Bull. Org. mond. Bull. Wid Hith Org.Sant) 1963, 28, 139-173

Tests for Addiction (Chronic Intoxication) of Morphine Type

H. HALBACH, Dr.med. Dr.-Ing.' & NATHAN B. EDDY, M.D.2

A survey is presented of laboratory and clinical methods for the determination of addiction liability of substances with morphine-like effects. Since physical dependence is the outstanding pharmacological criterion ofaddiction ofmorphine type, the procedures for its qualitative and quantitative assessment are described in detail.

CONTENTS Page Introduction ...... 139 Tests for appraisal of physical dependence in animals . . . 140 Tests for addiction (abuse) liability in former addicts . . . . 150 Tests for development of tolerance and physical dependence under clinical conditions ...... 156

Tests for detection of drug use and recidivism ...... 159

Discussion and summary ...... 161

Resum ...... 163

References ...... 164

Annexes ...... 166

INTRODUCTION The purpose of this definition was to aid in the characterization of substances which have been or In its seventh report, the WHO Expert Committee should be subjected to international narcotics on Addiction-Producing Drugs (1957) defined control. Some of the characteristics in the defini- addiction as follows: tion, the first and last particularly, are demonstrable " Drug addiction is a state of periodic or chronic intoxica- only through prolonged experience and are, in part tion produced by the repeated consumption of a drug at least, based upon impressions rather than upon (natural or synthetic). Its characteristics include: quantitative data: tolerance and physical dependence (1) an overpowering desire or need (compulsion) to can be measured quantitatively. continue taking the drug and to obtain it by any means; Expressing themselves in more strictly pharma- (2) a tendency to increase the dose; cological terms, Himmelsbach & Small (1937) said (3) a psychic (psychological) and generally a physical that addiction embraced three intimately related dependence on the effects of the drug; but distinct phenomena-tolerance, habituation (4) detrimental effect on the individual and on society." and physical dependence. They were speaking of the opiates, morphine and morphine derivatives, I Chief, Addiction-Producing Drugs, World Health but the statement applies to all synthetic substances Organization, Geneva, Switzerland. with morphine-like effect. Tolerance, the gradual 2 Consultant to the National Institutes of Health, Bethesda, Md., USA, and to the World Health Organiza- decrease in an effect developing during the repeated tion. administration of a drug, is measurable to the extent

1222 - 139 - 140 H. HALBACH & N. B. EDDY

that quantitative methods are available for investi- TESTS FOR APPRAISAL OF PHYSICAL DEPENDENCE gating the effect in question. It can occur with a wide IN ANIMALS variety of substances, whether or not morphine-like. Habituation is a psychic dependence, adaptation Since the abstinence symptoms on which the and mental conditioning to the repetition of an assessment of physical dependence is based occur effect manifested by craving for and efforts to bring on a high level of physiological organization, the about continuation of the drug's administration. experimental object used is as a rule the whole Its possibility in animals has been claimed (Krueger, animal. However, the occurrence of abstinence Eddy & Sumwalt, 1941b) and denied (Lindesmith, phenomena has also been shown in objects of a 1937). Currently efforts are being made to prove lower level of organization, such as tissue-cultures. its development and measure it quantitatively. Semura (1933), Sanjo (1934), Nakazawa (1937), and Physical dependence is an essential characteristic of Sasaki (1938) observed the development of tolerance opiate addiction. It is the distortion of physiological to the growth-inhibiting effects of morphine and processes which results from prolonged administra- certain of its derivatives in cultures of fibroblasts tion of a drug and which requires the presence of an and iris epithelial tissue, and furthermore, as a con- adequate amount of an addicting drug in the body sequence of the withdrawal of these drugs, either for the maintenance of physical equilibrium. Phy- restoration of growth or damaging effects. The sical dependence is demonstrated bythe appearance of curative effect of morphine and its derivatives on a characteristic syndrome of abstinence phenomena. the latter was also described and the more abrupt the withdrawal, the more pronounced were the abstin- Until comparatively recently the only means of ence signs (Kubo, 1939). However, these findings judging over-all addiction liability was the general did not lead to the development of methods of impression from prolonged clinical experience, and evaluation (Heubner et al., 1952); nor has this been under these circumstances years might elapse before the case with certain reactions in isolated organs a reasonably accurate appraisal was attained. The which might be interpreted as signs of abstinence establishment of the Addiction Research Center on the basis of a physical dependence, such as the at the Public Health Service Hospital for addicts at inhibitory effect of the withdrawal of morphine on Lexington, Ky., USA, led to the development of at the rabbit's heart (Wada, 1928) or the stimulation least semi-quantitative measurement of morphine- produced in the same way in preparations of intes- like properties as they related to addiction. Also the tines (Abe, 1930; Fujita, 1931; see also Paton, 1957). unequivocal demonstration of withdrawal pheno- A more intimate analysis of these phenomena might mena in animals, proving the universality among disclose some parallelism between the physical species of physical dependence as a pharmacological dependence reactions of single cells, tissues, and consequence, stimulated efforts to measure it quanti- isolated organs on the one hand and of the whole tatively. Therefore, there are now available tests animal organism on the other. applicable to animals and to man which permit an For practical purposes there are at present avail- early estimate of the relative risk of abuse and of able physical dependence tests in various animal addiction to be expected under clinical conditions. species with a varying degree of reliability, that is, In addition the production of nalorphine and other comparability to what happens in man. morphine antagonists and the discovery of their ability to precipitate an abstinence syndrome when Mice physical dependence exists has made possible early After prolonged administration of morphine and detection of physical dependence and developing analgesics with morphine-like effect mice do not addiction under usual clinical conditions. appear to react to their abrupt withdrawal with In this report we propose to describe these tests symptoms which are sufficiently regular and distinct for addiction under four heads: appraisal of physical for an assessment of physical dependence. In the dependence in animals; determination of addiction hope of finding a correlation between tolerance to (abuse) liability in former addicts; measurement of the toxic effects of morphine and morphine-like the development of tolerance and physical depend- substances and their addiction liability, it has been ence under clinical conditions; and detection of drug repeatedly examined whether mice can acquire a use and recidivism. Our purpose is to assess the tolerance to the toxic (lethal) effects of such drugs by relative importance, reliability and interpretation of their chronic administration in increasing doses. the tests and to stimulate their broader application. From an extensive survey of the literature and from TESTS FOR ADDICTION (CHRONIC INTOXICATION) OF MORPHINE TYPE 141 her own experiments, Fichtenberg (1951) concluded correlation (0.75 (P < 0.01)) was found between that mice do not, or not nearly so easily as several the Straub index and the "estimated " addiction other species, become tolerant to the toxic effects of liability in man in a series of drugs, including, inter morphine. Mercier and associates (1957) found that alia, phenazocine, hydromorphone, heroin, mor- mice acquired no tolerance to the LD50 of heroin, phine, methadone, pethidine, codeine, dextro- oxycodone, or pethidine, and only a partial and propoxyphene and nalorphine. For most of the incomplete tolerance to that ofmorphine, methadone drugs tested, a similar correlation was noted between and levorphanol. However, in the latter cases the addiction liability and " analgesic index " in mice development of tolerance was not uniform and was (LD5O/ED5O analgesic effect), but a specific exception difficult to compare because of different regimens of (apomorphine) throws doubt on the interchange- administration. ability of the indices. In view of the failure to establish a correlation between addiction liability and tolerance to the toxic Rats effects, the relation between the tolerance of mice to Joel & Ettinger (1926) reported on the occurrence the analgesic properties of the substance in question of withdrawal phenomena in rats and their relief by and its addicting properties has been investigated. the re-administration of morphine. On the basis of Using a modification of Woolfe & MacDonald's Barlow's (1932) observation that increased irritability test (hot plate; licking response) Jacob and associates was a measurable and rather constant response of (1958) examined a benzodioxane derivative (3570 CT) rats to the sudden interruption of chronic morphine which had, in mice, half the analgesic activity of administration, Himmelsbach and associates (1935) morphine. When given in equi-analgesic doses developed a method for the assessment of physical tolerance developed to the analgesic effect of both dependence. The drugs tested in this way (morphine, substances. However, when tested in monkeys (for codeine, heroin) were administered every 24 hours method, see page 148 of this report) 3570 CT did not for five to six weeks and then abruptly withheld. produce evidence of physical dependence. Con- Eddy & Himmelsbach (1936), applying in principle tinuous administration by means of subcutaneous the same method, found that desomorphine had to implantation of morphine (base) seemed to favour be given at shorter intervals in order to produce a the development of tolerance to various morphine significant response with regard to physical depend- effects (such as sedation, analgesia, Straub reaction) ence. According to Stanton (1936) the signs follow- and also the development of physical dependence, as ing abrupt withdrawal, after four weeks of morphine shown by the unmasking action of nalorphine; but injections, reached a peak within two to four days the symptoms of nalorphine-induced withdrawal of withdrawal. Fichtenberg (1951) reported that were not uniform enough for an evaluation ofphysi- rats tolerant to 50 mg of morphine subcutaneously cal dependence (Maggiolo & Huidobro, 1961). per 100 g body-weight became agitated and aggres- Correlations have also been sought between the sive on the second and third days after discontinua- Straub tail-reaction in mice and addiction liability tion of morphine, with loss of weight, either tem- in man. While the low tendency of mice to develop porary with recovery or continuing until death. tolerance to the effects of morphine refers also to the Motivated by the irregular results of withdrawal tail reaction (see Krueger, Eddy & Sumwalt, 1941a), experiments with rats, Mercier & Sestier(1954) meas- Shemano & Wendel (1960; also personal communica- ured the development oftolerance and physical depen- tion, 1962) believe that the determination of a dence by means of a discriminatory training test " Straub index" in mice might be useful for initial (choice between green and red drinking-water, with screening for potential addiction liability in man. electrical punishment for the latter). The discrimi- They reported that, when drugs were administered natory performance was totally abolished by a single intravenously, the wider the dosage separation subcutaneous dose of80mg ofmorphine perkg and, as between drug-induced Straub tail-reaction and a result of tolerance, reappeared during continuing death, the greater was the probability of high administration of increasing morphine doses of up addiction liability. Compounds with a narrow to 120 mg/kg daily. Thirty-six to forty-eight hours dosage separation are likely to be minimally or after the abrupt withdrawal of morphine the dis- mildly addicting. The degree of separation was criminatory performance was seriously disturbed, expressed by the Straub index (LD50/ED60 Straub but not completely abolished. Concomitant symp- reaction). A statistically significant rank-order toms appearing after the same interval were increased 142 H. HALBACH & N. B. EDDY

