Codeine and its alternates for pain and cough relief*

Bull. Org. mond. Sante 1969, 40, 721-730Bull. Wid Hitha Org. Codeine and its Alternates for Pain and Cough Relief* 5. Discussion and Summary NATHAN B. EDDY, M.D.,1 HANS FRIEBEL, Dr med.,2 KLAUS-JORGEN HAHN, Dr med.3 & HANS HALBACH, Dr med., Dr-Ing." This chapter concludes the survey of experimental and clinical data on the analgesic and antitussive properties of codeine and its potential therapeutic alternates. From an evaluation of their effectiveness on the one hand and the side-effects, including tolerance, dependence and abuse liability on the other, it would appear that the therapeutic goals of codeine could be achieved by other substances, except perhaps where analgesia, cough relief, and sedation are required simultaneously. The use of these other substances would, however, result in no particular gain andprobably no particular loss. CONTENTS CODEINE AND ITS ALTERNATES FOR PAIN RELIEF ANALGESIC ACTION ..... . . . . . . . 721 SIDE-EFFECTS ..... . . . . . . . . . . 723 DEPENDENCE AND ABUSE LIABILITY .... . 723 CODEINE AND ITS ALTERNATES FOR COUGH RELIEF ANTTrussIVE ACrION. . . . . . . . . . . . .723 Effectiveness and lack of undesirable side-effects, including tolerance, dependence and abuse liability, are obviously the leading characteristics to be consid- ered in the evaluation of codeine and its potential alternates. In the preceding parts of this article the information available on these characteristics for many different drugs has been reviewed. It remains to survey the picture as a whole in an attempt to assess whether an alternate is needed and, if so, to consider the progress that has been made in the search for one that is adequate. OTHR PHARMACODYNAMIC ECTS .... . 726 UNDESIRE SIDE-EFFECTS IN COUGH THERAPY 726 ABUSE LIABILITY . ........... . 728 .ui .................. . 729 RERENCEs ............... . 730 CODEI AND I ALTERNATES FOR PAN RELEF Analgesic action It was pointed out in Part I of this review that the greater part of the world's supply of codeine was used for pain relief, generally alone, if the route of administration was parenteral, but often. in combi- nation with APC or aspirin if the route was oral. It has been shown that codeine can, at a price, equal the analgesic effectiveness of morphine if the parenteral * This review of the analgesic and antitussive effects of 1 Consultant, National Institutes of Health, Bethesda, codeine and its alternates has been published in the Bulletin Md., USA. of the World Health Organization in five instalments. The 'Professor of Pharmacology and Toxicology, Universityfirst four instalments dealt, respectively, with the analgesic ' Profer Germacology address:cology, Drug action of codeine (Bull. WId Hlth Org., 1968, 38, 673-741); of Heidelberg, Germany. Present address: Chief, Drug its alternates for pain relief (Bull. Wld Hlth Org., 1969, 40 Safety, World Health Organization, Geneva, Switzerland. 1-53); the antitussive action of codeine (Bull. Wid Hlth Org., ' Department of Medicine, University of Heidelberg, 1969,40,425-454); and assessment of potential alternates with Germany. antitussive action (Bull. Wid Hlth Org., 1969, 40, 639-719). The five instalments will eventually be available as a joint 'Director, Division of Pharmacology and Toxicology, reprint. World Health Organization, Geneva, Switzerland. 2329 -721- 722 N. B. EDDY AND OTHERS TABLE 71 SUMMARY OF ANALGESIC EFFECTIVENESS OF ORAL DOSES Man, usual dose (mg/kg) S e(mg) effects a Dependence liability Single Per day Carisoprodol 130-185 350 1 050-1 750 -b None shown in man c Dextropropoxyphene 122 65 200-400 - <codeine Codeine 43 30-60 c.250 Dihydrocodeine 43-160 30-60 c. 250 ± Same as codeine Ethoheptazine >50 d 75-150 e 300-600 - None Etymide 47-57 75-150 450f ± Little or none Metofoline 12-55 30-60 180-360 - Little or none Fenyramidol As for codeineg 100-400 400-1 600 + None Prodilidine <codeine 50-150 150-450 + Little or none a Compared with codeine. b Drowsiness is estimated to occur in 10 % of patients. c Barbituate-like in dogs. d The subcutaneous ED5o is 34-44 mg/kg; no oral EDso has been recorded. e Practically always with aspirin. f Not yet introduced into clinical medicine. Figures based on clinical investigations. g Potency about the same as that of codeine; various comparisons. dose is large enough.' However, there are several more powerful analgesic agents to choose from for parenteral administration, and taking into account the size of the dose required to equal the