The use of diamorphine (heroin) in therapeutics
Author: C. VAILLE
Pages: 1 to 5
Creation Date: 1963/01/01
While the regulation of the use of narcotic drugs is necessary to prevent the spread of addiction, the following three points should be carefully considered, as Seevers (1962) has in fact suggested:
The nature and incidence of individual addiction, the nature of the "psychotoxic" effects and the physical effects on individuals and on society;
The advantages (medical, psychological, social) to society weighed against the effects produced by the loss of those advantages;
If, after investigation, the findings with regard to point 1 outweigh the findings under point 2, will that be an argument for the proposed regulation; can regulation be tightened up; will more stringent regulation cause serious social problems; and, if so, will those problems be greater or less than the anticipated gains?
The illicit use of diamorphine (or heroin) is undoubtedly more widespread than that of the other narcotic drugs in all countries where drug addiction is a social problem (Vaille & Stern, 1955). A pharmacological, sociological or therapeutic study should therefore provide the answer to the question so frequently asked: Should the use of heroin in therapeutics cease completely?
1 Communication to the Academy of Medicine (France), 9 February 1963.
Editor's note: During the 18th session of the Commission on narcotic Drugs, the French delegation stated that the French Government was studying closely the evolution of the consumption of heroin and would take whatever steps it felt were appropriate. Doctor J. Mabileau, Chairman of the Commission on Narcotic Drugs, was kind enough to forward to the editors of the Bulletin the following text of the recommendations made unanimously to the National Acadamy of Medicine:
The Academy of medicine, considering that therapeutic developments and especially the fact that no diamorphine was used during last two years in the hospitals in Paris and in the Institut Gustave, wishes to make the following recommendations: that follow the recommendations of the WHO concerning the of diamorphine (diacetylmorphine) (or heroin) in therapeutics; considering the best interest of patients, as well as of scientific research, asks that the decree of prohibition of the use of diamorphine provide for the two following exceptions to the general that the authorization for the use of that drug may be given Bureau of narcotics of the Ministry of Public Health and (1) for scientific research upon request from the persons for the research; (2) for therapeutic use upon request medical practitioner wishing to prescribe diamorphine to patient." recommendation was unanimously adopted on 25 March 1963.
Recent publications on human pharmacology controlled by reliable statistical data show the need for a re-examination of the Comparative physiological effects of morphine and heroin.
According to Eddy, Halbach & Braenden (1957), the classical studies agree that heroin is more addicting than morphine, that addiction to it develops more rapidly and that it is the drug of choice of a very great many addicts. This is probably due to the fact that heroin has a greater analgesic and antitussive potency, a larger emetic, constipatory and respiratory depressant effect, and reaches its peak sooner; its effective duration is shorter, and it has greater euphoric properties.
Pharmacological studies on human subjects carried out at the Lexington (Kentucky) hospital (United States) with post-addicts acting as volunteers tend to show that the qualitative differences between the two drugs are less marked than was thought, when the differences in dosage are more accurately measured.
Lasagna, Felsinger & Beecher (1955) showed that, after a single subcutaneous injection of morphine or heroin, former addicts were unable to identify the drug in nearly 50% of cases.
Fraser, Van Horn, Martin, Wolbach & Isbell (1961) found that subjects addicted to heroin or morphine by subcutaneous injection were also unable to distinguish between these two drugs with any certainty, and when the injections were abruptly cut off, presented withdrawal symptoms of approximately the same degree and duration.
Are not these observations inconsistent with the American addicts' predilection for heroin? As many prefer intravenous injection, Martin & Fraser (1961) were inclined to think that the real reason for their preference was in fact the method of injection. Their experiments confirmed this hypothesis. Former addicts were able to identify heroin and morphine very accurately when a single dose or repeated habituating doses were administered intravenously. Whereas patients showed no preference for one drug over the other with a single-dose injection, five-eighths said they preferred heroin once habituation had set in.
However, on the basis of the subjective observations of former addicts, no pronounced effect has been detected that gives any explanation of the preference for heroin. Equipotent doses of morphine and heroin have a comparable effect of similar duration when administered intravenously, and do not markedly differ in their capacity to produce euphoria, excitement, irritability, relaxation, drowsiness or sleep.
Although under these conditions the heroin abstinence syndrome is briefer than that for morphine, the culmination is virtually the same for both drugs. The variations in calculable phenomena observed by Martin & Fraser give no support to the contention that addiction to heroin develops faster than to morphine.
The ideas of classical pharmacology are thus evidently due for revision.
