Bull. Org. mond. Sante 1969, Bull. Wid Hitha Org. 40, 721-730
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 OTHR PHARMACODYNAMIC ECTS .... . 726 ANALGESIC ACTION ...... 721 UNDESIRE SIDE-EFFECTS IN COUGH THERAPY 726 SIDE-EFFECTS ...... 723 ABUSE LIABILITY ...... 728 DEPENDENCE AND ABUSE LIABILITY .... . 723
.ui ...... 729 CODEINE AND ITS ALTERNATES FOR COUGH RELIEF
ANTTrussIVE ACrION...... 723 RERENCEs ...... 730
Effectiveness and lack of undesirable side-effects, CODEI AND I ALTERNATES FOR PAN RELEF including tolerance, dependence and abuse liability, are obviously the leading characteristics to be consid- Analgesic action ered in the evaluation of codeine and its potential alternates. In the preceding parts of this article the It was pointed out in Part I of this review that information available on these characteristics for the greater part of the world's supply of codeine was many different drugs has been reviewed. It remains to used for pain relief, generally alone, if the route of survey the picture as a whole in an attempt to assess administration was parenteral, but often. in combi- whether an alternate is needed and, if so, to consider nation with APC or aspirin if the route was oral. It the progress that has been made in the search for one has been shown that codeine can, at a price, equal the that is adequate. 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, University first four instalments dealt, respectively, with the analgesic ' Profer Drug action of codeine (Bull. WId Hlth Org., 1968, 38, 673-741); of Heidelberg, GermacologyGermany. Presentaddress:cology,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 - 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 and broader pain control; even first-aid kits could more powerful analgesic agents to choose from for then contain adequate medication for the relief of parenteral administration, and taking into account severe pain in emergencies and the cost of drugs for the size of the dose required to equal the effects of the treatment of many painful conditions and the morphine it would be difficult to establish an cost of special care would be greatly reduced. These advantage for codeine. considerations certainly justify an intensive search for Moderate oral doses ofcodeine are effective against a better oral medication. moderate pain of many origins, probably not as Table 71 summarizes the analgesic effectiveness effective as we could wish, since the codeine is so and other data for some of the compounds produced frequently combined with APC in the hope that the so far; all these compouds were reviewed in Part 2 as effects of the two will be additive. The frequency of potential codeine alternates. The figures in Table 71 side-effects with oral doses is low and if moderate are our best estimates from the data reviewed. doses suffice then tolerance and dependence develop These figures are not impressive as far as any very slowly (Cass, Laing & Frederik, 1961, personal increase in analgesic potency is concerned; none of communication, 1963). Oral doses of codeine can the agents is more effective than codeine. Appar- produce respiratory depression, however (Bellville ently we have made no progress so far towards the et al., 1958). If the pain is severe, and large doses relief of severe pain via the oral route. Dextropro- must be used, the occurrence of side-effects will poxyphene is nearly always given with APC, and increase and dependence will develop more rapidly. ethoheptazine with aspirin, yet the combinations Oral administration has many advantages, but hardly equal codeine in the relief of mild to moderate there are conditions in which it is not feasible. If pain. All of these agents could be used where oral it were as effective and as safe as we would like it to codeine is indicated, but they offer no advantage in be, the physician's hands would be freed for better the production of greater comfort. On the basis of the figures presented, metofoline might equal codeine, 1 Houde, R. W. et al. (1960) Reported to the Committee not introduced into general medi- on Drug Addiction and Narcotics, National Academy of but it has yet been Sciences, Washington, D.C., USA, p. 2312. cal practice. The specific opiate antagonists have not CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 5 723 been included in the table, but among them may lie properties which are helpful in relieving the discomfort our best lead towards future improvement. often associated with a cough ... Codeine serves a need which is not presently met by other substances; ... [the Side-effects evidence] hardly justifies discontinuing its availability. In most cases the substances listed in Table 73 Seevers was thinking of reported abuse of codeine compare favourably with codeine in their production antitussive preparations, but his remarks are applic- of side-effects; some small advantage may have been able to the use of codeine generally. So we think it gained in this respect. Even with fenyramidol and fair to say that there are other substances available prodilidine the