (Searle)
0.50
n/a
ethynodiol diac
A
Micronor (Ortho-Cilag)
0.35
n/a
norethisterone
A, M
Noriday (Syntex)
0.35
n/a
norethisterone
A, M
0.75
n/a
levonorgestrel
A, C, M, P
Special use-POPs
Post-coital
Postinor (Medimpex)
Less suitable
Anovlar 21 (Schering)
50
4.00
H
norethist. acet
P
Conova 30 (Searle)
30
2.00
H
ethynodiol diac
A, C
Eugynon/ED (Schering)
50
0.50
H
norgestrel
A.C, M
Gravistat (Germed)
50
0.13
H
levonorgestrel
M
Loestrin 20 (Parke-Davis)
20
1.00
L
norethist. acet
A, M
Microgynon 30/ED (Schering)
30
0.15
H
levonorgestrel
A, C, M
Neogynon/ED (Schering)
50
0.25
H
levonorgestrel
A, C.M
Nordette (Wyeth)
30
0.15
H
levonorgestrel
A, C,M, P
Nordiol (Wyeth)
50
0.25
H
levonorgestrel
A, C, M
Ortho Novum (Ortho)
100
2.00
n/a
norethisterone
Ortho Novum 1/80 (Ortho)
80
1.00
L
norethisterone
C
c
Ovidon (Medimpex)
50
0.25
H
levonorgestrel
A, M
Ovostat (Organon)
50
1.00
n/a
lynestrenol
A
Ovostat 28 (Organon)
50
1.00
n/a
lynestrenol
A
Ovral (Wyeth)
50
0.50
H
norgestrel
A, C, M, P
Ovulen 50 (Searle)
50
1.00
H
ethynodiol diac
A, C, M
Rigevidon (Medimpex)
30
0.15
H
levonorgestrel
A, M
amount ot progestogen in milligrams; PRO POT = progestogen potency, expressed as high (H),
Key: UtS = amount ot oestrogen m
..
........................
. ...
M\. AuaitahllltV! A = Africa (29 products), C = Caribbean (25 products), M = Middle East (27 products), P =
medium (M), low (L), or not dVd"/dr^7.v/’ “hAirA f"nr nresCribing (low oestrogen and low progestogen potency): Second choice (either low oestrogen
Pakistan (6 products); «'ect
--- -Drosestoge n potency); Special Use: the progestogen-only pills which are recommended
With medium progestogen potency, u, .
=
containing oestrogen; less suitable = pills that are difficult to recommend, usually
for older women or tnose wno sune »
5
. wjfh a hjgh prOgestogen potency, or are unbalanced, in that the progestogen level is too high
because they contain a higher oestrogen ievei vuup
Sources: MIMS Africa (July 1991),
MIMS Caribbean (Jan 1991), MIMS Middle East (June 1990), QIMP (Pakistan, Mar-Aug 1990)
pill
161
Problem Drugs
Table 8B-1
The
162
The
8 B .
pill
Problem Drugs
Recommendations for action
1. Governments should review the oral
contraceptives on the market in their countries
with a view to reducing the number of products,
bearing in mind the overwhelming weight of
advice that suggests that low-dose pills are
safer.
2. Women should be provided with clear and
consistent objective information comparing the
advantages and disadvantages of the various
methods of contraception available. If a choice
is made to use an oral contraceptive, clear
instruction about its proper use should be
given, including the need for regular medical
check ups.
3. Where oral contraceptives are distributed as
part of family planning programmes, care
should be taken to ensure that adequate
equipment and training is available for health
workers to be able to perform the necessary
tests prior to dispensing, and that follow-up
services are available.
4. Manufacturers should stop the production
and marketing of high-dose oral contraceptives
with an excessive progestogen content.
5. Research should continue into the long-term
effects of the use of oral contraceptives,
particularly the effect on women who start to
take the pill at an early age or take it for many
years.
References:
1.
Gilman, A.G., Rail, T.W., Nies, A.S., and Taylor, R (eds), Goodman and
Gilman's The Pharmacological Basis of Therapeutics, New York, Pergamon
2.
Press, (8th edn) 1990, P1402
Berer, M., “Contraception", chapter 15 in: Phillips, A., Rakusen, ]. (eds) and
the Boston Women's Health Collective, The New Our Bodies, Ourselves (2nd
3.
UK edition), London, Penguin Books, 1989, P290
LaCheen, C, “Population control and the pharmaceutical industry", in:
McDonnell, K. (ed.), Adverse Effects. Women and the Pharmaceutical
4.
Industry, Penang, IOCU, 1986, pio8
Wharton, C and Blackburn, R., “Lower-dose pills”, Population Reports, Series
5.
6.
7.
A, No 7, Baltimore, Johns Hopkins University, Nov 1988, pi
Anon., “OC needs in developing countries", Scrip, No 1696. 28 Feb 1992, p2i
Anon., “Schering AG’s prospects", Scrip, No 1500, 28 Mar 1990, pio
Milne, R. and Vessey, M., “The pill and mortality - an overview", Journal of
8.
Public Health Medicine, Vol 14, No 1,1992, PP9-16
Anon., “US use of DCs at highest level since 1975". Scrip, No 1653, 20 Sep
9.
1991, p28
Anon., The US Market for Selected Products Associated with Fertility &
Infertility, New York, Frost & Sullivan, 1991
10.
Anon., “Decline of oral contraceptive use in Mexico", Scrip, No 1684,
11.
12.
13.
17 Jan 1992, p2O
Wharton and Blackbum, 1988, op cit, pi2
Ibid, pi3
Finger, W.R., “Using oral contraceptives correctly: progress on package
instructions", Network, Vol 12, No 2, Sep 1991, ppizj-17 and 27; Potter, L.S.,
“Oral contraceptive compliance and its role in the effectiveness of the
method", chapter 16 in: Caramer, JA and Spilker, B. (eds), Patient Compliance
in Medical Practice and Clinical Trials, New York, Raven Press, 1991, PP195-207
13a. Guillebaud, J., The Pill, Oxford University Press, (4th edn) 1991, PP58-65 and
14.
209-14
Gilmer, M.D.G., “Metabolic effects of combined oral contraceptives", chapter 2
in: Filshie, M. and Guillebaud, J. (eds), Contraception: Science and Practice,
London, Butterworth-Heinemann, 1989, PP31-2
Guillebaud, J., op cit, P70
Guillebaud, J„ Contraception: your questions answered. London, Churchill
Livingstone, (revised edn) 1991, ppi02-3 and 117
17.
Pike, M.C, Henderson, B.E, et al, "Breast cancer in young women and use of
oral contraceptives: possible modifying effect of formulation and age at use";
and Vessey, M.P., Lawless, M., et al, “Neoplasia of the cervix uteri and
contraception: a possible adverse effect of the pill", Lancet, No 8356, 22 Oct
1983, pp926-3o and 930-4
18.
UK National Case-control Study Group, “Oral contraceptive use and breast
cancer risk in young women", Lancet, No 8645, 6 May 1989, PP973-82
19.
Romieu, I., Willett, W.C., et al, "Prospective study of oral contraceptive use
and risk of breast cancer in women", Journal of the National Cancer Institute,
Vol 81, No 17,6 Sep 1989, PP1313-21
20.
Wingo, PA, Lee, N.C., et al, “Age-specific differences in the relationship
between oral contraceptive use and breast cancer", Obstetrics and
Gynecology, Vol 78, No 2, Aug 1991, PP161-70
21.
Staffa, JA, Newschaffer, C.J., et al, "Progestins and breast cancer: an
epidemiologic review”, Fertility and Sterility, Vol 57, No 3, Mar 1992,
15.
16.
PP473 91
Harlap, S., “Oral contraceptives and breast cancer: cause and effect?". Journal
of Reproductive Medicine, Vol 36, No 5, May 1991, PP374-95
23.
Thomas, D.B., "Oral contraceptives and breast cancer: review of the
epidemiologic literature", Contraception, Vol 43, No 6, Jun 1991, PP597-642
24.
Szarewski, A. and Guillebaud, J., "Contraception: current state of the art”,
British Medical Journal, Vol 302, 25 May 1991, ppi224-6
25.
McPherson, K„ “Combined progestin and estrogen (oral) and other forms of
hormonal contraception", Current Opinion in Obstetrics and Gynecology,
Vol 3,1991, PP486-90
26.
Djerassi, C, "The bitter pill", Science, Vol 245, 28 Jul 1989, pp356-6o
27.
Vessey, M.P., “Oral contraception and cancer", chapter 4 in: Filshie and
Guillebaud, 1989, op cit, p63
28.
Thomas, D.B., “The WHO Collaborative Study of Neoplasia and Steroid
Contraceptives: the influence of combined oral contraceptives on risk of
neoplasms in developing and developed countries", Contraception, Vol 43,
No 6, June 1991, PP695-710
29.
Guillebaud, 1991, Contraception, op cit, P43
30.
Anon., “Japan's wait for low dose 'pill"’, Lancet, Vol 339,4 Apr 1992, P865
31.
Guillebaud, 1991, Contraception, op cit, P152
32.
Vessey, 1989, op cit, PP63-4; Hsing, A.W., Hoover, R.N., et al, “Oral
contraceptive use and primary liver cancer among young women”, Cancer
Causes and Control, Vol 3,1992, PP43-8
33.
AMA, Drug Evaluations, Philadelphia, W.B. Saunders Co., (6th edn) 1986, P724
34.
Parish, P., Medicines: a guide for everybody, London, Penguin (6th edn,
revised), 1989, P247
34a. BMA and the Royal Pharmaceutical Society of Great Britain, British National
Formulary, London, BMA and The Pharmaceutical Press, No 23, Mar 1992,
pp23\83 and 286
35.
Ibid, P240
36.
Berer, 1989, op cit, P292
37.
Drife, J., “Complications of combined oral contraception", chapter 3 in: Filshie
and Guillebaud, 1989, op cit, P45
38.
Petitti, D.B. and Porterfield, D., "Worldwide variations in the lifetime
probability of reproductive cancer in women: implications of best-case, worst
case and likely-case assumptions about the effect of oral contraceptive use",
Contraception, Vol 45, No 2, Feb 1992, PP93-104
39.
Mishell Jr, D.R., "Contraception", New England Journal of Medicine, Vol 320,
No 12, 23 Mar 1989, PP777-87
40.
Parish, 1989, op cit, P247
41.
Guillebaud, 1991, Contraception, op cit, pno
42.
AMA, 1986, op cit, P720
43.
Mishell, 1989, op cit, PP777-87
44.
Anon., "FDA warns OC manufacturers", Scrip, No 1630, 3 Jul 1991, pi8
45.
von Eickstedt, K.-W., “Sex hormones and related compounds including
hormonal contraceptives", chapter 42 in: Dukes, M.N.G. and Beeley, L, (eds),
Side Effects of Drugs Annual 14, Amsterdam, Elsevier, 1990, P349
46.
BMA and the Royal Pharmaceutical Society of Great Britain, 1992, op cit,
P285
47.
Guillebaud, 1991, The Pill, op cit, P222
47a Lewis, RJ. and Hurden, E.L., “Breast feeding and drug treatment", in Hawkins,
D.F. (ed.), Drugs and Pregnancy, London, Churchill Livingstone. (2nd edn)
22.
1987, PP3O4-32
Gilman, Rail, et al, 1990. op cit, P1409
AMA, 1986, op cit, P723
LaCheen, 1986, op cit, pio8
Guillebaud, 1991, Contraception, op cit, P127
BMA and (he Royal Pharmaceutical Society of Great Britain, 1992, op cit,
P284
53.
Wharton, Blackbum, 1988, op cit, P9
48.
49.
50.
51.
52.
