Medical perspectives on international control of synthetic narcotics

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Medical perspectives on international control of synthetic narcotics

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Author: Maurice H. Seeders
Pages: 26 to 30
Creation Date: 1956/01/01

Medical perspectives on international control of synthetic narcotics

Ph.D., M.D. Maurice H. Seeders
University of Michigan This article was transmitted for publication in the Bulletin by Mr. Harry J. Anslinger, the Commissioner of Narcotics of the United States of America.

The United Nations Commission on Narcotic Drugs at its tenth session recommended to the Economic and Social Council a Turkish-Yugoslav draft resolution which would (1) invite governments to make the medical and allied professions aware of the special dangers, if any, of the new narcotic drugs placed on the market, and (2) recommend that governments prohibit the production and the use of such synthetic narcotics as they do not consider indispensable to the public health.

The Economic and Social Council, by a rather close vote, rejected the draft resolution. However, the Council did adopt another resolution, No. 588 E (XX), of which a paragraph (6) reads as follows:

"To warn the members of the medical and related professions when appropriate, of the special dangers to public health that might be caused by any new narcotic drugs placed on the market and to invite them to study the desirability and possibility of prohibiting the production and use of such synthetic narcotic drugs as they do not consider indispensable to public health."

Implementation of such a proposal even in its final form provides the distinct possibility that ignorance of the true facts as they relate to the interpretation of the phrase "indispensable to the public health" may have disastrous results. Well-meaning administrators may discard the scientific spadework of the last several decades just at a time when there is reason to hope for success in the dissociation of analgesia from addictive properties in this class of compounds.

Prior to the introduction of the draft resolution the Commission had available for study a paper (Bull. World Health Org. 13, 937-998, 1955) by the World Health Organization which examined whether any relationship existed between the structure of the molecule and the analgesic action of substances with morphine-like effects. They also had the benefit of hearing a statement by one of the authors of the paper, Dr. Nathan B. Eddy. As summarized in the report of the Commission to the Council (E/2768, paragraph 217):

"Dr. Eddy expressed the opinion that at the present time medical needs could in general be satisfied by the use of synthetic analgesics, without ill effects to the patient; that synthetic drugs differed from one another in addiction-liability just as did natural drugs, i.e., drugs derived from natural substances like opium; and that, while specific studies on this point would be undertaken in the near future, it could already be stated that the risk of addiction through the use of synthetic drugs was at least no greater than was the case through the use of natural drugs. Withdrawal of methadone, however, was considered less difficult for the addict than withdrawal of morphine. He also drew attention to the possibilities just beginning to appear of separating analgesic action from addiction-producing properties in certain kinds of synthetics."

Whereas the WHO paper and the statements of Dr. Eddy were clear in presenting an accurate factual account of the present situation, these data were not kept in proper perspective during the subsequent debate regarding the major problem at hand- the establishment of a resolution or protocol which would reduce all types of drug addiction at the world level.

Examination of the total transactions of the tenth session reveals that for purposes of debate, only such fragmentary evidence or statements best suiting the momentary needs of the proponents or opponents of this proposal appear in the record. Therefore each member of the Commission was obliged to reconstruct the total world picture of " synthetic" versus natural narcotics in the light of his own individual knowledge or experience in order to gain proper perspective. Since the largest clinical experience with "synthetics" has been obtained in the United States, most of the remarks pertain to the American situation. As would be inevitable in such debate, comparatively insignificant facts which are new and startling often carry undue weight in comparison with knowledge Which has become common property because of its age and ubiquity.

Had the original resolution been accepted by the Economic and Social Council without modification, it could have enunciated a policy which might have served as a serious obstacle to the further scientific development of the "synthetic" narcotics. Even in its present form the phrase "indispensable to public health" provides an open door for the exploitation of private economic interests since it would be most difficult to find agreement among even the most outstanding medical scientists concerning a list of substances which either scientifically or legally could be declared indispensable to the public health.

Is a drug that is highly valuable necessarily indispensable? A drug may be invaluable to one patient, for instance where the patient cannot for any one of several reasons use other narcotic agents, and yet the drug might not be considered indispensable to the public health.

The test should not be indispensability. On this basis one may also argue that there is nothing indispensable about the need for relieving pain. Indeed in certain emergencies physicians may for a while dispense with the task of relieving pain in order to first stem the flow of blood and combat shock. The term "indispensability" is a highly relative one in this context depending on the social mores and the prevailing local attitude toward physical suffering. It is a fact that some peoples are more tolerant of physical hardship and suffering than others. For instance, as a general thing, orientals endure pain, torture and death with greater equanimity than occidentals.

