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Nathan B. Eddy, Hans Friebel, Klaus-Jiirgen Hahn & Hans Halbach WORLD HEALTH ORGANIZATION ORGANISATION .MONDIALE DE LA SANT~ GENl:VE 1970 © World Health Organization 1970 Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. Nevertheless governmental agencies or learned and professional societies may reproduce data or excerpts or illustrations from them without requesting an authorization from the World Health Organization. For rights of reproduction or translation of WHO publications in toto, application should be made to the Division of Editorial and Reference Services, World Health Organization, Geneva, Switzerland. The World Health Organization welcomes such applications. Authors alone are responsible for views expressed in signed articles. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Director-General of the World Health Organization concerning the legal status of any country or territory or of its authorities, or concerning the delimitation of its frontiers. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. © Organisation mondiale de la Sante 1970 Les publications de l'Organisation mondiale de la Sante beneficient de la protection prevue par les dispositions du Protocole n° 2 de la Convention universelle pour la Protection du Droit d'Auteur. Les institutions gouvernementales et les societes savantes ou professionnelles peuvent, toutefois, reproduire des donnees, des extraits ou des illustrations provenant de ces publications, sans en demander l'autorisation a l'Organisation mondiale de la Sante. Pour toute reproduction ou traduction integrate, une autorisation doit etre demandee a la Division des Services d'Edition et de Documentation, Organisation mondiale de la Sante, Geneve, Suisse. L'Organi­ sation mondiale de la Sante sera toujours tres heureuse de recevoir des demandes a cet effet. Les articles signes n'engagent que Jeurs auteurs. Les designations utilisees dans cette publication et la presentation des donnees qui y figurent n'impli­ quent de la part du Directeur general de I' Organisation mondiale de la Sante aucune prise de position quant au statutjuridique de tel ou tel pays ou territoire, ou de ses autorites, ni quant au trace de ses frontieres. Sauf erreur ou omission, une majuscule initiate indique qu'il s'agit d'un nom depose. PRINTED IN SWITZERLAND CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF NATHAN B. EDDY, M.D. Consultant, National Institutes of Health, Bethesda, Md., USA HANS FRIEBEL, Dr.med. Chief, Drug Safety, World Health Organization, Geneva, Switzerland KLAUS-JURGEN HAHN, Dr.med. Department of Medicine, University of Heidelberg, Germany HANS HALBACH, Dr.med., Dr.-Ing. Director, Division of Pharmacology and Toxicology, World Health Organization, Geneva, Switzerland Page 1. Codeine, exclusive of its antitussive action . 3 2. Alternates for pain relief . 73 3. The antitussive action of codeine-mechanism, methodology and evaluation 127 4. Potential alternates for cough relief 157 5. Discussion and summary 239 Subject index . 249 WORLD HEALTH ORGANIZATION ORGANISATION MONDIALE DE LA SANT£ GENEVE 1970 This review of the analgesic and antitussive effects of codeine and its alternates was originally published, in five instalments, in the Bulletin of the World Health Organization (1968, 38, 673-741; 1969,40, 1-53; 1969,40, 425-454; 1969,40,639-719: 1969, 40, 721-730). Codeine and its Alternates for Pain and Cough Relief 1. Codeine, Exclusive of its Antitussive Action This report-the first ofa series on codeine and its alternates for pain and cough relief­ presents a detailed evaluation of experimental and clinical data concerning the analgesic action of codeine (the antitussive action will be assessed separately). The authors discuss the pharmacology of the drug, including side-effects and toxicity; effects on the respiratory, circulatory, digestive and urinary systems; tolerance, dependence and liability to abuse; metabolic effects; and mechanism ofaction. Though codeine is generally more toxic than morphine to animals on account of its convulsant action, it is less toxic to man, possibly because it produces less respiratory depression. Again, tolerance to its analgesic effects has been demonstrated in several animal species, but dependence in man is observed far less frequently than it is with morphine, and the abstinence syndrome is less intense. From their extensive review of the evidence available, the authors conclude that codeine is a good analgesic and that little risk to public health is likely to arise from its clinical use to relieve pain. CONTENTS INTRODUCTION • • • • 3 EFFECT ON BLOOD ENZYMES AND OTHER ENZYME ANALGESIC ACTION • • 6 SYSTEMS ..••. 37 SEDATIVE ACTION AND OTHER EFFECTS ON THE METABOLIC EFFECTS 39 NERVOUS SYSTEM • • • . • • • • 23 TOXICITY ...•. 