Chetley, A. Problem Drugs, Amsterdam,
Health Action International, 1993
?'a
LI3RARY
li '
8C. IUDs
■<\
AND
'
■1 ••'
o
documentation
y
uNtT
5 .^WGAtOB^^
Health Action International’s
coordinating offices:
HAI Europe
Jacob van Lennepkade 334T
1053 NJ Amsterdam
The Netherlands
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accion para la Salud
Avda. Palermo 531
Dpto. 104
Lima 13
Peru
Effecteooo [but safe?
Rosalind Hunt had an intrauterine device (IUD) fitted in
the days when doctors, encouraged by promotion from
manufacturers, thought it was a “good option ” for women
who had not had children. Rosalind subsequently devel
oped a painful infection in her uterus which was treated
with antibiotics. She also had the IUD removed. When she
later married and tried to have children, she discovered
that the infection had left her infertile - her Fallopian tubes
were blocked with scar tissue. She says of the IUD, “it was
a device promoted for people like me who had not had chil
dren but we were not adequately informed of the risks we
were taking”.1
Rosalind Hunt lives in England, where there is relatively
easy access to health care. Elvia Alvarado lives in a rural
area of Honduras and tells a different story:
“Methods like the IUD give lots of infections. And you have
to remember that when we get sick it’s hard for us to get to
a doctor. The nearest clinic is far away. And even if we could
see a doctor, we can’t afford to buy the medicine. I know a
woman who had to pay $60 to get rid of an infection in her
vagina. That’s more than most of us make in a month!”1
The IUD is one of the most widely used contraceptive
methods with more than 80 million users worldwide,
nearly 60 million of them in the People’s Republic of
China.3 Concern about the risk of infertility has led
to a decline in IUD use in industrialised countries in
recent years. An estimated 6% of women in the USA
and Europe use an IUD.’’ In the UK, the actual num
ber using an IUD is estimated at about 500,000 or
some 8 % of women using contraception. This makes
IUDs the third most popular method in the UK (after
condoms and the pill).5 In the USA in 1988, an esti
mated 700,000 women used the IUD (down from
more than 2.2 million in 1982),6 or about 3% of
women using contraception.7
How IUDs work
IUDs are either inert, copper-bearing or hormonereleasing plastic or metal devices inserted into the
uterus. How they act is nor absolutely certain, but it
is thought that they inhibit sperm and egg movement
and inhibit fertilisation.8 The current theory is that
the IUD causes a sterile inflammatory reaction in the
uterus so that the sperm or fertilised egg are rendered
ineffective by white blood cells. Copper is also toxic
to sperm and may have other effects which interfere
with conception, so this may be a factor in IUDs con
taining copper. The hormone-releasing IUDs alter
hormonal activity in the uterus and also make the
cervical mucus less permeable to sperm.5
Effectiveness
The IUD is highly effective. Pregnancy rates for
women with IUDs range from 1 to 4% each year.10
These failure rates are generally lower than failure
rates with barrier methods, which have the advantage
of fewer adverse effects. Unlike oral contraceptives,
the non-hormonal IUDs do not have systemic meta
bolic effects and thus can be used by women who
cannot use oral contraceptives because of age,
164 8 C .
IUDs
Problem Di
cigarette smoking, or certain pre-existing diseases,
such as hypertension. Continuation rates with IUDs
tend to be higher than many other forms of contra
ception due, at least in part, to the need to have a
trained health worker to remove the device. One fac
tor which can interfere with continuation and with
the effectiveness of rhe method is expulsion of the
device, since the uterus tends to expel foreign bodies.
Rates of expulsion range from one to almost 20 per
100 users, depending on the shape and design of the
IUD.11
If pregnancy occurs with an IUD in place, the risk (up
to 50%) of spontaneous abortion is greater than with
out an IUD; premature delivery and stillbirth may also
be more common. Ectopic pregnancy - when the
embryo becomes implanted in one of the fallopian
tubes rather than the uterus - is more common among
women who become pregnant when wearing an IUD
than without an IUD; its incidence is somewhere
between one in 20 and one in 30 pregnancies, com
pared to about one in 200 pregnancies among
non-IUD users.12 Because of the risks to both the fetus
and the mother, the IUD should be removed as soon as
pregnancy is diagnosed. If this cannot be done
(because the tail of rhe device is not visible) the World
Health Organization (WHO) says that the woman
“should be carefully counselled about the risks of con
tinuing the pregnancy.... If a woman continues her
pregnancy with an IUD in place, special obstetric care
is necessary because of an increased risk of premature
birth and a decreased likelihood of a live birth.”13
The Daikon Shield
Made of plastic, the Daikon Shield was oval in shape, with
small fins extending from its right and left sides, and a tail
string to facilitate proper placement and removal. It was
developed in the late 1960s and originally marketed by the
Daikon Corporation, which sold about 27,000 of these IUDs.
In June 1970, A H Robins acquired the product from the
Daikon Corporation and began sales and distribution in
January 1971.
Between 1971 and 1974, about 2.8 million Daikon Shields
were distributed in the USA and about 1.7 million in other
countries, including about 700,000 through the US Agency for
International Development (USAID). The company estimates
that 2.2 million Daikon Shields were actually used in the USA
and less than 1.4 million were actually used outside the USA.
The Daikon Shield was promoted by A H Robins as "the first
IUD specifically designed for women who had not yet had
children". However problems soon began to develop, caused
primarily by the tail of the device. (Many IUDs have a tail
which enables users to check whether the device is still in
place.) Unlike other IUDs, the tail of the Daikon Shield was
made up of several filaments enclosed in a sheath.
Experiments later showed that this tail acted like a "wick”
giving bacteria easy access to the uterus.
The result was serious PID for thousands of women, sterility,
and for at least 18 women, death. In 1973, Robins began
talks with the US Food and Drug Administration (FDA) on the
Adverse effects
safety of the product. In June 1974, Robins withdrew the
The most common adverse effect of the IUD is
increased blood loss - heavy or prolonged periods,
intermenstrual bleeding or spotting - often accompa
nied by pain and discomfort, and a discharge, either
watery or mucoid. This is also the commonest reason
for discontinuing the use of an IUD.14 A less frequent
but more severe adverse effect is perforation of the
uterus, which occurs in about one per 1000 inser
tions, almost always at the time of insertion.15
and other IUDs. In December 1974, the FDA completed its
Daikon Shield from the US market pending further study of it
study and said that the product could be marketed again with
a modified tail string under a special patient registry system.
Robins, however, chose not to remarket it. Sales were
discontinued outside the USA between July 1974 and March
1975.
A series of lawsuits was launched by women harmed by the
Daikon Shield and at least $500 million was paid out in
damages before Robins filed for protective bankruptcy in
Pelvic inflammatory disease
Another serious complication associated with IUD
use is pelvic inflammatory disease (PID). Although
all IUDs have been linked with PID, one in particular
- the Daikon Shield - was found to be especially haz
ardous. A large-scale study carried out in 1983 found
that the Daikon Shield carried at least a five-fold risk
of PID compared with all the other IUDs in use.16
(See the box on the Daikon Shield.)
August 1985. In January 1986, the company held
simultaneous press conferences in 20 major cities in an
attempt to reach all four million Daikon Shield users in 92
countries with the message that if they wanted to claim for
damages, they had to submit such a claim by 30 April 1986.
Approximately 192,000 claims were filed, most of which were
in the USA, where the company carried out the most
extensive publicity. A trust fund was set up with more than
$2,300 million to settle the claims.
ri (Cai)ada), The Daikon Shield - Background, information for
theUore«A|
PID is an infection within the fallopian tubes,
ovaries, or uterus. Its main symptoms are severe pain
or tenderness of the lower abdomen, discharge
(sometimes bloody) from the vagina, and fever. An
indication of the seriousness and prevalence of acute
PID is that it develops in an estimated 1% of young
UD??„
‘
n' a?,'985/early 1986)1 Pappert. A.. “The rise and fall of the
Industrv Penar,, mir-i i foo' Adverse Ft/ects: Women and the Pharmaceutical
conSnfte d8'
I986' P169: Ta,um' H J- a"d Connell, E.B.. "Intrauterine
Con racen
' C5ap,er 9 ,n: FilShi<J'
Times 13Anr iQRA
a"d GuHlebaui. J. (eds).
Practice' London, Butterworth-Heinemann, 1989,
pl56- Over C
a' a
rec°rds blocked in Daikon Shield claims’’, Sunday
NoSm°n ShieW TrUS‘ Se,tle™"t
166 8 C .
IUDs
Problem Drugs
use of an IUD may increase a woman’s risk of HIV
infection. According to a large European study,
among women with male HIV-positive sexual part
ners, those who were using an IUD for contraception
had the highest rate (40%) of HIV infection.25
Different types of IUDs
The most widely used IUD is the inert Ota ring device
which is prevalent in China. In the rest of the world,
copper-bearing devices are the favoured types, but
recently some hormone-releasing devices have been
tested. These offer both advantages and disadvan
tages. The main advantages of the latest type of IUD a device which releases 20 micrograms of the
progestogen levonorgestrel per day - are low rates of
pregnancy and possibly lowered incidence of PID. The
disadvantages include hormonal side effects and
bleeding disturbances, including absence of menstrual
periods.26 The other hormone-releasing IUD Progestasert - has been found to increase the absolute
risk of ectopic pregnancy by 1.5-1.8 times.27
There are no simple rules to the choice of device. As
long as there is no sensitivity to copper, any of the
copper-bearing IUDs could be used. A prime consid
eration in developing countries, however, is the lack
of access to adequate health care facilities for regular
check-ups and for removal and replacement. Because
the non-hormonal IUDs can cause heavy menstrual
bleeding, their use in women prone to anaemia may
not be advisable. Research is inadequate to deter
mine whether hormonal IUDs offer particular
advantages for women with anaemia.
Research into new IUDs has been hit by the backlash
that resulted from the litigation over the Daikon
Shield and later lawsuits against another US manu
facturer, G.D. Searle - maker of the Cu-7 and the
Tatum-T IUDs. At the end of January 1986, G.D.
Searle announced that it was withdrawing from the
US IUD market “because of the cost of defending the
products against lawsuits and the company’s inabil
ity to obtain adequate insurance”. Cu-7 was the most
frequently prescribed IUD in the USA. Searle esti
mated that about one million of the two devices were
in use in the USA and defended their “safety, efficacy
and medical utility”. The devices have been the sub
ject of 775 lawsuits against Searle during the 12 years
they were on the market in the USA.28 Only 20 cases
have gone to a full trial (Searle won 16), and more
than 450 suits were settled out of court. Some 300
are still pending.29 Nearly 200 women in New
Zealand and more than 200 women in Australia also
filed suits against the company.50
Not for everyone
Although most people agree with rhe WHO that the
IUD is “an important method of fertility regulation”
for women in both developed and developing
countries,21 it is not suitable for all women. Women
who have not completed their desired family size,
who have had an ectopic pregnancy, who have or
whose partners have multiple sexual partners, are not
suitable candidates for an IUD.22 The IUD should be
avoided in women with current pelvic infection,
known or suspected pregnancy, a distorted uterine
cavity, undiagnosed abnormal vaginal bleeding, sus
pected malignancy of the genital tract, or known
infection with human immunodeficiency virus (HIV).
Copper allergy is a contraindication to copper-carry
ing devices. Relative contraindications include a past
history of pelvic infection, valvular heart disease with
the risk of subacute bacterial endocarditis, uterine
scars, anaemia and fibroids.22 One expert notes that
the IUD “is especially suitable for women who have
completed their families and have contraindications
to the use of oral contraceptives”.2’1
Women who do use an IUD should be informed what
type of device it is, told how to check that it is still in
place, be advised to return to the clinic for an initial
examination within one to three months after inser
tion and thereafter annually, and be told what side
effects to expect. They should also be told what to do
in case of severe adverse effects such as PID or perfo
ration of the uterus.25 Before attempting insertions of
IUDs, clinicians should receive practical lessons from
someone with experience and be given a chance to
practice insertion using a small plastic model.26
Recommendations for action
1. Restrict the use of IUDs to women over 30 who
have already had children,37 or to younger women
only when they are certain they no longer want
children.
