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WORLD HEALTH ORGANIZATION MNH/83.7 ORGANISATION MONDIALE D! LA SANTE .. ' ,I ORIGINAL: ENGLISH/ t) I'(.AA ... ) '-I {\~ 'lr:r , ~',C,t...... J5.--iA. rl V{. rICI-.....l... FRENCH

{.;'.; '/'~ (,( 0 ' . v- J \"'''-C:.. ~\ C; ~ ~v '-.. SEVENTH REVIEW OF PSYCHOACTIVESUBSTANCES FOR INTERNATIONALCONTROL )

Geneva, 7-11 March 1983

" :

CONTENTS INDEXED

_, INTRODUCTION 1 SCOPE OF THE MEETING • 2 SOURCES AND NATUREOF DATA REVIEWED 2 REVIEW OF DRUGS FOR INTERNATIONALCONTROL 2 i 4.1 Alfentanil 2 . 4.2 Chloral hydrate • 3 :4.3 Paraldehyde • • • 3 4.4 Potassium bromide 3 ' 4.5 Buprenorphine 3 ,4.6 Butorphanol • 4 4.7 Cyclazocine 4 4.8 Nalbuphine 4 4.9 Pentazocine • • • • 4 WHO'S CANCERPAIN RELIEF PROGRAMME 5

.; CONSIDERATIONSOF FUTURE PROGRAMMES • • • • 5 LIST OF PARTICIPANTS 6 ~~ EX I ...... 8

INTRODUCTION

Dr Halfdan Mahler, Director-General of WHO, Dr Lu Rushan, Assistant tor-General of WHO,welcomed the participants in this meeting and expressed the concern of Tegarding the process of reviewing substances for international control.

Dr Norman Sartorius, Director, Division of Mental Health WHO, discussed with the ipants the conditions in the developing nations which must be considered in reaching regarding the recommendation of substances for international control. He referred ifically to a gradual change in the attitude of people towards pain. No longer is pain as a natural accompaniment of disease. The effective analgesics, widely available the developed countries of the world, must become available for legitimate medical needs P~tientsin the developing countries. This availability of analgesic drugs must however into account the fact that many such substances are capable of producing dependence and • consequence significant public health and social problems. Therefore, regulatory ·~'~~~I~ntsmust balance the legitimate medical need for psychoactive substances against lr possible abuse.

of this document does not constitute Ce document ne constitue pas une publication.

It should not be reviewed, 11 ne do it fair. I'ob;et d'aucun compte rendu ou racted or quoted without the agreement of resume ni d'aucune citation sans I'autorisation de e World Health Organization. Authors alone l'Organisation mondiale de la Sante. Les opinions • responsible for views expressed in signed expriml!es dins les articles signlk n'engagent que leurs auteurs. MNH/83.7 page 2

2. SCOPE OF THE MEETING

The charge given to the Group was:

2.1 The Director-General of WHO received a note verbale from the Se cretary-General of the United Nations from the Goverrunent of Belgiurr. (NAR/CL.24/ l982 DND 42l/11 0 -6» on 8 November 1982 requesting consideration of alfentanil for placement in ' Schedule I of the Single Convention, 1961.

2.2 Psychoactive substances from two classes were to be reviewed:

1. Sedative hypnotics: chloral hydrate, potassium bromide and paraldehyde which were to be compared to phenobarbitone which is currently in Schedule of the Convention on Psychotropic Substances, 1971.

2. Agonist-antagonist opioids: butorphanol, buprenorphine cyclazocine, nalbuphine, pentazocine, with comparison to morphine, nalorphine and naloxone.

The review of pentazocine was in response to a request made to WHO during the seven th special session of the United Nations Commission on Narcotic Drugs (E/1982/13 E/CN.7/678)',

3. SOURCES AND NATURE OF DATA REVIEWED

The participants were supplied with background documents covering the chemistry, pharmacology, toxicology, therapeutic usefulness, dependence potential, abuse liability, epidemiology of abuse, public health and social problems; the countries of the world wher~ each substance is marketed, the nature of domestic controls in these countries, illicit , . •:, manuiacture and traffic for each of the substances under review. The background document~••• ' were supplied by various participants as well as the United Nations Division of Narcoti~ INTERPOL, the International Narcotics Control Board and WHO.

In addition, information was obtained from the relevant pharmaceutical companies the International Federation of Pharmaceutical Manufacturers Associations. This info was presented in written form for all of the participants and in addition a hearing was on 2 March 1983 in which representatives of the concerned pharmaceutical houses (see Annex for list of the companies participating) met with a core group of participants of the Review Group and the Secretariat.

, ", The data presented for each substance were reviewed in the context of the criteria se,t forth for the inclusion of a substance in the Single Convention, 1961. If the Group decl.d that the substance did not meet the criteria for inclusion in Schedules I or 11 of the ' Single Convention it was next reviewed using the criteria for inclusion in Schedules I, It ; or IV of the Convention on Psychotropic Substances, 1971. The decisions reached by the will be reported on in this document in accordance with the above procedure.

