Contribution to the study of synthetic analgesic narcotics

Title

Contribution to the study of synthetic analgesic narcotics

Details

Author: C. Radoueo-Thomas
Pages: 18 to 25
Creation Date: 1956/01/01

Contribution to the study of synthetic analgesic narcotics

Dr. C. Radoueo-Thomas Lecturer at thc Geneva Faculty of Medicine, assisted by S. Radouco-Thomas and Gl. Nosal

The present paper will deal with the experimental and medical aspects of the synthetic analgesic-narcotics and with the medico-social problem that they constitute. The following case summary plainly illustrates the subject of this work and gives from the outset a clue to the basic features of the drugs we propose to study:

O. L., 42 years of age, medical practitioner.

Morphine addict since 1945 as a result of paroxystic pains due to a kidney disease.

Has undergone unsuccessfully several courses of detoxication.

In 1949, took to methadone instead of morphine.

Later, learning of the effects of ketobemidone, had a sample sent to him and began with intramuscular injections. Craving developed with extreme rapidity. Changed to intravenous injections and experienced a feeling of well-being and increased capacity for work. Found the new product more potent even than morphine.

As craving for the drug grew, the dose had to be steadily increased, and he soon reached 100 ampoules i.v. per day (10-15 ampoules 6-7 times a day).

His physical condition remained unchanged. Appetite good, no loss in weight, no general lassitude. Noted, however, a marked falling off in mental powers and loss of association of ideas. No longer able to make differential diagnoses. Persistent insomnia completed the picture.

Withdrawal of the drug immediately brings on an acute state of anxiety and excitement, more acute than with morphine or methadone.

When he entered the hospital voluntarily for detoxication treatment, his psycho-motor system was found to be in a state of extreme excitation. He became threatening, demanded his discharge or a dose of ketobemidone, declaring that this was not an opiate. He left the hospital six days after entering it. (Quoted by H. Sattes (36).)

This example shows clearly the dual character of these substances:

Their beneficial side: banishment of pain. They are analgesics.

Their evil side: their repeated use produces a state of addiction similar to the classical states brought about by natural and semi-natural drugs. They are also narcotics.

This dual property, analgesico-narcotic (32), is characteristic of these synthetic substances.

We shall study in turn their experimental, medical and social-medical aspects.

A. CHEMISTRY

Let us look at them under the various trade names which physicians and chemists find so difficult to cope with, and also as they really are.

When all the products now known as synthetic analgesics are listed together, their number is astonishingly large. This multiplicity, however, is only apparent and is solely due to the way in which different trade names are given to a single synthetic substance by the various pharmaceutical firms producing it.

In fact, the number of synthetic analgesic narcotics used in therapeutics is far smaller, at present about thirty. As can be seen from table I, they can be classed in three families:

The pethidine group, with pethidine at the head, followed by its derivatives-bemidone, ketobemidone, alphaprodine; betaprodine and meprodine.

The methyl-morphinan group, whose derivatives are the laevorotatory isomers, levorphanol and levometorphan, the dextrorotatory isomers dextrophan and dextromethorphan, the racemic forms-e.g., racemorphan and racemethorphan.

The methadone group, with methadone at the head. There are several derivatives in this group-methadol, acetylmethadol, phenadoxon, and their corresponding isomers.

To these three families may be added a fourth:

The dithienylbutenylamine group, study of which is still in the experimental and clinical stage.

A series of papers has been published dealing with the chemical aspects of these groups by Eddy (11), Eddy and al. (11 b), Gero (15), Glasson (16, 17), Lapiere (27), Lespagnol (28), May (29), Schaumann (37), Small (38), Wilbrandt (44) & Wolff (47).

A review of these substances was recently made by Braenden & Wolff (9) and by Braenden, Eddy & Halbach (8).

All these products have a common basic structure similar to that of morphine (figs. 1 and 2).

4 phenyl N-methyl-piperidine: morphine and its derivatives, pethidine and its derivatives, methyl-morphinan and its derivatives.

4 phenyl (or thienyl) N-methyl-pseudopiperidine: methadone and its derivatives, dithienylbutenylamine and its derivatives.

