World Health Organization

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Resolutions of the Economic and Social Council

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Pages: 45 to 47
Creation Date: 1957/01/01

World Health Organization

Expert Committee on Addiction-producing Drugs: Seventh Report [1]

The Expert Committee on Addiction-producing Drugs of the World Health Organization held its seventh session in Geneva from 18 to 24 October 1956 and made a report which was adopted by the Executive Board of the World Health Organization at its nineteenth session held in Geneva from 15 January to 30 January 1957 (resolution E/B.19.R,./7, Official Records of the World Health Organization, 1957, 76).

The main features are as follows:

Resolutions of the Economic and Social Council

Having taken note of the resolutions of the Economic and Social Council on technical assistance for narcotics control [2] the Committee was of the opinion that international symposia or seminars, participated in perhaps by the World Health Organization, United Nations and other international agencies, might be of particular value in this connexion. Such subjects as the following might be discussed: diagnosis of drug addiction, including the use of nalorphine for this purpose; treatment of drug addiction, prevention of drug addiction; basic research on the mechanism of addiction; sources of information and techniques for determining addiction liability of drugs; effectiveness versus disadvantages of narcotic drugs; and the relationship of chemical structure to analgesic action and other properties of narcotic drugs. Therefore, the Committee suggested that WHO explore the possibility of organizing symposia or seminars on these and related subjects as an adjunct to technical assistance.

Morphine and its Derivatives

Situation regarding Diacetylmorphine (heroin).-The Committee, noting the persistence of a relatively small residuum of licit use of diacetylmorphine as indicated in the reports of the Commission on Narcotic Drugs [3] and of the Permanent Central Opium Board,[4] nevertheless maintained its stand that diacetytmorphine is not indispensable and urged continuation of all possible measures, consistent with effective clinical practice, to bring about the replacement of diacetylmorphine by other agents which may be used with less risk to public health.

Synthetic Substances with Morphine-like Effect

Synthetic Substances of Morphinan Type

(+)-3-hydroxy-N-phenethylmorphinan designated also d-3-hydroxyo-N-phenethylmorphinan.-Referring to the notification from the Government of Switzerland requesting the exemption of (+)-3-hydroxy-N-phenethylmorphinan from the obligations of the International Conventions on Narcotic Drugs, the Committee considered carefully the argument in the memorandum accompanying that notification, and reviewed the recommendations with respect to 3-hydroxy-N-phenethyl-morphinan in its sixth report[5] to which exception is taken. The Committee was of the opinion that, when a substance exists as a racemate and its optical isomers and evidence was available on the addiction liability of the racemate or one of its isomers, the only course compatible with public safety was the application of narcotics control to all isomeric forms of the substance, as was done in the present instance, until or unless there was specific evidence to the contrary. The Committee was further of the opinion that argument by analogy could not in general be considered an adequate basis for exemption from narcotics control, more especially so for exemption of an optical isomer whose antipode had been shown to have strong addiction-producing properties. For such an exemption to be recommended there must be specific evidence on the absence of addiction liability, and specific or strong presumptive evidence on the impracticability of racemization or conversion to the optical form having addiction liability. Therefore, the Committee concluded that action on the request for exemption of(+)-3-hydroxy-N-phenethylmorphinan must be deferred until the necessary evidence becomes available.

Synthetic Substances of Dithienylbutenylamine Type

piperidino-1,1-di-(2'-thienyl)-1-butene.3-The Committee's attention was drawn to the above substance and to an enquiry regarding its manufacture which raised the question of its liability to produce addiction. Evidence had been presented previously that three members of the dithienyl-butenylamine group-namely, 3-dirnethylamino-l,l-di-(2'-thienyl)-l-butene (dimethylthiambutene 6,7 3-ethylmethylamino-l,l-di-(2'-thi-enyl)-l-butene (ethylmethylthiambutene) 6,7 and 3-diethylamino-l,l-di-(2'-thienyl)-l-butene (diethylthiambutene) 6, 8 were addiction-producing substances comparable to morphine and on the basis of this evidence each of these substances was subjected to international control measures in accordance with the provisions of'the 1948 Protocol. Furthermore, in its fourth session,[7] the Committee expressed the opinion that "the closest watch should be kept upon the development of new dialkyl-dithienylamines because those so far examined are so closely similar in their properties as to make the group of dialkyl-dithienylamines as a whole suspect with respect to addiction-producing properties".

It should be noted also that 3-piperidino-l,l-di-(2'-thienyl)-1-butene was shown to have an analgesic effectiveness equivalent to that of morphine.[9]

A survey [10] on the relationship between analgesic action and addiction liability showed that there existed for most of the drugs considered a parallelism in the order of intensity of these two effects and that this parallelism was apparent for the members of the dithienylbutenylamine group which were included.