motor activity, aggressiveness, squeaking, and hor- of etonitazene in the solution. With concentrations ripilation. All signs disappeared, generally within of 20 and 40 ,ug/ml of etonitazene, all signs of four days. With heroin, oxycodone, pethidine, morphine abstinence were suppressed but signs levorphanol and methadone, also, the disturbance resembling those of chronic morphine intoxication of the acquired behaviour could be demonstrated (increased locomotor activity, hyperthermia and and so could its re-establishment as a sign of toler- elevated oxygen consumption) were manifest. ance (Mercier & Mercier, 1957). After abrupt ces- Since the symptoms of spontaneous withdrawal in sation of these drugs, impairment of the performance rats have not always been sufficiently uniform and or other symptoms could, however, not be observed regular to form the basis of a reliable test method, equally well in all cases (possibly because of con- the nalorphine-precipitated withdrawal syndrome in siderable divergences in the dosages exceeding the rats has been examined, apparently with better equi-analgesic dose ratio). results. In the course of experimentation in the Addiction According to Hanna (1960) the demonstration of Research Center, Lexington, on the conditioning of nalorphine-induced withdrawal signs in rats (of drug-seeking behaviour, the effects of sudden with- about 250 g in weight) required the previous admi- drawal were studied by Wikler & Martin (personal nistration, conveniently by the intraperitoneal route communication, 1962) in rats tolerant to large doses and at intervals not exceeding four hours, of very of morphine (200 mg/kg/day and 320 mg/kg/day, large doses of morphine, beginning with 90 mg/kg, subcutaneously and intraperitoneally). Sudden with- with daily increases of 18 mg/kg until a dosage of drawal of morphine was followed by rapid subsi- 360 mg/kg every 4 hours was reached. This dosage, dence of the locomotor hyperactivity, hyperthermia which caused weight loss and sometimes death, and elevated oxygen consumption rates character- was maintained for 5 days. 10-20 mg of nalorphine istic of morphine-tolerant animals. These variables per kg, given intraperitoneally 30 minutes after the approached normal levels between the 8th and 12th last morphine injection, produced within a few hours of abstinence, but during this time the animals minutes increased motor activity and hyperexcita- began to exhibit a marked increase in the frequency bility, with brief convulsions in some animals. The of spontaneously occurring episodes of repetitive symptoms subsided after about two hours. As shaking of the skin of the entire body (" wet dog " Hanna remarked, the requirement of very large phenomenon). During the next 12-16 hours, these doses of morphine " may or may not be of value in episodes increased in frequency, and the rats became the evaluation of physical dependence liability of more irritable, showed more grooming activity and new compounds " in rats. diarrhoea, and began to lose weight; concomitantly, Kaymakcalan & Woods (1956) compared the body temperature and oxygen consumption rate fell symptoms of abrupt withdrawal from morphine further towards normal or even slightly subnormal with those produced by nalorphine in morphine- levels. These signs reached peak intensity between tolerant rats, that is, in animals which had received the 24th and 48th hours of abstinence and subsided morphine sulfate twice daily, subcutaneously, in thereafter. However, from the 4th day of abstinence doses increasing from 20 mg/kg to 100 mg/kg and onwards, for a period as yet undetermined, " wet had been maintained on the latter dose for 12-25 dog" counts, body temperature, metabolic rate days. In the course of the development of tolerance, and total daily water intake were slightly higher morphine produced less sedation and, instead, more in the formerly addicted rats than in the control and more central stimulation. While the abrupt animals. withdrawal of morphine generally resulted in mild In rats stabilized on a single dose of 200 mg/kg/day sedation only, the nalorphine-induced withdrawal of morphine intraperitoneally, increased " wet dog " syndrome included a marked increase in intestinal frequency and other signs of acute abstinence, activity with corresponding results appearing within similar to those described above, were noted before a few minutes and followed, after about 30 minutes, administration of the daily dose of morphine. If, by sedation that was distinctly greater than that however, the rats were permitted to drink an aqueous after abrupt withdrawal. The dose of nalorphine solution of etonitazene instead of water during the (10 mg/kg) was administered 2 or 12 hours after the interval between two daily doses of morphine, the last dose of morphine; in the case of the longer acute pre-injection abstinence syndrome was sup- interval the withdrawal symptoms were perhaps pressed to a degree depending on the concentration somewhat more pronounced. TESTS FOR ADDICTION (CHRONIC INTOXICATION) OF MORPHINE TYPE 143

