International aspects of problems associated with the use of psycho-active drugs

Sections

Abstract
Introduction
Terminology
Use and consumption
Drug advertising
Information and education
Effectiveness of drugs and assessment of results of therapy
Standards for controlled clinical trials in psychopharmacology
Studies on side effects
Special research issues
Summary

Details

Author: Tadeusz L. CHRUSCIEL
Pages: 35 to 48
Creation Date: 1976/01/01

International aspects of problems associated with the use of psycho-active drugs 1

Tadeusz L. CHRUSCIEL
Professor of Pharmacology, Deputy Director, Drag Research and Control Institute, 00-725 Warsaw, Poland, former Senior Medical Officer, Office of Mental Health, World Health Organization, Geneva.

Abstract

Problems of terminology, use and consumption, advertising, effectiveness and appropriate information and education on psychoactive drugs are outlined and advantages of international collaboration in attempts to establish standards for controlled clinical trials in psychopharmacology are discussed.

Introduction

The appropriate use and distribution of' psychoactive drugs is of particular concern because of (1) the large application of this pharmacological category in many ailments and diseases by physicians specialized in many disciplines; (2) overall effects upon behaviour of users of a considerable number of such drugs; (3) increasing consumption reported from a number of countries in recent years; and finally because of (4) occurrence of a particular side effect resulting from chronic use of a number of psychotropic and narcotic drugs: drug dependence. Some problems related to medical and non-medical use of psychoactive drugs are of international interest since they may occur at any time in any country; some other problems are of national concern. The existence of international problems related to narcotic drug use has been recognized for a considerable number of years; a number of international treaties has been adopted; and most recently an international instrument concerning control of some psychoactive drugs-the 1971 (Vienna) Convention on Psychotropic Substances-has been adopted by a United Nations conference, giving testimony to serious involvement of national health authorities.

Terminology

The first international problem is that there appears to be no common acceptance of definitions related to drug use. Active communication among researchers must involve a dialogue in terms which are understandable to all concerned. Even the simplest words, like "drug" or "medicament" have different connotations in various languages and it has been found necessary to set definitions before consider- ing any public health related pharmacological problems (WHO, 1969, 1972; Gvt. of Canada, 1973). Drug use can be subdivided into medical and non-medical use. These are, however, twin problems which cannot be studied separately (Halbach, 1973). Terminology concerning non-medical use is the most difficult one.

1 Based on a paper presented at the World Psychiatric Association Symposium on Special Problems in Psychiatry, London, 11-13 November, 1974.

Non-medical use concerns both medicaments and other psychoactive substances that are not usually administered for medical purposes (e.g. dimethyltryptamine and lysergid). The intention of the user determines the use of terms relative to medicaments. Acceptance of non-medical use of some substances by the population differs widely in different regions of the world. For example, use of alcohol is socially accepted in highly industrialized countries; this applies also to cannabis in India and khat ( Catha edulis L.) in the Yemen; the use of these and some other substances is, on the other hand, not tolerated by wide strata of the populations in other countries and it may even be illegal. This complicates obviously the task of defining non-medical use.

For the purposes of this paper the following definitions are adopted:

Drug: "Any substance that, when taken into the living organism, may modify one or more of its functions" (WHO, 1969);

Medicament: Any substance or product that is used or intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient (WHO, 1966, slightly modified).

Psychoactive: Acting on psychic function, mood, consciousness, perception or experience and/or behaviour.

Non-medical use: Use other than when indicated for generally accepted medical reasons (WHO, 1973; Gvt. of Canada, 1973).

Drug dependence: A state, psychic and sometimes also physical, resulting from the interaction between a living organism and a drug, characterized by behavioural and other responses that always include a compulsion to take the drug on a continuous or periodic basis in order to experience its psychic effects, and sometimes to avoid the discomfort of its absence (WHO, 1969).

Each of the above definitions of terms is subject to criticism. There is a need to discuss the use of terms in various countries and to propose such definitions that may be universally accepted.

Use and consumption

I use both terms to underline the ongoing dynamics of the continuous process and the measurable character of the process, within a given period of time, based on statistical analysis of concrete data.