effects of morphine it would be difficult to establish an advantage for codeine. Moderate oral doses of codeine are effective against moderate pain of many origins, probably not as effective as we could wish, since the codeine is so frequently combined with APC in the hope that the effects of the two will be additive. The frequency of side-effects with oral doses is low and if moderate doses suffice then tolerance and dependence develop very slowly (Cass, Laing & Frederik, 1961, personal communication, 1963). Oral doses of codeine can produce respiratory depression, however (Bellville et al., 1958). If the pain is severe, and large doses must be used, the occurrence of side-effects will increase and dependence will develop more rapidly. Oral administration has many advantages, but there are conditions in which it is not feasible. If it were as effective and as safe as we would like it to be, the physician's hands would be freed for better 1 Houde, R. W. et al. (1960) Reported to the Committee on Drug Addiction and Narcotics, National Academy of Sciences, Washington, D.C., USA, p. 2312. and broader pain control; even first-aid kits could then contain adequate medication for the relief of severe pain in emergencies and the cost of drugs for the treatment of many painful conditions and the cost of special care would be greatly reduced. These considerations certainly justify an intensive search for a better oral medication. Table 71 summarizes the analgesic effectiveness and other data for some of the compounds produced so far; all these compouds were reviewed in Part 2 as potential codeine alternates. The figures in Table 71 are our best estimates from the data reviewed. These figures are not impressive as far as any increase in analgesic potency is concerned; none of the agents is more effective than codeine. Appar- ently we have made no progress so far towards the relief of severe pain via the oral route. Dextropro- poxyphene is nearly always given with APC, and ethoheptazine with aspirin, yet the combinations hardly equal codeine in the relief of mild to moderate pain. All of these agents could be used where oral codeine is indicated, but they offer no advantage in the production of greater comfort. On the basis of the figures presented, metofoline might equal codeine, but it has not yet been introduced into general medi- cal practice. The specific opiate antagonists have not CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 5 been included in the table, but among them may lie our best lead towards future improvement. Side-effects In most cases the substances listed in Table 73 compare favourably with codeine in their production of side-effects; some small advantage may have been gained in this respect. Even with fenyramidol and prodilidine the difference in the other direction is probably not great enough to prevent their use, if there were other advantages. The use of codeine itself, however, is not limited to any great extent by its side-effects, so that this can hardly be a deciding factor in choosing between agents. Dependence and abuse liability Dihydrocodeine is quantitatively and qualitatively similar to codeine in this respect. The other agents in Table 72, however, may all have some slight advantage over codeine in respect of abuse liability. Except for propoxyphene, which has been used much more extensively than any of the others, and for which a few cases of abuse have been reported, abuse of the other potential codeine alternates has not come to our attention and narcotics control has not been recommended for any of them. This is not a very great advantage, however, as the restrictions on the use of codeine are slight and are enforced only in certain places. Although codeine is not the ideal oral analgesic and we should certainly keep looking for better ones, we should keep in mind the considered judgment which Wolff (1938) expressed 30 years ago: "In view of the vast and justified extension of codeine consumption throughout the world for several decades, the few primary and secondary cases [of dependence on it] together cannot be regarded as a danger topublic health ", to which he added "... wheth- er the medical use ofcodeine is a social danger may be answered in the negative ... The medical practitioner should not be alarmed .., and should not allow himself to be deterred from prescribing codeine freely in the usual small therapeutic doses." Seevers (1967) has recently summed up the situation by saying that codeine can be replaced in certain