Since the order of analgesic effectiveness was very similar for the piperidino dithienyl derivative and for the other dithienyl compounds whose addiction liability was known, the Committee believed it could be justifiably concluded that the addiction liability of 3-piperidino-1,1-di-(2'-thienyl)-l-butene would be comparable to that of morphine.

At the same time the Committee suggested that direct evidence on the addiction-producing properties of 3-piperidino-1,1-di-(2'-thienyl)-l-butene should be sought if clinical application of the compound is intended.

Synthetic Substances of Pethidine Type

1 - [2-( p- Aminophenyl)- ethyl]- 4- phenylpiperidine-4- carboxylic acid ethyl ester, designated also 1-2[2-( p-aminophenyl)- ethyl]-4- carbethoxy-4-phenylpiperidine.-A notification from the Government of the United States of America regarding, inter alia, the above designated drug, was before the Committee at its sixth session in 1955.[11] A complete report on the testing of this compound for addiction-producing properties now being available, the Committee was of the opinion that 1- [2-(p-aminophenyl)-ethyl] - 4-phenylpiperidine-4-carboxylic acid ethyl ester 12 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 1-[2-(p-aminophenyl)-ethyl]-4-phenylpiperidine-4-carboxylic acid etyhl ester 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. Therefore,

The Expert Committee on Addiction-producing Drugs

Recommends that its opinion with respect to 1-[2-(p-aminophenyl)-ethyl]-4-phenylpiperidine-4-carboxylic acid ethyl ester and its salts be communicated to the Secretary-General of the United Nations.

α-1- Methyl-3-ethyl-4-phenyl-4-propionoxypiperidine( alphame-prodine).13-Referring to the notification of the Government of the United States of America, the Committee was of the opinion that ∝-l-methyl-3-ethyl-4-phenyl-4-propionoxy-piperidine 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 ∝-l-methyl-3-ethyl-4-phenyl-4-propionoxypiperidine 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. Therefore,

The Expert Committee on Addiction-producing Drugs

Recommends that its opinion with respect to l-methyl-3-ethyl-4-phenyl-4-propionoxypiperidine (alphameprodine) and its salts be communicated to the Secretary-General of the United Nations.

12 Suggested name anileridine, not yet accepted as a proposed international non-proprietary name.

13 This name has been proposed as international non-proprietary name.The substance having this chemical designation has been examined under the code numbers Nu-1932 and Nu 2-1932 and without any doubt it corresponds stereochemically to alphaprodine.

2,4-diamino-5-phenylthiazole ; β-ethyl-β-methylglutarimide

The Committee took note of current research with these products as possible antagonists to some of the undesirable effects of morphine and related substances, and as possible adjuvants to analgesic action. It was particularly interested in the work going forward in several research centres to determine whether or not these agents affect the rate of development of addiction. The progress of these experiments will be watched very closely.

Abuse of Amphetamines

The Committee's attention was drawn to a progress report on the use and abuse of amphetamines in Japan, in which it was shown that a serious situation still exists, but that substantial amelioration had been attained by the vigorous enforcement of local control measures. The Committee was pleased to note, as a step toward amelioration of amphetamine abuse in other areas, the unanimous adoption by the Commission on Narcotic Drugs of a resolution [3] in which "it took note of the dangers arising from the abuse of amphetamines and recommended that governments should provide adequate measures of control to prevent such abuse ".

Definition of Habit-forming Drugs

Reviewing at this time the definition of addiction-producing and habit-forming drugs as drafted in its second session [14] and clarified in its third report [15] the Committee was of the opinion that the time was ripe for emphasizing again the distinction between addiction and habit. To this end the following definitions were approved:[16]

Drug addiction is a state of periodic or chronic intoxication produced by the repeated consumption of a drug (natural or synthetic). Its characteristics include:

  1. An overpowering desire or need (compulsion) to continue taking the drug and to obtain it by any means;

  2. A tendency to increase the dose;

  3. A psychic (psychological) and generally a physical dependence on the effects of the drug;

  4. An effect detrimental to the individual and to society.

Drug habituation (habit) is a condition resulting from the repeated administration of a drug. Its characteristics include:

  1. A desire (but not a compulsion) to continue taking the drug for the sense of improved well-being which it engenders;

  2. A tendency to increase the dose is not a prominent feature and may be absent;

  3. Some degree of psychic dependence on the effect of the drug is always present, but physical dependence, with a resulting abstinence syndrome, is absent;

