World Health Organization: Expert Committee on Drugs liable to Produce Addiction

Abstract

The Expert Committee on Drugs liable to Produce Addiction of the World Health Organization held its sixth session in Geneva from 24 to 29 October 1955 and made a report, which was adopted by the Executive Board of the World Health Organization at its seventeenth session, held in Geneva from 17 January to 2 February 1956 (resolution EB17.R3, Official Records of the World Health Organization, 1956, 68, 2). The main features are as follows:

Details

Pages: 37 to 40
Creation Date: 1956/01/01

World Health Organization: Expert Committee on Drugs liable to Produce Addiction

Sixth Report1

The Expert Committee on Drugs liable to Produce Addiction of the World Health Organization held its sixth session in Geneva from 24 to 29 October 1955 and made a report, which was adopted by the Executive Board of the World Health Organization at its seventeenth session, held in Geneva from 17 January to 2 February 1956 (resolution EB17.R3, Official Records of the World Health Organization, 1956, 68, 2). The main features are as follows:

REPORT ON THE TENTH SESSION OF THE COMMISSION ON NARCOTIC DRUGS OF THE UNITED NATIONS ECONOMIC AND SOCIAL COUNCIL

The Committee took particular note of the discussion of synthetic substances in the report on the tenth session of the Commission on Narcotic Drugs to the United Nations Economic and Social Council,2 and of resolution No. 588 (XX) D relating thereto, which was adopted at the twentieth session of the Council.3The Committee was of the opinion that any narcotic substance, whether synthetic or derived from a natural alkaloid, must be considered individually, and that for the purposes of control no distinction should be made between the group of natural alkaloids and their derivatives on the one hand and the group of synthetic substances on the other. Further reference to this point is made under the heading "Morphine and its derivatives".

The Committee was pleased to note the decision of the Commission on Narcotic Drugs to recommend that governments should limit their imports of coca leaf and crude cocaine in a manner analogous to that applicable to opium under the Protocol of 1953, and the decision to place cannabis drugs together with diacetylmorphine (heroin) and ketobemidone in the list of prohibited drugs (Schedule IV) to be included in the proposed Single Convention on Narcotic Drugs.

The Committee discussed the seriousness of the placing of drugs in any prohibiting list and expressed the view that it would welcome an opportunity to consider and give advice on substances which might be placed in that schedule.

The Committee was pleased to note further that in the provisions of the Single Convention the World Health Organization, as well as governments, should have initiative in notification of new substances and of changes in the position of substances under control regimes.

1

World Health Organization: Technical Report Series, No. 102.

2

United Nations, Economic and Social Council, Commission on Narcotic Drugs: Report . . . on the tenth session . . . 18 April to 12 May 1955 (document E/2768 - E/CN. 7/303).

3

United Nations, Economic and Social Council, Official Records, Twentieth Session, 5 July-5 August 1955. Supplement No. 1. Resolutions (document E/2795).

RESOLUTIONS OF THE UNITED NATIONS ECONOMIC AND SOCIAL COUNCIL

The Committee was pleased to note in resolution No. 588 (XX) E 4 on abuse of drugs (drug addiction), adopted by the United Nations Economic and Social Council, the recommendations with respect to the continuing effort to collect statistics on the incidence of addiction throughout the world, and with respect to initiation of a study of the best methods for the treatment of addicts.

The Committee took particular note of, and concurred in, the view expressed by the Commission on Narcotic Drugs that in the treatment of drug addiction methods of ambulatory treatment (including the so-called clinic method) are not advisable.

MORPHINE AND ITS DERIVATIVES

Situation regarding Diacetylmorphine (Heroin)

The Committee noted with satisfaction the resolution of the Commission on Narcotic Drugs of the United Nations Economic and Social Council urging all governments which have not heretofore done so to prohibit the use and manufacture of, and trade in, diacetylmorphine.5

It was reported to the Committee that, of the 20 States which have supplied estimates for diacetylmorphine for 1956, only 4 are not prepared to suppress the use of the drug; several of the others have announced that they will discontinue its use when present stocks are exhausted. It was emphasized that in general the estimates are significantly smaller than in former years and that over-all licit production has shrunk from 839 kg. in 1948 to 132 kg. in 1954. The Committee concluded from this information that more and more physicians throughout the world are finding it possible to substitute less dangerous drugs for diacetylmorphine, in accordance with the Committee's repeatedly expressed view on the replaceability of this dangerous addicting agent.

The small number of countries still persisting in the use of diacetylmorphine, the reduction in estimates for the next year, and the marked decrease in production of the drug reflect very gratifying progress in the campaign against diacetylmorphine.