It is evident from the debate in the Commission that the term "synthetic" as used in the resolution is considered to have a limited and specific meaning since synthetic morphine, heroin and other congeners of the opium alkaloids derived by relatively simple chemical manipulations of the morphine or thebaine molecule are not considered to be "synthetic ". The distinction implied in the resolution then is between "horticulturally derived" narcotic products whether natural or modified by synthetic procedures versus "laboratory derived" substances.

Judging from previous actions of the Commission, no major difference of opinion seems to exist in international discussions concerning:

  1. the desirability of eliminating certain "synthetics" (ketobemidone) as well as certain natural substances (heroin) from general use as being not indispensable to the public health because of their large addiction potential despite their potent analgesic and therapeutic activity.

  2. The desirability of declaring certain natural substances (morphine) as indispensable even though the addiction potential is very large and the therapeutic potency less than some of the "synthetics ". Even though no overt action of the Commission is apparent from the record, pethidine is tacitly accepted as indispensable even in states like France where other "synthetics" are barred in favour of heroin. It seems clear then that the term "indispensability ", when put to the practical test and using the Commission's own criteria, has no uniform scientific connotation but is applied to fit a wide variety of different circumstances.

The author is fully aware that legal definitions and decisions are sometimes in conflict with scientific fact, and that international protocol often involves propositions in which the interests of the minority are submerged to those of the majority. Even with these limitations in mind, a search for a logical basis of discussion of the original resolution invites the physician and medical scientist to propose two major questions:

  1. Is "indispensability" to the public health primarily a medical and social issue or is it an economic problem:

  2. Why should "synthetic" drugs as a class be less indispensable than natural drugs if the answer to the first question is medical-sociological rather than economic?

In spite of the affirmative vote in the Commission and the ambiguity which surrounds the term "indispensable" the consensus in the Commission seemed to support the view that the medical profession in each signatory State should furnish the data and the opinions upon which final decisions would be based. This view was supported firmly by the opponents of the original Turkish-Yugoslav resolution on the premise that no other professional group could conceivably establish the scientific basis for decision and that their opinions should prevail in each instance. In support of this premise it was pointed out by the United Kingdom representative that the wishes of the individual states had always been respected in this regard, citing as an example the individualistic position of France in deviating from the heroin ban at the instigation of its medical profession. In support of the original resolution the Turkish representative stated, "that if the freedom of the medical profession was to prevail over the judgment of international organizations, as the United Kingdom representative wished, international agreements on narcotic drugs would no longer be effective, for there would always be exceptions" (E/CN.7/SR.277, p. 8).

Despite this dissention, it seems reasonably fair to accept the majority position of the Commission-that in decisions involving dispensability or indispensability to the public health, medical should outweigh economic considerations. Reasoning from this premise, it seems logical for a member of the medical profession with a background of thirty years of study and pharmacologic experimentation in this specific field to review the overall proposal from the point of view of science and medicine. In order to keep such a review comparative (an aspect of the problem which could be easily lost sight of in the face of such statements as "alarming increase in the number of persons addicted to synthetic narcotic drugs" (E/CN.7/SR.275, p. 10)), the present world situation with the natural products must be brought again into sharp focus even though it is an" age-old" problem.

The author therefore proposes to adhere strictly to the scientific aspects of the problem in an attempt to answer the following question. From a medical and scientific viewpoint are "synthetic" drugs as a class less-or more-indispensable to the public health than" natural" drugs?

For clarity of presentation it is proposed to analyze the reasons which have been or might be presented in support of a categorical statement which must be true if there is a valid scientific or medical basis for legislating or establishing protocol against "synthetics" as a class.

National and international abuse and the potential hazards to health associated with the use of all "synthetic" narcotic drugs is greater than with the use of all "natural" narcotics.

A. INHERENT PROPERTIES OR CONDITIONS ASSOCIATED WITH THEIR PRODUCTION WHICH ENDOW "SYNTHETICS" WITH QUALITIES WHICH MIGHT MAKE THEM MORE HAZARDOUS AS A CLASS THAN THE "NATURAL" NARCOTICS.

1. The "synthetics" are easy to produce in the laboratory and hence more difficult to control than natural products.

At first glance this statement is impressive although no practical test of its validity has ever been made. Except for a single case, no evidence is available that synthetics are being produced illegally for addict use even though there has been an insignificantly small diversion of legally produced materials into illicit traffic. Since the raw intermediates of synthetic manufacture are used in the production of many other chemicals, it must be admitted that control at this source might be fairly difficult especially in view of the fact that the preparation of some of the synthetics involves comparatively simple chemical procedures and methods of manufacture are often a matter of public record.

