Codeine and its Alternates for Pain and Cough Relief

3. The Antitussive Action of Codeine-Mechanism, Methodology and Evaluation

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 127 PHARMACOLOGICAL COMPONENTS OF THE ANTITUSSIVE EFFECT • MECHANISM AND SIGNIFICANCE OF COUGH 128 136 ANTITUSSIVE ACTION OF CODEINE 143 METHODS FOR THE STUDY OF ANTITUSSIVE RESUME 153 ACTION 130 REFERENCES 154

INTRODUCTION of codeine has increased greatly in recent years (see Part 4) but the popularity of codeine continues and Codeine was first used as a therapeutic antitussive its annual consumption remains at a high level, paral­ agent soon after its separation as an alkaloidal entity leling the high frequency of need for relief of cough (Martin, 1834) and some of the earliest accounts of as a symptom, especially chronic cough. Bickerman dosage and of the circumstances of its use are sum­ (1960) estimated, not so long ago, that 13% of the marized by K.rueger, Eddy & Sumwalt (1943). population of the United States of America was more Codeine has indeed dominated the picture with than 65 years old and that there were not less than respect to the symptomatic management of cough, 1 300 000 chronic coughers. Watt (1958) estimated with only minor variations, and this situation has that in the United Kingdom of Great Britain and been influenced little by the intro,duction of sub­ Northern Ireland 10% of all prescriptions were for stances claimed to be superior in effectiveness and cough relief. The need for antitussive preparations safety (Domenjoz, 1952; Winter & Flataker, 1954; ' Heroin was introduced 50 years earlier as a superior Pellmont & Bachtold, 1954).1 antitussive but obviously proved itself to be less safe and, in spite of persistent claims as to its specificity, it has been The number of compounds alleged to possess anti­ banned from therapeutics in most countries. No further tussive action comparable with, or superior to, that reference to it will be made.

-127- 128 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 (lsbell & 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 Engelhom & Weller (1961, Friebel, 1960a, l960b; 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, E11 neurones, horn & Weller (1965) suggested that the E11 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. 3 129 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 (EJ on account of the activity ferently to drugs. They demonstrated that 2-amino­ of cough-specific Ell 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, in respect to which seem to exclude a close association with the res­ cough-provoking stimulation, summation of afferent piratory mechanism. Its functions can be looked upon tussive impulses and transformation of these im­ as summing the cough-inducing stimuli, co-ordina­ pulses for co-ordination of the respiratory muscu­ ting the respiratory musculature to initiate the cough lature to produce the explosive cough response. reaction and interrupting the respiratory rhythm in The functions of the cough reflex as a protective favour of the cough reaction (Kuhn & Friebel, device are: 1960b). (I) warning against noxious irritation and damage Summation of afferent impulses towards the pro­ in the airways from inhaled chemicals or foreign duction of cough was suggested by Stefko & Benson bodies; and (1953) and Bucher (1958). Experiments of Friebel & Hahn (1966) in conscious guinea-pigs gave evidence (2) clearing the airways by removal of the offend­ of a remarkable ability of the cough centre to store ing irritant. the afferent impulses. The animals reacted with an Cough is a symptom in a wide variety of diseases. explosive expulsion of air, on the average 2.8 seconds Inflammation of the respiratory tract can be accom­ after an appropriate electrical stimulation of the panied by increased irritability of the sensory recep­ tracheal mucosa was initiated. A response could tors and intrapulmonary tumours can evoke cough still occur with weaker stimulation up to a latency of by pressure on or involvement of sensitive receptors 16 seconds. If the stimulation was too weak to evoke and nerve fibres. The cough response via the auricu­ a cough reaction in 16 seconds, it did not produce lar branch of the vagus on account of inflammation, cough at all. The authors concluded that the sum­ etc., of the external auditory meatus is well known. mation of cough-inducing impulses served two pur­ Cough may be an allergic response, a consequence poses. It intensified the protective function of the of circulatory disturbances or it may be psychogenic. cough reflex and prevented unlimited activity of the Cough arises most commonly from a stimulus within cough reflex mechanism. Variability in the latency the respiratory tract, from infections or mechanical was the only specific modification of the intensity and irritation within the lumen (Bickerman, 1960b) or characteristics of the single cough response produced from inhalation of polluted air or tobacco smoke by variation in the intensity, duration and frequency (Phillips, Phillips & Thompson, 1956; Herzog, 1967). of stimulation. Obviously, the central part of the From the clinical standpoint, cough is probably the cough reflex arc was able to collect variable afferent most important mechanism of bronchial catharsis impulses and transform these into efferent reactions (Bickerman, 1960b). If cough is present for a consid­ of relative uniformity (Friebel & Hahn, 1966). erable time, adaptation may occur and the patient The efferent impulses of the cough reflex activated may become almost unaware of its occurrence; or, the respiratory muscles which normally carry out the the apprehensive person may exaggerate its intensity. movements of breathing, so that the normal respira­ When the cough is incapable of, or ineffective in, tory rhythm was interrupted or postponed (Kuhn & removing the provoking stimulus, tussive insuffi­ Friebel, 1960b). The moment of interruption varied. ciency results. In many suppurative diseases of the In 85 of 100 cough reactions recorded from electri­ lung, cough is unable to remove the thick, tenacious, cally stimulated conscious guinea-pigs, the explosive mucopurulent secretions which form constantly in blast began at the height of inspiration, in 12 it began response to the infection. The dry, hacking, irritative during expiration and in three at the moment of cough of some acute infections of the respiratory complete expiration. An interruption of inspirations tract, such as laryngitis, tracheobronchitis and per­ has never been observed (Hahn & Friebel, 1966). tussis, may by itself become a major factor in retard­ Rarely, an acceleration of the normal expiration, ing recovery by causing loss of sleep, inadequate food leading to a typical cough reaction, has been intake, nausea and emesis. In obstructive disease of

9 130 N. B. EDDY AND OTHERS the tracheobronchial tree, such as tumours, foreign visual or acoustical observation or instrumental bodies and chronic asthma, the cough reflex may recording of cough reactions. Winter & Flataker become self-perpetuating and the resultant severe (1954) used ammonia vapour and sulfuric acid aero­ paroxysms of unproductive coughing may cause sol; Friebel, Reichle & von Graevenitz (1955) intro­ serious debilitation of the chronically ill patient duced the inhalation of sulfur dioxide mixtures; (Bickerman, 1960b; Banyai & Johannides, 1956). Gosswald (1958) used citric acid; Silvestrini & Maffii Other consequences of severe protracted coughing are (1959) employed acrolein vapour; and Kroepfli (1950) pulmonary emphysema, fractures of ribs, cough syn­ blew soap powder against the tracheal mucosa. Each cope, urinary incontinence, post-operative disruption of these agents elicits cough by stimulation of chemo­ of abdominal incisions and spontaneous pneumo­ receptors and each has its advantages and limitations. thorax. The necessity of cough-depressing therapy Receptors sensitive to cough-provoking irritants for unproductive cough is acknowledged (Friebel, are spread throughout the trachea and bronchi 1963). (Larsell & Burget, 1924; Widdicombe, 1954). Thus the inhalation of gases, vapours and aerosols can METHODS FOR THE STUDY OF ANTITUSSIVE ACTION influence many of them, whereas the introduction of solid material such as soap powder will reach only Measurement of antitussive potency in animal experi­ a few in the trachea. But vapours, etc., inhaled via ments the nose and pharynx will also stimulate receptors There are many reports of attempts to assess anti­ therein, perhaps eliciting sneezing as well as coughing tussive potency in animals; 70 reports in respect of and making discrimination difficult if the response is codeine, arranged according to animal and method, recorded instrumentally, as it was by Winter & Pia­ have been summarized in Table 27, yielding a wide taker (1954). Rosiere, Winder & Wax (1956) and range of effective doses, from 0.3 to 100 mg per kg. LaBarre & Plisnier (1959) therefore directed the The variation is related mainly to the method, but air-flow through an opening in the trachea and had this has varied in detail, even when it was said to be to use anaesthetized animals or others with a chronic the same, in respect of the stimulus used to evoke tracheal fistula. cough, and analysis of the data has varied with the Irritants like citric acid, acetic acid, ether, acrolein, investigator. Generally, however, one can assume ammonia, sulfuric acid or sulfur dioxide have differ­ that the method and analysis were the same when ent cough-eliciting potency and the concentration for comparison was made in a particular case between cough threshold varies widely from less than 1.0% a new agent (or agents) and codeine. It is worth (sulfur dioxide) to 20.0% (citric acid) (Friebel, while, we believe, to discuss the methods, at least Reichle & von Graevenitz, 1955; Gosswald, 1958). in principle, the conditions of their application, and The duration of their action is also different and their significance, reliability and interpretation as depression of cough evoked by inhalation of sulfur means of measurement. dioxide requires a larger dose of codeine than cough induced by ammonia if the guinea-pig is the test ani­ Intrapleural injection. Systematic exploration of mal (Friebel, Reichle & von Graevenitz, 1954; Winter cough-depressing activity began with Ernst (1938), & Flataker, 1954). On the other hand, dogs show who reported cough thresholds in cats with artificial less difference according to the chemical irritant used. chronic pleuritis. The inflammation was produced It would be worth while to know to what extent the by intrapleural injection of iodine (Lugol's solution), effective dose of codeine for a particular species after which percussion of the chest wall produced a depends upon the physiological characteristics of the cough reaction. Though Ernst (1939) claimed the species or upon the stimulus and the details of the results were reproducible, the method has been used method. only infrequently with no effort towards its refine­ Not only does the irritant potency of the chemical ment. stimulant vary but also its effectiveness varies accord­ Irritating chemicals. Eichler & Smiatek (1940) ing to the concentration and absolute amount at the were the first to use irritating chemicals to stimulate site of stimulation. Amdur (1957), for example, coughing. Their basic procedure has been variously showed that the effect of sulfuric acid aerosols on modified. Usually the animals have been exposed to bronchial receptors more nearly approached that of the mixture of irritating gas, vapour or aerosol with sulfur dioxide gas the smaller the droplets of the air, in a chamber suitable for one animal and for aerosol. Also the smaller the droplets the more tran- CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 3 131 sient the effect and the faster the recovery. This is vagal loop and through these, stimuli were applied important for the stability of the cough threshold, in the unanaesthetized animal (dog). The method of since the usual procedure is to determine the thresh­ electrical stimulation which is most often employed old before and at intervals after drug administration. was devised by Domenjoz (1952). The superior A change in normal sensitivity of the receptor with laryngeal nerve was isolated in the anaesthetized cat time would influence the accuracy of the judgement and stimulated briefly; the number and duration of of the drug's effect. Therefore, limited stimulation stimuli required adjustment in the particular animal with adequate intervals for recovery have to be taken to elicit cough reliably. The technique of electrical into account, as they have been by some authors. stimulation with modifications has been employed Friebel, Reichle & von Graevenitz (1955) recorded in anaesthetized guinea-pigs (Krause, 1958), in in 3.8% of guinea-pigs a decrease in sensitivity unanaesthetized guinea-pigs (Kuhn & Friebel, 1960a, between two applications of sulfur dioxide 30 minutes 1960b) and in unanaesthetized dogs (Stefko & apart. If soap powder is blown into the trachea a Benson, 1953). The latter authors implanted elec­ considerable adaptation of the receptors has to be trodes in the tracheal wall, eliciting cough by stimula­ taken into account (Kroepfli, 1950) because the solid tion of adjacent nerve fibres and receptors, and irritant is scarcely removed from the site of applica­ Chakravarty et al. (1956) provoked cough by means tion. of electrodes placed stereotactically in the medulla One advantage of a chemical irritant as the cough of the decerebrate cat. stimulus is that it permits the use of many animals Various forms of electrical current have been used, in a single experiment, facilitating statistical analysis with changes in the shape of the single impulse (spike, of the results. This no doubt explains the frequency square or undulatory), and with variations in voltage, with which such stimuli have been employed. current, frequency and duration. There have been explorations, too, of interrelationships between volt­ Mechanical stimulation. Kase (1952) was the first age and frequency of stimulation for producing cough to describe a method for the production of cough by most effectively (Schroeder, 1951; Stefko & Benson, mechanical stimulation of the tracheal mucosa suit­ 1953) and most recently of the interrelationship able for the measurement of antitussive action. The between intensity, duration and frequency of thresh­ most sensitive area for such stimulation is at the old stimuli by Friebel & Hahn (1966). Variation in bifurcation of the trachea. It may be reached through these parameters within described limits had no the fenestrated wall of the trachea by various devices, appreciable effect on the intensity or characteristics bristles, catheters, etc., but these must be applied of the cough response, but the latent period between cautiously to avoid damaging the mucosa and the beginning of stimulation and the occurrence of causing a change in sensitivity and adaptation to the the cough could be decreased (Friebel & Hahn, 1966). stimulation (Larsell & Burget,. 1924; Widdicombe, 1 Electrical stimulation to produce cough has no 1954). The strength of the stimulus cannot be con­ physiological equivalent; it also requires operative trolled as accurately as with chemical or electrical preparation of the animal and testing immediately stimulation and the animal must be prepared opera­ after the operation can be influenced by the anaes­ tively. If mechanical stimulation is attempted imme­ thetic. Nevertheless the method has been used by diately after operation, sensitivity may be impaired many and has the advantage of exact measurement by the anaesthetic and later pulmonary infection may of stimulus strength and quality. ensue. The chief advantage of mechanical stimula­ tion is its simplicity and some of its drawbacks are ·Avoidance of anaesthesia in antitussive testing was avoided by the technique of Tedeschi et al. (1959). one of the conditions stressed by Schroeder (1951). These authors implanted an iron slug within the tra­ A cough-depressing action of some of the anaesthetic chea of a dog which could be made to vibrate against agents used in animals has been observed or referred the tracheal mucosa by bringing a strong electromag­ to by Schroeder (1951), Domenjoz (1952), Tedeschi net against the outside of the throat, thus eliciting a et al. (1959), Friebel & Kuhn (1962), Hahn & Friebel cough response. Mter some time, chronic inflamma­ (1966) and others. One might expect the effective tion with epithelial desquamation and loss of sensitiv­ dose of the antitussive, codeine for example, to be ity resulted. smaller in experiments performed under anaesthesia. but the data of Table 27 do not give such an indica­ Electrical stimulation. This method was introduced tion. by Schroeder (1951). Electrodes were attached to a Some of the methods for antitussive experiments 132 N. B. EDDY AND OTHERS

require the preparation of a tracheal fistula and In most experiments with rats and guinea-pigs, this causes the air passages to be exposed to dry drugs have been given subcutaneously; in cats intra­ laboratory air instead of air highly humidified by venous injection has been usual, whilst in dogs, all passage through the nose and throat of the animal. routes have been used. Intravenous injection has the Under this unnatural physiological condition there is advantage of requiring small doses and usually has evaporation and thickening of the bronchial secre­ a transitory effect, permitting comparison of repeated tion, impaired activity of the ciliated epithelium and doses; if several injections are given the possibility poorer transport of secretions (Perry & Boyd, 1941; of summation of subliminal stimuli or of tachyphy­ Dalhamn, 1960J. Even if the inspired air is humidified laxis cannot be disregarded. The mode of administra­ to 30 %, ciliary movement stops within 3-5 minutes tion takes on added importance when the results of opening the trachea. The impairment of mucus are considered in relation to man. In antitussive transport favours the formation of an immovable therapy in man, the oral route is usual, whilst in layer of secretion and a change in sensitivity to cough­ experiments in animals it is the exception. Therefore, provoking stimuli (Gordonoff, 1938). If the tracheal if antitussive effect is shown in the latter, one also fistula is maintained chronically, as proposed by Kase needs to know something of absorption and meta­ (1952, 1954, 1955) there is liability to respiratory bolism after oral administration, factors which infections (Rosiere, Winder & Wax, 1956), again have been largely disregarded in predicting clinical influencing the threshold for cough stimulation. effectiveness. Similar considerations must be borne in mind in con­ nexion with other operative procedures, implantation Measurement of antitussive potency in experimentally of electrodes, exposure of the laryngeal nerve, etc. induced cough in man The catalogue of factors which may influence cough Cough may be induced experimentally in man by threshold before and after drug administration is inhalation of an aerosol containing acetylcholine, long, varying with the working procedure, and they ammonia or citric acid, or by intravenous injection play a significant role in the variations in results of lobeline or paraldehyde. shown in Table 27. Hoglund & Michaelsson (1950) published the first There are also qualitative differences in the animal report on experimental cough provoked in healthy species used in the experiments. Guinea-pigs, cats volunteers by inhalation of an irritating chemical and dogs are to be preferred. Mice are too small for compound. The subjects respired through tubes fit­ discrimination between sneezing and coughing. Rats ted with valves to prevent expiration into the system. respond readily to sulfur dioxide inhalation by both Ammonia vapour (2 %) in the desired quantity was sneezing and coughing and, when tested repeatedly added to the inspired air by means of a syringe. The over a three-month period, showed decreasing sensi­ momentary closure of the glottis in response was tivity. Guinea-pigs, on the other hand, maintained a recorded by a pneumograph around the subject's constant sensitivity throughout 48 weeks (Friebel & chest. The method of Hoglund & Michaelsson, more Kuhn, 1964). In general, the smaller species require or less modified, has been used by Trendelenburg higher doses per kg of codeine than do the larger (1950), Blix (personal communication, 1952), Hahn species to produce the same effect; cough elicited & Willbrand (1952) and Gravenstein, Devloo & in guinea-pigs by ammonia is an exception to this Beecher (1954), with all except the latter showing rule. On account of their size, cats and dogs are elevation of the cough threshold by codeine. Tren­ amenable to all methods for antitussive testing and delenburg and some others relied on subjective obser­ to all routes of drug administration, but unanaesthe­ vation of apparent closure of the glottis, believing tized cats and dogs quickly learn to control partially that this was always in accord with mechanical their breathing, restricting the inhalation of irritating recording. Closure of the glottis was taken as the chemicals, so that they have to be checked carefully threshold response whether or not an explosive act to determine whether under undrugged conditions the of coughing followed and, according to Trendelen­ cough response remains the same. A further draw­ burg, the amount of ammonia causing this response back to the use of dogs is their ability to be trained was the indication of threshold. When this had been to the experimental procedure, and to develop a determined test substances were administered and voluntary cough response; the better the relation measurements of threshold continued every five between handler and animal the more ready the res­ minutes until the threshold quantity of ammonia ponse (Schlez, 1965). had returned to the original amount required. CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 3 133

Gravenstein, Devloo & Beecher (1954) could not observed a decrease in frequency of the citric-acid­ be certain why they failed to confirm the results of induced cough of 22.4% at the second and fourth the others. They called attention to two points, hours after 5 mg of codeine phosphate orally, a firstly that Hoglund & Michaelsson and the others decrease of 22.4-32.5% at the first second and third had not used a placebo as control or used double­ hours after 15 mg, and of 22.4-43.1% at each hourly blind conditions, and secondly they found that the observation after 30 mg of codeine. Changes in ammonia-mixture container lost ammonia readily. expiratory airflow differed occasionally from differ­ A lower concentration of ammonia would be less irri­ ences in cough frequency, and the latter yielded the tating and if it were used in later trials after an anti­ better dose-response curves. tussive agent it would make the latter appear effective. The method of Bickerman and his associates has This would not allow the threshold to return to its been employed by Rasch (1957), Archibald, Slipp & original value. Shane (1959), Morris & Shane (1960), Groszman, There are also other points at issue in the method. Birker & Casimir (1961), Calesnick, Christensen & While closure of the glottis (sudden pause in breath­ Munch (1961), Tannenbaum (1965) and Silson (1965), ing) was chosen as the indication of response, it who demonstrated a reduction in coughing after drug remains to be proven that this can be accepted as an administration, and by Gravenstein, Devloo & adequate indication for a cough reaction and whe­ Beecher (1954) and Sevelius, Lester & Colmore ther that reflex is influenced by the same drugs and (1965) who did not. Gravenstein, Devloo & Beecher by the same doses as the cough reflex. Trendelenburg said that the Bickerman technique did not distin­ (1950), as well as Hahn & Wilbrand (1952), ob­ guish between a noisy, explosive cough and one of served wide variations in threshold values depending little intensity, that the quantity of aerosol reaching upon weather conditions and psychological factors. the lungs could not be accurately controlled or deter­ Trendelenburg, however, did not think initial thres­ mined, and that double-blind conditions were diffi­ hold values influenced drug effects. Gravenstein, cult to maintain because of recognition by the sub­ Devloo & Beecher (1954) found the threshold more jects of other effects (sedative action, etc.). Sevelius, constant and reproducible, but observed no signifi­ Lester & Colmore nebulized different strengths of cant change after medication. citric acid solution, 5.0-25 %, to determine the con­ A method closely related in principle to that of centration which consistently produced maximum ammonia inhalation was introduced by Bickerman cough response, a different threshold from that used & Barach (1954) and by Bickerman et al. (1956). by Bickerman. In spite of emphasis on selection and Cough was induced by a 25% solution of citric acid training of normal volunteers, in all of their six deeply inhaled from a nebulizer through a tight-fitting subjects the cough response to the same dose of face mask and a constant oxygen flow of five litres irritant changed from hour to hour by as much as per minute. They recorded the number of coughs 50%. The subjects also definitely became adapted elicited and the expiratory air flow. The subject to the citric acid irritation and coughed progressively took three inhalations, resting two or three minutes less frequently on repeated exposures. Without between each. In drug potency tests the response was proper placebo control data a " false positive " drug recorded at zero time and hourly to four hours after effect could be ascribed to what was only adaptation. medication. Bickerman et al. (1957) later spoke of These authors were unable to distinguish between " trained" subjects, who worked with the method 15 and 30 mg of codeine and placebo. This statement through many months and showed a reasonable concerning adaptation to the stimulus is at variance degree of adaptation(" learning" factor) to the pro­ with Bickerman's experience, but Sevelius, Lester & cedure. This group worked under double-blind con­ Colmore required stronger citric acid concentrations ditions and was challenged with concentrations of and it is not clear whether or not residues of citric citric acid from 1.25-25.0% to determine a threshold acid on the tongue and in the throat were removed stimulus, arbitrarily set as that concentration of citric by rinsing as they were by Bickerman. Sevelius acid which evoked a total of not less than four coughs and his associates maintained that Bickerman's when inhaled five times. Since this threshold level procedure was considerably more complicated varied from subject to subject and sometimes in the than theirs since he examined 153 "normal" same subject from day to day, it was redetermined subjects to obtain 21 presenting relatively constant for each subject at the beginning of each test run. reactivity to the cough-provoking aerosol. Such Under these conditions Bickerman et al. (1957) selection not only reduces variation in the sen- 134 N. B. EDDY AND OTHERS sitivity of the cough reflex mechanism related to tive. Haslreiter's experience was similar, a posi­ smoking, chronic respiratory infections, etc., but will tive cough response to acetylcholine in most also reduce the influence of another factor, voluntary patients with chronic bronchitis, etc., and a nega­ or subjective control over the response, which may tive response in all healthy persons. Both Prime play a role in all experimentation on humans. The (1961) and Sevelius, Lester & Colmore (1965) found cough response can be voluntarily suppressed and that cigarette smokers, admitting to only a little initiated. habitual coughing, responded positively to acetyl­ Results obtained with the Bickerman method have choline. not always correlated well with clinical effectiveness Haslreiter (1959) and Prime (1961) used acetylcho­ of the agents tested, in the treatment of pathological line to attempt evaluation of cough depressants. The cough. Bickerman & Itkin (1960) failed to demon­ subject breathed his individual concentration (Hasl­ strate a cough-depressing effect with normethadone, reiter, 1959) or 1.0% (Prime, 1961) acetylcholine though such an effect has been well established in aerosol until coughing began or at most for 1 Y2 min­ animal experiments and clinical experience. On the utes and the number of coughs ensuing during the other hand, Woolf & Rosenberg (1964), using a tape­ next 20 minutes was counted. The subject then took recorder system as an objective measure of coughing, an inert tablet or one containing the cough depres­ found laevopropoxyphene inactive clinically, while sant and 20 minutes later the test was repeated. The Bickerman et al. (1957) and Calesnick, Christensen active and inactive tablets were administered in ran­ & Munch (1961) found it effective against artificially dom order to each subject. Prime compared the produced coughing. cough rates before and after medication with positive Recently Calesnick & Christensen (1967) have used results; Haslreiter determined the number of patients the citric-acid-aerosol method with a different end­ who did not cough after the test drug. Their results point, the latent period from beginning of inhalation did not correspond. Sevelius, Lester & Colmore under pressure through a tight face mask to cough (1965) could not confirm Prime's results either. In response and regarded a lengthening of this period nine subjects they were unable to distinguish between as indicative of cough suppression. They used only 30 mg of codeine phosphate and placebo, adminis­ males because females were too sensitive to reflex tered double-blind in random order with 60 or closure of the glottis which would prevent inhalation 120 minutes allowed for absorption. Prime admitted of a sufficient amount of the aerosol (25% citric acid). to them that his later experience was in accord with They also excluded persons who did not give a good theirs. It should also be mentioned that acetylcholine cough response before drugging or who failed to antagonists (hexamethonium, for example), not other­ show an antitussive effect with an exploratory dose wise antitussive, abolish the cough response to acetyl­ of 40 mg of codeine orally. Graded doses were given choline (Tiffeneau, 1955). with citric acid challenge hourly throughout four As indicated earlier, cough can be provoked in man hours. A good dose-response curve was obtained by intravenous injection of paraldehyde or lobeline. with 5.0-40.0 mg of codeine. Gravenstein, Devloo & Beecher (1954) found that Prime (1961), looking for a controllable agent for the usual dose required to produce a satisfactory artificial cough production, developed an observation cough response varied frc .n 0.25 to 0.5 m! in different of Tiffeneau (1955). The inhalation of a nebulized subjects (Konar (1959) usd 1.0 m!). The paraldehyde solution of acetylcholine regularly induced more or was injected into a vein of the forearm through a less coughing in certain persons. Prime also tried continuous 5.0% dextrose solution drip. The result ether and sulfur dioxide; both were effective, but the was a feeling of constriction of the chest and an taste and smell were objectionable and the latter as explosive cough which relieved the feeling. The used was so powerful that none wanted to repeat the coughing bout lasted 30-60 seconds and might be experience. In non-smokers, and persons without followed by an afterburst of coughing. When the respiratory infection under 30 years of age, Prime effective dose had been determined and repeated at found acetylcholine even at 1.0% completely ineffec­ 30 minutes, the antitussive was administered and tive, confirming the observations of Tiffenau (1955) the paraldehyde repeated at half-hour intervals for and Halsreiter (1959). However, in patients with 2 or 2V2 hours. Gravenstein, Devloo & Beecher chronic bronchitis, emphysema, asthma, fibrous investigated the effect of drugs on the response to tuberculosis, pulmonary sclerosis, or acute respira­ paraldehyde, and showed a difference between heroin, tory inflammation acetylcholine was 80-90% effec- 2.5 mg subcutaneously, and placebo, where the sub- CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 3 135 j ects were used as their own control, but not with Evaluation ofantitussive action against cough ofpatho­ codeine, 10 mg orally or 30 mg intravenously, or logical origin morphine, 5 mg subcutaneously, when the subjects were not their own controls. Konar (1959) also failed The crucial test for an antitussive is the study of to obtain a positive effect on the response to paral­ its effect in patients with spontaneously occurring dehyde with codeine or morphine. Gravenstein and cough of various origin. Most of the reports in this his associates deemed it unwise to continue with the connexion are based on clinical experience rather paraldehyde test because of pain at the site of injec­ than controlled clinical trial. Reliable, unbiased tion and phlebitis, fear on the part of the subject of evaluation and comparison should come from the the feeling of chest constriction, and variability in latter, but the former is supplementary and essential. the response. Covering a larger number of patients of more hetero­ geneous character, the general clinical observation Lobeline administered intravenously excites contributes to the knowledge of side-effects, unusual cough, presumably because of a direct effect on the adverse reactions and useful indications of applica­ cough centre (Chabrier, Giudicelli & Thuillier, 1950). tion and contraindication. The effective dose was 3.0-10.0 mg, and this dose caused a cough reaction of 10-20 seconds duration Here, as elsewhere, the clinical trial must fulfil some followed by about 60 seconds of polypnoea. The basic requirements of clinical pharmacology, double­ authors found that 80-100 mg of pholcodine blind procedure to avoid error by suggestion, inclu­ decreased the response to lobeline. They said, sion of placebo or standard drug of established effi­ however, that lobeline had to be used cautiously cacy for comparison, and randomization of drug because of possible toxic reactions. Hillis & Kelly administration to facilitate statistical analysis. This (1951) were unsuccessful in attempts to suppress the is not the place to discuss the design of specific clini­ cough response to 5.0 mg of a-lobeline, intravenously cal trials but certain features of the procedure, as in normal subjects, with codeine, morphine or heroin. applied to the evaluation of antitussives, must be The cough response was blocked by hexamethonium considered for better judgement of the significance iodine. of the data to be presented in respect to specific agents. In the main, two approaches to evaluation Bickerman & Barach (1954) said that artificial cough production should meet the following condi­ of efficacy, etc., have been developed-analysis of the tions: uniform and consistent response of the sub­ subjective judgement of effect by patient and/or ject to the same threshold stimulus; the eliciting agent observer, and objective measurement of changes in should be non-toxic and relatively simple in its appli­ number, severity, etc., of bouts of coughing during cation so that observations may be made on many specific periods of time with and without drug or subjects; and the results should be reproducible. placebo-and variations in each approach have None of the methods described meets these condi­ appeared almost from investigation to investi­ tions completely. The reviewers believe the citric­ gation. acid-aerosol technique to be the most promising, As much as 31 years ago, Davenport (1938) admin­ best developed, and least disturbing to the subject, istered codeine and closely related substances double­ but further efforts to develop methods for antitussive blind to coughing tuberculous patients and concluded evaluation should be encouraged. Artificially pro­ that the optimal oral dose of codeine was only 10 mg, duced cough, in volunteer subjects, is not the same and Himmelsbach et al. (1940) using placebo for as cough of pathological origin at least in strength, comparison, demonstrated worsening of the cough timing and persistence of cough induction, and one when the change was to the placebo from morphine cannot always expect to obtain the same drug res­ or codeine. It has been in the past 15 years, however ponse in both situations. Nevertheless, the experi­ since the discovery of the antitussive property of ments with artificial cough are worth while for deter­ dextromethorphan, that particular attention has been mination of carry-over of effectiveness in this and directed to quantification in evaluative efforts. other respects from laboratory animals to man, but Assessment of efficacy is of necessity a comparison should be accompanied by studies of absorption, between groups, as comparable as possible in size distribution and disposition for further information and composition, receiving different agents or in the on species parallelism. Then one has the background individual receiving two or more agents. He may be for interpretation of laboratory results and for clin­ asked to compare his condition at administration ical application. with that at fixed time intervals thereafter, or his 136 N. B. EDDY AND OTHERS condition during one period of medication, a day or reduction in bouts of coughing. Woolf & Rosenberg a week or longer, with that during another equal (1964) also compared their patients' judgement of period. He may be asked simply to judge improve­ change in coughing with the results recorded auto­ ment, no change or worsening, to express his prefer­ matically. An actual reduction in the number of ence for the agent used at one time over another, or coughs by 50% was recognized in only 36 of 90 cases. to judge the severity of the symptoms (number or The authors concluded that the majority of the severity of coughs, etc.) or of the change in the symp­ patients did not appreciate the extent to which their toms, whether slight, moderate, great or none. In cough varied from day to day and were frequently either of the latter judgements, numerical scales may unaware of the effect of antitussive preparations. be employed where the highest number means the Gravenstein, Devloo & Beecher (1954) reached the least effect, if the symptom is assessed directly, or the opposite conclusion, that their patients felt better and greatest effect if change is being judged. Alternatively thought they coughed less. results have also been expressed as a percentage of Various methods of statistical analysis of results, the group of patients reporting, according to the whether subjective or objective, have been used. It criterion employed. All of these methods have been may be of interest to mention Armitage's sequential used in the evaluation of antitussives and are analysis, since its applicability was first demonstrated probably best illustrated with specific results in the in an antitussive study (Snell & Armitage, 1957). It evaluation of codeine (see below). has the advantage of making evaluation possible Davenport (1938) mentioned the unsatisfactory use while the trial proceeds, avoiding undue continuation of kymographic recording of chest movements for or premature termination. No doubt conflicting determination of the frequency of coughing. Graven­ results in clinical trials are influenced by using too stein, Devloo & Beecher (1954) introduced a sound few patients. Improper dosage selection can also recorder, connected to a microphone, from which bias the results by destroying the double-blind feature numbers of bouts or numbers of individual coughs through the appearance of recognizable effects unre­ could be counted. The sound-induced electrical im­ lated to the one under examination. pulses were registered kymographically. This auto­ Finally, it is of interest to review the role of the matic record correlated well with that of a person placebo and the degree of effect which it has produced monitoring the cough by direct count. With minor in antitussive testing. Table 26 summarizes some variations the method has been employed by Krug placebo results, and is restricted to those reports (1964), Kleibel (1964), Kleibel, Steinhoff & Wild which could be interpreted in terms of the percentage (1965), Sevelius & Colmore (1967), and others. of the group of patients who improved. From these Woolf & Rosenberg (1964) used a tape-recorder to data an average analgesic effect of placebo of 22.8% register the actual sound of the cough, and this had may be calculated-somewhat less than the average the advantage for recording over prolonged periods figure (35.2 %) calculated by Beecher (1955) as the that the on-off switch was automatically operated by average percentage analgesic effect of placebo. One the sound. Others have overcome the prolonged other point was brought out by Renovanz & Liebrich observation difficulty by restricting the record to a (1965). On the basis of the patients' judgement of specified period, uniform from day to day and based improvement in frequency and intensity of coughing, upon survey of the coughing pattern throughout the placebo was less effective when compared with 24 hours. codeine, 29.0% and 32.3% reductions in number and The subjective and objective approaches to evalu­ intensity of cough, respectively, than when compared ation of antitussive action have been compared with with no medication, 40.4% and 60.9% reductions in different results. Gravenstein, Devloo & Beecher number and intensity. (1954) could not detect changes in cough counts to back up judgement of an antitussive effect of codeine compared with placebo. Nicolis & Pasquariello PHARMACOLOGICAL COMPONENTS OF THE A~TITUSSIVE (1962a, 1962b) recorded a significant reduction in the EFFECT number of coughs by codeine versus placebo when the patients' judgement of effect, based on a four­ Specific cough-depressant actions point scale, showed no difference. In another study, however, Pasquariello & Nicolis (1962) showed good The mechanisms of antitussive action have been correlation between patients' drug preference and discussed extensively by Bucher (1958), Bickerman O)DEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 3 137

TABLE 26 ANTITUSSIVE EFFECT OF PLACEBO MEDICATION

Patients Percentage I of patients Reference No. I Type improved

134 Adults and children; cough of various origin 5.2 Carter & Maley (1957) 44 Cough due to common cold 7.0 Parish (1959) 60 Chronic cough of various types 14.0 Haslreiter (1959) 65 Chronic cough 39.2 Di Gregorio (1960) 43 Chronic cough 35.6 Di Gregorio (1960) 25 Cough due to acute inflammation 28.5 Di Gregorio (1960) 50 Children; acute bronchitis 22.2 Abruzzi (1962) 50 Adults; non-productive cough 26.7 Abruzzi (1962) 18 Chronic cough of various types 23.0 Mulinos, Nair & Epstein (1962) 26 Tuberculous 6.0 Mulinos, Nair & Epstein (1962) 30 Chronic cough 39.9 Woolf & Rosenberg (1962) 46 Young patients; viral infections 7.5 Amler & Rothman (1963) 35 Cough of various origin 29.0 Schofield (1963) 127 Acute cough of various origin 40.4 Renovanz & Liebrich (1965)

(1960), Friebel (1960, 1963), Salem & Aviado (1964) presumably on receptors in the pharyngeal area. The and others. According to the structural organization inhalation of aerosols containing 1 % cocaine or 2% of the reflex arc, specifically-acting antitussives might procaine acting on receptors in the pharyngeal, tra­ exert this effect on the mechanoreceptors or on the cheal and bronchial regions, has been recommended chemoreceptors along the afferent fibres in the by Martini (1957) for the treatment of asthmatics medullary cough centre and, theoretically at least, troubled by irritative cough. In animal experiments, upon the responding structures. suppression of cough, provoked by mechanical stim­ ulation of the trachea, by local application of a pro­ Reflexogenic receptor area. Such a statement as caine solution has been demonstrated (Widdicombe, the following suggests that specific antitussive action 1954). Thus reduction of cough impulses at their site at the receptor site is known and the validity of such of origin by locally applied drugs is possible, perhaps action proven-" This new antitussive may well act usual, but none of the agents mentioned possesses a both centrally by depressing the cough centre and specific antitussive effect. " Local anaesthetics are peripherally by reducing the tussal impulses from only moderately selective" (Bucher, 1958). local irritation " (Chen, Biller & Montgomery, 1960) Attempts to obtain inhibition of receptors sensitive -but the drugs of choice for such peripheral inhibi­ to cough-provoking stimuli by oral or parenteral tion would be local anaesthetics having special affin­ administration of drugs have been made by Bein & ity for receptors responsive to tactile and chemical Bucher (1957), Ther & Lindner (1958), Sell, Lindner irritation. Direct application of local anaesthetics is & Jahn (1958) and others. The first attempts were the routine provision against undesired cough reac­ made with local anaesthetics. Kase (1955) tested the tions during bronchoscopy (Frey, Hugin & Mayrho­ cough-depressing effect of cocaine and procaine in fer, 1955). Tetracaine or lidocaine in one form or unanaesthetized dogs repeatedly stimulated by bris­ another are inhaled or sprayed over the laryngeal and tles pushed against the tracheal bifurcation. The tracheal surfaces. Ethoform (p-aminobenzoic acid drugs were injected into the femoral vein or into the ethyl ester), as an ingredient of antitussive lozenges, cisterna cerebello medullaris. The results were as is used against irritative pharyngeal cough, acting follows: 138 N. B. EDDY AND OTHERS

Drug Dose (mg/kg) Cough depression two sets of receptors, but a dose of 2.0 mg per kg IV Intra- No. No. of was sometimes lethal and was too close to the other­ cistern positive experiments wise effective dose to suggest any sort of cough­ Cocaine specific endoanaesthetic action. With tetracaine the hydrochloride 3.0 0 2 dose causing inhibition of the cough centre was 5.0 1 3 0.25-0.5 mg per kg, intravenously, and that for 7.0 3 3 10.0 3 3 diminution of the activity of the receptor systems 0.1 0 2 2.0 mg per kg; this again did not indicate that selec­ 0.3 2 2 tive action on the receptors was involved. Further­ 0.5 1 1 more, although many antitussives that have been 1.0 1 1 used clinically have also been shown to be local Procaine anaesthetics (e. g., isoaminile, clofedanol, pholcodine, hydrochloride 10.0 0 3 diphenhydramine, oxolamine, caramiphen, etc.) a 20.0 2 3 role for such action in promoting the antitussive 30.0 3 3 effect has not been proven experimentally or clini­ 0.1 0 2 0.3 1 2 cally, however reasonable this may seem. 0.5 3 3 Afferent nerve fibres. Specific pharmacodynamic blockade of fibres transmitting cough-inducing An effect was obtained but large intravenous doses afferent action potentials has not been demonstrated. were required and probably had only a small margin In special circumstances, interruption of the afferent of safety. Such doses would stimulate respiration pathways could be effected by section (cough pro­ and affect the blood pressure and cardiac rhythm. voked by the involvement of, or pressure from, a one­ The intravenous mean lethal dose for the cat was only sided bronchial tumour (Bucher, 1958) or by conduc­ 30-40 mg per kg for procaine and 15 mg per kg tion anaesthesia (Tomori et al., 1960)). for cocaine (Sollmann, 1957). Kase did not recom­ mend this antitussive effect or ascribe a peripheral Cough centre. The truly specific site of action of site of action; the smallness of the effective doses cough-depressing drugs may be presumed to be the when given into the cisterna suggests indeed that the cough centre, or its neuronal system, in the medulla. action was central. " In this area all factors leading to cough are united " Ther & Lindner (1958) studied the antitussive po­ (Bucher, 1958). However, even among the com­ tency of local anaesthetics, and found no correlation pounds acting at such a site the specificity of action, between it and surface anaesthesia on the rabbit the details of the response and the breadth of other cornea or conduction anaesthesia in the frog sciatic surrounding actions vary. Dextromethorphan and nerve. They used the superior-laryngeal-nerve-stimu­ noscapine, for example, have little of note other than lation technique (cat) and demonstrated cough antitussive action; other materials, such as codeine, depression most readily among substances related to pipazetate, 2-aminoindane, and hexobarbital act on tetracaine. They suggested that the presence of a broader scale. Hahn & Friebel (1966) studied the p-aminobenzoic acid in the molecule enabled the range of action of such a group, using unanaesthe­ compound to gain access to the cough centre. tized guinea-pigs and producing cough by stimulation Sell, Lindner & Jahn (1958) compared the endo­ of electrodes implanted in the trachea. Data recorded anaesthetic and antitussive properties of tetracaine, included the electric current at the cough threshold, the integration of the explosive expiration (the cough) benzonatate and related compounds in cats and guinea-pigs. The former was determined from the into the breathing rhythm, a kymographic record of transmission of stretch-receptor impulses arising in the cough reaction, and the sound of the cough before the lung, via the vagus nerve, and the latter from the and during treatment. They reported the following: transmission of mechanoreceptor impulses arising in (1) Hexobarbital-antitussive dose 70 mg per kg, the trachea, via the superior laryngeal nerve. The subcutaneously. The cough threshold was elevated antitussive activity was measured after electrical by 3.5 mA (the cough was somewhat modified when stimulation of the superior laryngeal nerve for central the stimulation was elevated above the threshold) evocation of cough. In these experiments benzona­ and there was somnolence to narcosis, and retar­ tate at 1.0 mg per kg, intravenously, depressed the dation of respiration. In contrast to normal the cough and the transmission of the impulses from the cough reaction began invariably with an inspiration. CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 3 139

The subsequent reduction in the cough response was mate the incoming stimuli and that this failure of slowed; in some cases animals coughed for three summation is the principal effect of the antitussive seconds after interruption of the cough-provoking compound, though it may also sometimes change current. A broadening of the kymographic V-record the character or form of the response. of the cough further illustrated the retardation of Some compounds affect the correlation between the response. Signs of closure of the glottis as a the respiratory cycle and cough. With hexobarbital, part of the event disappeared and the sound of the as was noted, the cough was initiated with an inspira­ cough was weakened. tion; the same was true in barbiturate-treated cats (2) Aminoindane-antitussive dose 14.5 mg per kg, (Kroepfli, 1950). In untreated cats, 16% of electric­ subcutaneously. The cough threshold rose quickly ally-provoked cough reactions began without the by 1.5 mA and showed no tendency to recover during introductory inspiration. the next three hours. Respiratory frequency was If the central action of antitussives were directed increased and there was motor excitement, piloerec­ primarily against the stimulus-summating function tion, secretion of tears and saliva. The explosive of the centre, this would explain the equal therapeutic expiration began during the expiratory phase of the effectiveness of these drugs against most forms of breathing cycle more frequently than is normal; it irritating cough. Codeine, dextromethorphan, pipa­ was never integrated into the breathing cycle as zetate, and benzonatate seem to be equally satisfac­ sometimes occurred before drugging. The sound of tory whether the cough arises from acute or chronic the cough increased and the kymographic record bronchitis, tuberculosis, emphysematous bronchitis, became irregular and broader in form. asthmatic bronchitis or bronchial carcinoma; the doses necessary for diminution of the cough are (3) Codeine phosphate-antitussive dose 15.4 mg about equal, and this is understandable only if they per kg, subcutaneously. The cough threshold was are acting uniformly on a central mechanism acti­ elevated by 0.5 mA for about three hours (a larger vated by all kinds of cough. The clinical significance dose of 30.8 mg per kg elevated the threshold by of the other cough modifications described by Hahn 0.9 mA). The noise of the cough was weakened and & Friebel (1966) has not been clarified. its kymographic record was simplified but not broad­ ened. Efferent activating structures. Inhibition of cough through an effect on responding structures has been (4) Pipazetate-antitussive dose 14.5 mg per kg, claimed for oxolamine (Silvestrini & Pozzatti, 1960) subcutaneously. The cough threshold was elevated and sodium dibunate (DeVleeschhouwer, 1954) as a by about 1.6 mA, and was still above normal after part of peripheral antitussive action. However, the three hours. The noise of the cough was decreased; respiratory centre is also in control of these structures the record was irregular and sometimes broader. and differentiation is not possible. (5) Dextromethorphan-antitussive dose 26.0 mg per kg, subcutaneously. The cough threshold was Effects other than specific cough-depressant action raised by 0.4 mA for three hours. Respiration was Cough-depressing substances, of course, exhibit unchanged. The explosive expiration began more other pharmacodynamic effects, which may be detect­ frequently (18 %) than is normal in the expiratory able at the antitussive dosage level and which may phase of the breathing cycle, and in 14% of cases at promote or even interfere with antitussive usefulness. the very end of expiration. The record showed numerous irregularities and broadening. The noise Respiratory effects, other than antitussive effects. of the cough was decreased only during the first Benzonatate, tetracaine and related substances, if 20 minutes. injected intravenously, diminish the spontaneous activity of the pulmonary stretch receptors, though Thus these compounds produced several different the margin between effective and toxic doses is small effects, only one common to them all, an elevation (receptor-depressing doses in cats are between 0.5 and of the cough threshold, which could be overcome by 2.0 mg per kg whilst depression of blood pressure, increasing the strength of the stimulation. The sen­ temporary arrest of respiration, and occasional death sitivity of the centre is decreased but it is not para­ occurs with doses of 2.0 or 3.0 mg per kg). Depres­ lysed. Based upon their experimental results Friebel sion of the pulmonary stretch receptors is probably & Hahn (1966) and Hahn & Friebel (1966) concluded not significant in antitussive action. Cutting off im­ that the centre temporarily loses the ability to sum- pulses from these receptors from the vagus, below 140 N. B. EDDY AND OTHERS the entrance of the superior laryngeal nerve, did not mechanism for both types of relief, but antitussive affect the cough response to electrical stimulation of action without analgesia implies a fundamental dif­ that nerve (Widdicombe, 1954; Sell, Lindner & Jahn, ference in the mechanisms involved. 1958). Pholcodine enhanced the Hering-Brauer pul­ Friebel, Reichle & von Graevenitz (1955) and monary-inflation reflex, which May & Widdicombe Reichle & Friebel (1955) assessed the antitussive and (1954) thought was secondary to bronchoconstriction analgesic potencies of a number of compounds in and indicated increased activity of the pulmonary guinea-pigs and rats by uniform methods (inhalation stretch receptors, yet pholcodine was equivalent to of sulfur dioxide and skin-twitch to radiant heat) with codeine as an antitussive. the following results: Many antitussives affect central regulation of res­ Antitussive Analgesic Ratio: piration. Friebel & Kuhn (1962) and Hahn & Friebel Agent ED50 ED50 analgesic/ (1966) demonstrated that hexobarbital decreased (mgjkg) (mgjkg) antitussil'e respiratory volume and frequency at doses below Guinea-pig those which affected the cough reflex mechanism. Methadone 1.6 3.7 2.31 Pentoxyverine 1 citrate, pipazetate and the piperidine Morphine 4.0 11.5 2.87 Normethadone 4.6 12.3 2.66 derivative, L 2909, depressed the cough reflex at a Pethidine 8.0 12.3 1.53 dose level which did not seem to affect respiration, Codeine 8.0 48.5 6.62 but pipazetate would increase the respiratory depres­ Ethylmorphine 13.0 43.0 3.30 sant effect of hexobarbital. 2-Aminoindane stimula­ Dihydrocodeine 14.0 80.0 5.71 ted respiration even when the respiratory centre was Rat depressed by previous administration of hexobarbital Methadone 1.0 1.8 1.80 and its antitussive effectiveness equalled that of MorPhine 3.0 2.3 0.76 codeine (Friebel & Kuhn, 1962; Kuhn & Friebel, Pethidine 5.6 8.2 1.46 1960a, 1960b). Again these results support the sug­ Normethadone 7.0 5.8 0.82 gestion that the respiratory centre, in its reactivity to Codeine 10.0 13.0 1.30 drugs, is to a considerable extent independent of the cough centre, that depression or stimulation of res­ The higher the ratio the greater the antitussive piration may be independent of antitussive effective­ specificity, and this was greater for codeine than for ness (Eichler & Smiatek, 1940; Haas, 1955; La morphine in both species in spite of the greater anal­ Barre & Plisnier, 1959), and that the degree of respira­ gesic effectiveness of the latter. These data further tory depression produced by many antitussives does support the independence (or dissimilarity) of the not impair their antitussive usefulness at usual thera­ two effects. A further illustration is pholcodine. peutic doses. Structurally closely related to codeine, it has com­ parable antitussive action but no analgesic action Analgesic effect. The virtually exclusive use of the (Kelentey et al., 1958; Cahen & Boucherle, 1961). opiates, or of analgesics related to morphine, for Many other authors have claimed equivalence to antitussive effect was interrupted by the observations codeine in clinical antitussive effectiveness for com­ of Pellmont & Bachtold (1954) and Winter & Flata­ pounds which lacked ability to relieve pain (Capello ker (1954), which demonstrated, on the one hand, & DiPasquale, 1955; Maurer, 1955; Carter & Maley, that the structurally related dextromethorphan, and, 1957; Cass & Frederik, 1958; Haslreiter, 1959; on the other hand, that the unrelated noscapine both Bickerman, 1960, Prime, 1961). depressed experimentally produced cough, although Analgesic compounds, at least compounds with both lacked analgesic action. a morphine-like analgesic effect, will depress the Cough and pain are nociceptive warning signals cough response, but compounds which depress the which can evoke reflex protective responses and which cough response are not necessarily analgesic. are perceived as discomforts of greater or less degree. Antitussives and analgesics suppress the response Sedative and tranquillizing effect. Gravenstein, under experimental conditions and make the per­ Devloo & Beecher (1954), failed to detect a decrease son feel better by decreasing his awareness of the in cough frequency and implied, at least, that the discomfort, apart from the suppression of the res­ sedative effect of codeine made the patient feel better ponse. This would seem to bring into play a similar and he thought he coughed less. Mter subcutaneous injection of hexobarbital in • Also known as carbetapentane. guinea-pigs the sequence of symptoms with increas- CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 3 141 ing dosage was sedation at 50 mg per kg (to anaesthe­ In man, as in laboratory animals, narcosis abo­ sia), depression of respiration and depression of lishes the cough reflex; in deep narcosis the mecha­ cough at 77 mg per kg (Friebel & Kuhn, 1962). Is nism is paralysed. Barbiturates and other sedatives, the depression of cough in hexobarbital-treated in sleep-inducing doses, are not expected to act as animals a specific antitussive action or a part of the cough depressants, though the sedation may be as general depression of reflexes? Hahn & Friebel useful an adjunct to cough therapy in some circum­ (1966) observed, in guinea-pigs in which cough was stances as simultaneous analgesia may be in others. elicited by electrical stimulation, that hexobarbital at 70 mg per kg, subcutaneously, first caused sedation Neuroleptic effect. Chlorpromazine, a standard (sometimes with delirium) followed by decrease in substance among neuroleptic compounds, and thio­ respiratory frequency and later, while in an anaesthe­ ridazine act similarly, protecting against vomiting, tized, condition by a retardation and decrease in the having moderate anticholinergic, adrenolytic and cough response which, as anaesthesia declined, out­ antihistaminic properties, and are both credited with lasted the respiratory depression. Throughout the strengthening the pharmacodynamic effects of opi­ period under hexobarbital the cough was always ates, barbiturates and other sedatives and anaesthe­ initiated by inspiration, which was not the case in tics. Both substances, according to Boissier & Pagny untreated animals. (1960a, 1960b), showed a good antitussive effect in guinea-pigs subjected to sulfuric acid aerosol. Pro­ Tedeschi et al. (1959) found an ED of 13.7 mg 50 methazine, which is weaker in its neuroleptic potency, per kg for pentobarbital sodium in unanaesthetized also depressed the cough reflex at higher doses. The dogs, for depression of cough due to mechanical authors believed that non-specific central depressant stimulation. However, the barbiturate was effective properties were mainly responsible for the cough­ only in doses which produced signs of neurological depressing effect. Kase & Yuizono (1959) tested deficit, marked ataxia and/or unconsciousness indi­ some compounds structurally related to chlorproma­ cating that " pentobarbital acts as a non-selective zine and found chlorpromazine in dogs, at 20 mg per antitussive agent". The cough response of decere­ kg intravenously, sometimes slightly effective, per­ brate cats to electrical stimulation has been abolished phenazine, prochlorperazine and other phenothia­ by thiopental, 4-12 mg per kg, intravenously (Matal­ zines more definitely effective against cough at equal lana & Borison, 1955). or smaller doses. Thus powerful neuroleptics affect Methaqualone, similar in its sedative effect to the the cough-reflex mechanism and act in this respect barbiturates, diminished by 50% the cough response like the opiate analgesics; absence of neuroleptic to electrical stimulation in narcotized cats at a dose action in substances related to chlorpromazine does of 4 mg per kg, intramuscularly (Boissier & Pagny, not exclude antitussive effectiveness. 1960a, 1960b). Up to 40 mg per kg, it also had an Tomori et al. (1960) studied the effect of neurolep­ antitussive effect in unanaesthetized guinea-pigs ex­ tics on tracheal and bronchial reflexes in man. Ten posed to sulfur dioxide, without producing sedation. patients under (1) ether-oxygen anaesthesia, (2) Certain hypnotics then may cause specific antitus­ autonomic blockade with the " lytic cocktail " or (3) sive effects. A broader examination of the antitussive blockade plus hypothermia, were stimulated mechan­ potency of sedatives (hypnotics) is desirable to deli­ ically in the lower trachea. Signs of positive reflex neate better the relation between sedation and cough activity were coughing and apnoea. A positive res­ relief. ponse failed to occur in 12% in (1), 26.5% in (2) and Lorenz (1962) studied the sedative and antitussive 46.9% in (3). The mechanism of the cough de­ effects of dipropylbarbituric acid, codeine, and a mix­ pressing effect is a matter for speculation, since the ture of the two in guinea-pigs and cats. In anaesthe­ composition of the " lytic cocktail " was not dis­ tized cats, stimulated electrically, the antitussive effect closed but may have contained chlorpromazine or of intravenous codeine was not increased by the addi­ pethidine or both. There may have been a deepening tion of the barbiturate. In unanaesthetized guinea­ of the ether narcosis or strengthening of the antitus­ pigs, however, the cough reflex was depressed by sive action of pethidine. smaller doses of codeine in the mixture than when it was given alone, subcutaneously or orally; the Ganglionic blockade. Three observations may jus­ sedative effect of the barbiturate in the mixture was tify a consideration of whether ganglionic blockade also enhanced. Whether this was potentiation of anti­ can influence the cough reaction. Tiffeneau (1955) tussive action or of sedation was not clarified. found that inhalation of hexamethonium instantly 142 N. B. EDDY AND OTHERS stopped the excessive cough reactions produced showed similar properties. Oxeladin exerted papa­ in man by inhalation of acetylcholine aerosol. Hillis verine-like spasmolytic action on the isolated ileum & Kelly (1951) suppressed the cough, produced in (David, Leith-Ross & Valiance, 1957) and on the human volunteers by intravenous injection of lobe­ tracheal chain preparation (Ozawa et al., 1962). The line, also by using hexamethonium. Korpas, Tomori thiambutene derivative, AT-327, had little spasmo­ & Ivanca (1957) studied the cough-depressing effect lytic effect (Kase et al., 1959). ofpentamethonium in cats. Doses, which were under Epinephrine caused no depression of the cough some experimental conditions slightly effective reflex, mechanically stimulated in unanaesthetized against cough reactions, were considerably higher dogs (Kase, 1955), but ephedrine, less effective as a than those which paralyse the cervical ganglion. bronchodilator, depressed the cough in 6 out of 12 Tests with quaternary salts of antitussive agents gave dogs, at a dose of 5.0 mg per kg, intravenously. no convincing evidence that ganglionic blocking con­ Increasing the dose to 10-20 mg per kg did not pro­ tributes to the cough-depressing effect. duce an effect in the dogs which did not respond. Methamphetamine 1 was more centrally exciting than Local anaesthetic effect. The role oflocal anaesthe­ ephedrine, and had antitussive (Kase, 1955) and sia in antitussive action has been discussed (see above, analgesic (Suter, 1951) properties. Part 3, section headed" Reflexogenic receptor area"). Codeine, as well as morphine, causes slight bron­ Spasmolytic and spasmogenic effects. The evidence choconstriction (Krueger, Eddy & Sumwalt, 1943; in this connexion may be summarized briefly. Konzett, 1955; La Barre & Plisnier, 1959) and the Some antihistamines depress experimental cough codeine bronchospasm can be relieved partly by in laboratory animals and in man (see Part 4). How­ isoprenaline (Friebel & Kuhn, 1962). Pholcodine ever, Boissier & Pagny (1960a, 1960b) concluded that also has a bronchoconstrictor effect comparable to antihistamines were not antitussives per se. They that of codeine (Plisnier, 1960). Antitussive potency could not demonstrate a parallelism of antihistaminic would not appear to be impaired, though warnings and antitussive potencies. with respect to impairment of respiratory function Atropine was tested in unanaesthetized dogs by have been expressed, especially if a bronchospastic Kase (1955). It had no cough-depressing action in condition already exists. doses of0.1-5.0 mg per kg, intravenously. Silvestrini All of this does not suggest any significant relation­ & Maffii (1959) observed no significant effect of ship of spasmolytic or spasmogenic effects to anti­ atropine on the acrolein-induced cough in guinea­ tussive action, though under some circumstances a pigs; the doses used were 1.0-5.0 mg per kg, sub­ potent bronchodilator may help in the relief of an cutaneously. Bobb & Ellis (1951) treated with atro­ associated condition. pine and curare unanaesthetized dogs, in which the Augmentation and reduction of bronchial secretion. vagus loop was electrically stimulated: both were Noscapine, 1.0-2.0 mg per kg, intravenously, in­ ineffective. creased bronchial secretion in anaesthetized rabbits Domenjoz (1952), Kase (1955) and Hara & Yanau­ (Konzett & Rothlin, 1954; La Barre & Plisnier, 1959; ra (1959) showed no definitive effect of papaverine Plisnier & Hernalsteen, 1959). The dose was sufficient in dogs and cats, though the doses were high in com­ to depress the cough. Caramiphen ethane disulfonate parison with that of codeine. This is discussed more also increased bronchial secretion in the same type of fully in Part 4. experiment at 6.0 mg per kg, intravenously (Plisnier, lsoaminile relaxes other smooth muscle, isolated 1957). Silomat, 40 mg per kg intravenously, increased rabbit uterus and intestine, and inhibits the peristal­ bronchial secretion in rabbits by 20-45% for 2-6 tic reflex (Krause, 1958; Graham, 1962). Clofedanol hours (Engelhorn, 1960). and nicodicodine relaxed the rabbit duodenum and Pholcodine, orally or subcutaneously in doses of relieved spasms induced by barium chloride or acetyl­ 0.1-50 mg per kg, did not cause a significant change choline (Cahen & Boucherle, 1964, 1965). Oxolamine in output of respiratory-tract fluid; nor did diphen­ was about as active as papaverine in its inhibitory hydramine (Bidwell & Boyd, 1952). effect on the tracheal chain preparation (Silvestrini Bedell & Seebohm (1959) warned against the use & Pozzatti, 1960; Balea & Buret, 1964). Caramiphen of codeine in patients with emphysema because of prevented or retarded bronchoconstriction provoked its drying effect. Boyd & Trainer (quoted by Boyd, in guinea-pigs by injection or inhalation of acetyl­ choline or histamine (Plisnier, 1957). Pentoxyverine 1 Also known as methylpropamine. CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 3 143