Medical-care expenditures are rising in a considerable number of both developed and developing countries, and in some of the richer countries the proportion of national income devoted to health is continuously increasing. Several countries may be spending as much as 10 per cent of their national income on health services before the year 2000. Staff and drug expenditures constitute the largest share of all health-service expenditures.

The costs of pharmacological treatment are growing; the consumption of drugs seems to be on the increase in a number of countries, particularly in the highly developed ones; new and more potent drugs are forthcoming; and a sufficiently high level of pharmacological treatment has become a standard general demand, difficult to be met in a considerable number of developing countries.

The consumption of psychoactive drugs is of particular concern because of its possible influence on human behaviour and their application as adjacent therapy in many kinds of pharmacological treatment schedules for various ailments.

AVAILABILITY

One of the important problems, and the one which is certainly most important in some developing countries is availability of psychoactive substances for legitimate medical purposes. It is a fact that while in a number of highly developed countries the choice of an appropriate drug and pharmacological treatment constitutes a difficult task to be accomplished by a specialist, the treating personnel in some developing countries face the reality of empty shelves in hospital pharmacies and a choice of drugs that is really negligible, if not nil.

Making psychoactive drugs available to all in need is, I believe, an important objective for national public health authorities in a number of countries. Since countries in need are numerous, it is an international problem requiring further consideration.

On the other hand, availability of psychoactive substances for non-medical use is another difficult problem, and all efforts are being made to prevent such drug use by controlling, for instance, availability.

Particularly in these areas the number of international problems is immense. Let me mention only two: the need for international collaboration and the measures that have to be taken to prevent the problems related to self-administration of drugs. To this end, a number of international drug instruments has been conceived and one of these, the Single Convention on Narcotic Drugs, 1961, met with almost universal recognition. However, the 1971 Vienna Convention on Psychotropic Substances is not yet in force, and a number of dangerous dependence-producing psychoactive substances can move relatively freely in international trade.

Preventive international collaboration in this area should probably concentrate on identification of problems, epidemiological studies on incidence and prevalence of drug-taking, experimental and occasional as well as dependent use, development of alternatives to such use, and collaboration in respect of preventive treatment and rehabilitation approaches.

In 1974 the World Health Organization initiated the implementation of its operational research programme in epidemiology of drug-taking. Guidelines for collection of data on incidence and prevalence of drug use have been drafted. These are now being field-tested, and wide international co-operation will hopefully lead to the success of this important global undertaking.

EXTENT OF USE

A survey conducted in 1973 by the Director of Research of the New York State Narcotic Addiction Control Commission found that one in five secretaries, one in four sales girls, one in seven teachers, one in six women with jobs outside the home, and one in eight housewives used tranquillizers (Bowes, 1974).

Another survey conducted among 1,200 adults in Toronto indicated that 23.8 per cent of the sample studied had at least one prescription for a psychoactive drug in the last year. Tranquillizers were the most commonly used (12.7 per cent) followed by barbiturates (8.6 per cent). For a large proportion of the users, the use of these drugs apparently was related to some medical or psychic problems, but this was not the case for an almost equally large number (Fejer and Smart, 1973).

The International Narcotics Control Board, an independent treaty body, noted in its 1973 report: "Even from the present limited evidence there are clear indications that, taken as a whole, abuse resorting to these (psychotropic) substances is not diminishing and that it is spreading to more countries, including some in Africa and in Asia. While it would seem that in certain places efficient police action combined with voluntary restraints adopted by doctors and pharmacists may have led to a fall in amphetamine consumption this is by no means a general phenomenon. On the other hand, there seems little doubt that misuse of barbiturates is on the increase" (INCB, 1973).

On the basis of a national sample of American adults, data on national patterns of use of psychoactive drugs were provided by Parry et al. (1973). During the year preceding the interview, 13 per cent of the men and 29 per cent of the women had used such prescription drugs. Over-the-counter (OTC) drugs were used by 10 per cent of adults.

Simmons (1973) stated, that

"The use of psychoactive drugs, tranquillizers, sedatives, etc. is increasing even more rapidly than general drug use. Between 1969 and 1972 there were approximately seven billion dosage units of amphetamines produced in the USA. The following approximate amounts of psychotropic drugs were distributed in the USA in 1969:800 million to one billion daily dosage units of minor tranquillizers (a 100 per cent increase in four years), 250 to 350 million daily dosage units of anti-depressant drugs (a 20 per cent increase in four years). For those three classes of psychotropic drugs combined, there were approximately one and a half to two billion daily dosage units distributed in 1969, representing a 65 per cent increase over a four-year period. That one and a half billion daily units represents 12 days of treatment for every man and woman in the USA over the age of 18."