2. Ensure that any woman who uses an IUD is first
given full information about the possible risks. It is
particularly important that women who have not
yet had a child should be clearly warned of the
possibility of infertility and encouraged to choose
an alternative method of contraception.
3. Ensure that no woman is fitted with an IUD
unless a detailed medical history is taken and tests
for vaginal and cervical infections (including
chlamydia and gonorrhoea) are carried out prior to
insertion; unless the device is inserted by a welltrained health worker; and unless she has access
to removal on request and to appropriate follow-up
care if PID develops. Women should be informed
about the signs of PID and uterine perforation and
be encouraged to seek immediate medical
attention if a complication develops.
8 C .
women annually and causes more illness in women
of 15-25 years of age than all other serious infections
combined. Worldwide. PID is a leading cause of
infertility. In the USA. the disease is responsible for
between five and 20% of all hospital admissions for
gynaecological problems' and the cost of treating
PID and its consequent illnesses is estimated at S3.5
billion a year.18 More than one million women in the
USA suffer from PID every year.19
The link between PID and IUDs is “one of the most
controversial topics in contemporary contraception”,
despite extensive research worldwide. Most studies
have found an increased risk of PID among IUD
users, in some cases up to nine times. However, the
most objective studies put the range of risk at between
1.5 and 2.6 times. Closer examination of the data sug
gests that the risk is greatest near the time of insertion
of the device.20 A recent study carried out by WHO’s
Special Programme of Research, Development and
Research Training in Human Reproduction con
firmed that the risk of PID was greatest closest to the
rime of insertion - in this case, six times more likely
during the first 20 days. The study also found that the
highest risks were among women who had not previ
ously had children, those who were the youngest (15
to 24 years of age), or those who lived in Africa.21
IUDs
No one is certain why women using IUDs are more
susceptible to PID. The association of the highest risk
with the time of insertion, however, suggests that bac
teria may be introduced during the insertion
process.22 Another factor seems to be the risk of
acquiring sexually transmitted diseases (STDs).
Chlamydia, one of the most common STDs, is asymp
tomatic in three out of four infected women. If a
woman infected with chlamydia or another STD has
an IUD inserted, the infection can spread and cause
PID.—a Women at low risk of acquiring STDs have lit
tle increased risk of IUD-associated PID.23 As a result
of recent studies, it now becomes apparent that
women who have a high risk of PID - which includes
those with a previous history of PID, women under
25 who do not have children, and all women who
have or whose partners have multiple sexual partners
-should use a different form of contraception.24
IUDs and AIDS
The relationship between IUDs and STDs should also
cause concern in settings where the spread of human
immunodeficiency virus (HIV) and acquired immun
odeficiency syndrome (AIDS) is prevalent. The IUD
does not offer any protection against HIV transmis
sion. Indeed, there is some evidence to suggest that the
Table 8C-1
Comparison of different types of IUDs
Device
Manufacturer
Country
Maximum
Duration'(years)
Pregnancy
Rate2/100
Continuation
Rate2/100
Copper-bearing
Lippes Loop Cu200
Ortho US
USA
10(?)
T Cu 200 Ag
Outokumpu Oy
Finland
6
1.2
5.6
50.0
15-20
1.8
59.7
1.0
50.1
1.8
51.6
T Cu 220 C
74.2
Ortho Canada
Canada
Outokumpu Oy
Finland
Ortho Canada
Canada
6
GynoMed
USA
4
TCu 380Ag
Outokumpu Oy
Finland
10-15
Nova T
Outokumpu Oy
Finland
6
Leiras
Finland
Multiload Cu 250
Multilan
Switz.
4
1.1-2.5
74.0-89.5
Multiload Cu 375
Multilan
Switz.
5
0.9
65.6
Alza
USA
1
1.9
n.a.
Leiras
Finland
6(?)3
0.1
75.3
T Cu 380A
Progestogen-bearing
Progestasert
(progesterone)
LNGT
(levonorgestrel)
Notes:
1. Maximum duration is a probable or theoretical figure: for the copper-bearing devices, the usual proven duration is accepted at
between three to five years
2. Pregnancy and continuation rates are both after two years, both per 100 women users
3. Not in widespread use yet
Sources: Lippes data from: Randic, L., et al, "The effect of adding copper onto Lippes Loop IUDs: results from a ten-year study in
Yugoslavia", Contraception, Vol 43, No 3, Mar 1991, pp229-39. other data on copper-bearing devices from: Tatum, H.J. and Connell,
E.B., "Intrauterine contraceptive devices", chapter 9 in: Filshie, M. and Guillebaud, J. (eds), Contraception: Science and Practice, London,
Butterworth-Heinemann. 1989, ppl48 and 164; data on Progestasert from: Sivin, I., "Dose- and age-dependent ectopic pregnancy rates
with intrauterine contraception", Obstetrics and Gynecology, Vol 78. No 2, Aug 1991. pp291-8; data on LNG T from: Sivin, I., Stern, J., et
al, "Prolonged intrauterine contraception: a seven year randomized study of the levonorgestrel 20mcg/day (LNg 20) and the copper
T380 Ag IUDs". Contraception, Vol 44, No 5. Nov 1991, pp473-8O
8 C .
References:
i.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Pownall, M., “Fears and lawsuits give IUDs an uncertain future", The
Independent, 2 Dec 1986
Lappe, EM. and Schurman, R., Taking Population Seriously, London,
Earthscan Publications, 1989, P48
Farley, T.M.M., Rosenberg, MJ., et al, “Intrauterine devices and pelvic
inflammatory disease: an international perspective", Lancet, Vol 339,
No 8796, 28 ter 1992, PP785-8
Mackenzie, D., “World Health Organisation supports the IUD", New Scientist,
12 Nov 1987, P35
Berer, M., “Contraception", chapter 15 in: Phillips, A., Rakusen, J. (eds) and
the Boston Women’s Health Collective, The New Our Bodies, Ourselves (2nd
UK edition), London, Penguin Books, 1989, P287
Farley, Rosenberg, et al, 1992, op cit, PP785-8
Graedon,). and Graedon, T., Graedon's Best Medicine: from herbal remedies
to high-tech Rx breakthrough, New York, Bantam Books, 1991, P352
WHO, Mechanism of Action, Safety and Efficacy of Intrauterine Devices,
Technical Report Series No 753, Geneva. WHO, 1987, p68
Tatum, HJ. and Connell, E.B., “Intrauterine contraceptive devices", chapter 9
in: Filshie, M. and Guillebaud,). (eds), Contraception: Science and Practice,
London, Butterworth-Heinemann, 1989, ppizj6-7
Berer, 1989, op cit, P289
Tatum and Connell, 1989, op cit, ppiso-i
Guillebaud, J., Contraception: your questions answered, London, Churchill
Livingstone, (revised edn) 1991, PP2134,222
WHO, 1987, op cit, PP49-51
Anon., “Does infection occur with modem intrauterine devices?", Lancet,
Vol 339, No 8796, 28 ter 1992, PP783-4
WHO, 1987, op cit, pZj6
Tatum and Connell, 1989, op cit, P157
Bumakis, T.G. and Hildebrandt, N.B.; “Pelvic inflammatory disease; a review
with emphasis on antibiotic therapy", Reviews of Infectious Diseases, Vol 8,
No 1, )an-Feb 1986, pp86-u6
Peterson, H.B., Galaid, E.I. and Cates Jr., W., “Pelvic inflammatory disease",
Medical Clinics of North America, Vol 74, No 6, Nov 1990, PP1603-15
Washington, A.E.. Cates Jr, W. and Wasserheit, J.N., “Preventing pelvic
inflammatory disease", Journal of the Amencan Medical Association, Vol 266,
No 18,13 Nov 1991, pp2574-8o
Washington, A.E., Aral, S.O., et al, “Assessing risk for pelvic inflammatory
disease and Its sequelae", Journal of the American Medical Association,
Vol 266, No 18,13 Nov 1991, pp258i-6
21.
Farley, Rosenberg, et al, 1992, op cit, PP785-8
22.
Mishell, D.R., "Contraception", New England Journal of Medicine, Vol 320,
20.
No 12, 23 Mar 1989, PP777-87
22a. Jacobson, J.L., Women’s Reproductive Health: the silent emergency,
(Worldwatch Paper 102), Washington, Worldwatch Institute, 1991, P27 and 33
23.
Washington, Aral, et al, 1991, op cit, PP2581-6; Farley, Rosenberg, et al, 1992,
24.
25.
26.
27.
op cit, PP785-8
Mishell, 1989, op cit, PP777-87
European Study Group, “Risk factors for male to female transmission of HIV,
British Medical Journal, Vol 298,1989, PP411-15
Toivonen, J., Luukkainen, T. and Allonen, H„ “Protective effect of intrauterine
release of levonorgestrel on pelvic infection: three years' comparative
experience of levonorgestrel- and copper-releasing intrauterine devices",
Obstetrics and Gynecology, Vol 77, No 2, Feb 1991, ppz6i-4
Sivin, I., “Dose- and age-dependent ectopic pregnancy rates with intrauterine
contraception", Obstetncs and Gynecology, Vol 78, No 2, Aug 1991, pp29i-8
28.
Anon., "Searle to End Sale of IUDs in US", International Herald Tribune, 1/2
29.
Feb 1986
Anon., "Searle favoured in latest US Cu-7 trial”, Scrip, No 1497,16 Mar 1990,
30.
PB
Anon., “IUD law suits in New Zealand/Australia", Scrip, No 1648, 4 Sep 1991,
pn
3t WHO, 1987, op cit, P71
32.
Tatum and Connell, 1989, op cit, pi6o
33.
Guillebaud, 1991, op cit, PP2313
34.
Mishell, 1989, op cit, PP777-87
35.
Tatum and Connell, 1989. op cit, ppi62-3
36.
Guillebaud, 1991, op cit, P241
37.
Makkonen, K. and Hemminki, E., “Different contraceptive practices: use of
contraceptives in Finland and other Nordic countries in the 1970s and 1980s",
Scandinavian Journal of Social Medicine, Vol 19, No 1,1991, pp32-8
IUDs
>
..
Chetley, A. Problem Drugs, Amsterdam,
8D. Injectables
1 ■ :
■'
■:<' .
LIBRARY
Health Action International, 1993
°'
»N0
;; i1
'> oOCUMcNTATlOW z
•
' -v
U N' "i*
''i
Health Action International’s
coordinating offices:
HAI Europe
Jacob van Lennepkade 334T
1053 N Amsterdam
The Netherlands
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accion para la Salud
Avda. Palermo 531
Dpto. 104
Lima 13
Peru
Not the first choke
“Long-acting hormonal contraceptives produce an almost
invariable disturbance o/ the menstrual cycle and this may
be a source of major concern to the woman.
Contraceptive methods such as injectables which
cause menstrual disruption are problematic in many
societies because bleeding interferes with praying,
fasting, sexual intercourse, and a woman’s feeling of
health and well-being.2 There is also uncertainty
about the long-term safety of injectable contracep
tives. Despite these difficulties, injectables play a
large role in family planning programmes in develop
ing countries.
The two major products are progestogens - synthetic
hormones modeled on the natural female hormone
progesterone. The leading product, depot medroxy
progesterone acetate (Depo-Provera or DMPA), is
manufactured by the American company, Upjohn,
while the German company, Schering, produces
norethisterone oenanthate (Norigest, Noristerat or
NET-OEN).