To avoid the risks of local irritation and infection TABLE 1 presented by frequent injections of the large quan- SYSTEM FOR SCORING ABSTINENCE SYNDROMES a tities of drug necessary for the production and demonstration of physical dependence, Lister & D b H c Ettles (personal communication, 1961) have admi- Signs (by day) (by hour) nistered the test drug dissolved in drinking-water. points limit points limit Because of the usually unpleasant taste this is pos- sible only with very low drug concentrations, that is, Yawning 1 1 1 1 with highly potent substances. The authors em- Lacrimation I I 1 1 ployed a compound with 1500 times the analgesic potency of morphine in an estimated initial daily Rhinorrhoea I 1 1 1 dose of 10 ,ug for rats weighing 35-45 g, and increased Perspiration I I 1 1 it within three weeks to 10 mg per rat per day. Then, Mydriasis 3 3 3 3 a withdrawal syndrome was precipitated by admi- Tremor 3 3 3 3 nistration of 3 mg of levallorphan per kg sub- Gooseflesh 3 3 3 3 cutaneously or intraperitoneally. The outstanding Anorexia (40% decrease in sign of withdrawal was stretching or writhing similar caloric intake) 3 3 to that produced in rats and mice by the intra- Restlessness 5 5 5 5 peritoneal administration of local irritants. The authors related this symptom to the gastro-intestinal Emesis (each spell) 5 5 5 Fever (for each 0.1'C rise withdrawal symptoms in man. By analogy with over mean addiction level) 1 1 10 Himmelsbach's system for scoring the abstinence Hyperpnoea (for each resp./ syndrome (see Table 1, opposite), the authors min. rise over mean addic- established the following scale for scoring antagonist- tion level) 1 1 10 precipitated (by levallorphan as well as by nalor- Rise in a.m. systolic BP (for each 2 mm Hg over phine) withdrawal symptoms in rats: mean addiction level) 1 15 1 10 Weight loss (a.m.) (for each Signs Points lb. from last day of addic- Stretching 5 tion) 1 Squeal on touching 4 Teeth chattering 3 a The total abstinence syndrome intensity per day or per hour Hypersensitivity to noise 3 is the sum of the points scored in the " D " or " H " columns, respectively, with due attention to the limits. Diarrhoea 2 b Kolb & Himmelsbach (1938). Sedation 2 c Himmelsbach (1939). Ptosis Chewing Pinna sensitivity 2 I A nalorphine-precipitated abstinence syndrome Ear twitch has also been demonstrated in l rats tolerant to Pilo-erection codeine, a substance with a much lower addiction Scratching potential than morphine (Kuhn- & Friebel, 1962). 25 For eight weeks the animals received daily three subcutaneous doses of codeine phosphate, beginning With suitable dosage of the addicting compound, with 10 mg/kg and rising, in three bi-weekly increases, physical dependence developed within one week, to 22.2 mg/kg per dose. After eight weeks, the last and the optimal dose of levallorphan for precipita- codeine injection was followed, 30 minutes later, by tion of abstinence signs was 2-3 mg/kg. the subcutaneous injection of 20 mg of nalorphine Lister & Ettles also demonstrated that the symp- per kg. The ensuing abstinence syndrome, with its toms following precipitated withdrawal of their peak between 15 and 20 minutes after nalorphine very potent compound could be suppressed, at least administration, comprised practically the same partially, by a moderate dose of the same compound symptoms as those observed by Lister & Ettles. or by the administration of morphine or another These symptoms were classified by Kuhn & Friebel potent analgesic. as follows: 144 H. HALBACH & N. B. EDDY