specified and limited situations, but: Judging from the continued popularity of codeine among physicians and laymen alike throughout the world in spite of the easy availability of the so-called I non-toxic ' preparations it seems illogical to abandon a drug like codeine which possesses, in one agent, not only antitussive properties but also pain relief and sedative properties which are helpful in relieving the discomfort often associated with a cough ... Codeine serves a need which is not presently met by other substances; ... [the evidence] hardly justifies discontinuing its availability. Seevers was thinking of reported abuse of codeine antitussive preparations, but his remarks are applic- able to the use of codeine generally. So we think it fair to say that there are other substances available that could be used as alternates for codeine, except perhaps where analgesia, cough relief and sedation are required simultaneously, but that the use of these other substances would result in no particular gain and probably no particular loss. Let us, however, continue to strive for better oral analgesia. CODEINE AND ITS ALTERNATES FOR COUGH RELIEF Antitussive action The sizes of the average single and daily doses of a substance in any cough therapy are criteria which indicate the efficacy of its cough-depressing action. Other criteria are the onset and duration of effect, the course of the dose-response curve and charac- teristics of action in terms of change in the frequency and intensity of coughing. Though the latter factors are perhaps less easily determined, they are of real importance in the evaluation of the total antitussive effect. For example, benzonatate differed from many other antitussives because of its sustained cough- depressing action, and homarylamine showed an increasing effectiveness from 10 to 20 mg, but no further increase from 20 to 40 mg (Bickerman & Itkin, 1960). Patients can assess a diminution in both severity and frequency of cough attacks and their subjective judgnent of a drug can be expected to include an integration of both effects. On the other hand, mechanical registration of cough (sound recording, etc.) usually deals only with cough frequency. Therefore, results regarding these effects which are based on subjective experience are not necessarily comparable with others based on mechanical recording. A comparison of antitussive effectiveness between codeine and its alternates, as well as among the alternates, is made exceedingly difficult by the wide differences in techniques, criteria and judge- ments that have been used. Nevertheless, the data collected in Table 72 give our best estimate from all sources of the average cough-depressing doses and related activities. Single and daily doses adminis- tered in therapy correspond fairly well with the 723 N. B. EDDY AND OTHERS CHARACTERISTICS TABl OF CODEINE ALTERNATES A Dosage (mg) Oth Agent Therapeutic ~ HatyAia Single Daily volunteersc experimentsd Analgesia | Sedation (±) Methadone 2.5 7.5 <C 2.5-15.0 <C =M =M Normethadone 7.5 15.0 Ineffectiveg <C >Ch =C Pholcodine 10.0 30.0 <C 10.0-15.0 <C Little or noneh Little or none Caramiphen 15.0 80.0 >C | C None h Dihydrocodeine 20.0 60.0 =C =C 1 C Dextromethorphan 20.0 60.0 6C.C None h Ethylmorphine 25.0 60.0 >C =C Nalorphine Like C =C =C =M <M Codeine 20.0 70.0 >M >M <M Some AT-327 >C 90.0 None h None h Pentoxyverine 25.0 100.0 =C None1' Dimethoxanate 25.0 =C None None h Pipazetate 30.0 100.0 =C >C None1h Sodium dibunate 100.0 =C Noscapine 30.0 100.0 >C >C None h None Clofedanol 35.0 120.0 >C None h None Clobutinol 40.0 120.0 >C 60: 40 =C None h None Isoaminile 40.0 140.0 6C Little or noneh None Diphenylpiperidinopropanol 40.0 160.0 >C 60:30 >C None h None Benzonatate 100.0 >C 100:30 =C None None Levopropoxyphene 100.0 400.0 >C 100 :15 >C Nonr h Benzobutamine 100.0 400.0 =C Slight Oxolamine 120.0 600.0 =C <C a C = codeine; M = morphine; P = procaine; Co = cocaine. b Average for adults. c Relation to codeine, equipotent cough-depressing doses. d Composite of experiments performed with different species, methods of cough stimulation and routes of administration. e Results of animal experiments and clinical experience. f See Part 1 (under respective compounds) and Eddy, Halbach & Braenden (1957). effective doses estimated from work with human volunteers. A major exception is Bickerman's (Bickerman et al., 1957) failure to show effectiveness of normethadone in normal subjects. Doses used in therapy do not correspond as well with the effective