difference in the other direction is that could be used as alternates for codeine, except probably not great enough to prevent their use, if perhaps where analgesia, cough relief and sedation there were other advantages. The use of codeine are required simultaneously, but that the use of itself, however, is not limited to any great extent by these other substances would result in no particular its side-effects, so that this can hardly be a deciding gain and probably no particular loss. Let us, factor in choosing between agents. however, continue to strive for better oral analgesia. Dependence and abuse liability Dihydrocodeine is quantitatively and qualitatively CODEINE AND ITS ALTERNATES FOR COUGH RELIEF similar to codeine in this respect. The other agents in Table 72, however, may all have some slight Antitussive action advantage over codeine in respect of abuse liability. The sizes of the average single and daily doses of Except for propoxyphene, which has been used much a substance in any cough therapy are criteria which more extensively than any of the others, and for indicate the efficacy of its cough-depressing action. which a few cases of abuse have been reported, Other criteria are the onset and duration of effect, abuse of the other potential codeine alternates has the course of the dose-response curve and charac- not come to our attention and narcotics control has teristics of action in terms of change in the frequency not been recommended for any of them. This is not and intensity of coughing. Though the latter factors a very great advantage, however, as the restrictions are perhaps less easily determined, they are of real on the use of codeine are slight and are enforced importance in the evaluation of the total antitussive only in certain places. effect. For example, benzonatate differed from many Although codeine is not the ideal oral analgesic other antitussives because of its sustained cough- and we should certainly keep looking for better ones, depressing action, and homarylamine showed an we should keep in mind the considered judgment increasing effectiveness from 10 to 20 mg, but no which Wolff (1938) expressed 30 years ago: "In further increase from 20 to 40 mg (Bickerman & view of the vast and justified extension of codeine Itkin, 1960). consumption throughout the world for several Patients can assess a diminution in both severity decades, the few primary and secondary cases [of and frequency of cough attacks and their subjective dependence on it] together cannot be regarded as a judgnent of a drug can be expected to include an danger topublic health ", to which he added "... wheth- integration of both effects. On the other hand, er the medical use ofcodeine is a social danger may be mechanical registration of cough (sound recording, answered in the negative ... The medical practitioner etc.) usually deals only with cough frequency. should not be alarmed .., and should not allow Therefore, results regarding these effects which are himself to be deterred from prescribing codeine based on subjective experience are not necessarily freely in the usual small therapeutic doses." Seevers comparable with others based on mechanical (1967) has recently summed up the situation by recording. A comparison of antitussive effectiveness saying that codeine can be replaced in certain between codeine and its alternates, as well as among specified and limited situations, but: the alternates, is made exceedingly difficult by the Judging from the continued popularity of codeine wide differences in techniques, criteria and judge- among physicians and laymen alike throughout the ments that have been used. Nevertheless, the data world in spite of the easy availability of the so-called collected in Table 72 give our best estimate from all I non-toxic ' preparations it seems illogical to abandon a sources of the average cough-depressing doses and drug like codeine which possesses, in one agent, not only related activities. Single and daily doses adminis- antitussive properties but also pain relief and sedative tered in therapy correspond fairly well with the 724 N. B. EDDY AND OTHERS TABl CHARACTERISTICS OF CODEINE ALTERNATES A Dosage (mg) Oth Agent Therapeutic ~ HatyAia Single Daily volunteersc experimentsd Analgesia | Sedation (±) Methadone 2.5 7.5 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 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 The therapeutic antitussive doses of codeine, volunteers. A major exception is Bickerman's summarized in an earlier table (Part 3, Table 29), (Bickerman et al., 1957) failure to show effectiveness permit the estimation of average oral doses of of normethadone in normal subjects. Doses used in 20 mg and 70 mg, single and daily, respectively, for therapy do not correspond as well with the effective adults. Table 72 shows that pholcodine, norme- doses in animal experiments, but the exceptions thadone and caramiphen would generally be used are mainly among the agents which must be ad- in smaller doses, dihydrocodeine, ethylmorphine ministered in higher doses than are required