Neither product is widely used as a contraceptive in
industrialised countries.’ For example, because of safety
concerns, DMPA was only approved for contraceptive
use by the US Food and Drug Administration (FDA) in
October 1992 - nearly 20 years after Upjohn first
applied for a licence.4 DMPA is available as a contra
ceptive in over 90 countries around the world, and
NET-OEN is marketed as a contraceptive in over 40
countries.5 The World Health Organization (WHO)
estimates that over 30 million women worldwide have
used injectable contraceptives and that about six million
women are currently using them.6 An estimated four
million use DMPA,7 and about one million use NETOEN.8 Locally produced brands in China and Latin
America account for the remaining usage. In addition,
clinical trials are underway in several developing coun
tries to test different versions of a monthly injectable
which contains both a progestogen and oestrogen.’
The first injectable progestogens were developed in
1953 by Karl Junkmann. In 1957, Junkmann and his
associates at Schering produced NET-OEN, and the
company began clinical trials. At about the same
time, Upjohn developed DMPA and began clinical
trials in 1963. The first major field trials for NETOEN were conducted in Peru and in 1967, Norigest
went on the market in Peru. It was withdrawn in
1971 and field trials were suspended after pituitary
and breast nodules were found in rats given Norigest.
However, family planning researchers concluded
that the findings in rats were not applicable to
humans,10 and NET-OEN went back on the market.
In 1981, WHO’s Toxicology Review Panel con
cluded that it was safe to introduce NET-OEN into
family planning programmes.11
DMPA has a similar history. Early animal studies
found breast cancer in beagles and endometrial can
cer in rhesus monkeys. However, once again,
researchers concluded that the animal studies were
not applicable to humans, and in 1978, WHO noted
that “the available evidence does not indicate a risk
of adverse effects associated with Depo-Provera
which would preclude the use of this drug as a con
traceptive.”12
Nonetheless, there are still concerns. In most cases, if
a carcinogenic effect is demonstrated in any one
species, particularly in an organ likely to be affected
by the drug, “this is considered to constitute evidence
of lack of safety. If a drug is found to produce cancer
in more than one species, the strength of the evidence
is increased.”13
How injectables work
Both injectables inhibit the production of hormones
by the pituitary gland, which in turn prevents ovula
tion. Studies also suggest that both drugs have an
effect on the production of cervical mucus, on the
169
VO, 8 D .
Injectables
Problem Drugs
fallopian tubes, and on the lining of the utenis, all of
which are assumed to play a role in reducing fertility.14
Group on Depo-Provera in the UK documented
many cases of women suffering bleeding irregulari
ties for several months after a single injection.-
The major difference between the two injectables is
the duration of contraceptive effect. DMPA is
released into the blood stream more slowly than
NET-OEN, and usually remains in the body longer.
NET-OEN is usually undetectable in the blood by
about 70 days after injection and its contraceptive
effect is thought to wear off by two to three months,
whereas DMPA is often still detectable in the body
up to nine months after injection, although the con
traceptive effect is thought to wear off by three to
four months.15
Other reported side effects include headaches, weight
gam, dizziness, abdominal discomfort, mood
changes, and loss of libido. There is also some evi
dence that the use of DMPA contributes to
reductions in bone density and therefore that it
should be considered a potential risk factor for osteoporosis.24 This is especially of concern for long-term
users and women at risk for other reasons.
The effectiveness of rhe two drugs in preventing preg
nancy is roughly the same. With DMPA the rate of
pregnancy ranges from 0 to 1 per 100 women-years,
and for NET-OEN from 0.01 to 1.3 per 100 womenyears.16 Generally, this means that injectables are
more effective than oral contraceptives.1'
The advantages of injectable contraceptives fall into
two categories: advantages to the administrators and
advantages to the users. In the first case, injectables
are seen as effective, convenient, easy to administer
and reversible. The early history of injectable contra
ceptive use is full of incidents where women were
simply “processed” in little more than a minute,25 or
where women were not informed about the nature of
the injection.26 Some of this abuse seems to be con
tinuing. There were reports that in East Timor in
1989, as a way of controlling the local population,
adolescents were being injected with contraceptives
without their knowledge or consent.27
Side effects
The most common side effects and the main reason
for discontinuation of injectables are disturbances in
the menstrual cycle. A leading gynaecologist says
that with injectables, the "disturbance of menstrua
tion is so marked and variable, both between patients
and within the same woman over time, that it has
been called ‘menstrual chaos’.”18
This menstrual chaos can take two forms: either an
absence of bleeding (amenorrhoea), or frequent
bleeding or spotting. DMPA causes amenorrhoea of
more than 90 days duration in up to 40% of women
during the first year of use. NET-OEN causes less
amenorrhoea, but the incidence of other types of
menstrual disturbance is similar to DMPA.19
Generally, 30 to 50% of women stop using injecta
bles during the first year.20 WHO says the reason in
one-quarter to one-half of cases is because of men
strual disturbances.21
WHO maintains that neither amenorrhoea nor fre
quent bleeding - providing it is not heavy - are likely
to pose any health problems for women. However,
WHO does point out that “menstrual irregularity
interferes with daily life and for sociocultural reasons
is totally unacceptable in some settings.”22
This is an important point. Even if the direct health
consequences are not considered severe, a woman
who finds the disruption in the menstrual cycle intol
erable has little choice but to live with it, for once the
injection is given, she will have to wait until the effect
wears off. At least in the case of DMPA, there is evi
dence that although the contraceptive effect may end
within about four months of an injection, rhe side
effects can be more long-lasting. The Coordinating
Advantages and disadvantages
From the point of view of a woman seeking con
traception, the major advantages reported are
effectiveness, convenience, freedom from the fear of
forgetting to take precautions, the ease of administra
tion and the fact that “it remains a woman’s secret”28
and partners cannot interfere with its use. This last
factor can be very important to women in repressive
cultural and family situations.
An important factor in the acceptance of injectable
contraceptives is undoubtedly the widespread (but
untrue) belief that medicines given by injection are
more powerful and more effective than medicines
taken orally.29
A possible cancer risk?
The most prominent disadvantage is menstrual dis
ruption. Another concern is that “there is not enough
evidence to provide clear assurances concerning any
long-term risks of injectables”.20 The possible risk of
cancer associated with the use of injectables is the
most serious of these doubts.
WHO undertook an extensive research project in 11
countnes to examine the relationship between the use
steroid contraceptives including DMPA and NETTa uthC flevel°Pment of cancer. WHO
concluded that there was no indication of an
"ver in
°f
breaSt’ WOmb’ ovary °r
here was nmen/Sln8 ?MPA?’ k also added *at
was no evidence of any increased risk of cervical
8 D .
A concern with all systemic contraceptives is the pos
sible effect on the later development of infants who
are exposed in utero as a result of contraceptive fail
ure or the initiation of contraception in a woman with
undiagnosed pregnancy. The human evidence avail
able on the effect of injectables on the fetus is difficult
to evaluate, primarily because of a lack of large-scale
studies. However, progestogens have been associated
with birth defects in both humans and animals. Two
recent cohort studies in Thailand found that early,
high-dose in utero exposure to DMPA can lead to low
birth weight, and to an increase in infant mortality.’5
A disadvantage that has become more important in
recent years is the possible risk of AIDS as the result
of the human immunodeficiency virus having been
transmitted via injections given with unsterilised
syringes. As WHO points out, “in many countries,
the sterilisation of needles and syringes by health
workers is not always satisfactory”.36
Contraindications and cautions
Special care should be taken in the use of injectables.
They are not first choice contraceptives. According
to WHO, the contraindications to the use of injecta
bles are:
• cancer of the breast or an undiagnosed breast
lump;
• active viral hepatitis A;
• cardiovascular disorders;
• coagulation or lipid disorders;
• undiagnosed abnormal uterine bleeding or other
symptoms of possible genital cancer;
• pre-existing or suspected pregnancy; and no ear
lier than six weeks after delivery.37
If injectables are used by breastfeeding women, their
babies receive small amounts of progestogens in the
milk. This has led to concern that progestogens
might have an adverse effect on neonatal growth or
subsequent development.”
WHO also notes that the use of injectable contracep
tives should be avoided if possible among young
adolescents and women over 40. This advice is due to
the lack of firm scientific information assuring safety.
With young adolescents, “caution is usually advised
if any hormonal method is prescribed within the first
2 years after the menarchc” (start of menstruation)
because rhe effects of administering hormonal con
traceptives on later sexual development and
reproductive function “are not fully understood”.
For women over 40, the use of any hormonal contra
ceptive can mask the start of the menopause. With
injectables, the disturbances in the menstrual cycle
may be mistaken for signs of the menopause and con
traception may be stopped prematurely. Also,
irregular bleeding in woman of this age may be a sign
of underlying gynaecological disease which should
be investigated.
In addition, WHO lists several “special problems”
where great care in the use of injectables should be
taken. These include abnormal liver function or
recent history of liver disease, and diabetes mellitus
or history of gestational diabetes.39
Controls necessary for proper use
A major conclusion about the use of any injectable
contraceptive is that, with many questions still unan
swered, caution should be used in administration,
and great care should be taken in preparing women
for its use and in detailed follow-up as to its effects.
The woman, preferably with her partner, should be
informed of the various contraceptive methods avail
able, and the risks and benefits of each method should
be clearly explained. Once the woman has made her
choice, counselling should provide accurate informa
tion about how the method works, known
contraindications, side effects to expect, and a
reminder that she is welcome to return to the clinic at
any time to discuss problems and any doubts that may
arise. With injectables, she should also be told that it
may be six months or more after the time of the last
injection before her fertility' returns.
A detailed medical history and physical examination
are needed to provide information on age, menstrual
history, obstetrical history, and any history of jaun
dice or other liver disease, cardiovascular disease or
diabetes. Regular follow-up, including annual pelvic
and breast examinations and a cervical smear, is also
recommended.40
There arc, of course, problems with suggesting that
injectable contraceptives should only be used in con
trolled situations with adequate follow-up. This
requires carefully designed family planning pro
grammes with well-trained staff who are not assessed
on their efficiency - “processing” a pre-set number of
women per day, month or year - but on their ability
to provide adequate, objective counselling and
Vi
Problem Drugs
j-jIt.hou8h a multi-country study reported in
1 984 did show a doubling of risk of cervical cancer in
women who used DMPA for five or more years.’2
There may be other causative factors such as the sex
ual activity of the women’s partners or their own
smoking practices. Another WHO study in five cen
tres to assess breast cancer risks found that risk did
increase within the first four years of initial use, par
ticularly among women under 35 years of age.
Despite this finding, the report of the study concluded
that women who have used DMPA for a long time
and who initiated use many years previously are nor
at increased risk of breast cancer.” One gynaecologist
has concluded that ‘‘there is no evidence” that injecta
bles cause cancer, “nor proof of the reverse”.’4
Injectables
Injectables
8 D .
Problem Drugs
support for women who come to them for advice.
Tight control is also needed over the distribution of
injectable contraceptives to prevent them becoming
available for purchase without a prescription or
examination.
Recommendations for action
1. If injectables cannot be provided safely and
respectfully and with a woman s fully informed
choice, they should not be provided.
2. This means acknowledging that injectables are
not first choice contraceptives and removing them
from the regular pharmaceutical market,
restricting their availability and use to those
settings where conditions for safe use can be met.
3. Any woman considering the use of an injectable
contraceptive should have been fully informed
about alternative methods, about the benefits and
side effects of injectables, and given time to
consider her choice.
4. If an injectable is chosen, the woman should be
carefully examined for any possible
contraindications, and after receiving the injection,
should be followed up to monitor any adverse
effects and take steps to minimise those effects.
5. Further research is needed on injectables to
better evaluate their long-term safety.
6. Research efforts need to be expanded to
improve the availability and convenience of
existing user-controlled methods of contraception
including barrier methods.