During 1970, five thousand million doses of tranquillizers, three thousand million doses of amphetamines, and five thousand million doses of barbiturates were produced in the USA (Stetler, 1974).

Bowes (1974) noted that chlordiazepoxide and diazepam account for almost seven out of every 10 dollars in drug-store purchases of so-called "minor tranquillizers", almost a quarter of a thousand million dollars of 1971 wholesale purchases.

In Poland data on consumption of pharmaceutical products are collected by a pharmaceutical department of the Ministry of Health and Social Welfare. The data published in the annual edition of the Statistical Bulletin 2 refer to the overall cost of drugs by therapeutic groups and to the number of tablets (ampoules etc.) of specific pharmaceutical preparations used throughout the calendar year. In 1975 the Polish Academy of Sciences initiated a special survey on drug consumption, attempting to compare morbidity with extent of drug use in various departments both in hospitals and in out-patient services.

2 Biuletyn Statystyczno-Informacyjny 1974r. Min. Zdr. i Op. Spol. Warszawa, 1974.

In view of the considerably increasing use, there is a great need to conduct drug consumption studies. Their results would constitute a basis on which prediction can be rationalized; such studies are just starting with WHO participation in a few developed countries.

COST OF USE AND ECONOMIC PRESCRIBING

The rapidly rising cost of medical care and closely related social services has become an economic problem.

Expenditures on pharmaceuticals or drugs, although often hard to measure as a separate cost item, may vary from 10-15 per cent of the total health service budget. However, when considering value for money, not only costs but effectiveness must be considered.

It is stressed that the economy of drug treatment is determined not only by the unit price of drugs but also, and more significantly, by their effectiveness and safety, and by the mode and frequency of their administration. Excessive drug prescription may be discouraged by making the consumer bear part of the costs, even if the health service is nationalized, or health care is provided under pre-paid schemes. Such arrangements exist in a number of countries in the form of 10-30 per cent participation of the patients in the cost of medicaments or by fixed sums laid down for prescriptions.

More often than not those who seek ways of economizing look to the nation's drug bill. In most countries the cost to the public health delivery system continues to rise. And there is a growing body of opinion that some psychotropic drugs prescribed are unnecessary or even dangerous.

In many health-care systems the list of drugs that may be prescribed subject to national public health or insurance refund for patients is limited, but, in general, steps are being taken to ensure that a representative sample of all therapeutic categories is listed, and "freedom to prescribe" may be exercized within the limits of the system. It is noted that some countries (for example the UK) allow physicians complete freedom to prescribe any drug within the National Health Service. The cost of use of a number of particularly expensive psychoactive drugs is an important issue in economic planning of preventive and treatment programmes on a national scale. Some of the most expensive ones are subject to substitution by probably equally effective drugs, but the decision-making process is slow and the relevant scientific data frequently missing.

The cost of drugs is also of importance to the individual consumer, whether insured or not, whether profiting from national or from private health delivery systems.

An important element in a prescriber's choice of drugs within the same pharmacological category is therefore the relative cost including social cost of each drug. For example, in the group of benzodiazepines there are at present eight compounds available on the United Kingdom market (chlordiazepoxide, diazepam, oxazepam, medazepam, lorazepam, chlorazepate, nitrazepam and flurazepam (Tyrer, 1974) and at least four other benzodiazepines are being tested in clinical practice. It has been indicated that the differences existing within the group of benzodiazepines are small or negligible, and indications for use are quite similar in many instances. The medical profession and the pharmaceutical industry, as well as public health authorities, need to be involved in a re-examination of this and other similar cases so as to give an authoritative advice to practitioners. The elements of usefulness, efficacy and safety are of primary importance, but the economic factor cannot be neglected. The governmental responsibility for ensuring that drugs are sensibly prescribed may call for measures aiming at avoiding unimaginative duplication within the drug industry and at monitoring of both drug efficacy and prescribing. Special educational measures for prescribers are required (McCarthy, 1974; Parish, 1971). The need for further fostering of development of clinical psychopharmacology training is evident. Facilities to study drug prescribing habits exist already in a number of countries or may be introduced, in particular because drug distribution is now computerized in some countries (e.g. MIDOS, an order-handling system using a UNIVAC 9400 computer, has been in existence since 1974 in Oslo) and some systems are being developed to analyse consumption of drugs. Application of electronic processing would greatly facilitate and speed up such studies.