It should, however, be noted that only one of the objective signs observed during the double-blind tests showed a statistically valid difference between morphine and heroin: after a single dose, morphine produces a greater degree of reddening of the conjunctivas. Furthermore, during prolonged intoxication (19 days) in which the daily doses administered intravenously are progressively increased to four doses amounting to 76 mg of diacetylmorphine hydrochloride and three doses of morphine sulphate amounting to 180 mg (whereas administered subcutaneously the doses run as high as 101 mg of heroin and 240 mg of morphine), the only appreciable difference was a much more frequent sensation of " pins and needles " with morphine (58 times with morphine administered intravenously as against 8 when administered subcutaneously, 3 times with heroin intravenously as against 0 subcutaneously out of a possible maximum of 152 in this statistical survey).
The equipotent doses of morphine and heroin were also accurately determined. The arbitrary nature of the choice of these doses in relation to therapeutic usage may be appreciated when it is remembered that before the lastwar (Vaille, 1962), Anselmino had given in his report to the League of Nations Advisory Committee on Traffic in Opium and Other Dangerous Drugs an equipotence of 15 mg of morphine against 5 mg of heroin, whereas the figures now given by the World Health Organization are 10 mg of morphine against 5 mg of heroin.
Eddy (1953) reported that pharmacologically heroin was twice to ten times more effective than morphine. Seevers & Pfeiffer (1936) reported that the same degree of analgesia could be obtained in human subjects with 1 mg of heroin as with 10 mg of morphine. Reichle & Coll (unpublished), quoted by Martin & Fraser (1961) estimated that 3.1 to 4.8 mg of heroin were equivalent to 10 mg of morphine administered subcutaneously for post-operative pain (i.e., 2.1. to 3.2 times more potent). Martin & Fraser (1961) obtained a potency of 2.1 to 3.2 for heroin administered intravenously to cured post-addicts as against 1 for morphine. The most interesting relevant figures in Martin & Fraser (1961) seem to be those relating to the effect on pupillary reactions, which are fairly easy to measure. To obtain a myosis of equal duration in man, the American experimenters required 2.58 mg (limit of confidence up to 95% for 2.08-3.19) with morphine salt as compared with 1 mg of diacetylmorphine salt.
The equipotence in gramme-molecules of morphine base is 2.89 against 1 mg of diacetylmorphine base (2.33-3.57, limit of confidence up to 95%).
In practice, Martin & Fraser accept that the ratio of comparison for human subjects is 4 mg diacetylmorphine hydrochloride to 10 mg morphine salt. They thus take a stand between the figures proposed to the League of Nations and those accepted by the United Nations.
As regards France, the point should be made that subjective comparisons between the effects of heroin and morphine have doubtless been distorted by pharmaceutical usage at the beginning of the century: morphine was, in fact, commonly used in ampoules of one cg morphine hydrochloride, whereas heroin was put up in 5 mg ampoules (R. Hazard, 1950). Not unnaturally, those engaged in therapeutics compared the effects of one ampoule of each drug; the next step was obviously to proclaim the superiority of heroin. The comparison was not in terms of equipotent doses, and the results were distorted in favour of heroin.
There is no need to dwell on the social evil due in certain countries to the use of heroin; this study will be restricted to a small sector of sociology - namely, international psychology; for the main aim is to sum up the basic attitude of the international bodies concerned.
Article 10 of the Convention for limiting the Manufacture and regulating the Distribution of Narcotic Drugs, of 13 July 1931, which deals with heroin, states:
"The high contracting parties shall prohibit the export from their territories of diacetylmorphine, its salts, and preparations containing diacetylmorphine or its salts.
"Nevertheless, on the receipt of a request from the government of any country in which diacetylmorphine is not manufactured, any high contracting party may authorize the export to that country of such quantities of diacetylmorphine, its salts, and preparations containing diacetylmorphine or its salts, as are necessary for the medical and scientific needs of that country, provided that the request is accompanied by an import certificate and is consigned to the government department indicated in the certificate.
"Any quantities so imported shall be distributed by and on the responsibility of the government of the importing country."
One of the official comments on this article made by the Opium Traffic Section of the League of Nations Secretariat (1937) will now be given:
"The reason for subjecting diacetylmorphine to the most stringent regime provided by the Convention is that it is generally regarded as the most dangerous of the opium derivatives. It is the only derivative of morphine which is known to be absorbed by sniffing and it is extremely toxic as compared with other opium derivatives. Its therapeutic value, moreover, was regarded by a number of delegations represented at the Conference as doubtful."
As early as 1923, the League of Nations Advisory Committee on Traffic in Opium and Other Dangerous Drugs had prepared a resolution recommending governments to give serious consideration to the problem of heroin. A definitive proposal for the abolition of its use was submitted to the Second Opium Conference in 1925, but was rejected. A similar proposal submitted to the 1931 Conference, although also rejected, finally took shape in article 10 of the 1931 Convention.