  4. Any detrimental effect is primarily to the individual.

Barbiturates

Evidence presented to the Committee indicated that the consumption of barbiturates continues to increase; the situation with respect to them has not ameliorated. It must be stated that barbiturates are habit-forming as defined above and in some circumstances can produce a drug addiction dangerous to public health, although differentiation among them with respect to the intensity of this liability cannot yet be made. The Committee continued to be of the opinion that control measures at the national level are sufficient at the present time, but need close attention and in some instances definite strengthening:

  1. Barbiturates, whatever the dose or admixture, should be dispensed only on prescription,

  2. A prescription should specify the number of times it may be refilled or repeated; and

  3. There should be a record of such prescriptions.

"Tranquillizing" Drugs

The Committee's attention was drawn to the very rapidly increasing use of those agents which are being described as "tranquillizers" and "ataraxics ". The Committee believed that these substances, diverse in their chemical characteristics but similar in their central sedative action, must be classed as potentially habit-forming. In addition, some evidence has been presented that, under conditions of excessive use, a characteristic withdrawal syndrome can appear. In this respect the "tranquillizers" and "ataraxics" resemble the barbiturates and should be subjected to national control. Their continuing clinical use should be followed very closely for an eventual evaluation of their relation to public safety.

Bibliography of Drug Addiction

The advantages and the difficulties of initiating and maintaining a compilation of material on drug addiction - not only titles of published papers, but also informative abstracts, as a centralized source of information in this field were discussed. The Committee was of the opinion that such a compilation would be very valuable and suggested that even a modest beginning toward the over-all objective of such a compilation would be worthwhile. Members offered to assist by making available some of their own material, and it was suggested that correspondence with members of the Expert Advisory Panel on Addiction-producing Drugs might result in additional offers of the same sort.

International Non-proprietary Names

Attention has been drawn again to the need for overcoming difficulties in the initiation of suggested international non-proprietary names for substances to be brought under narcotics control.[3]

In compliance with the 1948 Protocol, notifications were transmitted to the Secretary-General of the United Nations as soon as practicable after evidence became available on addiction liability, in some instances at a quite early stage in the development of a new compound, even before any decision as to marketing had been made. For some such compounds, the mechanism for selection of an international non-proprietary name has not yet been initiated.

The Committee is of the opinion that the procedure outlined in its fifth report still offers a means for facilitating and speeding up the selection of an international non-proprietary name. However, if this provision has not been or cannot be carried out so that a suggestion for a proposed name is not available when a notification with respect to a new narcotic drug is transmitted to the Secretary-General of the United Nations the government concerned might at that time request the World Health Organization to suggest an appropriate name.Lacking such a request, the World Health Organization should on its own initiative devise a proposed non-proprietary name.

The Committee suggested that the World Health Organization consider the appropriateness of again drawing the attention of governments to the procedure for speeding up selection of international non-proprietary names outlined in its fifth report, together with the alternative proposals mentioned above.

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1 Wld Hlth Org. techn. Rep. Ser.116.

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2 United Nations, Economic and Social Coundl, twenty-second session, International Control of Narcotic Drugs, resolutions D and E. (E/2929.)

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3 United Nations, Economic and Social Council (1956), Commission on Narcotic Drugs: Report ....on the eleventh session, 23 April to 18 May 1956. (E/2891-E/CN.7/315.)

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4 E/OB/11 (see Bulletin on Narcotics, Volume VIII, No. 1, p. 33).

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5 Wld Illth Org. techn. Rep. Ser. 1956, 102, p. 8, section 5.1.4 (see Bulletin, Vol. VII, No. 1, p. 37).

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6 Proposed international non-proprietary name.

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7 Wld Hlth Org. techn. Rep. Ser. 76, 9 (section 4.4).

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8 Wld Hlth Org. techn. Rep. Ser. 102, l0 (section 5.3) (see Bulletin, Vol. VIII, No 1, page 39).

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9 Green, A. F. (1953) Brit. J. Pharmacol. 8, 2.

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l0 Eddy, N. B., Halbach, H. & Braenden, O. J. (1956) Bull. Wld Hlth Org. 14, 353.

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11 Wld Hlth Org. techn. Rep. Ser. 102, 11 (section 5.4) (see Bulletin, Vol. VIII, No. 1, p. 39).

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14 Wld Hlth Org. techn. Rep. Ser. 21, 6 (section 6.1-3).

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15 Wld Hlth Org. techn. Rep. Ser. 57, 9 (section 6.1).

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16 That for drug addiction is substantially the same as in the second report; that for drug habituation is new.