Reconsideration of Certain Sections of the Fifth Report of the Committee on Request of the Executive Board at its Fifteenth Session 6

It is now almost universally recognized that diacetylmorphine is a dangerously addicting drug. Such was not always the case. Diacetylmorphine was introduced into medicine little more than fifty years ago as a non-addicting substitute for morphine, and this impression of relative safety was corrected only by accumulated clinical experience.

4

See footnote 3.

5

See footnote 2.

6

See Bulletin, Vol. VII, No. 2.

Pethidine also was introduced with the claim in some quarters of relative safety with respect to addiction liability, and again clinical experience is demonstrating the incorrectness of this claim. The Committee again concluded that pethidine is comparable to morphine in addiction liability; neither pethidine nor morphine is comparable to diacetylmorphine in this respect. The Committee was of the opinion that the rising trend in pethidine addiction 7 can be combated only by recognition of the danger and by as much care in the use of the drug as with morphine.8

The Committee wished to emphasize in this connexion its view that synthetic analgesic drugs differ from one another in addiction liability just as do drugs derived from natural substances such as opium; that members of each class must be considered individually with respect to inherent risk and therapeutic advantage; and that the risk of addiction through the use of synthetic drugs is neither greater nor less than the risk encountered through the use of morphine, related opium alkaloids, or substances derived therefrom.

The Committee concluded that morphine, related substances, and synthetic drugs are equally useful for medical needs, and that there is a wide range of potency available among members of each group.

SYNTHETIC SUBSTANCES WITH MORPHINE-LIKE EFFECT

Synthetic Substances of Morphinan Type

( - )-3-Hydroxy-N-allylmorphinan, also designated l-3-hydroxy-N-allylmorphinan (levallorphan)9

Referring to the notifications of the Government of Switzerland and of the Government of the United States of America, the Committee reviewed the evidence on levallorphan and found that, like nalorphine, when administered alone it produced dysphoria rather than euphoria and that it had not caused the appearance of tolerance or physical dependence. It would not relieve the abstinence syndrome or sustain a morphine addiction, but would precipitate abstinence phenomena if physical dependence on morphine or a morphine-like drug had been established.

The Committee also considered the conversion of levallorphan to levorphan. Such conversion, although possible, is so difficult that it is considered to be impracticable and to constitute no risk to public health.

The Committee was of the opinion that levallorphan cannot be considered either to be an addiction-producing drug or to be capable of conversion into an addiction-producing drug for the purposes of the 1931 Convention.

( - )-3-Methoxy-N-allylmorphinan

( - )-3-Acetoxy-N- allylmorphinan

Referring to the notification of the Governement of Switzerland, the Committee concluded that the position of these substances is analogous to that of levallorphan and that they cannot be considered either to be addiction-producing drugs

7

See Wld Hlth Org. techn. Rep. Ser., 1955, 95, 13. During the period covered in the Lexington report, the total number of addicts treated at the Public Health Service Hospital, Lexington, Kentucky, USA, irrespective of the drug of addiction, was 12 682.

8

See Wld Hlth Org., techn. Rep. Ser., 1955, 95, 10 (section 7.3.2).

9

Proposed international non-proprietary name.

or to be capable of conversion into addiction-producing drugs for the purposes of the 1931 Convention.

( - )-3-Hydroxy-N-propargylmorphinan

Referring to the notification of the Government of Switzerland, the Committee decided to reserve judgment with respect to the addiction liability of this substance until information is available on the results of its repeated administration.

3-Hydroxy-N-phenethylmorphinan

Referring to the notification of the Government of the United States of America, the Committee was of the opinion that 3-hydroxy-N-phenethylmorphinan, because it (1) produces morphine-like effects, (2) will suppress abstinence phenomena of a known morphine addiction, and (3) will sustain a morphine addiction, must be considered an addiction-producing drug comparable to morphine, and that 3-hydroxy-N-phenethylmorphinan and its salts should fall under the regime laid down in the 1931 Convention for the drugs specified in Article 1, paragraph 2, Group I.

The Committee noted further that the very great potency of 3-hydroxy-N-phenethylmorphinan with respect to the production of morphine-like effects and to the suppression of morphine abstinence phenomena indicates that the substance possesses particularly dangerous addiction-producing properties. It emphasized the desirability of avoiding the manufacture, import, and export of these substances, unless a definite therapeutic advantage can be shown.