doses in animal experiments, but the exceptions are mainly among the agents which must be ad- ministered in higher doses than are required for codeine. The therapeutic antitussive doses of codeine, summarized in an earlier table (Part 3, Table 29), permit the estimation of average oral doses of 20 mg and 70 mg, single and daily, respectively, for adults. Table 72 shows that pholcodine, norme- thadone and caramiphen would generally be used in smaller doses, dihydrocodeine, ethylmorphine and nalorphine in equal doses, and the others in higher doses than codeine. The average single or 724 CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 5 725 HTITUSSIVES COMPARED WITH THOSE OF CODEINE a armacodynamic actions, relative to codeine Bronchial Lcl Anti- Abs Respiratory Circulatory Gastro-intestinal oanaesthetic inflam- liabilityf Musculature Secretion aeshtc matory laiiy =M =M <M Like M )epression Decrease <M; >C > >ph,Z_C Little or none =CP None ittle or none =C Antispas- Antispas- Increase1 <Co h None modic? h modic? h mproved Little or none k Some h <C 1 Little or none Little or none Like C lepression Little or none Like M None ;epression Little Decreased Constriction h Decrease h Some h <M ncrease A Some h Spasmolytic h >ph No data .ittle or none Depression h Spasmolytic h Spasmolytic h Decrease > p h None done h Depression h Spasmolytic h <ph None )epression None h Spasmolytic <P h None ncrease h None h None h None h None ncrease h DepreSsion h Spasmolytic h Spasmolytic h Increase h None .ittle or none h Little or none h None Decrease h > p h None little or none Little or none None Increase h None h None <Ch Depression h Spasmolytic h Spasmolytic None <P < C .ittle or none h Little or none h Little or none h >P None .ittle or none h None Little or none None done None ione Spasmolytic h None done Depression? A Spasmolytic A Spasmolytic A Equal to P? A Some h None g See Part 4 for details. h In animal experiments. Prolonged effect. i In animal experiments; clinical experience conflicting. k Clinical observation; decreased in animal experiments. I Of non-opiate type occasionally; no physical dependence. daily dose is not necessarily a reliable indicator of the strength of antitussive action. It is the amount which experience has shown to be optimal in most instances for the particular preparation and which should be interchangeable in efficacy with the average dose of any of the other preparations. Dihydrocodeine and ethylmorphine are essentially I codeine-like and mainly economic considerations govern their use as codeine alternates. Significant antitussive action has been demonstrated for pholcodine, caramiphen, dextromethorphan, pipa- zetate, clobutinol,l levopropoxyphene and benzo- natate. Others are included in the table which have been considered alternates for codeine but for which available evidence does not permit a firm judgment of significance in this respect. Still others have I Also known as Silomat. N. B. EDDY AND OTHERS been described in Part 4 as showing indication of antitussive action and these may have value as leads for future work. Other pharmacodynamic effects The majority of coughers suffer from an acute or chronic inflammation of the throat or deeper air- ways. Acute cases have a self-limiting illness mostly of short duration and in a great many of them cough could probably be relieved or would disappear with the taking of a simple syrup which contained no active drug (Boyd, 1946). Others with chronic cough may have little idea of the variation in their cough from day to day and may be un- aware of, or unable to judge with any reliability, the effects of antitussive drugs (Woolf & Rosenberg, 1964). In some cases of coughing a degree of adapta- tion occurs so that the patient becomes less aware of his cough and pays scant attention to it. On the contrary the apprehensive person may tend to exaggerate the intensity and severity of his cough (Bickerman, 1960). Coughing is undoubtedly an extremely complex phenomenon and tussal hyper- reflexia may be treated at other levels of the reflex arc than the centre and in other ways than by action on the cough reflex mechanism (Silvestrini & Pozzatti, 1960). Pharmacological effects discussed in association with the antitussive action of drugs are analgesic, sedative, respiratory depressant, euphoriant, spasmo- lytic, local anaesthetic and anti-inflammatory and it is difficult to establish the therapeutic significance of such associations, based mostly on results in animal experiments. On the