International collaboration would promote progress in this area.

Drug advertising

INFLUENCE UPON PRESCRIBERS AND CONSUMERS

The advertising of both prescription and OTC drugs has an impact on drug use and misuse' by the public in highly developed countries. This impact on the general public may have undesirable repercussions resulting in inappropriate or unnecessary prescribing.

Not so apparent to the public are the huge promotional and advertising campaigns for prescription drugs directed at practitioners through medical journal advertisements, direct mailings, visits by representatives and other means. Drug companies increase their profits in proportion to their promotional expenditures. Pharmaceutical companies with advertising outlays of more than $50 million in 1966 had an average rate of return of 29.2 per cent between 1961 and 1965; those with advertising budgets between $10 million and $50 million had a rate of return of 19.7 per cent; and those spending less than $10 million earned 17.3 per cent (Price, 1974).

A great effort is being made in a number of countries to exercise some kind of control over advertising agencies and manufacturers of drugs to ensure accuracy of information provided by advertisements. In some countries, indeed, all kinds of advertising of drugs to the public is prohibited; however, in some other countries, advertising of drugs is flourishing, and inadvertently it is not the most adequate information that is being propagated. Inappropriate advertising may contribute to develop problems related to drug dependence.

In 1971, critics stated that mass-media drug advertising to the public was contributing to drug misuse by creating a climate of acceptance of the ethic "better living through chemistry". They called for a ban on drug advertising.

INFLUENCE UPON CONSUMPTION

The influence of advertising upon drug use and misuse in the USA was investigated in depth since 1971 by the National Council of Churches of Christ, and its panel conducted the hearings and noted in its findings and conclusions, among others, the following:

"Given no real evidence to the contrary, we are persuaded that there is a link between the promotion of legitimate drugs and drug misuse and abuse.

"The contention of the drug companies is that no such connexion exists. Yet drug companies' advertising presents a 'pain, pill, pleasure' model which functions to validate and reinforce values, attitudes and behaviour that encourage the misuse and abuse of drugs.

"The link between advertising and misuse and abuse is not a one-to-one causal connexion, nor is drug advertising the sole cause of drug misuse or abuse. The conviction that they are causally related, however, is based on evidence from the behavioural sciences and from the communications field and on the fact that drug manufacturers spend large sums to promote the consumption of drugs. Drug advertising and promotion cannot be divorced from a culture that increasingly looks to drugs and medication as a normal response to human problems.

"The degree to which drug advertising is a contributing factor to drug abuse and misuse is unknown.

"No major studies have been conducted on the impact of drug advertising on the drug-taking patterns of the population. Although advertising sells drugs, without a comprehensive, investigation there is no empirical basis for assessing the relative importance of the influence of advertising and drug misuse and abuse" (NCC, 1974).

It is apparent that studies in depth of the ways of management of the problem require further research at national level and a co-ordinated international effort. Although the awareness of the problem exists and some international agencies (e.g. WHO) have taken steps (WHO, 1957), more action is urgently needed to ensure that relevant and reliable information is given in an adequate way to all interested persons.

Information and education

DRUG INFORMATION

The potential consumer is everybody on this globe. And everybody who takes medication needs drug information and is affected by its quantity and quality. A survey was recently completed by the Food and Drug Administration on the safety of five categories of products used by 135 million consumers in the U.S.A. (Martin, 1973). The results revealed a number of misconceptions on the part of the consumers. Among them there was a belief that prescription medicaments were very safe, almost as safe as food, and less likely to cause injury than cosmetics and OTC medicaments. This and other misconceptions might lead to inappropriate use of psychotropic and other drugs and result in serious complications.