1954) recorded a decrease in bronchial secretion after Perhaps with greater significance for the therapeu­ dextromethorphan. Clofedanol (Boyd & Boyd, 1960) tic use of codeine in man, it would be interesting to and pentoxyverine (Levis et al., 1955) decreased the know if codeine could depress or abolish cough, in secretion of saliva and presumably of bronchial fluid. animals, which occurred spontaneously in bronchitis, There is no clinical evidence that antitussive ther­ for example. Stefko, Denzel & Hickey (1961) report­ apy is significantly affected by the changes in secre­ ed suppression of cough due to upper respiratory tion described. infection, in a dog for 30 minutes with 1.0 mg per kg and for 38 minutes with 2.0 mg per kg, orally. Exper­ ANTITUSSIVE ACTION OF CODEINE imentally produced cough in dogs has been abolished by codeine, if the conditions were adequate, for 40 Animal experiments minutes with 4.0 mg per kg, orally, for example, Many reports of attempts to evaluate the antitus­ when the cough was elicited by electrical stimulation sive effectiveness of codeine in animals are summa­ of the trachea. Chen, Biller & Montgomery (1960) rized in Table 27. These have been arranged by have reported complete suppression of cough pro­ species and by the method of cough production, duced in dogs by chemical stimulation. though the latter has not been uniform in detail, Other authors who have attempted to establish even when the cough-provoking stimulus was said to dose-effect relationships have not been successful in be the same. Some of these variations have been obtaining lOO% suppression of experimentally in­ discussed previously (see Part 3, section headed duced cough (Kallquist & Melander, 1957; Silves­ " Measurement of antitussive potency in animal trini & Maffii, 1959; Engelhom, 1960). The explana­ experiments "). Also the effective doses for the most tion may lie in the experiments of Rosiere, Winder part are indicative only of reduction or depression of & Wax (1956) which showed that complete inhibition the cough of varying degree, an ED50 having been of cough could be overcome by intensifying the calculated only in rare instances (those doses are cough-provoking stimulation, but that stronger stim­ marked in Table 27). Consequently, doses range ulation could be overcome only to a certain extent widely, even for similar methods and species, from by increasing the dose of codeine. 10 to 26 mg, subcutaneously or intraperitoneally, in Onset and duration of action of codeine in relation mice, rats and guinea-pigs with irritant vapour to experimentally induced cough in animals have inhalation, but calculated ED60s vary widely also, been studied by Winter & Flataker (1954), Kase 10 mg per kg and 13.5 mg per kg, subcutaneously, in (1955), Chen, Biller & Montgomery (1959), Engel­ rats, 25 mg per kg by the same route in guinea-pigs hom (1960), Stefko, Denzel & Hickey (1961), Kraus­ with sulfur dioxide inhalation. If ammonia vapour haar, Schunk & Thym (1964), Hahn & Friebel (1966), was used in guinea-pigs the effective dose was only and others. In conscious dogs, for example, some 0.3 mg per kg, subcutaneously. Even so the dose had cough-depressing action has been observed 15 min­ to be increased remarkably, to 12 mg per kg, if the utes after oral administration, peaks of action at drug was given orally. In rabbits also, with cough pro­ 45-60 minutes after ingestion (Chen, Biller & Mont­ duced by mechanical stimulation, there was a consid­ gomery, 1959; Stefko, Denzel & Hick~y, 1961) and erable ratio between oral and parenteral effective a duration of action mainly dependent upon the dose doses. In cats there was very wide variation in of codeine but usually not exceeding three hours. effective dosage. Electrical stimulation and intra­ Repetition of codeine doses at short intervals was venous administration were commonly used in this followed by tolerance to antitussive action (Kase, species but mostly in anaesthetized animals. The 1955; Friebel & Kuhn, 1964). In the experiments of anaesthetic, usually a barbiturate, possessing in itself Kase, dogs were injected intravenously daily. The some cough-depressing action (see above, Part 3, sec­ initial dose of 10 mg per kg depressed coughing for tion headed " Sedative and tranquillizing effect ") 20-30 minutes on the first day; the same dose was might be in part responsible for these variations, ineffective on the 14th day of administration. The because of differences in depth of anaesthesia, but cough-depressing effect, which reappeared when the there are many other variables in these experiments. dose was increased to 15 and 20 mg per kg, was The sensitivity of dogs to the cough-depressing action reduced again in 4-10 days. Friebel & Kuhn treated of codeine appears to be high and more uniform, guinea-pigs and rats with codeine, subcutaneously, with a dose range of only 0.5-7.5 mg per kg for three times a day for six to seven weeks. The daily various procedures and routes of administration. dose was increased from 20 to 110 mg per kg and 144 N. B. EDDY AND OTHERS

TABLE 27 ANTITUSSIVE ACTION OF CODEINE IN ANIMALS

Route I Effective Cough-provoking agent I Anaesthesia of admi- dose Reference nistration a (mg/kg)

Species: MOUSE

Sulfuric acid aerosol 0 se 10.0 Kelenty et al. (1957) Sulfuric acid aerosol 0 se 10.0b Kelenty et al. (1958)

Species : RAT

Sulfur dioxide vapour 0 se 10.0 b Friebel & Kuhn (1964) Sulfur dioxide vapour 0 se 10.0 b Reichle & Friebel (1955) Sulfur dioxide vapour 0 se 13.5 b Hengen & Kasparek (1958) Sulfur dioxide vapour 0 se 26.0 b Weidemeyer, Kramer & DeJongh (1960)

Species: GUINEA-PIG

Sulfur dioxide vapour 0 se 15.4b Friebel & Kuhn (1962) Sulfur dioxide vapour 0 se 20.0 Boissier & Pagny (1960) Sulfur dioxide vapour 0 se 19.0b Friebel & Kuhn (1964) Sulfur dioxide vapour 0 lP 30.0 Cahen & Boucherle (1964) Sulfur dioxide vapour 0 IV 10.0 Green & Ward (1955)

Ammonia vapour 0 0 12.0 Sail~ & Brunaud (1960) Ammonia vapour 0 se 0.3 b Graham (1962) Ammonia vapour 0 se 0.5-2.0 W nter & Flataker (1954) Ammonia vapour 0 se 1.0 Silvestrini & Maffii (1959) Acroleine vapour 0 se 3.5 Silvestrini & Maffii (1959) Acroleine vapour 0 lP 1.0-2.0 Silvestrini & Pozzatti (1961)

Species: RABBIT

Mechanical stimulation of the trachea 0 0 100.0 Furakawa & Okabe (1958) Mechanical stimulation of the trachea 0 IV 3.0-4.0 Furakawa & Okabe (1958) Mechanical stimulation of the trachea 0 IV 13.5 Graham (1962)

Species: CAT

Ammonia vapour + IV 1.5 Silvestrini & Maffii (1959) Ammonia vapour + IV 3.5 Pellmont & Bachtold (1954) Ammonia vapour + IV 10.0 Mulinos (1960) Ammonia vapour (+)C se 0.61 Engelhorn (1960) Ammonia vapour lP 15.0 Cahen & Boucherle (1964) Mechanical stimulation of the trachea (+)C IV 0.74 Engelhorn (1960)

Mechanical stimulation of the trachea + IV 3.0 Silvestrini & Maffii (1959) CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 3 145

TABLE 27 (continued)

Route I Effective Cough-provoking agent Anaesthesia of admi- dose Reference I I nlstration a I (mg/kg)

Species: CAT (continued)

Mechanical stimulation of the trachea + IV 10.0 Mulinos (1960) Mechanical stimulation of the trachea + IV 16.3 May & Widdicombe (1954) Sterile pleurisy 0 se 2.5-3.0 Van Dongen (1956) Soap powder insufflation + IV 1.5 Pellmont & B!ichtold (1954) Electrical stimulation of the superior laryngeal nerve + IV 1.0--3.0 Domenjoz (1952) Electrical stimulation of the superior laryngeal nerve (+)• 0 8.1 Engelhorn (1960) Electrical stimulation of the superior laryngeal nerve <+>· IV 0.52 Engelhorn (1960) Electrical stimulation of the superior laryngeal nerve lP 1.0 Cahen & Boucherle (1964) Electrical stimulation of the superior laryngeal nerve + IV 1.0 Plisnier (1958) Electrical stimulation of the superior laryngeal nerve + IV 1.5b Kohli et al. (1960) Electrical stimulation of the superior laryngeal nerve + IV 1.5 Levis, Preat & Moyersoons (1955) Electrical stimulation of the superior laryngeal nerve + IV 1.5 Klein (1958) Electrical stimulation of the superior laryngeal nerve + IV 0.5-2.0 Boissier & Pagny (1960a, 1960b) Electrical stimulation of the superior laryngeal nerve + IV 0.6-3.0 Haas (1955) Electrical stimulation of the superior laryngeal nerve + IV 4.0b Green & Ward (1955) Electrical stimulation of the medulla + IV 1.0-6.0 Matallana & Borrison (1955) Electrical stimulation of the medulla + IV 4.0-10.0 Chakravarty et al. (1956) Electrical stimulation of the trachea + IV 1.0 Toner & Macko (1952) Electrical stimulation of the trachea + IV 1.5 Silvestrini & Maffii (1959) Electrical stimulation of the trachea + IV 2.3 Green & Ward (1955)

Species: DOG

Sulfuric acid aerosol 0 0 0.5 Winter & Flataker (1952) Sulfuric acid aerosol 0 se 1.0 Silvestrini & Maffii (1959) Sulfur dioxide vapour 0 1.0 Chen, Biller & Montgomery (1960) Sulfur dioxide vapour + IV 1.0 Green & Ward (1955) Ammonia vapour 0 se 2.5-5.0 Winder & Rosiere (Personal communication, 1954) Ammonia vapour 0 se 2.0 b Rosiere & Winder (1955) Ammonia vapour 0 se 1.0-5.7 Winder & Rosiere (1955) Ammonia vapour 0 se 2.8 Winder et al. (1961) Ammonia vapour 0 se 1.0-5.7 Rosiere, Winder & Wax (1956)

10 146 N. B. EDDY AND OTHERS

TABLE 27 (concluded)

Route Effective Cough-provoking agent Anaesthesia of admi- I dose Reference I I nistration a (mg/kg)

Species: DOG (continued)

Mechanical stimulation of the trachea 0 se 3.31 b Tedeschi et al. (1959) Mechanical stimulation of the trachea 0 lP 7.5 Cahen & Boucherle (1964) Mechanical stimulation of the trachea + IV ea 1.0 Green & Ward (1955) Mechanical stimulation of the trachea 0 IV 2.0-4.0 Kase (1952) Tracheal electrodes 0 0 0.25-4.0 Stefko, Denzel & Hickey (1961) Tracheal electrodes se 3.5 Silvestrini & Maffii (1959) Tracheal electrodes 0 se 1.0-4.0 Stefko & Benson (1953) Tracheal electrodes 0 se 1.0-4.0 Benson, Stefko & Randall (1953) Tracheal electrodes 0 IV 2.0-4.0 Granier-Doyeux et al. (1959) Tracheal electrodes 0 2.5-3.5 Hara & Yanaura (1959) Tracheal electrodes + 5.0 Graham (1962) Pathological 0 0 1.0-2.0 Stefko, Denzel & Hickey (1961)

a SC = subcutaneous, lP = intraperitoneal, IV = intravenous, and 0 = oral. b Dose so marked is the calculated EDso. c ( +) = Light anaesthesia. from 20 to 150 mg per kg for the guinea-pigs and rats, decreased by a maximum of 5.2 in the normal sub­ respectively. The antitussive ED50 for guinea-pigs jects and by 5.9 in the asthmatics. In a later study increased from 19 to 55 mg per kg, and for rats from Bickerman et al. (1957) used individually determined 10.9 to 32.5 mg per kg. Tolerance in guinea-pigs citric acid aerosol concentrations as the cough­ decreased slowly over a period of 27 weeks; it could provoking stimulus and a pneumotachograph for be induced again but at a slower rate. The graph of cough registration. They demonstrated a statistically the onset and decline of tolerance was linear if log significant dose-related decrease in the cough res­

ED60s were plotted. ponse after oral doses of 5, 15 and 30 mg of codeine as shown below. Experimentally induced cough in man Initial Percentage decrease after The antitussive action of codeine on experimental­ Dose no. of (hours) (mg) coughs 2 3 4 ly produced cough in man has been studied exten­ Placebo sively by many authors with various methods. Most 2.67 -7.5 +2.5 +5.0 +25.0 have found it more or less effective, only a few have 2.81 +10.6 +1.3 -4.3 +12.8 failed to demonstrate a cough-depressing effect. The 3.33 -8.0 -12.0 -12.0 +2.0 results are summarized in Table 28. Codeine Bickerman & Barach (1954) subjected 21 selected 5 2.76 -17.2 -22.4'" -22.4'" -17.2 healthy adults and 17 patients with bronchial 15 2.22 -32.4'" -32.5'" -27.5'" -10.0 asthma to a 5-10% citric acid aerosol for five in­ 30 3.22 -32.8'" -43.1'" -34.5'" -22.4'" halations and obtained a fairly consistent cough * Significant difference. response, with a mean of 4.8 coughs in the normal subjects and 6.6 in the asthmatics. During the three­ Shane, Krzyski & Copp (1957), Rasch (1957), hour observation period following oral administra­ Archibald, Slipp & Shane (1959) and Calesnick, tion of a placebo or 30 mg of codeine in random Christensen & Munch (1961) demonstrated the anti­ order under double-blind conditions, the mean cough tussive effectiveness of 15 or 25 mg of codeine in response was not reduced after the placebo but was their experiments based in general on Bickerman's CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 3 147

TABLE 28 EFFECT OF CODEINE ON EXPERIMENTALLY INDUCED COUGH IN MAN

Route of No. and kind Cough-inducing agent Dose admi- Effect Criteria for evaluation Reference of subject (m g) nistra- lion a

21 Normal, selected 10% Citric acid aerosol 30 0 + Decrease in no. of coughs Bickermann & Barach (1954)

17 Asthmatics 30 0 +

13 Normal 5-15% Citric acid aerosol 10~0 se 0 Decrease in no. of coughs Gravenstein, Devloo & Bucher (1954) 20 Patients 15% Citric acid aerosol 32.5 0 + Decrease in no. of coughs Shane, Krzyski & Copp (1957) 20 Normal 10% Citric acid aerosol 25.0 0 + Percentage reduction in Rasch (1957) (syrup) cough 19 Normal, trained 10% Citric acid aerosol 5, 15, 30 0 + Percentage reduction in Bickermann et al. (1957) cough 14 Normal, selected 10-15% Citric acid aerosol 30 0 + Decrease in no. of coughs Archibald, Slipp & Shane (1959)

24 Mainly 10-15% Citric acid aerosol 30 0 (+)b Decrease in no. of coughs Groszman, Birker & tuberculous Casimir (1961) 70 Normal 25 % Citric acid aerosol 15 0 + Decrease in no. of coughs Calesnick, Christensen & Munch (1961) 6 Normal, selected 10% Citric acid aerosol 15 0 0 Decrease in no. of coughs Tannenbaum (1965) 30 + 6 Normal 5-25 %Citric acid aerosol 15-30 0 0 Decrease in no. of coughs Sevelius, Lester & Colmore (1965) 9 Normal Citric acid aerosol 30 0 + Increase in threshold Silson (1965) 32 Normal, selected 25% Citric acid aerosol 5-120 0 + Increase in latency Calesnick & Christensen (1967) 15 Normal Ammonia vapour 10-30 0 + Total rise in threshold Hoglund & Michaelsson (1950) Normal Ammonia vapour + Hahn & Wilbrand (1952) 6 Normal Ammonia vapour 10-40 0 + Total rise in threshold Trendelenbarg (1950) 30 Normal Ammonia vapour 20 0 + Increase in threshold Blix (personal communi cation 1952)

24 Normal Ammonia vapour 1~0 se 0 lncreasei n threshold Gravenstein, Devloo & Beecher (1954) Patients, respira- Acetylcholine aerosol, 1% 40 0 (+)b Decrease in no. of coughs Tiffeneau (1955) tory disease 120 Patients, Acetylcholine aerosol, 30 0 + Suppression of cough Haslreiter (1959) respiratory disease 0.1-1% 12 Patients, Acetylcholine aerosol, 1 % 16 0 + Decrease in no. of coughs Prime (1961) respiratory disease

12 Smokers Acetylcholine aerosol,! % 30 0 0 Decrease in no. of coughs Sevelius, Lester & Colmore (1965) 1 Normal Peppermint water spray, 40 se 0 Percentage reduction of Hillis (1952) 1:40 180 0 0 cough Normal Lobeline High IV 0 Suppression of cough Hill is & Kelly (1951)

5 Normal Paraldehyde 10-60 IV 0 Decrease in no. of coughs Gravenstein, Devloo & Beecher (1954) Normal Paraldehyde 0 Suppression of cough Konar (1959)

a 0 = oral, SC = subcutaneous, and IV = intravenous. b Slight effect. 148 N. B. EDDY AND OTHERS method. Tannenbaum (1965) obtained results which acetylcholine inhalation methods feasible for anti­ were not significant for a 15-mg dose of codeine but tussive testing. which showed significant cough suppression with Hoglund & Michaelsson (1950), who were the 30 mg compared with a placebo. Groszman, Birker first to develop a method for induction of cough, or & Casimir (1961) found a moderate antitussive effect its equivalent, experimentally in man, added amounts with 30 mg of codeine, orally, which was greater in of ammonia to the inspired air with human volun­ those tuberculous patients who responded only mod­ teers. The closure of the glottis and the momentary erately to a citric acid aerosol. pause in respiration which followed was considered Silson (1965) made his subjects inhale a fixed con­ a substitute for a cough response and the antitussive centration of citric acid aerosol continuously until a effectiveness of codeine was calculated from the cough response occurred. From the time for this to amount of codeine required to raise the threshold. occur and the concentration of the aerosol, a citric A dose-response curve was established for 10, 15, 20 acid threshold stimulus was calculated and effect was and 30 mg of codeine. Trendelenburg (1950) used the expressed as percentage increase of this threshold. same method and criteria and found a good dose­ An oral dose of 30 mg of codeine raised the threshold response relationship for 10-40 mg of codeine, orally, in the nine subjects tested. as shown below.

Calesnick & Christensen (1967) considered the Codeine Maximum Duration Total effect dose No. threshold of elevation latency of response (time elapsing between beginning (mg) of trials elevation (min) (%Xtime) of inhalation of a constant citric acid concentration (%) and occurrence of cough response) to be a purely 10 3 62 60 2 310 objective index useful for measuring antitussive po­ 20 15 119 72 4 695 30 5 91 100 4 780 tency. By this parameter a single oral dose of 5 mg 40 3 137 80 5 950 of codeine exerted a measurable antitussive effect, differing with statistical significance from the res­ In nearly all cases the threshold returned to the ponse to a placebo. A dose-response curve was initial value within the 3-4 hour observation period. plotted for doses of 5-120 mg with the maximum Hahn & Wilbrand (1952) and Blix (personal com­ effect at 40 mg of codeine. These authors also stud­ munication, 1952) also reported a depressing action ied the influence of the citric acid concentration in of codeine on ammonia-induced cough. the aerosol on the cough-suppressant effect of a Tiffeneau (1955), who initiated the use of an acetyl­ constant dose of 40 mg of codeine. When the amount choline aerosol for cough production, saw only a of citric acid provided supramaximal stimulation, a very moderate eff<(ct on the cough frequency by an gradual reduction in the antitussive effectiveness of oral dose of 40 mg of codeine. Haslreiter (1959) codeine occurred until a cough-suppressing action conducted a double-blind trial on 120 patients with could not be distinguished from the response to respiratory disease, who coughed in response to indi­ placebo. vidually determined concentrations of acetylcholine Gravenstein, Devloo & Beecher (1954) were unable aerosol. After 30 mg of codeine, orally, coughing to detect a cough-suppressing effect of oral doses bouts could not be induced with the same concentra­ of 30 mg of codeine, whether citric acid aerosols, tion of acetylcholine in 58% of the patients; coughing ammonia inhalations or intravenous paraldehyde bouts could not be induced in 6% of the patients injections were used as stimuli, because of the great after a placebo. Prime (1961) using a 1% acetyl­ variability in the reactions of the subjects. Other choline aerosol demonstrated a significant decrease antitussives used for comparison also failed to in the number of coughs in 12 patients, 20 minutes demonstrate effectiveness, except for heroin after after an oral dose of 20 mg of codeine. Comparison paraldehyde injection. was with a placebo in random order under double­ Sevelius, Lester & Colmore (1965) said that their blind conditions. subjects became adapted to the citric acid aerosol Other attempts to demonstrate an antitussive effect and consequently an antitussive effect of 30 mg of of codeine on cough induced by other procedures codeine was not demonstrated. Using an acetyl­ have failed. Hillis (1952) used a peppermint: water choline aerosol to induce cough, the effect of 30 mg spray (1 : 40). Codeine, 60 mg subcutaneously, or of codeine was no greater than that of a placebo whe­ 180 mg orally, did not reduce the number of coughs ther the post-drug test was made at 60 or 120 minutes. but morphine did. Hillis & Kelly (1951) injected Other authors have regarded the ammonia and lobeline intravenously. A substantial dose of mor- CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 3 149 phine or codeine did not block the resulting cough 87% experienced relief while only 14% of those on but hexamethonium was effective. According to placebo registered improvement. Di Gregorio (1960) Gravenstein, Devloo & Beecher (1954) and Konar demonstrated a good antitussive effect of 30 mg of (1959) the cough following intravenous injection of codeine, given three times a day, on acute as well as paraldehyde could not be influenced by codeine. on chronic cough. Gravenstein, Devloo & Beecher (1954) and Gra­ Clinical trials and experience (Table 29) venstein & Beecher (1955) devised an objective meth­ od of cough counting by means of a sound recorder The first report on a clinical trial of codeine as an and compared the results of therapy obtained by antitussive which might meet today's standards was subjective assessment of coughing with the actual by Davenport (1938). He compared, double-blind, cough counts. While a difference of statistical sig­ oral doses four times a day of dihydroisocodeine and nificance in the patients' judgement of antitussive codeine in tuberculous patients. Evaluation was by effectiveness of codeine and heroin against placebo subjective effect following medication and the two was found, at least in one of the two groups of drugs were judged equally effective. There was no patients, the cough counts did not show a corre­ comparison with placebo. The antitussive effective­ sponding difference. From this the authors suggested ness of codeine was accepted without question at that that the activity of antitussives, especially of codeine, time, though it had not been established for patholo­ consisted essentially in a modification of psycho­ gical cough in man by placebo comparison. Him­ logical factors so that patients felt better and thought melsbach et al. (1940) added placebo to a double­ they coughed less when changes in the cough fre­ blind comparison of morphine and codeine as quency did not occur. antitussives. The cough of the majority of the Proof to the contrary was obtained subsequently patients worsened when codeine was replaced by by Cavalieri et al. (1960), Nicolis & Pasquariello placebo and improved when the switch was to mor­ (1962a, 1962b) and Pasquariello & Nicolis (1962). phine. No change occurred when a 2-mg dose of They counted the number of coughs for a three-hour morphine was replaced by 10 mg of codeine. These period following the oral administration of 60 mg of authors believed 10 mg of codeine to be an optimal codeine or placebo and demonstrated a significant dose and 30 mg unnecessarily large. difference. The same patients were evaluated for Cass & Frederik (1953) compared 17 mg of codeine their subjective response. They preferred codeine, 4 times a day with 4 mg of dextromethorphan and 15 patients to 5, but scores based on patients' a placebo in 65 patients with chronic cough under judgement of cough intensity showed no marked double-blind conditions, and clearly established the difference between codeine and placebo. antitussive effect of codeine. Their patients identified Woolf & Rosenberg (1962) compared, in a double­ two of the three coded placebo medications correctly blind trial, codeine in syrup, 32.4 mg five times daily, as least effective and the three coded codeine prepa­ with the syrup alone and found a definite antitussive rations as most effective. The authors transformed effect of codeine by a preference-ranking scheme. In subjective assessment of cough severity into an aver­ a subsequent study (Woolf & Rosenberg 1964), in age cough-intensity score for each treatment. In which cough was sound-recorded over a 24-hour another trial Cass, Frederik & Andosca (1954) period, the syrup with codeine, 32.4 mg five times a demonstrated the ability of their patients to discern day, was significantly more effective compared with correctly differences in the antitussive effectiveness a control period and to a period of administration of three different doses of dextromethorphan. The of syrup alone. Thus they showed antitussive poten­ placebo medication was least effective and the cough­ cy for codeine by both subjective and objective intensity score of 15 mg of codeine lay between those methods of evaluation. of 12 and 18 mg of dextromethorphan. Sevelius & Colmore (1967) also found 15 mg of Abelmann, Gaensler & Badger (1954) found codeine, three times a day, more effective than 16.2 mg of codeine three times a day more effective placebo by subjective and objective methods. In than placebo, measured by days in which cough was 12 male hospitalized patients with chronic cough, improved. Haslreiter (1959) assessed the effect of the coughing pattern was determined for two days. 30 mg of codeine three times a day against placebo If the counts agreed within 20% the experiment was in a double-blind trial on 60 patients during a test continued with alternative administration of drug of pipazetate. Of the patients receiving codeine, and placebo. The reduction in the number of coughs -VI 0 TABLE 29 CLINICAL TRIALS AND EXPERIENCE WITH CODEINE AS AN ANTITUSSIVE

No. of Other drugs in the trial Eva- doses of No. of Type Duration Result Criteria patients of cough of trial lua- codeine/ (codeine/ for evaluation No. of I Drug rank Reference tion a day placebo) Drug doses/ Result (m g) day I (m g)

12 Tubercu- s 1 x10 9 out of 12 worse Patient's comparison Morphine 1x2 M=C>P Himmelsbach et al. lous on placebo (1940) 65 Chronic 5 days s 4x 17 Codeine most Cough intensity Dextromethorphan 4X4 D=XC Cass & Frederik effective score: O=none, (1953) 4=incessant cough 69 Chronic s 3x 15 1.262/1.488 Cough intensity Dextromethorphan 3x 6 1.365 D=C>P Cass, Frederik & score, as in preceding Dextromethorphan 3X12 1.283 Andosca (1954) reference Dextromethorphan 3x18 1.252 :z: 20 Chronic 7 days s 3x 16.2 Codeine 23.7% Improvement versus Caramiphen 3x10 11.5% C>Car>P Abelmann, Gaens- != placebo ler & Badger (1954) 28 Chronic 3 days s 3x 15 29/10 Cough score: Dextromethorphan 3x10 9 H>C>P=D Graven stein, better=1, same=O, Heroin 3x 5 39 Devloo & ~ worse= -1 Beecher (1954) Same Chronic 6 hours 0 3x10 88%/100% Cough count corn- Dextromethorphan 3x 10 91% Gravenstein, ~ pared b to placebo Heroin 3x 5 88% Devloo & as 100 Beecher (1954) 63 Chronic 10 days s 4x15 0.78/1.25 Cough intensity score Caramiphen 4x 10 1.05 C>D>Car>P Gravenstein, Dextromethorphan c 4x20 0.92 Devloo & Beecher ~ 4x10 0.86 (1954) "' 60 Chronic 30 days s 3x30 87%/14% Cough reduction Pipazetate 3x20 64% C>Pip>P Haslreiter (1959) based on 4-point scale 13 Chronic 5 days s 4x30 2.81/3.03 Cough-severity scale C>P Cavalieri et al. 13 Chronic 8 days s 4x30 2.13/1.88 improvement in 3 h C>P (1960) 21 Chronic 3 hours 0 1 x60 6.62/13.05 Observer cough C>P Cavalieri et al. count (1960) 65 Chronic s 3x30 75.%/39.2% Improvement based Oxolamine 3x 100 64.4% C>O>P Di Gregorio (1960) 43 Chronic s 3x30 64.7%/35.6% on better, same or Oxolamine 3x 100 64.2% C=O>P 25 Acute s 3x30 71.3%/28.5% worse Oxolamine 3X 100 82.3% O>C>P 34 Chronic 3 hours 0 1 x30 14.1 %/21.0% Observer cough C>P Nicolis & i count Pasquariello (1962b) 40 Chronic 3 hours 0 1 X60 9.8/14.5 I Observer cough count Benzobutamine 1 X250 10.4 C>B>P Pasquariello & Same Chronic 3 hours s 1 x60 Preference 17/5 Patient preference Benzobutamine 1 x250 15 first C>B>P Nicolis (1962) I I I ------TABLE 29 (continued)

- "-" - -- No. of Other drugs in the trial ---·---- Type Duration Eva- doses of Result No. of lua- codeine/ (codeine/ Criteria patients of cough of trial for evaluation Drug rank Reference tion a day placebo) Drug -~-···"Tdoses/ Result (m g) - day -- (m g)

(") 43 Chronic 5 days s 4x30 2.88/2.45 Cough intensity, C=P Nicolis & 8 56 Chronic 2 days s 4x30 3.02/3.43 average daily rating, C=P Pasquariello !:l 4-point scale C>P (1962a) ~ 30 Chronic 3 hours 0 1 x60 6.4/11.7 Observer cough count C>P Nicolis & 22 Chronic 3 hours 0 1 x60 8.2/13.5 Observer cough count C>P Pasquariello ~ 33 Chronic 3 hours 0 1 x60 9.6/14.5 Observer cough count C>P (1962a) 0 30 3 weeks s 3x 13.5 No difference Patient preference on lsoaminile 3x40 C=I=P Graham (1962) a weekly questioning > 51 Chronic s 2-4x 10-20 7.0%/23% Degree of complete Pholcodine 2-4x 10-20 100% Ph>C C

C>P Epstein (1962) lous relief I Same Tubercu- s 1 x20 36%/7% Degree of complete Pholcodine 1 x20 63% Ph>C>P Epstein (1962) "'>Tj lous relief ~ 30 Chronic 1 day s 5x 32.4 66.6%/33.3% Patient preference C>P Woolf& Same Chronic s 5x32.4 46.6 %/19.8 % Patient preference C>P Rosenberg (1962) ~z 30 Chronic 24 hours 0 5 x32.4 27/51 Average number of Laevopropoxyphene 5x100 57 C>H>L Woolf & coughs in 2 hours, Heroin 5x2.7 38 Rosenberg (1964) ~ tape recorded 0 37 Chronic 6 days s 4x 15 1.497/0.683 Cough-relief score, Silo mat 4x40 1.053 S>C>P Cass & Frederik (") 5-point scale 4x80 1.269 (1964) g 196 Acute 2 days s 3x40 67.7 %/29.0% Decrease in Silomat 3x60 56.9% C=S>P Renovanz & ~ frequency d 63.1% C=S>P Liebrich (1965) ~ 64.5 %/32.3 % Decrease in tl1 intensity d t: 12 Chronic 3 days s 3x 15 58.7%/16.6% Patient's judgement Ethyl dibunate 3x50 16.6% C>D=P Sevelius & :;1 '" of improvement Colmore (1967) w Same Chronic 24 hours 0 3x15 -107/+36 Change in cough count

------"------

a S = Subjective; 0 = Objective; cough count by various means. b Sound recorder and intermittent counting by observer. c Patients failed to discriminate between 10 and 20 mg of dextromethorphan. d Patients' judgement of improvement. -VI 152 N. B. EDDY AND OTHERS

TABLE 30 CODEINE DOSAGE REPORTED OR RECOMMENDED

Kind of patient Dosage (mg single or dally) Reference

Cough of various origin 64.5 Saundby (1879) Tuberculous 30 Schroder (1899) Cough of various origin 25-30 Behrens (1932) Cough of various origin 16.2-32.4 Pottenger (1934)

Severe cough 3~0 Fantus (1936) Tuberculous 1 or 2x20 Davenport (1938) Acute influenza 3x 10, with papaverine Moll (1953) Cough due to neurosis o(habit 64.8 every 3 h for 2 days Douglass (1954) Irritative cough in postoperative 3-4x 15-20 drops of 3% solution PrOssing (1960) Children with bronchial asthma Glaser (1961) 1-3 years of age 3-5

3-5 years of age 5~ 5-10 years of age 6-9 > 10 years of age 9-12 Acute and chronic cough 4x 12-30 Anonymous (1962) Cough due to cold 16.2 Glick (1963)

( -107) paralleled the subjective judgement of im­ A few investigators for various, and often un­ provement (seven of 12 patients improved a lot). known reasons have failed to demonstrate codeine Placebo and 50 mg of ethyldibunate included in the superiority over placebo subjectively or objectively comparisons showed no effect by the objective meth­ but the majority have found it superior in reducing od and only two of 12 claimed marked improvement cough frequency and intensity, and in giving relief with ethyldibunate or placebo. from cough as a symptom; in one-third of the trials Renovanz & Liebrich (1965) reported significant the difference has been proven statistically. The trials effectiveness of codeine in a controlled clinical trial have shown that a single dose of codeine of 30-60 mg, on 196 patients with acute cough. The trial was or a daily dosage of 45-160 mg, exerts an antitus~ive designed as a cross-over comparison of 40 mg of action on pathological cough in man which can be codeine, 60 mg of Silomat and placebo, each three demonstrated, taking into account certain precau­ times a day. The patients compared, by question­ tions. It is feasible, therefore, to use codeine as the naire, frequency and intensity of cough, effects on standard of comparison in testing other antitussives. mood and breathing, and sedation. Of the 62 pa­ Codeine has been referred to in many of the tients who received both codeine and placebo, a reports on clinical experience with new antitussives statistically significant majority rated codeine more and stated ratios of effectiveness are cited in the effective on frequency (67.7%) and intensity (64.5%) descriptions of these compounds in Part 4. In addi­ of cough. Placebo was rated more effective in respect tion, in many reports on the use of codeine in respi­ to these two parameters in 29.0 and 32.3 %. The ratory disease in adults and children, various recom­ differences for the other points compared were not mendations have been made in regard to dosage. A significant. few of these are noted in Table 30. CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 3 153

RESUME

LA CODEINE ET SES SUCCEDANES SEDATIFS DE LA DOULEUR ET DE LA TOUX: 3. LA SEDATION DE LA TOUX PAR LA CODEINE- MECANISME. METHODOLOGIE ET EVALUATION

Cette troisieme partie du rapport d'ensemble consacre caine, I 'ethoforme, le benzonatate, le caramiphene, le aux proprietes sedatives de la codeine et de ses succedanes clofedanol, la diphenhydramine, l'isoamimile, l'oxola­ expose en detailles donnees experimentales relatives aux mine et la pholcodine sont capables d'agir sur les recep­ voies qu'emprunte le refiexe de la toux et au mecanisme teurs peripheriques refiexogenes. Bien que le site speci­ de ce moyen de protection contre les irritations nocives fique d'action des drogues sedatives de la toux soit et les lesions des voies aeriennes par des agents meca­ probablement le<< centre de la toux *• situe dans la moelle, niques ou chimiques. Les etudes les plus recentes de sa on note entre les composes qui agissent a ce niveau nature et de son fonctionnement supportent l'hypothese (aminoindane, codeine, dextromethorphane, hexobarbi­ selon laquelle le refiexe est en grande partie independant tal, pipazetate) des variations portant sur la specificite de du mecanisme de la respiration. La toux est un symptome l'effet, les modalites de la reponse et l'ampleur des que !'on observe dans un tres grand nombre de maladies reactions accessoires. (infiammatoires, infectieuses, allergiques, circulatoires, Les substances qui apaisent la toux ont parfois d'autres psychiques). effets pharmacodynamiques qui accroissent ou, au On a mis au point toute une serie de methodes en vue contraire, diminuent l'efficacite de leur action specifique d'evaluer chez !'animal les effets sedatifs sur la toux de sur le refiexe. On examine a cet egard la fa~on dont la codeine ou d'autres drogues. On peut recourir pour l'aminoindane, le benzonatate, I 'hexobarbital, la pen­ provoquer la toux a des stimuli chimiques, mecaniques toxyverine, la pholcodine et le pipazetate agissent sur la ou electriques. Ces divers procedes font l'objet d'une respiration. Les analgesiques - du moins ceux dont description minutieuse et leurs avantages et desavantages !'action s'apparente a celle de la morphine - attenuent respectifs sont examines. la toux, mais des composes comme le dextromethor­ Pour juger de la valeur therapeutique d'une drogue, il phane, la noscapine et la pholcodine, qui ont un effet est particulierement utile d'apprecier son action sedative sedatif sur la toux, ne sont pas necessairement doues de sur la toux directement chez I 'homme. A cet effet, la proprietes analgesiques. Pour mieux comprendre les rela­ toux peut etre provoquee experimentalement au moyen tions entre !'attenuation de la douleur et la sedation de d'inhalations d'aerosols contenant de l'acetylcholine, de la toux, il faudra, par une etude experimentale plus pous­ !'ammoniac ou de l'acide citrique ou par !'injection de see, rechercher dans quelle mesure les sedatifs generaux lobeline ou de paraldehyde. Ces methodes ont rendu (hypnotiques) sont capables de combattre la toux. Les possibles de nombreuses experiences qui sont relatees en neuroleptiques comme la chlorpromazine, la perphena­ detail. Bien que la toux artificiellement induite chez un zine et la prochlorperazine modifient le mecanisme du sujet sain differe par maints caracteres de la toux d'origine refiexe de toux. On a montre que !'inhalation d'hexa­ pathologique, les etudes de ce genre permettent cependant methonium supprime la toux provoquee experimentale­ de definir les analogies entre les resultats obtenus chez ment chez l'homme par !'inhalation d'acetylcholine, !'animal et les donnees recueillies chez l'homme. 11 mais des tests utilisant des sels quaternaires de substances importe dans tous les cas de leur adjoindre des recherches sedatives de la toux n'ont pas permis d'apporter la concernant !'absorption, la distribution dans l'organisme preuve definitive du role du blocage ganglionnaire dans et le metabolisme des drogues experimentees afin de la suppression du reflexe. L'examen des donnees experi­ reunir davantage d'informations sur les similitudes entre mentales concernant un certain nombre de substances les especes. Ces donnees fourniront la base de !'inter­ douees de proprietes spasmolytiques ou spasmogenes ne pretation des resultats de laboratoire et des applications fait ressortir aucune relation precise entre ces effets cliniques. specifiques et !'action sedative sur la toux. Du point de L'evaluation des proprietes sedatives des drogues chez vue clinique, l'efficacite des substances actives contre la des malades presentant une toux de nature pathologique toux ne parait pas alteree lorsque leur emploi a pour re­ due a l'une ou !'autre cause doit etre menee en se confor­ sultat d'accroitre ou de diminuer la secretion bronchique. mant aux exigences fondamentales de la pharmacologie L'action de la codeine sur la toux provoquee, tant chez clinique. Diverses methodes utilisees a cet effet sont l'homme que chez !'animal, a fourni matiere a de tres decrites et discutees. nombreuses recherches. La plupart des experimentateurs Le cas d'un certain nombre de substances sedatives de assignent a la codeine une efficacite plus ou moins la toux est examine sous !'angle de leur lieu d 'action dans grande, et rares sont ceux qui n'ont pas constate une I'organisme: des produits doues de proprietes analge­ sedation de la toux apres administration de la substance. siques locales, comme la cocaine, la tetracaine, la lido- Pour la majorite des chercheurs qui ont procede a des 154 N. B. EDDY AND OTHERS essais cliniques, les effets calmants de la codeine, sur la raison de 30 a 60 mg en dose unique ou de 45 a 160 mg frequence comme sur l'intensite de la toux, sont supe­ quotidiennement, combat efficacement la toux patholo­ rieurs a ceux des placebos; dans un tiers des cas, la gique chez l'homme. 11 est des lors possible de l'utiliser difference d'action est statistiquement significative. Ces comme substance de reference pour les essais d'evaluation memes essais ont montre que la codeine, adrninistree a d'autres composes sedatifs de la toux.

REFERENCES

Abelmann, W. H., Gaensler, E. A. & Badger, T. L. (1954) Cahen, R. & Boucherle, A. (1961) C. R. Soc. Bioi. (Paris), Dis. Chest, 25, 532 155, 1034 Abruzzi, W. A. (1962) J. New Drugs, 2, 310 Cahen, R. &Boucherle, A. (1964) C. R. Soc. Bioi. (Paris), Amdur, M. 0. (1957) Amer. industr. Hyg. Ass. Quart., 158, 1021 18, 149 Cahen, R. & Boucherle, A. (1965) Fed. Proc., 24, 549 Amler, A. B. & Rothman, C. B. (1963) J. New Drugs, 3, Calesnick, B. & Christensen, J. A. (1967) Clin. Pharmacal. 362 Ther., 8, 374 Anonymous (1962) Practitioner, 188, 249 Calesnick, B., Christensen, J. A. & Munch, J. C. {1961) Archibald, D. W., Slipp, L. B. & Shane, S. J. (1959) Amer. J. med. Sci., 242, 560 Canad. med. Ass. J., 80, 734 Capello, G. & DiPasquale, S. (1955) Schweiz. Z. Tuberk., Balea, T. & Buret, J. (1964) Therapie, 19, 631 12,80 Banyai, A. L. & Johannides, M., Jr (1956) Dis. Chest, Carter, C. H. & Maley, M. C. (1957) Amer. J. med. Sci., 29, 52 233, 77 Bedell, G. N. & Seebohm, P. M. (1959) J. Amer. med. Cass, L. J. & Frederik, W. S. (1953) New Engl. J. Med., Ass., 169, 1699 249, 132 Beecher, H. K. (1955) J. Amer. med. Ass., 159, 1602 Cass. L. J. & Frederik, W. S. (1956) J. Lab. clin. Med., Behrens, H. 0. (1932) Ther. d. Gegenw., 73, 399 48, 879 Bein, H. J. & Bucher, K. (1957) Helv. physiol. pharmacal. Cass, L. J. & Frederik, W. S. (1958) Ann. intern. Med., 49, Acta, 15, 55 151 Benson, W. M., Stefko, P. L. & Randall, L. 0. (1953) Cass, L. J. & Frederik, W. S. (1964) Curr. ther. Res., 6, 14 J. Pharmacal. exp. Ther., 109, 189 Cass, L. J., Frederik, W. S. & Andosca, J. B. (1954) Amer. Bickerman, H. A. {1960a) In: Modell, W., ed., Drugs J. med. Sci., 227, 291 of choice, St. Louis, USA, Mosby Co., p. 493 Cavalieri, U., et al. (1960) J. Geront., 8, 981 Bickerman, H. A. (1960b) In: Gordon, B. L., ed., Clinical Chabrier, B., Giudicelli, R. & Thuillier, J. (1950) Ann. cardiopulmonary physiology, New York, Grune and pharm. franr., 8, 261 Stratton, p. 495 Chakravarty, N. K., et al. (1956) J. Pharmacal. exp. Ther., Bickerman, H. A. & Barach, A. L. (1954) Amer. J. med. 117, 127 Sci., 228, 156 Chen, J. Y. P., Biller, H. F. & Montgomery, E. G. (1960) Bickerman, H. A. & Itkin, S. E. (1960) Clin. Pharmacal. J. Pharmacal. exp. Ther., 128, 384 Ther., 1, 180 Dalharnn, T. (1960) Acta physiol. scand., 49, 242 Bickerman, H. A., et al. (1956) Amer. J. med. Sci., 232, Davenport, L. F. (1938) J. Pharmacal. exp. Ther., 64, 236 57 David, A., Leith-Ross, F. & Valiance, D. K. (1957) Bickerman, H. A., et al. (1957) Amer. J. med. Sci., 234, J. Pharm. Pharmacal., 9, 446 191 DeVleeschhauwer (1954) Arch. int. Pharmacodyn., 97, 34 Bidwell, S. M. R. & Boyd, E. M. (1952) J. Pharmacal. DiGregorio, M. (1960) Minerva med., 51, 4086 exp. Ther., 104, 224 Domenjoz, R. {1952) Arch. exp. Path. Pharmak., 215, 19 Bobb, J. R. & Ellis, S. {1951) J. Physiol., 167, 768 Douglass, B. E. (1954) Med. Clin. N. Amer., 38, 949 Boissier, J.-R. & Pagny, J. (1960a) Therapie, 15, 93 Eichler, 0. & Smiatek, A. (1940) Arch. exp. Path. Boissier, J.-R. & Pagny, J. (1960b) Therapie, 15, 97 Pharmak., 194, 621 Borison, H. L. (1948) Amer. J. Physiol., 154, 55 Engelhom, R. (1960) Arzneimittel-Forsch., 10, 785 Boyd, E. M. (1954) Pharmacal. Rev., 6, 521 Engelhorn, R. & Weller, E. (1961) Pflugers Arch. ges. Boyd, E. M. & Boyd, C. E. (1960) Canad. med. Ass. J., Physiol., 273, 614 83, 1298 Engelhorn, R. & Weller, E. (1965) Pf/ugers Arch. ges. Bucher, K. (1958) Pharmacal. Rev., 10, 43 Physiol., 284, 224 Bucher, K. & Jacot, C. {1951) Helv. physiol. pharmacal. Emst, A. M. (1938) Arch. int. Pharmacodyn., 58, 363 Acta, 9, 454 Emst, A. M. (1939) Arch. int. Pharmacodyn., 61, 73 CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 3 155

Fantus, B. (1936) J. Amer. med. Ass., 106, 375 Kase, Y., et al. (1959) Chem. pharm. Bull., 7, 372 Floersheim, G. L. (1959) Helv. physiol. pharmacal. Acta, Kelentey, B., et al. (1957) Arzneimittel-Forsch., 7, 594 17, 153 Kelentey, B., et al. (1958) Arzneimittel-Forsch., 8, 325 Frey, R., Hiigin, W. & Mayrhofer, 0. (1955) Lehrbuch Kleibel, F. (1964) Med. Welt (Stuttg.) 24, 1317 der Anaesthesiologie, Berlin, Springer-Verlag Kleibel, F., Steinhoff, E. & Wilde, W. (1965) Therapie- Friebel, H. (1960) Klin. Wschr., 38, 621 woche, 15, 1115 Friebel, H. (1963) In: Muller, W. A., ed., Klinische Physio­ Klein, B. (1958) Antibiot. Med., 5, 462 logie, Stuttgart, Thieme, vol. 1, p. 301 Kohli, R. P., et al. (1960) Ind. J. med. Res., 48, 193 Friebel, H. & Hahn, K.-J. (1966) Med. pharmacal. exp. Konar, N. R. & Dasgupta, S. (1959) J. Ind. med. Ass., (Base/), 14,78 32, 189 Friebel, H. & Kuhn, H.-F. (1962) Arch. exp. Path. Konzett, H. (1955) Wien. klin. Wschr., 67, 306 Pharmak., 243, 162 Konzett, H. & Rothlin, E. (1954) Experientia, 10, 472 Friebel, H. & Kuhn, H.-F. (1964) Arch. exp. Path. Korp:is, J., Tomori, Z. & Ivanca, I. (1957) Physiol. Pharmak., 246, 527 bohemoslov., 6, 111 Friebel, H., Reichle, C. & von Graevenitz (1955) Arch. Krause, D. (1958) Arzneimittel-Forsch., 8, 553 exp. Path. Pharmak., 224, 384 Kraushaar, A. E., Schunk, R. W. & Thym, H. F. (1964) Furakawa, F. & Okabe, M. (1958) lg. Kenkyyu, 28, 1643 Arzneimittel-Forsch., 14, 986 Glaser, J. (1961) Practitioner, 12, 715 Kroepfli, P. (1950) Helv. physiol. pharmacal. Acta, 8, 33 Glick, J. (1963) Delaware med. J., 35, 180 Krueger, H. M., Eddy, N. B. & Sumwalt, M. (1943) Pub!. Gordonoff, T. (1938) Ergebn. Physiol., 40, 53 Hlth Rep. (Wash.), Suppl. 165 Gosswald, R. (1958) Arzneimittel-Forsch., 8, 550 Krug, F. (1964) Med. Welt (Stuttg.), 18, 1026 Graham, J. D. P. (1962) J. New Drugs, 2, 43 Kuhn, H.-F. & Friebel, H. (1960a) Arch. exp. Path. Granier-Doyeux, M. et al. (1959) Arch. int. Pharmacodyn. Pharmak., 240, 18 121, 287 Kuhn, H.-F. & Friebel, H. (1960b) Med. exp. (Base/), 3, Gravenstein, J. S. & Beecher, H. K. (1955) Arzneitmittel­ 329 Forsch., 5, 364 LaBarre, J. & Plisnier, H. (1959) Arch. int. Pharmacodyn., Gravenstein, J. S., Devloo, R. A. & Beecher, H. K. (1954) 119, 205 J. appl. Physiol., 7, 119 Larsell, 0. & Burget, G. E. (1924) Amer. J. Physiol., 70, Green, A. F. & Ward, N. B. (1955) Brit. J. Pharmacal., 311 10, 418 Levis, S., Preat, S. & Moyersoons, F. (1955) Arch. int. Groszman, M., Birker, I. 0. & Casimir, F. (1961) Appl. Pharmacodyn., 103, 200 Ther., 3, 95 Lorenz, D. (1962) Arzneimittel-Forsch., 12, 1183 Haas, H. (1955) Arch. exp. Path. Pharmak., 225, 442 Martin (1834) Arch. gen. Med., 4, 2s, 692 Hahn, K.-J. & Friebel, H. (1966) Med. Pharmacal. exp. Martini, H. (1957) In: Niickel, H. Aerosol-Therapie, Stutt- (Base/), 14, 87 gart, Schattauer, p. 120 Hahn, L. A. & Wilbrand, H. (1952) Arch. int. Pharmaco- Matallana, A. & Borison, H. L. (1955) Fed. Proc., 14, 367 dyn., 91, 144 Maurer, H. (1955) Deutsch. med. Wschr., 80, 351 Hara, S. & Yanaura, S. (1959) Jap. J. Pharmacal., 9, 46 May, A. J. & Widdicombe, J. G. (1954)Brit. J. Pharmacal., Haslreiter, E. (1959) Arzneimittel-Forsch., 9, 769 9, 335 Hengen, 0. and Kasparek, H. (1958) Arzneimittel-Forsch., Moll, E. L. (1953) Practitioner, 170, 76 8, 620 Morris, D. J. & Shane, S. J. (1960) Canad. med. Ass. J., Herzog, H. (1967) Therapiewoche, 17, 532 83, 1093 Hillis, B. R. (1952) Lancet, 1, 1230 Mulinos, M. G. (1960) Toxicol. appl. Pharmacal., 2, 635 Hillis, B. R. & Kelly, J. C. C. (1951) Glasgow med. J., 32, Mulinos, M. G., Nair, K. G. & Epstein, J. G. (1962) N. Y. 72 Med. J., 62, 2373 Himmelsbach, C. K., et al. (1940) Pub/. Hlth Rep. (Wash.) Nicolis, F. B. & Pasquariello, G. (1962a) Clin. ter., Suppl. 158 23, 215 Hoglund, N. J. & Michaelsson, M. (1950) Acta physiol. Nicolis, F. B. & Pasquariello, G. (1962b) J. Pharmacal. scand., 21, 168 exp. Ther., 136, 183 Isbell, H. & Fraser, H. F. (1953) J. Pharmacal. exp. Ther., Ozawa, H., et al. (1962) J. pharmacal. Soc. Jap., 82, 1314 107, 524 Parish, F. A. (1959) Med. Tms (N.Y.), 87, 1488 Kiillquist, I. & Melander, B. (1957) Arzneimittel-Forsch., Pasquariello, G. & Nicolis, F. B. (1962) Clin. ter., 23, 226 7, 301 Pellmont, B. & Bach told, H. (1954) Schweiz. med. Wschr., Kase, Y. (1952) Jap. J. Pharmacal., 2, 7 84, 1368 Kase, Y. (1954) Chem. pharm. Bull., 2, 298 Perry, W. P. & Boyd, E. M. (1941) J. Pharmacal. exp. Kase, Y. (1955) Jap. J. Pharmacal., 4, 130 Ther., 73, 65 Kase, Y. & Yuizono, T. (1959) Chem. pharm. Bull., Phillips, A. M., Phillips, R. W. & Thompson, J. L. (1956) 7, 378 Ann. intern. Med., 45, 216 156 N. B. EDDY AND OTHERS

Plisnier, H. (1957) Etude comparative de /'action des deri­ Silvestrini, B. & Pozzatti, C. (1961) Brit. J. Pharmacal., ves de /'opium et de diverses substances synthetiques a 16,209 effet non morphinique sur le mecanisme de la toux, sur le Snell, E. S. & Armitage, P. (1957) Lancet, 1, 860 bronchospasme et sur la secretion bronchique, Thesis, Sollmann, T. (1957) Manual of pharmacology, 8th ed., Brussels Philadelphia, Saunders Plisnier, H. (1958) C. R. Soc. Bioi. (Paris), 152, 1267 Staehelin, R. (1914) Jahreskurse iirztl. Fortbild, 5, 32 Plisnier, H. (1960) C. R. Soc. Bioi. (Paris), 154,451 Stefko, P. L. and Benson, W. M. (1953) J. Pharmacal. Plisnier, H. & Hernalsteen, L. (1953) C. R. Soc. Bioi. exp. Ther., 108. 217 (Paris), 153, 363 Stefko, P. L., Denzel, J. & Hickey, I. (1961) J. pharm. Pottenger, F. M. (1934) Clinical Tuberculosis, 2nd ed., St. Sci., 50, 216 Louis, Mosby Co., p. 485 Suter, C. M. (1951) Medical chemistry, New York, J. Wiley Prime, F. J. (1961) Brit. med. J., 1, 1149 & Sons, p. 405 Priissing, G. (1960) Deutsch. med. J., 11, 95 Tannenbaum, F. J. (1965) Pharmacologist, 7, 77 Rasch, M. (1957) Nord. Med., 57, 629 Tedeschi, R. E. et al. (1959) J. Pharmacal. exp. Ther., 126, Reichle, C. & Friebel, H. (1955) Arch. exp. Path. Pharmak., 338 226, 558 Ther, L. & Lindner, E. (1958) In: Medizin und Chemie, Renovanz, H. D. & Liebrich, K. G. (1965) Arzneimittel­ Berlin, I. G. Farbenindustrie, vol. 6, p. 351 Forsch., 15, 1393 Rosiere, C. E. & Winder, C. V. (1955) J. Pharmacal. exp. Tiffeneau, R. (1955) Z. Aerosol-Forsch., 4, 116 Ther., 113, 46 Tiffeneau, R. (1957) Dis. Chest., 31, 404 Rosiere, C. E., Winder, C. V. & Wax, J. (1956) J. Pharma­ Tomori, Z. et al. (1960) Anesthetist, 9, 169 cal. exp. Ther., 116, 296 Toner, J. J. & Macko, E. (1952) J. Pharmacal. exp. Ther., Ross, B. B., Gramia, R. & Rahn, H. (1955) J. appl. 106,246 Physiol., 8, 264 Trendelenburg, U. (1950) Acta physiol. scand., 21, 174 Salem, H. & Aviado, D. M. (1964) Amer. J. med. Sci., Van Dongen, K. (1956) Acta physiol. pharmacal. neerl., 247, 585 4, 500 Salle, J. & Brunaud, M. (1960) Arch. int. Pharmacodyn., Watt, J. (1959) Pharm. Industrie, 21, 386 126, 120 Weidemeyer, J. C., Kremer, H. W. & DeJongh, D. K. Saundby, R. (1879) Brit. med. J., 1, 545 (1960) Acta physiol. pharmacal. neerl., 9, 501 Schlez, K. (1965) Ober die Verwendung des Vagusschlingen­ Widdicombe, J. G. (1954a) J. Physiol., 123, 55 hundes fiir die Wertbestimmung hustenstillender Sub­ Widdicombe, J. G. (1954b) J. Physiol., 123, 71 stanzen, Thesis, Heidelberg Widdicombe, J. G. (1961) Arch. exp. Path. Pharmak., 241, Schofield, P. B. (1963) Brit. J. Clin. Pract., 17, 583 415 Schroder, G. (1899) Ther. d. Gegenew., 1, 113 Widdicombe, J. G. (1964) In: Fenn, W. 0. & Rahn, H., Schroeder, W. (1951) Arch. exp. Path. Pharmak., 212,433 ed., Handbook of Physiology, Baltimore, Williams & Sell, R., Lindner, E. & Jahn, H. (1958) Arch. exp. Path. Wilkins, vol. 1, sect. 3, Respiration, p. 585 Pharmak., 234, 164 Sevelius, H. D. and Colmore, J. P. (1967) Clin. Pharmacal. Winder, C. V. & Rosiere, C. E. (1955) J. Pharmacal. exp. Ther., 8, 381 Ther., 113, 55 Sevelius, H., Lester, P. D. & Colmore, J. P. (1965) Clin. Winder, C. V., et al. (1961) J. Pharmacal. exp. Ther .. 133, Pharmacal. Ther., 6, 146 117 Shane, S. J., Krzyski, T. K. & Copp, S. E. (1957) Canad. Winter, C. A. & Flataker, L. (1952) Proc. Soc. exp. Bioi. med. Ass. J., 77, 600 (N.Y.), 81, 463 Silson, J. S. (1965) J. New Drugs, 5, 94 Winter, C. A. & Flataker, L. (1954) J. Pharmacal. exp. Silvestrini, B. & Maffii, G. (1959) Farmaco, Ed. Sci., 14, Ther., 112, 99 440 Woolf, C. R. & Rosenberg, A. (1962) Canad. med. Ass. J., Silvestrini, B. & Pozzatti, C. (1960) Arch. int. Pharmacodyn., 86, 810 129, 249 Woolf, C. R. & Rosenberg, A. (1964) Thorax, 19, 125 Codeine and its Alternates for Pain and Cough Relief *

4. Potential Alternates for Cough Relief

In this report-the fourth of a series on codeine and its alternates for pain and cough relief-an attempt is made to evaluate, on the basis of experimental and clinical data, and wherever possible in comparison with codeine, the effectiveness of a number of antitussive substances currently in clinical use. In the discussion of the undesired side-effects particular attention is paid to the risk of dependence and abuse.