other hand, antitussives that are highly specific in cough-depressing action and lack some or all of these other effects (dextro- methorphan, noscapine, clobutinol and others) have been employed successfully for the depression of cough of various origin. A multilocular action, including antitussive, analgesic and sedative effects, could be considered advantageous in special cases. An analgesic effect could be desirable if the cough were accompanied by pain. A sedative effect could support the anti- tussive action in apprehensive patients or if the cough were initiated or enhanced by central stimuli (" nervous " cough). Substances that have all of these therapeutic components are codeine, dihydro- codeine, ethylmorphine and normethadone. In asthmatic bronchitis combined antitussive and spasmolytic (bronchodilatory) therapy may be indicated occasionally. On the basis of animal experiments caramiphen, pentoxyverine, pipazetate, noscapine, isoaminile and oxolamine combine these pharmacodynamic effects. However, since the spasmolytic action of any of these is less powerful than that of epinephrine or isoprenaline, it would seem to be of minor practical importance. A drug possessing anti-inflammatory action in combination with antitussive efficacy would seem to be indicated theoretically in cases of acute or chronic cough originated by inflammation in the tussal reflexogenic area. Oxolamine, dextromethorphan and codeine have produced both actions in animal experiments, but again the additional effect seems hardly powerful enough. Oxolamine depresses cough in guinea-pigs at a dose of 10 or 20 mg per kg, intraperitoneally, but depression of experimentally produced inflammation requires 30 mg per kg by the same route (Silvestrini & Pozzatti, 1960). Other examples of combined actions, antitussive plus local anaesthetic, antitussive plus secretolytic, etc., though theoretically interesting have not been therapeutically verified. Undesired side-effects in cough therapy Side-effects which may be encountered with therapeutic doses of codeine are obviously of concern in the determination of suitability. Therapeutic doses administered for depression of cough are usually smaller than those for pain and, as a rule, the former are given orally and the latter paren- terally. For both reasons frequency and severity of side-effects would be expected to be, and are, less in the treatment of cough. Reports of side-effects with antitussive doses are summarized in Table 73. Cass & Frederik (1953, 1954) reported that drowsi- ness, nausea, vomiting and constipation were not more frequent with oral doses of not more than 20 mg of codeine than with placebo. Respiratory depression has been found to be significant with an oral dose of 60 mg of codeine (Bellville et al., 1958) but these authors discussed the contribution of indirect depression by codeine-induced drowsiness and sleep. A significant effect on blood pressure has not been observed after oral doses of codeine up to 90 mg, but the heart rate may be decreased. Again dihydrocodeine and ethylmorphine are very similar to codeine. Normethadone has been introduced into medicine only in combination with a sympathomimetic, which might convey an exhilarating effect, but animal experiments have shown a respiratory-depressant action and clinical experience generally has shown 726 CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 5 TABLE 73 SIDE-EFFECTS REPORTED WITH ANTITUSSIVE DOSES 0 0 0~~~~~~~~~~~~ 0 E :1%~~~ 0 0 0 D a 0 E >U 00 2 (D E_L 0 0 0 2 w ~ ~ ~ ~ ~ ~~~~~0~ a. . 0 o a. CO) Z 0 _j co 0 0 Drowsiness + + + + + + + + + + +a Dizziness + + + + + + + Lightheadedness + + Excitement + + + Restlessness + Insomnia + + Apprehension + Anorexia + + + + + Nausea + + + + + + + + + + Vomiting + + +b + +c + + + + Headache + + +b + + + + Tightness in chest + Abdominal discomfort + + +d + + + Constipation + + + + Diarrhoea + + + + + Urinary urgency + Visual disturbance + Sputum reduction + +e+ + Local reaction + +f +g + h + i +h,i +g,i Euphoria + a See Renovanz & Liebrich (1965). b With excessive dosage. c In accidental poisoning of a child, 180 mg. d Epigastric symptoms. e Modification not severe. f Allergic reactions; itching, erythema, urticaria, anaphylactic shock. g Erythema. h Skin rash. Skin rash, urticaria. Erythema, itching. some sedative effect. The other alternates do not differ substantially from codeine in the frequency of their side-effects. They are devoid, or practically devoid, of respiratory depressant activity. Some of them have