According to a recent WHO symposium (WHO, 1974a) OTC drugs used for self-treatment should, on principle, be sold in pharmacies only, but it should be recognized that in some countries geographical, manpower or other considerations may justify their sale elsewhere. To ensure their safety and efficacy, and also to keep the user properly informed, all formulations, labelling, package inserts, and advertising should be subject to approval by a drug control authority. The patient has the right to receive all essential information about his medication. This has to do with (a) somatic and psychic effects resulting from appropriate drug use; (b) adverse effects, if any, concomitant with the prescribed treatment schedule and/or resulting from deviation from such a schedule; and (c) duration of medication. Drug information must be accurate and cautiously worded in order not to frighten patients. Incomplete communication between the prescriber and the patient continuously cause unhappy episodes, such as suppositories being taken orally, implantation tablets being eaten etc. Every effort should be made by the physicians and pharmacists, learned societies, manufacturers and government agencies to improve drug information, but this is particularly important in medication with psychotropic drugs. Their use may have far-reaching, long-term significant effects influencing, through CNS, behaviour (which is consequently of social significance) and many functions of the body. The consumer, because of his pathological state, may be in need of a more detailed and easily understandable information. Hospital-based drug information services ("clinical pharmacy") are expanding rapidly in a number of countries to meet the needs of all health professionals. Further progress will lead to better medical care. There is a need to provide more services for the information of patients.

Improvement of information supplied to physicians is also an important task. The World Health Organization has recently undertaken a three-year feasibility study on an international information system on the quality, safety and efficacy of drugs (WHO, 1973a). It is hoped that these and other efforts at the international level will meet the need for information and education of ( a) consumers and ( b) prescribers, and would help to improve consumer communication.

CONTINUING EDUCATION

Continuing education constitutes another problem that is of interest to all drug prescribers. Typically, the prescribing physicians have had little formal instruction in the therapeutic, preventive and diagnostic uses of drugs. Very few medical schools offer a course in clinical pharmacology, e.g. in the United States only about one third. Accordingly, most practitioners acquire their knowledge after graduation from medical school. Sources of such information differ greatly from country to country. The sources may be abundant (and not always detailed enough nor appropriate) or simply not existent. Peers, colleagues, and supervisors continue to serve as primary sources of information. Advertisements, medical journals and reference books are also important (see section 4). In some geographical areas, formal continuing education programmes are implemented, but even in countries with highly developed postgraduate teaching systems, not enough attention has been given to practical problems of clinical pharmacological treatment. Educational activities devoted exclusively to drug therapy are rather small in number and their attendance is low. The quality of existing internal bulletins or newsletters on drugs, distributed in many hospitals, varies widely. The newly created professional - the clinical pharmacologist - may help in the future in educational approaches directed towards all health professionals.

Worthen (1973) indicates, on the basis of a survey of 14 quantitative studies published from 1940-1969 dealing with the influences of patients, pharmacists, professional journals, advertising, visits by representatives of pharmaceutical manufacturers and peers on the physician's prescribing habits that these influences should be taken into account when establishing a continuing educational programme for practising physicians.

Careful records of drug use in hospitals and out-patient clinics may be instrumental in identifying prescribing patterns and help to single out errors and unnecessary use. A recent study in Illinous indicated that, among others, antianxiety and anti-psychotic drugs hydroxyzine and dextropropoxyphene preparations were used in possibly unjustifiable quantities (Müller, 1973).

Surveying the prescribing of drugs of the medical staff is a formidable task. Only the new electronic data collection and retrieval systems may be used in such endeavours to give probably complete coverage. Computers for studies of the use of psychotropic drugs have already been employed; they began to serve educational purposes as well (Smetler et al., 1973). In the case of narcotic drugs, some countries have already developed special programmes based on computerization of all narcotic drug prescriptions in the country or a region of the country. Although such studies are costly, the data have proved very useful for a number of decision-making processes concerning availability of drugs, appreciation of the level of medical practice etc.

Effectiveness of drugs and assessment of results of therapy

The complexity of medical therapy in mental disorders calls for a careful assessment of its results. Psychotropic drugs may change their effectiveness subject to a number of environmental factors. It was reported that much lower doses of psychoactive agents were sufficiently active and much lesser amounts of drugs were necessary for completion of treatment in some European countries and in the Mediterranean area than in the U.S.A. Although genetic and nutritional factors may play a role, there is little doubt that the immediate surrounding has a direct effect on results of treatment. Psychosocial factors influence significantly the dosage, schedule of treatment and, the final outcome of therapy (Shepherd et al., 1968).