CONTENTS

PHENANTHRENE ALKALOIDS PHENOTHIAZINES 195 DIHYDROCODEINE 158 PIPAZETATE 196 ETHYLMORPHINE 158 DIMETHOXANATE 199 PHOLCODINE • 160 MEPROTIXOL • 200 NICOCODINE AND NICODICODINE 164 OTHER COMPOUNDS . N-OXIDES AND QUATERNARY SALTS 166 ANTIHISTAMINES 200 NALORPHINE • 167 BENZOBUTAMINE 201 BENZONATATE 202 DEXTROMETHORPHAN 169 CARAMIPHEN • 208 CLOBUTINOL • ISOQUINOLINE ALKALOIDS 210 CLOFEDANOL • NOSCAPINE 178 214 ISOAMINILE OTHER RELATED SUBSTANCES • 183 217 METHAQUALONE 219 METHADONE AND RELATED SUBSTANCES 0XELADIN • 219 METHADONE, ISOMETHADONE AND THEIR ISOMERS • 184 0XOLAMINE 219 NORMETHADONE 187 PENTOXYVERINE 224 LEVOPROPOXYPHENE 190 SODWM DIBUNATE 227 THIAMBUTENES • 193 R:EsuM:E . 229 PETHIDINE CONGENERS 194 REFERENCES 231

-157- 158 N. B. EDDY AND OTHERS

PHENANTHRENE ALKALOIDS substance without analgesic action, dextromethor­ phan, for example, would rank still higher. It may Dihydrocodeine be important that the substances with the highest Dihydrocodeine, differing from codeine only in the apparent antitussive specificity have a methoxyl saturation of the 7-8 double bond, was introduced in radical in the same relative position in the molecule. Germany as an antitussive more than 50 years ago Comparison of dihydrocodeine and codeine in other and has been used as such almost exclusively, species by various methods confirm their similarity though, like codeine, it possesses significant analgesic for antitussive effect (Table 31). properties. The earlier reports rated dihydro­ Therapeutic doses of dihydrocodeine for cough codeine more effective, sometimes twice as effective relief are of the same order as for codeine, the single as codeine (Fraenkel, 1913; Dahl, 1913) and, though dose and the daily amount and the side-effects being later clinical experience indicated these estimates to similar in kind and frequency. There have been no be exaggerated, dihydrocodeine continues in use as carefully controlled, double-blind studies of di­ an antitussive, principally as the bitartrate, 1 at doses hydrocodeine as an antitussive in man, for either similar to those for codeine phosphate. experimentally produced or pathological cough. Information on the dependence-producing properties of dihydrocodeine are discussed in Part 2 of this ~-CH, review in connexion with its analgesic action. (~-CH, In view of its close similarity to codeine, dihydro­ codeine is not very popular. The total estimated 6 world requirement for dihydrocodeine in 1967 OCH,/ "" O / ""OH OCH,/ "" O / ""OH amounts to only a little more than 6000 kg, whereas CODEINE DIHYDROCODEINE the estimated requirement for codeine is close to 150 000 kg (United Nations Drug Supervisory As methods have become available in recent years Body, 1967). Most of the codeine will be used for for measuring antitussive action in animals, dihydro­ analgesia and little of the dihydrocodeine will be so codeine has been evaluated, sometimes in com­ used, but the use of codeine for cough is still many parison with codeine, and occasionally evidence has times greater than that of dihydrocodeine. been sought of the specificity of its antitussive action Ethylmorphine compared with its analgesic action. Friebel, Reichle & von Graevenitz (1955) induced bouts of coughing When ethylmorphine was prepared by substituting in guinea-pigs by making them inhale sulfur dioxide ethyl ether in place of the familiar methyl ether of morphine (codeine), Schlesinger (1899) thought it and determined the ED50 of various agents for cough suppression. For dihydrocodeine bitartrate this was would be a more effective and better tolerated 14.0 mg per kg, for codeine phosphate 8.0 mg per analgesic and antitussive. However, from the beginning, clinicians (Korte, 1899a, 1899b; Janisch, kg, and for ethylmorphine hydrochloride the ED50 was 13.0 mg per kg, subcutaneously. They also de­ 1899; Schroder, 1899) used and recommended doses of the same order as those for codeine and, since termined the ED50 for these and other substances for analgesia in the same animals and divided the ethylmorphine failed to demonstrate any particular advantage it never attained the popularity or the analgesic ED50 by the antitussive ED50 as an indica­ tion of specificity; the larger the quotient the greater frequent use of codeine as an antitussive (Linz, 1943). the antitussive specificity. The quotient for codeine was 6.62, for dihydrocodeine 5.71, for hydrocodone ~N-CH, 4.6, for ethylmorphine 3.3 and for morphine 2.87. The quotients for some of the synthetics were still lower: normethadone, 2.66; methadone, 2.31; o-e pethidine, 1.53. On the above basis, whatever their OC,Hs/ "" O / ""OH absolute effective doses, codeine and dihydrocodeine ETHYLMORPHINE head the list in relative antitussive importance. One must not forget, of course, that on the same basis a There are few quantitative data on the antitussive 1 Also known as Paracodin. effect of ethylmorphine and few comparisons with CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 159

TABLE 31 CO:vi?ARISON OF THE ANTITUSSIVE ACTION OF DIHYDROCODEINE AND CODEINE IN ANIMAL EXPERIMENTS

I EDso (mg/kg) Ra1io Method Rout ea codeine/dihydro- Reference Dihydrocodeine I Codeine codeine

Species: GUINEA-PIG Inhalation of so, se 14.0 8.0 0.571 Friebel, Reichle & von Grae- I venitz (1955)

Species: DOG Electrical stimulation of the tra- IV 1.5 1.5 1.0 Hara & Van aura (1959) cheal mucosa

Inhalation of sulfuric acid vapour 0 1.0 b c. 1.0 Chen & Bill er (1959); Chen, Biller & Montgomery (1960)

Mechanical stimulation I lP 3.2 b 7.5 b 2.344 Cahen & Boucherle (1965)

Species: CAT

Mechanical stimulation IV c. 1.0 Ellis et al. (1963) Electrical stimulation superior laryngeal nerve IV c. 1.0 El lis et al. (1963)

Chemical stimulation lP 7.5 b 15.0 b 2.0 Cahen & Boucherle (1965)

a SC = subcutaneous; IV= intravenous; 0 = oral; lP =·intraperitoneal. b Not calculated ED,. but equally effective dose. codeine. Friebel, Reichle & von Graevenitz (1955) coughing, Winder & Rosiere (1955) and Rosiere, compared the two drugs in guinea-pigs made to Winder & Wax (1956) compared ethylmorphine and cough by inhalation of sulfur dioxide. The ED50s codeine at four dose levels with a placebo in cross­ for total suppression of the cough were 13.0 mg per over experiments in random order. The dose range kg for ethylmorphine hydrochloride, 8.0 mg per kg used for both was 1.0-5.7 mg per kg, subcutaneously. for codeine phosphate, subcutaneously, with a ratio They calculated a linear dose relationship for

between them of only 0.62. The ED50s for an codeine but were unable to do so for ethylmorphine. analgesic effect in the same animals, skin-twitch to The latter raised the cough threshold by a maximum radiant heat, were 43.0 and 48.5 mg per kg, respec­ 50-60%. Since its effect did not increase with dose, a tively, with a ratio of 1.12. If one divides the definite ratio to codeine could not be stated. It analgesic ED50 by the antitussive ED50, the ratio would have to be considered as < 1.0, the direction indicative of antitussive specificity is for codeine being consistent with the other observations. about twice that for ethylmorphine. Kase (1952) As stated earlier, the usual therapeutic antitussive compared ethylmorphine and codeine in dogs; the dose for ethylmorphine, either singly or daily, was trachea was stimulated mechanically through a of the same order as for codeine; it was not judged

tracheal fistula and intravenous BD 50s for cough sup­ more effective. In the early reports, admittedly, it pression were established as 5.0 mg per kg for ethyl­ was compared mostly for the relief of tuberculous morphine and 3.0 mg per kg for codeine, with a ratio cough often after prolonged use of morphine or of 0.6, as in the guinea-pig. The duration of effect codeine, so that cross-tolerance may have influenced was similar for both drugs the effect perhaps lasting the result. Stein & Lowry (1946) later reported a

a little longer with codeine at the ED50• little more favourably; they said that doses of 15- Using unanaesthetized dogs and determining the 22.5 mg of ethylmorphine, orally, were as effective minimal concentration of ammonia vapour to cause as 30-60 mg of codeine in cough due to tuberculosis N. B. EDDY AND OTHERS or malignancy. They were more interested in hydro­ respiration than codeine. Giudicelli, Chabrier & codone which they found more effective. Kristensson (1951) found that 10 mg per kg, intra­ Tolerance and physical dependence have been venously, in anaesthetized rabbits, depressed the reported after prolonged use of ethylmorphine respiratory rate 33% and respiratory depth 44%. (Meyer, 1933). Lambert (1936) said that these An equal dose of .codeine depressed the rate 31 % features developed more rapidly than with morphine, and the depth only 22%, whereas morphine de­ but he said also that ethylmorphine produced no creased the rate 94% but the depth of respiration euphoria. ·The possibility of dependence on ethyl­ only 47%. Kelentey et al. (1958) confirmed the anti­ morphine has been admitted by Plessner (1900), tussive effect of pholcodine, using mice and guinea­ Krijewski (1900), Wilcox (1923), Fishberg (1932) pigs in which cough was evoked by inhalation of and in editorials (J. Amer. med. Ass., 1925; J. Amer. 1.0% sulfur dioxide. They said that it was more med. Ass.,' 1926) but was not considered important. effective than codeine, 7 mg per kg of pholcodine Ethylmorphine is of course subject to narcotics con­ being equivalent to 10 mg per kg of codeine, sub­ trol, but because of its infrequent use it has not been cutaneously; in equal doses in repeated experiments, tested at the Addiction Research Centre, Lexington, pholcodine reduced the cough by 65.1 %, and Ky., USA. The estimated requirement for ethyl­ codeine by 47.2 %, on average. morphine in 1966 was just over 11 000 kg (United May & Widdicombe (1954) compared pholcodine Nations Drug Supervisory Body, 1966) and a part of with morphine and codeine by two r.nethods in cats that was used externally in ophthalmological anaesthetized with pentobarbital. Responses were practice. recorded from a body plethysmograph and stimula­ tion was mechanical, by a catheter passed down the Pholcodine trachea until it touched the bifurcation, or chemical, The preparation, general pharmacology and anti­ by inhalation of sulfur dioxide. They compared the 3 tussive effectiveness of pholcodine (0 -(2-morpho­ volume of the expired air after mechanical stimula­ Iinoethyl)-morphine), another of the ethers of tion and of the first inspiratory gasp after sulfur morphine, were described by Chabrier, Giudicelli & dioxide with the average of 10 preceding tidal Thuillier (1950) and many chemical, pharmacological volumes. It is questionable whether the inspiratory and clinical reports on the compound have appeared gasp and its suppression truly represent antitussive since. Chabrier prepared other ethers, including action, and in fact the investigators did report dimethylaminoethyl, diethylaminoethyl and piper- different quantitative effects on the expiratory effort and the inspiratory gasp; pholcodine was ~N-CH> much more effective than codeine on the former and less effective on the latter: o-e Average intravenous doses for reduction of response (mg/kg) 0/ "o/ "'OH Pho/codlne Codeine I Mechanically induced expiration 5.3 16.3 f\ 9 H. Chemically induced inspiration 15.1 11.2 0 N-C H. \__) Green & Ward (1955) stimulated electrically the superior laryngeal nerve in anaesthetized cats, and PHOLCODINE reported suppression of the induced cough by 2.0 mg per kg of pholcodine and 4.0 mg per kg of idinoethyl, and selected the morpholinoethyl com­ codeine, intravenously, a relationship similar to that pound as the most promising. Kelentey et al. (1958) found for mechanical stimulation by May & Widdi­ later prepared and examined morpholinoethyl ethers combe (1954). Green & Ward said that nalorphine of some morphine derivatives. Chabrier, Giudicelli antagonized the antitussive effect of codeine but not & Thuillier (1950) and Giudicelli, Thuillier & that of pholcodine. Plisnier (1960) used the same Chabrier (1950) found that 80-100 mg of pholcodine animal and the same technique, and also reported suppressed the cough produced by the intravenous that pholcodine was twice as effective as codeine. injection of lobeline in man and that it was more Mulinos (1960a, 1960b) added the observation effective than codeine against ·cough of various that the effect of pholcodine was of longer duration pathological origins. It also had a gre~ter effect on than that of codeine with equal intravenous doses of CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 161 each. He used pentobarbitalized cats and stimulated Other pharmacological effects of pholcodine have the trachea mechanically or by inhalation of a been reported, as follows: 0.6-1.0% ammonia-air mixture. At 15 mg per kg (1) Histamine release in the rat. This was greater the effect of pholcodine lasted 29 and 27 minutes than with codeine (Cahen & Aubron, 1960; Cahen against the two types of stimulation; the effect of & Boucherle, 1961b; Cahen et al., 1963) and greater codeine lasted 12 and 17 minutes. The difference was than with morphine in the dog when 4 mg per kg statistically significant. The cough mechanism was was given intravenously (Cahen & Aubron, 1960). not paralysed by either drug because prolonging the (2) An anti-histaminic effect (Kelentey et al., period of inhalation of ammonia could cause 1958; Plisnier, 1960). coughing in the drugged animals. Cahen & Boucherle (1961a) obtained a somewhat (3) An anti-acetylcholinic action (Kelentey et al., different result from those quoted above. They 1958). calculated the comparable antitussive doses for (4) No effect on the gastrointestinal tract (Kelen­ codeine and pholcodine as 2.3 and 3.5 mg per kg, tey et al., 1958). A 50% reduction in the rate of intravenously, in the cat. Ellis et al. (1963) said that propulsion through the gastrointestinal tract in the codeine always suppressed the cough produced in rat, with doses of 120-180 mg per kg, subcutane­ anaesthetized cats by mechanical stimulation of the ously (Cahen & Boucherle, 1961b; Cahen, 1961). trachea, electrical stimulation of the superior No increase in intrabiliary pressure or in duodenal laryngeal nerve and inhalation of ammonia; phol­ tone in patients after cholecystectomy with 10- codine suppressed that produced by mechanical and 20 mg, orally, when the same doses of codeine always electrical stimulation. The effect of pholcodine on increased the pressure, sometimes with colicky pain the response to chemical stimulation was not re­ (Jacobbson, Kewenter & Kock, 1961). The con­ ported. centration that effectively inhibited the peristaltic The net result of all of these experiments would reflex or the response of the longitudinal muscle of seem to be that pholcodine has an antitussive the isolated ileum of the guinea-pig was 50 f-Lg per potency about 1.6 times that of codeine and one m!; the effective concentration of codeine was 1.8 f-Lg which is highly specific, since in contrast to codeine, per m! for inhibition of the peristaltic reflex, 7.0 f-Lg pholcodine has little if any analgesic action (Cahen per m! for an effect on the longitudinal muscle & Boucherle, 1961a; Kelentey et al., 1958). (Gyang, Kosterlitz & Lees, 1964). The early result of Chabrier, Giudicelli & Thuillier (5) An anti-convulsant action in rats. A dose of (1950), that indicated an effect on respiration greater 75 mg of pentetrazole by itself was convulsant in all than that of codeine, has been quoted. May & animals; combined with 200 mg per kg of pholcodine Widdicombe (1954) found the two drugs similar, it was convulsant in only about 50%. A dose of sometimes decreasing, and sometimes increasing the 1.25 mg per kg of strychnine produced convulsions minute volume; the differences were less in vagoto­ in 60% of rats. Pretreatment with pholcodine mized animals. According to Cahen & Boucherle reduced the frequency of convulsions to 20% when (1961b) pholcodine had some effect on minute the dose was 50 mg per kg, to 13.3% when the dose volume, but codeine did not, when each was given was 150 mg per kg and to 6. 7% when the dose was to dogs at a dose of 4.0 mg per kg, intravenously. 450 mg per kg. Very small doses of morphine or Pholcodine did not cause a significant decrease in the codeine reduced convulsions slightly but 10 or quantity of respiratory tracts fluid or in its chloride 20 mg per kg as a pretreatment dose increased the content within three hours after 1.0-50 mg per kg, frequency of convulsions and the number of deaths. orally or subcutaneously, in unanaesthetized rabbits Pholcodine alone, up to 480 mg per kg, caused (Boyd, Daicur & Middleton, 1956). convulsions very infrequently (Cahen, Groskinsky Pholcodine was similar to codeine in the produc­ & Parisek, 1956, 1957; Cahen, 1959). tion of a variable but transient hypotensive effect (6) A mild tranquillizing action. In rats, 75-200mg when it was given intravenously in dogs and per kg, intraperitoneally, caused something similar cats (Kelentey et al., 1958; Plisnier, 1960; Cahen to a sleep pattern in the electroencephalogram; & Boucherle, 1961b). In anaesthetized dogs, 4 mg 50-400 mg per kg, subcutaneously, blocked the con­ per kg, intravenously, produced peripheral vaso­ ditioned response to an electric shock. Pholcodine dilation to which acute tolerancedeveloped (Cahen, decreased spontaneous activity in mice and at doses 1960). of 300 and 600 mg per kg, orally or subcutaneously,

11 162 N. B. EDDY AND OTHERS the hexobarbital sleeping time was lengthened response of normal volunteers to an intravenous (Cahen, 1962). dose ofO.l ml of paraldehyde, the standard dose for a Toxicity data are summarized in Table 32. reproducible effect. Bickerman & Itkin (1960) used Generally pholcodine was significantly less toxic "trained" subjects and citric acid aerosol as the cough than codeine, but this does not necessarily mean stimulus. Pholcodine at a dose of 10 mg, orally, a greater margin of safety for man. Since its respi­ was compared, in a double-blind cross-over design, ratory effect is comparable to that of codeine, with placebo and other antitussives, and produced a indeed sometimes greater, and because the offsetting significant decrease in cough frequency over the exciting action is less, the safety of pholcodine for four-hour period of observation. Its effect was man should be at least of the same order as for approximately equivalent to that of 15 mg of codeine. codeine. These results satisfactorily confirmed the The observations of Chabrier, Giudicelli & Thuil­ findings in experimental animals; results on clinical lier (1950) concerned the effect of pholcodine on a use are summarized in Table 33. Most of the reports lobeline-induced cough in man and indicated greater were favourable to pholcodine and few side-effects effectiveness than for codeine. Konar & Dasgupta were mentioned. However, the clinical trials were (1959) used paraldehyde as the cough-inducing not well controlled; nor were there good quantitative stimulus and also found pholcodine more effective. comparisons with codeine. Nevertheless one finds A dose of 16 mg of pholcodine was 90% effective, laudatory statements based on reviews and impres­ 30 mg of codeine was 75% effective in reducing the sions such as the following. Graham (1959) discussed

TABLE 32 THE LDsoS (mg/kg) FOR PHOLCODINE AND FOR CODEINE AS REPORTED FOR THE SAME ANIMAL AND THE SAME ROUTE OF ADMINISTRATION

Route of administration b Species Drug a Reference I IV I lP I se I 0 I

Mouse p 230 c 1010 Chabrier, Giudicelli & Kristensson c 60 c 134 (1950); Giudicelli, Chabrier & Kris- tensson (1951)

Mouse p _d 1917 Aurousseau & Navarro (1957) c _d 535 Mouse p 540 Kelentey (1958) Mouse p 1020 1480 Cahen (1961) e c 21·8 335 Mouse p 590 1860 Cahen & Boucherle (1961a) c 154 470 Mouse p 280 725 1000 Palecek & Mekulaskova (1963) c 92 165 255 Rat p 750 205/1141 Cahen (1961) c 530 470/490 Guinea-pig p 252 g Plisnler (1960) c 106K Rabbit p 300 Kelentey (1958)

a P = pholocodlne (usually the hydrochloride); C = codeine (usually the phosphate). b IV= Intravenous; lP =intraperitoneal; SC = subcutaneous; 0 = oral. c Doses calculated as base. As bromethylate, pholcodine was more toxic, the LDsos being 8 and 32.5 mg per kg respectively, for Intravenous and subcutaneous administration. For codeine bromethylate the corresponding LDso's were 50 and 365 mg per kg. d Mice survived 200 mg per kg of codeine and 400 mg per kg of pholcodine, subcutaneously (Aurousseau, personal communi­ cation, 1957). e Dogs were killed by 150 mg per kg of codeine, subcutaneously, but others survived that dose of pholcodine and only 1 of 2 was killed by 300 mg per kg of the latter. f The LDso was determined in two lots of rats; In both pholcodine was more toxic. g Amounts survived, mg per kg, when given by continuous intravenous infusion. TABLE 33 CLINICAL TRIALS OF ORAL PHOLCODINE AS AN ANTITUSSIVE

Patients Dosage regimen Comparisons Result Side-effects Reference No. J Kind ----

45 Chronic cough 4 mg per dose in syrup Heroin 3 mg in syrup; 15 pholcodine first; 9 heroin Snell & Armitage (1957) for 2 days syrup vehicle first; 4 placebo first a 154 Cough, various origin 1 or 2 x 5 mg 86-90% relief of moderate; Ryde (1960) --- 78-94% severe cough 25 Premedication for I 5 mg; occasional Complete suppression of None b Brown (1961) g plastic surgery second dose of 5 mg cough in 18 !!! I or 10 mg -- ~ 53 Acute cough (41) and 11 or 2 x 5 mg in tablets Excellent: severe SO%, None. Excellent patient Grabelle (1961) > chronic cough (12) I or in liquid every 4 h moderate 54%, mild cough 48%. acceptance Poor: 7.5% all groups i ~ 54 Acute or chronic I 5 mg, 2-20 times a day Acute cough: excellent 69%, Nausea in 8, some Heffron (1961) cough none 25%. Chronic cough: sedation, no analgesia a ! excellent 42%, none 26.6% > 28 Chronic cough ' 10 mg every 4 h Excellent 82% None Mull nos, Nalr & Epstein (1962) 16 Chronic cough 10-20 mg, 2-4 times Mu lions, Nair & Epstein ~ Marked relief, 100% a day (1962) ~ 17 Chronic cough 10-20 mg codeine, Marked relief, 70%, Mu linos, Nair & Epstein 2-4 times a day (1962) 18 Chronic cough Placebo, 2-4 times a day Marked relief, 23% Mulinos, Nair & Epstein ~ (1962) ~ 25 Postoperative 15 mg, 1-3 times a dayc Placebo, double-blind Poor compared with morphine None Mulinos, Nair & Epstein (1962) z 26 Tuberculous 10 or 20 mg once a day Random, cross-over Dose Complete None Mulinos, Nair & Epstein ~ trial with same dose of (mg) relief (%) (1962) tj codeine or placebo Pholcodine 10 30 20 63 Codeine I 10 21 ~ 20 36 I Placebo - 12 70 Acute upper 5-10 mg, 3 or 4 times Good 74.3%4 Erythema in 2, Thalberg (1962) ; respiratory episodes a day Poor 18.5% drowsiness in 1 ~ 27 Children, acute cough 5 mg Two drugs equally effective e Mild constipation in Kelly (1963) --26 Children, acute cough Codeine, 8 mg one-third of the patients 30 Cough, various origin 1 or 2 x 8 mg Placebo Relief, 17%; doubtful, 33%; Nausea, 1; constipa- Schofield (1963) none, 50%. Placebo: relief, lion, 1; drowsiness, 2. 29%; doubtful, 49%; none, 22% Placebo: nausea, 2 ------a Twelve of the patients did not distinguish between the three. Author judged c Intramuscular administration. pholcodine and heroin equivalent. d Subjective reports of patients returning for office interview. b Author's judgment, " Safe, effective agent for cough suppression " (pro­ e Only difference noted by author slightly longer effect with pholcodine (4 phylactic). Eight patients had no cough before surgery and are amonlil the llours) th~n with co!l\line (3 hours). 0'\ 1~ with complete suppre~eion, Loc;al ~n~~e~ltwtic u~ed for $ureery, -~ 164 N. B. EDDY AND OTHERS

cough suppressants in general and said that at It must be concluded that pholcodine has less that time pholcodine was most favoured and that a dependence-producing potentiality than codeine; considerable number of preparations containing it poor solubility further reduces the likelihood of abuse were on the market. He thought, however, that and none has been reported. However, pholcodine most patients with an acute cough did not need a is convertible to morphine in the same way as codeine cough suppressant. If they did they must expect to and for this reason the WHO Expert Committee pay a price for their relief with some gastrointestinal on Addiction Producing Drugs (1952) judged it to distress or some depression. Oswald (1959), also be assimilable to the drugs mentioned in Group 11 discussed antitussives generally, and said that of the 1931 Convention and recommended that it although codeine was simple and safe, pholcodine should be internationally controlled like codeine. represented a real advance because of its lower toxicity, fewer side-effects and no greater liability to Nicocodine and nicodicodine produce dependence. Vasselin (1960) and David The antitussive and other pharmacological effects (1961) expressed similar opinions, the latter stating of the nicotinic acid esters of codeine, dihydrocodeine also that pholcodine produced no euphoria. An and pholcodine have been reported, particularly by editorial in the British Medical Journal (1961) spoke Cahen and his collaborators. By analogy with other highly of pholcodine and more recently Salem derivatives in the morphine series in which substitu­ & Aviado (1964) again judged it to be more potent tion has been effected at carbon-6, formation of the than codeine. The evidence as a whole establishes ester should have increased activity, but Cahen pholcodine as an effective antitussive. judged that nicotinic acid esterification of codeine Cahen (1961) said that no tolerance to the anti­ and pholcodine was not particularly advantageous tussive effect of pholcodine developed in patients and the comparative figures shown in Table 34 sup­ using 60 mg a day for more than three months. This port the conclusion (Cahen & Boucherle, 1961a, is not conclusive, however, because no evidence of 1961b; Cahen et al., 1963). tolerance was seen with similar administration of Flecker (1961) measured the rate, depth and codeine (Cass, Laing & Frederik, 1961). minute volume of respiration, oxygen consumption, Isbell (personal communication, 1952) reported antitussive response to intravenous lobeline and that 400 mg of pholcodine, orally or subcutaneously, circulatory changes in normal adult males with produced no morphine-like effect in post-addicts. repeated small doses of codeine and nicocodine, intra­ Doses of 500 or 750 mg, orally or subcutaneously, venously. Comparable doses for respiratory effect every four or six hours in morphine-dependent per­ were 3.0-4.0 mg of codeine and 1.5-2.0 mg of nicoco­ sons, had little effect on morphine abstinence dine. The former caused no circulatory change; the phenomena. Signs of inflammation appeared at the latter sometimes increased and sometimes decreased site of injection. Giudicelli (personal communica­ the heart rate but did not change the blood pressure. tion, 1957), told of attempts by Dr Jean Delay to The subjective effect of nicocodine was pleasant as if detect morphine-like effects or dependence-support­ one were breathing cool fresh air. ing properties. Doses of 40-80 mg subcutaneously in Single doses ofnicocodine of 5 or 10 mg in 27 tuber­ normal volunteers produced no or very little eleva­ culous patients who had been receiving codeine gave tion of the radiant-heat threshold, no sedation and similar cough relief without side-effects. no euphoria. He gave 50 mg, subcutaneously, to two With respect to nicodicodine, Cahen & Boucherle patients, and 100 mg to four others, at the peak of the (1964, 1965) reported that it was more toxic for mice abstinence syndrome following abrupt withdrawal of than dihydrocodeine, the LD50 being 114 mg per morphine, without an ameliorating effect. He tried kg compared with 150 mg per kg, intraperitoneally; unsuccessfully to substitute pholcodine for morphine nicodicodine was similar to dihydrocodeine as an in four other dependent persons, and in 10 patients antitussive but had spasmolytic action. The anal­ with cough he gave at least 60 mg a day for eight gesic ED50s (mg/kg) for nicodicodine were as fol­ months. During a 48-hour withdrawal at three lows: Route• ED months and following abrupt withdrawal at eight 50 Mouse, hot-plate 0 125 months no abstinence phenomena were observed. Mouse, hot-plate lP 60 Heffron (1961) also reported no evidence of physical Mouse, writhing test 0 160 dependence after prolonged administration of phol­ Rat, tail-flick lP 50 codine or attempted substitution for other narcotics. • O=oral; IP=intraperitoneal. CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 165

TABLE 34 COMPARATIVE ACTIVITY OF THE NICOTINIC ACID ESTERS OF CODEINE AND PHOLCODINE

Nicotinic acid I Nicotinic acid Feature, species, dose, route a I Codeine ester of Pholcodine ester of codeine pholcodine

LDso mouse (mg/kg), lP 154 51 630 250 LDso mouse (mg/kg), 0 470 280 1860 940 LDso rat (mg/kg), I P 37 LDso rat (mg/kg), 0 840 Analgesia, mouse, hot-plate (mgfkg), se 200 150 None None Antitussive, cat, mechanical or chemical stimulation (mgfkg), IV 2.3 3.3 6.05 3.5 Antitussive, cat anaesthetized (mgfkg), IV 5.0 Antitussive, dog, unanaesthe­ tized (mgfkg), IV 5.0 Circulation, cat, IV Vase­ depression Reduction in blood pressure, dog (mm Hg), 4 mg, IV -10to-40 -10to-80 -41 to-90 -44to-91 Respiratory rate and volume, dog, 4 mg, IV Decreased Decreased Increased Increased Decreased propulsion, gastro­ intestinal tract, mice, 17 mg, se -47% -47% Decreased propulsion, gastro­ intestinal tract, mice, 180 mg, se -50% -38% Straub reaction, mice, 40 mg, SC 0 0 Straub reaction, mice, 480 mg, se 0 0 Excitement, cat, 60 mg, SC 0 0 Excitement, cat, 160 mg, SC 0 0 Histamine release + + +++ +++

alP= intraperitoneal; 0 = oral; SC = subcutaneous; IV= intravenous.

The antitussive doses, mg per kg, intraperitoneally, ter of Oddi. It restored flow through barium-con­ by different methods were: stricted guinea-pig ileo-colic sphincter. Doses of Nicodicodine Dihydro­ codeine 50 f.Lg per ml relaxed isolated rabbit duodenum and Cat, chemical stimulation 7.5 7.5 of 2.8 f.Lg per ml relaxed the spasm induced by barium Cat, electrical stimulation 1.0 or acetylcholine. Dog, mechanical stimulation 3.2 3.2 Deneau & Seevers 1 tested nicocodine in morphine­ Guinea-pig, chemical stimulation 30.0 dependent monkeys. At doses of 2.4 and 8 mg per kg, subcutaneously, it had no effect on the morphine A dose of 4 mg per kg of nicodicodine, intra­ abstinence syndrome. The highest dose was con- venously, in dogs, decreased intrabiliary pressure after barium chloride or morphine and blocked 1 Deneau, G. A. & Seevers, M. H. (1963) Bull. Drug neostigmine-morphine-induced spasm of the sphinc- Addict. Narc., Add. 1. 166 N. B. EDDY AND OTHERS vulsant. Hence, at safe doses nicocodine had no phy­ not influence the blood pressure in cats. Intestinal sical dependence capacity. Nevertheless, nicocodine is peristalsis was stimulated (Kelentey et al., 1957). hydrolysable to morphine and the WHO Expert The N-oxides were generally Iess toxic than the Committee on Addiction-Producing Drugs (1962) N-methyl analogues, as shown in Table 35. recommended its international control as a narcotic, Since theN-oxide is a quasi-quaternary compound, ~ike other convertible drugs in the morphine series. retaining to some extent antitussive activity but not analgesic activity, it is convenient to present here N-Oxides and quaternary salts some observations on the antitussive effect of other The N-oxides of morphine and of some of its quaternary ammonium compounds. derivatives have been made and some of these have Gruber (1961) reported that theN-oxide of levo­ been tested for antitussive activity; the activity was propoxyphene had approximately the same degree of materially reduced by the change. Kelentey et al. antitussive action in man as the hydrochloride or the

(1957) reported ED50s (mg/kg) for the N-oxides of naphthalene sulfonate. morphine, dihydrocodeine and hydromorphone, Hillis & Kelly (1951) found that hexamethonium subcutaneously, for suppression of cough induced by iodide suppressed a lobeline-induced cough in sulfur dioxide in mice. The ED60s were: 20 for the human volunteers. Korpas, Tomori & Ivanco (1957) N-oxides of morphine, 15 for dihydrocodeine, 1 for observed that 20 mg per kg of pentamethonium hydromorphone, and 5 for oxycodone; the ED60 of depressed, but did not abolish, the cough response of codeine itself was 10.4 They said that theN-oxides anaesthetized cats to mechanical irritation of the had no analgesic effect (hot-plate method, mice) up trachea. It did not depress significantly the cough to 100-200 mg per kg, subcutaneously. Hara & elicited by irritation of the pharyngeal region. Since Yanaura (1959) gave some additional comparative the dose for paralysis of the superior cervical gan­ figures. They used dogs, stimulated the trachea glion is only about 10 mg per kg, it is hardly likely electrically and injected the drugs intravenously. that this action is the cause of the antitussive effect. For codeine and codeine-N-oxide the effective doses Ivan (1959) also reported decreased antitussive were 1.5 and 12.0 mg per kg; for dihydrocodeine and action with quaternized compounds, N-benzyl­ dihydrocodeine-N-oxide they were 1.5 and 15.0. codeine iodide and N-benzyl norcodeine methiodide, The N-oxides of morphine, hydromorphone and compared with that of codeine hydrochloride. oxycodone depressed the frequency and volume of Whereas 2 mg per kg of the latter, intravenously, respiration in rabbits, but even sub-lethal doses did abolished the cough due to electrical stimulation of

TABLE 35 LD ..S (mg/kg) OF SOME N-OXIDE AND N-METHYL ANALOGUES

Compound I Animal I Route a I N-O xi de I N-Methyl I Reference

Morphine Dog I se 360 Hara & Yanaura (1959) Morphine Rabbit IV 170-220 250 I Kelentey et al. (1957) I Morphine Mouse se 2050-2350 540 Kelentey et al. (}957) Codeine Dog IV 767 120 Hara & Yanaura (1959) Codeine Rabbit IV 80-100 Kelentey et al. (1957) Codeine Mouse se 120 Kelentey et al. (1957) Dihydrocodelne Dog IV 1050 150 Hara & Yanaura (1959) Hydromorphone Rabbit IV 160 Kelentey et al. (1957)

Hydromorphone Mouse I se 2000 Kelentey et al. (1957) Oxycodone Rabbit IV 75-120 Kelentey et al. (1957) Oxycodone Mouse se 800-1200 Kelentey et al. (1957)

a SC = subcutaneous; IV = Intravenous. CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 167 the superior laryngeal nerve, 5 mg per kg of the superior to that of codeine but supporting quantita• quaternary salts had little effect. The latter were tive data were not presented. convulsant and more toxic than codeine and had the pharmacodynamic properties of other quaternary Nalorphine compounds. The specific opiate antagonist, nalorphine (N-allyl­ Somewhat better results have been obtained in normorphine), although showing little analgesic animals and man with bibenzonium bromide. Kiill- effect in animals, was shown by Lasagna & Beecher (1954) to have as great an analgesic action in man,

\ CH, = \ I CH -0 -CH,-CH,-N-CH, : I CH, CH, I NALORPHINB

BIBENZONIUM BROMIDE milligram for milligram, as morphine itself, against postoperative pain. However, the combination of quist & Melander (1957) found that at 10 mg per kg. 2 mg of nalorphine and 10 mg of morphine produced subcutaneously, the compound was as effective as analgesia and side-effects indistinguishable from codeine in suppression of cough induced by ammonia those achieved with 10 mg of morphine. The inhalation in guinea-pigs. Plisnier (1958) reported it peculiar and disturbing side-effects of nalorphine to be three times as potent as codeine against cough preclude its use as a clinical analgesic and would in cats after electrical stimulation of the superior interfere with its use for any purpose except an­ laryngeal nerve, but Wax, Winder & Peters (1962) tagonism of toxic effects. Nevertheless it was shown said that neither Rosiere & Winder nor Winter by Winter & Flataker (1954), and confirmed by (unpublished experiments) could confirm the anti­ others, that nalorphine has antitussive as well as tussive action of this compound. analgesic action and the details are worth consider­ Hahn & Wilbrand (1952) studied the antitussive ing because we now know many specific antagonists effect of bibenzonium bromide in normal, human and we know also that the frequency of their disturb­ volunteers and compared it with that of codeine and ing side-effects does not parallel their other actions. methadone. They used the methods of Hoglund & In the first experiments of Winter & Flataker Michaelsson (1950) and of Trendelenburg (1950) in guinea-pigs were used and cough was produced by which ammonia vapour is inhaled in increasing con­ inhalation of a mist containing 2.8% of ammonia; centration until there is closure of the glottis. The the coughs were counted for three-minute periods substances were given in a tablet or in syrup to and averaged for five animals. The difference patients who did not know what their dose contained. between two such counts an hour apart was small in Doses of 10 and 20 mg of bibenzonium bromide had untreated animals. Comparing codeine phosphate the same effect as equal doses of codeine phosphate and nalorphine hydrochloride at doses of 0.25- in elevating the threshold of response. Respiratory 2.0 mg per kg, subcutaneously, the effect of nalor­ depression was not observed. phine was a little less at the smaller doses, but at Alemquer & Leal (1962) reported on only six 2.0 mg per kg it was as great as that of codeine, the tuberculous patients treated with bibenzonium former giving a 34.8% reduction in the cough count bromide. Cough relief was rated numerically : and codeine a 27.3% reduction. 3=complete; O=none. Placebo gave a total score Winter & Flataker (1954) also compared nalor­ per day of 2-5.5, bibenzonium bromide at 30 mg per phine with codeine in dogs and in addition tried day 7.5, and at 60 mg per day 12. Dumittan (1963) various other related antagonists alone and in com­ reported a few more cases of cough due to respi­ binations with codeine. In the dogs, cough was ratory infection. A total of 21 patients received the produced by inhalation of N/2 sulfuric acid aerosol preparation in solution (2 mg per rnl), 15 ml four and drugs were given orally. There were two or times a day for six days. The effect was said to be three tests per animal per dose and the cough counts 168 N. B. EDDY AND OTHERS

(4 minutes) per dose per animal were averaged stimulation of the superior laryngeal nerve, and in before and at one and two hours after medication. dogs, cats and guinea-pigs by mechanical stimulation The average counts for codeine, the antagonists and of the trachea and by inhalation of sulfur dixoide. the mixtures are shown in Table 36. Drugs were given intravenously. Nalorphine in Among the compounds listed in the table N-allyl­ doses of 3-30 mg per kg failed to abolish cough and it norcodeine is the weakest and N-allylmorphinan did antagonize the antitussive action of morphine­ (levallorphan) the strongest specific antagonist. No like analgesics. The dose required for antagonism relationship is apparent between antagonistic potency varied w1th the dose and potency of the other agent and antitussive action and the addition of an an­ and was of the same order as was required to anta­ tagonist to codeine, at least in the ratios used, did not gonize other morphine-like actions. Nalorphine sup­ appear to interfere with the antitussive action. pressed the antitussive action of codeine whether the Winter & Flataker showed that nalorphine did not cough was provoked by electrical, mechanical or antagonize the antitussive action of codeine in chemical stimulation. N-Propylnormorphine was guinea-pigs. In the latter nalorphine also failed to also an effective antagonist to the antitussive action antagonize the antitussive action of noscapine or of codeine. Nalorphine did not antagonize the morphine. antitussive action of pholcodine or that of noscapine. Green & Ward (1955) reported differently. They In a dog in which spontaneous coughing, initiated by elicited cough in anaesthetized cats by electrical exposure to cold, was relieved by administration of

TABLE 36 NUMBER OF COUGHS PER DOSE PER DOG, BEFORE AND AFTER INHALATION OF N/2 SULFURIC ACID AEROSOL

Hours after treatment Dose Before Agent (mgfkg) treatment 1 2

Codeine phosphate 0.25 15 9 13 Codeine phosphate 0.5 20 6 11 Nalorphine.HCI 0.25 22 10 15 Nalorphine.HCI 0.5 22 7 Nalorphine+ codeine 0.125 + 0.125 23 10 14 N-AIIylnorcodeine.HBr 1.0 16 10 17 N-AIIylnorcodeine.HBr 2.0 33 5 16 N-AIIylnorcodeine + codeine 0.5 + 0.5 34 15 18 N-AIIylnorcodeine + codeine 2.0 + 0.5 17 0 8 N-AIIylnorhydrocodone tartrate 0.5 22 11 8 N-AIIylnorhydrocodone + codeine 0.25 + 0.25 30 4 8

N-Propylnormorphine-HCI 1.0 I 32 13 33 N-Propylnormorphine + codeine 0.5 + 0.5 24 18 21 N-Propylnormorphine + codeine 1.0 + 0.5 37 12 16 N-Methallylnormorphine.sulfate 2.0 41 16 20 N-Methallylnormorphine + codeine 2.0+ 0.5 34 19 24 N-Butylnormorphine.HCI 1.0 30 25 24 N-AIIylmorphinan.tartrate 1.0 38 44 38 N-A llylmorph in an. tartrate 2.0 32 27 22 N-A llylmorphi nan .tartrate 4.0 22 23 25 CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 169

3 mg per kg of codeine, intravenously, the coughing to synthesize morphine led to the production of a reappeared immediately upon injection of 1 mg per similar basic structure, a morphinan, differing from kg of nalorphine, intravenously. Green & Ward morphine in the absence of the oxygen bridge, a concluded that the antagonism of various morphine­ double bond and the aliphatic hydroxyl group. like effects by nalorphine was similarly brought about Modifications of morphinan, so far as possible along and that Winter & Flataker had used too small doses; the lines of the many members of the morphine series, they did not show that the small doses used by the naturally followed. The synthetic products were latter did not have an antitussive effect as described. racemic and the first to be introduced into medicine Bickerman & Barach (1954) compared codeine, was racemorphan, ( +) 3-hydroxy-N-methylmor­ nalorphine and placebo in human subjects, 21 nor­ phinan. When this was resolved, pharmacological mals and 17 asthmatics, in which coughing was comparisons proved that analgesic activity resided provoked by inhalation of citric acid aerosol. Drugs in the levo-component as is the case among natural were given orally. At a dose of 5 mg, nalorphine had alkaloids. This differentiation held generally for some effect and at 30 mg the effect was similar to that other morphinans including the codeine analogue, of 30 mg of codeine sulfate. The average cough methorphan. A by-product of this investigation, counts were as follows: however, was the demonstration that the dextro­ Average decrease in isomers, in particular dextromethorphan, ( + )3- number of coughs methoxy-N-methylmorphinan, in spite of the ab­ Interval after administra- lion (min) sence of analgesic action in the usual tests, were effec­ 120 Agent No. of 30 60 tive antitussives (Benson, Stefko & Randall, 1952, tests Normal subjects 1953; Pellmont & Biichtold, 1954; Reich1e & Friebel, Placebo 28 0.04 +0.04 +0.07 1955). The association of analgesic action with Nalorphine·HCI, 5 mg 30 1.9 2.6 2.2 optical isomerism in this series is consistent with the Nalorphine·HCI, 30 mg 19 3.0 3.2 3.3 differentiation of activity between isomers in other Codeine sulfate, 30 mg 33 3.2 3.7 5.2 chemical groups of analgesics, but the independent Asthmatics occurrence of antitussive effect is novel. It has, Placebo 30 0.4 +0.1 0.04 however, been confirmed many times over in animal Nalorphine·HCI, 5 mg 12 1.8 1.1 1.0 experiments and these are summarized in Table 37. Nalorphine·HCI, 30 mg 22 3.8 4.0 3.1 Codeine sulfate, 30 mg 27 3.0 4.5 5.9 ,-.~-N-CHJ Gravenstein, Devloo & Beecher (1954) were .,' "" ' unable to detect a significant difference, in 25 patients (+) with cough of pathological origin, between 15 mg of o--e / codeine and 20 mg of nalorphine or between either OCHJ drug and a placebo. The drugs were given orally for three-day periods, questionnaires were filled in DEXTROMETHORPHAN and in five patients coughs were counted. The patients felt better and thought they coughed less but this was Although dextromethorphan fails to diminish not borne out by the cough counts. The authors con­ response to nociceptive stimuli in the usual trials, it cluded that these agents had little real effect on has, according to Randall & Selitto (1958), an anti­ cough frequency. No mention was made of disturb­ inflammatory action and gives an appearance of ing side-effects with nalorphine, but the drug is analgesia in the presence of inflammation. For known from other studies to be not very effective example, when inflammation was produced in the orally; 20 mg orally is not nearly equivalent to 10 mg rat's foot by plantar injection of brewer's yeast, the parenterally. observations shown in Table 38 were reported. This anti-inflammatory activity resembles the DEXTROMETHORPHAN peripheral action of aspirin and paracetamol rather than the central action of codeine and may be Morphine and the other phenanthrene alkaloids related to a vasodepressor effe~t. of opium are optically active, levorotatory com­ Pellmont & Biichtold (1954) also reported an pounds; their dextroisomers are known, at least in anti-inflammatory action of dextromethorphan when part, but are not present in opium. In 1949 attempts inflammation was produced by mustard oil in mice. 170 N. B. EDDY AND OTHERS

TABLE 37 EFFECTIVENESS OF DEXTROMETHORPHAN ON EXPERIMENTAL COUGH IN ANIMALS

Method of cough Induction I Anaes- Reference thesla I (mgjkg)Dose I Route a I Result

Species: RAT Sulfur dioxide vapour 0 18.0 se I = EDoo Relchle & Frlebel (1955)

Species: GUINEA-PIG

Ammonia aerosol 0 1.0 se 4.2% decrease in cough res- Kiillqulst & Melander (1957) ponse b Acrolein aerosol 0 6.0 se Effective Maffii, Silvestrini & Banfi (1963) Acrolein vapour 0 3.5 se Ineffective Silvestrini & Maffii (1959) Acrolein vapour 0 5.0 se 13.4% inhibition Silvestrini & Maffii (1959) Acrolein vapour 0 7.0 se 67.1 %inhibition Silvestrini & Maffii (1959) Acrolein vapour 0 14.0 se 33% inhibition Silvestrini & Maffii (1959) Sulfur dioxide vapour 0 18.0 se = EDso Miller, Robbins & Meyers (1963) Sulfur dioxide vapour 0 14.0 se = EDso Friebel & Reichle (1956) Electrical stimulation of trachea 0 26.0 se Threshold elevation of 0.4 mA Hahn & Friebel (1966)

Species: RABBIT

Mechanical stimulation 4-8 IV Little or no effect Furukawa & Okabe (1958) Mechanical stimulation 10-20 IV Suppression of cough Furukawa & Okabe (1958) Mechanical stimulation 50 0 Little effect Furukawa & Okabe (1958) Mechanical stimulation 100 0 Effective after 30 m in c Furukawa & Okabe (1958)

Species: CAT

Sterile pleurisy 0 2.0 se Minimal effective dose Van Dongen (1956) Ammonia inhalation + 4.0 0 40% or more inhibition Stefko, Denzel & Hickey (1961) Ammonia inhalation + 2.0 IV Effective Silvestrini & Maffii (1959) Ammonia inhalation + 2.0 IV As effective as codeine Pellmont & Biichtold (1954) Soap powder insufflation + 1.5 IV As effective as 3.5 mg/kg of Pellmont & Biichtold (1954) codeine Electrical stimulation of supe- + 2.0 IV As effective as codeine, or Pellmont & Biichtold (1954) rior laryngeal nerve more effective Electrical stimulation of supe- + 2.0 IV Effective Maffil, Silvestrini & Banfi (1963) rior laryngeal nerve Electrical stimulation of supe- + 1.372 IV = EDsoforinhibition ofinspira- Kohli, Gupta & Blargava (1960) rior laryngeal nerve tory gasp Electrical stimulation of + 0.25-0.5 IV Decreased frequency of cough Chakravarty et al. (1956) medulla, stereotactically Electrical stimulation of + 1.0-2.0 IV Abolished cough C hakravarty et al. (1956) medulla, stemotactically Mechanical stimulation trachea + 5.1 lP = EDso Kas~ et al. (1959) Electric stimulation of medulla, 0 1-2 IV Effective Matallana & Borlson (1955) stereotactically a CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 171

TABLE 37 (continued)

Anaes­ Result Reference Method of cough induction thesia Route a I

Species: DOG

Sulfuric acid aerosol 0 1.0 0 28% inhibition Chen, Biller & Montgomery (1960) Sulfuric acid aerosol 0 7.0 0 Effective Maffil, Silvestrlnl & Banfl (1963) Electrical stimulation of trachea 0 1.0-2.0 se Effective Maffii, Silvestrlnl & Banfi (1963) Electrical stimulation oftrachea 0 2.0 se Marked effect Pellmont & Biichtold (1954) Electrical stimulation of trachea 0 2.0 se Effective Silvestrinl & Maffii (1959) Electrical stimulation of trachea 0 2.0 IV =EO,. Hara & Yanaura (1959) Electrical stimulation of trachea 0 1.0 se Approximate EDso Benson, Stefko & Randall (1953) Electrical stimulation of trachea 0 1.0 0 > 40% inhibition Stefko, Denzel & Hickey (1961)

Mechanical stimulation of 0 10.2 IV = EO,.• Kas~ et al. (1959b) trachea Pathological 0 4.0 0 > 40% Inhibition Stefko, Denzel & Hickey (1961)

a SC =subcutaneous; IV= Intravenous; 0 =oral; lP =intraperitoneal. b Ratio to codeine as 1.00 = 0.37. c Effectiveness increased relative to that of codeine by addition of pentobarbital. d Barbitalized or decerebrate animals. • Decerebrate animals. Doses of codeine for comparable effect, 1-6 mg per kg.