In a similar spirit, a compromise resolution (resolution VI) was included in the Final Act of the 1931 Convention:
" The Conference,
" Recognizing the highly dangerous character of diacetylmorphine as a drug of addiction and the possibility in most, if not all, cases of replacing it by other drugs of a less dangerous character,
" Recommends that each government should examine in conjunction with the medical profession the possibility of abolishing or restricting its use, and should communicate the results of such examination to the Secretary-General of the League of Nations."
The Single Convention on Narcotic Drugs, 1961 (Vaille, 1961), which is expected to replace in coming years the 1931 Convention in particular, likewise provides for special treatment of a group of narcotic drugs regarded as particularly dangerous which are listed in schedule IV. This schedule comprises cannabis, desomorphine, heroin and ketobemidone.
Under article 2, paragraph 5, a number of special measures concerning the narcotic drugs in schedule IV are laid down, in particular that "a party shall, if in its opinion the prevailing conditions in its country render it the most appropriate means of protecting public health and welfare, prohibit the production, use, etc .... "
Ever since the 1931 Convention came into force, the Permanent Central Opium Board has never failed to draw attention to the 1931 resolution, and to report on trends. Thus, the 1957 report stated that Belgium and France were the only two countries to export heroin in 1956, whereas five countries had still been exporting it in 1952. Only ten countries had consumed quantities in excess of 1 kg in 1956, as against eighteen in 1953. In 1957, three countries (Belgium, France, United Kingdom) had manufactured heroin. Seven countries had still been consuming heroin in that year. The number had fallen to five in 1959 and had remained at that level, with 40 kg consumed by the United Kingdom in 1961, 7 kg by Belgium, 3 kg by France and 1 kg each by Paraguay and Portugal.
The figures for heroin estimates are worth mentioning, because section IX of the Final Act of the 1931 Convention gives " two tons " as the figure officially considered at that time as a valid estimate of world consumption of that drug, based on the approximate average of world requirements for 1928, 1929 and 1930.
Although the estimates for consumption are always slightly in excess of actual requirements because they are supplied by the governments a year in advance for prior approval by the Supervisory Body set up under the 1931 Convention, they give some idea of the trend. The following are the figures for the past twelve years (world consumption in kg, year in parentheses): 464(1952), 295(1953), 338(1954), 259(1955), 176(1956), 141(1957), 123(1958), 104(1959), 103(1960), 80(1961), 57(1962), 54(1963).
France: Use in Therapeutics
The French view was summed up ten years ago in the Bulletin on Narcotics 2. It is worth reproducing to see whether it calls for revision in 1963.
G. Brouet (1953), after noting that the use of heroin was still justifiable for a few patients, such as those in the last stages of pulmonary tuberculosis or suffering from particularly painful types of cancer wrote:
" The clinical use of heroin is only admissible on certain conditions:
" (1) Its use should not be merely routine or customary, but should be justified by the complete or partial ineffectiveness of other drugs;
" (2) Heroin should, as a rule, be used only for incurables who have not long to live and are in pain, irrespective of whether they are suffering from cancer, pulmonary tuberculosis or heart disease;
" (3) The drug should be prescribed more cautiously in private practice than in hospitals, where the physician can control the dose and where it is practically impossible to encourage others to use the drug.
" If these conditions are fulfilled, there are hardly any arguments in favour of the removal of heroin from the pharmacopoeia of countries which have clear and well-observed legislation on the use of narcotic drugs. These are the conclusions reached by the Commission on Toxic Substances of the National Academy of Medicine in the report submitted by Professor Aubertin on 22 February 1949."
The Expert Committee on Drugs liable to produce Addiction (WHO) pursued the question of the value of heroin in therapeutics in the following years (Vaille & Stern, 1955). Its fifth report stated that the Expert Committee
"...wishes to draw attention to the very material progress which has been attained within the period of five years towards a complete recognition of the dispensability of diacetylmorphine. This progress has been materially assisted by the increasingly general acceptance by national and international bodies of the Committee's view as to the replaceability of diacetylmorphine in particular by less dangerous synthetic substances .... "
The question now is whether, in the light of the remarkable development in therapeutics during the past ten years, French doctors consider that the view taken by the Academy of Medicine in 1949 still holds good:
"...heroin differs from morphine owing to its potency in soothing cough and dyspnea in particular and is commonly used for diseases of the respiratory tract (especially tuberculosis) and in heart disease."