Signs Points morphine, heroin, hydromorphone, oxycodone, Stretching 3 hydrocodone, codeine, dionine, methadone and Chewing 2 pethidine the doses necessary to bring about the typi- Teeth chattering 2 cal excitation in cats. Although he did not relate Squeal on touching 2 Ptosis 2 them to analgesic effects or otherwise, it would appear Diarrhoea 1 that some relation might exist between them and Sedation 1 analgesic potency and, hence (see Eddy, Halbach & Increased movements 1 Braenden, 1956), physical dependence potency. Scratching 1 Tavat & Akcasu (1956) extended Akad's investiga- 15 tions to ketobemidone, levorphanol, dextrorphan, and levallorphan, using a simple device for recording Ptosis, sedation, and scratching-but not the motor activity. Relatively high doses of dextrorphan more distinctive signs-occurred also in animals and levallorphan were without effect-in parallel which were challenged with nalorphine after having to lack of addiction liability. Levallorphan antagon- received one single dose of codeine and, about half ized or prevented the exciting effects of morphine. as frequently, in the controls. However, the dif- Cullumbine & Konop (1959) examined a few more ference in the total point score between these animals substances-addicting and non-addicting-in the and those that had received codeine for eight weeks same way with essentially the same results, including was significant. the demonstration of the preventive effect of the antagonists. They also noted exceptions to the Rabbits parallelism between excitation in cats and addiction In rabbits, which have been used far less for studies liability in men, for example, in the case of apo- on morphine and its congeners than the other species morphine. They confirmed the rapid development included in this survey, morphine affects the carbo- of tolerance to the excitatory effects of these sub- hydrate metabolism in a typical way (see Krueger, stances (as already noted by Eddy & Himmelsbach, Eddy & Sumwalt, 1941c). The animal develops 1936) and concluded that the relation studied, tolerance to the hyperglycaemic effects of morphine although not strict, was"... sufficiently close to and reacts to its withdrawal after chronic adminis- suggest that the cat injection test could be used to tration by a transitory hyperglycaemia. For racemic indicate the danger of inducing addiction. . ." methadone and isomethadone as well as for their The value of the cat excitation method as a pre- I-isomers, a-acetylmethadol, pethidine, alphaprodine, liminary test would be improved by a check with and levorphanol, the same changes were found to specific morphine antagonists; the neutralizing occur (see Phatak & David, 1953). These authors effects of the latter in this respect have been described concluded that the withdrawal hyperglycaemia, by the aforementioned authors and earlier by Unna being seemingly related to the rate of development (1943), Hart & McCawley (1944), Wikler & Carter of tolerance to the hyperglycaemic effect, might (1952), and Winter et al. (1954). serve as an index of the addiction potential. How- Dogs ever, since physical dependence has so far not been proven to be in immediate relation to tolerance, the Abstinence symptoms in dogs addicted to mor- usefulness of such a test would have to be examined phine had already been observed and described by by its application to a large series of substances with many workers (see review by Schaumann, 1957) known physical dependence potency. when the introduction of pethidine and methadone into clinical practice stimulated new trials using this Cats species for the evaluation of physical dependence to In cats, medium dosages of morphine and pharma- substances of morphine type. cologically related substances produce a peculiar state Intact dogs. The morphine abstinence syndrome of central excitation, marked by mydriasis, tachy- in dogs as described by Plant & Pierce (1928), Tatum, pnoea, and seemingly hallucinatory behaviour (see Seevers & Collins (1929), Eddy & Reid (1934), and Schaumann, 1957; Wikler, 1944). This reaction is others includes muscular rigidity, tremor, convul- quite specific and has been utilized in the charac- sions, restlessness, yawning, salivation, lacrimation, terization of morphine-like analgesics (Eddy & rhinorrhoea, singultus, vomiting, diarrhoea, tachy- Himmelsbach, 1936). Akad (1952) examined for pnoea, pulse irregularities, hyperpyrexia, hydro- TESTS FOR ADDICTION (CHRONIC INTOXICATION) OF MORPHINE TYPE 145 philia, and loss of weight, with a peak 24-72 hours became more severe as the addiction proceeded and after abrupt withdrawal. The minimum dosages were more pronounced than those following the which the early authors considered necessary for the abrupt withdrawal of morphine or methadone after development of physical dependence signified by comparable periods of addiction. According to unmistakable abstinence symptoms were obviously Kaymakcalan & Woods (1954), 1.5 mg of nalor- sometimes too high; Wikler (1946, 1948) described phine per kg subcutaneously is sufficient to elicit the the appearance of a "mild, but characteristic" full abstinence syndrome in morphine-addicted dogs. abstinence syndrome in dogs when treated with two Carter & Wikler concluded that " by use of N- daily doses of 10 mg of morphine per kg during allylnormorphine and a large number of dogs, a periods of 83-158 days. useful rapid screening method for testing addiction- Under similar but not strictly comparable condi- liability of analgesics with opiate-like actions may tions as to dosage and duration of addiction, Wikler be developed ". This conclusion would not appear & Frank (1947) found that in dogs the " methadone to be invalidated by their finding (Carter & Wikler, abstinence syndrome appeared to be more rapid in 1954, 1955) that neither spontaneous nor nalor- onset, more severe and of shorter duration than that phine-precipitated abstinence symptoms occurred of morphine ", while Winter & Flataker (1950) after addiction to pethidine (possibly because of the found it somewhat less severe, but of similar dura- limitations imposed on dosage and frequency of tion. administration by the toxic effects of the drug). Two pethidine derivatives, piminodine and the A " normal " sensitivity of the dog (in relation to closely related 1-(2-phenylaminoethyl)-4-phenyl- what happens in man) to the physical dependence piperidine-4-carboxylic acid ethyl ester, were com- properties of piminodine and another pethidine pared with morphine by means of the abrupt with- derivative, as demonstrated by a typical abstinence drawal method in dogs (Woods et al., 1961). The syndrome following abrupt withdrawal, has also results would indicate that the relative sensitivities been found after nalorphine-induced withdrawal of the dog with respect to physical dependence on (Woods et al., 1961). substances of the morphine and pethidine group For the purpose of testing it would be advantage- resemble the situation in man, whereas, for example, ous if the period necessary for the development of monkeys are in this respect particularly sensitive physical dependence could be curtailed. In man to the pethidine group. This would speak in favour (Wikler and associates, 1953; Fraser et al., 1961a) of using dogs for predicting addiction liability in as well as in dogs (Wikler & Carter, 1953; Carter & man. Nevertheless, so far as is known, no systematic Wikler, 1954), tolerance and physical dependence attempts have been made to determine the value of can indeed be produced and demonstrated, parti- the abrupt withdrawal method in dogs for this cularly when precipitated by specific morphine purpose by extending the observations to a larger antagonists, in a measurable degree after a relatively number of morphine-like substances with a known short period of administration of morphine. Martin addiction potential. & Eades (1961) have shown that a single intravenous By administration of nalorphine the demonstra- infusion of morphine brings about tolerance and tion of abstinence symptoms in dogs is made simpler physical dependence in a reproducible and measur- and safer. After having ensured that nalorphine as able way. They considered that " the reproducibility such produced only mild sedation, Carter & Wikler and brevity of this method may recommend it for (1954) demonstrated the precipitation of character- preliminary screening of analgesic agents to identify istic withdrawal signs by subcutaneous administra- those that produce physical dependence ". The tion of 15 mg of nalorphine per kg in dogs addicted principle of this method is as follows. for 7 days or longer to morphine (5-10 mg/kg every In beagle dogs (between 7 and 19 kg in weight) 6 hours) or methadone (2-5 mg/kg every 6 hours). the following signs were measured every half-hour: In its most complete form, the abstinence syndrome pulse rate, respiratory rate, pupillary diameter, rectal consisted of restlessness, lacrimation, rhinorrhoea, temperature, skin-twitch reflex (on pinching the yawning, salivation, vomiting, urination, marked saddle area of the back), and hind-limb withdrawal tremors, and persistent digging, gnawing and rooting reflex (following the roughly measurable squeezing in the earth or sand, but considerable individual of the left lateral digit). Nalorphine alone did not variation, qualitative and quantitative, was observed. alter these signs significantly except for causing a The symptoms appeared within 5-20 minutes and slight miosis. The intravenous infusion of morphine 146 H. HALBACH & N. B. EDDY sulfate at the rate of 3 mg/kg hourly produced substitution without being itself capable of pro- within one to two hours the known effects and ducing physical dependence, that is, addiction of changes in the 6 parameters. To 3 of them- namely, morphine type (Eddy, Halbach & Braenden, 1956). miosis and depression of the skin-twitch and In the view of the authors the results of these tests withdrawal reflexes-as well as to the behavioural should be confirmed by a " direct addiction" test, depression, the animals developed a partial tolerance that is, chronic administration of the test substance after about three hours of infusion. Administration in increasing doses (as in the scheme described of nalorphine (20 mg/kg) after almost eight hours above for morphine) with abrupt withdrawal and of morphine infusion produced, within five minutes, relief of withdrawal symptoms by re-administration a striking reversal in the parameters measured, a of the test drug, with recording of motor activity reversal of the behavioural depression, and other during all stages of the experiment. symptoms of withdrawal. As to the dosage of the test drug, La Barre (per- La Barre (1959) and Desmarez (1960) have sonal communication, 1961) recommends its estab- attempted to simplify the measurement of the state lishment in relation to the LD1o0 (Knaffi-Lenz method of physical dependence by singling out and record- in guinea-pigs). The LD1oo of the test substance is ing those withdrawal symptoms which manifest determined and a fraction of this is used versus the themselves in changes of spontaneous motor activity. same fraction of the LD10o of morphine. To save To this end the animal is kept in a spacious cage, their animals, the authors of this method prefer not fitted for automatic mobility recording, during the to exceed one-fourth of the LD1oo. period of direct addiction or substitution and Chordectomized (" spinal ") dogs. In the course withdrawal of either morphine or a test substance. of research on neurophysiological mechanisms of The period of building up tolerance and physical addiction, Wikler has developed a method using dependence to the addicting agent extends over spinal dogs. With its distinct and readily reprodu- several months, owing to the relatively low doses cible effects this method could also be, and on a and their small increments. With morphine, for limited scale has already been, used to screen drugs example, the daily dosages per dog (of 6-8 kg weight) for the presence and degree of physical dependence were 10 mg subcutaneously for two months, 15 mg properties. Its relevant features, as described in in the third month, 20 mg for the following three detail by Wikler & Frank (1948), can be summarized months, and then 40 or 50 mg (divided into two as follows. doses daily) to accentuate the withdrawal effect. The experiments