Bull. Org. mond. Sat 1969, 40, 425-454 Bull. Wid Hithi Org.f Codeine and its Alternates for Pain and Cough Relief* 3. The Antitussive Action of Codeine- Mechanism, Methodology and Evaluation NATHAN B. EDDY, M.D.,1 HANS FRIEBEL, Dr. med.,2 KLAUS-JORGEN HAHN, Dr. med.8 & HANS HALBACH, Dr. med. Dr.-Ing.4 This report-the third of a series on codeine and its alternates for pain and cough relief-presents a detailed review of the physiology and pathophysiology of cough, the methods for the experimental and clinical measurement of the antitussive action of drugs, possible mechanisms of action of antitussive agents, and includes a compilation of experi- mental results and clinical experience with codeine as an antitussive. CONTENTS INTRODUCTION .... 425 PHARMACOLOGICAL COMPONENTS OF THE ANTITUSSIVE EFFECT . 434 MECHANISM AND SIGNIFICANCE OF COUGH . 426 ANTITUSSIVE ACTION OF CODEINE . 441 METHODS FOR THE STUDY OF ANTITUSSIVE RESUMt . 451 ACTION ..... 428 REFERENCES . .......... 452 INTRODUCTION respect to the symptomatic management of cough, with only minor variations, and this situation has Codeine was first used as a therapeutic antitussive been influenced little by the introduction of sub- agent soon after its separation as an alkaloidal entity stances claimed to be superior in effectiveness and (Martin, 1834) and some of the earliest accounts of safety (Domenjoz, 1952; Winter & Flataker, 1954; dosage and of the circumstances of its use are sum- Pellmont & Biichtold, 1954).5 marized by Krueger, Eddy & Sumwalt (1943). The number of compounds alleged to possess anti- Codeine has indeed dominated the picture with tussive action comparable with, or superior to, that of codeine has increased greatly in recent years (see * This review of the analgesic and antitussive effects of codeine and its alternates is being published in the Part 4) but the popularity of codeine continues and Bulletin of the World Health Organization in five instal- its annual consumption remains at a high level, paral- ments. The first, devoted to an assessment of codeine as a pain reliever, was published in Bull. WId Hlth Org., leling the high frequency of need for relief of cough 1968, 38, 673-741. The second instalment, on alternates as a symptom, especially chronic cough. Bickerman to codeine as an analgesic, was published in Bull. WId Hlth Org., 1969, 40, 1-53. The third presented here is (1960) estimated, not so long ago, that 13% of the devoted to the evaluation of codeine as an antitussive population of the United States ofAmerica was more agent. The fourth instalment will deal with potential than 65 years old and that there were not less than alternates for cough relief. The final instalment will con- sist of a discussion and summary of the preceding reviews. 1 300 000 chronic coughers. Watt (1958) estimated 1 Consultant, National Institutes of Health, Bethesda, that in the United Kingdom of Great Britain and Md., USA. Northern Ireland 10% of all prescriptions were for 'Professor of Pharmacology and Toxicology, Univer- sity of Heidelberg, Germany. Present address: Chief, Drug cough relief. The need for antitussive preparations Safety, World Health Organization, Geneva. 6 Heroin was introduced 50 years earlier as a superior ' Department of Medicine, University of Heidelberg, antitussive but obviously proved itself to be less safe and, Germany. in spite of persistent claims as to its specificity, it has been 'Director, Division of Pharmacology and Toxicology, banned from therapeutics in most countries. No further World Health Organization, Geneva, Switzerland. reference to it will be made. 2312 -425 426 N. B. EDDY AND OTHERS is clear and codeine is our standard of reference. biguus. The authors assumed connexions between However, two facts have given impetus to the search these neurones and the receptors characterized by for an adequate substitute-substances without anal- Widdicombe (1954). Under normal breathing condi- gesic action can exhibit antitussive potency and such tions these neurones are silent but become activated substances may be entirely devoid of morphine-like by noxious stimulation and may play an important dependence-producing properties (Isbell & Fraser, role in the central processing of cough-evoking stim- 1953). uli (Engelhorn & Weller, 1965). In recent years much attention has been directed The existence of other connexions of the cough to the mechanism of cough and its relief and to centre must be assumed and has been partially de- adequate methodology for the measurement of the monstrated. Section in the forward part of the pons, latter. This work will be discussed first and will be for example, weakens the cough response in the cat. followed by details of the antitussive action of Spread of excitation of the cough centre