for and nalorphine in equal doses, and the others in codeine. higher doses than codeine. The average single or CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 5 725 H TITUSSIVES COMPARED WITH THOSE OF CODEINE a armacodynamic actions, relative to codeine Bronchial Lcl Anti- Abs Respiratory Circulatory Gastro-intestinal anaesthetico inflam- liabilityf Musculature Secretion aeshtc matory laiiy =M =M 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 antitussive action has been demonstrated for the strength of antitussive action. It is the amount pholcodine, caramiphen, dextromethorphan, pipa- which experience has shown to be optimal in most zetate, clobutinol,l levopropoxyphene and benzo- instances for the particular preparation and which natate. Others are included in the table which have should be interchangeable in efficacy with the been considered alternates for codeine but for which average dose of any of the other preparations. available evidence does not permit a firm judgment Dihydrocodeine and ethylmorphine are essentially of significance in this respect. Still others have I codeine-like and mainly economic considerations govern their use as codeine alternates. Significant I Also known as Silomat. 726 N. B. EDDY AND OTHERS been described in Part 4 as showing indication of experiments caramiphen, pentoxyverine, pipazetate, antitussive action and these may have value as leads noscapine, isoaminile and oxolamine combine these for future work. pharmacodynamic effects. However, since the spasmolytic action of any of these is less powerful Other pharmacodynamic effects than that of epinephrine or isoprenaline, it would The majority of coughers suffer from an acute or seem to be of minor practical importance. chronic inflammation of the throat or deeper air- A drug possessing anti-inflammatory action in ways. Acute cases have a self-limiting illness combination with antitussive efficacy would seem to mostly of short duration and in a great many of be indicated theoretically in cases of acute or chronic them cough could probably be relieved or would cough originated by inflammation in the tussal disappear with the taking of a simple syrup which reflexogenic area. Oxolamine, dextromethorphan contained no active drug (Boyd, 1946). Others with and codeine have produced both actions in animal chronic cough may have little idea of the variation experiments, but again the additional effect seems in their cough from day to day and may be un- hardly powerful enough. Oxolamine depresses aware of, or unable to judge with any reliability, cough in guinea-pigs at a dose of 10 or 20 mg per kg, the effects of antitussive drugs (Woolf & Rosenberg, intraperitoneally, but depression of experimentally 1964). In some cases of coughing a degree of adapta- produced inflammation requires 30 mg per kg by tion occurs so that the patient becomes less aware the same route (Silvestrini & Pozzatti, 1960). of his cough and pays scant attention to it. On the Other examples of combined actions, antitussive contrary the apprehensive person may tend to plus local anaesthetic, antitussive plus secretolytic, exaggerate the intensity and severity of his cough etc., though theoretically interesting have not been (Bickerman, 1960). Coughing is undoubtedly an therapeutically verified. extremely complex phenomenon and tussal hyper- reflexia may be treated at other levels of the reflex Undesired side-effects in cough therapy arc than the centre and in other ways than by action Side-effects which may be encountered with on the cough reflex mechanism (Silvestrini & therapeutic doses of codeine are obviously of concern Pozzatti, 1960). in the determination of suitability. Therapeutic Pharmacological effects discussed in association doses administered for depression of cough are with the antitussive action of drugs are analgesic, usually smaller than those for pain and, as a rule, sedative, respiratory depressant, euphoriant, spasmo- the former are given orally and the latter paren- lytic, local anaesthetic and anti-inflammatory and terally. For both reasons frequency and severity of it is difficult to establish the therapeutic significance side-effects would be expected to be, and are, less in of such associations, based mostly on results in the treatment of cough. Reports of side-effects with animal experiments. On the other hand, antitussives antitussive doses are summarized in Table 73. that are highly specific in cough-depressing action Cass & Frederik (1953, 1954) reported that drowsi- and lack some or all of these other effects (dextro- ness, nausea, vomiting and constipation were not methorphan, noscapine, clobutinol and others) more frequent with oral doses of not more than have been employed successfully for the depression 20 mg of codeine than with placebo. Respiratory of cough of various origin. depression has been found to be significant with an A multilocular action, including antitussive, oral dose of 60 mg of codeine (Bellville et al., 1958) analgesic and sedative effects, could be considered but these authors discussed the contribution of