TABLE 38 REACTIONS INDUCED BY DRUGS WITH INFLAMMATION PRODUCED IN THE RAT'S FOOT BY PLANTAR INJECTION OF BREWER'S YEAST a

Analgesic action: Increase Temperature changes (deg C) Drug b Dose in pain threshold (mm Hg) c Anti-inflam- (mgfkg) matory action d Inflamed foot I Normal foot Inflamed foot I Normal foot I Normal skin I Dextromethorphan 6.25 58 0 0 0.16 -0.2 -0.1 Dextromethorphan 12.5 130 26 13 -1.9 -0.2 -0.3 Dextromethorphan 25.0 232 123 23 -2.3 +0.4 +0.1 Codeine 6.25 58 35 0 0 0 0 Codeine 12.5 144 92 0 0 0 0 Codeine 25.0 235 136 0 0 0 0

a After Randall & Selltto (1958). b Drugs were administered orally to 5 rats per dose. c Initial threshold for response 120 mm Hg. Observations at one hour after drug. d Decrease in circumference of Inflamed foot (mm). 172 N. B. EDDY AND OTHERS

Measurement of antitussive action in animals new agent was to be evaluated. Friebel & Reichle The figures for effective antitussive doses in the (1956) believed the guinea-pig superior to the rat as smaller animals are variable but relatively high; for the test animal for antitussive measurements. In cats and dogs they are more uniform and lower. their hands dextromethorphan was less effective than Onset and duration of action were about the same, codeine. The subcutaneous ED50 for dextro­ and were independent of species or cough stimulus. methorphan was 18 mg per kg in the rat against Hahn & Friebel (1966) calculated that the peak 10 mg per kg for codeine and 14 mg per kg in the effect occurred between 30 and 60 minutes and that guinea-pig against 8 mg per kg for codeine. Only the duration was in the neighbourhood of three Chakravarty et al. (1956) said that dextromethorphan hours. Stefko, Denzel & Hickey (1961) published was a definitely more effective antitussive than more extensive figures, showing the dose-effect codeine. They said that 4-10 mg per kg of the latter relationship at different times after administration was required to suppress cough as well as I or 2 mg and also gave a comparison with two doses of per kg of dextromethorphan. Their animals were codeine (Table 39). Observations were continued for anaesthetized or decerebrated and cough was only 120 minutes, but the effect of 4 mg per kg of elicited by stimulation through centrally placed codeine phosphate was still well in evidence at that electrodes. time and the effect of the same amount of dextrome­ Two unusual variations in the antitussive effect of thorphan was nearly as great. In other experiments, dextromethorphan should be noted. Silvestrini & Benson, Stefko & Randall (1953) found the two drugs Maffii (1959) obtained the maximum effect in the equally effective, but against pathological cough in guinea-pig with 7.0 mg per kg; double that dose dogs Stefko, Denzel & Hickey (1961) said that dex­ resulted in only 33 % inhibition. Furukawa & · tromethorphan was less effective than codeine. Fuji­ Okabe (1958) reported enhancement of the anti­ moto (1958) elicited cough, electrically, mechanically tussive effect of dextromethorphan by simultaneous and chemically, in unanaesthetized dogs and found administration of pentobarbital. The experimental dextromethorphan and codeine about equally effec­ animal was the rabbit and cough was induced by tive as suppressants, and he insisted that variability mechanical stimulation. These results have not been demanded the use of more than one method when a confirmed. Respiratory effect TABLE 39 Benson, Stefko & Randall (1953) found that TIME-EFFECT RELATION OF GRADED DOSES respiratory rate and minute volume in the an­ OF DEXTROMETHORPHAN FOR ANTITUSSIVE EFFECT IN aesthetized rabbit might be stimulated by dextro­ DOGS; COUGH ELICITED BY ELECTRICAL STIMULATION OF THE TRACHEA a methorphan. A dose of 2.0 mg per kg increased the minute volume by 22.8 %; 4.0 mg per kg increased No. of animals/ %inhibition of cough at the respiratory rate by 23.6% but the minute Oral dose I no. of 1---,-----,----.----- volume was increased by only about 4.0 %. Pellmont (mg/kg) experiments 15 min I 30 min 160 min 1120 min & Bachtold (1954) also said that small doses of

Dextromethorphan hydrobromide dextromethorphan stimulated respiration in the rabbit but that doses above 5.0 mg per kg caused 0.5 12/27 16 28 23 12 depression. In cats only depression of respiration 1.0 12/28 30 46 54 32 occurred (Chakravarty et al., 1956); and in guinea­ 2.0 15/30 42 63 68 44 pigs, according to Hahn & Friebel (1966), no signifi­ 4.0 13/28 44 76 84 54 cant respiratory change occurred with 26 mg per kg, subcutaneously. Qualitative changes in the bouts of 8.0 11/24 48 84 90 70 coughing, elicited by electrical stimulation of the 16.0 10/12 48 90 92 70 trachea, did occur and Chakravarty et al. (1956) said that the antitussive effect outlasted repiratory Codeine phosphate depression. 1.0 12/14 26 46 44 30 Capello & Di Pasquale (1955) used a 30-mg dose 4.0 12/16 48 I 88 99 78 of dextromethorphan to treat the cough of 23 tuber­ I I culous patients, and measured a number of facets of a From Stefko, Denzel & Hickey (1961). respiratory function before and after the treatment CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 173

was begun. Effective vital capacity ventilation, air systoles. In anaesthetized cats (mainly) and dogs, velocity index and oxygen extraction index were according to Gruhzit (1957), 1-2 mg per kg of significantly improved in most of the patients. dextromethorphan, intravenously, usually (40 of Gruhzit & Schub (1956) and Gruhzit (1957) 46 injections) caused a fall in systolic and diastolic injected dextromethorphan intravenously, or into blood pressure of a few to 100 mm Hg, lasting a few the right atrium in anaesthetized cats and dogs, and minutes to an hour. The effect diminished with produced respiratory depression very rapidly with repetition of the dose. Randall et al. (1953) said periods of expiratory apnoea. This was blocked by that three successive doses of dextromethorphan, barbiturates and by vagotomy and did not occur if 1.0 mg per kg, intravenously, decreased the blood the injection was into the aorta or left ventricle. The pressure by 120, 85 and 20 mm Hg; the duration of authors concluded that there was an effect on the the fall also diminished and the same dose after pulmonary chemoreceptors. Codeine produced a 1 mg per kg of levorphanol caused only a brief similar effect. 15-mm fall in pressure. The effect of levorphanol Randall et al. (1953) said that dextromethorphan after dextromethorphan was also diminished so that at a concentration of 0.01 molar had no effect on both acute tolerance and cross-tolerance developed. the respiration of rat brain slices and that a con­ Intra-arterial injection of dextromethorphan, 0.5 mg centration of more than 0.02% was required to per kg, increased peripheral blood flow and the produce a 50% inhibition of cholinesterase. authors concluded that there were both central and Boyd, Hicks & Trainor (1956) measured the out­ peripheral components in the hypotensive effect. put of respiratory-tract fluid in animals under light Pellmont & Bachtold (1954) found that the fall in urethane anaesthesia (mainly cats but a few experi­ blood pressure could be produced in the decapitated ments on rabbits and guinea-pigs). At a dose of cat further suggesting peripheral action. Slomka & 5 mg per kg and above, orally, dextromethorphan Goth (1956), however, said that there was no diminu­ decreased the output to about 40%. The mean tion in the hypotensive effect of repeated injections output in control animals was at the rate of 2.43 ml of dextromethorphan in dogs under pentobarbital per 24 hours and in the drugged animals 1.24 ml anaesthesia and, after these repeated injections, a per 24 hours. The inhibitory effect lasted only about histamine-liberator still caused a fall in pressure. one hour. There was no corresponding change in If the dose of histamine-liberator was repeated until viscosity, specific gravity or chloride content of the acute tolerance to it had occurred, dextromethorphan fluid. Van Dongen (1956) reported that 5 mg per then had no effect. Schallek & Walz (1954) com­ kg of dextromethorphan, subcutaneously, in the cat pared the two isomers of methorphan. In three inhibited ciliary movement. Barium sulfate blown experiments in dogs the dextroisomer caused an into the trachea, normally removed in two hours, average decrease in blood pressure of 33% and in was not completely removed until five hours after the heart rate of 21 %; the levoisomer decreased dextromethorphan. blood pressure only 3.0% but the heart rate 32%. Pellmont & Bachtold (1954) observed broncho­ Megemont et al. (1961) tested various compounds constriction with dextromethorphan, 1 or 2 mg on the isolated heart of Helix pomatia. The lowest per kg, intravenously, in decapitated cats but not in concentration of dextromethorphan to alter the intact animals. It was not reversed by papaverine, rhythm was 1 : 25 000, to cause cardiac arrest or by sympathomimetic or parasympatholytic com­ 1:12 500 and to potentiate the effect of acetyl­ pounds. choline 1:75 000. Pellmont & Bachtold (1954) reported an increase Other pharmacologic actions in intestinal tone with dextromethorphan. Gyang, A decrease in blood pressure after dextromethor­ Kosterlitz & Lees (1964) found the minimal con­ phan in dogs, cats and rabbits has been reported. centration to cause inhibition of the peristaltic reflex Leimdorfer (1955) found in dogs anaesthetized with in the isolated guinea-pig ileum to be 8.0 fLg, per ml, pentobarbital that 2 or 3 mg per kg of dextro­ whereas the corresponding concentration for codeine methorphan, intravenously, usually caused a sharp was 1.8 fLg per ml. fall in blood pressure with slowing of the heart. In spite of the lack of analgesic and overt sedative This could be prevented if small divided doses were actions with dextromethorphan, Schallek & Walz given even to the same total amount. After dextro­ (1954) described changes in the electroencephalo­ methorphan, epinephrine failed to cause extra- gram pattern in the dog. A dose of 1 or 2 mg per kg, 174 N. B. EDDY AND OTHERS

TABLE 40 TOXICITY OF DEXTROMETHORPHAN

LDso (mgfkg) Species Reference Intravenous Subcutaneous Oral

Mouse 37 275 165 Pellmont & B!lchtold (1954) Mouse 298 Eddy (unpublished data) Mouse 35 277 165 Benson, Stefko & Randall (1953) Mouse 157 Hara & Yanaura (1959) Mouse 153 Kase et al. (1959b) Rat 600 350 Ben son, Stefko & Randall (1953) Rat > 400 Randall et al. (1953) Rabbit 15 Ben son, Stefko & Randall (1953) Rabbit 19 Pellmont & Biichtold (1954) Dog 39 a Kase et al. (1959b) Dog > 10 > 20 Pellmont & Biichtold (1954)

a Minimal lethal dose. intravenously, decreased frequency and amplitude; were given codeine or heroin than after dextrome­ the levoisomer had a similar effect. thorphan or placebo (double-blind), but cough Toxicity figures for dextromethorphan are shown counts failed to confirm a difference. Bickerman in Table 40. (1961, 1962) has twice reviewed the newer anti­ Versie et al. (1962) reported a case of accidental tussives including dextromethorphan, and, contrary poisoning with dextromethorphan. A child who to the foregoing, obtained in his own laboratory a weighed 11.7 kg ingested 180 mg. Vomiting occurred significant decrease in cough produced experiment­ twice and no other serious difficulty was encoun­ ally in normal subjects (Bickerman et al., 1957). tered. Within 24 hours 34% of the dose was recov­ Cough was induced by a citric acid aerosol and ered in the urine. Metabolites identified by chro­ six to eight subjects were used per dose given orally. matography, in addition to dextromethorphan, The results are shown in Table 41. were ( + )3-methoxymorphinan and ( + )3-hydroxy­ morphinan. Willner (1963) also reported finding TABLE 41 the demethylated metabolites, 3-hydroxy-N-methyl­ EFFECT OF DRUGS ON EXPERIMENTALLY PRODUCED morphinan and 3-hydroxymorphinan; he did not COUGH a find 3-methoxymorphinan. The percentages of the %decrease in cough after doses recovered were 28.0%, 8.5% and 2.5% in one Drug Dose (m g) I group and 39%, 56% and 15% in another group I 1 h I 2 h I 3h ! 4h of three patients. The dose in the latter group was 1 50mg. Placebo -7.5 +2.5 +5.0 1 +25.0 Placebo +10.6 +4.3 -4.31 +12.8 Antitussive action in man Placebo -8.0 -12.0 -12.0 +2.0 Gravenstein, Devloo & Beecher (1954) and Dextromethorphan 5 -33.5 -20.8 -18.1 ' -12.7 Gravenstein & Beecher (1955) induced cough in normal subjects with intravenous paraldehyde, Dextromethorphan 10 -29.8 -24.6 -24.6 -26.3 ammonia vapour or citric acid aerosol and failed to Dextromethorphan 20 -23.9 -25.4 -33.8 -25.4 obtain evidence of antitussive action. The dextro­ Codeine 5 -17.2 -22.4 -22.4 -17.2 methorphan dose used was 30 mg, orally; but they Codeine 15 -32.4 -32.5 -27.51-10.0 also failed to show a significant effect with codeine Codeine 30 -32.8 -43.1 -34.5 -22.4 or heroin. Patients with pathological cough, the authors said, felt that they coughed less after they a From Blckerman et al. (1957). CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 175

There was less dose-relationship demonstrated doses were 10 and 20 mg of dextromethorphan and for dextromethorphan than for codeine, but there 15 mg of codeine, each four times a day for 10 days, was less dose-spread for the former than for the 63 patients completing the cross-over trial (Cass & latter. A dose of 10 mg of dextromethorphan was Frederik, 1956). very similar in its effectiveness to 15 mg of codeine. The results shown in Table 42 confirm the anti­ Calesnick & Christensen (1967) reported recently a tussive effect of dextromethorphan. A suitable dose different criterion for the detection of antitussive of it can be as effective as codeine and commonly action in ·normal subjects. They used only males the therapeutic doses are the same for both drugs. (medical students) because females were too sensitive to reflex closure of the glottis and this prevented Abuse liability inhalation of a sufficient amount of nebulized 25% Generally speaking in the past, compounds which citric acid. They also excluded persons who did produced morphine-like analgesia, except the specific not give a good cough response before drugging or opiate antagonists, have exhibited the ability to who failed to show an antitussive effect with 40 mg produce dependence of the morphine type. It was of codeine, orally. A lengthening of the latent most interesting, therefore, to determine whether period, the time from inhalation, under pressure dextromethorphan, which is not analgesic but is through a tight face mask, to the cough response, antitussive, also a characteristic morphine-like was arbitrarily set as the indication of cough sup­ action, would or would not show morphine-like pression. Graded doses of codeine were given, dependence-producing properties. The study was 5-120 mg, with citric acid challenge at hourly carried out at the Addiction Research Center, intervals for four hours; optimal suppression was Lexington, Ky., USA, by Isbell & Fraser (1952, obtained with 40 mg. The response curves of 10- 1953). In sharp contrast to the morphine-like effects 40 mg of codeine and 15-30 mg of dextromethorphan of the racemate and the levoisomer, dextromethor­ were parallel but codeine was judged to have 2.2 phan, given orally or subcutaneously to non­ times the potency of dextromethorphan on a weight tolerant former morphine addicts, in doses of basis or 3.3 times on a molar basis. In some experi­ 6-100 mg, exhibited no evidence of morphine-like ments radioactive dextromethorphan was adminis­ behaviour. Toxic symptoms (dizziness, diplopia, tered for determination of the plasma level and headache, nausea and vomiting) appeared following excretion in 24 hours. Urinary excretion accounted doses of 60 mg or more. In other experiments on for 42.7% of the dose administered, faecal excretion these post-addict subjects measurements of rectal for 0.12 per cent. All observations in these experi­ temperature, pulse and respiratory rate, blood ments were double-blind and drug administrations pressure, pupillary size and respiratory minute were randomized at three- or four-day intervals. volume were made before and at hourly intervals Clinical trials and reports on the effect of dextro­ after oral and subcutaneous administration of methorphan against cough of various origin are 75 mg of dextromethorphan. Comparison was with summarized in Table 42. The first of these trials was 30 mg of morphine, 60 mg of codeine and placebo, by Cass & Frederik (1953). Initially they compared orally and subcutaneously, in the same subjects. 4 mg of dextromethorphan and 15 mg of codeine None of these parameters was affected by the each given four times a day for five days to 65 patients dextroisomer. To patients who were dependent on with chronic cough. Both were judged by the patients morphine and who were stabilized on 120-300 mg and the observer as better than placebo, but codeine per day, doses of about 90 mg of dextromethorphan, at the dose used was more effective. In a second repeated once, were given orally and subcutaneously series (Cass, Frederik & Andosca, 1954) three doses at the peak of the abstinence syndrome, 28 and of dextromethorphan, 6, 12 and 18 mg, one dose of 32 hours after abrupt withdrawal of morphine. There codeine, 15 mg, and placebo were compared in was no effect at all on the intensity of the abstinence 69 patients. Administration of each was three times phenomena. In five other patients, stabilized on a day for seven days. All of these doses were given 60 mg of morphine four times a day, a dose of orally. The severity of cough was rated numerically 75-100 mg of dextromethorphan was given in place and the sums of scores for relief established a dose­ of each morphine dose. Signs of abstinence appeared effect relationship and approximate equivalence of at the same time and developed with the same inten­ dextromethorphan and codeine on a weight basis. sity as when the morphine was discontinued without This was confirmed in a third series in which the any substitution. Dextromethorphan was corn- --.1 "' TABLE 42 SUMMARY OF CLINICAL ANTITUSSIVE EFFECTIVENESS OF DEXTROMETHORPHAN

' Patients Dosage and regimen of administration Result Reference No. I Type

65 Chronic cough 4 x 4 mg per day About half as effective as codeine, 4 x 17 Cass & Frederik (1953) mga

42 Tuberculous; 45 other chronic cough 2 - 5 x 5 mg per day Effective b Buchegger & Frisch (1954)

69 Chronic cough 3 x 6 mg, 12 mg or 18 mg per day, for 7 days Cough intensity scores: Cass, Frederik & Andosca 6 mg 1.36 (1954) 12 mg 1.28 18 mg 1.25 f: Codeine, 15 mg 1.26 c !"' Placebo 1.48 a 453 Mostly children 3 x 2, 5 or 10 mg per day, children As good relief in small groups as with Hottinger (1954) 0 codeine or hydrocodone d >< 3 x 5-20 mg per day, adults

46 Chronic cough 4 x 4 mg per day, 3 days to 6 months Moderate to marked relief, 71.7% e Ralph (1954) ~ 98 Chronic cough 4 x 15 mg per day, 3 days to 6 months Moderate to marked relief, 89.6% Ralph (1954) 23 Tuberculous 30 mg per day Marked improvement! Capello & Di Pasquale (1955) ~ 120 Acute and chronic cough 3 or 4 x 10 mg per day Slower and briefer but as effective as eo- Kummer (1955) "' dei ne 79 Bronchitis Effect definite in 37, very good in 27 u Maurer (1955) >100 Tuberculous 2or3x 10or20mgperday Effect as good as with codeine in 25 patients, Steiger (1955) sometimes better h

120 Mo'stly tuberculous 7.5-15 mg, average 12.9 mg per day Cough suppressed 49, less 16 i Tiinnerhoff & Schwabe (1955)

73 Tuberculous 20-30 mg, average 28.8 mg per day Cough suppressed 23, less 27 Tiinnerhoff & Schwabe (1955)

4-8 x 20 to 30 mg per day These doses gave better cough control Zettel (1955)

63 Chronic cough 4 x 10 mg and 4 x 20 mg per day for 10 Cough score: placebo, 1.15; 20 mg, 0.92; 10 Cass & Frederik (1956) days mg, 0.86; codeine, 15 mg, 0.78 J 150 Pneumothorax, bronchoscopies 30 mg single dose Effective Grafe (1958) TABLE 42 (continued)

-----~------Patients Dosage and regimen of administration Result Reference No. I Type I 119 Children 5-27 mg according to age, per day 84 Improved k Huperz (1958) ~ 100 Cough of various origin 3 x 15-22.5 mg per day Good in 74; prompt relief lasting 4-5 hours I Skursky (1959) ~ 0 22 Children, per dose group 15 or 30 mg per dose, 3-5 days Score: frequency severity Gruber & Carter (1961) Blank 60 62 a 15mg 36 36 30 mg 24 24m 100 Chronic cough 15 mg per dose, for 1 week 74% effective Simon (1962) ~ 28 Children, acute cough 4 x 30 mg plus 325 mg aspirin per day, 3-5 Complete relief= 0; no relief = 4. Aspirin Carter (1963) days alone scored 75 and 73 for frequency and se- ~ verity of cough, dextromethorphan 16 and 16

65 Children, ambulatory and hospitalized 15 mg + phenylpropanolamine+ antihis- In both groups relief was better with both Reece et al. (1966) ~ !amine; 75 mg + phenylpropanolamine; mixtures than placebo, but not differentfrom placebo each other ~z ~ a Fewer side-effects than with 17 mg of codeine. b No narcosis, euphoria or tolerance in a period of 6 months. § c Side-effects: Placebo: nausea 3, drowsiness 2. Codeine: nausea 13, drowsiness 18, constipation 3. :I: Dextromethorphan, 18 mg: nausea 2, drowsiness 2, constipation 2. a No side-effects or sedative action. • On 60 mg a day: nausea 2, dizziness 2. Generally in same patient 15 mg was as effective as 30 mg of codeine. I Respiratory function increased significantly. No euphoric effect or tolerance. I g Side-effects Infrequent. In 14 patients, 10 mg was compared with 15 mg codeine. Definite effect37.5%, very good39.1%;for codeine definite effect64.3%, very good 7%. ~ "No evidence of tolerance In treatment for 6 months to 300 days. Compared In small groups, 10 mg was as effective as codeine. 1 Authors considered dextromethorphan and codeine equally effective. k No side-effects. I In 10 cases of spastic bronchitis, breathing was easier after 1.0% aerosol. m Lower score I ndlcates better result...... -..J --..J 178 N. B. EDDY AND OTHERS

pletely ineffective in suppressing signs of abstinence amount of dextromethorphan taken previously. from morphine. The authors concluded that dextro­ Neither the patients nor the observers could detect methorphan was devoid of addiction liability, that any difference between the effect of the alcohol alone is, devoid of morphine-like dependence-producing and of alcohol plus dextromethorphan. The doses properties. On this evidence dextromethorphan, a of the latter used alone had had no detectable effect. compound produced in the laboratory and, there­ These two experiments throw no light on the alleged fore, not automatically subject to international pleasurable response to dextromethorphan abuse. narcotics control, was not subjected to such control and was Specifically excluded from national nar­ cotics control in the United States of America. JSOQIDNOLINE ALKALOIDS Curiously, in spite of the above negative results, Noscapine 1 there has been some limited and sporadic abuse of dextromethorphan. Degkwitz (1964) reported three Isolated by Robiquet (1817) more than 150 years ago, noscapine is a levorotatory alkaloid of opium cases, males 19-21 years old, who claimed to have taken 20-100 tablets of 15 mg of dextromethorphan based upon isoquinoline instead of phenanthrene. daily. The effects were described as a feeling of well-being, reinforcement of awareness and apprecia­ tion of visual and auditory sensations with exagger­ /0-o/'] ated attention to details. Other effects included CH''--O-""'- ivN-CH, increased sociability, meaningless hilarity, pupillary I OCH, CH-0 dilatation, slurred speech and slight ataxia. As the I I effects wore off, restlessness and sleeplessness -C.=O remained. In some respects the effects were like -ocH. those of cannabis. The patients had had experience 0I of the latter and thought its effects less intense; they OCH. also drank beer excessively to enhance the effects. NOSCAPINE They claimed to know others who abused the drug as they did. During hospitalization no withdrawal phenomena were seen and after discharge the It is the second most abundant in opium, though its patients resumed the use of dextromethorphan. content varies widely. Originally it was believed to A few other widely separated instances of abuse of have only narcotic properties and the older reports preparations of dextromethorphan have come to our on its pharmacological action were conflicting and of attention. There has been no indication of physical little practical significance (Krueger, Eddy & Sum­ dependence and the roles of suggestion, and of the wait, 1943). Winter & Flataker (1954) first demon­ surrounding circumstances and the accompanying strated its antitussive activity in animal experiments. ingestion of alcoholic beverages is not clear. In guinea-pigs in which cough was induced by After the first report of the abuse of dextro­ ammonia inhalation and in dogs exposed to sulfuric methorphan the possibility of the modification of its acid aerosol, noscapine produced almost as much effect by alcohol was considered and Fraser (personal reduction of coughing as codeine. In guinea-pigs communication, 1961) performed two pilot experi­ without drug, coughs per three minutes per ammonia ments. Four patients (post-addicts) in a fasting inhalation ranged from 10 to 40 and varied less than state were given oral doses of 150, 200, 250 and 10% in two trials in the same animals on the same 300 mg of dextromethorphan. The effects were very day. The reduction in the number of coughs per minor; the drug was not identified as "dope" and 3 minutes is shown below and was dose related for the patients did not like its subjective effects. In the both codeine and noscapine: second experiment four similar patients were given Subcutaneous dose 0.25 1.0 2.0 (mgfkg) • 0.5 36, 72, 75 and 100 mg of dextromethorphan. Two Codeine phosphate 3.2 (25) 18.4(20) 21.5 (50) 27.3 (20) days later each was given repeated doses of 95% Noscapine hydro­ alcohol until intoxication was marked or up to chloride 3.1 (15) 10.9(15) 16.5(15) 28.0(5) a maximum of four times 0.239 ml per kg at * Numbers in parenthesis are the numbers of animals treated. 30-minute intervals. After another two days each was given the same amount of alcohol and the ' Also known as narcotine; Nectadon. CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 179

In dogs the coughs were counted before and at the 30 mg dose significantly depressed response to hourly intervals after oral administration of the drug low oxygen concentration. with two or three tests per dog. The average number Konzett & Rothlin (1954) said that 1.0-3.0 mg of coughs was : per kg of noscapine intravenously had no effect on the bronchial musculature, or caused dilatation, Dose Before Time after drug (h) (mgfkg) drug 1 2 3 while codeine caused constriction. They used anaesthetized cats and mechanically controlled 0.5 17 2 5 17 Codeine phosphate respiration under constant pressure. Konzett (1955) 0.5 32 8 16 35 Noscapine 0.5 19 2 11 14 said further that noscapine decreased blood pres­ hydrochloride 1.0 28 0 16 12 sure by vasodilatation and had other slight anti­ spasmodic effects. Weaver et al. (1957) reported Most authors have confirmed that noscapine has an bradycardia and vasodilatation after intravenous antitussive effect in animals (see Table 43), but that noscapine in anaesthetized dogs. The effect was it is less than that of codeine. maximal with 2.5-5.0 mg per kg and was cumulative Chen, Biller & Montgomery (1960) found the with repetition of small doses at short intervals. maximal antitussive action of noscapine in dogs, Injected into a coronary artery noscapine increased 1.0 mg per kg, orally, at 30 minutes and found that coronary blood flow, and injected into the femoral its duration of action was hardly two hours. Winter artery increased peripheral blood flow, without in & Flataker (1954) reported a slightly longer duration either case changing the systemic blood pressure. of action of subcutaneous doses. They saw no Acute tolerance to these peripheral effects de­ tolerance to the antitussive action. veloped readily. The authors thought that the effects. Noscapine has not shown a significant respiratory except the bradycardia, were due to histamine libera­ depressant effect. Haas (1955) measured a slight tion. Segal (1959), on this point, said that in limited increase in both respiratory rate and minute volume experimental studies in asthmatics, noscapine did after intravenous doses of 3 and 5 mg per kg in not have significant antihistaminic or cholinolytic anaesthetized cats. LaBarre & Plisnier (1959a, effect. 1959b) and Plisnier, Hemalsteen & LaBarre (1959) Gyang, Kosterlitz & Lees (1964) claimed good observed an increase in pulmonary ventilation in the correlation between analgesic action and inhibitory anaesthetized dog after 1.0 mg per kg of noscapine, effect on the peristaltic reflex in the isolated guinea­ intravenously, while the same dose of codeine always pig ileum. The approximate minimal concentration caused bronchoconstriction. The latter authors was 0.05 fLg of base per ml for morphine, 1.8 fLg for found that 1.0 or 2.0 mg per kg of noscapine, codeine and 22.0 fLg for noscapine. The analgesic intravenously, in rabbits increased bronchial secre­ potency ratios were 1.0 for morphine 0.08 for codeine tion by 40%. Barlow (1933) considered the respira­ and 0.0 for noscapine. tory effect of noscapine relatively unimportant. Noscapine does not have an analgesic effect. Even at 42 mg per kg, subcutaneously, in rats it had Reichle & Friebel (1955) found no increase in the only about the equivalent of one-fourth the effect of reaction time (skin-twitch to radiant heat, in rats) morphine on respiratory rate and the response to with doses up to 200 mg per kg.

C02 was increased. Bellville et al. (1958) measured Noscapine is less toxic than codeine in animals. respiratory minute volume and response to C02 m Some of the LD50s (mg/kg) that have been reported five normal human subjects. Doses were given orally for the hydrochloride and phosphate are shown in in random order to each subject at least 36 hours Table 44. apart, comparing 60 mg of codeine with 30 and 90 mg Winter & Flataker (1961) found that 50 mg per of noscapine and placebo. Codeine was depressant; kg of nalorphine was ineffective against the lethal noscapine was not. The latter was not significantly effect of noscapine in mice; both drugs were given different from placebo. Harris (1965), also using intravenously. The same authors administered nos­ normal subjects, compared the effects of oral doses capine chronically in dogs and rats; 30 mg per kg. of 50 and lOO mg of noscapine and of 30 and orally, five days a week for 13 weeks in the former. 60 mg of codeine, on responses to low oxygen con­ and 0.05-0.5% in the diet for three months in the· centrations and to C02 • Neither dose of noscapine latter. No signs of toxicity were seen in the· dogs .. had any effect on either response. Both doses of Concentrations of 0.2-0.5% in rats produced moder­ codeine depressed slightly the response to C02 and ately enlarged livers with slight increase in liver lipid_ 180 N. B. EDDY AND OTHERS

TABLE 43 RESULTS OF ANTITUSSIVE TESTING OF NOSCAPINE IN ANIMALS

Tusslgenlc stimulus Result Reference

Species: RAT SOt vapour 16.0 se EOoo; less potent than codeine Reichle & Frlebel (1955) Frlebel & Relchle (1956)

Species: GUINEA-PIG. so, Inhalation 18.5 se EO .. ; codeine EOso 8.0 Friebel & Relchle ,(1956) Ammonia 1.0 se Average decrease in coughs per Kiillquist & Melander (1957) 5 min at 60 min = 2.4. For same dose of codeine= 10.0 Acrolein 1.0 se 11% inhibition of cough Silvestrini & Maffii (1959); 2.0 se 34% inhibition of cough Maffii, Silvestrini & Banfi (1963) 3.5 se 47% inhibition of cough (Equivalent codeine dose 4.0 mg) Antigen aerosol 1.0-4.0 se Cough inhibltedb Winter & Flataker (1955a, 1955b) codeine ineffective

Species: CAT

Electrical stimulation superior 30.0 IV EOoo; codeine EOoo 4.0 c Green &Ward (1955) alryngeal nerve Sterile pleurisy 1.0-5.0 se Ineffective Van Oongen (1956) Mechanical stimulation of trachea 0.1-1.0 se As effective as codeine c Konzett & Rothlin (1954); Konzett (1955) Mechanical stimulation of trachea 22.4 lP EO .. ; codeine EOoo 1.79° Kasi\ et al. (1959) Mechanical stimulation of trachea 5-10 IV Always antitussive d Mulinos (1960b) or ammonia vapor Electrical stimulation superior 3.0 IV Cough abolished;" also by codeine Haas (1955) aryngeal nerve 3.0 mg/kg IV Electrical stimulation superior 0.75 IV Equal depression of cough reflex as LaBarre & Plisnler (1959a, 1959b) laryngeal nerve with codeine 1.0 m g c Electrical stimulation superior To 10.0 IV Ineffective c Silvestrini & Maffii (1959) laryngeal nerve

Sneezing attacks induced 15.0 IV Expirato~ thrust decreased; equiv- Boner (1962) alent co eine dose 2.0

Sulfuric acid aerosol 1.0 0 Slight inhibition, less than with Chen, Biller & Montgomery (1960) codeine Sulfuric acid aerosol 1.0 se Equal to same dose of codeine Silvestrinl & Maffii (1959) Electrical stimulation tracheal 8.0 se Less effective than 4.0 mg codeine Maffii, Silvestrini & Banfi (1963) mucosa Electrical stimulation superior 0.75 IV Equal to 1.0 mg of codeine LaBarre & Plisnier (1959a, 1959b) laryngeal nerve Electrical stimulation surface 12.0 IV EO .. ; codeine EOso1.5 Hara & Yanaura (1959) of trachea Mechanical stimulation of trachea 22.2 IV EOso; codeine EOso 3.76 Kasi\ (1955a); Kasi\ et al. (1959)

a SC = subcutaneous; IV= Intravenous; lP =Intraperitoneal; 0 = oral. b Guinea-pig was sensitized. c Cat was anaesthetized. d Cat was barbltalized. CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 181

TABLE 44 TOXICITY OF NOSCAPINE HYDROCHLORIDE AND CODEINE P.HOSPHATE

LDoo (mg/kg) Species Route a Reference I Noscapine Codeine I I

Mouse . 0 2 784 535 Aurousseau & Navarro (1957) Mouse se 198 (181) IJ 191 (135) IJ Kas6 et al. (1959) Mouse se 514 248 Aurousseau & Navarro (1957) Mouse se > 30QOC Winter & Flataker (1961) Mouse IV 83 Winter & Flataker (1961) Rat 0 c. 1 600 Winter & Flataker (1961) Rat (1 month) lP 850 Drommond, Johnson & Poe (1950) Rat (2-4 months) lP 875 Drommond, Johnson & Poe (1950) Rat (adult) lP 600 Drommond, John son & Poe (1950) Dog se 325 Hara & Yanaura (1959) Dog IV 75 Hara & Yanaura (1959)

Dog IV 80 (73) 98 (69) Kas~ et al. (1959)

a 0 = oral; SC = subcutaneous; IV= Intravenous; lP = intraperitoneal. IJ Figures in parentheses are for free base. c Poor absorption from subcutaneous tissues, probably accounts for the wide range of results by this route of administration.

Cooper & Hatcher (1934) found that 300 mg per and the doses of noscapine were 5 and 15 mg; these kg, intramuscularly, or 20-25 mg per kg, intraven­ doses were as effective as 30 mg of codeine. A later ously, of noscapine caused convulsions in cats but study by Bickerman et al. (1957) with 19 trained, the animals survived; 40 mg per kg, intravenously, healthy adults concluded that noscapine was, at the was fatal. Only a small fraction of the dose was most, equally as potent as codeine. The mean per­ detectable in the urine. Veds111 (1961) determined centage decrease in the number of coughs, with blood levels and urinary excretion after oral doses in these subjects, is shown below: man. After doses of 2 and 6 mg per kg in man the Time tifter administration (h) plasma concentration increased more rapidly with Dose (mg) 1 2 3 4 the higher dose. The drug disappeared from the Placebo 7.5 +2.5 +5.0 +25.0 plasma in six hours but less than 1.0% of the dose Placebo +10.6 +1.5 4.3 +12.8 was excreted in the urine, half of it conjugated. The Placebo 8.0 +12.0 12.0 +2.0 subjects complained of slight drowsiness and Codeine, 5 17.2 22.4* 22.4* 17.2 nausea. Codeine, 10 32.4* 32.5* 27.5* 10.0 Lasagna et al. (1961), looking for an anti-tumour Codeine, 15 32.8* 43.7* 34.5* 2.4* effect, gave large doses of noscapine to 32 cancer Noscapine, 5 31.9* 19.1 19.1 6.4 patients, four doses per day, ranging from 1-6 g per Noscapine, 10 30.0* 16.7* 23.3* 20.0* day up to 42 days. The symptoms were nausea, Noscapine, 15 35.5* 39.5* 37.4* 26.7* epigastric burning, abdominal pain, vomiting and • Significant difference. some drowsiness, generally more severe with the Gravenstein & Beecher (1955) in contrast, though larger doses, but one patient took 4 g per day for they used three different methods to evoke cough in 37 days without toxic signs. normal subjects, inhalation of ammonia or citric A depressant effect of noscapine on experimental acid aerosol or intravenous injection of paraldehyde, cough in man was shown by Bickerman & Barach could detect no consistent depression of the cough (1954). The cough stimulus was a citric acid aerosol response with noscapine or codeine. 182 N. B. EDDY AND OTHERS

There have been few clinical reports and judge­ 90 mg dose of noscapine, and in 27 patients with ments of noscapine as an antitussive and the trials dihydrocodeine. have generally been poorly controlled. Those that Blankart (1963) employed noscapine in 35 cases, are available represent mainly the impressions either in a tablet mixture with 7.5 mg per tablet or as gained by the investigators. Segal, Goldstein & a 15% solution in a syrup. Satisfactory results were Attinger (1957) made 54 trials of noscapine in doses obtained in acute respiratory infections and no side­ of 15-60 mg in 51 patients with broncho-pulmonary effects were seen. Absire-Laupretre & Dailly (1962) disorders. There was some antitussive effect in and Rohr (1962) also used noscapine as the active 94%. No side-effects were reported. In a later ingredient of a mixture. The former gave 10 mg of review Segal (1959) described the use of 30 or the alkaloid per dose in a syrup or as a suppository. 60 mg of noscapine compared with benzonatate, They said that respiration was increased in depth administered as an aerosol in the treatment of without change in rate; there was bronchodilatation bronchial asthma and found its action better sus­ and thinning of secretions but no gastrointestinal tained. change or other side-effect. They found it a particu­ Alemquer, Leal & Gomes (1960) compared equal larly advantageous preparation for children. Rohr doses of noscapine, in terms of alkaloidal base said that the effect was excellent in 54% and good in (60 mg), as the hydrochloride and as the resinate, 32% of patients and that there were no side-effects with 10 mg of hydrocodone in 18 tuberculous attributable to the medication. patients. The hydrochloride of noscapine and hydro­ A group of physicians (Practitioner, 1962) under­ codone were equally effective; the results with the took to compare noscapine combined with a resin to resinate were better than either. Side-effects were prolong its action, with codeine in cases of acute or least with the resinate, nausea and vomiting occur­ chronic cough of any origin. The doses were 15- ring in only three patients. The hydrochloride pro­ 30 mg of noscapine and 12-30 mg of codeine, two duced nausea in seven patients, vomiting in four, to four times a day for four to seven days. The dizziness in four, and pruritus and anorexia in two results (number of cases) were as follows: patients. Acute cough Chronic cough Com- Com- Peeters (1961) concluded that noscapine was 50% Partial No p/ete Partial No p/ete relief relief relief relief more effective than codeine as an antitussive, basing relief relief this judgement upon its use in 104 patients with all Noscapine 31 5 8 10 7 4 types of cough. The dose was 15 mg as a tablet or Codeine 13 14 9 7 6 I 30 mg as a suppository. There was marked improve­ Some patients received both drugs. In 17 noscapine ment in 61 %, some improvement in 22% and no was preferred, in 9 codeine was preferred and in 9 effect in the remainder. If the optimal dose of there was no preference. In terms of complete relief codeine is 10 mg orally (Davenport, 1938), or the and preference, noscapine was superior; in terms of average dose 20 mg, the result with noscapine failure to get any relief, codeine was better. hardly seems to rate as 50% greater. Banyai (1959, 1960) in two reviews of cough, its Carrizo (1961) reported an excellent antitussive mechanism and control, judged hydrocodone best effect with 25 mg of noscapine every six hours for among the available antitussives, codeine was 15 days, in nine cases, six of whom were suffering second, and noscapine was equal to codeine and was from silicotuberculosis. also bronchospasmolytic. His judgment of the Barasz et al. (1962) used noscapine to prevent therapeutic dosage was 5-10 mg of hydrocodone, cough accompanying bronchoscopy and compared 15-30 mg of codeine and 30-60 mg of noscapine. it with dihydrocodeine. In all, 100 patients were The Council on Drugs of the American Medical given 60 mg of noscapine hydrochloride; marked Association (1958) said in respect of noscapine: relief occurred in 25, some relief in 42, and no relief in 33. A dose of 15 mg of dihydrocodeine bitartrate The pharmacological action upon which the clinical has given to 120 patients and marked relief occurred use of noscapine is based resides in its ability to suppress the cough reflex in experimentally induced cough in in 14, some relief in 51, and none in 55. A 90-mg animals and human volunteers and in patients with dose of noscapine was given to 20 patients but the respiratory disease. The drug reduces the frequency and result was no better; marked relief occurred in 1, intensity of coughing paroxysms. Its antitussive potency some relief in 8 and none in 11. Nausea occurred in under these experimental conditions is approximately 33 patients with the 60-mg dose and in 8 with the equal, milligram for milligram, with that of codeine, both CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 183 drugs having approximately the same onset and duration (1955). This Committee concluded that noscapine of action. Therapeutically effective doses of noscapine had no addiction liability. are essentially devoid of the unpleasant side effects of Winter & Flataker (1954) observed no tolerance to codeine and except for occasional instances of nausea the antitussive action of noscapine. They tested five (which rarely proceed into vomiting) its side effects are negligible ... moderately large doses have no morphine­ dogs initially with 2.0 mg per kg of noscapine orally like effects in former addicts and no alleviating effect on against cough induced by sulfuric acid aerosol. Then the morphine abstinence syndrome. Further, virtually the drug was given at the rate of 30 mg per kg, per no tolerance to the antitussive effect of the drug has day (except Sunday), for 13 weeks. The initial been demonstrated. reduction in cough was from 33 to 9 and with the The data quoted above do not fully support the same challenging dose, 24 hours after the last dose milligram for milligram equivalence with codeine. of 30 mg per kg per day, the reduction in cough was Carefully controlled, double-blind studies in patho­ from 27 to 5. logical cough of various origins would clarify the point. Although it is an isoquinoline and not Other related substances chemically morphine-like and has no analgesic Other naturally occurring isoquinoline alkaloids, action, noscapine was tested at the Addiction Re­ papaverine and narceine, and a number of related search Center (Lexington, Ky., USA) with negative substances, have been tested for antitussive activity; results and these were accepted by the WHO Expert the structural formulae of some of the compounds Committee on Drugs Liable to Produce Addiction that have been tested are shown in the accompanying

TABLE 45- ANTITUSSIVE ACTIVITY OF SOME NATURALLY OCCURRING ISOQUINOLINE ALKALOIDS

Dose Agent Method Route a I Result Reference I (mg/kg) I

Papaverine Electrical stimulation supe- 10 IV Brief suppression Domenjoz (1952) rior laryngeal nerve, cat

Papaverine Mechanical stimulation tra- 10-20 IV Brief suppression Kas~ (1955a) chea, dog Papaverine Electrical stimulation tra- 8 IV EO .. equivalent to 1.5 mg/kg Hara & Yanaura (1959) cheal mucosa, dog codeine Narceine so, inhalation, mouse and 50 se Equal to 10 mgfkg codeine Kelentey, Stenszky & guinea-pig Gzollner (1958) Ethylnarceine Effective suppressant Gloesener (1961) Cotarnine Ammonia inhalation, 0.5-1.0 0 Ineffective Winter & Flataker (1954) guinea-pig Hydrastine Ammonia inhalation 0.5-1.0 0 Ineffective Winter & Flataker (1954) guinea-pig Hydrastinine Ammonia inhalation 1.0-8.0 0 8.0 mg equal to 1.0 mg Winter & Flataker (1954) guinea-pig noscapine

Homarylamine b Electrical stimulation 8.0 0 Equal to 1.0 mg codeine Stefko, Denzel & Hickey trachea, dog (1961) Homarylamine Ammonia inhalation 16.0 0 Equal to 0.5 mg codeine. Stefko, Denzel & Hickey anaesthetized cat Also effective at 16 and (1961) 32 mg against pathological cough in dogs Homarylamine Citric acid aerosol, man 10,20 0 20 mg briefly effective; Bickerman & ltkin (1960) and 40 40 mg equal to 15 mg codeine Amines related Effective Takagi, Fujizawa & ldeguchl to homarylamine (1958)

a IV = intravenous; SC = subcutaneous; 0 = oral. b Brown f1958). 184 N. B. EDDY AND OTHERS

STRUCTURAL FORMULAE OF SOME ISOQUINOLINE ALKALOIDS AND RELATED SUBSTANCES THAT HAVE BEEN TESTED FOR ANTITUSSIVE ACTIVITY CH, CH,o-~ CH,O-~N ~=0:i~~(CH•)•(;H, CH, CH,O l I C=O I 0-ocH. -COOH I 0 -OCH, OCH, I OCH• PAPAVERINE NARCEINE

~-(1(1 ~-~N-CH•

CH,O OH COTARNINE ------o--0) Q:l_•_ -0-::::,__ I N-CH· ! CH,-0 : I ~o-nn I _/C=O ~-~N-CH, I 0 -OCH• OH I OCH, HYDRASTININE HYDRASTINE

CH, CH,O---o~ ~fHCH, CH,O-- ""-- CONH, I Rt N/ CH, CH,-o-~'fH' ""R, ------a- V HN-C H. R, and R, = CH,, C,H,, CoHs HOMARYLAMINE figure. For the most part they are much less effective Its analgesic activity, side-effects and dependence­ than noscapine or codeine; some results are shown producing liability, qualitatively morphine-like in Table 45. throughout, are exhibited chiefly by the levoisomer, although the dextroisomer is active in all three METHADONE AND RELATED SUBSTANCES respects at higher dosages.

Methadone, isomethadone and their isomers 0 r-\.,l Methadone, (±)6-dimethy amino-4,4-diphenyl-3- ~c/C-CH.-CH. heptanone, was introduced into general medical practice after 1946: it became widely available and / ''-cH,-CH-N(CH,)• known under many names (United Nations, 1963). 0 I It is completely synthetic, is prepared in racemic CH, form and is easily resolved into its optical antipodes. METHADONE CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 185

0 Eddy, Halbach & Braenden (1957). As a morphine­ 11 like agent, racemic methadone was expected to be 0 ""' /C-CH.-CH• a cough suppressant and this was confirmed by c animal experiments and clinical observations. The / ""cH-CH.-N(CH•)• results of experiments in animals are summarized in 0 I CH• Table 46. For methadone, as for other antitussives, effective doses are generally higher for small animals ISOMETHADONE than for the larger mammals, so that Schaumann The properties of methadone and its derivatives (1957) has criticized the use of the former for anti­ have been reviewed Braenden, Eddy & Halbach tussive testing. Nevertheless, they are commonly (1955), Eddy, Braenden & Halbach (1956) and employed and consistent results are obtained.

TABLE 46 THE ANTITUSSIVE EFFECTIVENESS OF (±)-METHADONE IN ANIMAL EXPERIMENTS COMPARED WITH THAT OF CODEINE

EDso (mgfkg) Ratio I Reference Method I Anaes-1thesla Route a methadone/ Methadone I Codeine codeine

Species: RAT so.-vapour inhalation 0 se 1.0 10.0 10.0 Reichle & Friebel (1955)

Species: GUINEA-PIG so.-vapour inhalation 0 se 1.6 8.0 5.0 Friebel, Reichle & von Grae- ven itz (1955)

Species: CAT Mechanical stimulation trachea + IV 0.11 2.53 23.0 Kase et al. (1959a) Electrical stimulation, superior + IV 0.3 b Domenjoz (1952) laryngeal nerve Electrical stimulation, superior + IV 0.15 c c.1.0 c. 6.6 Toner & Macko (1955) laryngeal nerve Electrical stimulation, superior + IV 0.05 4.0 80.0 Green & Ward (1955) laryngeal nerve Electrical stimulation, superior + IV 0.15 a 2.0 13.0 Mattis (personal communi- laryngeal nerve cation, 1954)

Species: DOG Ammonia vapour inhalation 0 se 0.2-0.28 e 4.0-5.7 c. 9.0 Rosiere, Winder & Wax (1956) Mechanical stimulation, trachea 0 IV 0.8 Kase (1955b) Mechanical stimulation, trachea 0 IV 0.6 Kase (1955b) Mechanical stimulation, trachea 0 IV 1.0 a Kase (1955b) Mechanical stimulation, trachea 0 IV 0.11 3.76 34.2 Kase et al. (1959a) Electrical stimulation, vagus nerve 0 IV 0.25 r Schroeder (1951) Pathological cough 0 0 0.21 Smith (1963)

a SC = subcutaneous; IV= intravenous; 0 = oral. b The dose given was as effective as 3.0 mg per kg of codeine. c The dose given was said to be effective. a The dose given suppressed cough completely. • Doses given were as effective as 1.0-5.7 mg per kg of codeine. I Effective for treatment of animals other than cats and horses: for which it should not be used because of exciting effect. 186 N. B. EDDY AND OTHERS

Reichle & Friebel (1955) determined the ED50 of lated the vagus electrically, reported effective doses methadone for suppression of cough provoked in of 0.2-0.28 mg per kg, intravenously. rats by inhalation of a sulfur dioxide-air mixture, Some of these investigators compared directly the as 1.0 mg per kg, subcutaneously. For suppression antitussive effect of methadone with that of codeine of cough similarly induced in guinea-pigs the ED50 (see Table 46) in rats, guinea-pigs, cats and dogs. was 1.6 mg per kg, subcutaneously (Friebel, Reichle The results show unequivocally that methadone was & von Graevenitz, 1955). Experimentally induced the more potent, the ratio of potency ranging from cough in cats was suppressed by intravenous doses 5 :1 to 80: 1, even in the same animal with a of 0.5-0.8 mg per kg (Kase et al., 1959a). The cough similar method. Guseva (1956) also said that was induced by mechanical stimulation of the methadone was the more potent and recommended trachea at its bifurcation in lightly anaesthetized that it should be subjected to clinical trial. animals. Domenjoz (1952), Toner & Macko (1952), It is interesting to compare the doses for equal Green & Ward (1955) and Mattis (personal com­ effect, analgesic and antitussive, and their ratios one munication, 1954) stimulated electrically the isolated to another for the (±), (-) and ( +) forms of superior laryngeal nerve in anaesthetized cats. The methadone and isomethadone. Reichle & Friebel different results reported by these authors (Table 46), (1955) calculated these ratios of analgesic to anti­ using an essentially similar technique, may have been tussive effectiveness from results obtained in rats due to the choice of anaesthetic, the depth of and these figures are given in Table 47. The figures narcosis, the manner of stimulation or another do not suggest any particular selectivity for either detail of the method. The doses ranged from 0.05 to effect but they do indicate a considerable degree of 0.3 mg per kg, intravenously. Similar results have activity for the (+)-isomers, differing on this point been obtained in dogs, the doses ranging from 0.11 from results related to optical isomerism in the to 0.28 mg per kg, intravenously. An early report morphinan series. In the latter the (+)-isomers are of Kase (1955a) of an effective dose of 0.8 mg per kg, generally inactive analgesically but active against intravenously, was not confirmed by later experi­ cough. ments. He and his collaborators (1959) prepared The experimental proof of the ant tussive action of their dogs by making a tracheal fistula and then in methadone in man was obtained by Trendelenburg the unanaesthetized animal stimulated the tracheal (1950), Bickerman & Itkin (1960) and Rasch (1957). mucosa by pushing a bristle towards the bifurcation. From their results (Table 48) it is evident that doses

They reported an antitussive ED50 of 0.11 (0.08-0.14) of 1.75-2.5 mg of methadone orally correspond in mg per kg, intravenously. Rosiere, Winder & Wax antitussive action to 15-20 mg of codeine, giving a (1956) using dogs which were made to inhale ratio of effectiveness of 6:1-11.4:1, very much like ammonia vapour, and Schroeder (1951) who stimu- the ratios for subcutaneous doses in animal experi-

TABLE 47 COMPARISON OF ANALGESIC AND ANTITUSSIVE EDsoS OF METHADONE AND ISOMETHADONE IN RATS

Ratio analgesic/ EDsos of isomers EDsos relative to Test I (-)-isomer antitussive I (-) I <±> I (+) (-) ! (±) I (+) (-) I (±) I (+)

Methadone Analgesia (skin-twitch) 1.1 1.63 27.3 Antitussive (SQ.-vapour) 0.74 1.35 36.5 1.49 1.80 1.11

lsomethadone Analgesia (skin-twitch) 1.7 28.0 1.0 16.5 Antitussive (SO.-vapour) 1.4 22.0 1.0 16.0 1.21 1.27 I I I I CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 187

TABLE 48 ANTITUSSIVE DOSES OF METHADONE IN EXPERIMENTAL COUGH IN MAN

Method [ Dose (mg) [ Route Result Reference

Ammonia inhalation 1.25-7.5 Oral 1.75 mg methadone= 20.0 mg codeine Trendelenburg (1950) Citric acid aerosol 2.5 Oral Equals 15.0 codeine Bickerman & ltkin (1960) Citric acid aerosol 10.0 Oral Superior to 25.0 mg codeine Rasch (1957)

ments. Recording the effects of increasing doses, methadone and isomethadone by the absence of one Trendelenburg (1950) observed that the maximal methyl group. Experimentally it has shown analgesic response was obtained with 5 mg and Bickerman & and antitussive effects which were significantly less Itkin (1960) said that the duration of a considerable than those of methadone but greater than those of decrease in cough frequency with a 2.5 mg dose was pethidine or codeine (Eddy, Touchberry, & Lieber­ two hours. A decrease in the intensity of the cough man, 1950; Friebel, Reichle & von Graevenitz, 1955; paralleled a change in its frequency. Side-effects with Reichle & Friebel, 1955). The results of antitussive antitussive doses included drowsiness, euphoria and testing in animals and of direct comparisons with nausea. codeine are summarized in Table 49. On the basis The results of clinical studies with methadone of these results the effects of normethadone com­ were reviewed by Eddy, Halbach & Braenden (1957) pared with those of codeine are more consistent and in general are in line with experimental results though not as great as those of methadone, but there in animals and man. Most authors recommended a is still no particular indication of specificity in dose of 1.5-5 mg as the cough suppressant equivalent respect to either analgesic or antitussive action of the usual dose of codeine. However, since metha­ (Table 50). done is morphine-like in its dependence-produc­ Bickerman & Itkin (1960) attempted to evaluate ing liability, ar\d since agents having no dependence­ the effectiveness of normethadone against experi­ producing property have been introduced, interest mentally induced cough in man. Having determined in it as an antitussive has waned, as it has also for the minimal effective concentration of citric acid the dextroisomer. aerosol, the drug was administered orally and the number of coughs per aerosol inhalation were Normethadone counted at hourly intervals. Whereas methadone at Norrnethadone, 6-dimethylamino-4, 4-dipheny 1-3- a 2.5 mg dose had decreased the cough frequency hexanone, has been tested experimentally as an considerably over a two-hour period, normethadone antitussive but has been used clinically as such only at a dose of 7.5 mg was ineffective, in most trials it as a mixture with p-hydroxyephedrine,1 1-(4'­ was essentially like a placebo. hydroxyphenyl)-2-methylamino propan-1-ol hydro­ The earlier clinical experience with normethadone chloride, a sympathomimetic, added partly to bring was reviewed by Eddy, Halbach & Braenden (1957). about bronchodilatation. Normethadone is also a Table 51 summarizes these reports and some more completely synthetic substance, differing from recent ones. The results appear to be remarkably satisfactory in spite of the negative result of Bicker­ man & Itkin (1960) and the poorer relief than was obtained with codeine in experimental animals. Reported side-effects have been very few: one child, given an adult dose by mistake, was very sleepy but otherwise suffered no ill effect (Heimendinger, 1952). One case of poisoning was reported by NORMETHADONE Ziehme (1960): a two-year-old child was given 75 mg of norrnethadone in the usual cough mixture. There was repeated vomiting, the child was cyanotic • p-Hydroxyephedrine is also known as Suprifen; the mixture is known as Ticarda. with slow respiration, loss of reflexes and miosis and 188 N. B. EDDY AND OTHERS

TABLE 49 THE ANTITUSSIVE EFFECTIVENESS OF NORMETHADONE IN ANIMAL EXPERIMENTS COMPARED WITH THAT OF CODEINE

Anaes- I ED .. (mgfkg) I Ratio I Method I Route a thesia codeine/ Reference Normethadone [ Codeine normethadone

Species: RAT Ammonia inhalation se 0 0.75 >0.75 >1.0 Kraushaar, Schunk & Thym (1964) so.-vapour inhalation se 0 7.0 10.0 1.4 Relchle & Friebel (1955) SO.-vapour Inhalation se 0 4.7 13.5 0.9 Hengen & Kasparek (1958) so.-vapour inhalation lP 0 14.0 26.0 1.85 Wledemeijer, Kramer & de Jongh (1960)

Species: GUINEA-PIG SO,-vapour Inhalation se 0 1.7 Friebel, Reichle & von 4.6 I . 8.0 I Graeven itz (1955)

Species: CAT Electrical stimulation superior IV + 0.2 b 1.0 5.0 Plisnier (1957) laryngeal nerve Electrical stimulation superior IV + 0.3 1.5 5.0 Kohli, Gupta & Blargava (1960) laryngeal nerve

Irritation of sterile pleurisy se 0 2.0° Schaare (1958)

Species: DOG Mechanical stimulation trachea I IV 0 1.2 Kase et al. (1959a)

a SC =subcutaneous; lP = intraperitoneal; IV =Intravenous. I> Effective dose, not a calculated EO,., c Complete suppression of coughing for 6-7 hours.