However, control of the manufacture of the "synthetics" may not be an insurmountable problem. Acetic anhydride is used in the conversion of morphine to heroin and although acetic anhydride is used for many other purposes, such as the manufacture of aspirin, any sudden or unexplained demand by individuals who have no known legitimate use for it has been a signal to enforcement officers to investigate. In a similar way both diphenylacetonitrile and dimethylaminoisopropyl chloride are used primarily in the manufacture of methadone although small quantities of both of these chemicals may be used for other purposes. However; any unexplained increase in their production or sale could be used to instigate an investigation.

In other instances the production of the synthetics can only be carried out by higly trained specialists because of certain dangers present in manufacture. In making pethidine, for example, it is necessary to go through the production of nitrogen mustard types of compounds which present severe hazards to workmen because of their very great toxicity. It is difficult to see how" underground" operators could have the necessary resources in both equipment and scientific personnel to carry out this reaction without encountering disastrous results. Despite the fact that synthetics have been produced in the United States for sixteen years, only one instance of illicit manufacture-and that on a relatively small scale-has ever been encountered.

In discussing this problem before the Commission, the Turkish representative stated, "It was an undeniable fact that while the raw materials of natural alkaloids had been under control for the past forty years (author's italics) the raw materials used in the manufacture of synthetic drugs were not controlled, and moreover, were virtually uncontrollable" (E/CN.7/ SR.275, p. 9).

One must infer from this statement that the Turkish representative really meant that international protocol governing opium had been in full force during the period cited, since it is quite obvious that effective control has never even been approached. It is of great significance to the present discussion that one can find no dissenting opinion offered by any member of the Commission to a statement made a few days later by its Chairman, the representative of France. In discussing a Model Code for application of the 1953 Protocol for Limiting and Regulating the Cultivation of the Poppy Plant, the Production of, International and Wholesale Trade in, and Use of Opium, he said,

"Much ground has been covered since the first conference in Shanghai and the New York conference, but although progress had certainly been made in those forty-four years, it was limited. This was not surprising. The 1953 Protocol alone would not be a final end to the illicit traffic in illegal use of opium. There were still many social problems to be solved before the goal was reached, and they were beyond the scope of the international bodies dealing with narcotics. Their decisions must be realistic enough to be applicable and at the same time be a step forward" (author's italics) (E/CN.7/SR.279,p. 12).

The world production of opium is just as large now as it has ever been and probably much larger. It is clear that ideological differences and economic pressures assure that the illegal world demandfor the opium alkaloids, however large, will certainly be supplied, partially by diversion of the cultivation or the production capacity of those who ostensibly adhere to protocol, but who in reality do not.

These are the facts. In the absence of a problem in being, it becomes difficult to find, a priori, a logical basis for differentiation between "synthetic" or natural products on the basis of supply alone.

2. The "synthetics"do not possess any pharmacological characteristics which give them therapeutic advantages over natural products.

It seems hardly necessary to adduce all of the evidence which is available to refute this statement. Suffice it to point out that synthetic narcotics are now known which individually surpass the natural product in every known category where the latter are therapeutically defective; less respiratory depression (pethidine); less gastrointestinal effect (pethidine); better oral effectiveness (levorphan, methadone); greater duration of action (levorphan); less tolerance development (methadone); less physical dependence and primary addiction liability (methadone). Although no single agent possesses all these advantages, the above facts alone suggest strongly that the search for such a desirable compound is likely to be met with success.

The "synthetics" produce greater euphoric effects than the natural products and more easily induce "craving" and ultimately addiction in non-addicts who are given the drug for therapeutic purposes.

A test of this statement can be made by determining the number of primary addicts to the synthetic narcotics. While this is not an easy figure to determine, some data are available for pethidine. Since the American experience has been used as the principal basis for arguments in the support of limitations of" synthetics ", it seems pertinent to review this situation. Comparative figures of pethidine production and American consumption for 1946 and 1953 are:

 

Total production(ounces)

American consumption(ounces)

1946 123,362 101,102
1953 313,968 270,566

In a recent study Rasor at Lexington has reported on a total of 453 pethidine addicts which were treated in this institution in a 39-month period. Of these 63% were primary addicts. More than half listed chronic illness as a basis for the addiction and physicians for their principal, if not exclusive, source of supply. Of the total number 91% were admitted voluntarily for the treatment of their condition.