were made after recovery from With this scheme tolerance to the sedative effects chordectomy between D-10 and D-12 and return of of morphine develops within several days following the reflexes to a stable level. Single doses of mor- each increase in dosage, but the sudden cessation of phine (2-100 mg/kg) produced marked and typical morphine during the first four to five months is not changes in certain mechanically elicited and graphi- followed by a noteworthy increase in motor activity. cally recorded hind-limb reflexes. Most promi- This symptom appears clearly and with a statistical nent were the depression of the ipsilateral flexor significance only when the withdrawal is effected and crossed extensor reflexes. During chronic after at least four months' duration of this regimen. administration of morphine, tolerance developed to With animals thus made physically dependent on its depressing action on these reflexes, as manifested morphine and using the recorded motor activity as by increased reflex responses between injections. the parameter for physical dependence, two types Abrupt cessation of morphine was followed by their of tests can be carried out: (a) the suppression test, further increase; 30 hours after withdrawal, rhythmic in which a single dose of the test substance is admini- movements of flexion and extension of the hind- stered eight to ten hours after withdrawal of mor- limbs began and increased, and were accompanied phine, and (b) the substitution test, in which the later by the same withdrawal symptoms as seen in last dose of morphine is replaced by the test sub- intact dogs, such as tachypnoea, tachycardia, rise stance. If the test drug suppresses the increase in in temperature, yawning, lacrimation, rhinorrhoea, motor activity in (a) or prevents it in (b) this is vomiting, and diarrhoea, reaching a peak at about valued as a strong argument in favour of its mor- the same time (72nd to 90th hour) as the " running " phine-like addicting character-on the basis of the movements. With methadone the same effects experience that no substance is hitherto known appeared, but within a shorter sequence, and, as in which produces these effects of suppression or the intact dog, the abstinence syndrome of either TESTS FOR ADDICTION (CHRONIC INTOXICATION) OF MORPHINE TYPE 147 drug could be suppressed by the other. Thus this in 1923 but not reporting them until 1931, made preparation offers the elements essential for the more extensive observations on attempted addiction demonstration of physical dependence and enables experiments in monkeys, employing morphine, objective recording of specific symptoms. heroin and codeine. The drug was given in one daily While abstinence phenomena following abrupt dose for three months and twice daily thereafter, withdrawal appear in the spinal dog only after a Sundays and holidays excepted. The dose of mor- long period of addiction, they can be demonstrated phine was increased from 7 or 8 mg to 200 mg per by means of a single dose of nalorphine after two or animal per day in eight to ten months. By the three days of addiction (Wikler & Carter, 1953). The seventh month the withdrawal symptoms were so effect of nalorphine alone on the ipsilateral flexor severe after 40 hours of abstinence, that is, from the and crossed extensor reflexes was qualitatively the Saturday afternoon to the Monday morning dose, same as that of morphine but quantitatively less. that an additional dose was given on Sunday However, after pre-treatment with as little as 0.5 mg morning. They said that morphine "caused marked of morphine per kg every six hours for two or dependence, shown by a crouching posture, facial three days, 15 mg of nalorphine per kg precipitated distortion, hypersensitiveness, fall in temperature, a typical abstinence syndrome resembling closely and, in one case, death on withdrawal of the drug ". that produced in spinal dogs by the abrupt with- Monkeys made tolerant to large doses of morphine, drawal after weeks or months of addiction. Onset, heroin or codeine were tolerant to large doses of all intensity and duration of the nalorphine-induced three drugs; the dependence produced by morphine withdrawal syndrome appeared to be related to the or heroin was satisfied by the other drug, but not duration of addiction to morphine and the dose of by codeine. nalorphine, that is, the longer the animal had been This was the background situation when metha- addicted to morphine the smaller was the dose of done came to general attention in 1946 and stimu- nalorphine necessary to produce a complete abs- lated tremendous activity in the synthesis of com- tinence syndrome. This opens prospects for the pounds which might have morphine-like activity. quantitative testing of the physical dependence Seevers and his associates tested many of these new capacity of unknown substances. Relevant in this compounds in the monkey and in 1950 he proposed connexion appear the observations by Wikler & a programme to determine the value of this animal Carter that the nalorphine-induced withdrawal for predicting addiction liability to the newer syndrome as measured by the reflex changes in synthetic analgesics. The plan in the main was to spinal dogs was more intense than the abstinence carry out in the monkey all of the procedures syndrome seen in the same animals after abrupt employed in man at the Addiction Research Center withdrawal; and further that, after subsidence of in Lexington (single-dose administration, substitu- the reflex hyperactivity following withdrawal of tion for morphine and direct addiction) and to morphine, nalorphine had the same depressing compare the results obtained with substances which effects on reflexes as before addiction to morphine. were tested in both monkey and man. Seevers' pro- Interestingly, the impossibility of demonstrating in posal was incorporated into the research programme the intact dog either spontaneous or nalorphine- of the Committee on Drug Addiction and Narcotics induced abstinence symptoms following addiction of the National Research Council (USA) and to pethidine (Carter & Wikler, 1954, 1955) was also the work in this connexion of his laboratory at the encountered in the spinal dog (Carter & Wikler, University of Michigan still continues under the 1955) and possibly for the same reason-namely, sponsorship and support of the Committee. the limitations to dosage and frequency of applica- It was shown early that results in the monkey with tion set by the toxic effects of pethidine. many different chemical types were qualitatively like Monkeys those obtained in man and that when strong mor- phine-like properties were manifested in the monkey Tatum, Seevers & Collins (1929) demonstrated the this could be taken as a safe prediction of what occurrence of abstinence phenomena when mor- would happen in man. From this earlier work there phine was abruptly withheld from monkeys which has been developed a screening programme in which had received the drug daily. The starting dose was more than 350 agents have been tested and which only 2 mg/kg and was increased by about 2 mg each has proved of very great value to all those interested week. Kolb & DuMez, beginning their experiments in the addiction liability, and hence the safety, of 148 H. HALBACH & N. B. EDDY potentially valuable medicinal agents. It is this mediate intensity are present. If left untreated the screening programme which will be described here.' abstinence signs increase in intensity progressively It has been demonstrated in animal and man that over the next several hours, but the administration of any chemical substance capable of complete sup- morphine or any drug with morphine-like physical pression of all of the specific signs of morphine dependence capacity results in a partial or complete abstinence is capable of creating physical depend- suppression of the signs of abstinence. If the dose of ence during chronic administration. Therefore, the the test drug is in excess of that required to produce primary and principal objective of the screening complete suppression of the abstinence symptoms, procedure is to ascertain whether or not the test typical signs of narcotic depression result. drug is capable of complete suppression of all A pre-selected quantity of the test drug and abstinence signs in the morphine-dependent monkey. 3 mg/kg of morphine sulfate are administered sub- If suppression is not complete the procedure deter- cutaneously by someone other than the observer, mines the degree to which the total spectrum of each drug to two monkeys. The intensity of the signs is affected. The abstinence suppression potency abstinence signs or drug depression is graded just is termed physical dependence capacity. Its deter- prior to and at intervals of 1/2, 1, 2, 3 ... 6 hours mination is initially qualitative but serves a range- after administration, or until the monkeys have finding function for the subsequent quantitative returned to the pre-injection level of excitability. If study of potency relative to morphine. the dose of the test drug produces less effect than 3 mg/kg of morphine, the dose is doubled for a Physical dependence capacity is characterized as: subsequent test. This procedure is repeated until a High, when the drug produces complete suppres- dose which is approximately equivalent to 3 mg/kg sion of all abstinence signs with doses which reveal of morphine is determined or until side-effects no other overt pharmacological effect; appear in such intensity as to preclude further Intermediate, when complete suppression of all testing. By this procedure it is ascertained whether abstinence signs is obtainable, but only with doses the drug has high, intermediate, low, or no physical which elicit other pharmacological actions, mani- dependence capacity. fested by such signs as stupor, ataxia, tremors, etc.; Further testing is done with all drugs which have Low, when some suppression of abstinence signs been found to have high or intermediate physical is induced, but attempts to produce more or com- dependence capacity. Its purpose is twofold: to plete suppression with larger doses is prevented by extend the series of animals to confirm the original the intervention of toxic effects such as coma, con- estimate of physical dependence capacity, and to vulsions, etc.; determine accurately the potency of the test drug None, when the drug fails to produce any specific relative to morphine. It must be stressed that suppression of the morphine abstinence signs. physical dependence capacity and single-dose absti- Non-specific depressants may obscure individual nence suppression potency are not synonymous and signs. may not even parallel each other in relation to mor- the former is of A of 50 to 100 phine. Only major predictive colony monkeys (Macaca mulatta) as it relates to in man. For is maintained in a state of physical dependence by the significance addiction subcutaneous administration of 3 mg/kg of morphine example, a compound of relatively low potency, sulfate six hours without 20.0 mg/kg equivalent to 3.0 mg/kg of morphine, every interruption. After may have a high physical dependence capacity and a stabilization period of 60 days these monkeys can in its be used for testing at weekly intervals. in this respect be equal to morphine potential For testing, regular morphine injections are with- as a drug of abuse, only requiring larger quantities held for 12-14 hours until abstinence signs of inter- to be effective. In the quantitative study five single-dose suppres- sion treatments are each administered to five mon- 'We are indebted to Dr M. H. Seevers, Professor of Pharmacology, and to Dr Gerald A. Deneau, Associate keys in a Latin square pattern at weekly intervals. Professor of Pharmacology. University of Michigan Medical These are X (the dose of the test drug which is School. for permission to describe their methods. They are currently preparing for publication a series of reports on approximately equipotent to 3 mg/kg of morphine), this programme. A great deal of credit is also due to Samuel 1/2X, 2X and two controls, 3 mg/kg of morphine Irwin, Duncan McCarthy and Richard Burns, who have been closely associated with the development of the pro- sulfate and a placebo (a saline injection). The cedures. experiment is conducted on a double-blind basis TESTS FOR ADDICTION (CHRONIC INTOXICATION) OF MORPHINE TYPE 149