advantageous in special cases. An analgesic effect indirect depression by codeine-induced drowsiness could be desirable if the cough were accompanied and sleep. A significant effect on blood pressure has by pain. A sedative effect could support the anti- not been observed after oral doses of codeine up to tussive action in apprehensive patients or if the 90 mg, but the heart rate may be decreased. Again cough were initiated or enhanced by central stimuli dihydrocodeine and ethylmorphine are very similar (" nervous " cough). Substances that have all of to codeine. these therapeutic components are codeine, dihydro- Normethadone has been introduced into medicine codeine, ethylmorphine and normethadone. only in combination with a sympathomimetic, which In asthmatic bronchitis combined antitussive and might convey an exhilarating effect, but animal spasmolytic (bronchodilatory) therapy may be experiments have shown a respiratory-depressant indicated occasionally. On the basis of animal action and clinical experience generally has shown CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 5 727 TABLE 73 SIDE-EFFECTS REPORTED WITH ANTITUSSIVE DOSES 0 0 0~~~~~~~~~~~~ 0 E :1%~~~ 0 0 0 0 D 2 (Da 0E_LE 0 >U 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 lamine), but the relation of such action to antitussive differ substantially from codeine in the frequency of therapy is not important. Most of the other side- their side-effects. They are devoid, or practically effects that have been seen (Table 73) have also devoid, of respiratory depressant activity. Some of occurred in placebo-treated patients and their them have produced circulatory effects in animal frequency has rarely been weighed against their experiments related mainly to vasodilatation (3- occurrence in the latter. The table is not quantitative; methylamino-1,1-di-(2-thienyl)-but-l-ene, pentoxy- it is only a statement of what has been noted; for verine, dimethoxanate, noscapine, isoaminile, oxo- single substances this will be more complete the 728 N. B. EDDY AND OTHERS more extensively and thoroughly the compound has and, by virtue of their non-addiction liability and been examined. A few side-effects have been re- minimum side effects, will in course of time supplant ported with alternates when there has been no com- the preparations employed today". parison with placebo or codeine-decreased visual Coughing is a mixed blessing. It can be a dis- acuity and urinary urgency (levopropoxyphene); tressing symptom, whose physiopathological effect, apprehension (clofedanol); tightness in the chest at the worst as in cough syncope, can be disastrous. (pentoxyverine); reduction of secretion (caramiphen, Yet its importance as a diagnostic symptom is pentoxyverine, levopropoxyphene). In comparative obvious and it is no exaggeration that its physio- studies no side-effect has been reported for codeine logical function of clearing the bronchial tree of which has not been seen with another substance, foreign matter is essential to life. One has only to with the exception of mild euphoria (and this has contemplate the frequency with which unconscious- been seen with dihydrocodeine and normethadone). ness or weakness of the respiratory muscles is On the whole, potential codeine alternates have followed by aspiration pneumonia (Swyer, 1956). not produced serious side-effects, and those observed Cough depressants should smooth down the cough have not occurred with disturbing frequency. At the but not obliterate the activity ofthe reflex mechanism. same time, it has not yet been shown conclusively The ideal antitussive might well be one which, that any of the newer drugs has advantages or although reducing the number of ineffective coughs, disadvantages over codeine in respect of side-effects. permits an adequate flow rate in the remaining coughs so as to aid bronchial drainage (Bickerman Abuse liability et al., 1957). At the same time in some circum- Methadone and normethadone produce depend- stances short-lived complete obliteration of the ence of the morphine type; codeine, dihydrocodeine cough may be desirable, in endoscopies (such as and ethylmorphine can do so also, but with quite laryngoscopy, bronchoscopy, oesophagoscopy) and different significance. Dextromethorphan and iso- in surgical procedures in the neighbourhood of the aminile have been abused, sporadically. Methadone, cough reflex area. The introduction of instruments it has been pointed out, is too morphine-like for any into the trachea and bronchi causes forceful stimula- continued interest in its antitussive action. Nor- tion of mechanoreceptors quite different from the methadone has definitely greater abuse potential slowly increasing irritation of sensitive organs by than codeine. The dependence-producing properties inflammation or accumulation of secretions. One of codeine and dihydrocodeine have been fully may wonder whether codeine or any of its alternates discussed in Part 1 and in Part 2, respectively, and will, in safe dosage, reliably suppress such strong and the abuse of dextromethorphan in Part 4. No