Synthetic Substances of Methadone Type

4-Morpholino-2,2-diphenyl ethyl butyrate, designated also ethyl-2,2-diphenyl-4-morpholinobutyrate

Referring to the notifications of the Government of Italy and of the Governement of the United States of America, the Committee was of the opinion that 4-morpholino-2,2-diphenyl ethyl butyrate, because it produces marked and prolonged morphine-like effects comparable to those of other addiction-producing substances related to methadone, must be considered an addiction-producing drug comparable to morphine and that 4-morpholino-2,2-diphenyl ethyl butyrate and its salts should fall under the regime laid down in the 1931 Convention for the drugs specified in Article 1, paragraph 2, Group I.

4-Dimethylamino-1,2-diphenyl-3-methyl-2-propionoxybutane

Referring to the notification of the Governement of the United States of America, the Committee was of the opinion that 4-dimethylamino-l,2-diphenyl-3-methyl-2-propionoxy-butane, because it (1) will only partially suppress the abstinence phenomena of a known morphine addiction, and (2) will in part sustain a morphine addiction, must be considered as having no greater addiction liability than codeine, and that 4-dimethylamino-l,2-diphenyl-3-methyl-2-propionoxybutane and its salts are assimilable to the drugs mentioned in Group II of the 1931 Convention.

4, 4-Diphenyl-6-piperidino-3-hexanone

The Committee's attention was drawn to the above substance, which has been marketed in Hungary under the name of Hexalgon and has been mentioned in the estimates for that country.

The Committee noted that in previous reports 4,4-diphenyl-6-dimethylamino-3-heptanone (methadone) and 4,4-diphenyl-6-piperidino-3-heptanone were shown to be closely related chemically and to have similar pharmacological properties and similar addiction liability. It is now apparent that 4,4-diphenyl-6-dimethylamino-3-hexanone and 4,4-diphenyl-6-piperidino-3-hexanone are likewise chemically and pharmacologically similar. 4,4-Diphenyl-6-dimethylamino-3-hexanone has been shown to have addiction liability. Because of these analogies, the Committee concluded that 4,4 diphenyl-6-piperidino-3-hexanone must be considered as also having addiction liability.

Synthetic Substances of Dithienylbutenylamine Type

3-Diethylamino-1,1-di-(2'-thienyl)-l-butene (diethylthiambutene10)

Referring to the notification of the Governement of the United Kingdom of Great Britan and Northern Ireland, the Committee was of the opinion that 3-diethylamino-1,1-di-(2'-thienyl)-l-butene, because it (1) produces morphine-like effects, (2) will suppress abstinence phenomena of a known morphine addiction, and (3) will sustain a morphine addiction, must be considered an addiction-producing substance comparable to morphine, and that 3-diethylamino-l,l-di-(2'-thienyl)-l-butene and its salts should fall under the regime laid down in the 1931 Convention for the drugs specified in Article 1, paragraph 2, Group I.

Synthetic Substances of Pethidine Type

1-[2-(p-Aminophenyl)-ethyl]-4-phenylpiperidine-4-carboxylic acid ethyl ester, designated also 1-[2-(p-aminophenyl)-ethyl]-4-car-bethoxy-4-phenylpiperidine

1-( 2-Hydroxy-2-phenyl-ethyl)-4-phenylpiperidine-4-carboxylic acid ethyl ester, designated also 4-carbethoxy-l-(2-hydroxy-2-phenyl-ethyl)-4-phenylpiperidine

The Committee considered the notification of the Government of the United States of America with regard to these substances and noted particularly that, whereas the analgesic effectiveness of both compounds experimentally is about three times that of pethidine, the dose of 1-[2-( p-amino-phenyl)-ethyl]-4-phenylpiperidine-4-carboxylic acid ethyl ester to produce morphine-like effects is significantly greater than the dose of morphine for a similar effect. Recognizing that the information available at the present time is of a preliminary nature, the Committee decided to defer its opinion with respect to the addiction liability of both compounds.

Synthetic Substances of Hexamethyleneimine Type

1,-3 Dimethyl-4-phenyl-4-propionoxyhexamethyleneimine

Referring to the notification of the Government of the United States of America, the Committee was of the opinion that 1,3 - dimethyl - 4 - phenyl- 4 -propionoxyhexamethyleneimine, because it (1) produces morphine-like effects, (2) will suppress abstinence phenomena of a known morphine addiction, and (3) will sustain a morphine addiction, must be considered an addiction-producing drug comparable to morphine, and that 1,3-dimethyl-4-phenyl-4-propionoxyhexamethylenei-mine and its salts should fall under the regime laid down in the 1931 Convention for the drugs specified in Article 1, paragraph 2, Group I.