FIG. 1. - Common basic structure

Full size image: 2 kB, FIG. 1. - Common basic structure

Thus in their chemical structure and also, as we shall see. from their pharmacology and addictive properties, these various groups and morphine are closely related. We therefore feel that these synthetic derivatives may be regarded as synthetic morphinomimetics. [1] (33)

As in other branches of pharmacological chemistry (31), this similarity in structure suggests a relationship between structure and activity.

FIG. 2. - Chemical structure of synethetic analgesic narcotics

Full size image: 4 kB, FIG. 2. - Chemical structure of synethetic analgesic narcotics

Table I

PETHIDINE GROUP

Official denomination

Registered trade mark®

Manufacturer or distributor

Country

Pethidine, or
Adolan, Alodan
Lab, Gerot-Chem. Fharm,
Austria
 
Adolens
Salci
Italy
Demerol (N.N.R.)
Algil
Maggioni
Italy
 
Antidol
Lab. Farbio
Italy
Isonipecainum (Swiss
Bi-phen-al
Allied Drug Inc.
U.S.A.
Pharmacopeia)
Centralgin
Amino AG
Switzerland
 
Demerol
Frederik Stearns & Co.
U.S.A.
Meperidine (U.S.P.)
Demerol HC1
G. Breon & Co.
U.S.A.
 
Dodonal
Riedel de Haën AG
Federal Republic of Germany
Piridosal (French Pharmacopeia)
Dolantal
Bayer Products Ltd.
U.K.
 
Dolantine
Farbwerke Hoechst
Federal Republic of Germany
 
Dolarenil
Paramed
Federal Republic of Germany
 
Dolenal
Zent S.p.A.
Italy
 
Dolestin
Teva Middle East...
Israel
 
Dolisina
C. Erba
Italy
 
Doloneurin
OPG--Utrecht
The Netherlands
 
Dolosal
Spécia
France
 
Dolosil
De Angeli
Italy
 
Mefedina
Farmitalia
Italy
 
Mendelgina
Mendelejeff
Italy
 
Pantalgine
Union Chimique belge
Belgium
 
Sauteralgyl
Lab. Sauter S.A.
Switzerland
 
Simesalgina
Simes S.A.
Italy
 
Spasmedal
Medinova
Switzerland
 
Suppolosal
Spécia
France
Derivatives
 
 
 
Bemidone
Hoechst 10446 2
Farbwerke Hoechst
Federal Republic of Germany
Ketobemidone
Cliradon
Ciba A.G.
Switzerland
 
\ alpha / beta K - 4710 2
Winthrop-Stearns, Inc.
U.S.A.
Prodines
Nisentil
Hoffmann-La Roche
U.S.A.
 
\ alpha / beta Nu - 1779 2
Hoffmann-La Roche (?)
U.S.A.
Meprodines
Nu - 1932 2
Hoffmann-La Roche (?)
U.S.A.

Table I

METHADONE GROUP

Official denomination

Registered trade mark®

Manufacturer or distributor

Country

Methadone, or
 
 
 
 
Adanon
Winthrop-Stearns, Inc.
U.S.A.
Methadone (d-l)
Algidon
Lab. Farmac.
Belgium
(U.S.P., N.N.R.)
Algolysin
SANABO
Austria
 
Algoxale
Sigurta Farmaceutici
Italy
Amidone
Butalgin
I.G. Farbenfabriken
Federal Republic of Germany
 
Deptadol
Camille Corvi
Italy
Miadone
Dolophine
Lilly & Co.
U.S.A.
 
Fenadon
FARINT
Italy
 
Heptadon
E. Bertalanffy
Austria
 
Heptanal
Treupha S.A.
Switzerland
 
Ketalgin
Amino A.G.
Switzerland
 
Mecodin
Chemapol S.A.
Czechoslovakia
 
Mepecton
Pharma-Union
Belgium
 
Mephenon
Pharma-Union
Belgium
 
Methadone
Abbot Lab.
U.S.A.
 
Moheptan
Paramed S.A.
Switzerland
 
Physeptone
Burroughs, Welcome & Co.
U.K.
 
Physeptone Linctus
Burroughs, Welcome & Co.
U.K.
 
Polamidon "C" (Hoechst 10820)
Farbwerke Hoechst A.G.
Federal Republic of Germany
 
Zefalgin
ZEF, G. Zambon & Co.
Italy
l-Methadone
Levadone
Carlo Erba S.p.A.
Italy
d-l Isomethadone
-
-
-
Derivatives
 
 
 
d-l Methadol
-
-
-
d-l Acetylmethadol
-
-
-
Phenadoxone
Heptalgin
Glaxo Laboratories
U.K.