FIG. I with respect to test drug versus morphine versus TIME-EFFECT CURVES, OBTAINED FROM THE SAME FIVE placebo and from the peaks of the average time- MONKEYS IN SINGLE-DOSE SUPPRESSION TESTS, FOR A effect curves which are obtained for each treatment TEST DRUG AT THREE DOSAGES (X2X, X, AND 2X), (see Fig. I) a dose-effect curve (see Fig. 2) is estab- MORPHINE SULFATE (3 mg/kg) AND A PLACEBO a lished. The potency of the test agent relative to morphine is determined from this curve. In some cases the physical dependence potential of a test drug is also investigated by chronic adminis- tration to monkeys which have not previously received narcotic analgesics. After the dose equi- potent to 3 mg/kg of morphine has been determined by the single-dose suppression technique, this dose is administered for 31 days at intervals (usually two to six hours) which correspond to its duration of action so that the monkeys are continuously under the influence of the drug. If there is evidence of waning effect (tolerance) the individual dose is increased. The development of physical dependence is monitored on the 14th and 28th days of treatment by administering 2 mg/kg of nalorphine. As in man the administration of nalorphine precipitates an abstinence syndrome of one-half to four hours' a In all cases the average pre-inlection abstinence (with- duration, the severity of which corresponds to the drawal) severity was grade 3. The average maximum effect of each treatment is represented by the differences P to Q for 'AX, degree of physical dependence which has developed. P to S for X, P to T for 2X, and P to R for morphine, and Is zero On the 31st day of treatment drug administration is for the placebo. terminated abruptly and the monkeys are observed After Deneau & Seevers (1961). for the following 7-14 days for signs of abstinence, graded according to the schema below. In the single-dose suppression technique, effective FIG. 2 doses of test drugs reduce the intensity of abstinence DOSE-RESPONSE CURVE OF THE TEST DRUG WHOSE signs more or less completely, or, having brought TIME-EFFECT CURVES ARE SHOWN IN FIG. I a about complete suppression, may then produce typical signs of narcotic depression. In all of the tests described abstinence signs are graded, two grades for each classification, according to Seevers' classification of abstinence signs (Deneau & Seevers, 1961) and narcotic depression is graded (again two grades for each classification) according to Irwin's classification of the effects of narcotic analgesics in the monkey (Irwin, 1954). These classifications are as follows: For abstinence signs: Mild (may be considered as of no significance by the untrained observer): Apprehension, continual yawn- ing, rhinorrhoea, lacrimation, hiccup, shivering, IJ perspiration on face, chattering, quarrelling and 1/2X Y X 2X fighting; I/2X DOSE (mg/kg) Wo 2360 Intermediate: Intention tremor, anorexia, pilomotor activity, muscle twitching, rigidity and holding the a The three points on the curve represent the effects P to Q, abdomen (cramps); P to S and P to T in Fig. 1. A dose of Y is equivalent to 3 mg/kg of morphine sulfate. Severe: Extreme restlessness, assumption of peculiar After Deneau & Seevers (1961). attitudes, vomiting, severe diarrhoea, erection and 150 H. HALBACH & N. B. EDDY