TABLE 50 COMPARISON OF EQUALLY EFFECTIVE ANALGESIC AND ANTITUSSIVE SUBCUTANEOUS DOSES FOR NORMETHADONE AND CODEINE

EO .. (mg/kg) Ratio Drug I analgesic/ I Reference IAnalgesic [Antitussive. antitussive

Species: RAT Methadone 1.8 1.0 1.82 Reichle & Friebel (1955) Normethadone 5.8 7.0 0.82 Reichle & Frlebel (1955) Codeine 13.0 10.0 1.3 Reichle & Friebel (1955)

Species: GUINEA-PIG Methadone 3.7 1.6 2.31 Friebel, Reichle & von Graevenitz (1955) Normethadone 12.2 4.6 2.66 Friebel, Reichle & von Graevenitz (1955) Codeine 48.5 8.0 6.62 Friebel, Relchle & von Graevenitz (1955) TABLE 51 CLINICAL EXPERIENCE WITH NORMETHADONE a AS AN ANTITUSSIVE

Patients Duration Dosage Result of effect Side-effects Remarks Reference No. I Type

30 Severe tuberculous 1 or 2 x 3-12 drops per Satisfactory in most About 8 h None Excessive sputum Buchheim & day cases. All had opiates decreased in a few Angermann (1951) ~ cases

Tuberculous 1 or 2 x 15 drops per Good relief 5~h None Prompt, 10-15 min Berger (1951) ~ day :=i "' 80 Tuberculous 15-20 drops per dose Satisfactory 2~h None Prompt, 15-20 mln Morawetz (1951) >

30 Other 15-20 drops per dose Satisfactory 2~h None Prompt, 15-20 mln Morawetz (1951) 50 Cough of various Satisfactory 10-12 h Prompt, 5 ·20 mln Rless (1951) types Cough of various 10-12 drops for adults Satisfactory Promotes sleep by Riess & Tonjes (1951) types relief of night coughing I and children over 10 years ~ 32 Persistent cough of 20 drops per dose, Satisfactory in all 3-4 h Drowsiness in child Prompt action Helmendlnger (1952) various origins adults but 3 given adult dose ~ 10 Cough of various All improved Some sedation Glammarinaro & origins Angoletto (1952) ~ 77 Children with acute or Very good in most About 6 h If pain present also Kelllng (1952) chronic cough relieved Recommended as substitute for codeine ~ 55 Cough of various 3 x 15 drops daily Good in 30, fair In 20 None Schmidt (1960a) origins ~ 130 Flu epidemic 7.5 per day, one day Excellent 39.5%, Codeine 30 or 40 mg Voiculescu & ~ only some 21.2% per day In 84 patients. Neuman (1959) ~ Excellent 20.5%, some 33.4%

a Administered as Ticarda

.... 00 IC 190 N. B. EDDY AND OTHERS convulsions occurred. Levallorphan was used in believe that the exhilarating effect of the sympatho­ treatment and the child recovered. mimetic amine might increase patient liking for the Van Lessen (personal communication, 1953) preparation and increase rather than decrease the appears to have been the first to observe dependence risk of abuse. World consumption of normethadone on a normethadone cough-mixture. The patient for 1966 was estimated at nearly 500 kg in more than began taking it on his own initiative and shortly felt 20 countries, I 0 of which indicated consumption of unable to work without it. A partial morphine-like 10 kg or more. Normethadone should now be abstinence syndrome was seen on withdrawal. available for medical use only on prescription but Blihler (1954), Ebermann (1954), Burckhardt & cases of abuse continue to appear. The Federal Orzechowski (1954) and Halbach (1955) reported Republic of Germany indicated 2 that in 1966 among single cases; Prokop & Jost (1958) and Cieslak 1580 persons shown by their criteria to have abused (1955) two cases each and Schmid (1954) six cases, narcotics of natural origin, 25 used codeine and nearly all during 1954 and 1955. Many of these among 1857 persons who abused other drugs patients had used various opiates before turning to 42 were using a mixture of normethadone and the normethadone mixture but they showed definite p-hydroxyephedrine. For the same year the same signs of physical dependence on attempted with­ country estimated its consumption of codeine to be drawal. Nerreter (1957), however, said that he had 8310 kg and of normethadone only 200 kg. used the preparation in 84 patients during a six­ month period, had seen some tolerance but no Levopropoxyphene 3 indication of dependence. Propoxyphene, a-4-dimethylamino-1 ,2-dipheny 1- Schaumann (personal communication, 1957) at­ 3-methyl-2-propionyloxybutane also synthesized as a tempted a survey of drug abuse in Germany by per­ racemate, is easily resolved into its dextro- and sonal inquiry and secured records of 810 cases. Of Ievoisomers. Silvestrini & Maffii (1959), Robbins & this total 29 people used only the mixture of norme­ Miller (1960) and Miller, Robbins & Meyers (1963), thadone andp-hydroxyephedrine; in 15 others it was while showing that the dextroisomer showed both used after or with another opiate. Codeine was the analgesic and antitussive action in experimental only drug used by 25 persons and it was used with animals, reported that the Ievoisomer was essentially other agents by two more. Schaumann argued that antitussive only. Gruber (1961) also reported that abuse of the normethadone-p-hydroxyephedrine the N-oxide of the Ievoisomer, administered as the mixture was comparable to abuse of codeine. How­ naphthalene sulfonate had significant antitussive ever, it had not long been on the market and the action. number of persons using the mixture was far less than the number using codeine. Isbell & Fraser (1955) tested the dependence­ producing properties of normethadone and reported that its potential was less than that of methadone but greater than that of codeine. Doses of 45-60 mg, orally or subcutaneously, produced morphine-like effects in non-tolerant individuals and 60 mg sub­ cutaneously, every six hours, substituted adequately LEVOPROPOXYPHENE for morphine in individuals dependent on the latter, and stabilized on 240-320 mg of morphine sulfate The results of Silvestrini & Maffii (1959) with the per day. The World Health Organization Expert propoxyphene isomers and with codeine, using Committee on Drugs Liable to Produce Addiction various methods to elicit cough, are summarized in (1958) recommended full international narcotics con­ Table 52. For the guinea-pig and the cat with two trol for normethadone on the basis of the foregoing methods of stimulation the effective doses were very evidence and rejected a request for exemption from similar with all three substances, but with an control of the preparation Ticarda, 1 considering that the added ingredient was not likely to affect abuse ' Report for 1966 by the Government of the Federal liability. In fact further experience would lead us to Republic of Germany on the traffic in opium and other narcotic drugs. . . . (Unpublished United Nations document No. NAR/AR.41/1967-GE.67-12771). ' A mixture of normethadone and p-hydroxyephedrine. • Also known as Novrad. CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 191

TABLE 52 COMPARISON OF ANTITUSSIVE EFFECTIVENESS OF PROPOXYPHENE ISOMERS AND CODEINE WITH COUGH INDUCED BY DIFFERENT METHODS IN LABORATORY ANIMALS a

Equieffective doses (mgfkg) Method Route b (-)-Propoxyphene I (+ )-Propoxyphene Codeine

Species: GUINEA-PIG Acrolein inhalation se 3.5 3.5 3.5

Species: CAT Ammonia inhalation IV 2.0-3.0 2.5-3.0 1.5 Mechanical stimulation IV >4.0 >4.0 3.0 Electrical stimulation laryngeal nerve IV 3.0 1.5

Species: DOG Electrical stimulation trachea se >10.o 3.5

a From Silvestrini & Maffii (1959). b SC = subcutaneous; IV = intravenous. electrical stimulus to evoke cough levopropoxy­ antitussive effect. They did not test the levoisomer. phene was less effective than codeine in the dog and The results in animals are qualitatively similar to the cat. Using ammonia inhalation and the dog, results in man on cough induced by citric acid Winder et al. (1961) calculated ratios of effectiveness aerosol (Bickerman et al., 1957; Calesnick, Christen­ for dextropropoxyphene compared with codeine sen & Munch, 1961), which are summarized in of 1.5 for peak antitussive effect and 1.1 for total Tables 53 and 54. Bickerman et al. counted the

TABLE 53 EFFECTIVENESS OF PROPOXYPHENE ISOMERS AND CODEINE IN REDUCING COUGH EVOKED BY CITRIC ACID AEROSOL IN NORMAL INDIVIDUALS a

Initial % decrease in coughs at Drug I Oral dose I average I (mg) no. 1 h I 2h I 3h I 4h

Placebo 2.61 - 7.5 + 2.5 + 5.0 +25.0 Placebo 2.87 +10.6 + 1.3 - 4.3 +12.8 Placebo 3.33 - 8.0 -12.0 -12.0 + 2.0

(±)-Propoxyphene 65 2.08 - 6.0 - 8.0 -26.0 b -12.0 (± )-Propoxyphene 130 1.97 -21.7b -29.0 b -15.8b - 7.2 ( + )-Propoxyphene 32.5 2.21 - 7.5 - 5.9 - 3.8 -11.3 ( + )-Propoxyphene 65 2.00 -44.4 b -38.9 b -16.7 -25.0

(-· )-Propoxyphene 32.5 2.00 -27.8 b -22.3 -27.8 b -13.9

(-)-Propoxyphene 65 2.10 -33.3 b -31.7b -34.9 b -19.0

Codeine 5 2.76 -17.2 -22.4 b -22.4 b -17.2

Codeine 15 2.22 -32.4 b -32.5 b -22.5 b -10.0 Codeine 30 3.22 -32.8 -43.1 -34.5 I -22.4 a Taken from Bickerman et al. (1957). Propoxyphenes administered as the hydrochiorides. b Represent significant differences. 192 N. B. EDDY AND OTHERS

TABLE 54 EFFECTS OF LEVOPROPOXYPHENE AND CODEINE ON THE AVERAGE NUMBER OF COUGHS PER CITRIC ACID INHALATION a

Oral No. of coughs Drug dose I subjectsNo. of I (m g) Initial I 1 h I 2h I 3h I 4h

Placebo 18 3.22 2.96 2.98 2.97 3.02 (-)-Propoxyphene 25 14 3.40 2.60 2.50 2.30 2.70 (-)-Propoxyphene so 16 3.48 2.43 2.18 2.00 2.18 (-)-Propoxyphene 100 11 3.27 2.63 2.36 2.09 1.72 Codeine 15 11 3.16 2.09 2.09 1.54 1.54 I a Taken from Calesnick, Christensen & Munch (1961). Levopropoxyphene was administered as the naphthalene sulfonate. coughs and measured the flow rate of exhaled air in origin, and these are summarized in Table 55 response to the minimal concentration of citric acid The results with oral administration as the naphtha­ aerosol before and at hourly intervals after a lene sulfonate are consistent as regards dose with the placebo, racemic propoxyphene, its isomers or results with experimentally induced cough. Side­ codeine. At least six normal subjects received all effects have been minor; Calesnick, Christensen & agents. The results are the average percentage Munch (1961) saw none in normal individuals up to differences from initial cough frequency per aerosol the 100 mg dose, and Bickerman (1962) saw only one inhalation. Calesnick, Christensen & Munch (1961) adverse reaction at 130 mg. Abruzzi (1962) said that used a similar method to evoke cough in normal the result was unsatisfactory in two children because subjects and averaged the number of coughs per of the occurrence of nausea, but that no side-effects aerosol inhalation before and after medication. They were encountered in adults. Ernst & Jeffrey (1962) compared only the levoisomer with codeine. From noted a feeling of urinary urgency in four patients, the figures of Table 53 it may be concluded that the tremor in one and nausea in none and Chernish et al. effect of 32.5 mg of levopropoxyphene fell between (1963), interviewing the subjects after a week of drug that of 5 and 15 mg of codeine and that the effect of administration, reported side-effects as follows: 65 mg was between that of 15 and 30 mg of codeine. Number of patients of 24 reporting the side-effect The result with levopropoxyphene shown in Table 54 Levopropoxyphene Placebo was definitely less than the antitussive effect of 50 mg 100 mg codeine. In another place Bickerman (1961) re­ Abdominal distress 1 1 viewed the effect of the levoisomer with a similar Nausea 4 4 conclusion. Vomiting 1 Boyd & Boyd (1962), using cats and rabbits, Loose stools 1 Headache 4 3 measured respiratory-tract fluid output before and Dizziness 1 hourly for three hours after administration of levo­ Drowsiness 1 propoxyphene subcutaneously, as the hydrochloride, Decreased visual acuity in doses of 9-729 mg per kg and orally, as the naphthalene sulfonate, in doses of 2-1250 mg per Tests for dependence-producing properties have kg. Four animals were used per dose and the highest been carried out with the racemate and dextropro­ dose of each salt killed one of the animals. There poxyphene, but none have been done with the levo­ was no significant or ~onsistent change in the isomer. However, the conclusion was that the volume output of respiratory tract fluid, so that this liability was significantly less than with codeine and apparently could not be a factor in the antitussive that the risk to public health was so low that narco­ action. tics control was not warranted. Therefore, it is not There are only a few reports of the clinical use of expected that the levoisomer will have any signifi­ levopropoxyphene against cough of pathological cant abuse potential. \

CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 193

Thiambutenes 327), synthesized by Kitamura et al. (1962). This might be considered a cyclized analogue of 3-dime­ The analgesic, side-effect and dependence-pro­ thylamino-1, 1-di-(2'-thienyl)-but-1-ene, a morphine­ ducing potencies of the thiambutene derivatives have like analgesic, and it has been investigated by Kase been described by Eddy, Halbach & Braenden (1957) et al. (1959a). Its antitussive effect was slightly less and the chemical characteristics which relate them in cats (electrical stimulation of the superior laryn­ to morphine-like structures by Braenden, Eddy & geal nerve) and slightly greater in dogs (mechanical Halbach (1955). Doyle & Mehta (1964) have dis­ stimulation of the trachea) than that of codeine, cussed their structures in relation to antitussive with intravenous administration of the citrate and action. Further, Kase et al. (1955) showed that phosphate, respectively. If AT-327 was injected into substitution of a piperidino-group for the dimethyl­ the cisterna cerebellomedullaris the effective dose to amino- or diethylamino-group in the thiambutene suppress stereotactically placed electrical stimulation molecule enhanced its antitussive activity without of the expiratory pacemaker area in the medulla of affecting analgesic activity and in connexion with the cat was only a fraction of the amount required by their hypothesis of a specific relationship of piperi­ intravenous administration. The authors assumed dine to antitussive action extended their studies to direct action on a cough centre. The antitussive such non-analgesic compounds as dithienylethanols effect was not antagonized by nalorphine, but that and propanols (Kase & Yuizono, 1959; Kase, effect of the dimethylamino analogue was. Yuizono & Muto, 1963). AT-327 showed the Straub tail phenomenon but One compound in accord with the theory was had no analgesic effect by the tail-flick method in 1-methyl-3-di-(2'-thienyl) methylene-piperidine (AT mice up to two-thirds of the LD50• In urethanized rabbits doses above 1.0 mg per kg, intravenously, r-~~ caused a transitory fall in blood pressure, without a slowing of the heart, and a slight increase in the depth "'s /"' C=(l of respiration. Movements of a Langendorff per­ / s"'/ "N/ fused heart were depressed and perfused vessels of 1_1_lj \ the rabbit ear were dilated. The drug showed local CH a anaesthetic activity. It did not protect against 1-METHYL-3-DI-(2 1 THIENYL)METHYLENE-PIPERJDINE histamine-induced bronchoconstriction in guinea-

TABLE 55 RESULTS OF CLINICAL TRIALS OF LEVOPROPOXYPHENE AS ANTITUSSIVE IN NON-TUBERCULOUS COUGH

Average dose (mg) Results (%) No. of I I Reference cases Single Daily Excellent I Good I Moderate I Non;

47 adults 50 300 70 17 13 Bickerman (1962) 31 adults 130 482 76 16 6 Bickerman (1962) 126 adults 100-600 66 26 6 2 Erns! & Jeffrey (1962)

50 adults 100-200 600 92.9 a Abruzzi (1962) or more 42 adults 50-100 - b Chernish et al. (1962) 50 children 100-200 78.3a Abruzzi (1962) 26 children 50 - c Carter (1963)

a Satisfactory relief. . b Prisoners reporti~g at sick-call vo.:ith cough as a symptom. Results significantly better than w1th placebo (double-blind). The durat1on of the effect averaged 2.2 h with placebo 2 9 h with th 50 mg dose and 3.4 h with 100 mg. ' · e c ~ahch do.s~ given wiT!h 325 mg_of aspirin. Cough improved in 77%, a significantly better result th an Wl 1 aspirin a 1one. he durat1on of effect averaged 4.2 h.

13 194 N. B. EDDY AND OTHERS

pigs, but was spasmolytic in guinea-pig and rabbit although Eddy, Halbach & Braenden (1957) con­

intestine. The LD50 in mice was 37.6 mg per kg of cluded that its action in this respect was minimal. the citrate, 22.2 mg per kg of the base, subcutane­ Whatever its antitussive potency, however, it cannot

ously, and the LD50 in dogs was 74.8 mg per kg of be considered as an alternate to codeine because it the citrate, and 44.1 mg per kg of the base, intra­ has dependence-producing properties of the mor­ venously. Toxic doses caused excitement, restless­ phine type: the analogues, however, have been ness, tremor and convulsions in mice, anorexia, synthesized with that end in view. One such analogue increased respiration, salivation and weakness in is ethyl 1-(2-carbamylethyl)-4-phenyl-4-piperidine dogs but no hypnosis. Neither tolerance nor carboxylate (WIN-13187). cumulative action was seen when 5 or 6 mg per kg were given to dogs, intravenously, daily for 62-65 days; increasing the dose to 10 mg per kg for 23 days and then to 20 mg per kg for two weeks still did not result in tolerance to the antitussive effect. Tolerance to the antitussive effect of morphine or codeine develops in two to four weeks. No withdrawal CHo-CHo-CONH. symptoms were induced by injection of nalorphine near the termination of the prolonged administration WIN-13187 of AT-327. AT-327, at a dose of 80-100 mg orally per day, The compound had approximately one-half the gave relief of cough in most of the 45 patients with antitussive potency of codeine phosphate in cats and cough due to acute respiratory infections, complete its effect was not antagonized by nalorphine. It had relief in 13 %, marked improvement in 64% and no no analgesic effect in rats up to 120 mg per kg and effect in 22%. Administration for 10-30 days in depressed only slightly the respiratory rate and blood 13 patients yielded no evidence of tolerance and no pressure. Its toxicity was low but convulsions untoward reactions were seen with daily doses in occurred in rats at 500 mg per kg (Winthrop Labo­ excess of 100 mg. ratories, personal communication, 1962). ' Sugimoto et al. (1960) treated 31 tuberculous Bickerman & Itkin (personal communication, patients with AT-327. The cough relief with a 1962) tried WIN-13187 in normal volunteers against 90-mg dose was marked in nine, but absent in nine cough induced by citric acid aerosol. Some anti­ others. tussive effect was observed with 50 mg, orally, but Nair & Haar (1956) reported on the pharmacolo­ this was less than with smaller doses of codeine. gical properties and clinical effectiveness of 1-ethyl- Wolbach & Fraser (personal communication, 1962) 3-di-(2'-thienyl)-methylenepiperidine, the next higher concluded from tests on post-addict volunteers that analogue of AT-327. the physical dependence-producing potency of Kase & Yuizono (1959) described antitussive WIN-13187 was very low, less than that of codeine activity but no analgesic action in dithienyl ethanols or of dextropropoxyphene. and propanols with piperidine representing the Charlier et al. (1961) described a phenethyl tertiary amine, but they were less effective in electri­ piperidine derivative, 1-phenethyl-4-propargyl-4-pro­ cally stimulated anaesthetized cats than the cor­ pionoxypiperidine (L-2909), possessing both anal­ responding thiambutenes. gesic and antitussive properties in animals. No trials in man have come to our attention. As an antitussive in the anaesthetized cat (electric stimulation of the PETHIDINE CONGENERS The main interest in the very many phenyl­ piperidine derivatives synthesized and examined after the discovery of pethidine has focused on potential analgesic action. Pethidine has been reported to have antitussive action (Lenzi, 1941; Linz, 1943; Friebel, Reichle & von Graevenitz, 1955; Reichle & Friebel, 1955; Green & Ward, 1955; Kase, 1955a; Guseva, 1956; Bickerman, 1962), CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 195 superior laryngeal nerve) 0.5 mg per kg, intraven­ In rats, mice and dogs it has analgesic potency ously, was equivalent to 1.5 mg per kg of codeine comparable to codeine (Winder et al., 1961; see phosphate; in the dog (mechanical stimulation of the Part 2, section headed " Prodilidine "). These trachea) 1.0 mg per kg, intravenously, was superior authors showed that it was also an antitussive agent, to 2.0 mg per kg of codeine; and in the guinea-pig but in dogs exposed to inhalation of ammonia it was (inhalation of ammonia aerosol) 5 mg per kg, sub­ less effective than codeine. In the same animals cutaneously, was equivalent to 30 mg per kg of 3.5 mg of prodilidine per kg were less effective than codeine. In guinea-pigs the average number of 2.8 mg per kg of codeine. Again no clinical trials of coughs induced by the aerosol before and after prodilidine as an antitussive have come to our 40 mg per kg of L-2909, orally, was 29.4 and 7.4 and attention. after 100 mg per kg of codeine, orally was, 25.9 and 7.3. PHENOTHIAZINES By two methods in mice (pinching the tail and electrical stimulation of .the feet) L-2909 had a Boissier & Pagny (1960) studied, among others, a greater analgesic effect than pethidine. This com­ number of phenothiazines to look for a relation be­ parison was by intraperitoneal injection. The tween cough-depressant action and other properties. authors said that L-2909 did not provoke broncho­ They conCluded that neither the basic phenothiazine spasm, inhibit intestinal motility or depress respira­ structure nor the antihistaminic properties implied tion or circulation. any specific antitussive effect but that such relief of cough as did appear probably resulted from general sedative action. They compared antihistaminic, neuroleptic and antitussive potencies of a number of compounds and the results are given in Table 56: cough was induced in guinea-pigs by sulfuric acid aerosol. The neuroleptic phenothiazines had a good anti­ tussive effect in anaesthetized cats in which the superior laryngeal nerve was stimulated. PRODILIDINE Winter & Flataker (1955a, 1955b) reported that an antihistaminic phenothiazine (or cortisone) Also conveniently considered at this point is suppressed the cough produced by a specific antigen prodilidine, related to alphaprodine but differing aerosol in sensitized guinea-pigs. This was, however, from the latter in containing pyrrolidine in place of a specific antihistaminic effect. Codeine had no piperidine as the heterocyclic component. influence on this type of cough.

TABLE 56 ANTIHISTAMINIC, NEUROLEPTIC AND ANTITUSSIVE EFFECTS OF SOME PHENOTHIAZINES ADMINISTERED INTRAPERITIONEALLY TO GUINEA-PIGS a

Agent Dose Anlihistaminic Neuroleptic % suppression (mgfkg) effect effect of cough

Promethazine 7.5-50 Good Slight 60-77 Thiazinamium 7.5-15 Good None 18-86 Chlorpromazine 1-3 Moderate Good 25-59 Thioridazine 1.5-7.5 Moderate Good 18-51 Alimemazine 1.0-7.5 Moderate Good 38-47 Dimethoxanate 7.5-20 None None 10-72 Codeine 7.5-25 - - 14-60

a Cough was produced by sulfuric acid aerosol. 196 N. B. EDDY AND OTHERS

Pipazetate 1 tussive dose of codeine decreased the respiratory rate by 5% and the minute volume by 21 %. Pipazetate, Kase & Yuizono (1959) reported studies which however, after hexobarbital, increased the respira­ indicated that the introduction of a piperidino group tory-depressant effect of the latter. in the molecule contributed to antitussive activity. Von Schlichtegroll observed spasmolytic activity, This occurred with analgesic compounds and with bronchodilatation and a local anaesthetic effect others which had a depressant effect on the central with pipazetate. Laffan (1961) said that the drug nervous system. They did not test pipazetate had no sedative effect in mice or rats. Its oral LD60 [piperidinoethoxyethy I azaphenothiazine-1 0-carbo­ was 80 mg per kg for the dog, 207 mg per kg for xylate hydrochloride], but other reports on its mice and 530 mg per kg for rats; the intravenous action support their conclusion. LDso for the same species ranged from 8 to 17 mg per kg. Convulsions preceded death but there was little excitement at subconvulsant doses. Sublethal doses did not affect the blood pressure, though there was cardiac arrhythmia. Histamine, serotonin or acetylcholine were not antagonized in vivo or in vitro.

Schmidt (1960b) reported an LD50 of 97 mg per kg, intraperitoneally, and 214 mg per kg, orally, in mice

P!PAZETATE and 70 and 500 mg per kg by the same routes in rats. The effect of pipazetate against experimental In unpublished experiments, von Schlichtegroll, cough in man has been tested by Haslreiter (1959), Prime (1961) and Hammer! & Pichler (1962). quoted by Libal (1960), found an antitussive ED50 for pipazetate of 22 mg per kg, subcutaneously, in Haslreiter determined the response in 120 patients to guinea-pigs in which cough was induced by chemical concentrations of acetylcholine aerosol between irritation. With 32-64 mg per kg, orally, in cats a 0.1 and 1.0% and on the following three days again marked suppression of cough induced by electrical determined the response after 20 mg of pipazetate, stimulation of the laryngeal nerve was observed. 30 mg of codeine, and placebo, double-blind in Laffan (1961) reported that pipazetate had 60% randomized order. Not only was a higher concentra­ of the potency of codeine in reducing cough due to tion required to elicit any response 30 minutes after electrical stimulation of the tracheal submucosa in either drug but the response was suppressed com­ dogs. pletely in 41 % of those treated with pipazetate, Friebel & Kuhn (1962) compared the antitussive in 53% of those who had codeine; complete sup­ effectiveness of pipazetate with that of other agents pression occurred in only 6% of those who had the including codeine. Cough was induced in guinea­ placebo. Prime also used an acetylcholine aerosol, 1.0% pigs by sulfur dioxide inhalation and an ED50 was calculated from the animals failing to respond concentration in 12 subjects, and counted the coughs 30 minutes after subcutaneous injection of the drug. that resulted during a 20-minute period. The medications were pipazetate 20 mg, codeine 30 mg The ED50 was 14.5 and 15.4 mg per kg for pipa­ zetate and codeine, respectively. Hahn & Friebel and placebo in random order. The mean number of (1966) concluded that the effect of both drugs was coughs evoked before, and 20 minutes after each to inhibit the ability of the cough centre to summate were: placebo 13.7 and 14.5, codeine 12.1 and 7.0: afferent impulses. The suppressant effect of 14.5 mg pipazetate 13.9 and 5.1. The difference from placebo per kg of pipazetate, subcutaneously, could be was statistically significant and similar for the two overcome by increasing the afferent impulses, set up drugs, but Prime said later, according to Sevelius, by electrical stimulation through electrodes in the Lester & Colmore (1955), that he could not reproduce trachea of unanaesthetized guinea-pigs. his results with the acetylcholine procedure. Friebel & Kuhn (1962) found that the antitussive Hammer! & Pichler used a 7.5% citric acid aerosol dose of pipazetate in guinea-pigs decreased the in 18 subjects and reported a reduction in the cough respiratory rate by 10% without changing the minute response after treatment with pipazetate. volume. In the same series of experiments, the anti- Clinical experience with pipazetate in cough of various types is summarized in Table 57. All report 1 Also known as Selvigon and Theratuss. an antitussive effect with less than 20% complete TABLE 57 CLINICAL REPORTS ON EFFECTIVENESS OF PIPAZETATE, ORALLY OR RECTALLY

Patients Dosage, single or per day (m g) Results Reference No. I Type -

160 Various 3x 20 or 30 compared with codeine Placebo: very good, 7%; good, 7%; some, 12% a Haslreiter (1959) Codeine: very good, 33%; good, 54%; some, 6% Pipazetate: very good, 23%; good, 41%; some, § 25% zt!l -- m 90 Tuberculous 3x 20 or 30 In 47, a rapid and very good effect b Schmidt (1960b) ~ -- ;:j "' 57 Tuberculous 5x20 Good in 45, some in 4. No side-effects c Golden (1960)

----

324 Various 20 - 320 per day For irritative cough about90% effective, for asthma Greif (1960) 50% effective and for malignancies no better than Itr1 codeine. No side-effects d "' --- 2l ~ 58 Chronic cough, mostly tuberculous 15 compared with 20 mg of codeine Codeine slightly better e Li bal (1960) ;e 20 compared with 30 mg of codeine Two drugs equally effective z --- ~ 603 Acute and chronic cough 3x 20 or 40 for 7 days Very good, 45; good, 40; none, 18. No side-effects Pia!!, Rowell & Woolas (1960) --- § ::c 77 Acute and chronic cough 3x 20 or 40 for 7 days Excellent, 20; good, 19; fair, 9; poor, 7 f Phillips & Guillaume (1961) --- ~ 49 Various Usually 4x20: range 60-150 per day Excellent, 8; good, 22; fair, 13; poor, 6 g Gefter (1961) ,..~ ---

90 Various Usually 1.0 mg/kg per day Effective especially in acute bronchitis, but in Dietel & Kllditz (1962) some 1.5 or 2.0 mg/kg needed

45 Various 3 x 20, rectally Effective h Pellanda (1962)

..... \0 -..I ~ TABLE 57 (continued)

Patients Dosage, single or per day (mg) Results Reference No. I Type

86 Various, college students 41 cases, 60 per day Excellent, 6; good, 19; fair, 9; poor, 7 Murphy, Heath &. Sansocie (1962) 14 cases, 80 per day ,Excellent, 7; good, 3; fair, 2; poor, 2; side-effects, 2 31 cases, 1 00 per day Excellent, 18; good, 4; fair, 0; poor, 9; side-effects, 6 --- 20 All but 2 tuberculous 10 orally or 20 rectally Excellent or satisfactory in 17i Freidinger (1962)

---

61 Children, acute respiratory infection 2, 3 or 4x 10 rectally Relief in 50. Some side-effects J Fischman (1962) :z: . 70 Children, acute respiratory infection 20 per day in 22,40 per day in 21,30 or Excellent, 24; good, 30; fair, 10 k Rehermann (1962) !"' 60 per day rectally in others a0 ...: 116 Mostly children 15 to 160 per day i Excellent, 2; very good, 32; improvement, 75: no Amler &. Rothman (1963) ~ side-effects 0 47 Adolescents: compared with placebo 3 or 4x 10 or 20 per day Excellent, 34; good, 9; none, 4: for placebo, excel- in 46 others, double-blind lent, 5; good, 3; none, 38. Side-effects: nausea, ~ diarrhoea, abdominal distress ~ "' I 172 Children, various 10 or 20 rectally, to 100 per day !Improvement in 86.6%. Duration 2-4 hours. Drow- Beckloff &. Hewitt (1963) si ne ss in 4, erythema in 2.

a The results noted were for double-blind trials. Usual dose. was 6x20 mg per day and as much as 320 mg per day could be given without side-effects. No tolerance and no respiratory depression. b Effective in 10-20 min, duration 4-6 hours. c Effective usually in 10-20 m in, duration 3-8 hours. a Effective in 10-30 min, duration 3-8 hours. • Double-blind trials; 251 and 242 doses In first, 225 and 277 doses In second comparison. f Only 65 patients reported. No liver damage, blood change, skin rash or change in blood pressure. u Retains its effectiveness and usually without adverse effects with larger dose. The patient on 150 mg showed only restlessness and insomnia. He: did not respond to pipazetate or codeine. 11 Effective in 15 min, duration 4-5 hours. Author thought it was both a local anaesthetic and a spasmoly1ic agent. i Most taking codeine, which could be reduced or discontinued after pipazetate started. Severe nausea in 3, some in a few others. The doubled dose, rectally, was no more effective than the oral dose. J Codeine previously in 21, but was Ineffective in 18; all but two of these responded to pipazetate. Drowsiness in 6, erythema in 2, loose stools In 2. "No adverse effects, except 6 refused medication on account of bitter taste. CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 199 failures. There were three trials, double-blind, com­ recorded graphically and diminution in the height paring pipazetate with placebo or codeine or both. of the record was the criterion of effect. Tests were The usual dose ranged upwards from 10 mg and the repeated after intravenous drug administration until total per day was usually 60-100 mg, a little more the height of the record returned to the pre-drug than the usual daily dose of codeine for antitussive level. Approximate effect. There seem to have been very few side-effects ED., (mg/kg) however, nausea being the most common complaint. (I) Dimethoxanate hydrochloride 1.6 The bitter taste has been avoided by the use of (2) Diethyl congener hydrochloride 0. 7 suppositories, especially in children, but for such (3) Isopropyl congener hydrochloride 0.6 use the dose was usually doubled. (4) Codeine phosphate 1.2 Greif (1960) observed good results with pipaze­ tate in 34 patients, in preparation for bronchoscopy, Orally 7.5 mg per kg of (1) equalled an intravenous and Prime (1961) said that 10 mg, intravenously, dose of 1.5 mg per kg. It had no anticholinergic or 10 minutes prior to bronchoscopy facilitated the antihistaminic effect. At 25 mg per kg, subcutane­ procedure and diminished the amount of local ously, it had no effect on spontaneous activity of the anaesthetic required. rat or on the pentobarbital sleeping time in mice and Pipazetate does not seem to affect respiration in no analgesic effect. At 2.8 mg per kg, intravenously, normal humans, according to pulmonary function it had no significant respiratory or circulatory effect tests on 20 subjects (Hammed & Pichler, 1962). It in anaesthetized dogs. It did have antispasmodic increased repiratory volume in 20 of 23 asthmatics action. In rats a barium meal should have left the and in 13 of 30 patients with spastic bronchitis stomach in 90 minutes; when drugs were given orally indicating a bronchodilatory effect. 40 minutes before the barium meal the ED50 for Tolerance to the antitussive effect of pipazetate 50% retention of the meal was about 30 mg per kg has not been reported and La Barre (personal for (1), 40 mg per kg for (2), 90 mg per kg for (3) communication, 1963) said that at a dose of 12.5 mg and 50 mg per kg for (4). The group showed about per kg of pipazetate had no effect on the hyper­ the same range of antispasmodic effect on the isolated activity of abstinence in morphine-dependent dogs. guinea-pig ileum. The LD50 mg per kg, orally, for these compounds was: Dimethoxanate 1 Mouse Rat Dimethoxanate is 2-dimethylaminoethoxyethyl (1) Dimethoxanate hydrochloride 580 1500 phenothiazine-tO-carboxylate. Boissier & Pagny (2) Diethyl congener hydrochloride 150 290 (3) Isopropyl congener hydrochloride 94 175 (4) Codeine phosphate 600 615 ('~'''!{ 5 "0""' ~N/ # The toxicity of (2) and (3) was increased more than I I antitussive potency. Compound (1) had no effect on COOCH.CH.OCH.CH.N(CH•)• growth in rats when it was given in various per­ DIMETHOXANATE centages in the diet for 30 weeks, nor did it show any toxic effects in dogs during a year's treatment. In (1960) drew attention to the tertiary aminoethoxy­ man, 25 mg, orally, had a rapid antitussive effect ethyl carboxylate side chain and suggested its lasting three to seven hours (Chappel, Stegen & possible significance for antitussive action, since it is Grant, 1958). a component of other effective antitussives (see Klein (1958) described a mild local anaesthetic benzonatate, oxeladin). and antispasmodic effect of dimethoxanate. He Chappel, Stegen & Grant (1958) made the ob­ found it a less effective antitussive in cats than servation that congeners of dimethoxanate in which codeine. Both drugs were given intravenously, the alkyl of the amine was ethyl or isopropyl were 1.5 mg per kg, to ten animals. Codeine caused more effective as antitussives. In lightly anaesthe­ partial to complete suppression of cough in all the tized cats cough was induced by electrical stimula­ cats, whereas dimethoxanate was effective in only tion of the superior laryngeal nerve. The cough was seven. On the other hand, Boissier & Pagny ( 1960) found it slightly more effective than codeine both in 1 Also known as Cothera. guinea-pigs (sulfuric acid aerosol inhalation) and in 200 N. B. EDDY AND OTHERS cats (superior laryngeal nerve stimulation) and Chen, only the duration of action of equal doses, intra­ Biller & Montgomery (1960) confirmed this in dogs. venously, in anaesthetized cats in which the superior Each drug was given at 1.0 mg per kg, orally. laryngeal nerve had been stimulated electrically. Dimethoxanate caused 88% inhibition of cough, Wmter (1966) tested meprotixol in five normal lasting longer than six hours in half of the animals; subjects, in a double-blind cross-over comparison codeine caused only 69% inhibition, the effect with placebo. The cough stimulus was citric acid disappearing in three hours. aerosol, with the minimal effective concentrations Parish (1959) carried out a double-blind test on being individually determined. The dose was 30 mg, 139 patients with allergic rhinitis or common cold, orally. The mean reduction in number of coughs with cough the major complaint. A bland syrup was was 56% at one hour, 50% at two hours, 26% at compared with the same syrup containing dimetho­ three hours and 10% at four hours. The maximum xanate, 25 mg per dose over a period of three to effect of placebo was a reduction of 12% at three five days. Of the 95 patients receiving the drug, hours. A dose of 20-35 mg of meprotixol, intra­ 85 experienced excellent cough control; of the other venously, not double-blind, also produced satisfac­ 44 receiving placebo only three obtained relief. tory reduction of cough. Parish reported few side-effects, slight drowsiness or Winter (1966) administered oral doses of 20 mg nausea in 12 and a skin rash in one. of meprotixol or a placebo twice daily to 10 normal Klein (1963) treated 15 patients with chronic persons. A questionnaire completed at the end of cough with 50 mg of dimethoxanate per day in the trial indicated only doubtful side-effects, and S)'rup. After three weeks, substitution of placebo these were more frequent with the placebo. resulted in immediate increase in cough with relief again when dimethoxanate was resumed. These OTHER COMPOUNDS patients had received hydrocodone previously and 12 of them judged dimethoxanate superior. Effect Antihistamines was rapid in onset and lasted three to five hours. Antihistamines are the principal components of Klein obtained satisfactory results in another 50 many preparations designed for treatment of upper patients with respiratory infections and observed no respiratory tract infections and some antitussive side-effects. action has been attributed to them. Loew, Kaiser & Meprotixol Moore (1945) reported more than 20 years ago, on the pharmacological properties of the benzhydryl Meprotixol is a thioxanthene, containing sulfur ether, diphenhydramine 1 (2-diphenylmethoxy-N,N­ in the ring structure but no nitrogen, and a C:i­ dimethylethylamine), and a few years later Domenjoz methylaminoalkyl side chain. Moller Nielsen & (1952) demonstrated its ability to suppress cough, Neuhold (1959) described it as having only a slight elicited by electrical stimulation of the superior laryngeal nerve in lightly anaesthetized cats. He obtained a similar result with another antihistamine, N-(p-chlorobenzyl)-N-(2-pyridyl)-N,N-dimethylethy­ lenediamine. Kase (1955a) also showed that diphenhydramine abolished coughing in dogs MEPROTIXOL following mechanical stimulation of the trachea. The minimal effective dose was 5 mg per kg, intra­ central depressant effect but a marked antitussive venously. At 10 mg per kg, cough was suppressed effect. Houghs et al. (1966) said that it was slightly in all animals for a maximum of 44 minutes, but neuroleptic, potentiated barbiturate anaesthesia, there was a rise in blood pressure and repeated prolonged ethanol-sleeping-time and was anti-con­ convulsions in some animals. According to Kase, vulsant. It was a strong bronchoconstrictor, local N-(p-methoxyphenyl)-N·(2-pyrimidyi)-N,N-dimethyl­ anaesthetic and anti-inflammatory agent. Its LD50 in ethylenediamine acted like diphenhydramine at an mice was 60 mg per kg intravenously, 125 mg per intravenous dose of 20 mg per kg. He did not kg intraperitoneally and 420 mg per kg orally. They think, however, that these compounds were suitable compared meprotixol with codeine for antitussive for clinical application. effect and claimed that the former was four times more effective, and longer acting; but they reported • Also known as Benadryl. CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 201

Wax, Winder & Peters (1962) have compared more obtained a dose-related suppression of cough with recently the antitussive effect of diphenhydramine codeine but no significant effect with mepyramine. with that of codeine, 4 and 8 mg per kg of the These authors co~tcluded that antihistamines were former and 4 mg per kg of the latter, subcutaneously. not antitussives per se and we would agree. Although They determined the minimal cough-inducing con­ antitussive action has been shown with some of them, centration of ammonia vapour applied through an clinical effectiveness is not well documented and the in-dwelling tracheal cannula in unanaesthetized dogs. results do not at the moment suggest any advantage Both medications and a placebo (the normal saline of these agents for cough relief. vehicle) were given in random order to each of ten Benzobutamine dogs at intervals of not less than five days. The cough-suppressant effect of diphenhydramine was The pharmacology of benzobutamine (N-(2-ben­ estimated to be 0.4 times as potent as codeine but zoyloxymethyl- 2- phenylbutyl)-N,N-dimethylamine the peak of its effect occurred later, 45-75 minutes was described by Maffii, Silvestrini & Banfi (1963) after injection compared with 30 minutes for codeine. and special attention was given to its antitussive The authors judged the site of action to be central. action. Wax, Winder & Peters (1962) quoted Bickerman as c. H. having found 30 mg of diphenhydramine hydro­ chloride approximately equivalent to 15 mg of 0-~-CH.N(CH,). codeine phosphate, both orally, in suppressing cough CH. induced by citric acid aerosol in humans. Kiill::tvist & Melander (1957) measured the anti­ o~-~0 tussive action of chlorcyclizine (1-(p-chloro-a­ 0 phenylbenzyl)-4-methylpiperazine) and codeine in guinea-pigs in which cough was elicited by ammonia BENZOBUTAMINE inhalation. They said chlorcyclizine was twice as The authors used a number of methods and species effective as codeine, but the number of experiments and made comparisons with codeine as follows: was small, a consistent dose-effect relationship was not shown for codeine and apparently both drugs Cough stimulus Route • Effective dose (mg per kg} were not used in the same animals. The doses of Benzo- but a- Codeine each drug used were 0.5, 1.0 and 2.0 mg per kg, sub­ mine cutaneously. These authors also tried chlorcyclizine Guinea- in seven hospitalized patients with long-standing pig Acrolein aerosol se 3.5 4.0 severe cough. They combined a dose of 20 or 30 mg Cat Electrical stimulation with 200 or 300 mg of glycerylguaiacolate and superior laryngeal compared the effect with that of the guaiacolate nerve IV 0.5-1.0 1.5 alone. The mixture and the control were given three Dog Sulfuric acid aerosol se 1.0 1.0 or four times a day on alternate days. They con­ Sulfuric acid aerosol 0 5.0 cluded a statistically significant superiority of the Electrical stimulation 8.0 mixture, without interference with the expectorant tracheal submucosa se 4.0 effect of the guaiacol and without side-effects. • SC=subcutaneous; IV=intravenous; O=oral. Silvestrini & Maffii (1959) and Boissier & Pagny Benzobutamine, 10 mg per kg, subcutaneously, (1960) compared mepyramine1 (2-[(2-dimethylamino­ caused no apparent respiratory depression in bar­ ethyl) (p-methoxybenzyl)amino]pyridine) and co­ bitalized rats. It was about equal to lidocaine as a deine in guinea-pigs. The former used acrolein local anaesthetic and was spasmolytic on the isolated vapour and the latter sulfuric acid aerosol to elicit gut of the guinea-pig. A dose of 40 mg per kg, cough. The acrolein-induced cough was depressed intraperitoneally, prevented electroshocks seizures by codeine at doses of 3.5-5.0 mg per kg but not but toxic doses caused convulsions in mice. The significantly by mepyramine at doses of 1.0-5.0 mg LD50 of benzobutamine in mice was more than per kg, subcutaneously. Boissier & Pagny gave 1000 mg per kg, subcutaneously, and that of codeine 7.5-25.0 mg per kg of each drug intra peritoneally and . 200 mg per kg. Long-term administration (6 months) of benzobutamine in rats produced no pathological 1 Also known as Neoantergan. changes. 202 N. B. EDDY AND OTHERS

Pasquariello & Nicolis (1962) carried out two experiments in dogs. Clamping the trachea near the clinical trials with benzobutamine. In a group of end of inspiration immediately arrested respiratory 38 patients with chronic bronchitis single doses of movements. After a pause intrapleural pressure fell 250 mg of benzobutamine and 60 mg of codeinf- and and the respiratory effort resumed. Benzonatate a placebo were compared on successive days. The lengthened the apnoeic period. criterion was the number of coughs in a three-hour Bucher (1956) demonstrated more directly that period following oral administration. The average benzonatate acted on the pulmonary stretch­ for benzobutamine was 10.4, for codeine 9.8 and for receptors. He recorded action potentials from the placebo 14.5. The difference from placebo was vagus nerve in the cervical region, and showed a significant for both drugs. The patients ranked decrease in the impulses originating in the stretch benzobutamine best 15 times, codeine best 17 times receptors after benzonatate had been administered and placebo best 5 times. intravenously. Langrehr (1963) confirmed Bucher's In the second trial the authors gave 47 patients observations. He found that 1.0-5.0 mg per kg of 400 mg of benzobutamine or placebo daily for benzonatate, intravenously, in lightly anaesthetized seven days, cross-over in random sequence and dogs and cats paralysed various afferent receptors, recorded the cough count for 23 of each 24 hours. including the lung stretch-receptors. He too re­ The average was 18.8 for benzobutamine, and 23.2 corded action potentials, in appropriate afferent for placebo, a significant difference. Again the pathways. Hansen & Zipf (1960a, 1960b) demon­ patients were asked to express a preference: benzo­ strated the peripheral action of benzonatate in other butamine was judged superior to placebo 12 times, ways. In guinea-pigs, under artificial respiration, the equal 13 times, inferior five times. afferent impulses in the pulmonary vagus originated by veratrine were suppressed by benzonatate and 1 Benzonatate electrical activity of the nerve fibres set up by Benzonatate, 2,5,8,11,14,17 ,20,23,26-nonoxaocta· bronchoconstriction following application of hista­ cosan-28-ol p-butylaminobenzoate, is unique in that mine or acetylcholine was also suppressed by the drug. The authors referred to this as endoanaesthe­ sia. Benzonatate produced changes in the electro­ H.C.NH- 0 -COO(CH.-CH.O)• CH, cardiogram of the guinea-pig indicating bradycardia and block (Reicherts, Zipf & Hansen, 1957). Mean­ BENZONATATE while, Bein & Bucher (1957) determined the effect of its antitussive activity is claimed to be based not benzonatate on nerve conduction when it was only upon central action but also upon inhibition of applied directly to a frog's sciatic nerve and also excitation of peripheral stretch-receptors. The determined its local anaesthetic effect in other ways. latter action was demonstrated first. The impulses The ED60 for conduction anaesthesia was the con­ 4 arising in these receptors in the action of inspiration centration of 1.4 X 10- g(litre, for infiltration 4 are transmitted by the vagus nerve to the respiratory anaesthesia 2.2 x t0- g/litre and for surface an­ 4 centre and promote the following expiration, a aesthesia 2.2 x t0- g/litre. The same authors also regulatory mechanism known as the Hering­ determined a central effect of the drug by recording Breuer reflex. Kroepfli (1950) showed in experiments anterior-root potentials following posterior-root on cats that the extent of expiration and the intensity stimulation in anaesthetized cats and rabbits, and of coughing were correlated with the amplitude of by inhibition of polysynaptic reflexes brought about the preceding inspiration. According to Bucher & by stimulation of the peroneal nerve. The ED50 for Jacot (1951), prevention of excitation of the stretch the effect on spinal reflexes was 1.0 mg per kg, receptors in the cat by clamping the trachea, or by intravenously; the ED50 for the effect on the stretch pneumothorax, suppressed the cough response to receptors was 0.4 mg per kg also intravenously. mechanical stimulation. This afforded evidence of a Even though they found that benzonatate in­ relation between modification of the Hering-Breuer hibited vagal impulses arising from receptors in the reflex and the intensity of coughing and drew atten­ tracheal mucosa responsive to mechanical stimula­ tion to a possible mechanism of antitussive drug tion, Sell, Lindner & Jahn (1958) considered that the action. Goth & Goldenberg (1960) reported related drug exerted its antitussive action mainly centrally. It also inhibited response to stimulation of the • Also known as Tessalon. superior laryngeal nerve and to stimulation of the CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 203 vagus, peripheral to the entrance of the superior tracheal mucosa through previously implanted elec­ laryngeal fibres, and there was no correlation between trodes (see Table 59). Delayed onset of action of its antitussive action and the intensity of the effect benzonatate was apparent too in the data of Chen, on the receptors (endoanaesthesia). In addition, Biller & Montgomery (1960) who administered the ~ection of the vagus, peripheral to the superior compound orally in doses of 1.0-1.5 mg per kg and laryngeal, did not influence the antitussive effective­ determined the cough response to sulfuric acid ness of benzonatate. Unfortunately the doses re­ aerosol in unanaesthetized dogs. The delay was quired for consistently significant effect in these probably due to slower absorption because intra­ experiments were in the toxic range. venous administration was effective promptly. Whatever the mechanism of its action, the anti­ Precise comparison with codeine for antitussive tussive effect of benzonatate has been reported potency is difficult because of the difference in the repeatedly for experiments in animals. These are time of action of the two drugs just referred to; ~ummarized in Table 58. they are both active against experimental cough in There was indication of delayed onset and per­ the same dose range. ~istence of antitussive action of benzonatate com­ Bucher (1961) checked the ability of benzonatate pared with codeine and dextromethorphan when oral to antagonize the effect of histamine or epinephrine doses were given to unanaesthetized dogs in which on the elasticity of rabbit lung. Against either, the .cough was induced by electrical stimulation of the dose causing 50% antagonism was > 2 mg per kg .