4. REVIEW OF DRUGS FOR INTERNATIONAL CONTROL 4.1 Alfentanil

In response to a notification from the Government of Belgium requesting the additi on of alfentanil to Schedule I of the 1961 Convention, the Group, in conformity with Arti~l,, "~~~ .. paragraph 3 (Hi) of that Convention, examined relevant evidence and found that alfent anU has a pharmacological profile closely resembling that of morphine.

The Group concluded unanimously therefore, that alfentanil is liable to similar abuse ~ ~"·-Ul. productive of similar ill-effects as the drugs in Schedule I of the Single Convention, i9611\·~.IIJ"~'

The G;:oup unanimously reconnnended that alfent anil be includ ed in Schedule I of the ' SiD,I Convention, 1961. i

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4.6 Butorphanol

The Group, after reviewing the data concluded that butorphanol did not meet the criter ia for inclusion in either Schedules I or 11 of the Single Convention, 1961 as set forth in Article 3, paragraph 3 (iii).

In addition, the Group concluded that butorphanol did not meet the criteria for scheduling in the Convention on Psychotropic Substances, 1971. The Group recognized, however that butorphanol does produce a state of dependence and central nervous system depression resulting in disturbances of behaviour and hence satisfies the criteria set forth in Article 2, paragraph 4 (a). However, the Group concluded that there is currently not sufficient evidence that butorphanol is being or is likely to be abused so as to constitute a public health and social problem warranting the placing of butorphanol under international control.

4.7 Cyclazocine

The Group, after reviewing the data concluded that cyclazocine did not meet the criter ia for inclusion in either Schedules I or 11 of the Single Convention, 1961 as set forth in Article 3, paragraph 3 (iii). In addition the Group concluded that cyclazocine did not m et the criteria for scheduling in the Convention on Psychotropic Substances, 1971.

4.8 Nalbuphine

The Group, after reviewing the data concluded that nalbuphine did not meet the crite ria for inclusion in either Schedules I or 11 of the Single Convention, 1961 as set forth in Article 3, paragraph 3 (iii).

In addition, the Group concluded that nalbuphine did not meet the criteria for scheduling in the Convention on Psychotropic Substances, 1971. The Group recognized, howeve~ that nalbuphine does produce a state of dependence and central nervous system depression

resulting in disturbances of behaviour and hence satisfies the criteria set forth in ,~ Artic le 2, paragraph 4 (a). However, the Group conc luded that there is current ly not ';!' sufficient evidence that nalbuphine is being or is likely to be abused so as to constitute a public health and social problem warranting the placing of nalbuphine under international , control. ~

4.9 Pentazocine 'l The Group, after reviewing the evidence, unanimously concluded that pentazocine should be placed under international control. Following extensive discussion, the Group consi dered how pentazocine should be controlled. It was then decided by vote that pentazocine did not satisfy the criteria for inclusion in Schedules I or 11 of the Single Convention, 1961 as', s t forth in Article 3, paragraph 3 (iii).

The Group next considered whether pentazocine should be placed in Schedule 11 of the Convention on Psychotropic Substances, 1971. By vote it was decided that pentazocine sboubl not be included in Schedule 11. By vote it was decided that pentazocinz should be recommended for inclusion in Schedule III of the Convention on Psychotropic Substances.

This recorrnnendation was based on the evidence demonstrating that pentazocine did have ch <, capacity to produce (a) a state of dependence and (b) central nervous system changes resultial in disturbances of mood and behaviour. In addition, pentazocine is being abused so as to constitute a public health and social problem warr~ntingthe placing of the substance under international control. The extent of the abuse of pentazocine, as well as its establ ished medical usefulness was the basis for the Group's decision to recommend that pentazocine be included in Schedule III of the Convention on Psychotropic Substances, 1971. ..-.... ~ MNH/83.7 page 5

WHO'S CANCER PAIN RELIEF PROGRAMME

Dr M. Swerdlow, a WHO consultant, outlined the WHO Cancer Pain Relief Programme and stressed the need for safe, effective analgesics. Of particular concern was the problem of ~rovidingsuch medications to patients in the developing countries where medical practitioners are only limitedly available. He cautioned the Group that these considerations must be taken account when considering international regulations of analgesic drugs.

CONSIDERATIONS OF FUTURE PROGRAMMES

(i) WHO's Programme for Pain Relief in Cancer:

WHO's programme for international control and pain relief should have a close collaboration in the future. It will be helpful to know of the current use of analgesics in this programme and the relation of therapeutic use to abuse of analgesics in this context.

(ii) Drugs to be considered for future review:

The agenda for the next two reviews is established. At the review meeting to be held in September 1983 the benzodiazepines and certain related drugs will be reconsidered for possible international control. At the review meeting to be held in March 1983, amphetamine-like drugs not currently under international control will be reviewed. The subsequent review will consider uncontrolled barbiturates and related compounds. As stated in the report of the Sixth Review of Psychoactive Substances for International Control 01NH/82.44), the following list of topics were to be considered in future review meetings:

(1) Derivatives and congeners of tetrahydrocannabinols with regard to their dependence potential, abuse liability and therapeutic usefulness.