MORPHINAN GROUP

Official denomination

Registered trade mark®

Manufacturer or distributor

Country

Levorphanol
Levo-Dromoran
Hoffmann-La Roche
Switzerland, U.S.A.
Racemorphan
Cetarin
Bayer
Federal Republic of Germany
Dextrorphan
-
-
-
Levomethorphan
-
-
-
Racemethorphan
-
-
-
Dextromethorphan
Romilar
Hoffmann-La Roche
Switzerland

Possession of a common basic structure is, however, neither essential nor in itself sufficient. For example, the dextrorotatory isomers of the methyl-morphinan group do not produce addiction and have no analgesic effect.

This observation is something of an afterthought. We felt it worth while making, however, as it sheds light on and gives unity to the study of synthetic analgesic-narcotics.

B. PHARMACOLOGICAL ACTIONS

As already stated, these products are synthetic morphinomimetics. We shall not dwell on the pharmacological properties of the different groups, but shall merely summarize, with morphine as the point of reference, their clinical effects.

MORPHINE, in a single therapeutic dose (10-15 mg.), has in man a main action on the central nervous system and a series of secondary actions.

The main effect on the central nervous system is biphasic: excitatory-depressant.

The initial phase of excitation (agitation, insomnia, vomiting, hyperreflexia) is the only one among certain animals. In man it is transitory (pre-phase).

In the depressive phase the superior encephalic structures and the spinal structures are generally depressed and inhibited:

Pain centre-analgesia;

Sleep/wakefulness centre-hypnosis;

Respiratory centre-bradypnoea;

Coughing centre-antitussive action;

Emetic centre-anti-emetic action;

Vagal centre of the heart-bradycardia;

Vasomotor centre-hypotension, etc.

The inferior (medullary) structures, however, remain generally excited and awake (hyperreflexia, convulsions, etc.).

The secondary effects are seen on the peripheral nervous system (somatic and autonomic) and the effectors.

In therapeutic doses morphine has:

A localized spasmogenic action, particularly on the pupil, gastro-intestinal tract (spastic constipation), and urinary system;

A diaphoretic action, but an inhibitive action on the other exocrine secretory glands (salivary glands, etc.).

What are the specific features of each group of synthetic morphinomimetics?

In the MORPHINAN group the laevorotatory derivatives generally have an action of the morphine type, both qualitatively and quantitatively. Their safety margin is of the same order. They offer some small advantages: they are less hypnotic, have a more lasting effect, and act when given by the mouth.

The dextrorotatory derivatives have no analgesic action, but a marked antitussive effect.

The derivatives of the METHADONE group are characterized by an action which, though qualitatively of the same type as morphine, is quantitatively different.

In equivalent doses their analgesic action is stronger than that of morphine (2 : 1), but their other activities (emetic, hypnotic, respiratory inhibitive, constipating, etc.) are weaker. When given by the mouth the drug works efficiently but has a nauseous effect.

The PETHIDINE family might be described pharmacologically as hypomorphine, both qualitatively and quantitatively. Their analgesic action is less (in intensity and duration) than that of morphine, but is free from most of its undesirable features-soporific effect, respiratory depression, constipation, etc.

The other advantages of pethidine are a spasmolytic action by depressing the parasympathetic system, and its action by the mouth.

In order to give a pharmacological definition of the drug it is necessary to estimate its toxicity at the same time that its efficacy is considered. The knowledge of the effective and toxic doses, minima (D5), median (D50) and maxima (D95) toxic doses will permit the calculation of the indices which indicate its margin of safety, its tolerance. This margin of safety is sufficient for the acute toxicity of synthetic morphinomimetics. At this point we simply state these facts, but in the last part of this work we shall study some aspects of the problem of chronic intoxication (addiction).

In conclusion, comparative pharmacological study shows that all these products are synthetic morphinomimetics related to morphine in the following descending order: levo-morphinan, methadone, pethidine.

C. THERAPEUTIC USES

After this brief review of the various pharmacological effects of synthetic morphinomimetics, let us see to what extent and where the clinician has been able to turn them to account.