TABLE 58 ANTITUSSIVE EFFECTIVENESS OF BENZONATATE IN ANIMALS

Anaes- Dose R a Cough Cough stimulus thesia I (mg/kg) I oute Iinhibition Reference

Species: GUINEA-PIG Acrolein aerosol + Maflil, Silvestrlnl, & Banfi (1963) Acrolein aerosol >50% Silvestrin i & Mafli i (1959)

Species: CAT Soap powder insufflation + >0.3 IV + Bucher (1956) Ammonia vapour inhalation + 2.0 0 100% Stefko, Denzel & H1ckey (1961) Electrical stimulation superior laryngeal nerve + c. 1.0 IV + Silvestrini & Maflii (1959) Electrical stimulation superior laryngeal nerve + 1.5 IV + Maflii, Silvestrini & Banfi (1963)

Species: DOG

Sulfuric acid aerosol 0 1.0 0 57% Chen, Biller & Montgomery (1960) Sulfuric acid aerosol 0 1.5 0 76% Chen, Biller & Montgomery (1960) Sulfuric acid aerosol 0 5.0 0 + Maflii, Silvestrini & Banfi (1963) Sulfuric acid aerosol 0 >1.0 se + Maflii, Silvestrini & Banfi (1963) Electrical stimulation tracheal mucosa 0 >8.0 se + Maflii, Silvestrini & Banfi (1963) Electrical stimulation tracheal mucosa 0 4-10 se 50% Silvestrini & Maflii (1959) Electrical stimulation tracheal mucosa 0 1-4 se 33-90% Stefko, Denzel & Hickey (1961) Respiratory infection 0 2.0 0 + Stefko, Denzel & Hickey (1961)

a SC = £Ubcutaneous; IV= intravenous; 0 = oral, 204 N. B. EDDY AND OTHERS

TABLE 59 PERCENTAGE INHIBITION OF COUGH AFTER ORAL ADMINISTRATION OF DRUGS TO UNANAESTHETIZED DOGS a - No. of Time after administration (min) Drug Dose (mg/kg) dogs/no. I of expts 15 I 30 I 60 I 120

Benzonatate 0.5 4/4 0 17 38 11 Benzonatate 1.0 4/4 0 33 82 14 Benzonatate 4.0 4/4 0 61 90 40 Benzonatate 8.0 4/4 0 75 90 46 Benzonatate 16.0 4/4 0 90 100 58 Codeine 1.0 12/14 26 46 44 30 Dextromethorphan 1.0 12/28 30 46 54 32

a Cough induced by electrical stimulation through electrodes implanted in the trachea. After Stefko, Denzel & Hickey (1961). intravenously. The author did not relate this to doses used. Gregoire et al. used an acetylcholine antitussive action. He also reported (Bucher, aerosol in ten normal subjects. Most subjects 1956) the acute toxicity figures for benzonatate given coughed when the concentration of the aerosol below: was 0.5 mg per litre. The dose of benzonatate was LDso (mgfkg) 10 mg, intravenously. The number of coughs was Intravenous Subcutaneous Oral reduced in all but one subject, on the average from Mouse 10 100 400 17.4 to 6.2 per subject. The authors said that 100 mg Rabbit 5 200 >2000 orally was ineffective. Bickerman & Itkin used 16 Cat 4 " trained " normal subjects and citric acid aerosol, determining for each the effective concentration and Mice given one-tenth the lethal dose, subcutaneously, repeating this with cough counts and expiratory for 16 consecutive days showed no abnormality, but flow-rate measurements at 1, 2, 3 and 4 hours after rabbits given the drug daily in a similar dose relative drug administration. They used placebo, pholcodine to the LD50 developed paralysis and convulsions by and other potential antitussives for comparison in the tenth day, because of cumulative action in this these subjects and codeine. in others. The change'! species (Bucher, 1956). with placebo were small and might be either a Benzonatate has been tested against experimen­ decrease or an increase. Doses of 10 mg of phol­ tally induced cough in man by Shane, Krzyski & codine or 100 mg of benzonatate reduced the number Copp (1957), Gregoire, Thibaudeau & Comeau of coughs significantly, usually more than 25% at (1958) and Bickerman & Itkin (1960). Shane et al. each hourly determination. The authors considered used 15% citric acid aerosol as the tussigenic agent these doses equivalent to 15 mg of codeine. on three occasions, several days apart, in 20 subjects. The reports of clinical experience with benzonatate The over-all average was eight coughs per patient are summarized in Table 60. In only three instances per stimulus. Following the same procedure and (Wilson, Farber & Mandel, 1958; Darke et al., 1959; counting the coughs produced one hour after an oral Simon, 1960) were observations made double-blind dose of 100 mg of benzonatate or 32 mg of codeine and rarely was there any direct comparison with the averages were 1.7 and 4.7, respectively. Com­ codeine. Simon (1962) reported a comparison that paring the results in the individual patients the was not completely double-blind, of 100 mg of average cough count was reduced by 2 or more in benzonatate, 50 mg of sodium dibunate, 15 mg of 16 of the 20 persons and completely suppressed in dextromethorphan and 25 mg of clofedanol, the only 1 after codeine; for benzonatate the figures were first three as tablets, the last in syrup. Each was 19 of 20 and 5, a superior effect for the latter at the given for a week in randomized order usually four TABLE 60 CLINICAL ANTITUSSIVE EFFECTIVENESS AND SIDE-EFFECTS OF BENZONATATE

Patients Dosage regimen (mg) I Route a I Result Reference No. I Type - 86 Various, many chronic, some asthma- 5-10/day se Clear-cut cough-inhibiting action; eases asthma- Cavalca (1956) tic 100-200/day R tic breathing ('l 250-300/day 0 § 2 124 Chronic cough 68, acute infection 45, 0 Very good, 42; good, 36; none, 28. Equal to 10 mg Naegeli (1956) t'1 other 11 codeine b ~ -- 0 90 Tuberculosis 80, chronic bronchitis 10 5-10 per day se Good inhibition of cough in all without side-effects Vergani & Pergani, 1956 ::j 150-250 per day 0 or tolerance "' -- 46 Establishment of pneumothorax 20 IV Satisfactory control of cough. No undesirable Aletti & Palatresi (1956) effects -- - 31 Pleurogenic cough 5 per dose IV Very good, 9; good, 6; none, 1 Herzog (1956) i"' 144 Bronchogenic cough 5-10 per dose se Very good, 20; good, 32; none, 2 50-100 per dose 0 Very good, 27; good, 41; none, 2 c ~ -- 30 Various IV Equivalent to codeine, 20 mg, three times a day, Neuman (1956) ~ more prolonged; no side-effects. Very good, 21; 0 lnsufflclent, 3 ~

137 Mostly tuberculosis 5 to 20 per dose IV Good 82 d Glullano & Rosaa (1956) 100 per dose 0 I nsufflclent 14 i 59 Various 150 to 450 per day 0 Remarkable Inhibition • lullanl & Pagnotta (1957) ~ -- ~ 59 Chronic cough, some with asthma 1-2x 50, three times a day 0 Excellent 83%. No effect on asthma f Simon (1957a, 1957b) -~'>

60 Chronic emphysematous bronchitis 7.5 per dose IV Some relief of dyspnoea 60%. No side-effects g Marx (1957)

25 Children, various 1.0-1.5/kg per dose I M, Good or very good f Masi (1957) 8.0-10.0/kg per dose or 6.0-8.0/kg per dose 0 - N 0 VI N ~ TABLE 60 (confined)

Patients I Dosage regimen (mg) Route a I Result Reference lo. I Type I I

81 I Elderly, various IV EffEctive, 97.6% h Kauchtschischwili (1957) or 0 --

21 Cough due to cancer with pulmonary 100 per dose, every6-8 hours 0 Effective 80.9%; persistent, no side-effects Ruffinl (1957) involvement -- --- 35 Various 150-300 per day 0 Mostly good. No side-effects Basabe, Gentile & Crocionl (1957) ------?! 10 Bronchial asthma 2.5-10 per dose IV Most felt breathing easier Michelson & Schiller (1957) !J' tl 0 415 Chronic bronchitis, various 4-6x 50 per day 0 Good antitussive effecl i Hanke (1958) ...: -- > ~ 83 Tuberculosis 5-450 per day IV Generally good i Husen (1958) 0 or 0 ~ ~ -- --- (ll 17 Mostly emphysema 5 per dose IM Improved Wilson, Farber & Man del (1958) 20 Mostly emphysema 150-200 per day 0 Much improved, 9; improved, 9 37 Tuberculosis 0 Significant improvement k

------100 Tuberculosis 50, various 50 3x 50-100 per day 0 Good; no side-effects Valent! & De Palma (1958) --

32 Various, children and elderly 10% aerosol twice daily Good, 20; moderate, 10 l Francetti (1958) -- 26 Chronic asthmatic bronchitis, elderly 100-300 per day 0 Excellent, 5; good, 13; moderate, 8 Goglia (1959)

22 During anaesthesia Up to 20 per dose IV Manipulations about airway better tolerated Bai rao et al. (1959) TABLE 60 (concluded)

Patients Dosage regimen (mg) I Route a I Result Reference No. I Type -

Pharyngitis, tracheobronchitis Aerosol Improvement through surface anaesthesia Segal (1959) --· g 130 Acute respiratory infection Excellent, 58.3%; some, 13.8; none, 27.9 m Voiculescu & Newman (1959) IV £!] orO z -- t!l 23 Dyspnoea due to pulmonary disease 100 per day 0 Double-blind compared with placebo; no benefit Darke et al. (1959) ~ -- a 45 Asthmatic bronchitis, pulmonary 0 Superior to codeine but not to hydrocodone n Slmon (1960) emphysema -- ~z 100 Acute or chronic cough 100-200 per day 0 Excellent or good, 82%. Better in chronic cough Matlin (1960) -- ~ 51 Chronic respiratory disease 50 up to every 4 h. 0 Excellent, 90%; moderate, 10% 0 Simon (1963) ~ '"d ~ Few Cough following irritation of external 5 se Cough reflex blocked without side-effects I Diamant (1957) z I meatus > I ----- ~ a SC =subcutaneous: R = rectal; 0 = oral; IV =intravenous; IM =intramuscular. (") b Mild side-effects in 6 patients, fewer than with codeine. Duration of effect 5-6 hours. Tolerance apparent in 3-4 weeks. § c No side-effects. No changes in circulation or respiration. ti: a Oral doses had a local anaesthetic effect. No other side-effects. e Well tolerated. No depressing effect on circulation or respiration. I No side-effects. No changes in blood count or urinalysis. ~ g No respiratory depression. Most patients improved, respiration increased. !:l h Effect lasted 8-9 hours. No evidence of tolerance in 120 days of administration. .,.. l Seven patients accustomed to codeine or hydrocodone did not respond to benzonatate. Duration of effect 4-6 hours. i Not effective in opiate-dependent persons. k Last group double-blind, cross-over comparison with placebo. Mild erythema and itching reported twice. I One child had insomnia and agitation, believed not to be drug Induced. m In another group of 84 patients, codeine 3 or 4x 10 mg per day: Excellent, 20.5%; some, 33.4%; none, 46.1%. n Given double-blind in combination with bronchodilator mixture. 0 Excellent local anaesthetic effect in throat in 79%. One patient discontinued because numbness in throat caused dysphagia. Patients held lozenge in mouth until dissolved. 8 208 N. B. EDDY AND OTHERS times a day. The patients were 100 males with chitis or emphysema; the intravenous doses were 5, chronic cough of various origin who had not received 10 mg, 15 or 20 mg of benzonatate, the higher doses a narcotic mixture within the past year. The results being divided into smaller doses of 5 or 10 mg. They were scored at the end of the week for cough relief also failed to note any antitussive effect with 100 mg and, after two or more drugs had been used, for per day, orally, in 20 dyspnoeic patients in whom patient preference. The scores were as follows: the comparison was with placebo on a double-blind, random-order basis. Feinsilver (1961) measured Relief Preference pulmonary function in three emphysematous patients Benzonatate 74 22 before and 15 minutes after 10 mg of benzonatate, Sodium dibunate 92 72 intravenously. Tidal and minute volume were Dextromethorphan 82 6 increased slightly in all three. Feinsilver also used Clofedanol 100 0 benzonatate to supplement premedication for bron­ The results of clinical experience were generally choscopy. The patients were given 100 mg of good, the loca1 effect of oral doses probably being a seconal, orally, at two hours and 10 mg of morphine contributing factor. Also most authors indicated a plus 0.6 mg of atropine, subcutaneously, at one hour good duration of action. It is curious that two before examination. In addition in most patients reports (Hanke, 1958; Wilson, Farber & Mandel, hexylcaine was applied locally immediately before, 1958) mentioned ineffectiveness if tolerance to an and during the procedure. Whatever the other opiate had developed. The occurrence of tolerance medication, the use of the larger doses of benzonatate to benzonatate on prolonged administration has may have been helpful. The ease of examination been admitted (Naegeli, 1956) and denied (Vergani & was recorded in categories as follows: Pergani, 1956; Kauchtschischwli, 1957). All reports No. of patients in each category which mention them stress that side-effects are Dose (mg) Route • Excellent Good Fair infrequent. Herzog (1956), Iuliani & Pagnotta (1957) 100 0 1 6 4 and Marx (1957) said that there was no circulatory 10 IM 1 6 2 or respiratory depression. The last maintained that 5 IV 8 5 2 in most cases of improvement in respect to cough, 10 IV 21 3 1 respiration was increased. • O=oral; IM=intramuscular; IV=intravenous. There have been a few direct measurements of It was observed that when benzonatate was given, respiratory function after benzonatate. Michelson & touching the carina did not cause coughing. Schiller (1957) measured respiratory function in ten Cattaneo (1959) also used 5 or 10 mg of benzo­ patients with bronchial asthma which had existed for natate, intravenously, as a supplement in preparation five years or more. The dose of benzonatate was for laryngoscopy or bronchoscopy. It was combined 2.5-10 mg, intravenously. Increase in rate and depth with topical anaesthesia and, in the author's opinion, of respiration and in minute volume occurred in facilitated the procedure. Lineback (1962) found the 10 of 12 trials. Central stimulation of respiration drug useful for suppression of a troublesome gag was assumed. There was no consistent change in reflex in nose and throat examinations. He used 5 or the circulation. Marx (1957) applied various respi­ 10 mg, intramuscularly, in 22 patients. He also said ratory-function tests to 10 normal volunteers and that 100 mg, orally three times a day controlled to 20 patients with chronic emphysematous bron­ postoperative coughing. Only four such cases were chitis. The dose was 7.5 mg, intravenously. Normal reported. respiration was not changed. The patients felt that breathing was easier and in those whose cough was Caramiphen 1 lessened, respiration usually increased. There was Caramiphen [bis-(diethylaminoethyl 1-phenyl-1- no evidence of an effect on the bronchi. Respiration cyclopentane carboxylate) ethane disulfonate], was was never depressed. Hanke (1958) said that 14-20 first reported by Martin & Hafliger (1946), and by days treatment with four to six times 50 mg per day Geigy (1950) and was introduced initially as a relaxant, increased spirometer values in 180 tuberculous and only later as an antitussive. Domenjoz (1952) patients and increased the apnoeic pause from 4 to tested it in cats and found it equivalent to codeine 7 to 8 to 18 seconds. Darke et al. (1959) found no in suppressing the cough evoked by electrical significant change in minute volume in four normal and seven other volunteers who had chronic bron- 1 Also known as Taoryl, and Toryn. CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 209 stimulation of the superior laryngeal nerve or by guinea-pigs. The doses used were 0.5-3.0 mg per mechanical irritation ofthe trachea. Toner & Macko kg, intravenously, and 2.0-8.0 mg per kg, intra­ (1952) confirmed the antitussive action but said that peritoneally (Plisnier, 1957). Codeine, of course, is as far as intensity and duration of action were a bronchoconstrictor. Toner & Macko (1952) demonstrated significant protection with caramiphen in guinea-pigs against the bronchospasm of furfuryl CH.SOoH trimethyl ammonium iodide. The effective dose was I 50 mg per kg, intraperitoneally. Caramiphen also relieved the intestinal contraction produced by the same agent in rabbits and was in this respect one­ CARAMIPHEN tenth to one-half as active as atropine. The tracheo-bronchial secretion in rabbits was concerned 5 mg per kg of cararpiphen was about the increased by 6.0 mg per kg of caramiphen but was same as 1 mg per kg of codeine phosphate. Matal­ not affected or decreased by codeine (Plisnier, 1957). lana & Borison (1955) reported similar effects of Caramiphen at doses of 0.5-2.0 mg per kg and caramiphen and codeine, 1.0-6.0 mg per kg intra­ codeine at doses of 2.5-5.0 mg per kg, intrave­ venously, against cough produced by electrical nously, caused a fall in blood pressure in dogs stimulation of the medulla in decerebrate cats. This narcotized with pentobarbital sodium. Caramiphen work was described in greater detail by Chakravarty was a local anaesthetic in a 2.0% solution applied to et al. (1956). The latency of the cough elicited was the rabbit's cornea. It was not analgesic up to 100 mg increased in dose-related fashion. When complete per kg, intraperitoneally, in rats and did not protect suppression of the cough was attained, it would mice against the lethal effect of pentetrazol although occur again if the strength of the stimulus was it had some anticonvulsant action at 75 mg per kg, increased. Equipotent doses of codeine were 4-10 mg intraperitoneally (Toner & Macko, 1952). According per kg. Caramiphen suppressed the cough com­ to Schoetensack & Hallmann (1964) caramiphen pletely without remarkable change in pulmonary did not suppress veratramine tremor in mice and ventilation. rats, but postural tremor in monkeys with electrolytic Plisnier (1954), using electrical stimulation of the thalamus or mid-brain lesions was reduced by small superior laryngeal nerve and intravenous injection doses, such as 0.25-1.25 mg per kg, intramuscularly in anaesthetized cats, said that the ratio of the (Vermier & Unna, 1963). - antitussive effect to that of codeine was 1.25, but if Swoboda (1950) reported the intravenous LD50 of toxicity was taken into account it was only 0.77. caramiphen in mice as 80 mg per kg, Plisnier (1957)

The effect of caramiphen was less uniform than that reported the intravenous LD50 in guinea-pigs as of codeine. Granier-Doyeux et al. (1959), with a 61.5 mg per kg, both doses being in the codeine simi,ar technique, obtained a 35.5% inhibition of range of lethality. Toner & Macko (1952) said that cough at 45 minutes with 1.0 mg per kg of codeine only 2 of 20 mice were killed by 2000 mg per kg, phosphate, and 38.7% inhibition with the same dose orally, but the drug has also been ineffective orally of caramiphen. Stefko, Denzel & Hickey (1961) as an antitussive. They found no evidence of toxicity found caramiphen very effective against cough of caramiphen when oral doses of lOO mg per kg induced by inhalation of ammonia vapour in an­ were administered daily to rats and dogs for one to aesthetized cats if it was given intravenously but three months. ineffective if it was given orally. In dogs also, oral The antitussive effect of caramiphen disulfonate doses as high as 32 mg per kg were ineffective when in normal volunteers has been tested by Blix (per­ cough was produced by electrical stimulation sonal communication, 1952) and by Bickerman through electrodes implanted in the trachea. Similar (1961, 1962). The former used 30subjects, determining oral doses had no effect on spontaneously occurring the cough threshold as the effective concentration of cough in dogs with upper respiratory tract infections. ammonia inhalation and administering both cara­ Antitussive doses of caramiphen appeared to have miphen and codeine to all, each drug first in half of no effect on pulmonary ventilation in dogs (Toner & the subjects. Comparable figures for 10 mg of Macko, 1952) or cats (Chakravarty et al., 1956), but caramiphen and 20 mg of codeine phosphate were: the drug was effective in relieving bronchoconstric­ percentage increase in threshold, 80.2% and 79.0%; tion brought about by histamine or acetylcholine in duration, 119 and 112 minutes; total effect (rise in

14 210 N. B. EDDY AND OTHERS

Antitussive ED" (mg/kg) threshold xtime), 5916 and 5773. There was con­ anaesthetized cats siderable individual variation in response, this being Method Route • Clobu- Codeine greater after caramiphen. Blix selected nine of his lino/ subjects for a repeat experiment, including the three Electrical stimulation superior laryngeal nerve IV most and the three least sensitive to ammonia. 0.51 0.52 Ammonia inhalation IV 0.60 0.61 These received 2.0 mg of caramiphen on two occa­ Mechanical stimulation sions, 5.0 mg on two occasions and 20 mg once. trachea IV 0.74 0.74 The 20 mg dose was less effective than a smaller Electrical stimulation superior amount, from which Blix concluded that there was laryngeal nerve 0 6.1 8.1 an optimal dose beyond which no further improve­ • IV=intravenous; O=oral. ment occurred. Bickerman said that caramiphen Clobutinol had no analgesic effect (tail-flick to was less effective than an equal dose of codeine. radiant heat in rats, tail-pinch in mice, electrical Clinical experience with caramiphen disulfonate is stimulation of tooth pulp in rabbits). When admin­ summarized in Table 61. Good relief of cough has istered with codeine, it diminished the analgesic been reported with doses of 10 and 20 mg, but not effect of the latter. It had local anaesthetic action uniformly so, and there are only two double-blind when applied to the cornea but did not affect the controlled trials. Few side-effects have been re­ action potentials of the vagus or phrenic nerve in ported. Swoboda (1950) and Vedrilla (1952) rabbits. Engelhorn (1960) concluded that the site of commented on a spasmolytic action, but Voiculescu its antitussive action was central. & Neuman (1959) said that caramiphen was less In the action potential experiments the interval effective in bronchitis when emphysema and asthma between bursts of impulses for inspiration was were also present. Both decreased (Abelman, shortened, whereas with codeine the interval was Gaensler & Badger, 1954) and increased (Swoboda, lengthened. A dose of 5 mg per kg, intravenously, in 1950; Vedrilla, 1952) expectoration have been rabbits increased the respiratory rate and larger reported. Caramiphen does not appear to possess doses antagonized to some extent the respiratory­ distinct advantage over codeine (Brit. med. J., 1964). depressant effect of 5-20 mg per kg of morphine. There has been no report of tolerance or de­ A dose of 10 mg per kg of clobutinol increased pendence. bronchial secretion in rabbits by 20-45% for two to six hours. It prolonged the barbiturate sleeping time 1 Clobutino/ and suppressed nicotine-convulsion-induced changes Clobutinol, p-chloro-a-[2-(dimethylamino )-1-me­ in the electroencephalogram. It did not affect blood thylethyl]-a-methylphenethyl alcohol was selected pressure or intestinal motility. Its acute toxicity was from a large number of aryl butanols and pentanols very like that of codeine. The LD50s (mg per kg) for its antitussive potency and studied extensively by in rats were :

Route Clobutino/ Codeine CHa CHa Intraperitoneal 130 175 Subcutaneous 370 315 Cl-0- CH2-T -- tH-CH2-N(CHa)2 Oral 600 535 OH When rats were given 200 mg per kg of clobutinol CWBUTINOL orally every day for four to six months no deaths occurred and no histological changes were detected. Engelhorn (1960). He measured its antitussive Renovanz & Liebrich (1965) studied the effect of effect by a number of experimental methods and clobutinol against cough induced by 15% citric acid found it to be essentially the same as that of codeine aerosol in 18 selected human volunteers. They in lightly anaesthetized cats. The results are shown excluded subjects who did not cough with this con­ below. In unanaesthetized guinea-pigs the ED50 for centration of aerosol, those who did cough after a suppression of the cough response to sulfur dioxide saline aerosol, and those who showed a positive was 8.35 mg per kg, subcutaneously, also very close effect with a placebo. Oral doses of 60 mg of clobu­ to that for codeiP'\ 7.9 mg per kg. tinol and 40 mg of codeine were compared and the mean counts of coughs within one minute of the • Also known as Silomat. aerosol application, and one, two and three hours TABLE 61 CLINICAL EXPERIENCE WITH CARAMIPHEN DISULFONATE

Patient Dosage Result Side-effects Reference No. I Type

- Non-specific, irritative 1 or2x10 mg Stopped cough in 60-70% Slight vertigo in some. Well tole- Liechti (1950) cough rated to 100 mg/day 12 Whooping cough 1 or 2x 10 mg Marked, 1; good, 99; poor or none, 10 Liechti (1950) --- g 45 Cough of various origin 10 mg a.m. and noon, 20 mg Very good, 44.4%; good, 20.0%; none, Swoboda (1950) tT1 at night 35.6%. Usually as good, sometimes z better than opiates tT1 -- 3 or 4x20 mg Satisfactory None after prolonged administra- Birkner (1952) tion ~ --- Bronchoscopy 60-80 mg, 30-45 mi n before Undesirable if much secretion be- Hudson (1952) a cause patients have no inclination to cough -- ~ 10 mg every 6 h Effective. Unproductive cough im- Well tolerated Segal & Dulfano (1952), proved in many patients (1953) -- 112 Cough of various origin, 30-100 mg/day Effective in measles and whooping Well tolerated prolonged ~ with Sporn (1952) children cough; very effective in 82 cases tra- administration "' cheobronchitis -- ~ 100 Cough of various origin 10 mg every 4-6 h to 5 doses Excellent, 76; fair, 12 Mild nausea in 6, perhaps because Snyder (1953) per day of taste ~ -- I z 20 Chronic irritating cough 3x 10 mg compared with Complete relief, 2; good, 5; slight, 6. None in 18, nausea in 3, dizziness Abelmann, Gaensler & 3x16.2 mg codeine Less effective than codeine. Cross- in 2 Badger (1954) over ~ -- 63 Persistent cough 4x10 mg compared with Less effective than codeine. Cross- Cass & Frederik (1956) 4x15 mg codeine over -- ~ 139 Cough, influenza 3-5x 10 mg Excellent, 69.4%; some, 14.0%. Better Voiculescu & Neuman than codeine 4x7.5 mg/day. Not (1959) cross-over --- ; 73 Most had acute respir'll- 2-3x 20 or 30 mg Excellent None Dreyer (1961) tory infection .j::o. -- 12 Severe cough with acute 20 mg Equal to codeine. Not cross-over Fewer side-effects Glick (1963) respiratory infection -- 76 Cough of various origin 50-120 mg per day Good, 39%; moderate, 5%, of 46 Dizziness in 1 Ved rill a (1952) patients with acute cough

-~--- 3x20 mg Effect less consistent and reliable Banyai (1960) than with opiates

------~ 212 N. B. EDDY AND OTHERS after drug administration showed about equal anti­ Riebel (1960) reported 91 cases with cough of tussive effects. Individual variations among patients, various origin and severity. The dose of clobutinol however, precluded statistical analysis and raise was 30 or 40 mg, it was effective in 15-30 minutes and some question of the methodology in this experiment. the effect lasted five or six hours. There were no The same authors did get statistically validated side-effects and no evidence of tolerance. Fifty results in 231 patients with cough of various origin. patients given single doses of 60 mg showed no This trial was carried out by 12 physicians in dif­ significant change in respiratory rate or minute ferent clinical settings. Administration of clobutinol, volume or respiratory exchange. codeine and placebo was double-blind in random Paul (1962) gave 20 mg of clobutinol two to four order on successive days and the effect was de­ times a day to 55 patients with spastic bronchitis, termined by means of a questionnaire. There was no tuberculosis or tracheobronchitis. The result was significant difference or preference between the two very good in 24 and good in the others, without side­ drugs, both were significantly better than placebo. effects. Moia et al. (1962) said that clobutinol orally The occurrence of side-effects was about the same was effective in 60% of patients with chronic pul­ for all three medications. monary disease and Monti (1963) obtained satisfac­ <::;ass & Frederik (1964) also carried out a double­ tory relief of postoperative cough in 54% of 110 blind trial in 37 patients with chronic cough. Each patients and good relief in another 21 %. medication was given orally four times a day for six Kleibel (1964) compared clobutinol with opiate days with the order of administration randomized. antitussives, recording the cough by means of a Degree of cough relief was given a numerical value microphone. He concluded that it was inferior to the and an average relief score for the week was cal­ opiates. culated as shown below: Cela & Soccio (1963) found clobutinol as effective Average relief score as codeine; it was well. tolerated, without respiratory depression, constipation or allergic reaction. They Codeine sulfate 15 mg 1.497 used 50-60 mg in the treatment of cough of various Clobutinol 80mg 1.269 origin. Diphenylhydramine 50mg 1.062 Cuocolo, Messina & Carbone (1962) said that Clobutinol 40mg 1.053 clobutinol was a valuable contribution to the con­ Placebo 0.683 trol of cough in surgical patients. The differences wi!re statistically significant and it was Gerland (1960), Lachmer & Werner (1963) and also shown that there was an upward trend in effec­ Czermak (1963) reported on the use of clobutinol in tiveness through the day and through the week, the children. Gerland treated 145, from infants to trend being greatest with codeine: in other words the 14-year-olds, about half of whom were ambulatory. patients coughed less during the latter part of the The dose was 10-15 mg for the youngest, 40 mg for day and of the week. It is possible that this was a the oldest. The results were very good in 112; the trend in the natural history of the cough and not a drug was least effective in pertussis. Lachmer & cumulative effect of treatment. Side-effects through­ Werner treated 74 children and 82 adults, using out were too few for analysis. three or four times 40 mg, orally, or two parenteral Clinical usage falls into two categories, patholo­ doses per day. The effect was prompt and lasted gical cough of various origin including cough in three to five hours. Czermak used clobutinol in children, and prophylactic use in premedication and 82 children with pertussis, intravenously or intra­ in connexion with endoscopies. Nagorny (1960) muscularly, and found that the latter was always used an oral dose of 40 mg (120 mg per day) in effective. Compared with 87 cases not treated with 80 patients with severe cough and obtained very clobutinol, the frequency and intensity of cough good relief in 70. The 10 poor results were in paroxysms diminished two or three weeks earlier. patients tolerant to opiates. Over a four-month There are ten reports of the use of clobutinol, one period there was no weakening of the effect, no side­ might say prophylactically, in bronchoscopies, etc. effects and no respiratory depression. Nagorny The number of cases, the procedure followed, the also used 30 mg, parenterally, with good results dose and route of administration and the results are equal to those with hydrocodone. The effect ap­ summarized in Table 62. The results were generally peared in 10-15 minutes and lasted three or four good. It is perhaps noteworthy that in the one hours. outstanding failure (the results of MacHale & TABLE €2 USE OF CLOBUTINOL TO PREVENT COUGHING IN BRONCHOSCOPIES AND OTHER SURGICAL PROCEDURES

No. Procedure Dose (mg) Route a Result Comment Referance

90 Bronchoscopies and 30 IV in 77 I Better than with hydrocodone No side-effects Nagorny (1960) bronchographies IM in 13 ~~ ~ 32 Bronchoscopies 20 IV in 20 Very good in all Hypotension in 4 b Paul (1962) ~ IM in 12 ~~ --~ ·-··-- ~ Bronchoscopies Cough suppressed completely, Codeine preparations suppressed Villar (1962) 50%; partially, 21.5 cough completely 12%, partially 33% a --- 216 Bronchoscopies Clobutinol or No advantage over no drug Same number with troublesome Mac Hale & Springett (1962) no drug cough in each group ~ --- 86 Ophthalmic operations 120 66 0 or Excellent Pulse and respiratory rate and blood Vicente Preto & Serrano ~ 20 IM pressure increased slightly (1962) --- ~ '"d 107 Endoscopies 1-4x20 Very good, 80% No nee Moia et al (1962) > --- z 193 Pre- and postoperative 20 every 8h IM Satisfying in all No side-effects Luciano et al. (1963) > --- ~ 178 Mostly bronchoscopies IM Good in 162 Kronberger (1963)

~~- 53 Bronchoscopy or 1-2x20 with IV Reduced failures due to cough Fourage (1963) i laryngoscopy I local I anaesthetic I ~ 120 Pre-anaesthetic Laryngeal spasm in 3, coughing I When atropine was used in 84 cases Henriquet & Rochira (1963) .;. (barbiturate) in 2 spasm In 7, cough in 4

a IV = intravenous; IM = lntrarruscular; 0 = oral. b Given in combination with phenothiazine which may have caused the hypotension. c No respiratory depression indicated in spirometric measurements in 40 cases. Hepatic function tests, urinalysis, blood examination and electrocardiogram In 15-25 cases showed no changes.

N -w 214 N. B. EDDY AND OTHERS

Springett, 1962), the medication procedure was species and they do show significant suppression of double-blind. experimentally produced cough. In addition a delay in onset and a longer duration of action than with 1 Clofedano/ codeine have been reported. Stefko, Denzel & Clofedanol, 2-chloro-a-(2-dimethylaminoethyl) Hickey (1961) found that, in dogs in which cough was benzhydrol, is one of many diphenylpropane com­ produced by electrical stimulation of the trachea, pounds which have been tested for antitussive oral codeine developed its peak effect in 30-60 activity (Lindner & Stein, 1959). Its structure was minutes and that an equally effective antitussive dose of clofedanol was only beginning to show an effect at /Cl that time, and reached its peak 120-150 minutes after administration. A similar result was seen in 0 ~ cats. A dose of 0.5 mg per kg of codeine depressed HO-C-CH,-CH,-N(CH,), a cough of moderate strength for 31 minutes; the J / comparable effect of clofedanol, 8.0 mg per kg, 0 lasted for 90 minutes. The persistence of the effect CLOFEDANOL of clofedanol was also observed by Chen, Biller & given by Lorenz et al. (1960) and has the basic group Montgomery (1960). Goswald (1958) gave 20 mg in position-3, in contrast to the compounds tested by per kg of clofedanol, subcutaneously to guinea-pigs Linder & Stein where it was in position-2. daily for eight days and saw no tolerance in this short The experimental results in the testing of clofe­ period to its antitussive action. danol for antitussive action in comparison with Chen, Biller & Montgomery (1960) could detect codeine are summarized in Table 63. The ratios to no analgesic effect of clofedanol in mice or rats with codeine are not consistent for different methods in doses of 5-20 mg per kg, intraperitoneally. They the same species, although they were somewhat used both the hot-plate and the tail-pinch methods. more consistent for similar methods in different It did show, however, some local anaesthetic action, both on dermal infiltration in guinea-pigs and on ' Also known as Detigon and Ulo. corneal instillation in rabbits. A 0.2 ~la solution pro-

TABLE 63 EQUIPOTENT ANTITUSSIVE DOSES (BASED ON PEAK EFFECT) OF CLOFEDANOL AND CODEINE

Method Route a 11 Clofedanol[ Codeine I co~~ii~e/ I Reference I (mg;kg) clofedanol

Species: GUINEA-PIG Citric acid aerosol se 20.0 20.0 1.0 Gosswald (1958) Ammonia inhalation se 0.75 0.8 1.1 Kraushaar, Schunk & Thym (1964) Sulfuric acid aerosol se 25.0 20.0 0.8 Boissier & Pagny (1960) I

Species: CAT Electrical stimulation superior laryngeal nerve IV 2-8 0.5-2 c. 0.25 Boissier & Pagny (1960) Ammonia inhalation 0 8.0 0.5 0.06 Stefko, Denzel & Hickey (1961)

Species: DOG Sulfuric acid aerosol 0 0.4 0.5 1.25 Chen, Biller & Montgomery (1960) Electrical stimulation trachea 0 8.0 2.0 0.25 Stefko, Denzel & Hickey (1961) Electrical stimulation vagus se 2.0 2.0 1.0 Gosswald (1958)

a SC = subcutaneous; IV= intravenous; 0 = oral. CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 215 duced about the same duration of local anaesthesia and acted normally. Again no pathological changes as a 2.0% solution of procaine, but a 1.0% solution attributable to the treatment were observed. Tested was locally irritating. for antitussive activity near the conclusion of the Data on the acute toxicity of clofedanol are sum­ study no evidence of tolerance development was marized in Table 64. Codeine data given by the detected and no withdrawal phenomena were seen in same authors are included. The two compounds are the rats or dogs when daily administration was sus­ not greatly different in this respect. Central stimula­ pended for 48 hours at 20 and 23 weeks, respectively. tion occurred with clofedanol and convulsions occur­ In this connexion Deneau (personal communica­ red with near fatal doses. Chronic toxicity studies tion) found that clofedanol given in doses of 5-30 mg have been carried out for six-month periods in rats per kg, subcutaneously, to monkeys stabilized on and dogs (Chen, Biller & Montgomery, 1960). Rats morphine had no suppressant effect on morphine received the drug in their diet in amounts of about abstinence phenomena and, therefore, appeared to 2.0 and 20 mg per kg per day. Their food consump­ have no physical dependence capacity of morphine tion remained about normal, as did activity and type. The largest dose caused convulsions. behaviour. There were no pathological blood or Noel (1962) reported 55% inhibition of cough tissue changes. Dogs received the drug in capsule, induced by citric acid aerosol in normal human sub­ also 2.0 and 20.0 mg per kg for six days a week. jects by 25 mg of clofedanol and 18% inhibition by After the first few days the animals ate, gained weight 11 mg of codeine. Clinical observations on clofeda-

TABLE 64 ACUTE TOXICITY OF CLOFEDANOL

Clofedanol Animal Route a Codeine I Reference Dose tolerated LDso (mg/kg) LDso (mg/kg) I I (mg/kg)

Mouse IV 70 78 Gosswald (1958) Mouse IV 68 Boissier & Pagny (1960) Mouse se 150 115 Gosswald (1958) Mouse se 186 Chen, Biller & Montgomery (1960) Mouse se 240 Boissier & Pagny (1960) Mouse 0 175 237 Chen, Biller & Montgomery (1960) Mouse 0 495 Boissier & Pagny (1960) - Rat IM 200 Taccani (1959) Rat 0 175 266 Chen, Biller & Montgomery (1960) Rat 0 350 250 Gosswald (1958) Rat 0 420 Taccani (1959)

Guinea-pig se 200 100 Gosswald (1958)

Rabbit se 50 b Gosswald (1958)

Cat 0 80 b 50 (lethal) Gosswald (1958)

Dog se 30 Gosswald (1958) Dog 0 20 Chen, Biller & Montgomery (1960) Dog 0 5 Gosswald (1958)

a IV = intravenous; SC = subcutaneous; 0 = oral; IM = intramuscular. b Lethal dose. 216 N. B. EDDY AND OTHERS

TABLE 65 CLINICAL OBSERVATIONS ON THE ANTITUSSIVE ACTION OF CLOFEDANOL

Patients I Dosage (mg) Result(%) I I Side-effects and comments Reference No. Type Single Daily Good !Moderate IPoor or I I I none I

134 Children 65 22 13 In 3 patients a Richter et al. (1962) 72 Children 12.5-25 71 15 14 None Nathan (1962) 32 Severe cough 20-50 60-120 73 - 27 - PrOssing (1960) 78 Moderate cough 20-50 60-120 86 - 14 _b PrOssing (1960) 43 Tuberculous 30-55 90-175 67 16.5 16.5 In 2 patients c Oswald (1961) I 84 Acute infection 20-30 I 60-120 86.5 12 1.5 None cl I Voiculescu & Neuman (1959) I 40 Various I 90 7.5 2.5 None Ghisleri (1960) 239 Various 50 30 20 -· Noel (1962) 30 Adults 30-60 60-180 80 - 13.3 In 5 patients f Saunders (1961)

50 100-150 Satisfactory None Taccani (1959)

174 Various g 25-35 75-140 Satisfactory None Schriier (1960) 12 Children c.5 c. 15 Satisfactory None Saunders (1961) 108 Various 20-25 60-150 Satisfactory None Linden, V. zur (1958) c.160 Children " Remarkable " In a few patients" Kubowski (1960) c. 318 Adult " Remarkable " -

a Drowsiness in 2, urticaria in 1. Onset a little slow. b In 14 of 17 patients codeine less effective. In 18 months saw no evidence of tolerance. c Tremor in 1, palpitation in 1. cl Result better than with 30-40 mg of codeine per day. e 20 mg equivalent to 22 mg of codeine. f Trembling and apprehension In 3, vomiting 1, urticaria 1. g Including 89 tonsilectomies; in these, effect believed to be in part local anaesthetic. h In children a few cases of poor appetite; nausea and vomiting in 3. nol are summarized in Table 65. It is remarkable far as we are aware. Also the clinical studies reported that in the clinical reports onset was usually said to are in the main impressions and not double-blind be prompt; slowness was noted only once. Dura­ comparisons, and on this account, though clofedanol tion was usually 2-14 hours. In addition Simon would seem to be an antitussive, the advantages of (1962) treated 100 patients with four different anti­ the compound must be considered unproven. tussives in successive weeks, benzonatate, dibunate, dextromethorphan and clofedanol; the last material 1, 1-Diphenyl-2-piperidinopropan-1-ol. This was was given at the rate of 25 mg four times a day and another of the series of diphenyl compounds tested had the greatest effect in reducing cough frequency. for antitussive action and was selected for marketing Smith (1963) estimated the effect of clofedanol, at 0.2 mg per kg orally, as promising for its veterinary use in dogs and Bickerman (1961, 1962), Morais & Da Silva (1961) and Szasz (1961) reviewed clofe­ danol. along with other antitussives, expressing their own personal opinions, which were generally favourable. Finally, when an effect on respiration has been mentioned, a depressant effect has been denied but no controlled quantitative study has been made so 1, 1-DIPHENYL-2-PIPERIDINOPROPAN-1-ol CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 217 as a component of a cough preparation.1 Data with guinea-pigs received 10 mg per kg, orally, five days respect to it are very meagre and include only one a week for six weeks. The rats gained weight and clinical report. showed no pathological changes. The guinea-pigs Lindner & Stein (1959) found that the compound also gained weight but two of five animals showed reduced the cough produced in anaesthetized cats by fatty infiltration of the liver and one animal had a electrical stimulation of the superior laryngeal parenchymatous degeneration of the liver. Dogs nerve. A dose of 2 mg per kg, intravenously, re­ were given 5 mg per kg, subcutaneously, five times a duced the cough about 50%, an effect comparable to week for four weeks. One of two animals showed that of I .0 mg per kg of codeine. An oral dose of fatty infiltration of the liver and of some renal 8 mg per kg was also effective. Both the racemate tubules. and its optical isomers had a similar potency in Bickerman & Itkin (1960) tried two doses of the respect to antitussive action. Boissier & Pagny diphenylpiperidinopropanol, 30 and 60 mg, orally in (1960) examined the antitussive action in guinea-pigs normal subjects and determined the effect on citric exposed to sulfuric acid aerosol and in cats in which acid aerosol induced cough. A significant suppres­ the superior laryngeal nerve was stimulated. Com­ sant effect was observed for one hour only with the parable doses of codeine, clofedanol and the piperi­ smaller dose but for the four hour period of observa­ dine compound were 20, 25 and 22 mg per kg, tion with the larger. Pozetto & Traminer (1963) subcutaneously, for 50-100% suppression of cough treated 63 patients with cough of various origin with in the guinea-pig and 0.5-2.0, 2.0-8.0 and 1.5-6.0 mg 2.3-4.3 mg per kg per day of diphenylpiperidino­ per kg, intravenously, for 40-60% suppression in propanol orally. The number of coughing bouts cats. There was no respiratory depression with these decreased 74.2 %. Expectoration was not modified. antitussive doses. No cardiovascular, renal or digestive effects were Diphenylpiperidinopropanol had no analgesic noted. One may conclude that 1, 1-diphenyl-2- effect in mice up to 200 mg per kg, subcutaneously. piperidinopropan-1-ol is similar to clofedanol in its Intravenous injection of 2-3 mg per kg in unanaes­ action. thetized cats and 5 mg per kg in rabbits had no /soaminile 2 substantial influence on respiratory rate or minute volume, but 3-4 mg per kg, intravenously, in an­ Isoaminile, 4-dimethylamino-2-isopropyl-2-phenyl­ aesthetized cats lowered the blood pressure moderat­ valeronitrile, is a basic tri-substituted acetonitrile, ely and transiently. Intravenous injection of 2 mg one of a group of nitriles synthesized for analgesic per kg in anaesthetized dogs reduced the pulse rate effect (Stiihmer & Funke, 1957). However, Krause and raised the blood pressure temporarily. The (1958) showed in animal experiments that it had compound had little spasmolytic effect on the isol­ little or no analgesic effect, but had as good an anti­ ated intestine. Tone and peristalsis in the intestine tussive action as codeine. in situ in dogs and cats were increased by 2 mg per kg, intravenously. There was no indication of sedative action but the local anaesthetic effect was remarkable. A 0.25% solution equalled in this respect a 1.0% solution of procaine applied to the frog ischiadic nerve (Lindner & Stein, 1959).

The acute toxicity (LD50) for the diphenylpiperi­ CH. dinopropanol was reported by Lindner & Stein ISOAMINILE (1959) as 40, 300 and 750 mg per kg, intravenously, subcutaneously and orally, respectively, in mice and From observations on the whole group it was by Boissier & Pagny (1960) as 51, 352 and 784 mg inferred that, in basic tri-substituted acetonitriles per kg for the same routes of administration and with two asymmetric carbon-atoms, the compounds species. Dogs given 15 mg per kg intravenously in which these are adjacent are effective analgesics survived but had severe convulsions. Studies on without antitussive action, while those in which the subacute toxicity \\-ere carried out also by Lindner & asymmetric centres are separated by another carbon Stein (1959) in rats, guinea-pigs and dogs. Rats and are antitussives with little or no analgesic action.

• Component of diphepanol. • Also known as Peracon, Dimyril. 218 N. B. EDDY AND OTHERS

Krause (1958) and Graham (1962) determined the codeine in the rabbit but less effect in dogs and cats. antitussive effectiveness of isoaminile in animals, It appeared to have some bronchodilatory effect. It compared it with codeine and observed other produced bradycardia, and a vasodilatory effect in pharmacological effects. Krause used narcotized dogs and inhibition of intestinal and uterine activity guinea-pigs and stimulated the trachea electrically. in rabbits. Isoaminile was more toxic than codeine;

Given intravenously the antitussive doses were its LD50s, intravenously, were 55, 20 and 20 mg per 5.4 mg per kg for isoaminile and 7.0 mg per kg for kg for mouse, rabbit and dog, respectively, compared codeine, making the former 1.3 times more potent. with 90 and 60 mg per kg for mouse and rabbit for

Graham used guinea-pigs (ammonia inhalation), codeine. Krause said that the LD50s of isoaminile in rabbits (mechanical stimulation) and dogs (electrical mice were 65 mg per kg intravenously, 240 mg per kg stimulation of the trachea). The antitussive doses for subcutaneously and 720 mg per kg orally. Subacute isoaminile and codeine varied for the species and toxicity studies in mice, rats and dogs revealed no were 0.5 and 0.3 mg per kg, subcutaneously, in the pathological changes, except a moderate increase in guinea-pig, 7.0 and 13.5 mg per kg, intravenously, in lymphocytes and reticulocytes in rats. the rabbit and about 5.0 mg per kg for the dog, Christoffel & Kolberg (1958) tested the antitussive showing definite superiority for isoaminile only in effect of isoaminile in ten normal adults. Inhalation the rabbit. Both authors found the analgesic effect of of citric acid aerosol (7.5 %) produced on the average isoaminile far inferior to that of codeine in both mice 8.3 coughs initially, and only 3.1 coughs 20 minutes and guinea-pigs. According to Krause, isoaminile after 40 mg of the drug orally, according to the diminished the rate and volume of respiration in authors a significant difference. Clinical observations anaesthetized dogs, cats and guinea-pigs at 5.0 mg for antitussive effectiveness are summarized in per kg, intravenously. Graham found a greater Table 66. Generally, however, these have not been decrease in minute volume with isoaminile than with well-controlled or double-blind except for Graham's

TABLE 66 CLINICAL OBSERVATIONS ON THE ANTITUSSIVE EFFECT OF ISOAMINILE

--,-----P_a_ti_e_nt_s____ l Dose (mg) I Result I Side- I effects Reference No. [ Type Single [ Daily Good [ Moderate[ None

136 Various 122 9 5 None a Peterse n (1960) 126 Various 40 160 95 28 3 Rimoldi (1960) 172 Various 20-40 60-240 90 5 5 None b Brenner-Godderz (1959) Irritative cough c 21.3-43 Very good Muysers & Siehoff (1960)

62 Various 20-40 60-120 Equal to codeine d Eidmann (1959) 38 Tubercular 30-60 150-250 Good e None Schmiedel (1959) 58 Severe cough 30-80 90-320 Good! None Christoffel & Kolberg (1958) 40 120 Good None Schumacher (1959) 92 Various 40 120-150 Good None Feser (1960) 55 Acute and chronic Good None Virchow (1961) 25 Chronic bronchitis 21.5 64.5 Ineffective Graham (1962) 30 Chronic bronchitis 40 120 Ineffective Graham (1962) I

a In cases of chronic bronchitis no tolerance developed. b Judged superior to codeine principally because of absence of side-effects. c Used in irritative cough in patients undergoing pulmonary function tests. d Generally comparable to codeine, but result was poor in patients who had been receiving considerable narcotics. e Generally good, except that in severe tuberculosis less effective than 30 mg of codeine. f Effects lasted for 4-5 h. g Patients could not distinguish isoaminile or codeine from placebo. CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELJEF. 4 219

(1962), though they do indicate that the authors David, Leith-Ross & Vallance (1957) found its considered the drug effective. Morais & Da Silva antitussive activity in animal experiments (guinea­ (1961) reviewing many antitussives and Schumacher pig and dog) similar to that of pentoxyverine, con- (1959), though he gives few details, agree. In the one double-blind study by Graham, comparing iso­ 0"-._ /COOCHzCH.OCH.CH.N(C.Hsh aminile with placebo in one small group and with c codeine in another, no antitussive effect was demon­ /"--.. strated, but the patients in the second group also CHo CHz failed to recognize any greater effect with codeine I I than with placebo. The dose of codeine was 13.5 mg, CH. CH. orally, three times a day. The reports listed in OXELADIN Table 66 indicate that few if any side-effects have been encountered with isoaminile but that there was eluding, therefore, that the pentane ring was not no indication of advantage over codeine; in some essential. According to Kohli, Gupta & Blargava ED for complete suppression of cough cases it was judged inferior. Recently abuse has been (1960) the 60 observed (Ladewig, 1969). due to electrical stimulation of the superior laryngeal nerve in anaesthetized cats was 1.22 mg per kg for Methaqualone 1 oxeladin and 1.5 mg per kg for codeine, both intra­ venously. The duration of effect of the two drugs was Methaqualone, 2-methyl-3-o-tolyl-4(3H)-quinazo­ similar. By another method (mechanical irritation) linone, is a non-analgesic, barbiturate-like hypnotic Ozawa et al. (1962) found oxeladin a little weaker with some antihistaminic and local anaesthetic prop­ than codeine, administered intraperitoneally in erties. Boissier & Pagny (1959) reported that it had an guinea-pigs. lf the tannate was used and the drug given orally, it was as effective as codeine. These authors said that oxeladin had strong anti-spasmodic

action. Its LD50 in mice was 244 mg per kg, subcu­ taneously, and not less than 1500 mg per kg, orally. David, Leith-Ross & Valiance (1957) found local anaesthetic action but did not think this contributed to the antitussive effect. They also found oxeladin METHAQUALONE two to four times as toxic as codeine according to the species and the route of administration. ·No toxic effects followed chronic administration in rats. antitussive effect in animal experiments, suppressing Konar & Halder (1964) induced cough in patients in guinea-pigs the cough due to inhalation of sulfur by intravenous administtation of 0.1 ml of paral­ dioxide. At a dose of 4.0 mg per kg, intramuscularly, dehyde both initially and after oxeladin 30 mg it suppressed the cough due to electrical stimulation orally four times a day. Without the antitussive, of the superior laryngeal nerve in anaesthetized cats. paraldehyde produced an average of 8.9 bouts of In both species it was less effective than codeine. No coughing in 91% of the patients; after oxeladin it clinical use of methaqualone as an antitussive has produced an average of 7.3 bouts in 71 %; not a very come to our attention, but cases of abuse and de­ impressive effect. Further careful clinical evaluation pendence on the substance have been reported is not yet available. (Madden, 1966; Ewart & Priest, 1967). Oxolamine 3 Oxeladin 2 Oxolamine, 5-[2-( diethylamino )ethyl]-3-phenyl-I, Oxeladin, 2-(2-diethylaminoethoxy)ethyl2-ethyl-2- 2, 4-oxadiazole, is one of a series of aryl-alkylamino­ phenylbutyrate, was synthesized by Petrow, Ste­ alkyl-1,2,4-oxadiazoles studied by Silvestrini & phenson & Wild (1958), and is closely related to Pozzatti (1960) in their search for a peripherally pentoxyverine; one has only to imagine the breaking acting antitussive. It seemed to possess local of the pentane ring. anaesthetic and antispasmodic properties which previous work (Silvestrini & Maffii, 1959) indicated • Also known as Melsedin. • Also known as Pectamol. • Also known as Perebron. 220 N. B. EDDY AND OTHERS

were desirable. This group of workers depended cological properties of oxolamine in animals. Both principally upon acrolein as the irritating agent to evoked cough in guinea-pigs with irritant-vapour provoke cough and their results are not entirely con­ inhalation and in cats by electrical stimulation of the sistent with those of others. superior laryngeal nerve and both made compari­ sons with codeine. Their results are summarized N-0 in Table 67. These results, though limited in extent, indicate an 0--C~ I - 'N=C-CH.CH.N(C•H•)• antitussive action in the codeine range which Silves­ OXOLAMINE trini & Pozzatti thought depended on anti-inflam­ matory and spasmolytic effects in the lung and to a Silvestrini & Pozzatti (1961) and Balea & Buret lesser extent on central depression of the cough (1964) reported on the antitussive and other pharma- reflex.

TABLE 67 ANTITUSSIVE EFFECTIVENESS OF OXOLAMINE COMPARED WITH THAT OF CODEINE

Cough stimulus Dose Compound (mg/kg) I Route a %inhibition of cough I I I Species: GUINEA-PIG Acrolein Oxolamine HCIII 0.5 lP 16 Acrolein Oxolamine HCI b 1.0 lP 29 Acrolein Oxolamine HCIII 2.0 lP 39 Acrolein Codeine HCIII 1.0 lP 15 Acrolein Codeine Clll 2.0 lP 33 Ammonia Saline b lP 19.6 Ammonia Oxolamine HCIII 0.5 lP 49.5

Ammonia Codeine phosphate 11 1.0 lP 44.5 Ammonia Oxolamlne phosphate c 3.0 lP 26.9 Ammonia Oxolamine phosphate c 5.0 0 31.6 Ammonia Oxolamine citrate r 3.0 lP 24.3 Ammonia Oxolamine citrate c 5.0 0 29.2 Ammonia Codeine phosphate c 3.0 lP 13.9 Ammonia Codeine phosphate c 5.0 0 29.5

Species: CAT Electrical stimulation laryngeal Oxolamine HCI b 2.0 IV 50 In 1 animal of 4 for 20 min nerve Electrical stimulation laryngeal Oxolamine HCIII 5.0 IV 70-80 In 2 animals of 4 for 40 min nerve Electrical stimulation laryngeal Oxolamine HCI b 10.0 IV 100 in 7 animals of 8 for >60 min nerve Electrical stimulation laryngeal Oxolamine phosphate c 4.2 IV nerve Electrical stimulation laryngeal Oxolamine citrate c 5.5 IV nerve Electrical stimulation laryngeal Codeine phosphate c 1.0 IV l""'"' "'"''" nerve

alP = Intraperitoneal; 0 = oral; IV =intravenous. b Experiments reported by Silvestrinl & Pozzat11 (1961). c Experiments reported by Balea & Buret (1964). CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 221

In mice an effect on spontaneous activity was kidney, lung, brain, and heart, but none was found noticed first at a dose of 75 mg per kg of oxolamine, in the blood. In cats and rabbits none could be intraperitoneally. At 100 mg per kg activity was found five minutes after intravenous administration decreased to a greater extent but with ataxia, and of 20 mg per kg and in man only very small amounts, lethal doses caused convulsions. In cats 50 mg per kg 3-8 mg, were found in the urine when 1 g of oxola­ had no apparent effect on the central or autonomic mine was taken, orally, in 24 hours. nervous systems; in rabbits 20 mg per kg, intra­ Clinical experience with oxolamine as an antitus­ venously, had no effect on the alarm reaction but sive is summarized in Table 68. While this table depressed the righting-reflex briefly; and even indicates the effectiveness in children and adults, the 100 mg per kg, subcutaneously, had little effect on statements are for the most part based on uncontrol­ pole-climbing in rats (Silvestrini & Pozzatti, 1961). led or poorly controlled subjective responses. Other Oxolamine was similar to aspirin in its effect in the effects are mentioned-anti-inflammatory, in acute Randall & Selitto anti-inflammatory test but it was inflammation of the tracheo-bronchial tree, anti­ ineffective by the hot-plate and writhing analgesic pyretic, in acute influenza, and spasmolytic, in techniques. Its anti-inflammatory effect was con­ asthmatic bronchitis; whether or not these are of firmed recently by Dahlgren & Dalhamn (1966) who therapeutic significance needs to be determined. reported that 80 mg per kg had a somewhat greater The dosage of oxolamine has ranged from effect than 30 mg per kg of phenylbutazone. They 10-20 mg per kg per day in children and from used guinea-pigs and acrolein as the irritant. Oxo­ 400-1000 mg per day in adults, and these levels have lamine was a local anaesthetic for the cornea of the been generally well tolerated, though vomiting, rabbit at a concentration of 1.0-1.5% and was about epigastric distress and anorexia have been reported as effective as papaverine against various spasm­ occasionally. The possibility of respiratory depres­ ogenic agents when the test object was the isolated sion seems to have been disregarded and tolerance intestine or the tracheal chain preparation. At 5 mg has not been reported, even in cases of silicosis per kg, intravenously, oxolamine produced a tran­ treated for six months. sient fall in blood pressure. No evidence of toierance Repaci (1960) compared oxolamine with codeine was ascertained by Silvestrini & Pozzatti (1961) or and placebo in elderly patients with acute and Balea & Buret (1964). chronic cough, probably double-blind cross-over in Silvestrini & Pozzatti (1961) detern1ined the acute random order. The results (numbers of patients) toxicity of oxolamine by various routes in mice and were: rats: Cough relief Do•e/day Good Moderate None LD,. (mg per kg) mice 4x 100 mg Oxolamine hydrochloride 63 206 465 929 Oxolamine 20 12 8 4x 30mg Oxolamine citrate 351 Codeine 19 12 8 Codeine hydrochloride 67 125 286 365 Placebo 3 8 28 LD,. (mg ppr kg) rats Gregorio (1960) also compared oxolamine with Oxolamine hydrochloride 185 1 650 codeine, giving the former in syrup, 100 mg three times a day and the latter, 30 mg three times a day, in Neither the hydrochloride (100 mg per kg, intra­ cases of acute respiratory infection and chronic peritoneally, daily for 45 days) nor the citrate cough. In addition he gave both drugs for the pain (500 mg per kg, orally, daily for six months) affected of rheumatism and of dental procedures. His the blood picture or body weight or caused detect­ results in percentage of patients improved were: able tissue changes in rats, started on the test at one month. Nor did oxolamine have any effect on re­ Cough r./ief ( % improved) No. of Acute No. of Chronic production or on the offspring in mice, rats, and patients cough patients cough rabbits (Balea & Buret, 1964). Oxolamine 51 82.3 126 64.2 According to Palazzo & Corsi (1962), oxolamine Codeine 21 71.3 91 71.4 disappeared very rapidly after oral or parenteral Placebo 34 28.5 114 37.7 administration, causing them to surmise that it Pain relief ( % improved) No. of Rheu- No. of Dental acted through a metabolite which was not identified. patients mat ism patients In rats only 2% was found in the urine and about Oxolamine 36 66.6 12 75.0 another 2% in the faeces after oral administration in Codeine 36 66.6 14 71.4 rats. Very small amounts were found in the liver, Placebo 36 22.2 13 15.3 ~ N

TABLE 68 CLINICAL RESULTS WITH OXOLAMINE AS AN ANTITUSSIVE

Patients Dosage (mg) Result Side-effects Reference No. I Type ~~- ~~~---

20 Acute cough 4-5x 100-200/day Excellent in most cases Well tolerated Corbella (1960a)

11 4-5x 100-200/day Generally good Deidda (1960)

19 Elderly, chronic cough 4x 100/day Good, 8; fair, 5; doubtful, 5 Maccaferrl & Troccoli (1960)

43 Children Large doses required Duration 3-6 h a Testaferratl & Francalancia ;z: (1960) !:1

37 Cough of various origin Good in most cases Araki, Kitamura & Kagami tl (1961) ~ 8 Asthmatic bronchitis Excellent, 4; some, 4 Araki, Kitamura & Kagami > (1961) z 0 -- 70 Cough of various origin 4x 100/day Generally satisfactory in all types a Giudici & Legnani (1961) ~ ~ 10 Asthmatic bronchitis 500-600/day, 10-15 days Advantageous Langer (1961) "' -- 36 Chronic cough Cough diminished in 90% b Melis (1961)

67 Acute and chronic cough Usually 280 mg as base Highly satisfactory Rottini, Marri & Calandra (1961) -- 12 Recurrent bronchitis 800 first day; 400/day for Effective or preventive Tropia (1961) 40 days -- 23 Tuberculosis 400-670 as base per day for Effective. Vital capacity increased in No renal. hepatic or blood Sozio et al. (1961) 12 days many cases c changes or interference with respiratory function

~- ---~------TABLE 68 (continued)

Patients Dosage (mg) Result Side-effects Reference No. I Type

65 Cough of various origin, 16 years of age or less, 400- Cough decreased in 82% d Umehara et al. (1961) including 47 influenza 600/day; adults, 800-1200/day § !!l 18 Asthmatic bronchitis Effective a Audo-Gianotti & Ferrero z (1962) • m > 10 Acute and chronic cough Positive antitussive action a No respiratory depression Canepa et al. (1962) a -- a 14 Acute and chronic cough Very good, 8; moderate, 4; none, 2 Elefante (1962) > 10 Pleuritis Moderate in most Elefante (1962) ~ 4 Neurotic Good, 1; slight, 3 Elefante (1962) -- 124 Children, acute cough 10-20 mgfkg/day Very good, 50-75% Vomiting, 9 Lorenzi (1962) ~ 9 Children, chronic cough Treated 12·28 days Good, 3; moderate, 1; poor, 2 Lorenzi (1962) ~ -- '"C > 17 200 every 4 h Good, 9; moderate, 8 Well tolerated Machella & Campolungo (1962) z > -- z 0 70 Children, acute cough Cough diminished DeBellis & Caniglia (1963) n -- 10 Tuberculosis Up to 5x 100/day Good None Gabrielli (1963) ~ ::g 18 Silicosis 600/day for 180 days Improvement with increased capacity Epigastric distress, 7, first few Nissardi et al. (1963) days -- ~ ~ Children, acute or allergic 200-1200/day in 4-6 doses Excellent I Well tolerated Chaptal, Jean & Jarrige (1964) cough

a Anti-inflammatory effect reported. b Improvement in expectoration. c Spasmolytic action reported. d Antipyretic effect reported.