Studies on evaluation of effectiveness of psychoactive medicaments are being carried out in a number of countries on a long-term research basis. Progress of such research is relatively slow.

Unfortunately studies on the effect of environmental factors on the usefulness of psychoactive drugs are practically non-existent. Such research would indeed require international planning and collaborative efforts going beyond national boundaries.

The evaluation of effectiveness of psychotropic drugs is particularly difficult and a high level of technical expertise is necessary, not to mention the cost and time factors involved. This burden can, however, be relieved if close links among appropriate research institutions are established. Fostering international collaboration in this area is a formidable task for learned societies at the national level and for international associations (e.g. International Union of Pharmacology, World Psychiatric Association). The World Health Organization is continuously trying to arrange for close collaboration between outstanding and developing research institutions. It established a network of WHO Collaborating Centres on Psychotropic Drugs; altogether there are 23 centres of this kind (including two international and four regional ones) now existing on all continents. There is a great need to further develop such activities and to increase their scope.

Standards for controlled clinical trials in psychopharmacology

In a number of countries, special governmental regulatory agencies set legal rules under which clinical trials may be conducted. These agencies usually also review the evidence for safety and efficacy of a compound to determine whether a drug may be marketed and made generally available for physicians.

It is common for pertinent drug-law provisions not to deal with standards. It is through rule-making and regulatory decisions of these agencies that standards for the conduct of clinical trials are established. Controlled clinical trial based on statistical analysis is considered to be the best way of ascertaining that treatment will benefit the patient.

Standards for clinical trials touch upon ethical, legal and scientific issues.

Clinical studies for the evaluation of psychotropic drugs presented at international symposia and conferences provide a great variety of methods. Some groups of researchers stick to a certain number of elements in their trials, while others attach greater importance to different ones, thereby frequently neglecting some issues.

Internationally accepted criteria for establishing objectives of clinical trials in psychopharmacology, selection of patients, choice of clinical and statistical methodology and choice of evaluation methods do not exist. While it seems to be unlikely that a general world-wide consensus relative to all problems involved might be reached soon, there is, I think, a likelihood that a minimum set of standards that would make the results of studies acceptable to regulatory agencies might be recommended by the scientific community.

Some approaches at national level already exist and a book has been published that deals with methodology of clinical trials (Levine et al., 1971).

In one country, a set of guidelines for psychoactive drug testing has already been published in 1972 and a revised set in 1974 (FDA 1972, 1974).

A group of psychiatric clinics and hospitals in a few countries sharing a common language set up in 1965 a special common documentation system of psychiatric findings and agreed to use the same forms for computer processing of collected data (Scharfetter, 1971). It was necessary to agree to standard procedures in this interesting international undertaking.

Clinical standards must be based on scientific principles. Thus progress in research should always be considered and standards cannot be established if appropriate scientific evidence is missing. If this approach is used, then it is necessary for the scientific community to state at any point in time what it considers to be proper standards. In other words, the standards have to be changed in accordance with the progress of research.

In the area of research in clinical psychopharmacology in the United States, for example, the American College of Neuropsychopharmacology (ACNP) and the Psychopharmacology Branch of the National Institute of Mental Health (NIMH) made continuing efforts towards the development of standards. Setting up international standards of controlled clinical trials would help establish world-wide acceptable guidelines or assessing new drugs on the basis of their safety and effectiveness. This is of particular interest to developing countries, which lack the necessary facilities and a sufficient number of clinical researchers trained and experienced in the evaluation of drug therapy.

The need is also being felt for an international certification scheme governing the quality of drugs in international commerce (WHO, 1972). The international organizations are more and more frequently asked to take action in this respect.

It is, I think, appropriate to emphasize that neither careful pre-clinical investigations nor appropriately conducted clinical trials can provide complete protection against the unpredictable. However, setting standards, as has been shown in the food industry, minimizes the inevitable risk. In establishing standards it is important to foresee the possible intervening factors. They may differ in various pathological states and entities. Interaction of drugs, bio-availability and pharmacokinetic characteristics of new products are now being carefully considered. The results of these studies carried out in a considerable number of countries are thus relevant to the development of a national drug policy and the work of regulatory agencies. International co-ordination of such studies would certainly help to speed up the progress.