to the vomit- codeine and later (in Part 4) by a discussion of the ing centre is well known, connexions with the respi- potential alternates. ratory centre must exist, and considerable voluntary control, even suppression of cough is possible (Kuhn & Friebel, 1960a, 1960b; Engelhorn & Weller, 1961; MECHANISM AND SIGNIFICANCE OF COUGH Friebel & Hahn, 1966; Hahn & Friebel, 1966). Reviews of this topic have been prepared by Bucher Efferent impulses from the cough centre, co-ordi- (1958), Bickerman (1960), Friebel (1963) and nating movements of the glottis, the diaphragm and Widdicombe (1964). Cough is a protective reflex, the abdominal and intercostal muscles in the act of the purpose of which is to remove irritating materials coughing, pass over the recurrent, the phrenic, the or sensations from the respiratory tract, and as such intercostal and other nerves. its pathways include sensitive receptors, afferent nerve Cough is understood as an explosive expulsion of fibres, central connexions with a " relay station in air resulting in the " generation of a high-linear-velo- the arc for cough reflex" (May & Widdicombe, city air stream with high kinetic energy available for 1954), and efferent nerves. Experiments of Larsell the acceleration and displacement of an object in the & Burget (1924) and Widdicombe (1954) demonstra- airway" (Ross, Gramiak & Rahn, 1955). These ted two types of receptors: one in the trachea, sensi- authors assume the explosive expulsion of air to be tive to mechanical stimuli, the other throughout the the product of substantial elevation of intrapleural tracheobronchial tree, responding chiefly to irritating pressure and sudden opening of the glottis. Equali- chemical stimuli. The afferent nerve fibres, which zation of pressure in the trachea with the outside air conduct the action potentials arising in these recep- creates a pressure differential along the bronchial tors, pass along the superior laryngeal nerve and the tree and the bronchi narrow passively. This allocates vagus, entering the medulla with the vagus root. a key position in the expulsion of air to the move- Section of the vagus below the point at which it is ments of the glottis. These movements, at least the joined by the superior laryngeal nerve does not sub- initial closure of the glottis, are centrally controlled stantially affect the cough threshold of anaesthetized independently of intrathoracic pressure and are car- cats (Sell, Lindner & Jahn, 1958), indicating probably ried out even if no air-flow occurs. The other factor that the stretch receptors in the lung (Bucher & Jacot, to bring about the air expulsion is the force of the 1951) take little part in the cough reflex. Cough- muscular contractions. Even if the movements of exciting impulses from the pharynx are carried in the glottis are inhibited, or the expired air goes out the glossopharyngeal nerve. through a tracheal fistula, remarkable blasts of air The existence of a specific cough centre located can be produced (Floersheim, 1959). in the dorsolateral region of the medulla close to The act of coughing is often, but not necessarily, the respiratory centre was suggested by Borison initiated by an inspiration (Staehelin, 1914; Trende- (1948) and by Chakravarty et al. (1956). This sug- lenburg, 1950; Widdicombe, 1954, 1961; Kuhn & gestion was confirmed by Engelhorn & Weller (1961, Friebel, 1960a,- 1960b; Friebel & Hahn, 1966; Hahn 1965), who localized a central mechanism for the & Friebel, 1966). This is not consistent with a very adaptation of the activity of the respiratory system to close correlation between the central portion of the acute changes in its environment in the lower pons cough reflex arc and the respiratory centre. Engel- and medulla. Its nervous components, E, neurones, horn & Weller (1965) suggested that the EQ neurones were localized in the caudal end of the nucleus am- belonged to an independent sensitive mechanism for CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 3 427 the protection of the lung against noxious stimula- recorded. Engelhorn & Weller (1965) observed in tion. Friebel & Kuhn (1962) in this connexion show- anaesthetized cats an inhibition of the activity of ed that the cough and respiratory centres reacted dif- expiratory neurones (Ea) on account of the activity ferently to drugs. They demonstrated that 2-amino- of cough-specific E, neurones. indane stimulated respiration in conscious and The newer information on the organization and narcotized guinea-pigs but depressed the cough reflex function of the cough reflex mechanism, therefore, mechanism. In fact the cough reflex mechanism con- supports the hypothesis of its independence, in the tains peculiarities in its function and organization main, of the respiratory mechanism,