produced circulatory effects in animal experiments related mainly to vasodilatation (3- methylamino-1,1-di-(2-thienyl)-but-l-ene, pentoxy- verine, dimethoxanate, noscapine, isoaminile, oxo- lamine), but the relation of such action to antitussive therapy is not important. Most of the other side- effects that have been seen (Table 73) have also occurred in placebo-treated patients and their frequency has rarely been weighed against their occurrence in the latter. The table is not quantitative; it is only a statement of what has been noted; for single substances this will be more complete the 727 N. B. EDDY AND OTHERS more extensively and thoroughly the compound has been examined. A few side-effects have been re- ported with alternates when there has been no com- parison with placebo or codeine-decreased visual acuity and urinary urgency (levopropoxyphene); apprehension (clofedanol); tightness in the chest (pentoxyverine); reduction of secretion (caramiphen, pentoxyverine, levopropoxyphene). In comparative studies no side-effect has been reported for codeine which has not been seen with another substance, with the exception of mild euphoria (and this has been seen with dihydrocodeine and normethadone). On the whole, potential codeine alternates have not produced serious side-effects, and those observed have not occurred with disturbing frequency. At the same time, it has not yet been shown conclusively that any of the newer drugs has advantages or disadvantages over codeine in respect of side-effects. Abuse liability Methadone and normethadone produce depend- ence of the morphine type; codeine, dihydrocodeine and ethylmorphine can do so also, but with quite different significance. Dextromethorphan and iso- aminile have been abused, sporadically. Methadone, it has been pointed out, is too morphine-like for any continued interest in its antitussive action. Nor- methadone has definitely greater abuse potential than codeine. The dependence-producing properties of codeine and dihydrocodeine have been fully discussed in Part 1 and in Part 2, respectively, and the abuse of dextromethorphan in Part 4. No evidence of ability to produce dependence of the morphine type, or instance of abuse has come to our attention with any of the other substances in Table 72, but we must continue to be alert in this connexion. Finally one needs to ask, as in an editorial in the British Medical Journal (1964), whether the anti- tussives available at present satisfy the expectations of physicians and patients. The editorial stressed again the frequency with which cough is due to an acute upper respiratory infection needing nothing more than a simple syrup for symptomatic relief and said: " If something more than this is required the well-established official preparations should be perfectly adequate, and there is at present no good reason for recommending any of the newer, more elegant and usually more expensive drugs." At the same time Doyle & Mehta (1964) expressed the firm belief: " . . . that newer synthetic antitussives signifi- cantly more potent than codeine will be discovered and, by virtue of their non-addiction liability and minimum side effects, will in course of time supplant the preparations employed today". Coughing is a mixed blessing. It can be a dis- tressing symptom, whose physiopathological effect, at the worst as in cough syncope, can be disastrous. Yet its importance as a diagnostic symptom is obvious and it is no exaggeration that its physio- logical function of clearing the bronchial tree of foreign matter is essential to life. One has only to contemplate the frequency with which unconscious- ness or weakness of the respiratory muscles is followed by aspiration pneumonia (Swyer, 1956). Cough depressants should smooth down the cough but not obliterate the activity of the reflex mechanism. The ideal antitussive might well be one which, although reducing the number of ineffective coughs, permits an adequate flow rate in the remaining coughs so as to aid bronchial drainage (Bickerman et al., 1957). At the same time in some circum- stances short-lived complete obliteration of the cough may be desirable, in endoscopies (such as laryngoscopy, bronchoscopy, oesophagoscopy) and in surgical procedures in the neighbourhood of the cough reflex area. The introduction of instruments into the trachea and bronchi causes forceful stimula- tion of mechanoreceptors quite different from the slowly increasing irritation of sensitive organs by inflammation or accumulation of secretions. One