continued masturbation, inflammation of the eyelids of Michigan Medical School under code number, and conjunctiva (insomnia), continual calling and suggesting a starting dose based upon the pharma- crying, lying on the side with eyes closed, and cological data. When the tests have been completed marked spasticity; the results are reported to the Executive Secretary, Very severe: Docility in the normally excitable animal, who transmits a copy to the producer and upon dyspnoea, pallor, strabismus, dehydration, weight loss, prostration, circulatory collapse, and occasion- mutual agreement reveals the nature of the agent ally death. to the investigators. The results may be the deter- mining factor either in the abandonment of interest It will be noted that these signs fall into four in the compound, should its physical dependence categories of hyper-irritability: sympathetic, para- capacity be high without compensating advantages, sympathetic, psychic (behavioural) and somatic or in the decision to subject it to further laboratory (neuromuscular). Whereas morphine will suppress and clinical testing, including addiction liability all signs of the syndrome evenly to an extent de- testing in man. In some unequivocal cases the tests pendent upon the dose, many narcotic analgesics in the monkey may also be the basis for a recom- fail to suppress one or another category of signs to mendation for narcotics control. the same extent as the remainder of the syndrome. For this reason grades of abstinence intensity during TESTS FOR ADDICTION (ABUSE) LIABtLITY the suppression test are assigned according to the " behavioural signs and not on the basis of the entire IN FORMER ADDICTrS abstinence syndrome. Given a new substance whose morphine-like For narcotic depression. The central nervous properties and addiction liability are to be deter- system depression which is produced by narcotic mined, the investigators at the Addiction Research analgesics in the monkey is a combination of two Center at Lexington must assume responsibility factors, referred to collectively as stupor: a de- with respect to the risks involved in carrying out creased awareness of, and diminished responsiveness tests in man. Accordingly, they have indicated that, to environmental stimuli, and a decrease in the prior to the initiation of tests, they wish to be degree of apprehension, as indicated by alteration supplied with information upon the general pharma- in behaviour, once his attention has been gained. cology of the compound, including its toxicity and The classification of stupor is: relative potency, evidence that it has been admini- Mild: Inattentive to ordinary movements and actions stered to man and that it may be a useful thera- of other monkeys within the cage and of the observer peutic agent, its relative potency in man and some outside the cage; indication of the side-effects which it may produce. Intermediate: Attention gained by other monkeys They request that the data on the general pharma- within the cage only by strong threatening gestures cology of the compound include information on and attentive to the observer only when extra- acute and chronic toxicity, on relative potency with ordinarily loud noises are made or the latch on the respect to analgesic, antitussive and/or constipating cage door is opened (a strong conditioned stimulus); action, on whether or not the actions of the drug are Severe: Responds only to such exteroceptive stimuli as antagonized by one of the specific antagonists such shouting or clapping the hands loudly near its ear, extent or to being touched by other monkeys or the ob- as nalorphine, on the rate and of dosage server; increase in chronic administration in attempted Very severe: Comatose and cannot be roused by any determination of tolerance, on whether or not stimuli. tolerance develops and cross-tolerance to morphine In the actual of the for example, and on physical dependence capacity operation screening procedure in monkeys and acute tolerance and physical de- a request for testing is made by the interested party in All such informa- to the Executive of the Committee on pendence development dogs. Secretary tion is pertinent to the establishment of dosage Drug Addiction and Narcotics of the National the of the Research Council A of the schedules and to safety of investigation (USA). sample drug in man. is submitted to him, together with information as to agent its chemical identity, such pharmacological data as 1 We are indebted to Dr Harris Isbell, Director, to are available and the reason for interest in the Dr H. F. Fraser, Associate Director, and to their associates He and at the Addiction Research Center for permission to describe compound. codes the compound forwards their methods, of which not all details have been published it to the pharmacology laboratory of the University previously. TESTS FOR ADDICTION (CHRONIC INTOXICATION) OF MORPHINE TYPE 151

The subjects in the studies at Lexington are former phine, approximately 240 mg per day. The dose opiate addicts, male, coloured or white, in good was given 30 hours after abrupt discontinuance of physical condition, who are serving a sentence for morphine, when the withdrawal syndrome was violation of the narcotic laws and who have volun- reaching its peak. The subsequent course of absti- teered for the experiment. nence intensity was compared with that to be Single-dose administration for the determination of expected in otherwise untreated individuals. A morphine-like (euphorigenic) more adequate procedure has since been devised effects a procedure that can be repeated on the same Starting with small doses-their actual size is individual at weekly intervals because the abstinence based upon previous experience with the drug- syndrome is never allowed to reach a seriously a new agent is administered by various routes, disturbing intensity. Thus double-blind cross-over depending upon its solubility and other physical observations can be made comparing, in the same properties. The dose is then increased, two or three individual, one or more dose levels of one or men being given the drug at each dose level, until a more experimental agents, a placebo and a stan- definite effect is obtained or signs indicative of im- dard dose of morphine (Fraser & Isbell, 1960a, pending toxicity are seen. Up to this point admini- 1960b). stration is on a single-blind basis, the nature of the drug being unknown only to the patient, who is, A group of 5-12 individuals is given morphine however, allowed to express his feelings about it in subcutaneously regularly, the dose being built up comparison with his previous drug experience. An rapidly to 240 mg per day and stabilized at that level idea of relative potency thus having been arrived at, for not less than 30 days. Beginning with the evening the next step is administration on a double-blind dose (10 p.m.) and continuing through 24 hours a basis, identity of drug and dose being unknown to coded substance (experimental drug, placebo or both patient and immediate observers. Two dose standard morphine dose given as an unknown) is levels of the new agent are given at weekly intervals administered in place of the regular morphine doses. in random order with two comparable doses of a Beginning the next morning, 14 hours after the last standard of similar potency and a placebo as regular dose of morphine, observations are made at controls to a group of eight to twelve individuals. regular intervals, recorded and evaluated according Administrations are continued until each individual to the Himmelsbach (1939) hourly score for abstin- in the group has reccived each of the medications. ence phenomena (Table 1). The substitution pro- Certain objective measurements may be made before cedure is repeated at weekly intervals until each and at intervals after each dose, such as pupil size, individual has received in random order at least one respiratory rate and minute volume, blood pressure dose level of the experimental drug, a saline injection and body temperature, and both the patient and the as a placebo, the regular stabilization dose of mor- observer are required to fill out a " Single-dose phine and perhaps one or more dose levels of one attitude questionnaire" (see Annexes 1 and 2). or more other agents. The mean hourly Himmels- It will be noted that both the subject and the observer bach score for all patients for each agent is plotted are asked to check whether the agent seems to be an and a comparison is made between the experimental opiate (" dope ") or is like some other drug, the agent and morphine or placebo. If the drug is degree of the patient's liking for the drug and the ineffective as a morphine substitute, the graph of frequency of opiate-like symptoms. The mean of abstinence phenomena intensity will coincide with the group for all observations with each medication that obtained after the administration of a placebo. is determined and plotted for comparison with the If it is morphine-like in some degree, the graph of standard and the placebo. The results obtained in a abstinence phenomena observed will approximate typical experiment are illustrated in Fig. 3. Both to that obtained after continuation ofmorphine as an patients and observers agreed very well in their unknown during the substitution period or will fall evaluation of the drugs and the frequency of opiate- between the placebo and morphine graphs, depend- like symptoms paralleled changes in pupillary ing upon the effectiveness of the dose used as a diameter. morphine substitute (see Fig. 4). A more direct and perhaps simpler comparison is obtained by Substitution for morphine summing for each agent for each individual the Formerly a single dose of the agent under investi- hourly point scores and calculating the mean total gation was given to individuals stabilized on mor- abstinence score for 24 hours (TAS-24). This score