Indications

We shall show first the therapeutic uses of the major action of the drug-i.e., its analgesic action-and then those of its minor effects (antitussive, hypnotic, etc.).

1. Therapeutic uses based on the analgesic effect

Synthetic substances are widely used in all fields of medicine, particularly surgery, obstetrics and internal medicine.

A. In surgery they are used for minor operations, and in the pre-operatory phase (pre-anaesthetic medication), and in the post-operatory phase after major operations.

They have also been administered for post-traumatic shock.

The choice analgesic is pethidine.

Frommel and Radouco-Thomas have recently effected a comparative study of pethidine and morphine in anaesthetic premedication (13, 14).

B. In obstetrics pethidine has been successfully administered before delivery and for post-delivery pains. Its advantages are that it upsets the mother least and does not cause foetal asphyxia.

C. In internal medicine the synthetic analgesic-narcotics are used for the same purposes as morphine.

  1. Spasmodic syndromes of smooth muscles : acute vascular occlusion, biliary and nephretic colic. It should, however, be pointed out that, like morphine, the synthetic analgesic-narcotics relieve pain solely by acting on the centre; their spasmogenic action generally aggravates the local condition. "These drugs lull both the patient and the physician to sleep ".

Pethidine, having some spasmolytic action, has also been widely used for bronchial spasm. It has checked many asthmatic attacks.

  1. Various algias of nervous origin (neuralgia, myalgia), migraines, algias of the locomotor, respiratory and genital organs (dysmenorrhea) etc.

In all medicine the relief of pain by synthetic derivatives, as by morphine, is a symptomatic relief. It is the resultant of a subjective cortical factor (suppression of anxiety state) and an objective diencephalic factor (blocking of pain tracts).

2. Therapeutic uses based on antitussive effect

The antitussive effect of most of the synthetic products studied is hardly greater than that of morphine, and not so good as that of codeine.

However, the dextrorotatory derivatives of the methylmorphinan series seem to be the right specifics for this effect as they have no analgesic action and do not produce addiction.

3. Other pharmacological effects

Their hypnotic, constipating and antidyspneic action has little or no therapeutic value.

Contra-indications

Synthetic analgesic narcotics should, like morphine, be given to children and old persons with care.

Furthermore, owing to the danger of addiction, repeated doses of the drugs must not be given in chronic ailments or syndromes.

An exception may, however, be made for intense and persistent pain in incurable disease.

This brief expose shows that the pharmacological effects and the therapeutic applications of synthetic morphinomimetics are, in general, the same as those of morphine. Some advantages, however, such as efficacy when administered by mouth, longer action (methadone) and analgesic effects with less dangerous side-effects lead to their replacing the natural alkaloids.

There is a question as to whether this tendency is justified.

An objective, experimental and clinical review of the pros and cons of the three main groups leads to the following conclusions:

The methadone and particularly levomorphinan groups have no substantial advantage over morphine.

As for pethidine, it represents a true improvement, less by its (antalgic, spasmolytic, etc.) activity, but by its superior tolerance to that of morphine and to that of other synthetic morphinomimetics.

Unfortunately, its therapeutic qualities have lead to an abusive medical use which transformed that useful and easy to administer drug into one of the most dangerous narcotics.

D. Addiction

The introduction of synthetic analgesic-narcotics has strengthened the therapeutic anti-pain arsenal, but it has also added a new chapter to the problem of classical addiction.

It is now just as fitting to talk of pethidinism, methadonism and levomorphinanism as of morphinism.

The works of Andrews (1), Anslinger (2, 3, 4, 5), Himmelsbach (18), Isbell, Fraser et al. (12, 19, 20, 2l, 22, 23, 24, 25, 26), Nathan (30), Rasor and Crecraft (35), Sattes (36), Vaille and Stern (39, 40), Wieder (41), Wickler (42, 43), Wolff (45, 46, 48) and others (38a, 38b) constitute a large contribution to the study of these drug addictions.

Medical problem

Before considering the social problem (which is much larger than has hitherto been suspected) of addiction to synthetic analgesic-narcotics, we will make a brief review of some of its medical aspects: aetiology; clinical picture, and some elements of its physiopathology; treatment; prognosis.

How is addiction to pethidine, methadone and levomorphinan acquired?

Most cases of addiction to synthetic analgesic-narcotics have a medical origin (1, 2, 3, 10, 35, 36, 39, 40, 41).