sudden stimulation. Statements in the literature on evidence of ability to produce dependence of the this point are conflicting and there may be need for morphine type, or instance of abuse has come to our a stronger agent for this specific purpose. attention with any of the other substances in For most indications codeine is still that anti- Table 72, but we must continue to be alert in this tussive which is prescribed most frequently. A connexion. major factor supporting its popularity is the rarity of Finally one needs to ask, as in an editorial in the serious side-effects and of misuse. Another may be British Medical Journal (1964), whether the anti- the combination of antitussive, pain-relieving and tussives available at present satisfy the expectations calming effects, perhaps appreciated by more of physicians and patients. The editorial stressed physicians and patients than is generally realized. again the frequency with which cough is due to an Observations of Gravenstein, Devloo & Beecher acute upper respiratory infection needing nothing (1954), Woolf & Rosenberg (1964) and Renovanz & more than a simple syrup for symptomatic relief and Liebrich (1965) support the importance ofthe psycho- said: " If something more than this is required the logical element in the genesis of cough and of the well-established official preparations should be suggestion of Swyer (1956) "... that the patient's perfectly adequate, and there is at present no good satisfaction might have resulted from euphorogenic reason for recommending any of the newer, more or hypnotic effects ". elegant and usually more expensive drugs." At the But since non-dependence-producing antitussives same time Doyle & Mehta (1964) expressed the firm are available, is the very small risk of codeine belief: " . . . that newer synthetic antitussives signifi- dependence which may be connected with antitussive cantly more potent than codeine will be discovered therapy outweighed by therapeutic preference? It is CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 5 729 our opinion that the danger of development of (1) they possess significant cough-depressing dependence under the conditions of the usual cough- potency; depressing regimen is so small and the advantage of (2) they depress cough of different pathological its manifold actions sufficiently large that it would origins; seem illogical to abandon the drug generally from (3) their frequency of side-effects is no greater, antitussive therapy. However, if it is thought perhaps less, than for codeine; and desirable to attempt to suppress a chronic cough, even low abuse liability may have more weight and (4) they are devoid, or practically devoid, of abuse one of the alternates may be preferred. liability. On theoretical grounds several of the codeine For none of them, however, is our quantitative and alternates have these properties desired in a perfect practical knowledge complete enough to establish cough depressant: 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 avantage sur la codeine. A l'exception du propoxyphene, De faibles doses de codeine, administrees par voie qui a ete le plus largement utilise et qui a donn6 lieu a orale, agissent sur les douleurs peu intenses d'origines quelques cas d'abus, les dventuels succ6danes de la tres diverses, mais il semble que l'efficacite du produit ne codeine n'ont jamais ete accuses d'etre a l'origine d'em- soit pas entierement satisfaisante car on lui associe tres plois abusifs et aucun d'entre eux n'a fait l'objet de frequemment de l'acide acetylsalicylique et de la phena- mesures restrictives dans le cadre du contr8le des stupe- cetine. L'administration par voie orale entraine rarement fiants. Neanmoins, si l'on en juge par sa vogue persistante des effets secondaires, et si les doses sont peu dlev&s aussi bien parmi les m6decins que dans le public - en I'accoutumance et la dependance de type morphinique depit de l'existence sur le marche de preparations dites n'apparaissent que tres lentement. Lorsque l'intensite de * non toxiques * - il semble illogique d'abandonner la douleur oblige a augmenter les doses, les reactions un medicament comme la codeine qui tout en presen- secondaires sont plus marquees et la d6pendance se tant des proprietes analgesiques et s6datives generales manifeste plus rapidement, d'oiu la necessite de recherches est aussi actif contre la toux. poussees en vue de decouvrir un analgesique actif par voie orale donnant de meilleurs resultats. La codeine et ses succIdanrs sedatifs de la toux Les donnees experimentales recueillies dans le cadre La grande variet6 des techniques et des criteres utilises de ces recherches n'ont pas permis jusqu'a present de par les differents chercheurs, ainsi que leurs divergences deceler une substance dotee d'un pouvoir analgesique d'opinion, rendent particulierement ardu tout essai plus 6leve que celui de la codeine; aucun succ6dane n'est d'evaluation comparative des propri6tes sedatives de la aussi efficace que cette dernire. C'est peut-etre parmi les toux de la codeine et de ses succedanes. On note