The likelihood of such controls being in place in
developing countries is remote. That, combined with
deficiencies in the basic health infrastructure in many
countries has to cast a serious shadow of doubt on
rhe suitability of injectable contraceptives. In 1982,
the Swedish International Development Authority
(SIDA), adopted a formal policy against supplying
DMPA. A SIDA official said the reason for the deci
sion “was not medical but the fact that it would be
difficult and expensive to control its proper use in
rural areas in developing countries”.41
Many questions about safety and assurance of
informed consent remain unanswered. While some
health workers and the pharmaceutical companies
involved argue that there are no reasons to worry
about the widespread introduction of injectables,
other health workers, women’s groups, consumer
groups and some governments have found ample
cause for worry.
References
i.
2.
3.
4.
5.
6.
7.
Fraser, I.S., “Systemic hormonal contraception by non-oral routes", chapter 7
in: Filshie, M. and Guillebaud, J. (eds), Contraception: Science and Practice,
London, Butterworth-Heinemann, 1989, pii7
WHO, Creating Common Ground: Women's Perspectives on the Selection and
Introduction of Fertility Regulation Technologies, WHO/HRP/iTT/91, Geneva,
WHO, 1991, P25
Berer, M., “Contraception", chapter 15 in: Phillips, A., Rakusen, J. (eds) and the
Boston Women’s Health Collective, The New Our Bodies, Ourselves (2nd UK
edition), London, Penguin Books, 1989, P296
Anon., “Depo-Provera approved in the US”, Scrip, No 1768.6 Nov 1992, P19
Fraser, op cit, pii3
WHO, Injectable Contraceptives, Geneva, WHO, 1990, p2
Hardon, A, “Contraceptive research: women’s perspectives", chapter 2 in:
Mintzes, B (ed), A Question of Control: Women's Perspectives on the
Development and Use of Contraceptive Technologies, Amsterdam, WEMOS
Women and Pharmaceuticals Project/HAI, 1992, pi2
8.
Anon., “Long-acting steroids provide new options", Network, Vol 9, No 3,
9.
10.
11.
12.
13.
Spring 1988, p2
Khanna, ]., van Look, P.FA, and Griffin, RD. (eds), Reproductive Health: a Key
to a Brighter Future, Geneva, WHO, 1992, P89
Rinehart, W. and Winter, J., “Injectable progestogens - officials debate but use
increases", Population Reports, Series K, No 1, March 1975, ppKi-Ki6
WHO, 1990, op cit, PP5-6
Ibid, ps
Coney. S., “A living laboratory: The New Zealand connection in the marketing
of Depo-Provera", in: Davis, P. (ed.), For Health or Profit?Medicine, the
Pharmaceutical Industry and the State in New Zealand, Auckland, Oxford
University Press, 1992, P119-43
WHO, 1990, op cit, PP4-5: Guillebaud, J., Contraception: your questions
answered, London, Churchill Livingstone, (revised edn) 1991, pi8$
15.
WHO, Facts about injectable contraceptives, Geneva, Special Programme of
Research Development and Research Training in Human Reproduction, 1982.
(Reprinted from: Bulletin of the Wortd Health Organisation, 60(2): 1982,
ppi99-2io)
14.
16.
17.
Guillebaud, op cit, pi86
WHO, 1990, op cit, pzo
18.
19.
20.
21.
22.
23.
24.
Guillebaud, op cit, P189
Fraser, op cit, pii7
Hardon, op cit, pi2
WHO, 1990, op cit, pi2
Khanna, et al, op cit, P89
Berer, op cit, P298
Cundy, T., Evans, M., et al, “Bone density in women receiving depot
medroxyprogesterone acetate for contraception", British Medical Journal,
Vol 303,6 Jul 1991, PP13-16
25.
Rinehart and Winter, op cit, ppKi-Ki6
26.
LaCheen, C, "Population control and the pharmaceutical industry", in:
McDonnell, K. (ed.). Adverse Effects: Women and the Pharmaceutical Industry
Penang, IOCU, 1986, puo
27.
Vittachi, A, "The healer myth”, New Internationalist, Sep 1992, pzi
28.
Mintzes, op cit, P48
29.
WHO. 1990, op cit, pi4
30.
Berer, op cit, P299
31.
WHO, 1990, op cit, PP78-9
32.
WHO, Special Programme of Research Development and Research Training in
Human Reproduction, "Breast cancer, cervical cancer, and depot
medroxyprogesterone acetate". Lancet, 24 Nov 1984. ppi2O7-S
33.
WHO Collaborative Study of Neoplasia and Steroid Contraceptives, “Breast
cancer and depot-medroxyprogesterone acetate: a multinational stud/
Lancet, Vol 338. 5 Oct 1991, PP833-8
34.
Guillebaud, op cit, P198
35.
Pardthaisong, T. and Gray, R.H., “In utero exposure to steroid contraceptives
and outcome of pregnancy" and Gray, R.H. and Pardthaisong, T.. “In utero
36.
exposure to steroid contraceptives and survival during infancy", American
JXS' V°' % N° " 15 “ '951' PP7’5'803 3"d
37.
WHO, 1990, op cit, P17
38.
Fraser, op cit, P119
39- Ibid, ppi7, 66-7
40. WHO, 1990, op cit, PP55-7,66-68 and 8o-i
4''
,"form,at!’n *°Sram- "l-ong-Acting Progestins - Promise and
Prospects , Population Reports, Series K. No 2. May 1983, pK-24
Chetley, A. Problem Drugs, Amsterdam,
Health Action International, 1993
r-’z-'
LIBRARY
AND
<
documentation
8E. Implants
Health Action International’s
coordinating offices:
HAI Europe
Jacob van Lennepkade 334T
1053 NJ Amsterdam
The Netherlands
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accion para la Salud
Avda, Palermo 531
Dpto. 104
Lima 13
Peru
It took 24 years to develop, test and approve an implantable
device, Norplant, that can prevent pregnancy for as long as
five years. It took less than two weeks for Norplant to be
billed as a new method of coercion. Within days of it being
licensed in the USA, a Philadelphia newspaper published a
racist editorial suggesting that Norplant might be of use in
the fight against black poverty; a judge in California
included the use of Norplant as part of the sentence against
a woman found guilty of child abuse; and the state legisla
ture in Kansas held hearings on a bill to encourage mothers
receiving state welfare benefits to get the implant. Norplant's
creator, Dr Sheldon Segal, commented at the time: “We
created a method to enhance reproductive freedom and
people keep finding ways to use it for the opposite purpose.
These practices were also condemned by the Board of
Trustees of the American Medical Association.2
The first contraceptive implants, made of flexible,
non-biodegradable tubes (Silastic) filled with hor
mones and placed under the skin, were developed in
the 1960s. At least 10 hormones were tested in clinical
trials, but the most promising was levonorgestrel. The
US Population Council sponsored most of the research
on implants and developed the system known as
Norplant that is now manufactured by the Finnish
company, Leiras. Norplant consists of six silicone
rods, each filled with 36mg of levonorgestrel, which
are inserted under the skin of a woman’s upper arm.
The hormone is then slowly and fairly consistently
released into the body, retaining its contraceptive
effect for five years. Its main mechanism of action is
suppression of ovulation,3 but it also makes the cervi
cal mucus less penetrable by sperm and the lining of
the uterus less able to accept a fertilised egg.4
Norplant was first registered in Finland in 1983, and
has since been approved in a total of 26 countries
worldwide. About 1.5 million women have used or
currently use Norplant around the world.3 The
developers believe that this method is so safe and
effective that it can be considered as “reversible
sterilisation”, and is likely to become very popular.6
By the year 2000, there could be between four and
seven million Norplant users in industrialised coun
tries and 15 to 25 million users in developing
countries.7
Efficacy
The overall (cumulative) pregnancy rate for the
entire five years is only 2.7 to 3.9 per 100 users.
This means that during the method's five-year
period of effectiveness, around three to four out of
every 100 users are likely to become pregnant.
173
174 8 E .
Implants
Problem Drugs
Norplant’s effectiveness is correlated with a
woman's weight. Heavier women, particularly
those who weigh more than 70 kilograms (approx
imately 154 pounds), have a higher probability of
becoming pregnant after the second year of use than
lighter women. The cumulative pregnancy rate after
five years of use for women weighing over 70 kg is
8.5 per 100 women.8
Fertility apparently returns rapidly when the implant
is removed. One study found that 50% of women
conceived within three months and 86% within one
year of removal of the implant.9 The Population
Council suggests that the figure might be as high as
88% within one year.10
Proposed coercive Norplant legislation
in the US: 1991 to early 1993
Proposals still pending in February 1993
Incentives for women on welfare (public assistance)^
Arizona and Washington: $500 + $50/year;
Colorado: $100;
Tennesseee: $500 for Norplant or vasectomy.
Reduced benefits without Norplant
Florida: welfare $258/month without Norplant,
$400/month with Norplant, regardless of number
of children;
South Carolina (2 bills): 1) no benefits to families
with 2 or more children unless the mother has
Norplant inserted, 2) no increase in payments with
Menstrual disturbances
and other adverse effects
Implants, like other progestogen-only contracep
tives, do disrupt the menstrual cycle. Irregular
menstrual bleeding is the most common side effect,
and the main reason for discontinuation.11 A study of
234 Norplant users in the USA found that only 27%
had regular menstrual cycles, 66% had irregular
cycles and 7% had a complete absence of menstrual
bleeding (amenorrhoea). By rhe fifth year of use,
62% of users had regular cycles, while 38% had
irregular cycles, and there were no reports of amen
orrhoea.12 Overall, in clinical and field trials
throughout the world, 60 to nearly 100% of
Norplant users experienced irregular menstrual
bleeding, usually at its most severe within the first six
months after implantation.13
an additional child unless the mother uses
Norplant;
Mandated Norplant use
Washington: involuntary insertion of Norplant with
a court order for mothers of fetal alcohol syndrome
or drug-addicted babies.
1991 and 1992 legislative poposals
which have been rejected or withdrawn
Incentives for women on welfare
Kansas, Louisiana and Texas;
Reduced benefits without Norplant
Mississipi: welfare, food, housing and disability
benefits cut if women with 4 or more children
refuse Norplant;
Mandated Norplant use
Kansas and Colorado: condition for probation for
women convicted of drug offences;
Other side effects include headache (reported by
about 4 to 24% of women in different studies), dizzi
ness, loss of appetite, weight changes (both gain and
loss), nervousness, mood changes, breast tenderness,
pain in the lower abdomen, pain and infection at the
implant site, hair loss, acne and other skin prob
lems.14 Studies indicate that between 20 to 30% of
pregnancies in Norplant users are ectopic.15
As the Medical Letter points out, “menstrual irregu
larities and other adverse effects may make the
implants unacceptable to some patients”.16 Implants
are not recommended for use in breastfeeding
women, because the effects of the hormone on
infants are not known.17
Like other hormonal methods, little is known about
the possible long-term effects of implants. Equally, the
effect of leaving the implant in place longer than five
years is not fully known. The dose of progestin
released gradually diminishes, leading to concerns that
the risk of ectopic pregnancy or pregnancy with fetal
exposure to progestin is higher.170 The fact that it
happens is clear: 14 of 52 women followed up in Brazil
were found to still have Norplant in place for longer
Ohio: drug rehabilitation or Norplant for mothers
of drug-addicted babies;
South Carolina: court orders for Norplant
authorised for mothers of babies testing positive
for illegal drugs.
Note: Women on welfare receive contraceptives, including Norplant.
free of charge in all states.