10

Proposed international non-proprietary name; approved common name in the United Kingdom of Great Britain and Northern Ireland.

1 -Methyl-4-phenylhexamethyleneimine-4-carboxylic acid ester, designated also 4-carbethoxy-1-methyl-4-phenylhexamethyleneimine

1,3-Dimethyl-4-phenylhexamethyleneimine-4-carboxylic acid ethyl ester, designated also 4-carbethoxy-l,3-dimethyl-4-phenylhexa-methyleneimine

1,2-Dimethyl-4-phenylhexamethyleneimine-4-carboxylic acid methyl ester, designated also 4-carbmethoxy-l,2-dimethyl-4-phenyl-hexamethyleneimine

Considering the notification of the Government of the United States of America with respect to these three substances, the Committee noted that the evidence on addiction- liability was negative for each of them. The Committee decided, however, to make no recommendation with respect to their control at this time, but proposed that a very close watch be kept on further experimentation and any clinical use of these compounds.

***

The following drugs, in pursuance of the views communicated by the World Health Organization, were accordingly brought under international control by notification of the Secretary-General dated 21 December 1955:

  1. To 1,3-dimethyl-4-phenyl-4-propionoxyhexamethyl-eneimine;

    3-diethylamino-1,1 -di(2'-thionyl)-1 -butene (proposed international non-proprietary name: die-thylthiambutene);

    3-hydroxy-N-phenethylmorphinan; 4-morpholino- 2,2-diphenyl ethyl butyrate; and all of their respective salts was applied the regime laid down in the 1931 Convention for the drugs specified in Article 1, Paragraph 2, Group I, of that Convention;

  2. To 4-dimethylamino-l,2-diphenyl-3-methyl-2-propion-oxybutane and its salts

    was applied the regime laid down in the 1931 Convention for the drugs specified in Article 1, Paragraph 2, Group II, of that Convention.

ABUSE OF AMPHETAMINE

The Committee took note of the memorandum presented by Dr T. Masaki on the amphetamine problem in Japan, and had its attention drawn to the occurrence of abuse of amphetamine and amphetamine-like substances in other areas to an extent which constitutes a hazard to public health. The Committee noted that stern measures are already being taken by one of the governments concerned to meet the situation, and that suggestions have been made for local measures for improvement in other areas. The Committee proposed, as it had done previously, to keep close watch on the situation, but was of the opinion that abuse of amphetamine continued to be a local problem and not one for international action.

PETHIDINE

The Committee took note of the replies which had been received to the circular letter of the Director-General, pursuant to its recommendation,11bringing to the attention of governments and the medical profession throughout the world the dangerousness of the addiction potentiality of pethidine and the need for care in its use as with morphine.

11

Wld Hlth Org. techn. Rep. Ser., 1955, 95, 10 (section 7.3.2).

The replies indicate a willingness to assist in the implementation of the warning. The Committee was pleased to note the publication of the warning in a number of medical journals and the intent of the World Medical Association to prepare a document on the subject for distribution to all national medical associations.

The Committee drew attention to one source of difficulty in the recognition of the danger with respect to pethidine, namely, the multiplicity of names under which the drug is marketed, so that, in some instances at least, the physician is not aware that the drug with which he is dealing is in fact pethidine. The same difficulty can arise when a new drug which is liable to produce addiction is introduced in different countries under different names.

The Committee was of the opinion that the difficulty could be met, as is already done in some countries, by the identification of the new drug in each instance by its recommended (or proposed) international non-proprietary name - for example, by the use of the international non-proprietary name on labels and in all descriptive matter - and suggested that WHO should consider the appropriateness of drawing the attention of governments to such a procedure.

In this connexion the Committee noted that the Commission on Narcotic Drugs had already recommended governments to use, whenever possible, in documents concerned with the implementation of the international treaties on narcotics, the non-proprietary names proposed by WHO in addition, where they so desire, to the chemical or proprietary names or both.12

INTERNATIONAL NON-PROPRIETARYNAMES

The Committee was pleased to note the favourable response to the suggestions made at its fifth session,13and transmitted in the circular letter of the Director-General under the date of 21 April 1955, designed to speed up the selection of an international non-proprietary name for a drug which may come under international narcotics control. Replies from governments indicated that efforts are being made to implement the Committee's suggestions.

12

Wld Hlth Org., techn. Rep. Ser., 1952, 57, 12 (section 10).

13

Wld Hlth Org., techn. Rep. Ser., 1955, 95, 11 (section 10).