N N \.H 224 N. B. EDDY AND OTHERS

The attempt was made to improve the effective­ 60 mg per kg of codeine phosphate, 58% inhibition ness of oxolamine by combining it with tetracycline for 45 minutes. in patients suffering from acute and chronic inflam­ Plisnier (1957) reported just the opposite relation­ mation of the upper respiratory tract or from ship between the two drugs. He used the same tuberculosis (Bassi & Citerni, 1962; Borgo, 1962; method to evoke cough and said the effective dose Balli, 1963; Mulargia, 1964). The results showed no of pentoxyverine was one and a half times that of striking difference between the effects of oxolamine codeine by intravenous injection. Also the effect of and of the combination. the former was less constant and of shorter duration. He calculated the effectiveness of pentoxyverine in 5-[2- ( diethylamino) ethyl]-3- (]-phenyl) propyl-1, relation to that of codeine as being in the ratio 2,4,-oxadiazole. In a further study of oxadiazole 0.66:1.0 or, taking relative toxicity into account, as derivatives Silvestrini & Pozzatti (1963) reported that only 0.11: 1.0. On the other hand, Granier-Doyeux this compound, which is also known as AF 634, was et al. (1959) confirmed the earlier reported relative similar to oxolamine in its pharmacological proper­ potency, producing cough in unanaesthetized dogs ties but had a more intense smooth-muscle relaxant by electrical stimulation through electrodes im­ action. (See Table 69). planted in the trachea. Administered intravenously, 1.0 mg per kg of pentoxyverine suppressed the res­ H ,/N-0 ponse completely at 15 and 30 minutes, whereas -c-c' : 4.0 mg per kg of codeine was necessary for almost 0- I "N=t-CH.-CH.-N(C•H•)• CH. complete suppression at 30 and 45 minutes. With I both, the effect had disappeared at about 60 minutes. CH, Stefko, Denze! & Hickey (1961) compared pentoxy­ AF 634 verine and codeine by three methods. Both were given orally and with both the onset and the duration Pentoxyverine of the effect were approximately the same. The doses A number of esters of phenylcycloalkane carbo­ of each to produce 40% inhibition of cough res- xylic acids have been synthesized by Morren (1953) ponse were: Method Pentoxyverine Codeine and evaluated pharmacologically by Levis, Preat & (mg/kg) (mg/kg) Moyersoons (1955). The most potent appeared to Electrical stimulation implanted be pentoxyverine, 1 the diethylaminoethoxyethyl ester tracheal electrode, dog 1.0 1.0 of phenylcyclopentyl carboxylic acid. Inhalation of ammonia, cat 4.0 0.5 Pathological cough, dog 8.0 1.0 Friebel & Kuhn (1962) elicited cough by sulfur dioxide inhalation in guinea-pigs; they used pentoxy­ verine citrate and codeine phosphate. The sub­

cutaneous ED50 was 50.0 mg per kg for the former PENTOXYVERINE and 15.4 mg per kg for the latter. At the effective antitussive dose, codeine decreased the minute The antitussive action of the compound was volume by 21%, pentoxyverine increased it by 9 %; determined by the method of Domenjoz (1952), the latter, however, prolonged the respiratory electrical stimulation of the superior laryngeal nerve depressant effect of hexobarbital. Levis, Preat & in the cat, and comparison was made with codeine Moyersoons (1955) also said that pentoxyverine did phosphate in the same animals. Administered intra­ not affect the respiration of dogs at 1.0 mg per kg, venously, 1.0 mg per kg of pentoxyverine hydro­ intravenously, but caused a transient fall in blood chloride produced 77.5% inhibition of the cough pressure. response, the effect lasting 37 minutes; 1.5 mg per Pentoxyverine had some spasmolytic action kg of codeine phosphate produced 71.0% inhibition, against acetylcholine in rabbits and guinea-pigs the effect lasting 40 minutes. Administered orally, (Plisnier & LaBarre, 1955; Plisnier, 1957), was the relation of effectiveness was the same: 40 mg per mydriatic in mice and was a local anaesthetic with kg of pentoxyverine, 62% inhibition for 30 minutes; both surface application and infiltration, which was 2.4-3.0 times as effective as novocaine (Levis, 1 Also known as carbetapentane or Toclase. Preat & Moyersoons, 1955). CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 225

TABLE 69 COMPARISON OF THE PHARMACOLOGICAL EFFECTIVENESS OF AF-634 AND OXOLAMINE

AF-634a Oxolamine b Effect Animal Dose Route c I Result o... I Route c I Result I (mg/kg) I I (mg/kg)

Antitussive Acrolein inhalation Guinea- 0.25 lP 20% inhibition pig 0.5 lP 41.4% inhibition 0.5 lP 16% inhibition 1.0 lP 53.1% inhibition 1.0 lP 29% inhibition 2.0 lP 53.3% inhibition Electrical stimulation Cat 50 IV 100% supression in 2.0 IV 50% suppression in laryngeal nerve half the animals 1 animal of 4 5.0 IV 70-80% suppression in 2 animals of 4 10.0 IV 100% suppression in 7 animals of 8 Analgesic Writhing test Mouse I Upto50 se Ineffective Up to se Ineffective Hot-plate Mouse Up to 50 se Ineffective Up to se Ineffective Randaii-Selitto test Rat 30 se Effective, 4 h 20-40 se Effective, 21 h Anti-Inflammatory Randaii-Selitto test Rat 20 se 15% inhibition 40 se 5% inhibition Granuloma test Rat 40 0 Ineffective 40 se Ineffective 80 0 Ineffective Anti-pyretic Rat 0 Equivalent to aspirin 0 200mg =100mg aspirin

Anti-spasmodic Isolated intestine Guinea- 0.8!'g/ml acetylcholine inhibition 5.0,g/ml acetylcholine inhibition pig 2.0!'g/ml histamine inhibition 5.01'g/ml histamine inhibition 0.6,g/ml barium chloride inhibition 5.0!'g/ml barium chloride inhibition LD so Mouse 107 IV - 63 IV - 390 lP - 206 lP - 720 se - 465 se - 1270 0 - 929 0 - a From Silvestrini & Pozzatti (1963). b From Silvestrini & Pozzatti (1961). c lP = intraperitoneal; IV= intravenous; SC =subcutaneous; 0 =oral.

The last authors reported the acute toxicity of With a dose of 30 mg per kg of pentoxyverine, pentoxyverine and codeine, mg per kg: subcutaneously, daily for 30 days, 80% of mice survived; with a dose of 100 mg per kg, orally, Pentoxyverine Route* Codeine (mgfkg) (mg/kg) daily for 30 days, all mice survived. Mouse 0 230 375 Clinical use of pentoxyverine (Table 70) indicates Rat 0 830 850 antitussive activity without analgesia or other effects Mouse IV 26 67 on the central nervous system. The reports are based Rat IV 25 54 principally upon investigators' judgments. Local • O=oral; IV=intravenous. anaesthetic, spasmolytic and atropine-like proper-

15 ~ 0'1

TABLE 70 CLINICAL EXPERIENCE WITH PENTOXYVERINE

Patients Dosage regimen Result Side-effects Reference No. I Type I I

28 Irritative cough Better than codeine Deporter (1954) - Acute respiratory infection 4x25 mg/day Very effective No side-effects

- Chronic cough Mainly favourable Jamar (1955) 8 Asthmatic cough Other medication preferred because ex- pectoration not facilitated -- 51 4x 25 mg/day as tablet or 4 or Very good, 31; good, 16. Better than No undesirable side- Van Howrde (1956) :z 5x22.5 mg/day as syrup 30 mg codeine effects !"

Small groups: bronchoscopy Satisfactory In all groups, less resis- Sironl (1956) during anaesthesia, with local lance to endotracheal tube anaesthesia ~ >

557 Cough of various origin 7-25 mg per dose Excellent, 406; fair, 99. Placebo, 5.2% Carter & Maley (1957) ~ effective a -- A specific antitussive in all types of Hausmann (1957) ~ cough -- 56 Bronchoscopy Subcutaneously, not very effective. In- Barranco & Cottone (1958) !ravenously or by Instillation, effective b

139 Influenza Up to 25 mg/day Excellent 69.4%, 14.0% c Voiculescu & Neuman (1959) -- - 70 Acute cough Excellent 80%, good 18.5% Side-effects less than Robin (1961) with placebo

------

a Small doses, 7-10 mg; 143 patients, 76.7% effective; 25 mg dose; 163 patients, 99.4% effective. b Because of difference by different routes both local and central action interfered. c In another group of 84 patients, codeine, 3 or 4x 10 mg/day: excellent, 20.5%; some, 33.4%. d Administered as sustained-release tablet; In 31 patients, one or two tablets per 12 h; in 34 patients, two tablets per four hours. CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 227 ties do not appear to contribute to the effect. three doses of the experimental drug. Both drugs Although Deporter (1954), Hausmann (1957) and were most effective when the response to the aerosol Carter & Maley (1957) considered it effective against was moderately severe (10-20 coughs). Ba 10 611 most or all types of cough, the Council on Drugs of was equal to codeine at 25 mg and according to the AMA (1956) stated, " available clinical evidence percentage decrease in cough response more effective suggests that the effectiveness of the drug is limited than the codeine dose used at 50 and 100 mg. to the acute type of cough. . . . Further and better­ Bickerman & Itkin (personal communication, controlled observations are needed to establish the 1962) determined the minimal concentration of citric clinical usefulness .... " Partial reviews of the acid aerosol in each of their trained subjects and effectiveness of pentoxyverine have been written administered the drug to be tested on a double-blind by Banyai (1960) Bickerman (1961, 1962), Morais basis immediately after this determination. There & Da Silva (1961) and David (1961), expressing was no significant variation at four-hourly cough their judgments but adding no quantitative data. counts after repeated placebo administration. Doses Tolerance or dependence on the drug has not been of 15 and 30 mg of codeine reduced the cough reported. response over the four-hour period of observation but 25 mg of Ba 10 611 did not, thus disagreeing 1-( f3- Morpho/inoethyl) -1-cyc/openteny/-cyc/open­ with the previous investigators. tan-2-one ( Ba 10 611). This compound 1 is another cyclopentane derivative and one of a series of cyclo­ Sodium dibunate 2 alkenones claimed by Veberwasser (1962) to have Both the 2,6- and the 2, 7-di-tert-butyl naphthalene­ antitussive properties. Attempts to confirm this in sulfonates have been made and patented (Homer, man have been made in three series of observations. 1961), although pharmacological studies and clinical In each instance citric acid aerosol was used as the trials were started about ten years earlier (Clerc, cough stimulus. Archibald, Slipp & Shane (1959) 1952). Menard et al. (1961) indeed showed that selected 14 normal subjects by careful screening of sodium dibunate was a mixture of both the 2,6- and 65 volunteers. A dose of 30 mg of codeine or 25 or 2,7-dibutyl compounds. The antitussive effect of 50 mg of Ba 10 611 reduced the number of coughs at sodium dibunate was demonstrated by DeVleesch­ one hour after administration by about the same houwer (1954) in urethanized dogs exposed to sul­ extent. In another trial in these 14 patients 30 mg of furic acid aerosol. The intravenous injection of codeine suppressed the cough response completely in 10-20 mg per kg completely suppressed the cough three patients; 25 mg ofBa 10 611 did not accomplish response. The author thought that the action was complete suppression in any patient, but the average peripheral, on the respiratory tract. Chakravarty number of coughs was about the same as after et al. (1956) confirmed the antitussive action by a codeine and the authors concluded that the two different method and with a different conclusion. agents were equally effective. Decerebrated cats (mid-collicular transection) were stimulated electrically in the dorsolateral region of the medulla. The drug was injected intravenously 1\ and its effect, decrease in intensity and rate of the \//1j-cH.CH.-N 0 A=o1 \_/ I !

BA 10 611

Groszman, Berker & Casimir (1961) used 24 vol­ unteers, 22 of whom were tuberculous, and compared SODIUM DIBUNATE 30 mg of codeine with 25,50 and 100mgofBa 10 611. The mean number of coughs in response to 10-15% response, was apparent ten minutes after injection citric acid aerosol was 12.8 with no drug given, and persisted for at least two hours. Even when the 12.1 after codeine, and 10.5, 8.7 and 6.4 after the 'Also known as Becantex, Becantyl, Linctussal, L-1633. and variously described as the 2,6-isomer (as shown in the. 1 Also known as Melipan. structural formula) or the 2,7-isomer. 228 N. B. EDDY AND OTHERS cough was completely suppressed an increase in stim­ of sodium dibunate. With larger doses, 30-50 mg ulus strength evoked a good response. Equivalent per kg, there was an initial hypotensive effect doses were 10-20 mg per kg of sodium dibunate and followed by a slight, transient increase in pressure 4-10 mg per kg of codeine phosphate. These authors (de Vleeschhouwer, 1954). Plisnier (1957) saw no judged the effect to be central and that of dibunate change in the blood pressure of anaesthetized cats most selective of the agents tried (thiopental, codeine, with 1.0 mg per kg, intravenously. dextromethorphan, caramiphen). The minimal lethal dose of sodium dibunate in Plisnier (1957) compared sodium dibunate and guinea-pigs was 250 mg per kg, subcutaneously. codeine phosphate in cats, in which cough was There was ataxia and spastic death (de Vleesch­ produced by stimulation of the superior laryngeal houwer, 1954). Clerc (1952) said that the average nerve, and said the latter was less effective, 0.66 mg lethal dose for rats was 8-10 mg per kg, orally. Daily per kg being equivalent to 1.0 mg per kg of doses of 5 or 10 mg per kg for three weeks appeared codeine, both intravenously. Long action was not to have no systemic toxic effect, but there was local confirmed. irritation with necrosis of tissue at the site of in­ Friebel, Reichle & von Graevenitz (1955), using jection. sulfur dioxide inhalation in guinea-pigs and sub­ Clinical observation has been meagre and only cutaneous injection of sodium dibunate, obtained one double-blind trial has come to our attention. irregular results, not suitable for calculation of an Clerc (1952) gave 12 patients with cough of various

ED50• Pain at the site of injection may have been a origin doses of 40-150 mg (approximate average factor in the irregularities. 100 mg) of sodium dibunate daily in syrup or as Shemano, Beiler & Hitchens (1962) compared suppository. Results were good in nine, moderate ethyl 2, 7-di-tert-butyl-naphthalenesulfonate with co­ in one. Eight children were treated with 20-60 mg deine sulfate for antitussive action by various daily with a good result in seven, and 12 children experimental methods in dogs and cats. The with whooping cough received 20-45 mg daily with dibunate was always less effective. With sulfuric the result good in four, moderate in six. Tolerance acid aerosol one-half to one-fourth as effective as was not observed. Grignon & Albertin (1953), codeine, with a vibrating slug in the trachea one­ reported similarly. Froehlich & Hertzog (1953) sixtieth, with mechanical stimulation of the trachea treated about 60 tuberculous patients with sodium in cats one-fifth as effective and with electrical dibunate, in tablet, syrup or suppository form, stimulation of the superior laryngeal nerve in cats, generally with rapid onset and good effect, some­ effective but less so than codeine. Its oral toxicity in times better than other previously tried antitussives. dogs was low, slight sedation only with 5 mg per kg. There were no side-effects. Simon (1957a) com­ There was no effect on blood pressure, and no pared 150-300 mg of benzonatate with 90 mg of analgesia or other morphine-like property. sodium dibunate, daily in 59 patients with emphy­ According to de Vleeschhouwer (1954) sodium sema and asthmatic chronic bronchitis. The patients dibunate in doses of 5-20 mg per kg, intravenously, were questioned weekly and the result was judged did not depress the respiration of anaesthetized excellent in 83% with benzonatate, 53% with rabbits and larger doses, 30-50 mg per kg, increased dibunate. Neither affected the asthmatic attacks. the respiratory rate. Chakravarty et al. (1955) and No side-effects were seen. Plisnier (1957) also saw no respiratory depression Keech (1963) tried the ethyl dibunate in 86 with cough-depressing doses in anaesthetized ani­ patients, mostly acute upper respiratory infections. mals. The latter reported that 8 mg per kg of There was good relief in 77, or 90%, with no sodium dibunate intraperitoneally did not influence side-effects. The dose was 50 mg every four to the bronchospasm evoked in guinea-pigs by in­ six hours. Out of 37 patients who had taken other halation of acetylcholine or histamine and 3 mg medication unsuccessfully 32 obtained satisfactory per kg, intravenously, did not affect the broncho­ relief. constriction in dogs after intravenous acetylcholine Recently Sevelius & Colmore (1967) reported a or histamine. Nor did the 4 mg per kg of dibunate, double-blind, well-controlled comparison of ethyl intravenously, affect the tracheobronchial secretion dibunate with codeine phosphate and placebo (the of rabbits. vehicle in which the other medications were given Blood pressure, heart rate and carotid sinus orally). They used 12 male hospitalized patients with reflexes in dogs were not affected by 2-20 mg per kg emphysema and chronic bronchitis, recorded cough- CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 229 ing from a throat microphone and each patient Degree of improvement (no. of patients) completed a questionnaire, reporting results and Dibunate Codeine Placebo Little 4 I 5 preferences. All previous antitussive and antibiotic Some 6 4 5 medication was discontinued for several days but A lot 2 7 I the patient was allowed to continue his smoking as usual. Each man spent five days in a special room­ Change in cough counts (no. o.f patients) two days for recording the usual coughing pattern Decreased 3 11 3 (the experiment was continued only if the cough Increased 8 1 9 counts on these days agreed within 20 %), a drug Average change in cough count day, a placebo day and a drug day. The order of the +6 -107 +36 drugs was randomized, but placebo was always given between. The doses were 50 mg of dibunate and Corbella (1960) tried a related compound (2,6-di­ 15 mg of codeine, three times a day. There were no tert-butyl-4-bromotriethanolamine naphthalene) in changes in vital capacity, no significant difference in 25 patients with cough of various origin. Only two sputum volume and no side-effects were noted or three doses per day were needed for a good throughout. There were no significant differences in result (75-85 %). cough counts with dibunate and placebo and for Hengen & Kasparek (1958) reported antitussive these two medications the correlation was poor trials in rats of a combination of dibunate and between the patients' responses as shown by the normethadone and Pitarma Sabino (1960) used the questionnaire and cough counts. The correlation same combination in 26 patients with cough of was better for codeine and the cough count was various origin. The result was satisfactory in four decreased in all but one patient. and there was improvement in the others.

RESUME LA CODEINE ET SES SUCCEDANES SEDATIFS DE LA DOULEUR ET DE LA TOUX: 4. LES SUCCEDANES POTENTIELS ACTIFS CONTRE LA TOUX

La dihydrocodeine a ete le premier calmant de la toux a La nicocodine et la nicodicodine, produits resultant de etre utilise comme succedane de la codeine, bien qu'elle )'esterification par l'acide nicotinique respectivement de n'ait fait l'objet d'une evaluation experimentale et cli­ la codeine et de la dihydrocodeine, ne semblent pas pre­ nique que recemment. Sa posologic, ainsi que la nature et senter d'avantages particuliers sur les alcaloides dont elles la frequence des reactions secondaires qu'elle provoque, sont derivees. Chez le singe dependant a l'egard de la sont semblables a celles de la morphine. Son aptitude a morphine, les epreuves de substitution utilisant la nico­ engendrer la dependance a ete examinee dans le deuxieme codine ont donne des resultats negatifs. article de la presente serie. Les N-oxydes et les sets quaternaires de la morphine et On estime que l'efficacite de )'ethylmorphine contre la de ses derives, de meme que d'autres composes d'ammo­ toux est du meme ordre que celle de la codeine. On nium quatemaire, n'ont pas fait preuve d'une efficacite admet aussi qu 'elle peut susciter des phenomenes de tole­ superieure a celle de la codeine. rance et de dependance physique; ce demier aspect n'a La nalorphine temoigne, chez l'homme et chez I'animal, toutefois pas ete etudie de fa90n systematique, etant d'une action sedative de la toux quasi semblable a celle donne que les applications therapeutiques de la substance de la codeine, mais elle n'est pas utilisee en therapeutique sont assez limitees. en raison de ses effets secondaires genants. Administree en A en juger par les resultats de )'experimentation sur meme temps que la codeine, elle ne diminue pas I'efficacite l'animal et par les donnees cliniques, l'action sedative de de cette derniere. la toux de la pho/codine est superieure d'environ 50% a Le dextromethorphane a fait l'objet de nombreuses celle de la codeine; cette substance provoque des effets recherches, tant chez l'animal que chez l'homme. 11 est secondaires dont la frequence et l'intensite ne sont pas depourvu de toute propriete analgesique, mais son plus fortes, quand elles ne sont pas plus faibles, que celles action sedative de la toux chez )'animal egale et surpasse des reactions succedant a l'emploi de la codeine. La meme legerement celle de la codeine. Le fait a ete confirme pholcodine n'engendre pratiquement aucune tolerance ou au cours d'observations faites sur des sujets normaux dependance physique lorsqu'on l'administre pendant de chez lesquels la toux avait ete artificiellement provoquee. longues periodes. Les essais cliniques ont fait ressortir une quasi-similitude 230 N. B. EDDY AND OTHERS d'action du dextromethorphane et de la codeine. Chez la fois sur la douleur et sur la toux. Les observations !'animal, on a decele un certain nombre d'effets secon­ effectuees sur l'homme apres induction experimentale de daires - stimulation de la respiration, hypotension et la toux et les donnees cliniques permettent d'attribuer au action anti-inflammatoire - mais ces phenomenes ne se levopropoxyphene une action sedative sur la toux cinq manifestent guere aux doses normalement utilisees chez fois moins forte environ que celle de la codeine. 11 ne pro­ l'homme. L'administration a d'anciens morphinomanes voque que des effets secondaires mineurs. Si !'on en juge non tolerants de doses de dextromethorphane plusieurs d 'apres les essais auxquels ont ete soumis le racemique et fois superieures aux doses therapeutiques n'a pas entraine le dextro-isomere, les risques d'abus de levopropoxy­ d'effets subjectifs ou objectifs de type morphinique et n'a phene paraissent extremement limites. pas fait disparaitre les signes d 'abstinence de la morphine. Derives de la pethidine. La pethidine ne peut etre Cependant, quelques cas, sans grande gravite et spora­ utilisee comme succedane de la codeine en raison de sa diques, d'abus de dextromethorphane ont ete signales; faible action calmante sur la toux et de son pouvoir par certains aspects, les reactions observees rappelaient les toxicomanogene eleve. On a procede a des experiences au effets produits par l'abus du cannabis plutot que les moyen de certains de ses derives (WIN-13187, L-2909, effets morphiniques. prodilidine), mais ces composes se sont reveles moins C'est seulement en 1954 qu'on a decouvert !'action actifs que la codeine. lis n'ont pas fait l'objet d'essais sedative sur la toux de la noscapine, le deuxieme, en quan­ cliniques. tite, des alcaloides de !'opium. On peut considerer qu'elle Les experiences effectuees avec les derives de la pheno­ agit sur la toux provoquee experimentalement chez des thiazine montrent que leur action sedative sur la toux sujets sains dans une mesure tout au plus equivalente a n'est probablement pas specifique mais doit etre attribuee celle de la codeine. Les observations cliniques faites plutot a leurs proprietes sedatives generales et peut-etre a jusqu'a present semblent indiquer qu'il en va de meme leurs effets antihistaminiques. Le pipazetate et le dime­ en cas de toux pathologique. Aux doses therapeutiques thoxanate ont fait l'objet de recherches cliniques dont les efficaces, ce medicament est completement depourvu resultats concordent avec les donnees experimentales d'effets secondaires adverses. Bien que sa structure soit recueillies chez !'animal. Les doses de pipazetate amenant du type isoquinoline et differe de celle de la morphine, et une sedation efficace de la toux sont legerement supe­ malgre qu'elle soit exempte d'action analgesique, la rieures a celles de la codeine, avec des reactions secon­ noscapine a fait l'objet d'experiences destinees a deceler daires (surtout des nausees) peu frequentes, et elles ne une aptitude eventuelle a susciter une dependance de type suscitent apparemment aucun phenomene de tolerance ou morphinique. Les resultats de ces epreuves ont ete de dependance physique de type morphinique. Quant au negatifs. dimethoxanate, aussi bien !'experimentation menee sur La methadone a ete l'un des premiers produits dotes !'animal a !'aide de techniques diverses que les essais d'effets de type morphinique a etre synthetise. Son effi­ cliniques permettent de lui assigner une efficacite du cacite presumee contre la toux a ete demontree par meme ordre que celle de la codeine, avec des effets secon­ t'experimentation sur !'animal et par des essais cliniques. daires insignifiants. Le racemique est environ cinq a dix fois plus actif que la Les essais cliniques ont montre que la benzobutamine codeine; les effets secondaires consistent en somnolence, pouvait etre utilisee comme succedane de la codeine, a la nausees et euphorie. En raison de sa tendance a engendrer condition d'etre administree a des doses quatre a cinq fois une dependance de type morphinique et de la mise sur le superieures. marche de preparations qui n'offrent pas cet inconvenient, On a demontre que le benzonatate, en plus de son 'la methadone, de meme d 'ailleurs que le dextro-isomere, a action centrale, a des effets inhibiteurs sur les recepteurs ete de moins en moins utilisee comme calmant de la toux. pulmonaires du nerf pneumogastrique. Le produit Les experiences effectuees chez !'animal montrent que, n'agit qu'avec uncertain retard- du a la lenteur de son compares a ceux de la codeine, les effets de la norme­ absorption apres administration par voie orale - ce qui thadone sont plus uniformes, quoique moins marques, que rend malaisee toute comparaison precise avec la codeine les effets de la methadone. Alors que ce produit agit sur en ce qui regarde les proprietes sedatives de la toux. Les la toux provoquee experimentalement chez l'homme doses de benzonatate et de codeine qui combattent effica­ essentiellement a la maniere d'un placebo, les observations cement la toux provoquee experimentalement chez diniques lui assignent en revanche une efficacite satisfai­ I 'animal sont du meme ordre de grandeur. Par contre, sante. Ses effets secondaires sont relativement rares, mais pour supprimer la toux provoquee artificiellement chez il presente la meme aptitude que la morphine a engendrer l'homme, il faut administrer des doses de benzonatate de 'la dependance. Cette propriete toxicomanogene n'est pas loin plus elevees. Lors des essais cliniques, et avec des affaiblie si, comme c'est le cas dans une preparation com­ dosages similaires, on a obtenu en general de bons resul­ merciale utilisee en therapeutique clinique, on associe a la tats qui, en partie du moins, sont probablement dus a normethadone un sympathomimetique a action broncho- !'action locale exercee par le medicament en cas de prise 1ytique (p-hydroxyephedrine). par voie buccale. On n'a observe que peu de reactions Le levopropoxyphene est essentiellement un calmant de secondaires. Des phenomenes de tolerance sont apparus fa toux, alors que chez !'animal le dextro-isomere agit a apres administration prolongee du produit. CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 231

Caramiphene. Au cours d'etudes pharmacologiques 11 est egalement difficile de porter un jugement definitif relativement poussees, on a pu mettre en evidence l'effi­ sur I'isoaminile qui n'a ete soumis qu'a un petit nombre cacite du produit en cas de toux d'origines diverses; il est d 'essais cliniques dtlment controles. On a signale que ce dote par ailleurs d'une certaine activite spasmolytique et produit etait efficace contre la toux a des doses de 40 mg anesthesique locale. Les observations effectuees par la (prise unique) et de 160 mg (dose quotidienne), les suite sur des volontaires normaux ainsi que les donnees valeurs correspondantes pour la codeine etant de 20 et cliniques indiquent que !'action sedative sur la toux du 70 mg respectivement. Les effets secondaires, pour autant caramiphime est equivalente, ou meme legerement supe­ qu'ils existent, ne sont que rarement observes. rieure, a celle de la codeine. La substance entraine rare­ L'oxolamine a ete davantage etudiee a !'occasion de men! des effets secondaires et !'on n'a signale aucun cas de recherches visant a decouvrir un sedatif de la toux a tolerance ou d'abus. action peripherique. 11 semble qu'elle soit dotee de pro­ Clobutinol. De nombreux essais cliniques, dont certains prietes anti-inflammatoires et spasmolytiques et, dans une effectues par la methode du doubie anonymat, portant sur moindre mesure, d'une action depressive centrale. Sur la des malades souffrant de toux d'origines diverses ont base de donnees cliniques, insuffisamment etayees il est montre de fa4;on assez uniforme que les doses therapeu­ vrai par des essais bien controles, on lui reconnait une tiques efficaces du clobutanol etaient de peu superieures a efficacite tberapeutique aux doses de 120 mg (prise celles de la codeine. On a obtenu generalement de bons unique) et de 600 mg (dose quotidienne). resultats quand on a utilise ce produit preventivement a De toute une serie d'esters de l'acide phenylcyclo­ !'occasion de bronchoscopies ou d'autres examens du pentyl-carboxylique, la pentoxyverine se montre la plus meme genre. Les effets secondaires ont ete rares et sans active contre la toux. Les observations cliniques indiquent gravite. que cette activite sedative specifique (pour des dosages Des experiences de divers types realisees chez !'animal legerement superieurs a ceux de la codeine) n'est pas ont montre que le clofedanol etait depourvu de tout effet associee a des effets centraux, analgesiques ou autres. Les analgesique mais possedait des proprietes sedatives de la proprietes analgesiques locales et les effets de type atro­ toux. Le fait a ete confirme chez l'homme, a la fois par pinique qui ont ete deceles chez !'animal ne semblent pas des observations cliniques et par la demonstration d 'un intervenir dans !'action sedative de la toux. effet inhibiteur de la toux artificiellement provoquee, mais Des experiences intensives chez !'animal auxquelles a !'absence d'essais cliniques methodiques rend toute eva­ ete soumis le dibunate de sodium (un naphtalenesulfonate luation definitive impossible. Pour obtenir une efficacite a noyau substitue), il ressort que cette substance a surtout egale, on doit donner des doses de clofedanol deux fois une action centrale. On peut conclure du petit nombre de superieures environ a celles de la codeine. Aucun pbeno­ donnees cliniques disponibles que le dibunate de sodium mene de tolerance ou de dependance physique n'a ete doit etre administre a des doses un peu plus elevees que constate apres administration prolongee de la substance celles de la codeine, qu'il n'entraine pas d'effets secon­ au rat et au chien, et les tentatives de substitution chez le daires notables et qu'il n'engendre pas la dependance. singe dependant a l'egard de la morphine ont echoue. Le Dans le souci d'une information complete, et eu egard diphenylpiperidinopropanol, dont la structure chimique est a leur interet therapeutique, le cas d'autres substances est apparentee a celle du clofedanol, n'a pas non plus fait egalement examine dans le present travail, bien que les l'objet d'une etude approfondie. Ses doses therapeutiques recherches qui leur ont ete consacrees n'aient pas abouti sont, semble-t-il, du meme ordre de grandeur que celles a la mise au point d'agents tberapeutiques utilisables en du clofedanol. clinique.

REFERENCES

Abelmann, W. H., Gaensler, E. A. & Badger, T. L. (1954) Audo-Gianotti, G. B. & Ferrero, S. (1962) Policlinico, Dis. Chest, 25, 532 Sez. prat., 69, 1056 Abruzzi, W. A. (1962) J. New Drugs, 2, 310 Araki, H., Kitamura, Y. & Kagami, T. (1961) Minerva Absire-Laupretre, Y. & Dailly, R. (1962) Gaz. med. Fr., med., 52, 3745 69, 3153 Archibald, D. W., Slipp, L. B. & Shane, S. J. (1959) Alemquer, M. de & Lea!, F. (1962) J. med. (Porto), 49, Canad. med. Ass. J., 80, 734 839 Aurousseau, M. & Navarro, J. (1957) Ann. pharm.fran~ .• Alemquer, M. de, Lea!, F. & Gomes, F. (1960) J. med. 15, 640 (Porto), 43, 681 Bairao, G. S. et al. (1959) Rev. bras. Anest., 1, 47 Aletti, L. & Palatresi, R. (1956) Gaz. int. Med. Chir., 61, Balea, T. & Buret, J. (1964) Therapie, 19, 631 1660 Balli, R. (1963) Minerva otorinolaring, 13, 310 Amler, A. B. & Rothman, C. B. (1963) J. New Drugs, 3 Banyai, A. L. (1959) Geriatrics, 14, 621 362 Banyai, A. L. (1960) Gen. Pract. Clin., 21, 83 232 N. B. EDDY AND OTHERS

Barasz, Z. et al. (1962) Praxis, 12, 317 Cahen, R. (1962) Therapie, 17, 311 Barlow, 0. W. (1933) J. Lab. clin. Med., 18, 785 Cahen, R. & Aubron, S. (1960) C.R. Acad. Sci. (Paris), Barranco, G. & Cottone, D. (1958) Acta anaesth. 251, 3111 (Padova), 9, 171 Cahen, R. & Boucherle, A. (1961a) C.R. Soc. Bioi. Basabe, H., Gentile, F. A. & Crocioni, U. (1957) Sem. (Paris), 155, 1034 med. (B. Aires), 110,766 Cahen, R. & Boucherle, A. (1961b) J. Physiol. (Paris), Bassi, M. & Citemi, S. (1962) Rif. med., 16, 635 53,286 Beckloff, G. L. & Hewitt, M. I. (1963) Amer. J. med. Sci., Cahen, R. & Boucherle, A. (1964) C.R. Soc. Bioi. (Paris), 246,285 158, 1021 Bein, H. J. & Bucher, K. (1957) Helv. physiol. pharmacal Cahen, R. & Boucherle, A. (1965) Fed. Proc., 24, 549 acta, 15, 55 Cahen, R., Groskinsky, E. & Parisek, P. (1956) Proc. Bellville, J. W. et al. (1958) J. Pharmacal. exp. Ther., 122 Soc. exp. Bioi. (N. Y.), 92, 305 5A; Anesthesiology, 19, 545 Cahen, R., Groskinsky, E. & Parisek, P. (1957) J. Benson, W. M., Stefko, P. L. & Randall, L. 0. (1952) Pharmacal. exp. Ther., 119, 137 Fed. Proc., 11, 322 Cahen, R. et al. (1963) Arch. int. Pharmacodyn., 143, 466 Benson, W. M., Stefko, P. L. & Randall, L.O. (1953) Calesnick, B. & Christensen, J. A. (1967) Clin. Pharmacal. J. Pharmacal. exp., Ther., 109, 189 Ther., 8, 374 Berger, F. (1951) Munch. med. Wschr., 2, 83 Calesnick, B., Christensen, J. A. & Munch, J. C. (1961) Bickerman, H. A. (1961) Med. Clin. N. Amer., 45, 805 Amer. J. med. Sci., 242, 560 Bickerman, H. A. (1962) Clin. Pharmacal. Ther., 3, 353 Canepa, F. et al. (1962) Arch. E. Maragliano Pat. Clin., Bickerman, H. A. & Barach, A. L. (1954) Amer. J. med. 18, 641 Sci., 228, 156 Capello, G. & Di Pasquale, S. (1955) Schweiz. med. Bickerman, H. A. & Itkin, S. E. (1960) Clin. Pharmacal. Wschr., 12, 80 Ther., 1, 180 Carrizo, A. R. (1961) Pren. med. argent., 48, 59 Bickerman, H. A. et al. (1957) Amer. J. med. Sci., 234, 191 Carter, C. H. (1963) Amer. J. med. Sci., 245, 713 Birkner, F. (1952) Wien. med. Wschr., 102, 213 Carter, C. H. & Maley, M. C. (1957) Amer. J. med. Sci., Blankart, R. (1963) Ther. Umsch., 20, 403 233, 77 Boissier, J.-R. & Pagny, J. (1959) Med. exp. (Base!), 1, Cass, L. J. & Frederik, W. S. (1953) New Eng. J. Med., 368 249, 132 Boissier, J.-R. & Pagny, J. (1960) Therapie, 15, 93 Cass, L. J. & Frederik, W. S. (1956) J. Lab. clin. Med., Boissier, J.-R. & Pagny, J. (1960) Therapie, 15, 97 48, 879 Boner, H. (1962) Helv. physiol. pharmacal. Acta, 20, 316 Cass, L. J. & Frederik, W. S. (1964) Curr. ther. Res., 6, Borgo, M. (1962) Policlinico, Sez prat., 69, 1572 14 Boyd, C. E. & Boyd, E. M. (1962) J. New Drugs, 2, 23 Cass, L. J., Frederik, W. S. & Andosca, J. B. (1954) Boyd, E. M., Daicur, A. 0. & Middleton, R. J. (1956) Amer. J. med. Sci., 227, 291 Ther. Umsch. 13, 254 Cass, L. J., Laing, J. T. & Frederik, W. S. (1961) Curr. Boyd, E. M., Hicks, R. N. & Trainor, A. V. (1956) ther. Res., 3, 289 Arch. int. Pharmacodyn., 114, 424 Cattaneo, A. D. (1959) Minerva anest., 25, 373 Braenden, 0. J., Eddy, N. B. & Halbach, H. (1955) Bull. Cavalca, A. (1956) Gaz. int. Med. Chir., 61, 1653 Wld Hlth Org., 13, 937 Cela, G. & Soccio, N. (1963) Gazz. med. ita!., 122, 61 Brenner-Godderz, L. (1959) Med. Klin., 54, 2004 Chabrier, P., Giudicelli, R. & Kristensson, K. 0950) Brit. med. J., 1961, 2, 1549 C.R. Acad. Sci. (Paris), 231, 289 Brit. med. J., 1964, 1, 1165 Chabrier, P., Giudicelli, R. & Thuillier, J. (1950) Ann. Brown, H. D. (1958) U.S. Pat. No. 2,820,739 pharm. fran(:., 8, 261 Brown, W. S. (1961) Curr. ther. Res., 3, 185 Chakravarty, N. K. et al. (1956) J. Pharmacal. exp. Ther., Bucher, K. (1956) Schweiz. med. Wschr., 86, 94 117, 127 Bucher, K. (1961) Helv. physiol. pharmacal. Acta., 19, 84 Chappel, C. I., Stegen, M. G. P. & Grant, G. A. (1958) Bucher, K. & Jacot, C. (1951) Helv. physiol. pharmacal. Canad. J. Biochem., 36, 475 Acta., 9, 454 Chaptal, J., Jean, R. & Jarrige, J. C. (1964) Ann. Pediat., Buchheim, K. L. & Angermann, B. (1951) Dtsch. med. 11, 384 Wschr., 76, 1278 Charlier, R. et al. (1961) Arch. int. Pharmacodyn., 134, Buchigger, G. & Frisch, P. {1954) Med. Klin., 49, 1846 306 Biihler, F. (1954) Medizinische, No. 2, p. 1245 Chen, J. Y. P. & BilJer, H. F. (1959) Fed., Proc., 18, 376 Burckhardt, H. & Orzechowski, G. (1954) Arch. Toxikol., Chen, J. Y. P., BilJer, H. J. & Montgomery, E. G., Jr. 15, 135 (1960) J. Pharmacal., exp. Ther., 128, 384 Cahen, R. (1959) C.R. Acad. Sci. (Paris), 249, 1288 Chemish, S. M. et al. (1963) Ann. Allergy, 21, 677 Cahen, R. (1960) C.R. Acad. Sci. (Paris), 250, 3530 Christoffel, P. & Kolberg, H. (1958) Med. Klin., 35, 1507 Cahen, R. (1961) Bull. Narcot., 13, No. 2, p. 19 Cieslak, G. (1955) Nervenarzt, 26, 30 CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 233

Clerc, B. (1952) D'un nouveau sedatif de la toux, Thesis, Fraenkel, A. (1913) Munch. med. Wschr., 60, 522 Paris Francetti, L. (1958) Gazz. med. ita/., 117, 213 Cooper, N. & Hatcher, R. A. (1934) J. Pharmacal. exp. Freidinger, J. (1962) J. Med. Ass. Ala., 32, 61 Ther., 51, 411 Friebel, H. & Kuhn, H.-F. (1962) Arch. exp. Path. Phar­ Corbella, E. G. (1960a) Minerva med., 51, 4077 mak., 243, 162 Corbella, E. G. (1960b) Osped. maggiore, 48, 137 Friebel, H. & Reichle, C. (1956) Arch. exp. Path. Phar­ Council on Drugs, AMA (1956) J. Amer. med. Ass., 161, mak., 229, 400 970 Friebel, H., Reichle, C. & von Graevenitz, A. (1955) Council on Drugs, AMA (1958) J. Amer. med. Ass., 167, Arch. exp. Path. Pharmak., 224, 384 993 Froehlich, W. & Hertzog, J. (1953) Praxis, 42, 974 Cuocolo, R., Messina, N. & Carbone, M. (1962) Rass. Fujimoto, T. (1958) Folia pharmacal. jap. 54, 1317 int. Clin. Ter., 42, 587 Furukawa, T. & Okabe, M. (1958) lgaku Kenkyu, 28, 1643 Czermak, L. (1963) Dtsch. med. J., 14, 21 Gabrielli, A. (1963) Policlinico, Sez. med., 70, 125 Dahl, W. (1913) Dtsch. med. Wschr., 39, 1304 Gefter, W. I. (1961) Penn. med. J., 64, 1137 Dahlgren, S. & Dalhamn, T. (1966) Acta pharmacal. Geigy, J. R. (1950) Swiss Patent, No. 272, 708 (Kbh.), 24, 286 Gerland, W. (1960) Med. Welt. (Stuttg.), 49, 2611 Darke, C. S. et al. (1959) Brit. med. J., 1, 622 Ghisleri, G. (1960) Minerva med., 51, 3102 Davenport, L. F. (1938) Pub/. Hlth Rep. (Wash.), Suppl., Giammarinaro, G. & Angoletto, L. (1952) Gazz. med. No. 145 ita/., 111, 179 David, A., Leith-Ross, F. & Valiance, D. K. (1957) Giudicelli, R., Chabrier, P. & Kristensson, R. (1951) J. Pharm. Pharmacal., 9, 446 Therapie, 6, 146 David, J. C. (1961) J. Christ. med. Ass. India, 36, 183 Giudicelli, R., Thuillier, J. & Chabrier, P. (1950) Progr. De Bellis, U. & Caniglia, A. (1963) Policlinico, Sez. med., med. (Paris), 7, 191 70, 57 Giudici, G. & Legnani, F. (1961) Minerva med., 52, 3752 Degkwitz, R. (1964) Nervenarzt, 35, 412 Giuliano, V. & Rossa, G. (1956) Minerva med., 46, 1502 Deidda, C. (1960) Minerva med., 51, 4059 Glick, J. (1963) Delaware med. J., 35, 180 Deporter, H. (1954) Brux.-med., 34, 422 Gloesener, E. (1961) Farmaco, Ed. prat., 16, 457 Diamant, M. (1957) Pract. oto-rhino-laryng. (Base/), 19, Goglia, G. (1959) Gaz. int. Med. Chir., 63, 2754 339 Golden, W. (1960) Ther. d. Gegenw., 99, 133 Dietel, K. & Koditz, H. (1962) Ther. d. Gegenw., 101, 133 Gosswald, R. (1958) Arzneimittel.-Forsch., 8, 550 Di Gregorio, M. (1960) Minerva med., 51, 4086 Goth, P. S. & Goldenberg, M. (1960) Fed. Proc., 19, 375 Domenjoz, R. (1952) Arch. exp. Path. Pharmak., 215, 19 Grabelle, B. N. (1961) J. med. Soc. New Jersey, 58 563, Doyle, F. P. & Mehta, M. D. (1964) Advanc. Drug Res., 1, Grafe, G. (1958) Medizinische, 43, 1741 107 Graham, J. D. P. (1959) Practitioner, 183, 344 Dreyer, H. H. (1961) Ther. d. Gegenw., 100, 608 Graham, J. D. P. (1962) J. New Drugs, 2, 43 Drommond, F. G., Johnson, C. C. & Poe, C. F. (1950) Granier-Doyeux et al. (1959) Arch. int. Pharmacodyn., Acta pharmacal. (Kbh), 6, 235 121, 287 Dumittan, S. H. (1963) J. Med. (Porta), 50, 961 Gravenstein, J. S. & Beecher, H. K. (1955) Arzneimitlel­ Ebermann, H. (1954) Munch. med. Wschr., 96, 922 Forsch., 5, 364 Eddy, N. B., Halbach, H. & Braenden, 0. J. (1956) Gravenstein, J. S., Devloo, R. A. & Beecher, H. K. Bull. Wld Hlth Org., 14, 353 (1954) J. appl. Physiol., 7, 119 Eddy, N. B., Halbach, H. & Braenden, 0. J. (1957) Green, A. F. & Ward, N. B. (1955) Brit. J. Pharmacal., Bull. Wld Hlth Org., 17, 569 10, 418 Eddy, N. B., Touchberry, C. C. & Lieberman, J. (1950) Gregoire, F., Thibaudeau, Y. & Comeau, M. (1958) Can. J. Pharmacal. exp. Ther., 98, 121 med. Ass. J., 79, 180 Eidmann, W. (1959) Munch. med. Wschr., 101, 676 Greif, S. (1960) Wien. klin. Wsclzr., 110, 943 Elefante, E. (1962) Gazz. med. ita/., 121, 160 Grignon, J. L. & Albertin (1953) Sem. Hop. Paris, 29, Ellis, G. P. et al. (1963) J. med. Chem., 6, 111 2999 Engelhom, R. (1960) Arzneimittel-Forsch., 10, 785 Groszman, M .. Berker, I. 0. & Casimir, F. (1961) Appl. Emst, C. E. & Jeffrey, M. (1962) Arizona Med., 18, 221 Ther., 3, 95 Ewart, R. B. L. & Priest, R. G. (1967) Brit. med. J., 2, 92 Gruber, C. M., Jr., & Carter, C. H. (1961) Amer. J. med. Feinsilver, 0. (1961) Curr. ther. Res., 3, 451 Sci., 242, 443 Feser, A. (1960) Hippokrates ( Stuttg.), 31, 28 Gruhzit, C. C. (1957) J. Pharmacal. exp. Ther., 120, 399 Fischman, M. E. (1962) Arch. Pediat., 79, 332 Gruhzit, C. C. & Schub, Y. (1956) J. Pharmacal. exp. Fishberg, M. (1932) Pulmonary tuberculosis, 2nd ed., Ther., 116, 25 Philadelphia, Lea & Febiger Guseva, E. N. (1956) Farmakol. i. Toksikol., 19, 17 Flecker, A. (1961) Wien. med. Wschr., 111, 114 Gyang, E. A., Kosterlitz, H. W. & Lees, G. M. (1964) Fourage, M. (1963) Scalpel (Brux.), 116, 511 Arch. exp. Path. Pharmak., 248, 231 234 N. B. EDDY AND OTHERS

Haas, H. (1955 ;Arch. exp. Path. Pharmak., 225, 442 Kauchtschischwili, G. M. (1957) Gazz. med. ita/., 116, 149 Hahn, K.-J. & Friebel, H. (1966) Med. Pharmacal. exp., Keech, H. G., Jr. (1963) Penn. med. J., 66, 39 14, 87 Kelentey, B. E., Stenszky, E. & Gzollner, F. (1958) Arch. Hahn, L. A. & Wilbrand, H. (1952) Arch. int. Pharma­ exp. Path. Pharmak., 233, 550 codyn., 91, 144 Kelentey, B. et al. (1957) Arzneimittel-Forsch., 7, 594 Halbach, A. (1955) Dtsch. med. J., 6, 117 Kelentey, B. et al. (1958) Arzneimittel-Forsch., 8, 325 Hammed, H. & Pichler, 0. (1962) Wien. klin. Wschr., 74, Kelling, H. W. (1952) A.'rztliche Praxis, 4, May 24 739 Kelly, D. F. (1963) Northw. Med. (Seattle), 62, 871 Hanke, F. (1958) Praxis, 47, 610 Kitamura, S. et al. (1962) Japanese Patent No. 3586 Hansen, K. & Zipf, F. (1960a) Arch. exp. Path. Pharmak., Kleibel, F. (1964) Med. Welt (Stuttg.), No. 24, 1317 238, 78 Klein, B. (1958) Antibiot. Med., 5, 462 Hansen, K. & Zipf, F. (1960b) Arch. exp. Path. Pharmak., Klein, B. (1963) Folia Clin. int. (Barcelona), 13, 608 240, 253 Kohli, R. P., Gupta, G. P. & Blargava, K. P., (1960) Hara, S. & Yanaura, S. (1959) Jap. J. Pharmacal., 9, 46 Indian J. med. Res., 48, 193 Harris, E. A. (1965) Brit. J. Pharmacal., 24, 532 Konar, N. R. & Dasgupta (1959) J. Indian med. Ass., 32, Haslreiter, E. (1959) Arzneimittel-Forsch., 9, 769 189 Hausmann, M. (1957) Med. Neuheit., 63, 1 Konar, N. R. & Halder, A. (1964) J. Indian med. Ass., Heffron, C. E. (1961) J. New Drugs, 1, 217 43, 66 Heimendinger, J. (1952) Praxis, 41, 323 Konzett, H. (1955) Wien. klin. Wschr., 67, 306 Hengen, 0. & Kasparek, H. (1958) Arzneimittel-Forsch., Konzett, H. & Rothlin, E. (1954) Experientia (Base/), 8, 620 10,472 Henriquet, F. & Rochira, G. (1963) Minerva anest., 29, Korpas, J., Tomori, Z., & Ivanco, J. (1957) Physiol. 25 bohemoslov, 6, 111 Herzog, H. (1956) Schweiz. med. Wschr., 86, 96 Korte, J. (1899a) Munch. med. Wschr., 46, 503 Hillis, B. R. & Kelly, J. C. (1951) Glasgow med. J., 32, 72 Korte, J. (1899b) Ther. Mh., 13, 33 Hoglund, N. J. & Michaelsson, M. (1950) Acta physiol. Krause, D. (1958) Arzneimittel-Forsch., 8, 553 scand., 21, 168 Kraushaar, A. E., Schunk, W. A. & Thym, H. F. (1964) Homer, Ltd. (1961) South African Patent, No. R61/217 Arzneimittel-Forsch., 14, 986 Hottinger, A. (1954) Schweiz. med. Wschr., 84, 1372 Krijewski, M. (1900) Thesis, Paris Hougs, W. et al. (1966) Acta Pharmacal. (Kbh.), 24, 3 Kroepfii, P. (1950) Helv. physiol. pharmacal. Acta., 8, 33 Hudson, E. H. (1952) Lancet, 1, 310 Kronberger, L. (1963) Wien. med. Wschr., 113, 280 Huperz, R. (1958) Medizinische, 43, 1105 Krueger, H. M., Eddy, N. B. & Sumwalt, M. (1943) Husen, J.-H. (1958) Tuberk.-Arzt., 12, 248 Pub/. Hlth Rep. (Wash.), Suppl. 165 lsbell, H. & Fraser, H. F. (1952) J. Pharmacal. exp. Kukowski, H. (1960) Ther. d. Gegenw., 99, 36 Ther., 106, 397 Kummer, A. (1955) Praxis, 44, 132 lsbell, H. & Fraser, H. F. (1953) J. Pharmacal. exp. Ther., La Barre, J. & Plisnier, H. (1959a) Arch. int. Pharma­ 107, 524 codyn., 119, 205; Bull. Narcot., 11, No. 3, p. 7 Isbell, H. & Fraser, H. F. (1955) J. Pharmacal. exp. Ther., La Barre, J. & Plisnier, H. (1959b) 6• Congr. int. Thera­ 113, 29 peut., Strasbourg, p. 113 Iuliani, G. & Pagnotta, G. (1957) G. Clin. med., 38, 589 Lachmer, 0. & Werner, H. (1963) Wien. med. Wschr., lvan, J. (1959) Acta pharm. hung., 5, 234 113, 195 Jacobbson, B., Kewenter, J. & Kock, N. G. (1961) Acta Ladewig, D. (1969) Schweiz. med. Wschr., 99, 781 chir. scand., 122, 407 Laffan, R. (1961) Pharmacologist, 3, 66 Jamar, J. (1955) Int. Rec. Med., 168, 735 Lambert, A. (1936) New Engl. J. Med., 215, 72 J. Amer. med. Ass., 1925, 85, 459 Langer, M. (1961) Minerva med., 52, 3747 J. Amer. med. Ass., 1926, 87, 1412 Langrehr, D. (1963) Arch. exp. Path. Pharmak., 245, 427 Janisch, T. (1899) Munch. med. Wschr., 46, 1729 Lasagna, L. & Beecher, H. K. (1954) J. Pharmacal. exp. Kiillquist, I. & Melander, B. (1957) Arzneimittel-Forsch., Ther., 112, 356 7, 301 Lasagna, L. et al. (1961) Cancer Chemother. Rep., Kase, Y. (1952) Jap. J. Pharmacal., 2, 7 No. 15, p. 33 Kase, Y. (1955a) Jap. J. Pharmacal., 4, 118 Leimdorfer, A. (1955) Fed. Proc., 14, 92 Kase, Y. (1955b) Jap. J. Pharmacal., 4, 130 Lenzi, S. (1941) Rass. int. Clin. Ter., 22, 215 Kaze, Y. & Yuizono, T. (1959) Chem.pharm. Bull., 7, 378 Levis, S., Preat, S. & Moyersoons, F. (1955) Arch. int. Kase, Y., Yuizono, T. & Muto, M. (1963) J. med. Chem., Pharmacodyn., 103, 200 6, 118 Libal, H. (1960) Med. Welt (Stuttg.), 7, 383 Kase, Y. et al. (1955) Chem. pharm. Bull., 3, 364 Liechti, J. (1950) Schweiz. med. Wschr., 80, 484 Kase, Y. et al. (1959a) Clin. pharm. Bull., 7, 372 Linden, V. zur (1958) Medizinische, No. 23, p. 959 Kase, Y. et al. (1959b) Chem. pharm. Bull., 7, 378 Lindner, E. & Stein, L. (1959) Arzneimittel-Forsch., 9, 94 CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 235