Sources: Alan Guttmacher Institute. State Reproductive Health Monitor:
legislative Proposals and Actions. Feb 1993, vol. 4(1) p6: Alan
Guttmacher Institute, Norplant: Opportunities and Perils For Low-Income
Women Special Report HI, December 1992
8 E .
than five years. Because the clinical trial they were
taking part m had been stopped, the doctors who had
inserted the Norplant had left the area and other doc
tors did not know how to remove the implants.18
Disadvantages
Certainly a serious disadvantage of Norplant is that
women are dependent on health workers for removal
of the implant. A study carried out in the Dominican
Republic, Egypt, Indonesia and Thailand during
1986-/ found instances in all four countries where
removal on demand did not occur to the satisfac
tion of the user".19
Cost is another important disadvantage. The
implant is one of the most expensive contraceptive
options available - roughly double the cost of the
pill and 18 times the cost of an IUD.20 Even in the
USA, a review of Norplant in the Contraceptive
Technology Update commented that the price of the
device, approximately US $300, plus insertion and
removal costs, will prevent many low-income
women from using it.21
The financial costs of Norplant for family planning
programmes in developing countries may lead to a
deterioration of other health services, as scarce
resources are used to train health workers to provide
the implants. The cost may also prevent the removal
of the implants before the end of the five-year period.
In Thailand, for example, “because of the cost of the
method, women are routinely informed when choos
ing Norplant that the implants are appropriate for
long-term spacing and will not be removed for minor
side-effects.”22 Dr Sulaiman Sastrawinata, Executive
Director of the Coordinating Board of Indonesian
Fertility Research, says that Norplant “is an expen
sive method if it is not used for the [five-year] period
it is meant to cover”.23 Health and family planning
workers may be under some pressure to ensure that
women do not stop using the implants prematurely.
Conditions for use
Norplant is a technology that requires a high stan
dard of health care if it is to be administered safely. It
is questionable whether such standards can be
achieved in many developing countries, where most
users are found. It is also questionable whether suffi
cient training and education can be provided for
those who are inserting and removing the implants.
The report of the four-country study in the
Dominican Republic, Egypt, Indonesia and Thailand
concluded that “service providers need further tech
nical training in Norplant insertion, counselling, and
removal.”24
Information for women themselves is also far from
ideal. In Bangladesh, for example, one of the first
advertisements used to recruit women for the clinical
Implants
trial of Norplant described it in glowing terms as “a
wonderful innovation of modern science”.25
The Population Council recognises the need for care
in introducing Norplant because of its design. The
Population Council says that it seeks settings for the
introduction of Norplant where women can receive:
0 a real choice of methods;
• accurate, balanced information;
0 an easy relationship with the service provider;
° gentle, correct insertion;
“ sensitive management of problems;
• access to removal on demand; and
° five-year removal.26
However, even where the Population Council has
sponsored introductory trials or provided technical
assistance to introduce Norplant in family planning
programmes, these conditions are nor always met.27
In Finland, one survey of physicians who had experi
ence of inserting Norplant found that none of them
considered the implant to be a first choice contracep
tive. Similar findings are reflected in the literature
about Norplant use in Finland: all the articles pub
lished in the 1980s suggest that Norplant should not
replace existing methods in Finland and that the
main market will be in developing countries.28
Policy makers from countries which have not yet
introduced Norplant need to consider whether it
provides an advantage over existing contraceptives.
Can they meet acceptable guidelines for service deliv
ery, including removal on request? Can they afford
the cost of providing Norplant in the long run,
including the cost of continued training in insertion
and removal and the cost of follow-up of users to
monitor their health and ensure that the implants are
removed after five years?
Indonesia was the first country to use Norplant on a
large scale, with more than 886,000 women having
received the implant between 1987 and 1990. The
implants proved highly successful when inserted by
trained workers in a sterile environment in clinics,
but problems arose when Norplant was included in
the so-called “safari” programme - a programme
where health workers visit a village for a day to
recruit as many women as possible to use contracep
tion. In such circumstances, individual counselling
and information about side effects “tend to be mini
mal”. A study by the Population Council found that
many health workers received no formal training in
insertion and removal techniques, leading to
implants being placed deep in the muscle and their
incomplete removal. The risk of infection was com
pounded by a lack of sterile equipment. Failure to
identify already pregnant women also led to the
implants having to be removed from a number of
women. No abnormalities have yet been found in
babies carried to term by these women, but
176 8 E .
Implants
Problem Drugs
Norplant’s effects on fetal development are not
known, although progestogens generally are known
to be potentially teratogenic. Despite a Population
Council recommendation that the programme
should proceed more slowly to allow time to train
providers properly, the Indonesian government has
started the programme in six more cities.29
Recommendations for action
1. If implants cannot be provided safely and
respectfully and with a woman’s fully informed
choice, they should not be provided.
2. This means accepting that implants are not
first choice contraceptives, removing them from
the regular pharmaceutical market, and restricting
their availability and use to those settings where
conditions for safe use can be met. Their inclusion
in most current family planning programmes will
have to be reconsidered.
3. Any woman considering the use of an implant
should have been fully informed about alternative
methods and should have had the opportunity to
try other methods for acceptability.
4. A woman who chooses an implant should first
have been informed about the benefits and side
effects of implants, and have been carefully
examined for any possible contraindications. After
receiving the implant she should be followed up
for any adverse effects and have access to
removal on request.
5. Research efforts should be focused on
improving the availability and convenience of
existing user-controlled methods of contraception
including barrier methods.
It is not enough to say that certain conditions must be
met and then turn a blind eye when they are not met;
Norplant has a design which makes it prone to abuse
because of the need for surgery for removal. Norplant
was developed to have certain qualities: high effective
ness over a long period of time. These are useful
qualities for family planning services which aim to
reduce population growth quickly. However, this also
means a lack of control by women and a high fre
quency of side effects that interfere with rhe quality of
daily life.
References
1.
2.
Goodman, E., “Help to plan family size, not control the women", International
Herald Tribune, 20 Feb 1991, P9
Board of Trustees, AMA, "Requirements or incentives by government for the use
of long-acting contraceptives ’, loumal of the American Medical Association, Vol
267, No 13,1 Apr 1992, ppi8i8-21
Segal, S.J., Alvarez-Sanchez, F., et al, “Norplant implants: the mechanism of
contraceptive action", Fertility and Sterility, Vol 56, No 2, Aug 1991, PP273-7
4.
Berer, M„ “Contraception", chapter 15 in: Phillips, A., Rakusen, J. (eds) and
the Boston Women's Health Collective, The New Our Bodies, Ourselves (2nd
UK edition), London, Penguin Books, 1989, P300
5.
Mintzes, B., Hardon, A. and Hanhart, J. (eds), Norplant: Under her Skin,
Amsterdam, Women’s Health Action Foundation and WEMOS, 1993, p2
6.
Guillebaud,)., Contraception: your questions answered, London, Churchill
Livingstone, (revised edn) 1991, pzoz
7.
Stanley, B„ “At arms length", IDRC Reports, Oct 1990, P19
8.
WHO, Norplant Contraceptive Subdermal Implants. Managerial and Technical
Guidelines, Geneva, World Health Organisation, 1990; Ollila, E., Kajesalo, K,
and Hemminki, E., “Experience of Norplant by Finnish family planning
practitioners", in: Mintzes, et al, op cit, PP47-68
9.
Anon., "A subdermal progestin implant for long-term contraception", The
Medical Letter, Vol 33, No 839,8 Mar 1991, P17
10.
Population Council, Norplant: A summary ofScientific Data. New York,
3.
Population Council, 1990
11.
Anon., “Long-acting steroids provide new options", Network, Vol 9, No 3,
Spring 1988, P7; Liskin, L, Biackbum, R. and Ghani, R. “Hormonal
contraception: new long-acting methods" Population Reports, Series K, No 3,
Baltimore, Population Information Program, 1987
12.
Shoupe, D., Mishell. Jr., D.R., et al, “The significance of bleeding patterns in
Norplant implant users", Obstetrics and Gynecology, Vol 77, No 2, Feb 1991,
13.
pp 2 56-60
Townsend, S., “Norplant: safe and highly effective", Network, Vol 11, No 4, Dec
1990, p6
14.
Berer, op cit, P300; Anon., Medical Letter, op cit, pi8
15.
Shoupe, et al, op cit
16.
Anon., Medical Letter, op cit, pi8
17.
Berer, op cit, P300
17a Mintzes, et al, op cit, pz
18.
Garcia, G. and Dacach, S., “Norplant - five years later [Brazil]", in: Mintzes, et
al, op cit, PP69-79
19.
Zimmerman, M„ Haffey, ]., et al, "Assessing the acceptability of Norplant
implants in four countries; findings from focus group research", Studies in
Family Planning, Vol 21, No 2, Mar/Apr 1990. P99
20.
Stanley, op cit, P19
Anon., “Arrival of Norplant may be bittersweet for clinics," Contraceptive
Technology Update, Vol 12,1991. ppi-5
Zimmerman, et al, op cit, P99
Finger, W., Programmatic challenges: training, counseling and removals"
Network, Vol 11, No 4, Dec 1990, PP9-12
24.
Zimmerman, et al, op cit, PP92-1O3
25- UBINIG -The Norplant trial: an investigative study on the methodology and
an,cal issues", The Hygeia. Vol 3. Nos 1 and 2,1988 Dan-lune), 0019 34
26.
Beattie, K, Introduction of new contraceptive methods: an opportunity for
21.
22.
23.
RrZ°!lnaSn
p,e;spraive in femily planninS P'°8™mes", in: Mintzes.
B'i
A P"es,'on ^Control: Women's Perspectives on the Development
and Use of Contraceptive Technologies. Amsterdam, WEMOS Women and
Pharmaceuticals Project/HAI, 1992, p26
27.
Zimmerman, et al, op cit, PP92-103
28.
Ollila, et al, op cit, PP47-68
29.
Anon.. "Problems with Norplant in Indonesia". Scrip, No 1611. 26 Apr iMt,
Chetley, A. Problem Drugs, Amsterdam,
Health Action International, 1993
' ’ ?
'
Vc\
documentation
Health Action International’s
coordinating offices:
/, 'h
HAI Europe
Jacob van Lennepkade 33/J
UNIT
9A. Hormone reptacement
therapy
1053 N) Amsterdam
The Netherlands
HAI Clearinghouse/ARDA
c/o IOCU
PO Box 1045
10830 Penang
Malaysia
AIS Latin America
Accldn para la Salud
Avda. Palermo 531
Dpto. 10/4
Lima 13
Peru
Seimg
fouth
Women are seen by the industry as "the market”. At one
symposium on menopause in Toronto sponsored by
Ayerst, a representative from the industry commented to
one of the organisers that the percentage of tvomen taking
Premarin [conjugated oestrogen/ was notably lower than
in the United States. He added. "There's a huge untapped
market out there!”1
Take a population of healthy women in their late 40s
or early 50s, women who are about to experience the
end of menstruation (menopause), and convince
them that they are running out of time, that their
youth will be lost forever. Then tell them the good
news: there’s a way to hold back the hands of time with oestrogen therapy. As one manufacturer,
Wyeth/Ayerst, is fond of telling women all over the
world: “Time waits for no woman... until she begins
using... Premarin (conjugated estrogens)”.2 In
Pakistan in 1990, women who used Premarin, were
promised “a gift of time”.’ In 1990 in New Zealand,
Schering advertised its oestrogen preparation in blew
Zealand Doctor with the headline: “So a woman can
continue to enjoy being a woman”.4 In the United
States, Ciba-Geigy told women that “the change of
life” did not mean they had to change their partici
pation in sports, or that men would no longer be
interested in them. All they needed to do was use
Ciba’s Estraderm (transdermal oestrogen).-'
Promoting oestrogens for postmenopausal women is
a profitable business. The leading product in the field
of “hormone replacement therapy” (HRT) is WyethAyerst’s Premarin. It ranked 25th in terms of global
sales in 1991, with total sales of $569 million.6 In
1992, Premarin became the most widely prescribed
drug in the USA. It also became Wyeth’s best-selling
product worldwide, with total sales of $642 million,
accounting for over 17% of the company’s pharma
ceutical turnover.
Time waits for no woman.
... Until she begins using
Wyeth/Ayerst ad for
Premarin plays on
fears of aging,
QIMP, Pakistan,
1990
A Gift of Time
At her age she's
estrogen deficient.
and subject to
menopausal changes...