cepen- antagonistes sp;cifiques des opiaces que l'on pourra dant une concordance satisfaisante entre les donnees trouver un produit susceptible de remplacer avantageuse- recueillies au cours de l'utilisation therapeutique et les ment la codeine. niveaux d'efficacite determines par l'experimentation sur Sous le rapport des effets secondaires, beaucoup des des volontaires. La concordance entre les doses th6ra- succedanes etudies supportent avec succes la comparaison peutiques et les doses efficaces chez l'animal est moins avec la codeine, et on peut estimer qu'a cet 6gard certains reguliere, mais les divergences concernent principalement progres ont e realises. Ce facteur ne doit cependant pas les substances qui exigent des dosages superieurs a ceux orienter de fa$on decisive le choix de l'un ou l'autre de la codeine. produit de remplacement, etant donne que l'emploi de la L'activite de la dihydrocodeine et de l'ethylmorphine cod6ine n'est en aucune maniere limite par l'existence de est essentiellement du meme ordre que celle de la codeine. reactions secondaires. La pholcodine, le caramiphene, le destromethorphane, le En ce qui concerne l'aptitude a engendrer la depen- pipazetate, le clobutinol, le levopropoxyphene et le ben- dance et l'abus, seule la dihydrocodeine fait preuve de zonatate font preuve d'une efficacit6 notable contre la propriet6s essentiellement semblables a celles de la toux. En general, la pholcodine, la normethadone et le codeine, tant du point de vue quantitatif que qualitatif. caramiphene doivent etre administres A des doses infe- Tous les autres produits presentent a cet egard un leger rieures aL celles de la codeine, la dihydrocodeine, l'ethyl- 730 N. B. EDDY AND OTHERS morphine et la nalorphine as des doses dquivalentes, et les quence facheuse. Par ailleurs il n'est pas demontre de autres succedanes a des doses superieures. D'autres facon indiscutable que l'une ou l'autre de ces substances substances paraissent dgalement dotees d'une certaine nouvelles presente a cet egard des avantages ou des activite; elles permettront peut-etre d'orienter les futures inconvenients par rapport a la codeine. recherches. La methadone et la normethadone engendrent une D'autres effets pharmacologiques des mddicaments dependance de type morphinique. L'usage de la codeine, actifs contre la toux sont examines en connexion avec de la dihydrocodeine et de 1'ethylmorphine comporte un leur action specifique: effets analgesiques, calmants de la risque semblable, mais dans une mesure beaucoup douleur, depresseurs de la respiration, euphorisants, moindre. On a signale ici et la des cas d'emploi abusif du spasmolytiques, anesthesiques locaux et anti-inflamma- dextromethorphane et de l'isoaminile. Jusqu'a present, toires. I1 est malaise d'apprecier l'interet therapeutique rien ne permet de penser que l'une quelconque des autres de ce genre d'associations, decelees principalement a substances sedatives de la toux deja mentionnees cr6e l'occasion d'experimentations sur I'animal. une dependance de type morphinique ou soit a l'origine On pourrait tirer parti, dans certaines indications, de d'abus. la polyvalence d'activite therapeutique de medicaments Dans la plupart des indications, la codeine reste le efficaces contre la douleur et la toux et dotes par surcroit medicament sedatif de la toux le plus frequemment d'effets analgesiques. Parmi les substances rentrant dans prescrit. Son succes est dCi au fait qu'elle est rarement a cette categorie, il faut citer la codeine, la dihydrocodeine, l'origine de reactions secondaires ou d'abus et qu'en 1'ethylmorphine et la normethadone. outre elle associe 'a son action calmante sur la toux des L'experimentation sur I'animal montre que le cara- effets sedatifs generaux. En theorie, plusieurs des succ& miphene, la pentoxyverine, le pipazetate, la noscapine, danes de la codeine possedent les qualites exigees d'un l'isoaminile et l'oxalamine, ont en plus de leur action medicament veritablement actif contre la toux: efficacite calmante sur la toux, une action spasmolytique. I1 est marquee, quelle que soit l'affection qui provoque le donc indique d'utiliser ces medicaments dans les cas de reflexe; frequence d'effets secondaires egale ou meme bronchite asthmatique, bien que leurs effets broncho- inferieure a celle des reactions succedant a l'emploi de dilatateurs soient moins marques que ceux de certains la codeine; et impuissance quasi totale 'a engendrer agents adrenergiques. l'abus. I1 reste qu'aucun d'entre eux n'a fait l'objet d'une Dans l'ensemble, les eventuels succedanes de la codeine etude suffisamment complete pour que l'on puisse fixer n'entrainent pas d'effets secondaires notables, et les un ordre des priorites en matiere d'utilisation thera- reactions observees ne se produisent pas avec une fre- peutique. REFERENCES Bellville, J. W. et al. (1958) Anesthesiology, 19, 545 Doyle, F. P. & Mehta, M. D. (1964) Advanc. Drug Bickerman, H. A. et al. (1957) Amer. J. med. Sci., 234, Res., 1, 107 191 Eddy, N. B., Halbach, H. & Braenden, 0. J. 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