4() SIDE-EFFECTS AND TOXIC REACTIONS 25 TOLERANCE, DEPENDENCE AND ABUSE LIABILITY 45 RESPIRATORY EFFECT •••• 31 METABOLISM OF CODEINE 58 CIRCULATORY EFFECT • • • • 33 EFFECT ON GASTROINTESTINAL TRACT AND OTHER RESUME •• 62 SMOOTH MUSCLE 34 REFERENCES 63 INTRODUCTION loid as the methyl ether of morphine was not Codeine, C1sH210aN, the methyl ether of mor­ established until 1881 (Grimaux, 1881), although phine, was first isolated in 1832 by Robiquet speculation to this effect had appeared earlier (1832, 1833), who found it as an impurity accom­ (Matthiesson & Wright, 1870; Wright, 1872). panying morphine which had been extracted from Codeine is found in opium in much smaller opium. Gerhardt (1842, 1843) was the first to amount than morphine, usually between 0.2% and obtain analytical values corresponding to the true 0.8 %. It has not been reported as appearing in empirical formula, but the character of the alka- any plant other than the poppy and has been 8l594 -3 4 N. B. EDDY AND OTHERS found in only two species of Papaveraceae. It is an increasing rate as time went on. In 1928, in the the second alkaloid to appear in the young plant, USA alone, the consumption of codeine amounted being detectable about 30 days after the seed to 3844 kg (US Treasury Department, Bureau of has sprouted. According to Rapport, Stermitz & Narcotics, 1928). In 1934, the first year for which Baker (1960), the sequence in biosynthesis, con­ figures are available, world manufacture of co­ firmed by feeding experiments with radioactive deine totalled 17 tons (Permanent Central Opium material, is thebaine to codeine to morphine. Board, 1948); in 1947, 42 tons (Permanent Central Poppy seeds do not contain codeine (Kerbosch, Opium Board, 1949); in 1953, 67 tons; and in 1910). 1963, 118 tons (Permanent Central Opium Board, The first therapeutic trials of codeine were re­ 1964). In the USA, with a population increase ported in 1834. Barbier (1834), having given doses of about 50% from 1928 to 1963, codeine con­ of one or two grains orally, noted the occurrence sumption increased almost fivefold, to 18 877 kg. of slc~p without a feeling of heaviness, pain relief Initially, of course, codeine was derived from in some cases and euphoria on one occasion; Mar­ opium, but, as therapeutic needs increased, it was tin (1834) reported improvement in tubercular obtained more and more by conversion of mor­ cough after only one quarter of a grain of codeine phine. Of the reported world manufacture of orally; and Gregory (1834) of Edinburgh seems to morphine, 65% was converted to codeine in 1934, have performed the first clinical pharmacological 80% in 1948, and slightly more than 90% in 1963. experiment with codeine. He gave it as the citrate A United States Pharmacopeia and National to some of his students and said that three grains Formulary survey of 10 000 prescriptions in 1931- orally had no effect, but that six grains caused 32 revealed that codeine was an ingredient in just acceleration of the pulse, a feeling of warmth under 900 of them. In 1940, at a meeting of the about the head and an exhilaration of the spirit. American Pharmaceutical Association in Rich­ There was also generalized itching, and later de­ mond, Va., M. J. Andrews reported that another pression, nausea and vomiting. Robiquet (1834), survey, covering 19 000 prescriptions, listed co­ who placed great importance on the role of co­ deine as an ingredient in 2190 per 10 000. This deine in the action of opium, was surprised that later survey covered the states of Maryland, Penn­ Gregory saw so little effect and attributed this to sylvania, Ohio, Virginia, West Virginia and the the use of a salt instead of the free base. Gregory District of Columbia. In later tabulations the fre­ may have used a very impure sample of codeine quency of codeine-containing prescriptions was or, not too unlikely at that time, his students may lower, but such prescriptions still appeared well up have been using opium, so that this was a very on the list of popular remedies (FDC Reports, early record of cross-tolerance. Probably for simi­ 1965), and today codeine continues to be one of lar reasons, Garrod •(1864) also failed to obtain an the drugs most often used in medical practice. analgesic effect even with doses of five grains of Currently, 60-75% of the codeine used in the USA codeine. Later, when effects with codeine were is in analgesic medication and only about 25% obtained, there was a very general belief that these in cough mixtures (estimate of the US Bureau of were due to the presence of morphine as a con­ Narcotics), but 25% is almost 5000 kg, or more taminant, hence the weak and variable action (cf. than 70 000 000 fluid ounces of cough syrup. the current suggestion (Adler, 1962, 1963 ; San­ There has been a levelling-off trend in the world filippo, 1953b; Johannesson & Schou, 1963), consumption of codeine in recent years (Perma­ supported in part by the studies of metabolites, nent Central Opium Board, 1964), but the con­ that codeine acts mainly through the morphine sumption remains high-a fact that is the more produced by demethylation in vivo).

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