Whereas the natural and semi-natural analgesic-narcotics are known to all drug addicts, the synthetic ones are still very little known. They are rarely chosen at the outset for their narcotic effect (except by physicians and medical auxiliaries). They are prescribed for the patient as analgesics. Indisputable proof of this is given by the statistics collected by Rasor & Crecraft (35) from 457 cases of addiction to pethidine. We have summarized them in table II.

Thus 81 per cent of cases of addiction to pethidine are of medical origin.

Table II

   

Origin

%

 
 
 
Surgical
24.7
 
 
 
operational
 
 
 
 
algias post
 
 
 
Somatic
traumatic
 
 
 
 
 
 
81
 
 
Medical
37.2
 
Medical
 
Asthma, migraine, various algias
 
 
 
Mental anxiety, depression, etc.
 
19.1
 
Non-medical
 
 
 
19

Synthetic narcotics, administered for their therapeutic effect, also bring about a false euphoria, which some addicts say is greater than that of morphine. Some morphine addicts have become pethidine, methadone or levomorphinan addicts for this reason. Isbell quotes the remark of a methadone addict: "If God made anything better than that, He kept it for Himself".

It is this euphoria which the patient continues to seek even after the underlying psychosomatic trouble which was the reason for treatment has disappeared.

Physiopathological data and clinical picture

We consider addiction to synthetic drugs, like any other addiction, to be an adaptation syndrome.

Under the prolonged stress-effect of the drug the organism of the addict undergoes a process of adaptation leading, as in essential hypertension, to a high-level state.

The addict lives in a new state of biochemical equilibrium, or rather pseudo-equilibrium. Abrupt withdrawal of the drug causes the upset of this equilibrium, and this is a main characteristic of the abstinence syndrome.

The concept of the adaptation syndrome enables us to divide addiction into three successive periods:

The period of latency, during which repeated administration of the drug leads to tolerance and psycho-physiological dependence. This process is particularly rapid with pethidine and even more so with ketobemidone (10, 36).

The period of effective addiction, corresponding to the period of pseudo-equilibrium characterized by the classical addiction triad. Addicts to methadone and levomorphinan present a picture of the depressive type, as with morphine.

Drugs of the pethidine type, on the other hand, determined at the level of the central nervous system show a syndrome of psychomotor excitation of the parasynpathicolytic type.

The withdrawal period. Abrupt withdrawal upsets the patient's equilibrium and so leads, as with natural and semi-natural drugs, to a psycho-physiological abstinence syndrome. This is less intense than in classical addiction, but often lasts longer. Hence we feel that the use of these products in the substitution treatment of other types of addiction is very much open to question.

How are synthetic-drug addicts to be treated?

By the classical withdrawal treatment in special institutions. Measures should at first be medical treatment, with or without symptomatic treatment of the abstinence syndrome. Psychotherapy follows, and finally social rehabilitation. Convalescence is the most critical part of the cure. "Withdrawal is nothing, consolidation everything."

FIG. 3. - Consumption of morphine, pethidine and methadone per million inhabitants

Full size image: 7 kB, FIG. 3. - Consumption of morphine, pethidine and methadoneper million inhabitants

This brings us to the prognosis of such addicts. As with addiction to morphine or its derivatives, there is no complete cure, only a suspension of need. The ex-addict is a potential addict, or, as Wolff calls him, a latent addict (48). For some reason or other he may take to the drug again, all the more probably as these drugs are easier to obtain than morphine.

After this brief review of the medical problem, we shall consider a few special aspects of the social-medical problem of synthetic analgesic narcotics?

Social medical problem

The considerable literature on the subject shows that the synthetic analgesic-narcotics are just as harmful as morphine and its derivatives, both to the individual and to society. Anslinger (3, 4), Vaille and Stern (39, 40) and Wolff (45, 46) emphasized the gravity of the problem.

Addicts, as we have seen, are mainly recruited among sufferers from certain chronic diseases. In bringing them relief, a second malady is created just as dangerous as the first, or even more so; they go out of the frying-pan into the fire.

The drugs are also harmful to society, since their addicts, like all others, are unproductive and socially disruptive.

What steps have been taken, and with what results?

A Protocol was concluded in 1948 which facilitated the extension of international control to synthetic analgesic narcotics. As a result, measures similar to those applied to morphine and its natural derivatives have been taken for synthetic substances.