Time for PREMARIN.
the most widely
prescribed natural
estrogen replenishment
PROVIDES LASTING
COMFORT THROUGH
MENOPAUSE
, /.■klUtcs vxometer
qrr.ptar.irJgntS'^x*
asscciatcd depression
■ ptinvots/revencs atropwc
vaV/tutis*
HELPS
MAINTAIN
HEALTHY
BONES
> PREMAHIN 0.625 mg
djjy pro-ides the
HELPS MAINTAIN
PREMENOPAUSAL
UPID LEVELS
. PREMARIN 0625 mg
pxy increases
HOL-cMcsterol and
decreases LDL and tel
cho’estcrrt'
DURING THE 'ESTROCEN-LE5S' YEARS
In the Philippines (PIMS, Dec
1988), Wyeth/Ayerst states
that the indication for
Premarin is "the estrogen
deficiency state characteristic
of the menopause and post
menopause"
From 'Flusher to Fractures'
177
9 A .
Hormone
replacement
therapy
Problem Drugs
Profitable it may be, but does it have anything to do
with health? Is there any reason why 30% of post
menopausal women in the USA, and 10% of
Australian and British women8 should consume
powerful hormones that are known to be associated
with an increased risk of some forms of cancer? Yes,
says the pharmaceutical industry, often with the sup
port of vocal enthusiasts in the medical profession,
and from some women themselves. No, not really,
says the overwhelming body of scientific evidence.
Menopause is not an illness
Whether or not women have chosen to have children,
the menopause marks a transition in a woman’s life
as the end of her reproductive years. How a woman
experiences the menopause depends on the attitudes
that she and society have towards aging in women,
together with the extent and quality of her relation
ships with others.9 "Menopause is not a disease, but
a life-cycle transition,” says medical anthropologist,
Margaret Lock.10 For most women, it is accom
plished with minimal discomfort or need for medical
intervention.11
Some women, however, may experience a variety of
symptoms during rhe menopause - hot flushes,
sweating, sleep and mood disturbances, dryness in the
vagina. The hot flushes and vaginal dryness can be
directly attributed to the change in the levels of hor
mones. So, hormone manufacturers have promoted
the use of oestrogen as a way to deal with what has
been called the “deficiency state” of menopause.12
The whole concept of hormone replacement therapy
is itself promotional. The hormones are not missing-,
they do not need to be replaced. Indeed, there are
other options to treat these symptoms, as the box on
the following page indicates.
However, efforts to convince women otherwise have
a long history. During the 1960s, a New York gynae
cologist, Dr Robert Wilson, is credited with
mobilising opinion within medical circles and among
women to use oestrogen to eliminate the unpleasant
effects of the menopause. In 1963, with the aid of
$1.3 million from the pharmaceutical industry, he set
up the Wilson Foundation to promote oestrogen.
Within 10 years, sales of oestrogen quadrupled in the
USA. By 1975, oestrogen was one of the top five best
selling drugs in the USA. The bubble burst when
studies were published in the same year that linked
oestrogen use to an increased risk of endometrial
cancer.13 Since that rime, further studies have demon
strated without doubt that the long-term use of
oestrogen only (unopposed oestrogen) leads to a
three- to eight-fold increase in risk of endometrial
cancer.1"1 This has led to the practice of combining
oestrogen with a progestogen - which is thought to
counteract the effects of unopposed oestrogen.15
However, there are still unresolved questions about
what effect combined therapy might have.
£EstradermTTSi
De mcmbraanplcistcr
'
Geigy calls Estraderm a “true-tonature" substitute. Climacterium Journaal, March 1992
9 A .
Hormone
replacement
therapy
Osteoporosis
Osteoporosis - the loss of bone mass resulting in
bones that are brittle and liable to fracture - is a sig
nificant and increasing problem in health care as
populations grow older. Nonetheless, osteoporosis is
rare in healthy premenopausal women with no his
tory of fractures.29 The decline in bone density is a
natural aging process. There are two major types of
osteoporosis: senile and postmenopausal. The causes
of senile osteoporosis are related to the aging process
and the condition is usually found in people over 70
years of age. It affects twice as many women as men.
Postmenopausal osteoporosis is primarily linked to
hormonal changes following menopause and the
condition may be detected at any time from age 51 to
75. Although hormonal changes are important, they
are nor the only cause, as men can also suffer from
this form of osteoporosis; however, the ratio of
women to men is six to one. Ultimately, age-related
bone loss accounts for more bone loss than can be
attributed to the menopause.30
Dramatic statistics are often used to focus attention
on the severity and cost of osteoporosis. It is an
expensive disease because it can lead to a high number
of hip and other fractures in elderly patients which
often require hospitalisation and follow-up care. In
1992, thecost of treating osteoporotic hip fractures in
the USA was estimated at some $7 billion.11 There are
700,000 reported cases of hip fracture each year in
Europe, Japan and the USA, and about 20% of
patients die within six months from complications.32
However, these deaths may be more connected with
poor nutritional intake among the elderly rather than
to the fracture or the osteoporosis.33
These hip fractures also may have little or nothing to
do with postmenopausal osteoporosis. Hip fractures
are more likely to occur after the age of 70 and result
from age-related osteoporosis. HRT seems to be of
little benefit. The most effective therapy is increased
calcium intake.34
A study carried out in Australia found that bone loss
can be slowed or prevented by exercise with either
calcium supplementation or HRT. Although the exercise-HRT approach was more effective than
exercise-calcium, it also caused more side effects, and
therefore required medical supervision. As a result,
rhe researchers concluded that if a common interven
tion was to be selected for all women, it would have
to be increasing dietary calcium intake plus exercise.35
A question that is not always asked about medical
treatments, but one which is becoming increasingly
important in the light of economic constraints on
health care systems in most countries, is how costeffective they are.
Preliminary' findings from one health region in the UK
suggest that the use of HRT for 10 years from the time
Non-drug therapy to prevent bone loss and
fractures
Strategies for preventing osteoporosis work best when
started early in life:
• Ensure sufficient dietary calcium in the teen years
(this helps achieve optimal bone mass at maturity);
• Engage in exercises that place moderate stress on
bones, such as walking, jogging and racquet sports;
• Stop smoking;
• Continue moderate exercise and avoid immobility
after the age of menopause, to help keep bone
density loss at a minimum;
• Minimise the risk of falling: in the home, avoid loose
rugs, poor lighting, slippery surfaces; wear footwear
that is supportive and provides a good grip; avoid
unnecessary use of psychotropic drugs, many of
which cause dizziness.
Sources: Urrows, S T , Freston, M.S., and Pryor, D.L., "Profiles in
osteoporosis", American Journal of Nursing, Dec 1991. pp33 9;
Breslau. N.A.. “Osteoporosis Management". Seminars in Nephrology,
Vol 12, No 2, Mar 1992. ppi 16 26: Forbes, A.P., "Fuller Albright: his
concept of postmenopausal osteoporosis and what came of it", Critical
Orthopaedics and Related Research, No 269, Aug 1991, ppl28141
of menopause would lead to a reduction of hip fractures
20 years in the future of only some 5-10%, a reduction
that would not result in any net cost savings.36
An analysis of HRT use in Australia found that
although HRT for women with menopausal symptoms
was generally cost-effective, for postmenopausal
women who were not suffering from symptoms,
prophylactic HRT for osteoporosis was not costeffective.37
If HRT is given to prevent osteoporosis, it must be
continued for at least 10 to 15 years. Stopped earlier,
it seems to accelerate bone loss.38 In other words, it
does not prevent, but merely postpones the inevitable
bone loss. Also, HRT only appears to be effective in
postmenopausal osteoporosis. If fractures occur in
postmenopausal osteoporosis, they are more likely to
be spinal. Five to 30% of women who are receiving
HRT at a dosage level considered to be sufficient to
prevent bone loss nonetheless still suffer a reduction
of bone density.39 As well, most deaths in women
with low bone mineral density are unrelated to the
occurrence of fractures - “an observation that
should be taken into account when estimating the
need for and cost-effectiveness of bone-density
screening and fracture prevention programmes”.40
9 A .
replacement
therapy
osteoporosis, and protection against heart disease are often portrayed as being available in a trouble
free form. Although the widespread use of HRT is
largely confined to industrialised countries and,
within those countries, HRT is primarily used by
women in higher socio-economic groups,45 the phar
maceutical industry is also promoting HRT in
developing countries.
What started as a sales campaign that “exploited
existing socially-caused fears about aging and loss of
status”46 related to the menopause has now incorpo
rated the fear of osteoporosis and the fear of heart
attack as additional reasons to use HRT. Instead of
more sales hype and emotive advertising, it is time
for careful examination of the proper role of HRT.
Clearing up misconceptions
Women who experience the menopause are not ill.
Exposing them to a daily dose of hormones that are
known to have the potential to cause life-threatening
illness is nor a decision to be taken lightly. So, why
take HRT?
If the reason is to deal with the symptoms of
menopause, then the number of women who need to
use HRT is limited, and the duration of therapy
should also be limited. In any event, there are effec
tive non-drug alternatives which should be
recommended first, as they are more cost-effective
with less risk of adverse effects. If HRT is chosen,
then by using the lowest possible dose to deal with
the symptoms and by tapering off the dosage gradu
ally, it should be possible to avoid a return of the
symptoms once the HRT is stopped.
If the reason is prophylactic treatment of osteoporo
sis, then serious consideration needs to be given to
the possibility that a woman may be on HRT for 30
years or more. There is no evidence yet to demon
strate what effects, either beneficial or adverse, such
long-term therapy might have, although there are
concerns about a possible increased risk of breast
cancer with long-term therapy. There is also no solid
evidence to show that rhe use of HRT will guarantee
that a woman will not suffer from the ill effects of hip
fractures later in life.
If the reason is prophylactic treatment of cardiovas
cular disease, there is not enough evidence to justify
such therapy.
The clear message is that HRT is a therapy that has a
limited usefulness. However, the pharmaceutical
industry is pouring money into promoting HRT for
as many women as possible.
In much of today’s promotion, the three possible
advantages — no menopausal symptoms, no fear of
Recommendations for action
1. HRT should not be recommended for
widespread use by all menopausal or post
menopausal women.
2. Further research is required including
controlled trials to study the overall benefits and
risks of HRT.
3. Strict controls need to be introduced on the
promotion of HRT.
4. Women considering using HRT to deal with the
symptoms of menopause or for prevention of
chronic disease should receive full, independent
information about the risks and benefits, including
non-drug options. For disease prevention, this
should include an assessment of their personal
risk and information on the effects of the specific
type of therapy recommended on clinically
meaningful endpoints such as hip fractures, heart
attacks and stroke.
181
Problem Di
Dr Fred Benjamin, associate director of obstetrics and
gynaecology at Queens Hospital in New York, claims
that “the worldwide consensus of doctors is that unless
there is a contraindication, every menopausal woman
should be given estrogen indefinitely to prevent
osteoporosis and because of its other beneficial
effects".-" There is definitely not a global consensus. Dr
Neil Breslau of the University of Texas South Western
Medical Center, Center for Mineral Metabolism and
Clinical Research, points out that “not every woman
who becomes menopausal will develop osteo
porosis.
Only about one woman in four is likely to
develop severe and disabling osteoporosis in her later
years.4’ According to Hans-Olav Adami, a leading
Swedish researcher on HRT, “Randomised control
trials are needed to provide the necessary basis for
widespread preventive use of HRT”44
Hormone
9 A .
Hormone
replacement
therapy
There are problems with some of the studies. As with
oral contraceptives, the dosage and type of HRT has
changed over the years, making it difficult to evaluate
the therapy being used today. Much of the research
refers to high dosage forms of oestrogen-only therapy
(unopposed oestrogens). Also, it is not always clear
whether previous use of oral contraceptives has been
taken into account in ascertaining risk.22
In addition to concerns about cancer, HRT is not
without adverse effects, some of which are severe.