In the following table is listed the domestic consumption of pethidine in the United States of America in comparison with the other principal narcotics, "synthetic" and natural, for 1953. They are as follows:

"Synthetics"

Pethidine
270,566 oz.
76,570,178
doses
(100 mg.)
Methadone
6,942 oz.
1,964,386
doses
(10 mg).
 
 
78,534,464
doses
 

Natural

Morphine
53,071 oz.
150,190,930
dose
(10 mg.)
Dihydromorphinone
3,662 oz.
5,181,730
doses
(2 mg.)
 
 
155,381,660
doses
 

In this summary other natural alkaloids such as codeine, ethyl morphine, and dihydrocodeinone have been discounted inasmuch as they are largely used as antitussives or in small amounts in liquid preparations and do not constitute or create a potential addiction hazard. Other "synthetics" have also been discounted since data are not available concerning their consumption, although it is known to be small.

An analysis of the figures indicates that American physicians prescribe the "synthetic" narcotics, pethidine and methadone in approximately one-third of all instances in which a potent analgesic is required. It is certain that the average 140 cases per annum of pethidine addiction listed by Rasor is not an accurate guide to the total number of U.S. cases of addiction with this substance. This figure gains relative significance, however, when the estimated 60,000 narcotic addicts in the U.S. is considered, of which 93.7% are believed to be addicted to heroin, morphine, or other natural drugs. Since only 6.3 % or 3,780 are believed to be addicted to synthetic drugs and only a few instances of primary methadone addiction are known to exist, it is exceedingly difficult to find much actual or comparative evidence on which to build a serious case against the "synthetics ". This is especially true since they have been in extensive use for 10 years and the consumption in 1953 is still less than 3 times that of 1946.

4. Tolerance development is more rapid with the "synthetics", requiring more rapid increase in daily intake to retain analgesic effects.

To the contrary, tolerance development is more delayed in most instances, especially with methadone.

5. The degree of physical dependence is greater with the" synthetics ", thus inducing more profound withdrawal signs.

To the contrary, the degree of physical dependence to pethidine and methadone is dearly less than of most of the natural products. Only with ketobemidone is there clinical evidence of excessive danger in this respect. This compound had rightfully been subjected to severe restriction at national and international levels (at least until use in those countries permitting its availability for medical use can confirm the estimated hazard).

6. The toxicity is greater with the "synthetics ", resulting in more cases of accidental poisoning, and the treatment of poisoning is more difficult.

To the contrary, no greater inherent toxicity resides in the "synthetics ". Nalorphine (N-allylnormorphine) is capable of antidoting effectively the toxicity of all of the" synthetics" in common use.

B. PROVEN HAZARDS ASSOCIATED WITH ACTUAL USE WHICH DISTINGUISH "SYNTHETICS" FROM NATURAL NARCOTICS.

1. Physicians being unaware of, or careless with, the hazards of the "synthetics" are producing greater injury to the public than with the natural products.

There is some apparent evidence to support such a statement in view of the experience with pethidine in the United States as detailed above, especially since the known cases are almost exclusively connected in some way with legitimate therapeutics, both as to origin of use and source of drug. Considered alone, this fact is sufficient cause for alarm to initiate educational measures among physicians for its correction. When considered in perspective, however, one must recall that a similar situation arose in the United States with respect to dihydromorphinone which was exploited initially as a nonaddicting agent. Even heroin was introduced for the treatment of morphine addiction! The therapeutic benefits of pethidine are sufficiently impressive to American physicians to cause them to select this compound to produce almost one-third of the effective "potent analgesia ". Its use has provided a clear-cut reduction in dangerous hazards in obstetrics, respiratory disease, old age and so forth. When weighed against these advantages the addiction hazard shrinks materially. From a scientific point of view it would be difficult to refute the statement that therapeutic abuse of pethidine whether through ignorance or design would be less hazardous than comparable abuse of morphine.

2. Psychologically defective individuals prefer "synthetics" to the natural products as a vicarious substitute for their feelings of inferiority and therefore become addicted more easily.

This statement is clearly contrary to the facts when applied to any of those drugs which are now in common use. Possibly some new synthetic may emerge which may fit this category; possibly it applies to ketobemidone; but there appears to be no difference of opinion among either scientists or regulatory bodies concerning the banning of individual compounds which fit into this category.

3. Addicts long-addicted to the natural products pre]hr the "synthetics" and transfer their addiction to the "synthetics" whenever possible.

There is no evidence of any type to substantiate this statement.