La Barre & Plisnier (1957) showed that the antitussive properties of heroin were exceeded by much less dangerous substances; in tuberculosis treatment especially, antibiotics have practically overcome the problem of coughing.
In 1959 we wrote that the sharp drop in the figures for French consumption of heroin made it impossible still to assert that the freedom of healing required the continued authorization of the use of heroin in medicine. This has been confirmed by the facts; and most French therapists concur. The figures for consumption in the Paris hospitals also bear this out. Heroin consignments ceased at the end of 1961, and in 1962 none was supplied to the hospitals of the Assistance publique in Paris.
The fact that the annual consumption of ampoules of diacetylmorphine hydrochloride at the Gustave Roussy Institute (Villejuif) fell from 133 in 1954 and 155 in 1955 to 36 in 1956 and 7 in 1957 and has now completely ceased should suffice to set at rest surviving doubts as to the possible value of heroin for certain cancer cases.
See Bulletin on Narcotics, vol. V, No. 2.
The most cogent reply to the first point raised by Seevers is the statement by Professor H. Fischer of Zurich to the WHO Committee of Experts in January 1949:
"If one takes into consideration the harm brought about in the world by diacetylmorphine since its appearance and the thousands of heroin addicts who have fallen victims to the drug, the disappearance of diacetylmorphine from world markets could only be considered as a boon and a step in the right direction."
It can safely be said that the considerations set out above provide good grounds for the belief that the advantages to society likely to ensue from the abolition of the use of heroin in therapeutics outweigh the disadvantages.
Although the results of pharmacological experiments on animals to show the value of heroin were debatable, more recent pharmacological work on human subjects has cast strong doubts on any manifest superiority of heroin, provided that the doses are equipotent and other things are equal. It may well be asked whether it is not the therapeutic habit of using ampoules containing relatively large doses of heroin that has led to the belief that heroin is definitely superior as an antitussive or analgesic.
Consequently, the recommendations so often repeated by the international organizations since the 1931 Conference that the use of heroin should be prohibited should now meet with a favourable reception.
If ever the maxim was true that the sole purpose of a good law is to give sanction to a de facto situation, this is surely a case in point; the Paris hospitals have not been using heroin for more than a year now.
If France endorsed that view, it would no longer be one of the very few countries which are still on record as permitting the use of heroin.
Lastly to abolish the use of heroin would not set a precedent contrary to the important principle of the freedom of healing, since under the 1961 Convention France has already prohibited the use of all the other narcotic drugs in schedule IV: cannabis, desomorphine and ketobemidone, as well as khat and a great many synthetic narcotic drugs.
A more complete bibliography will be found in MARTIN & FRASER (1961).
BROUET, G.: The use of heroin in therapeutics. Bulletin on Narcotics, vol. V, No. 2, 1953, pp. 17-18.
EDDY, N. B.: Heroin (diacetylmorphine): laboratory and clinical evaluation of its effectiveness and addiction liability. Bulletin on Narcotics, vol. V, No. 2, 1953, pp. 39-49.
EDDY, N. B., HALBACH, H. & BRAENDEN, O. J.: Synthetic substances with morphine-like effects, Bulletin World Health Org., 1957, 17, pp. 569-863.
HAZARD, R.: Précis de thérapeutique et de pharmacologie. Masson et Cie. Edit., Paris 1950, p. 1043.
6 LA BARRE, J. & PLISNIER, H.: La diacétylmorphine (héroïne) peut-elle étre encore considérée comme une médication antitus- sigéne irremplaçable? Gazette des Hôpitaux, N o spécial, November 1957.
MARTIN, W. R. & FRASER, H. F.: A study of physiological and subjective effects of heroin and morphine administered intravenously in post-addicts. The Journal of Pharmacology and Experimental Therapeutics, 1961, 133, pp. 388-399.
SEEVERS, M. H.: Medical perspectives on habituation and addiction. The Journal of the American Medical Association, 1962, 181, pp. 92-98.
League of Nations: Historical and technical study on the 1931 Convention.No.C. 191 M. 136-1937 XI.
VAILLE, C. & STERN, G.: Les stupéfiants fléau social. Expansion scientifique française, édit. Paris 1955, p. 200.
VAILLE, C.: Dix ans de contrôle administratif des stupéfiants. La Semaine des Hôpitaux (La Semaine médicale professionnelle et médico-sociale), 40, 1959, pp. 963-980.
VAILLE, C.: Convention unique de 1961 sur les stupéfiants. Annales pharmaceutiques françaises, 1961, XIX, pp. 69-93.
VAILLE, C.: De la consommation des stupéfiants. La Presse médicale, 12, 1962, pp. 599-602.