Lineback, M. (1962) Clin. Med., 69, 1806 Neumann, P. (1956) Rev. med. Suisse rom., 76, 738 Linz, A. (1943) Dtsch. Aerztebl. No. 4 Nissardi, G. P. et al. (1963) Clin. ter., 27, 693 Loew, Kaiser & Moore (1945) J. Pharmacal. exp. Ther., Noel, P. R. (1962) Brit. J. Dis. Chest, 56, 70 83, 120 Oswald, N. C. (1959) Brit. med. J., 1, 292 Lorenz, R. et al. (1960) German patent No. 1,080,568 Oswald, W. (1961) Med. Welt (Stuttg.), 3, 154 Lorenzi, L. (1962) Gazz. med. ita!., 121, 128 Ozawa, H. et al. (1962) J. pharmac. Soc. Jap., 82, 1314 Luciano, F. et al. (1963) Clin. ostet., ginec., 65, 728 Palazzo, G. & Corsi, G. (1962) Arzneimittel-Forsch., 12, Maccaferri, A. & Troccoli, B. (1960) Minerva med., 51, 545 4069 Palecek, F. & Mekulaskova, J. (1963) Cs. Farm., 12, 89 MacHale, S. J. & Springett, V. H. (1962) Tubercle Parish, F. A. (1959) Med. Tms (N.Y.), 87, 1488 (Edinb.), 43, 450 Pasquariello, G. & Nicolis, F. B. (1962) Clin. ter., 23, 226 Machella, M. & Campolungo, A. (1962) Gazz. med. ita/., Paul, K. (1962) Wien. Z. inn. Med., 43, 129 121, 158 Peeters, E.-G. (1961) Scalpel (Brux.), 114, 945 Madden, J. S. (1966) Brit. med. J., 1, 676 Pellanda, R. (1962) Praxis, 51, 1120 Maffii. G., Silvestrini, B. & Banfi, S. (1963) Nature, 199, Pellmont, B. & Bachtold, H. (1954) Schweiz. med. 916 Wschr., 84, 1368 Martin, H. & Hatliger, F. (1946) U.S. Patent Petersen, M. T. (1960) Dtsch. med. J., 11, 235 No. 2,404,488 Petrow, V., Stephenson, 0. & Wild, A. M. (1958) J. Marx, H. H. (1957) Arzneimittel-Forsch., 7, 663 Pharm. Pharmacal., 10, 40 Masi, A. (1957) Rivist. Clin. pediat., 59, 87 Phillips, K. D. & Guillaume, E. W. (1961) Practitioner, Matallana, A. & Borison, H. L. (1955) Fed. Proc., 14, 367 186, 238 Matlin, E. (1960) Clin. Med., 67, 2011 Pitarma Sabino, A. C. (1960) J. Med. (Porta), 43, 996 Maurer, H. (1955) Dtsch. med. Wschr., 80, 351 Platt, M. L., Rowel!, S. S. & Woolas, K. D. (1960) Brit. May, A. J. & Widdicombe, J. G. (1954) Brit. J. Phar­ J. clin. Pract., 14, 991 macal., 9, 335 Plessner, F. (1900) Ther. Mh., 14, 80 Megemont, C. et al. (1961) C.R. Soc. Bioi. (Paris), 155, Plisnier, H. (1954) Therapie, 9, 737 1505 Plisnier, H. (1957) Etude comparative de /'action des Melis, A. (1961) Minerva med., 52, 3756 derives de /'opium et de diverses substances synthetiques Menard, M. et al. (1961) Canad. J. Chem., 39, 729 a effet non morph nique sur le mecanisme de la toux, sur Meyer, F. M. (1933) Munch. med. Wschr., 80, 732 la bronchospasme et sur la secretion bronchique, Thesis, Michelson, A. L. & Schi!ler, I. W. (1957) J. Allergy, 28, Brussels 514 Plisnier, H. (1958) C. R. Soc. Bioi. (Paris), 152, 1267 Miller, J. A., Jr, Robbins, E. B. & Meyers, D. B. (1963) Plisnier, H. (1960) C.R. Soc. Bioi. (Paris), 154, 451 J. pharm. Sci., 52, 446 Plisnier, H., Hernalsteen, L. & La Barre, J. (1959) Moia, V. et al. (1962) Brux.-med., 42, 1123 C.R. Soc. Bioi. (Paris), 153, 363 Maller Nielsen, J. & Neuhold, K. (1959) Acta pharmacal. Plisnier, H. & La Barre, J. (1955) C.R. Soc. Bioi. (Paris), (Kbh.), 15, 335 149, 1070 Monti, G. B. (1963) Clin. ter., 26, 448 Pozetto, H. & Traminer, J. (1963) Lyon med., 209, 829 Morais, M. & Da Silva, J. L. (1961) Portugal med., Practitioner, 1962, 188, 249 45, 32 Prime, F. J. (1961) Brit. med. J., 1, 1649 Morawetz, H. (1951) Med. Welt., 20, 1416 Prokop, H. & Jost, F. (1958) Wien. klin. Wschr., 70, 172 Morren, R. G. (1953) Belgian Patent No. 520,998 Priissing, G. (1960) Dtsch. med. J., 11, 95 Mulargia, A. (1964) Policlinico, Sez. med., 71, 204 Ralph, N. (1954) Amer. J. med. Sci., 227, 297 Mulinos, M. G. (1960a) Pharmacologist, 2, 98 Randall, L. 0. & Selitto, J. J. (1958) J. Amer.pharm. Ass., Mulinos, M. G. (1960b) Toxicol. appl. Pharmacal., sci. Ed., 47, 313 2, 635 Randall, L. 0. et al. (1953) Arch. exp. Path. Pharmak., Mulinos, M. G., Nair, K. G. & Epstein, I. G. (1962) 220,26 N. Y. St. J. Med., 62, 2373 Rasch, M. (1957) Nord. med., 57, 629 Murphy, V. S., Heath, M. M. & Sansocie, C. C. (1962) Reece, C. A. et al. (1966) Amer. J. Dis. Child., 112, 124 J. Amer. Coli. Hlth Ass., 11, 153 Rehermann, R. L. (1962) Curr. ther. Res., 4, 487 Muysers, K. & Siehoff, F. (1960) Arzneimittel-Forsch., Reicherts, P., Zipf, H. F. & Hansen, K. (1957) Arzneimit- 10, 663 tel-Forsch., 7, 739 Naegeli, H. R. (1956) Praxis, 45, 56 Reichle, C. & Friebel, H. (1955) Arch. exp. Path. Phar­ Nagorny, S. (1960) Med. Klin., 55, 2254 mak., 226, 558 Nair, K. G. & Haar, 0. H. (1956) N.Y. St. J. Med., 56, Renovanz, H.-D. & Liebrich, K. G. (1965) Arzneimittel­ 1773 Forsch., 15, 1393 Nathan, L. A. (1962) Appl. Ther., 4, 830 Repaci, M. (1960) Minerva med., 51, 4072 Nerreter, W. (1957) Medizinische, No. 11, 389 Richter, I. B. et al. (1962) Western Med., 3, 138 236 N. B. EDDY AND OTHERS

Riebel, A.-F. (1960) Arzneimittel-Forsch., 10, 794 Silvestrini, B. & Pozzatti, C. (1961) Brit. J. Pharmacal., Riess, 0. (1951) Privatklin. u. Sanat., 4, 78 16,209 Riess, 0. & Tonjes, H. (1951) Med. Wschr., 6, 415 Silvestrini, B. & Pozzatti, C. (1963) Arzneimittel-Forsch., Rimoldi, R. (1960) Gaz. ita!. Tuberc., 14, 243 13,798 Robbins, E. B. & Miller, J. A., Jr, (1960) Pharmacologist, Simon, S. W. (1957b) Ann. Allergy., 15, 521 2,98 Simon, S. W. (1957a) Ohio St. med. J., 53, 1426 Robin, B. A. (1961) Med. Ann. D. C., 30, 525 Simon, S. W. (1960) J. Am. Geriat, Soc., 8, 107 Robiquet, E. (1817) Ann. Chim. Phys., 5, 275 Simon, S. W. (1962) J. Am. Geriat. Soc., 10, 653 Rohr, J. H. (1962) Curr. ther. Res., 4, 21 Simon, S. W. (1963) Ohio St. med. J., 59, 687 Rosiere, C. E., Winder, C. V. & Wax, J. (1956) J. Phar­ Sironi, G. (1956) Minerva anest., 22, 413 macal. exp. Ther., 116, 296 Skursky, J. (1959) Wien. med. Wschr., 109, 507 Rottini, E., Marri, G. & Calandra, P. (1961) Minerva Slomka, M. B. & Goth, A. (1956) J. Pharmacal. exp. med., 52, 3758 Ther., 116, 52 Ruffini, E. (1957) Gaz. int. Med. Chir., 62, 725 Smith, C. R. (1963) Mod. vet. Pract., 44, No. 12, p. 34 Ryde, C. (1960) Svensk. Lak.-Tidn., 57, 797 Snell, E. S. & Armitage, P. (1957) Lancet, 1, 860 Salem, H. & Aviado, D. M. (1964) Amer. J. med. Sci., Snyder, G. G. (1953) Laryngoscope, 63, 1008 247, 585 Sozio, M. et al. (1961) Minerva med., 52, 3760 Saunders, D. C. (1961) Practitioner, 186, 367 Spom, 0. (1952) Praxis, 41, 615 Schaare, U. (1958) Medizin, No. 45, p. 1838 Stefko, P. L., Denzel, J. & Hickey, M. (1961) J. pharm. Schaumann, 0. (1957) Morphin und morphiniihnlich Sci., 50, 216 wirkende Verbindungen, Handbuch der experimentellen Steiger, J. (1955) Praxis, 44, 1081 Pharmakologie, vol. 12, Heidelberg, Springer Stein, P. & Lowry, P. (1946) Amer. Rev. Tuberc., 53, 345 Schallek, W. & Walz, D. (1954) Proc. Soc. exp. Bioi. Stiihmer, W. & Funke, S. (1957) German patent (N.Y.), 87, 233 No. 946,500 Schlesinger (1899) Munch. med. Wschr., 46, 1361 Sugimoto, N. et al., (1960) Chem. pharm. Bull., 8, 745 Schlichtegroll, A. von (1960) quoted by Libal, H. (1960) Swoboda, H. (1950) Praxis, 39, 1108 Med. Welt (Stuttg.), 7, 383 Szasz, V. (1961) Orv. Hetil., 102, 1751 Schmid, J. (1954) Dtsch. med. Wschr., 79, 1191 Taccani, G. (1959) Minerva med., 50, 4396 Schmidt, F. (1960a) Med. Welt, 9, 505 Takagi, E., Fujizawa, T. & Ideguchi, Y. (1958) Jap. Schmidt, F. (1960b) Praxis, 49, 1001 Patent No. 8779 Schmiedel, R. (1959) Ther. d. Gegenw., 98, 239 Testaferrati, A. & Francalancia, L. (1960) Minen·a med., Schoetensack, W. & Hallmann, G. (1964) Arzneimittel- 51, 4064 Forsch., 14, 428 Thalberg, R. E. (1962) West. Med., 3, 473 Schofield, P. B. (1963) Brit. J. clin. Pract., 17, 583 Toner, J. J. & Macko, E. (1952) J. Pharmacal. exp. Ther., Schroder, G. (1899) Ther. d. Gegenw., 1, 113 106, 246 Schroeder, W. (1951) Arch. exp. Path. Pharmak., 212, 433 Trendelenburg, U. (1950) Acta physiol. scand., 21, 174 Schroer, R. (1960) Z. Hats-, Nas.- u. Ohrenheilk., 8, 183 Tropia, G. (1961) Minerva med., 52, 3750 Schumacher, G. (1959) Ther. d. Gegenw., 98, 581 Tiinnerhoff, F. K. & Schwabe, H. K. (1955) Klin. Wschr., Segal, M. S. (1959) J. Amer. med. Ass., 169, 1063 33, 576 Segal, M. S. & Dulfano, M. J. (1952) Quart. Rev. Allergy, Umehara, S. et al. (1961) Minerva med., 52, 3741 6, 399 United Nations (1963) Narcotic drugs under international Segal, M. S. & Dulfano, M. J. (1953) Gen. Pract., 7, 57 control: multilingual list (UN Document No. EjCN7/ Segal, M. S., Goldstein, M. M. & Attinger, E. 0. (1957) 436) Dis. Chest, 32, 305 United Nations Drug Supervisory Body (1966) Estimated Sell, B., Lindner, E. & Jahn, H. (1958) Arch. exp. Path. world requirements of narcotic drugs in 1966, New Pharmak., 234, 164 York, United Nations (Document No. E/DSB/23/ Sevclius, H. & Colmore, J. P. (1967) Clin. Pharmacal. Add. 1) Ther., 8, 381 United Nations Drug Supervisory Body (1967) Estimated Sevelius, H., Lester, P. D. & Colmore, G. P. (1965) Clin. world requirements of narcotic drugs in 1967, New Pharmacal. Ther., 6, 146 York, United Nations (Document No. E/DSB/24/ Shane, S. J., Krzyski, S. E. & Copp, S. E. (1957) Can. Add. 1) med. Ass. J., 77, 600 Valenti, S. & De Palma, M. (1958) Gazz. med. ita!., 117, Shemano, 1., Beiler, J. M. & Hitchens, J. T. (1962) Fed. 194 Proc., 21, 336 Van Dongen, K. (1956) Acta physiol. pharmacal. neerl., Silvestrini, B. & Maffii, G. (1959) Farmaco, Ed. sci., 14, 4, 500 440 Van Howrde, A. J. (1956) Int. Rec. Med., 169, 513 Silvestrini, B. & Pozzatti, C. (1960) Arch. int. Pharma­ Vasselin, M. (1960) France med., 23, 151 codyn., 129, 249 Veberwasser, H. (1962) U.S. Patent No. 3,032,553 CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 4 237

Vedrilla, R. (1952) Wien. med. Wschr., 102, 529 Winder, C. V. et al. (1961) J. Pharmacal. exp. Ther., 133, Vedsi'J, S. (1961) Acta Pharmacal. Toxicol., 18, 157 117 Vergani, F. & Pergani, E. (1956) Gazz. med. ita!., 115, 200 Winter, C. A. & Flataker, L. (1954) J. Pharmacal. exp. Vernier, V. G. & Unna, K. R. (1963) Arch. int. Pharma- Ther., 112, 99 codyn., 141, 30 Winter, C. A. & Flataker, L. (1955a) J. Pharmacal. exp. Versie, R. et al. (1962) Ann. MM. leg., 42, 561 Ther., 113, 55 Vicente Preto, L. & Serrano, G. J. (1962) Medicina, 30, Winter, C. A. & Flataker, L. (1955b) J. exp. Med., 101, 511 17 Villar, T. (1962) J. MM. (Porto), 49, 1006 Winter, C. A. & Flataker, L. (1961) Toxicol. appl. Phar­ Vleeschhouwer, G. R. de (1954) Arch. int. Pharmacodyn., macal., 3, 96 97, 34 Winter, F. 0. (1966) Acta Pharmacal. (Kbh.), 24, Virchow, C. (1961) Praxis, 50, 660 134 Voiculescu, M. & Neuman, M. (1959) Med. Klin., 54, 2305 WHO Expert Committee on Addiction-Producing Wax, J., Winder, C. V., & Peters, G. (1962) Proc. Soc. Drugs (1952) Wld Hlth Org. techn. Rep. Ser., 57 exp. Bioi. (N. Y.), 110, 600 WHO Expert Committee on Drugs Liable to Produce Weaver, L. C. et al. (1957) Fed. Proc., 16, 345 Addiction (1955) Wld Hlth Org., techn. Rep. Ser., Wiedemeijer, C., Kramer, H. W., & De Jongh, D. K. 95 (1960) Acta physiol. pharmacal. near!., 9, 501 WHO Expert Committee on Drugs Liable to Produce Wilcox, W. H. (1923) Brit. med. J., 2, 1013 Addiction (1958) Wld Hlth Org. techn. Rep. Ser., Willner, K. (1963) Arzneimittel-Forsch., 13, 26 142 Wilson, R. H. L., Farber, S. M. & Mandel, W. (1958) WHO Expert Committee on Addiction-Producing Drugs Antibiot. Med., 5, 565 (1962) Wld Hlth Org. techn. Rep. Ser., No. 229 Winder, C. V. & Rosiere, C. E. (1955) J. Pharmacal. exp. Zettel, G. (1955) ;1.'rztl. Praxis, 7, 51 Ther., 113, 55 Ziehme, E. (1960) Kinderiirztl. Praxis, 28, 101 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Codeine and its Alternates for Pain and Cough Relief*

5. Discussion and Summary

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 and probably no particular loss.

CONTENTS

CoDEINE AND ITS ALTERNATES FOR PAIN REUEF OTHER PHARMACODYNAMIC EFFECTS 244 ANALGESIC ACTION 239 UNDESIRED SIDE-EFFECTS IN COUGH THERAPY 244 SIDE-EFFECTS . 241 ABusE UABILITY 246 DEPENDENCE AND ABUSE UABIUTY 241 RESUME . 247 CoDEINE AND ITS ALTERNATES FOR COUGH REUEF ANTITUSSIVE ACTION . 241 REFERENCES 248

Effectiveness and lack of undesirable side-effects, CODEINE AND ITS ALTERNATES FOR PAIN RELIEF 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

-239- 240 N. B. EDDY AND OTHERS

TABLE 71 SUMMARY OF ANALGESIC EFFECTIVENESS OF ORAL DOSES - Man, usual dose Animals, EDso I (m g) Side- I I Dependence liability (mg/kg) I effects a I Single I Per day

Carisoprodol 130-185 350 1 050-1 750 _b None shown in man c Dextropropoxyphene 122 65 200-400 - Ethoheptazine >SOd 75-1soe 300-600 - None Etymide 47-57 75-150 450/ ± Little or none Metofoline 12-55 30-60 180-360 - Little or none Fenyramidol As for codeineY 100-400 400-1 600 + None Prodilidine

a Compared with codeine. b Drowsiness is estimated to occur in 10% of patients. c Barbituate-like in dogs. d The subcutaneous EDso 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. 1 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 of codeine 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, • Houde, R. W. et al. (1960) Reported to the Committee but it has not yet been introduced into general medi­ on Drug Addiction and Narcotics, National Academy of Sciences, Washington, D. C., USA, p. 2312. cal practice. The specific opiate antagonists have not CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 5 241 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 Antitussive action in Table 72, however, may all have some slight 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 judgment of a drug can be expected to include an danger to public health", to which he added" ... wheth­ integration of both effects. On the other hand, er the medical use of codeine 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 wide differences in techniques, criteria and judge­ Judging from the continued popularity of codeine 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 • 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

16 242 N. B. EDDY AND OTHERS CODEINE AND ITS ALTERNATES FOR PAIN AND COUGH RELIEF. 5 243

TABLE!2 CHARACTERISTICS OF CODEINE ALTERNATES AS,NTITUSSIVES COMPARED WITH THOSE OF CODEINEa

Dosage (mg) ' Otheqharmacodynamic actions, relative to codeine

Agent Therapeutic b Bronchial I Anti- Healthy Animal Local Abuse Analgesia e Sedation Respiratory Circulatory Gastro-intestinall inflam- Single Daily volunteers c experiments d !' I anaesthetic liability/ I I I I I i' I Musculature I Secretion I I matory I :; (±) Methadone 2.5 7.5 Ch =C Depression Decrease C Pholcodine 10.0 30.0 C Little or none =C >PII,i None Caramiphen 15.0 60.0 >C =C Noneh Little or none =C Antispas- Anti spas- lncreasej C =C =M >C Dextromethorphan 20.0 60.0 .;;c >C Non eh Improved Little or none k Someh C =C =C Little or none Little or none Like C Nalorphine Like C =C =C =M M >M C 90.0 None" Noneh !Increase h Someh Spasmolytic h >Ph No data Pentoxyverine 25.0 100.0 =C Noneh Little or none Depression h Spasmolytic 11 Spasmolytic h Decrease >Ph None Dimethoxanate 25.0 =C None" Noneh Noneh Depression h Spasmolytic h C None h Depression Noneh Spasmolytic C >C Noneh None Increase h Depression h Spasmolytic h Spasmolytic h Increase h None Clofedanol 35.0 120.0 >C Noneh None ' Little or none h Little or none h None Decrease h >Ph None

Clobutinol 40.0 120.0 >C60:40 =C Noneh None I Little or none Little or none None Increase h None 11 None lsoaminile 40.0 140.0 .;;c Little or none h None C60:30 >C Noneh None Little or none h tlittle or none h Little or none h >P None 100.0 Benzonatate >C 100:30 =C None None 1 Little or none h None Little or none None Levopropoxyphene 100.0 400.0 >C100:15 >C Noneh , None None Benzobutamine 100.0 400.0 =C Slight \None Spasmolytic h None Oxolamine 120.0 600.0 =C

a C = codeine; M = morphine; P = procaine; Co = cocaine. g See Part 4 for details. b Average for adults. h In animal experiments. c Relation to codeine, equipotent cough-depressing doses. Prolonged effect. d Composite of experiments performed with different species, methods of cough stimulation and routes of administration. j In animal experiments; clinical experience conflicting. e Results of animal experiments and clinical experience. k Clinical observation; decreased in animal experiments. I See Part 1 (under respective compounds) and Eddy, Halbach &. Braenden (1957). I Of non-opiate type occasionally; no physical dependence. effective doses estimated from work with human The therapeutic antitussive doses of codeine, daily dose is not necessarily a reliable indicator of antitussive action has been demonstrated for volunteers. A major exception is Bickerman 's summarized in an earlier table (Part 3, Table 29), the strength of antitussive action. It is the amount pholcodine, caramiphen, dextromethorphan, pipa­ (Bickerman et al., 1957) failure to show effectiveness permit the estimation of average oral doses of which experience has shown to be optimal in most zetate, clobutinol, 1 levopropoxyphene and benzo­ of normethadone in normal subjects. Doses used in 20 mg and 70 mg, single and daily, respectively, for instances for the particular preparation and which natate. Others are included in the table which have therapy do not correspond as well with the effective adults. Table 72 shows that pholcodine, norme­ should be interchangeable in efficacy with the been considered alternates for codeine but for which doses in animal experiments, but the exceptions thadone and caramiphen would generally be used average dose of any of the other preparations. available evidence does not permit a firm judgment are mainly among the agents which must be ad­ in smaller doses, dihydrocodeine, ethylmorphine Dihydrocodeine and ethylmorphine are essentially of significance in this respect. Still others have ministered in higher doses than are required for and nalorphine in equal doses, and the others in codeine-like and mainly economic considerations codeine. higher doses than codeine. The average single or govern their use as codeine alternates. Significant 1 Also known as Silomat. 244 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 24S.

TABLE 73 SIDE-EFFECTS REPORTED WITH ANTITUSSIVE DOSES

c: CD ~ .c: CD "'c. CD ., .c: I CD ., c: c. c: 0 c: :I >. CD CD .c: c: .D >< CD -~ CD CD 0 0 CD c: .c: .., >< :0 c: c: 0 > 0 ., c: ~ c. c: 0 CD :0 c. E >. "' c: ! .E .D c: 0 .E >< .c: .., E ·c. .., ~ c: ~ :I .E c. 0 :I 'Qj u ~ -a; N u "' N "'u .., 0 .. 1< .sc: .. :0 .,"' ~ 0 c: 0 .D E 0 .. > "' 0 .. 0 .c: i;; CD CD c. 0 0 0 >< 0: u a. u c a. 0 0: Ill z u !! ...I"' Ill"' 0 u

Drowsiness + + + + + + + + + + I +a Dizziness + + + + + + + Lightheadedness + + i Excitement + + + Restlessness + Insomnia + + Apprehension + Anorexia + + + + + I Nausea + + + + + + + + + + Vomiting + + +b + +c + + + + Headache + + +b + + + + Tightness in chest + Abdominal discomfort + + +d + + + Constipation + + + + Diarrhoea + + + + + Urinary urgency + Visual disturbance + Sputum reduction + +· + + Local reaction + +I +H +h +i +h,i +g,j 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. I 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-1-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 246 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 of the 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 of the 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. 5 247 our opm10n 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, (4) they are devoid, or practically devoid, of abuse even low abuse liability may have more weight and 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.

RESUME

LA CODEINE ET SES SUCCEDANES SEDATIFS DE LA DOULEUR ET DE LA TOUX: 5. DISCUSSION ET RESUME

La codeine et ses succedanes sedatifs de la douleur avantage sur la codeine. A !'exception du propoxyphene, De faibles doses de codeine, administrees par voie qui a ete le plus Jargement utilise et qui a donne lieu a orale, agissent sur Jes douleurs peu intenses d'origines quelques cas d'abus, Jes eventuels succedanes de la tres diverses, mais il semble que J'efficacite du produit ne codeine n'ont jamais ete accuses d'etre a J'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 controle des stupe­ cetine. L'administration par voie orale entraine rarement fiants. Neanmoins, si l'on enjuge par sa vogue persistante des effets secondaires, et si Jes doses sont peu elevees aussi bien parmi les medecins que dans le public - en l'accoutumance et la dependance de type morphinique depit de !'existence sur le marche de preparations dites n'apparaissent que tres Jentement. Lorsque l'intensite de <> - il semble illogique d'abandonner la douleur oblige a augmenter Jes doses, Jes reactions un medicament comme la codeine qui tout en presen­ secondaires sont plus marquees et la dependance se tant des proprietes analgesiques et sedatives generales manifeste plus rapidement, d 'oil la necessite de recherches est aussi actif contre la toux. poussees en vue de decouvrir un analgesique actif par La codeine et ses succedanes sedatifs de la toux voie orale donnant de meilleurs resultats. Les donnees experimentales recueillies dans le cadre La grande variete des techniques et des criteres utilises de ces recherches n'ont pas permis jusqu'a present de par Jes differents chercheurs, ainsi que Jeurs divergences deceler une substance dotee d'un pouvoir analgesique d'opinion, rendent particulierement ardu tout essai plus eleve que celui de la codeine; aucun succedane n'est d'evaluation comparative des proprietes sedatives de la aussi efficace que cette derniere. C'est peut-etre parmi les toux de la codeine et de ses succedanes. On note cepen­ antagonistes specifiques des opiaces que l'on pourra dant une concordance satisfaisante entre les donnees trouver un produit susceptible de remplacer avantageuse­ recueillies au cours de I 'utilisation therapeutique et les ment la codeine. niveaux d'efficacite determines par !'experimentation sur Sous le rapport des effets secondaires, beaucoup des des volontaires. La concordance entre les doses thera­ succedanes etudies supportent avec succes la comparaison peutiques et Jes doses efficaces chez l'animal est moins avec la codeine, et on peut estimer qu'a cet egiud certains reguliere, mais Jes divergences concement principalement progres ont ete realises. Ce facteur ne doit cependant pas les substances qui exigent des dosages superieurs a ceux orienter de fa9on decisive le choix de J'un ou l'autre de la codeine. produit de remplacement, etant donne que l'emploi de la L'activite de la dihydrocodeine et de !'ethylmorphine codeine n'est en aucune maniere limite par J'existence de est essentiellement du meme ordre que celle de la codeine. reactions secondaires. La pholcodine, le caramiphene, le destromethorphane, le En ce qui conceme I '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 efficacite notable contre la proprietes 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 Jeger rieures a celles de la codeine, la dihydrocodeine, l'ethyl- 248 N. B. EDDY AND OTHERS morphine et la nalorphine a des doses equivalentes, et les quence facheuse. Par ailleurs il n'est pas demontre de autres succedanes a des doses superieures. D'autres fa~n indiscutable que l'une ou )'autre de ces substances substances paraissent egalement dotees d'une certaine nouvelles presente a cet egard des avantages ou des activite; elles permettront peut-Ctre d'orienter les futures inconvenients par rapport a la codeine. recherches. La methadone et la normethadone engendrent une D'autres effets pharmacologiques des medicaments dependance de type morphinique. L'usage de la codeine, actifs contre la toux sont examines en connexion avec de la dihydrocodeine et de I '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. 11 est malaise d'apprecier l'interet tberapeutique 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 cree ]'occasion d'experimentations sur ]'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 tberapeutique 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 du 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 ]'ethylmorphine et la normethadone. outre elle associe a son action calmante sur la toux des L'experimentation sur ]'animal montre que le cara­ effets sedatifs generaux. En tbeorie, plusieurs des succe­ mipbene, 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. 11 est marquee, quelle que soit !'affection qui provoque le done 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. 11 reste qu'aucun d'entre eux n'a fait l'objet d'une Dans I'ensemble, les eventuels succedanes de la codeine etude suffisamment complete pour que ]'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. (1957) Bickerman, H. A. (1960) In: Gordon, B. L., ed., Clinical Bull. Wld Hlth Org., 17, 569 and cardiopulmonary physiology, New York, Grune Gravenstein, J. S., Devloo, R. A. & Beecher, H. K. (1954) & Stratton, p. 495 J. appl. Physiol., 7, 119 Bickerman, H. A. & Itkin, S. E. (1960) Clin. Pharmacal. Renovanz, H. D. & Liebrich, K. G. (1965) Arzneimittel­ Ther.,1,180 Forsch., 15, 1393 Boyd, E. M. (1946) Lancet, 2, 735 Seevers, M. H. (1967) In: International Narcotics En­ Brit. med. J., 1964, 1, 1165 forcement Officers Association, Proceedings of the Cass, L. J. & Frederik, W. S. (1953) New Engl. J. Med., meeting of the ... , Montreal, 1966 249, 132 Silvestrini, B. & Pozzatti, C. (1960) Arch. int. Pharma- Cass, L. J., Frederik, W. S. & Andosca, J. B. (1954) Amer. codyn., 129, 249 J. med. Sci., 227, 291 Swyer, P. R. (1956) Canad. med. Ass. J., 75, 524 Cass, L. J., Laing, J. T. & Frederik, W. S. (1961) Curr. Wolff, P. 0. (1938) Bull. Hlth Org. L. o. N., 7, 546 ther. Res., 3, 289 Woolf, C. R. & Rosenberg, A. (1964) Thorax, 19, 125 SUBJECT INDEX

Acetamides, 101 N-Benzylcodeine iodide, 166 Acetonitriles, 217 N-Benzylnorcodeine methiodide, 166 AF-634 Bibenzonium bromide, 167 See 5-[2-(Diethylamino)ethyl]-3-(1-phenyl)propyl-1 ,2, N-Butylnormorphine, 168 4-oxadiazole CL-427 Alimenazine, 195 See Prodilidine (-)N-Allyl-3-hydroxymorphinan Caramiphen [bis-(Diethylaminoethyl 1-phenyl-1-cyclo­ See Levallorphan pentane carboxylate)ethane disulfonate], 142, 150, N-Allylnorcodeine, 168 153, 208, 231, 242, 244, 245, 246 N-Allylnormorphine Carbetapentane See Nalorphine See Pentoxyverine Alphaprodine, 13 Carbifene · Amines related to homarylamine, 183 See Etymide p-Aminobenzoic acid ethyl ester Carisoprodol [2-Methyl-2-propyl-1 ,3-propanediol carba­ See Ethoform mate isopropyl carbamate; N-Isopropyl-2-methyl-2- 2-Aminoindane, 116, 129, 138, 140, 153 propyl-1,3-propanediol dicarbamate; Soma], 73, 76, Aminophthalidylalbanes, 116 77, 119,240 Anaesthesia, 131, 141 Chlorcyclizine [Chlorocyclizine; 1-(p-Chloro-a-phenyl­ Analexin benzyl)-4-methylpiperazine], 201 See Fenyramidol 2-Chloro-a-(2-dimethylaminoethyl)benzhydrol Anileridine, 13 See Clofedanol Antagonists, specific opiate N-(p-Chlorobenzyl)-N-(2-pyridyl)-N,N-dimethylethylene­ See also by name, Levallorphan, Nalorphine, etc., 117, diamine, 200 119, 168, 240 p-Chloro-a-[2-(dimethylamino)-1-methylethyl]- a-methyl­ Antihistamines, 142, 195, 200, 201 phenethyl alcohol APC [Aspirin, phenacetin, caffeine], 17, 83 See Clobutinol Arylbutanols, 210 ( ±) 1-(p-Chlorophenethyl)-6,7 -dimethoxy-2-methyl-1,2,3, Arylpentanols, 210 4-tetrahydroisoquinoline Aspirin, 13-17, 74, 75, 83, 103, 104, 111, 115, 118 See Metofoline AT-327 [1-Methyl-3-di-(2 'thienyl)-methylene-piperidine], 1-(p-Chloro-a-phenylbenzyl)-4-methylpiperazine 142, 193, 242 See Chlorcyclizine Atropine, 142 1-(p-Chlorophenyl)-2,3-dimethyl-4-dimethylamino­ Ba 10 611 [Melipan; (,8-Morpholinoethyl)-1-cyclopentyl­ butan-2-ol cyclopentan-2-one], 227 See Clobutinol Ban dol 1-(o-Chlorophenyl)-1-phenyl-3-dimethylaminopropan- See Etymide 1-ol Barbiturates See Clofedanol See also Hexobarbital Chlorpromazine, 141, 195 Becantex See Sodium dibunate Clobutinol [Silo mat; p-Chloro-a-[2-(dimethylamino )-1- Becantyl methylethyl]-a-methylphenethylalcohol; 1-(p-Chloro­ See Sodium dibunate phenyl)-2,3-dimethyl-4-dimethylamino-butan-2-ol], Benadryl 19,142,210,231,242,244,245 See Diphenhydramine Clofedanol [Chlofedianol; Detigon; 2-Chloro-a-(2-di­ Benzhydryl-diethylaminoethanol methylaminoethyl) benzhydrol; 1-(o-Chlorophenyl)- See Diphenhydramine 1-phenyl-3-dimethylaminopropan-1-ol], 142, 204, Benzobutamine [N-(2-Benzoyloxymethyl-2-phenylbutyl)­ 214, 217, 231, 242, 245, 246 N,N-dimethylamine], 150, 201 Cocaine Benzonatate [2,5,8, 11,14,17 ,20,23,26-Nonoxaoctacosan- See Local anaesthetics 28-ol-p-butylaminobenzoate; Nonaethyleneglycol Codeine 3, 28, 46, 53, 59, 74, 127, 130, 138, 140, 142, 147, methyl ester of p-(n-butylamino) benzoic acid], 138, 150, 152, 158, 160, 161, 162, 163, 166, 171, 173, 174, 153, 182, 202, 228, 230, 241, 242, 245 179, 180, 195, 210, 215, 225, 239, 240, 242, 244, N-(2-Benzoyloxymethyl-2-phenylbutyl)-N,N-dimethyl­ 245 amine Codeine combinations, 14, 15, 17, 82, 83, 88, 92 See Benzobutamine Codeine glycosides, 19

249- 250 SUBJECT INDEX

Codeine nicotinic acid ester Cothera See Nicocodine See Dimethoxanate Codeine N-oxide, 166 Cyclazocine [2-Cyclopropylmethyl-2 '-hydroxy-5,9-di- Codeine resinate, 19 methyl-6,7-benzomorphan], 118 Codeine versus Antagonists, 168 Cycloalkenones, 227 Codeine versus AT-327, 142, 193, 242 2-Cyclopropylmethyl-2 '-hydroxy-5 ,9-dimethyl-6, 7-benzo­ Codeine versus Ba 10 611, 227 m orphan Codeine versus Benzobutamine, 201, 242 See Cyclazocine Codeine versus Benzonatate, 203, 205, 242 N-Cyclopropylmethyl-3-hydroxymorphinan Codeine versus Bibenzonium bromide, 167 See Cyclorphan Codeine versus Caramiphen, 208, 209, 211, 242 Cyclorphan [N-Cyclopropylmethyl-3-hydroxymorphinan], Codeine versus Carisprodol, 74, 75, 240 119 Codeine versus Chlorocyclizine, 201 Darvon Codeine versus Clobutinol, 213, 242 See Dextropropoxyphene Codeine versus Clofedanol, 214, 242 Detigon Codeine versus Codeine plus aspirin, 17 See Clofedanol Codeine versus Codeine-N-oxide, 166 Dexamphetamine, 18 Codeine versus Dextromethorphan, 169, 172, 174, 175, Dextromethorphan [( + )3-Methoxy-N-methylmorphin­ 242, 245 an], 138, 140, 143, 149, 150, 153, 158, 203, 204, 229, Codeine versus Dextropropoxyphene, 51, 78, 79, 80, 82, 242, 244, 245, 246 83, 88, 90, 191, 240 Dextromethorphan plus Alcohol, 178 Codeine versus Dihydrocodeine, 94, 158, 240, 241 Dextropropoxyphene [Darvon; a-(+ )-4-Dimethylamino- Codeine versus Dimethoxanate, 199, 242 3-methyl-1,2-diphenyl-2-propionyloxybutane], 51, 58, Codeine versus Diphenhydramine, 201 78, 97, 103, 104, 111, 113, 114, 116, 119, 191, 240 Codeine versus Diphenylpiperidinopropanol, 217, 242 Dextropropoxyphene combinations, 82, 83, 88 Codeine versus Ethoheptazine, 98, 99, 240 Dialkylamino-1,2-diphenyl butanols, 78 Codeine versus Ethyl dibunate, 228 Dibunate plus Normethadone, 229 Codeine versus Ethyl morphine, 158, 242 Dibunate, Sodium Codeine versus Etymide, 102, 103, 240 See Sodium dibunate Codeine versus Fenyramidol, 104, 105, 240 2,6-Di-tert-butyl-4-bromotriethanolamine naphthalene, Codeine versus Heroin, 51 229 Codeine versus Isoaminile, 218, 242 2,6-and/or 2,7-Di-tert-butyi naphthalene-sulfonate, sodi­ Codeine versus L-2909, 195 um salt Codeine versus Levopropoxyphene, 190, 242 See Sodium dibunate Codeine versus Meprotixol, 200 2-(2-Diethylaminoethoxy) ethyl 2-ethyl-2-phenylbutyrate Codeine versus Mepyramine, 201 See Oxeladin Codeine versus Methadone, 185, 187, 242 2-Dimethy laminoethoxyethy !-phenothiazine-! 0-carboxy l­ Codeine versus Methaqualone, 219 ate, 199 Codeine versus Metofoline, 51, 108, 109, 111, 113, 240 Diethylaminoethoxyethyl phenylcyclopentyl carboxylate Codeine versus Morphine, 20, 21, 22, 41, 51 See Pentoxyverine Codeine versus Nalorphine, 167, 242 Diethylaminoethyl morphine, 160 Codeine versus Nicocodine, 164, 165 is-[Diethylaminoethyl-1-phenyl-1-cyclopentane carboxy­ Codeine versus Normethadone, 187, 188, 242 late]ethane disulfonate Codeine versus Noscapine, 178, 179, 180, 242 See Caramiphen Codeine versus Oxeladin, 219 5-[2-(Diethylamino )ethyl]-3-phenyl-1 ,2,4-oxadiazole Codeine versus Oxolamine, 220, 221, 242 See Oxolamine Codeine versus Pentazocine, 118 5-[2-(Diethylamino)ethyl]-3-(1-phenyl)-propyl-1 ,2,4-oxa­ Codeine versus Pentoxyverine, 224, 242 diazole; [AF-634], 224 Codeine versus Pethidine, 51 Diethylcongeners of dimethoxanate, 199 Codeine versus Phenothiazines, 195 Dihydrocodeine [Paracodin], 12, 94, 108, 119, 140, 158, Codeine versus Pholcodine, 165, 242 164, 166, 182, 229, 240, 241, 244, 246 Codeine versus Pipazetate, 196 Dihydrocodeine nicotinic acid ester Codeine versus Prodilidine, 114, 195, 240 See Nicodicodine Codeine versus Promethazine, 195 Dihydrocodeine-N-oxide, 166 Codeine versus Sodium dibunate, 228, 242 Dihydrocodeine pectinate, 96 Codeine versus Thiambutenes, 193 Dihydroisocodeine, 149 Codeine versus Win-13, 187, 194 Dimethoxanate [Cothera; 2-Dimethylaminoethoxyethyl Cotarnine, 183 phenothiazine-10-carboxylate], 195, 199, 242, 245 SUBJECT INDEX 251

Dimethoxanate congeners, 199 Ethyl 1-methyl-4-phenyl-4-hexamethyleneimine carboxy­ (±)6-Dimethylamino-4,4-diphenyl-3-heptanone late See Methadone See Ethoheptazine 6-Dimethylamino-4,4-diphenyl-3-hexanone Ethylmorphine [Dionin], 39, 140, 158, 229, 242, 244, 246 See Normethadone Ethyl narceine, 183 2-Dimethylaminoethoxyethyl phenothiazine-10-carboxy­ Etymide [Etomide; Carbiphene; Bandol; 2-Ethoxy-N­ late methyl-N-[2-(methylphenethylamino) ethyl]-2,2-di­ See Dimethoxanate phenyl-acetamide], 101, 120, 240 2-[(2-Dimethylaminoethyl)-(p-methoxybenzyl)amino]­ Fenyramidol [Phenyramidol; Analexin; a-(2-Pyridyl­ pyridine aminomethyl) benzyl alcohol], 104, 106, 120, 240 See Mepyramine Fortral Dimethylaminoethyl morphine, 160 See Pentazocine 4-Dimethylamino-2-isopropyl-2-phenylvaleronitrile Heroin, 12, 31, 39, 51, 93, 135, 149, 150, 163 See Isoaminile Hexamethonium, 141, 153, 166 (±)6-Dimethylamino-5-methyl-4,4-diphenyl-3-hexanone Hexamethyleneimines, 97, 99 See Isomethadone Hexobarbital, 138, 140, 153 a-(+ )-4-Dimethylamino-1,2-diphenyl-3-methyl-2-butanol Homarylamine, 183, 241 propionate ester Hydrastine, 183 See Dextropropoxyphene Hydrastinine, 183 a-(-)-4-Dimethylamino-1,2-diphenyl-3-methyl-2-butanol Hydrocodone, 160, 182, 200, 207 propionate ester Hydromorphone, 48 See Levopropoxyphene Hydromorphone-N-oxide, 166 9-[3-(Dimethylamino) propyl]-2-methoxy-thioxanthene- fl-Hydroxyalkylaminopyridines, 104 9-ol; 5-Dimethylaminopropyl-5-hydroxythioxanthene 1-K-1 See Meprotixol See Metofoline ( ±)-5,9-Dimethyl-2-dimethylalkyl-2' -hydroxy-6, 7- benzo­ lndanes, 116, 120, 129, 138, 139, 140, 153 morphan Isoaminile [Dimyril; Peracon; a-lsopropyl-a-(fl-dimethyl­ See Pentazocine aminopropyl)phenylacetonitrile citrate; 4-Dimethyl­ 1-Dimethylamino-3-phenylindane, 116 amino-2-isopropyl-2-phenylvaleronitrile ], 142, 151, 1 ,2-Dimethyl-3-phenyl-3-pyrrolidyl propionate 153,217,242,244,245,246 See Prodilidine Isomethadone [( ±)6-Dimethylamino-5-methyl-4,4-di- Dimyril phenyl-3-hexanone], 184 See lsoaminile Isopropylcongener of Dimethoxanate, 199 Dionin a-Isopropyl",ar(fl-dimethylaminopropyl)phenylacetonitrile See Ethylmorphine citrate Diphenhydramine [Benadryl; Benzhydryl-diethyamlino­ See Isoaminile ethanol], 142, 153, 200, 201 N-Isopropyl-2-methyl-2-propyl-1 ,3-propanediol dicarba­ 2-Diphenylmethoxy-N,N-dimethylethylamine mate See Diphenhydramine See Carisoprodol Diphenyl propanes, 214 Isoquinolines, 105, 178 I ,1-Diphenyl-2-piperidinopropan-1-ol, 216 L-1633 Diphepanol See Sodium dibunate See I 1-Diphenyl-2-piperidinopropan-1-ol L-2909 Dithienyl ethanols, 194 See 1-Phenethyl-4-propargyl-4-propionoxypiperidine Dithienyl propanols, 194 Levallorphan [(-)-3-Hydroxy-N-allyl morphinan], 61, Ephedrine, 142 168 Epinephrine, 142 Levopropoxyphene[Novrad; a-(-)-4-Dimethylamino-1 ,2- Ethoform [p-Aminobenzoic acid ethyl ester], 137 diphenyl-3-methyl-2-butanol propionate ester], 78, Ethoheptazine [Ethyl-1-methyl-4-phenyl-4-hexamethyl- 134, 151, 190, 230, 242, 245, 246 eneimine carboxylate], 96, 98, 99, 240 Levopropoxyphene-N-oxide, 166, 190 Ethoheptazine plus Aspirin [Zacterin], 98, 99 Levorphanol, 13, 20, 95, 173 2-Ethoxy-N-methyl-N-[2-(methylphenethylamino)-ethyl]- Linctussal 2,2-diphenyl-acetamide See Sodium dibunate See Etymide Local anaesthetics, 137, 139, 142, 153 Ethyl-!-< 2-carbamylethyl)-4-phenyl-4-piperidine carboxy­ Melipan late [Win-13187], 194 See Ba 10611 Ethyl dibunate, 151, 228 Melsedin Ethyl 2. 7-di-tert-butyl-naphthalenesulfonate, 228 See Methaqualone 252 SUBJECT INDEX

Meprobamate, 73, 75 Nicodicodine [6-Nicotinic acid ester of dihydrocodeine], Meprotixol [9-[3-(Dimethylamino)propyl]-2-methoxy-thi­ 142, 164, 165, 229 oxanthene-9-ol], 200 6-Nicotinic acid ester of codeine Mepyramine [Neoantergan; 2-[(2-Dimethylaminoethyl)­ See Nicocodine (p-methoxybenzyl) amino] pyridine; N-(p-Methoxy­ 6-Nicotinic acid ester of dihydrocodeine benzyl)-N-(2-pyridyl)-dimethylaminoethylamine],201 See Nicodicodine Methadone [( ± )6-Dimethylamino-4,4-diphenyl-3-hepta- Nicotinic acid ester of pholcodine, 164, 165 none hydrochloride], 140, 158, 184, 230, 242, 246 Nonaethyleneglycol methyl ester of p-(n-butylamino) Methadone isomers, 184 benzoic acid N-Methallylnormorphine, 168 See Benzonatate Methamphetamine, 142 2,5,8,11 ,14,17 ,20,23,26-Nonoxaoctacosan-28-ol-p-butyl­ · Methaqualone [Melsedin; 2-Methyl-3-o-tolyl-4(3H)-quin­ aminobenzoate azolinone], 16, 141, 219 See Benzonatate Methopholine Norcodeine, 60 See Metofoline Normethadone [6-Dimethylamino-4,4-diphenyl-3-hexa­ N-(p-Methoxybenzyi)-N-(2-pyridyl)-dimethylaminoethyl­ none], 134, 140, 158, 187, 230, 242, 244, 245 amine Normethadone plus Dibunate, 229 See Mepyramine Noscapine [Narcotine; Nectadon], 140,168,178,230,242, ( +) 3-Methoxy-N-methylmorphinan 244, 245 See Dextromethorphan Novrad 2-(o-Methoxyphenoxymethyl)-5-oxazolidone See Levopropoxyphene See Metoxadone Orphenadrine, 18 N-(p-Methoxyphenyi)-N-(2-pyrimidyl)-N,N-dimethylene­ Oxadiazoles, 219, 224 diamine, 200 Oxeladin [Pectamol; 2-(2-Diethylaminoethoxy) ethyl- 1-Methyl-3-di-(2 'thienyl) methylene-piperidine 2-ethyl-2-phenylbutyrate], 142, 219 See AT-327 N-Oxides, 166, 229 1-Methyl-3-phenylpyrrolidines, 117 Oxolamine [Perebron; 5-[2-(Diethylamino) ethyl]- Methylpropamine, 142 3-phenyl-1,2,4-oxadiazole], 139, 142, 150, 153, 219, 2-Methyl-2-propyl-1,3-propanediol carbamate isopropyl 231, 242, 244, 245 carbamate Oxycodone-N-oxide, 166 See Carisoprodol Papaverine, 6, 12, 142, 183 2-Methyl-3-o-tolyi-4(3H)-quinazolinone Paracodin See Methaqualone See Dihydrocodeine Metofoline [Methopholine; Versidyne, 1-K-1; 1-p-Chloro­ Pectamol phenethyl-6, 7-dimethoxy-2-methyl-1 ,2,3,4-tetra­ See Oxeladin hydroisoquinoline], 51, 58, 105, 119, 240 Pentamethonium, 142, 166 Metofoline plus Aspirin, 111 Pentazocine [Fortral; Talwin; (±) 5,9-Dimethyl- Metoxadone [2-(o-Methoxyphenoxymethyl)-5-oxazoli- 2-dimethylalkyl-2' -hydroxy-6,7-benzomorphan], 117 done], 95 Pentoxyverine [Carbetapentane; Diethylaminoethoxy­ Morphine, 6, 7, 12, 14, 20, 21, 22, 26, 31, 34, 41, 51, 58, ethyl phenylcyclopentyl carboxylate], 140, 142, 79, 80, 81, 92, 95, 96, 97, 105, 108, 110, 116 143, 153, 219, 224, 231, 242, 244, 245, 246 Morphine-N-oxide, 166 Peracon 1-(fl Morpholinoethyl)-1-cyclopentenyl-cyclopentan-2-one See Isoaminile SeeBa 10611 Perebron 0 3-(2-Morpholinoethyl)-morphine See Oxo1amine See Pholcodine Pethidine, 13, 20, 51, 60, 82, 83, 95, 96, 97, 99, 101, 102, Nalorphine [N-AIIylnormorphine], 78, 81, 87, 92, 96, 101, 108, 112, 113, 140, 158, 194 103, 116, 117, 160, 167, 179, 193, 194,,229, 242 Pethidine congeners, 194, 230 Narceine, 183 1-Phenethyl-4-propargyl-4-propionoxypiperidine Narcotine [L-2909], 194 See Noscapine Phenothiazines, 141, 195 Nectadon 2-(2-Phenylethanolamino)-pyridine See Noscapine See Fenyramidol Neoantergan Phenyramidol See Mepyramine See Fenyramidol Neuroleptics, 141 Pholcodine [(03-(2-Morpholinoethyl)-morphine)]. 135, Nicocodine [6-Nicotinic acid ester of codeine], 142, 164, 140, 142, 151, 153, 160, 164, 168, 204, 229, 242, 245 165, 229 Pholcodine nicotinic acid ester, 164 SUBJECT INDEX 253

Phthalimides, 116, 117, 120 Soma Piminodine See Carisoprodol See Prodilidine Spasmolytics, 142 Pipazetate [Piperidinoethoxyethylazaphenothiazine-10- Sq 10 269 carboxylate], 139, 140, 150, 153, 196, 242, 244, 245 See Etymide Piperidinoethoxyethylazaphenothiazine-1 0-carboxylate Tal win See Pipazetate See Pentazocine Piperidinoethyl morphine, 160 Taoryl Placebo, 28, 82, 83, 103, 105, 137, 146, 149, 245 See Caramiphen Procaine Tessalon See Local anaesthetics See Benzonatate Prodilidine [Piminodine; CL-427; 1,2- Dimethyl-3-phenyl- 3-pyrrolidyl propionate], 92, 114, 120, 195, 240 Tetracaine, 138, 139 Prodilidine plus Aspirin, 115 Thalidomide, 117 Propoxyphene, 78, 79, 81,90, 91, 93,102,103,190 Theratuss See also Dextropropoxyphene See Pipazetate d-Propoxyphene Thiambutenes, 193 See Dextropropoxyphene Thiazinamium, 195 /-Propoxyphene Thioridazine, 141, 195 See Levopropoxyphene Ticarda [Norrnethadone plus Suprifen] N-Propylnormorphine, 168 See Norrnethadone a-(2-Pyridylaminomethyl)benzyl alcohol Toclase See Fenyramidol See Pentoxyverine N-[2-(2'-Pyridyl)ethyl]phthalimide, 116 Toryn Pyrrolidines, 117, 120 Quaternary salts, 142, 166 See Caramiphen Ro 4-1778/1 Tussukal See Metofoline See 1,1-Diphenyl-2-piperidino-propan-1-ol Romilar Ulo See Dextromethorphan See Clofedanol Selvigon Versidyne See Pipazetate See Metofoline Silomat Win-13 187 See Clobutinol See Ethyl 1-(2-carbamylethyl)-4-phenyl-4-piperidine Sodium dibunate [Becantex; Becantyl; Linctussal; carboxylate L-1633; 2,6-and/or 2,7-di-tert-butyl naphthalene­ Zactirin compound [Ethoheptazine plus Aspirin] sulfonate], 139, 204, 227, 231, 245 See Ethoheptazine WHO Publications may be obtained through: Les publications de l'OMS peuvent etre obtenues aupres de:

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