These include headaches, breast tenderness, nausea,
mood changes, dizziness, fibroids, and vitamin
imbalances.23 Oestrogen “may promote the develop
ment of certain classes of infections, particularly of
rhe genitourinary tract”,24 and has also been linked
to an increased risk of gallbladder disease.25
A lower risk of
cardiovascular disease?
Two research findings in the mid-1980s brought
HRT back into fashion. First, some studies found
that women who used HRT were less likely to suffer
heart attacks; and second, some studies found that
the natural process of rhe decline in bone density was
less severe among women who used HRT.
The risk of coronary heart disease among women
who take oestrogens post-menopausally is 50%
Non-drug approaches
for menopausal symptoms
• Stopping smoking;
• Decreased alcohol and caffeine intake;
• Weight-bearing exercise (walking, cycling, dancing,
upper body workouts, aerobics, skipping, jogging);
• A diet rich in calcium and vitamin D, with plenty of
vegetables and fruit;
» Relaxation techniques, meditation, or massage to
reduce stress and depression;
• Maintaining regular sexual activity (for insomnia
and/or vaginal dryness);
• Oil-based or water soluble lubricants for vaginal
dryness;
• Wearing several layers of light clothing or carrying a
folding fan to feel more comfortable in the event of
|
hot flushes;
• Joining a support group.
’
Sources: in: Phillips. A.. Rakusen, J (eds) and the Boston Women's
Healtn Collective. The New Our Bodies. Ourselves (2nd UK edition),
London. Penguin Books. 1989, pp454-9; National Women's Health
Network, Taking Hormones and Women's Health: Choices. Risks, Benefits,
Washington. 1989. pp6 7
lower than among women who do not use HRT.
There is also some indication of a similar reduction
in the risk of stroke,26 although a 10-year follow-up
of more than 48,000 women in the Nurses’ Health
Study in rhe USA was not able to detect any change
in the risk of stroke.27
However, there are problems with the use of HRT as a
protective or preventive measure against heart disease.
First, the evidence is based on rhe use of unopposed
oestrogen only. Second, in most cases it is based on
observational studies which may be biased by selec
tion: because of their social and economic status, rhe
women who were taking oestrogen might have been
healthier and therefore at less risk anyway from heart
disease. Not all rhe studies were able to control for
this. Third, lifestyle changes are important preventive
measures against heart disease that have not been ade
quately tested against drug therapy. In the absence of
randomised clinical trials, the supporting data to rec
ommend the widespread use of a drug for disease
prevention is not available. Also lacking is the data to
show what impact using oestrogen with a progestogen
would have. Thus, the use of HRT to prevent cardio
vascular disease is probably not a valid indication.28
Problem Drugs
Risk of breast cancer
The possibility of an increased risk of breast cancer
among users of oestrogen also caused sales to drop in
many countries during the late 1970s and early
1980s. Breast cancer is the most common cancer in
women in developed countries.16 The use of oestro
gen replacement therapy for 15 years is associated
with a 30% increase in the risk of breast cancer,
according to a meta-analysis of 16 studies.17 An
analysis of 10 studies of HRT use for more than eight
years found a 25% increase in the risk of breast can
cer.18 A prospective study of more than 23,000
women in Sweden found that there was a 10%
increase in the risk of breast cancer among those who
took oestrogen replacement therapy. The risk
increased with the duration of the therapy; women
who used HRT for more than nine years had a 70%
increase in the risk of breast cancer. The study also
found that the addition of a progestogen “offered no
protection against the development of breast cancer”
although the number of women using combination
HRT was small.19 Another meta-analysis of 37 orig
inal studies found a 6% increase in the risk of breast
cancer overall, but a 63% increase among long-term
users (more than 12 years).20 One major prospective
study in the USA - the Nurses' Health Study - found
no increased risk among past users, even those with
more than 10 years of use; however, it found a 36%
increase in risk among current users.21
79
182 9 A .
Hormone
replacement
therapy
Problem Drugs
References:
1.
2.
3.
4.
Ford, A.R., “Hormones, getting out of hand'’, in: McDonnell, K. (ed.), Adverse
Effects: Women and the Pharmaceutical Industry, Penang, IOCU, 1986. pp27%o
Advertisement, AI/AtS Caribbean, January 1991, inside front cover
QIMP, Vol 22. Nos 1/2, Atar-Aug 1990. facing p/o
Coney, S., “The exploitation of fear: hormone replacement therapy and the
menopausal woman", in: Davis, P. (ed.), For Health or Profit?: Medicine, the
Pharmaceutical Industry, and the State in New Zealand, Auckland, Oxford
University Press, 1992, ppi/9-207
5.
US Congress, Office of Technology Assessment, The Menopause, Hormone
Therapy, and Women's Health, OTA-BP-BA-88, Washington, US Government
Printing Office. May 1992, P71
6.
Anon., “Top 25 products in 1991", Scrip. No 1717,13 May 1992, p28
7.
Anon., "New products boost AHP in 1992", Scrip, 1817, 4 May 1993, ppi8-i9
8.
Coney, op cii
9.
Roberts, P.J., “The menopause and hormone replacement therapy: views of
women in general practice receiving hormone replacement therapy", British
Journal of General Practice, Vol 41, Oct 1991, PP4214
10.
Lock, M„ “Contested meanings of the menopause". Lancet, Vol 337, 25 May
1991, PP1270-2
11.
National Women’s Health Network, Taking Hormones and Women’s Health:
Choices, Risks, Benefits, Washington, 1989, pp2 and 6
12.
Ford, op cit
13.
Coney, op cit
14.
Grady, D. and Emster, V., “Invited commentary: Does postmenopausal therapy
cause breast cancer?", American Journal of Epidemiology, Vol 134, No 12,
15.
1991, ppi396-t4oo
Anon., “FDA committee recommends approval of oestrogen/progestogen
use". Scrip. No 1632,10 Jul 1991, p24
16.
Sillero-Arenas, M„ Delgado-Rodriguez, M., el al, “Menopausal hormone
replacement therapy and breast cancer, a meta-analysis", Obstetrics and
Gynecology, Vol 79, No 2, Feb 1992, PP28694
17.
18.
19.
Anon., “Breast cancer risk with long-term HRT", Scrip, No 1613.3 May 1991, P25
Grady and Emster, op cit
Bergkvist, L, Adami, H-O., et al, “The risk of breast cancer after estrogen and
estrogen-progestin replacement", New England Journal of Medicine, Vol 321,
No 5, 3 Aug 1989, PP293-7
Sillero-Arenas, et al, op cit
Coloitz, GA, Stampfer, M.J., et al, “Prospective study of estrogen replacement
therapy and risk of breast cancer in postmenopausal women”, Journal of the
American Medical Association, Vol 264, No 20,28 Nov 1990, PP264853
22 Goddard, M.K., “Hormone replacement therapy and breast cancer,
20.
21.
endometrial cancer and cardiovascular disease: risks and benefits", British
Journal of General Practice, Vol 42, Mar 1992, ppizo-5
23.
24.
O'Donnell, M., “improving on nature”, International Management, Oct 1992,
P87; Phillips, A, Rakusen, ]. (eds) and the Boston Women's Health Collective,
The New Our Bodies, Ourselves (2nd UK edition). London, Penguin Books,
1989. P457
Styrt, B and Sugarman, B., “Estrogens and infection", Reviews of Infectious
Diseases, Vol 13,1991, PPI139-50
25.
26.
National Women's Health Network, op cit, P9
MacLennan, A., “Women, cardiovascular disease and hormone replacement
therapy", Medical Journal ofAustralia, Vol 156, 20 Jan 1992, PP77-8
27.
Stampfer, M.J., Coldilz, GA., et al. "Postmenopausal estrogen therapy and
cardiovascular disease; ten-year follow-up from the Nurses' Health Study",
New England Journal of Medicine, Vol 325, No 11,12 Sep 1991, PP7S6-62
28.
Barrett-Connor, E. and Bush, T.L., “Estrogen and coronary heart disease in
women", Journal of the American Medical Association, Vol 265, No 14,10 Apr
1991, ppi86i-7
Urrows, S.T., Freston, M.S., and Pryor, D.L., “Profiles in osteoporosis",
American Journal of Nursing, Dec 1991, PP33-39
30.
Rubin, C.D., “Southwestern Internal Medicine Conference: Age-related
osteoporosis ”, American Journal of Medical Sciences, Vol 301, No 4, Apr 1991,
PP281-98
31.
Gallagher, J.C., "Pathophysiology of osteoporosis”, Seminars in Nephrology,
29.
Vol 12, No 2, Mar 1992, ppiO9-i5
Anon., The European Market for Osteoporosis Treatment Products, London,
Frost and Sullivan, 1992
33.
Phillips and Rakusen, op cit, P469
34 Rubin, op cit
35.
Prince, R.L., Smith, M., et al, “Prevention of postmenopausal osteoporosis: a
comparative study of exerase, calcium supplementation, and hormonereplacement therapy". New England Journal of Medicine. Vol 325, No 17, 24
Oct 1991, PP1189-95
36.
Pitt. FA and Brazier, J„ “Hormone replacement therapy for osteoporosis",
Lancet, Vol 335, 21 Apr 1990, P97S
37.
Cheung. A.P. and Wren, B.G., “A cost-effectiveness analysis of hormone
replacement therapy in the menopause", Medical Journal ofAustralia, Vol 156,
2 Mar 1992, PP312-16
38.
Urrows, et al, op cit; US Congress, op cit, P38
39.
Stevenson, J.C., Cust, M.P, et al, “Effects of transdermal versus oral hormone
replacement therapy on bone density in spinal and proximal femur in
postmenopausal women", Lancet, Vol 336,4 Aug 1990, pp26s-9
40.
Browner, W.S., Seeley, D.G., et al, "Non-trauma mortality in elderly women
with low bone mineral density". Lancet, Vol 338,10 Aug 1991. PP355-8
41.
Eagan, A.B., “The estrogen fix”, A1s„ Apr 1989, PP38-43
42.
Breslau, NA, "Osteoporosis: Management", Seminars in Nephrology, Vol 12,
No 2, Mar 1992, ppil6-26
43.
Forbes, A.P., “Fuller Albnght: his concept of postmenopausal osteoporosis
and what came of it", Critical Orthopaedics and Related Research, No 269.
Aug 1991, PP128-141
44.
Adami, H-O., "Long-term consequences of estrogen and estrogen-progestin
replacement", Cancer Causes and Control, Vol 3,1992, PP83 90
45.
Coney, op cit
46.
ibid
32.
^^i Proble'm Drugs was-firSt pSJ6WSfeBteHi^V986,and-'has been used
1
by tens of thousands of health workers, pharmacists, policy
makers, activists, researchers, students, journalists and others
around the world. It has been translated into Arabic, Bangla,
French, Indonesian and Spanish. This is an updated and revised
version, with revisions based on a user survey.
A few comments about the first edition of Problem Drugs:
"Very useful...gives us the information which cannot be
obtained from manufacturers.”
- Tanzanian Bureau of Standards
“The recommendations are generally clear, entirely
acceptable, and obviously necessary."
- The Lancet
“Its findings, particularly with respect to the developing
countries, are disquieting.”
- British Medical Journal
“Health educators love it.”
- ■ Health educator, National Population Bureau, Nigeria
“Essential and thought provoking reading’
- Nursing Times
pro
ISBN 90-74006-06-X losbl.
Health Action International (HAI) is an informal network of over
150 consumer, health, development action and other public
interest groups involved in health and pharmaceutical issues in
70 countries around the world. HAI actively promotes a more
rational use of drugs through research, education, action
campaigns, advocacy and dialogue.
-------------------------------------------------------------------------------------- —------------------------------------- -—
- Media
PROBLEM DRUGS.pdf
Position: 619 (11 views)