Various recommendations were also made by the competent international bodies (Commission on Narcotic Drugs, Economic and Social Council, World Health Organization) to meet the problems arising from the development of synthetic analgesic narcotics.

Have these regulations succeeded in checking the growing danger of addiction to synthetic analgesic narcotics?

Figure 3 shows the variations during recent years in rates of consumption of drugs per million inhabitants in four different countries (USA, France, United Kingdom and Switzerland)(34)

It will be seen that:

Consumption of morphine and methadone are either somewhat on the decline or stationary.

Consumption of pethidine is rising, particularly in the Anglo-Saxon countries.

Does the pharmacological and therapeutic evidence justify this trend?

The therapeutic range of morphine is becoming more and more restricted, which explains the trend of the consumption curve.

The same is true of methadone, which, as pointed out in the section on, is only a quantitatively modified morphine. After rising for a period, its consumption appears to have reached a plateau.

As for pethidine, the inordinate growth of its consumption may be partly due to its replacing morphine (owing to its almost complete freedom from the unpleasant effects which accompany the use of morphine as an analgesic), but is mainly due to its use in new fields.

At the same time a large increase is to be noted in the number of addicts to synthetic analgesic-narcotics. Figure 3 shows the trend of the number of pethidine addicts in the Lexington Hospital between 1946 and 1953. From 6 in 1946/47, their number rose to 457 in 1950-53.

It is not easy to explain the increase in such addiction despite all the international measures taken.

If we consider the various production and use factors: marketing (manufacturer), prescription (physician), dispensing (pharmacist), and consumption, we note the following:

The consumption factor is not to blame, as there cannot at the moment be any increase in demand. The man in the street, familiar with the habit-forming nature of the main natural drugs, is not even aware at present of the very existence of synthetic drugs. He will not himself go after them. Nor are the patients responsible at the outset. Believing they are getting the right treatment, they unwittingly become slaves to the drug and wake up one day to find themselves addicts.

The dispensing factor enters into only a very few cases. There are cases in the literature of dispensary pharmacists who have advised patients to take such products (10), and even of some who have dispensed them in hospital sizes. This problem seems no longer to arise, however, as the inclusion of these analgesic synthetic drugs in the list of narcotic drugs subject to control represents an insurmountable barrier for the pharmacist. Control is less strict in hospitals, however, and this fact, according to statistics, conduces to addiction among medical and auxiliary staff (35).

The prescription factor is much more important and complex; whereas for morphine and its derivatives addictions of medical origin are found in 30-40 per cent of the cases (35, 40), with synthetic analgesic narcotics they are much more numerous and may reach 81 per cent (35). The evidence in the literature suggests that the increase in the number of addicts to synthetic analgesic drugs is bound up with the tendency to prescribe them too readily (3, 4, 10, 35, 39, 40).

We have seen (table II) that of the 457 pethidine addicts in the Lexington Hospital, 81 per cent were of medical origin. In only 10-20 per cent of these cases was pethidine treatment justified. The remaining 90 per cent were patients with mental and physical troubles such as anxiety, overwork, dysmenorrhea, migraine, asthma, etc., for which treatment with synthetic analgesic-narcotics was not indicated at all and at times even contra-indicated.

To take only one example, it may be wondered how pethidine could come to be prescribed regularly in the treatment of asthma. The reason is fairly simple. The virtues of this drug as a spasmolytic have been greatly, and quite correctly, praised. In addition to relieving the asthmatic paroxysm, pethidine induces a state of pseudo-euphoria. It is hence easy to understand that the patient will prefer this drug to sympathomimetic, parasympathicolytic, and antihistamine drugs.

The problem, mutatis mutandis, is the same for all chronic ailments, whether medical or surgical.

The general therapeutic use of synthetic analgesic-narcotics is distinguished by a readiness to prescribe them which is at times astonishing. Physicians who would hesitate to prescribe morphine, for fear of inducing addiction, are much more ready to prescribe a synthetic analgesic. There seems to be a prejudice in favour of the synthetic drugs due to under-estimation of their addictive qualities.