may wonder whether codeine or any of its alternates will, in safe dosage, reliably suppress such strong and sudden stimulation. Statements in the literature on this point are conflicting and there may be need for a stronger agent for this specific purpose. For most indications codeine is still that anti- tussive which is prescribed most frequently. A major factor supporting its popularity is the rarity of serious side-effects and of misuse. Another may be the combination of antitussive, pain-relieving and calming effects, perhaps appreciated by more physicians and patients than is generally realized. Observations of Gravenstein, Devloo & Beecher (1954), Woolf & Rosenberg (1964) and Renovanz & Liebrich (1965) support the importance of the psycho- logical element in the genesis of cough and of the suggestion of Swyer (1956) "... that the patient's satisfaction might have resulted from euphorogenic or hypnotic effects ". But since non-dependence-producing antitussives are available, is the very small risk of codeine dependence which may be connected with antitussive therapy outweighed by therapeutic preference? It is 728 CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 5 our opinion that the danger of development of dependence under the conditions of the usual cough- depressing regimen is so small and the advantage of its manifold actions sufficiently large that it would seem illogical to abandon the drug generally from antitussive therapy. However, if it is thought desirable to attempt to suppress a chronic cough, even low abuse liability may have more weight and one of the alternates may be preferred. On theoretical grounds several of the codeine alternates have these properties desired in a perfect cough depressant: (1) they possess significant cough-depressing potency; (2) they depress cough of different pathological origins; (3) their frequency of side-effects is no greater, perhaps less, than for codeine; and (4) they are devoid, or practically devoid, of abuse liability. For none of them, however, is our quantitative and practical knowledge complete enough to establish therapeutic priority. RltSUMlt LA CODtINE ET SES SUCCtDANIS SIDATIFS DE LA DOULEUR ET DE LA TOUX: 5. DISCUSSION ET RESUME La codeine et ses succ&dane's sedatifs de la douleur De faibles doses de codeine, administrees par voie orale, agissent sur les douleurs peu intenses d'origines tres diverses, mais il semble que l'efficacite du produit ne soit pas entierement satisfaisante car on lui associe tres frequemment de l'acide acetylsalicylique et de la phena- cetine. L'administration par voie orale entraine rarement des effets secondaires, et si les doses sont peu dlev&s I'accoutumance et la dependance de type morphinique n'apparaissent que tres lentement. Lorsque l'intensite de la douleur oblige a augmenter les doses, les reactions secondaires sont plus marquees et la d6pendance se manifeste plus rapidement, d'oiu la necessite de recherches poussees en vue de decouvrir un analgesique actif par voie orale donnant de meilleurs resultats. Les donnees experimentales recueillies dans le cadre de ces recherches n'ont pas permis jusqu'a present de deceler une substance dotee d'un pouvoir analgesique plus 6leve que celui de la codeine; aucun succ6dane n'est aussi efficace que cette dernire. C'est peut-etre parmi les antagonistes sp;cifiques des opiaces que l'on pourra trouver un produit susceptible de remplacer avantageuse- ment la codeine. Sous le rapport des effets secondaires, beaucoup des succedanes etudies supportent avec succes la comparaison avec la codeine, et on peut estimer qu'a cet 6gard certains progres ont e realises. Ce facteur ne doit cependant pas orienter de fa$on decisive le choix de l'un ou l'autre produit de remplacement, etant donne que l'emploi de la cod6ine n'est en aucune maniere limite par l'existence de reactions secondaires. En ce qui concerne l'aptitude a engendrer la depen- dance et l'abus, seule la dihydrocodeine fait preuve de propriet6s essentiellement semblables a celles de la codeine, tant du point de vue quantitatif que qualitatif. Tous les autres produits presentent a cet egard un leger avantage sur la codeine. A l'exception du propoxyphene, qui a ete le plus largement utilise et qui a donn6 lieu a quelques cas d'abus, les dventuels succ6danes de la codeine n'ont jamais ete accuses d'etre a l'origine d'em- plois abusifs et aucun d'entre eux n'a fait l'objet de mesures restrictives dans le cadre du contr8le des stupe- fiants. Neanmoins, si l'on en juge