4. National and international drug rings in recognition of all of the facts stated above are abandoning the smuggling and" pushing" of natural products in favour of the "synthetics" whenever this is possible.

There is practically no known illicit trade either at the national or international level with the" synthetics" although a few instances of diversion from legal manufacture are known. It is an economic dictum that supply will meet demand if the profit motive is adequate. It would be difficult to visualize a greater profit on "synthetics" than now exists for the natural products. A controlled supply is essential to high profit. Even to a scientist it is difficult to believe that international dealers in narcotics could glut the market with "cheap" synthetics.

Narcotic thieves always prefer the natural products when given a choice. Not a single instance is known in the United States where a large scale theft of synthetics occurred when the burglarized vaults contained both natural and synthetic drugs. The thieves invariably stole the natural products and left the synthetics behind.

5. "The rise in the addiction to 'synthetic' drugs brought about a corresponding increase in illicit traffic in natural narcotics" (E/CN.7/SR.276, p. 7).

This is a statement by the representative of France in supporting the original resolution and made without supporting evidence. It is not in accord with the American experience and seems most unlikely on theoretical grounds. Certainly in the United States there is no evidence whatever that addiction to synthetic drugs has had any tendency to increase addiction to the natural narcotics.

Certain other facts must be considered before any sound conclusion can be drawn regarding policies for international control. The argument was offered by the proponents of the original resolution that the type of prohibitions suggested were not intended to, nor would they, interfere with scientific advances in this field. Such an argument is neither scientifically nor medically realistic. The final test of hazard of a new analgesic agent, whether it relates to its capacity to induce euphoria, rapid tolerance, physical dependence, and the other factors which constitute" addiction ", can only be determined in normal man, in fact in many normal men, under conditions of therapeutic use. Animal experiments, or small-scale preliminary trial on post-addicts as conducted at Lexington, field results which, although the best obtainable at the screening level for new compounds, are recognized to be inconclusive.

In the United States, as elsewhere, evaluation of a new narcotic analgesic which is proposed for distribution to the profession follows a certain pattern. First is the determination of "scientific indispensability ". Scientific "indispensability" is based solely upon a favourable advantage/disadvantage ratio on all tests on animals and post-addicts. If such a ratio is significantly greater than unity, the drug may then be given the "medical and social indispensability" test. This test is carried out on a limited scale under actual conditions of clinical application by persons qualified to make an accurate clinical appraisal of the situation. If a favourable ratio is still obtained, that is, if the therapeutic advantages outweigh its hazards of use, then for ail practical purposes this substance could be declared "indispensable to the public health" and actually is by tacit understanding.

Under the resolution as initially proposed the final clinical test to determine "medical and social indispensability" could ,.be effectively outlawed and superior therapeutic agents might never be discovered.

There are other reasons which can be considered from a scientific point of view which bear upon the original resolution. The type of medical practice regarding administration of narcotics differs widely in the several states, ranging from elaborate hospitalization under constant supervision to hand to-hand transfer of narcotics to ambulatory patients. The same situation applies to laws and their enforcement. The inference is that it is not possible to strike an average for clinical practice or of laws governing its control, thereby precluding the uniform standards required of international protocol.

Trends in world events can so profoundly influence the individual and mass psychology of a nation that unpredictable crises may arise which have no counterpart at the world level, for example, there is the amphetamine situation in Japan. To use such an isolated instance as the basis of international protocol against amphetamine would hardly constitute proper perspective. Fortunately, good perspective has been retained in the logical decision of the Expert Committee on Drugs Liable to Produce Addiction of WHO to continue study of this problem but to make no recommendation for general international control.

In summary, the conclusion is inescapable that the great preponderance of evidence favours the view that there is no scientific basis for either legislation or protocol which would create an artificial class distinction based upon chemical origin which can serve satisfactorily as a foundation for retaining the natural products and prohibiting the use of the "synthetics"

On the contrary, the scientific and medical advances m the synthetic narcotic field have been so rapid that even to-day very few natural products are indispensable to the public health. The evidence in favour of the "synthetics" is so impressive when subjected to comparative analysis that the author is tempted to predict that the day is not far distant when the Commission will be confronted with resolutions which would propose to abolish forever the cultivation and production of all" horticulturally derived" narcotics.

To this observer, a statesmanlike and logical approach to international control appears in the statement of the Chairman of the Commission regarding the opium problem. It is to be hoped that his philosophy may serve equally well as a basis for further deliberations. "The decision must be realistic enough to be applicable and at the same time a step forward."