Well standardized and validated rating scales are greatly needed, and the use of those already existing should be fostered as opposed to the use of unvalidated "personal favourite" scales.

I am joining Dr. J. Levine (Levine, 1974) in suggesting that international standards for clinical trials should address themselves to such issues as ( a) design or plan; ( b) conduct; ( c) conditions of trial; and ( d) documentation. However, I do not believe that rigidly set rules should be implemented. And it is obvious that application of standard methods requires well-trained clinical staff, a process which is expensive and time-consuming.

The most difficult problem in setting standards may be insufficient knowledge about basic mechanisms of both disease and action of drugs. There is, therefore, little opportunity to establish rigidly defined testing procedures in a number of attempts to test psychiatric disorders. It seems that it is better at this point of time to rely upon expert guidance of scientists outlining general principles for drug-testing. Several World Health Organization technical reports were published on these subjects (WHO, 1967, 1968, 1969, 1971 and 1974). They deal with the quality of medicaments, safety of their use and therapeutic effectiveness: A general review of guidelines was undertaken in October 1974 (WHO, 1975).

Nevertheless setting standards for clinical psychopharmacological trials with appropriate accounting for transcultural intervening factors remains a target for international action. A group (the "Wittenborn group") of interested industrial and university pharmacologists considered in a series of meetings the international acceptability of FDA guidelines for the evaluation of psychotropic drugs. The constitution of the World Health Organization lists among the functions of the organization the development, establishment and promotion of international standards with respect to food, biological, pharmaceutical and similar products (WHO, 1974b). WHO should therefore co-ordinate existing efforts and handle specific programmes.

Studies on side effects

Studies on safe and effective use are of great importance, and collaborative efforts to assay effectiveness and safety of medical use are of great value to all nations. Another side of the coin is presented by the need to restrict use of some psychoactive drugs because of various considerations, primarily their safety of use.

A recent study indicated that psychoactive drugs represented more than half the total quantity of drugs used by 400 patients admitted to a toxicological emergency department in Paris (Evreux, 1972).

The World Health Organization has, for a number of years, been actively involved in international collaborative studies on side effects of drugs.

The WHO Research Centre for Monitoring Adverse Reactions to Drugs was established in 1971 (Royall, 1973). It is collecting, storing and analysing reports of suspected adverse reactions to all categories of drugs with the objective of helping to identify possible drug safety problems that require further detailed investigation. About 60,000 cases concerning suspected adverse reactions to approximately 3,000 drugs have been collected in the master file. Special computer programmes and techniques have been developed to investigate the filed data and to retrieve requested information. Nineteen national monitoring centres are participating in this programme. It is hoped that growing understanding of advantages of international collaboration in this area will lead to the establishment of a global monitoring system providing early warning on suspected dangerous effects of new drugs, with the objective of preventing iatrogenic, drug-related diseases.

Special research issues

There is a need to develop internationally based research concerning drug surveillance and drug use. These terms refer to two fundamentally different types of studies; they have often been used interchangeably, but it is suggested that studies on drug surveillance (or monitoring) should be understood to mean studies concerned with clinical and, particularly, adverse effects of drugs, while drug usage studies are concerned with identifying which drugs are used in particular environments, and describing how they are used (Miller, 1974).

There is, finally a great need for an increase in the responsibility for directing research efforts towards such unresolved scientific issues that may help to develop badly wanted long-term multidisciplinary, collaborative national or preferable international research oriented towards preventive approaches and operational epidemiological research.

It is hoped that attempts to resolve the international problems related to drug use will help to provide better health services for the benefit of mankind.

Summary

Increasing consumption and extended use of psychoactive substances both in accepted medical practice and in self-administration are of particular concern to national authorities and appropriate international bodies. The international character of these problems calls for international co-operation in solving basic problems such as terminology, and practical approaches like availability, extent and cost of use, appropriate advertising and information and education directed at the public and the prescriber. International acceptance of criteria for formulating objectives of clinical trials on psychoactive drugs, criteria for the selection of patients and choice of methodology would greatly contribute to a rational use of existing drugs and help to develop and evaluate new ones. The active role of, among others the World Health Organization in attempts to solve international drug problems is discussed.

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