par sa vogue persistante aussi bien parmi les m6decins que dans le public - en depit de l'existence sur le marche de preparations dites * non toxiques * - il semble illogique d'abandonner un medicament comme la codeine qui tout en presen- tant des proprietes analgesiques et s6datives generales est aussi actif contre la toux. La codeine et ses succIdanrs sedatifs de la toux La grande variet6 des techniques et des criteres utilises par les differents chercheurs, ainsi que leurs divergences d'opinion, rendent particulierement ardu tout essai d'evaluation comparative des propri6tes sedatives de la toux de la codeine et de ses succedanes. On note cepen- dant une concordance satisfaisante entre les donnees recueillies au cours de l'utilisation therapeutique et les niveaux d'efficacite determines par l'experimentation sur des volontaires. La concordance entre les doses th6ra- peutiques et les doses efficaces chez l'animal est moins reguliere, mais les divergences concernent principalement les substances qui exigent des dosages superieurs a ceux de la codeine. L'activite de la dihydrocodeine et de l'ethylmorphine est essentiellement du meme ordre que celle de la codeine. La pholcodine, le caramiphene, le destromethorphane, le pipazetate, le clobutinol, le levopropoxyphene et le ben- zonatate font preuve d'une efficacit6 notable contre la toux. En general, la pholcodine, la normethadone et le caramiphene doivent etre administres A des doses infe- rieures aL celles de la codeine, la dihydrocodeine, l'ethyl- 729 730 N. B. EDDY AND OTHERS morphine et la nalorphine as des doses dquivalentes, et les autres succedanes a des doses superieures. D'autres substances paraissent dgalement dotees d'une certaine activite; elles permettront peut-etre d'orienter les futures recherches. D'autres effets pharmacologiques des mddicaments actifs contre la toux sont examines en connexion avec leur action specifique: effets analgesiques, calmants de la douleur, depresseurs de la respiration, euphorisants, spasmolytiques, anesthesiques locaux et anti-inflamma- toires. I1 est malaise d'apprecier l'interet therapeutique de ce genre d'associations, decelees principalement a l'occasion d'experimentations sur I'animal. On pourrait tirer parti, dans certaines indications, de la polyvalence d'activite therapeutique de medicaments efficaces contre la douleur et la toux et dotes par surcroit d'effets analgesiques. Parmi les substances rentrant dans cette categorie, il faut citer la codeine, la dihydrocodeine, 1'ethylmorphine et la normethadone. L'experimentation sur I'animal montre que le cara- miphene, la pentoxyverine, le pipazetate, la noscapine, l'isoaminile et l'oxalamine, ont en plus de leur action calmante sur la toux, une action spasmolytique. I1 est donc indique d'utiliser ces medicaments dans les cas de bronchite asthmatique, bien que leurs effets broncho- dilatateurs soient moins marques que ceux de certains agents adrenergiques. Dans l'ensemble, les eventuels succedanes de la codeine n'entrainent pas d'effets secondaires notables, et les reactions observees ne se produisent pas avec une fre- quence facheuse. Par ailleurs il n'est pas demontre de facon indiscutable que l'une ou l'autre de ces substances nouvelles presente a cet egard des avantages ou des inconvenients par rapport a la codeine. La methadone et la normethadone engendrent une dependance de type morphinique. L'usage de la codeine, de la dihydrocodeine et de 1'ethylmorphine comporte un risque semblable, mais dans une mesure beaucoup moindre. On a signale ici et la des cas d'emploi abusif du dextromethorphane et de l'isoaminile. Jusqu'a present, rien ne permet de penser que l'une quelconque des autres substances sedatives de la toux deja mentionnees cr6e une dependance de type morphinique ou soit a l'origine d'abus. Dans la plupart des indications, la codeine reste le medicament sedatif de la toux le plus frequemment prescrit. Son succes est dCi au fait qu'elle est rarement a l'origine de reactions secondaires ou d'abus et qu'en outre elle associe 'a son action calmante sur la toux des effets sedatifs generaux. En theorie, plusieurs des succ& danes de la codeine possedent les qualites exigees d'un medicament veritablement actif contre la toux: efficacite marquee, quelle que soit l'affection qui provoque le reflexe; frequence d'effets secondaires egale ou meme inferieure a celle des reactions succedant a l'emploi de la codeine; et impuissance quasi totale 'a engendrer l'abus. 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