This distinction, by no means justified, but unfortunately fairly widespread in the medical profession, between the capacity of natural and of synthetic analgesic-narcotics for producing addiction, is the stumbling-block of the whole system. Thus, through insufficient knowledge, physicians are unfortunately a contributory factor in many cases of synthetic drug addiction. Are they to be blamed?

By no means.

They are lost in the maze of trade names which prevent them from recognizing the synthetic analgesic narcotics. Carrier (10) mentions a family physician who refused to prescribe a long course of pethidine for fear of addiction and prescribed ketobemidone instead !

Furthermore, physicians learn about synthetic drugs through medical literature and prospectuses which dwell mainly on their therapeutic virtues (analgesic and antitussive effects, etc.), leaving capacity for producing addiction in the background.

One cannot expect the practitioner, overwhelmed with work, to settle down to study all the new drugs which are continually appearing in the various branches of medicine.

He is obliged to rely on the information given him. In that case, his readiness to prescribe is very understandable. Thus the social factors in the rise of the synthetic analgesic-narcotics include weaknesses which seem to escape the existing regulations.

How can this state of affairs be remedied?

As Vaille (39) noted, synthetic analgesic-narcotics appear to be in a category of their own as far as the prevention of abuse of narcotics is concerned. In addition to the regulations which are adopted from time to time at the higher level by international organizations, they call for more active collaboration at the lower levels. At the present moment, as we have seen, it falls largely to the physician to limit the spread of synthetic drug addiction at the lower level.

To enable him to play his part effectively, national health authorities and professional medical associations must make a greater effort to alert the members of the medical profession to the special dangers inherent in the continuously increasing number of synthetic analgesic narcotics. These authorities and organizations must in particular assist the efforts of the World Health Organization and the Economic and Social Council intended to make mandatory the use of international uniform non-proprietary names for all narcotic drugs. There are considerable legal difficulties in adopting a system of international non-proprietary names which could be used in all countries. Some names intended for international use may have been or may be appropriated by private firms under national trade mark laws. It is obvious that the international efforts in this field must be supplemented by action including legislation on the national level.

For the time being, as we have stated, the physician is the man responsible for limiting addiction to synthetic analgesic narcotics. In order to enable him to play his part in a more efficient way, several measures have been envisaged. If adopted, they would constitute a useful complement to the control exercised by the international organs.

These measures have to deal with the all but insoluble problem of nomenclature. This question was dealt with several years ago by Blanc et al. (6, 7) for pharmaceutical compounds in general: he stated that the multiplicity of denominations is likely to create difficulties in the day-to-day work of the physician or the pharmacist and in the therapeutic research which goes on in the world (6). But if the situation can be progressively clarified in some fields, it is especially difficult in the field of synthetic analgesic-narcotics.

It seems, however, that there is a possible way out now-namely, to take as the standard name for each drug the name adopted in the international pharmacopeia, and as the specific name that of the producing firm. Thus one would speak of Pethidine-Maggioni, Pethidine-Hoechst and Pethidine-O.P.G. and not of Algil, Dolantine, Doloneurin, etc.

As applied to narcotics the generic name of the pharmacological family is itself, as we have seen, a second source of misunderstanding. The literature discussing their therapeutic uses describes them as synthetic central analgesics, whereas the bodies and specialists concerned with their addictive capacity generally call them synthetic drugs.

Neither of these descriptions gives a clue to the twofold action of these substances; and that is why we have used a term which we feel to be more in accordance with the facts - namely, synthetic analgesic-narcotics. This we have deliberately used throughout this paper.

There is no question here of a new terminology. Our object is much more modest-namely, to help those who control the use of synthetic analgesic-narcotics at the consumption level, and particularly the physician and the chemist.

We hope that as a result the efforts of the international and national bodies will meet with more effective collaboration from these workers at ground level.

The statement of pros and cons that we have drawn up shows that the synthetic analgesic-narcotics, rationally used, are a powerful weapon in the struggle against pain and one which may well have a place of honour in the therapeutic arsenal. However, each of these drugs hides a serious danger of addiction and, if they are misused, the worthy Dr. Jekyll may become a dangerous Mr. Hyde.

1

A word borrowed by analogy from the nomenclature of drugs acting on the autonomic nervous system.

1

The names in italics represent the international non-proprietary names proposed for the International Pharmacopoeia.

2

These drugs are not commercial products.

1

The names in italics represent the international non-proprietary names proposed for the International Pharmacopoeia.

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