(2) Derivatives and congeners of sedativ~hypnotic, anxiolytic and stimulant substances (e.g. amphetamine derivatives, khat) already scheduled or proposed for scheduling under both the 1961 and 1971 Conventions. (3) Analgesic drugs not subjected to international control. (4) Sedative, hypnotic and anxiolytic drugs not subject to international control. (5) Precursors and intermediates of drugs listed in schedules of both Conventions. (6) Synthetic and natural stimulants already scheduled under the 1971 Convention. (7) Antipsychotic and antidepressant drugs with dependence potential and abuse liability.

The Group also recommended that in preparation for the forthcoming review meetings, the United Nations agencies concerned, and particularly the United Nations Division of Narcotic Drugs, be requested to indicate, whether the substances:

(a) have been recently seized from illicit traffic, and (b) have been put under national control because of their abuse potential and dependence liability.

(iii) The Group considered the report from the working group which met on 3 and 4 March 1983 for Consultation for the Development of Guidelines for the WHO Review of Psychoactive Substances for International Control. The Group concluded that the report would be of great value in standardizing WHO's procedures as well as providing detailed information on the procedures used by WHO to reach a recommendation for placing a substance under international control. This information may be helpful to the members of the United Nations Narcotics Commission, regulatory agencies in the countries of the world as well as to the pharmaceutical manufacturers. It was, therefore, recommended that this document be published and widely disseminated.

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/ v tional Institute on Drug Abuse

Dr D. Jasinski, National Institute on Drug Abuse, Addiction Research Centre, P. o . Box 5180, Baltimore, Maryland 21224, USA

Hr A. Duncan, Food and Drug Administration, 5600 Fishers Lane, Rockvill e , Ma ryland 20857, USA

WHOSecretariat

Dr A. Arif, Senior Medical Officer in charge of Drug Dependence Programme, Division o f Menta l Health, WHO, Geneva

Mr. R. J. Gallagher, Legal Officer, Office of the Legal Counsel, WHO, Geneva

I. Khan, Senior Medical Officer, Division of Mental Health, WHO, Geneva (Secretary)

Sartorius, Director, Division of Mental Health, WHO, Geneva

Swerdlow, Consultant, Cancer unit, Division of Noncammunicable Diseases, WHO, Geneva

Observers

Dr J. V. Brady , Professor of Behavioral Biology, Chairman CPPD, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, Maryland 21205, USA

H. Coper, Institute of Neuropsychopharmacology, Free Universit y of Berlin, 1000 Berlin, It Ulmen a11ee 30, Federal Republic of Germany

Mr H. McClain Jr., Chief, Drug Control Section, Drug Enforcement Administration, 1405 Eye Street, N.W., Washington D.C., 20537, USA

Dr L. Rossini, Head, Professor, Department of Pharmacology, WHO-ITA National Collaborating Drug Monitoring Centre, University of Ancona, Medical School, 601000 Ancona, Italy

Mrs B. Wissgott, Bundesministerium f~rGesundheit und Umwelt-schutz, International pharmaceutical affairs, Landsh-Harysch 55-57, Vienna, Austria. MNH/83.7 page 8

ANNEX I

DISCUSSIONS WITH PHARMACEUTICALCOMPANIES

1. Company presenting: Bristol Myers (USA)

Product: Butorphanol

Representatives: Dr Irwin Pacht er, Former Vice-President of Research & Development at Bristol Laboratories - consultant Dr Janice Wohltmann, Group Marketing Director at Bristol Laboratories

2. Company presenting: Sterling Drug Inc. (USA)

Product: Pentazocine

Representatives: Dr George S. Goldstein, Vice-President and Medical Director, Sterling-Winthrop Laboratories , USA Dr John B. Spooner, Medical Director, Sterling-Winthrop Group Ltd., UK Dr J. Gene Hinson, Vice-President, Sterling Drug Inc., President, Sterling Afries t Middle-East, Southern Europe Dr William R. Martin, Consultant, Professor and Chairman, Dept. of Pharmacology, ·' " :.,~ , University of Kentucky School of Medicine, Lexington Mr Charles B. O'Keefe Jr., Consultant, 1907 Huguenot Road, Richmond, Virginia 23235. USA Roger M. Rodwin, Esq., Assistant General Counsel, Sterling Drug Inc., 90 Park Avenue, New York, N.Y. 10016, USA

.:~,:

."u 3. Company presenting: Reckitt and Colman (UK)

Product: Buprenorphine

Representatives: Dr J. W. Lewis Or Varey, Medical Director

4. Company presenting: DuPONT de Nemours (USA)

Product: Nalbuphine

Representatives Dr William K. Schmidt, Senior Research Pharmacologist Dr Newton C. Birkhead, Director of Medical Research Or Robert I. Taber, Director of Research, DuPont Company, Glenolden Laboratory, Glenolden, Pa. 19036, USA Dr Leonard Cook, Manager, CNS Disease Research.