2 152 H. HALBACH & N. B. EDDY

FIG. 3 RESULTS OF SINGLE-DOSE ATTITUDE QUESTIONNAIRES, FILLED OUT BY PATIENTS AND OBSERVERS, AND DECREASE IN PUPILLARY DIAMETER AFTER SINGLE DOSES OF DIPHENOXYLATE (70 mg), CODEINE (140 mg) AND A PLACEBO a

POSITIVE ATTITUDE SCORE .30 - oo-o_e-.1.2

.25.25 T A ^ A *2 /L0tC0/P= +-o----LRS=io.2±2.62D Mt > m ~~~~~DIPHENOXYLATE WU WL T RS 2.4±1.13 B: 0 Ln .20 0 u .8 z~~~~~~~~~~

.1- CODEINE .-DEIN T.6= 1 .5t 2 5

u 0 T RS -1.9 ±1.23

1.5 _ 1L-.0I _/S~~~~~~~~~~~~~~0APLACEBO .05 PLACEBO .2 AATRS=1.0±0.27

/T RS =0.0

1.75 -OPIATE SYMPTOMS DECREASE IN PUPILLARY DIAMETER

1.50 --3.0

/ D~~~IPHENOXYLATET RS= 13.6±3.61 ,1.25 5-2.5

ui ~ /E DIPHENOXYLATE 'n 1.00 *Z -2.0

CODEINE S > .75 ~T RS 15.2+3.28 15 C O D E I u 0 T RS 18.9±+ 3.32

.25 PLACEBO TRS 1.10.30 ..5 PLACEBO ~T -7 .7 .0

~~~~~~~~~~A /II

2 4 6 8 10 12 14 2 4 6 8 10 12 14

HOURS AFTER DRUG

WhO 2363

a The maximum number of positive answers hourly for identification as "dope" = 1.0; for positive attitude (liking) score = 4.0; and for frequency of opiate symptoms = 7.0. Each point on each curve represents the average of data obtained on 8 men, each of whom had diphenoxylate and codeine three times and the placebo once. The TRS values (total response scores for 14 hours) repre- sent the mean of the areas under the curves ± standard errors. After Fraser & Isbell (1960c). will be high (150 or more) for placebo substitution in the 24-hour experiment. An attempt is made to and low (50 or less) for morphine continuation. substitute the new drug at such a dose and interval In many instances, especially if the 24-hour of administration as to maintain the addiction; that substitution does not completely suppress the is, to prevent completely the appearance of abstin- appearance of abstinence phenomena, substitu- ence phenomena which would have occurred as a tion may be continued for 10 days. Individuals are result of the cessation of morphine administration. stabilized on morphine and substitution is begun as Whether or not this is attained, one gets an impres- TESTS FOR ADDICTION (CHRONIC INTOXICATION) OF MORPHINE TYPE 153

FIG. 4 10-day substitution with another agent can be carried 24-HOUR SUBSTITUTION OF PROPOXYPHENE FOR out if a direct comparison of two new agents in the MORPHINE a !~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ same individual is desired. Direct addiction 30 If previous experience has shown a compound to be significantly more or less effective than morphine, if it is a new chemical type, and particularly if its 25 _ introduction into clinical practice is contemplated, L) a direct addiction experiment may be undertaken. zu w L 20 Individuals previously addicted to morphine or a related drug and free of drugs for some months are given the new agent regularly at an interval and dose XV) 5OD m zzIL 10 and by a route deemed appropriate according to previous experience. The dose is increased as Z 10 rapidly as possible, avoiding, of course, cumulative effects and toxic reactions. The objective is to o- -o 0 P P increase the dose, if possible, by a schedule parallel- 5 ing that leading to stabilization on morphine in the 0 0 0 0MORPHINE experiments already described. The direct addiction attempt may be continued for 30, 60, or 90 days V 4, 14 15 16 17 18 19 20 21 22 23 24 or longer, and is followed by abrupt withdrawal; HOURS OF ABSTINENCE a comparison is then made with similar periods wHO 2361 of administration and withdrawal of morphine. During the latter part of such direct addictions, a a The total dose of propoxyphene was 2400 mg, given orally in six doses of 400 mg each. In control experiments, using the few days before withdrawal, patients are challenged same subjects and the same schedule, placebo capsules or by administration of a small dose (3, 5 or 10 mg) injections of morphine were given. The subjects were told only that other drugs were being tested. Each point on the placebo of nalorphine. If signs of abstinence are preci- and propoxyphene curves represents the average scores on the same 11 subjects; each point on the morphine curve represents pitated by nalorphine, these are compared with the the average score of 9 of these subjects. P signifies that the withdrawal syndrome observed subsequently. point Is significantly different from the corresponding point for the placebo, and M that the point is significantly different from Recently a modification of the above procedure the corresponding point for morphine, indicating some sup- pressive effect on abstinence from morphine. has been tried, shortening the addiction period and Reproduced, by permission, from Fraser & Isbell (1960a). affording cross-over data on the same individuals (Fraser & Isbell, 1960b; Fraser et al., 1961b). Eight drug-free former addicts were selected and to each sion of the individual's satisfaction with the substi- was assigned in random order a coded medication tute. At the end of 10 days the substituted drug is to be administered on a double-blind basis in as- replaced by placebo, the change not being revealed cending dosage for a period of 18 or 19 days. The to either patient or observer. Throughout the 10 days medications were placebo capsules, morphine of substitution and for a week of withdrawal (pla- capsules, codeine capsules, morphine for subcuta- cebo admpinistration), observations are made daily for neous injection and four experimental drugs, one in signs of abstinence and evaluated according to the capsule form, the others for subcutaneous adminis- Kolb & Himmelsbach (1938) daily point score tration. The initial dosage (except of the placebo, (Table 1). The score during the withdrawal period is of course) was usually that judged to be equivalent compared with the abstinence syndrome after abrupt in effectiveness to morphine on the basis of 24-hour withdrawal of morphine, affording a qualitative and substitution; it was, however, sometimes less than the quantitative appraisal of the withdrawal symptoms equivalent in order to avoid toxic reactions (Fraser et after the substituted drug. al., 1961b, p. 378, footnote 1). Since no difficulty is It is possible to re-stabilize the individual on experienced usually in increasing morphine dosage morphine and subsequently to withdraw him abruptly in former addicts to 240 mg a day in 18 days, such for a comparative appraisal of his morphine absti- a regimen of administration of morphine was nence intensity; or, after re-stabilization, a second employed and a schedule of increasing dosage for 154 H. HALBACH & N. B. EDDY

all other drugs was arranged which would parallel An alternative short direct addiction test has been that for morphine. Since tolerance to new agents employed by Fraser and his associates which is may or may not develop as rapidly as tolerance to especially applicable to the evaluation of intra- morphine, patients were watched for depth of seda- venously administered drugs (Fraser et al., 1961a). tion and toxic reactions and the increasing dosage A typical experiment employing this technique is schedule was halted or modified as necessary. described as follows: In a single-blind study six On the 19th or 20th day, the exact time being subjects received drugs intravenously and one known to the person preparing the drugs, but not to subcutaneously becau;e all of his superficial veins the patient or the observer, a placebo (capsule or were sclerosed. A " sample " of a high dose of each injection according to which the patient had been drug was given at 3-day intervals-180 mg of receiving) was substituted and continued on the I-K-l (1-(p-chlorophenethyl-6,7-dimethoxy 2-methyl- same schedule for 10 days. Then each individual was 1 ,2,3,4-tetrahydroisoquinoline), 180mg ofd-propoxy- started on another of the series of medications, again phene, 120 mg of codeine and 30 mg of morphine assigned in random order, and the whole procedure -in randomized order. Each patient rated each was repeated until each individual had received each of these drugs on the single-dose attitude question- of the eight preparations. naire (see Annex 1) and after each had received Throughout drug administration and placebo all four sample doses he was asked to review substitution, the following observations were made his response to each on the questionnaire and to three times daily; rectal temperature, respiratory rate them in order of preference, 1 to 4. In this pre- rate, pulse rate, blood pressure and the usual ferential ballot morphine ranked first, d-propoxy- observations for abstinence signs according to the phene second, and codeine and I-K-1 equal and last. Kolb & Himmelsbach scoring system. Caloric It was explained to each subject that he would intake was measured daily; body-weight was re- then receive, in randomized order, all the sample corded each morning, and hours of sleep, hours drugs which he elected to take in increasing doses of inactivity (lying horizontally on bed, whether or for seven days, with a withdrawal period of three not asleep) and hours of initiative activity (off the days between each drug phase. However, after his ward in various voluntary pursuits) were recorded rating of the single doses, a subject could elect not at half-hour intervals daily. For each withdrawal to take any of them during the seven-day phase, to period a total abstinence score for 10 days (TAS-10) take one or more of them, or after starting any was calculated. These scores for all drugs indivi- particular drug to stop at any time during the seven dually and as means for all patients were compared days, go on to the next drug or discontinue entirely with the scores for placebo and all other drugs were without penalty. At the end each subject was asked compared similarly with morphine and with each again to rate the drugs in order of preference. other. The daily amounts of the drugs were as follows: At 7 p.m. on each day of the experiment each for I-K-1 and d-propoxyphene, 360 mg (divided into patient completed a questionnaire dealing with the three equal doses) on the first and second days and subjective effects of the drug he was receiving, and 480, 600, 600, 720 and 720 mg (divided into four concurrently a separate questionnaire dealing with equal doses) on the third to seventh days; for mor- the behavioural changes was completed by the phine, 60, 60, 80, 100, 100, 120 and 120 mg (divided observer (see Annexes 3 and 4). These recorded such into four equal doses); and for codeine, 240, 240, things as recognition of the drug as an opiate, the 320, 400, 400, 480 and 480 mg (divided irnto four patient's liking for it and inclination towards con- equal doses). All drugs were administered intra- tinuation of its use, and judgement of its strength. venously (with the one exception noted above) The results of this experiment as revealed by the slowly over a 2-minute interval. Nalorphine (3 mg) chronic dosage attitude questionnaires are shown in or a placebo, on a randomized double-blind basis, Fig. 5. All ratings of patients and observers were was injected subcutaneously at 9 a.m., that is, three tabulated, but the figure is restricted to the para- hours after the last dose of an experimental drug, meters: identified as " dope ", estimate of " strength," on the sixth or seventh day of the test. Observations and " would like to take drug daily ". The data for abstinence signs were made also on the three days were analysed for statistical differences between between drug administrations. drugs by the paired " t" test, using total responses Morphine was definitely the preferred drug in for the first 18 days on each drug and a placebo. this series; it was taken by all the subjects, one dis- TESTS FOR ADDICTION (CHRONIC INTOXICATION) OF MORPHINE TYPE 155

FIG. 5 RESULTS OF CHRONIC DOSAGE ATTITUDE QUESTIONNAIRES: COMPARISON OF RATINGS OF PATIENTS AND OBSERVERS IN A SHORT-TERM ADDICTION TEST (18-19 DAYS) INVOLVING SEVEN DRUGS AND A PLACEBO a IDENTIFIED AS 0 DOPE OR OPIATES P A P A P A P A P A P A P A P A °0 oc 7 U U 0~~~~~~

2 0 4 hiK ~~~~~~~~~~~~~~~~~~~~c0 4 0 IL w- 25 = e on m

0

2D hi o~~~~~~~~~~~~~~ NO 0 U) - u DONrT CARE 2 hi~ ~~ 4 4d X t EYES 0 2 ~~~~ 4 o

lO'~~~ 0 0 hi 0 usi N hi . z ~ ~ ~ 2IP PATIENTS 00 m"~~imr AsAIDES

0 - WOULD LIKE TO TAKE DAILY" w 0PA P A P A P A P A P A P A P A

taI0 75 u a z 0~~K Z- hi .4 -'")' z CL Z CY 0~~~~~~~'.",

wo m -Ob x b

9.)O* 0 a A significant difference (P<0.05) between morphine subcutaneously and the other drugs, Including the placebo, Is shown by the symbol"1 m ",between codeine orally and the other drugs by the symbol"1 c ", and between the placebo orally and the other drugs by the symbol p"p R 1132 = diphenoxylate ; 7296A = d-3-methoxy-N-phenethylmorphinan. Reproduced, by permission, from Fraser et al. (1961 b).

continuing it, however, on the second day because of start the 7-day course of addiction and only three nausea. d-Propoxyphene was taken by all the completed the course. Those taking codeine intra- subjects and by two of them for the whole period of venously complained that all they felt was a tem- seven days; the average duration of administration porary pins-and-needles sensation. Although all for all subjects was 5.3 days. Even though five men the subjects elected to take I-K-1 for the seven days, identified the drug as " dope ", five discontinued it was feasible to administer it to only two subjects d-propoxyphene for such reasons as pain at the site (for 2.5 and 6.3 days, respectively) because it induced of injection, nausea, loss of appetite, dizziness and severe phlebitis and venous thrombosis. All pa- nervousness. One patient took d-propoxyphene tients complained that with I-K-1 morphine-like intravenously for seven days, but his veins became effects were absent or very weak and there was pain progressively occluded; successive injections of the at the site of injection. higher doses had to be given in different veins and This short-term direct addiction technique has the as much as 45 minutes was spent locating a suitable following advantages: The programme is less rigid vein. As to codeine, two patients elected not to in design than in the original long-term technique 156 H. HALBACH & N. B. EDDY and permits the former addicts to make elections develop very early, perhaps even with the first dose, among drugs and on how long they wish to take an and increased in intensity with continued adminis- agent before trying another. Furthermore, as indi- tration. However, the results with methadone cated above, it brings out rapidly differences among indicated that the intensity of abstinence signs pre- drugs respecting the quality of the subjective effects cipitated by nalorphine was not necessarily a basis and characteristics of a drug which determine its for the prediction of the intensity of abstinence which suitability for intravenous administration-for ex- would follow abrupt withdrawal, since withdrawal ample, its solubility and its local irritant and/or of methadone was followed by a slowly developing thrombotic properties. The primary deficiency of and relatively mild abstinence syndrome (Isbell et the method is that it does not evaluate adequately al., 1947). Nevertheless, if morphine or another the degree of physical dependence. It does, however, morphine-like analgesic were given for chronic pain give valuable information on the subject's immediate and if nalorphine (or another specific antagonist) like or dislike of a drug by his usually preferred route were given periodically during such administration of administration and, hence, on whether or not he in fixed amount and in fixed relation to the last dose would be inclined to use it thus if it were available of the analgesic, followed by observation for charac- to him. teristic abstinence symptoms, the appearance and intensity of such symptoms could be a measure of the time required for, or the rate of development of, TESTS FOR THE DEVELOPMENT OF TOLERANCE AND physical dependence. The procedure should be PHYSICAL DEPENDENCE UNDER CLINICAL CONDITIONS applicable to any form of chronic administration. A direct attack upon the question of addiction liability in clinical practice was initiated about Parenteral administration of potentially addicting 25 years ago under the auspices of the Commit- agents tee on Drug Addiction of the National Research From a population of patients with inoperable Council (USA). Selected subjects with chronic cancer individuals are selected who have persistent pain were given morphine or another comparable pain of an intensity to warrant the application of an analgesic in an amount and at an interval just opiate. Their histories are scanned to select those sufficient to control their pain. At 2- or 3-week with little previous narcotic experience and each intervals the analgesic was withheld for a period up patient is screened by an initial " allyl test" to rule to 24 hours and careful hour-by-hour observations out already existing detectable physical dependence. were made for the appearance of abstinence pheno- A suitable patient is started on subcutaneous mena. Recurrence of pain was the major difficulty administration of the medication, coded to provide and often made the period of withdrawal so short double-blind conditions. The patient remains on that that no signs of abstinence could be expected (Eddy medication throughout the study, other analgesics & Himmelsbach, 1936; Lee, 1942). being avoided entirely and, so far as possible, other The production of morphine antagonists, as sedatives. The initial dose is that determined pre- mentioned earlier, has made possible a new line of viously to be equivalent to 10 mg of morphine per attack. Wikler, Fraser & Isbell (1953) showed that 60 kg of body-weight, but it is adjusted if necessary nalorphine would precipitate abstinence phenomena by 10% increments within the first few days to in subjects who had received 15-30 mg of morphine provide adequate relief in the individual patient. four times daily for 3-7 days, or 10 mg of methadone Repetition of the dose is based on the demand of the four times daily for 2-5 days, or 15 mg of heroin patient because of the return of pain. The dose is four times daily for 2 days. Later.in the addiction increased only as necessary to maintain adequate period with any one of these drugs, the same dose of relief. As a check on the adequacy of pain relief, nalorphine precipitated a more intense abstinence with the first dose of coded medication and with a syndrome. Indeed, later during continued metha- single dose at weekly intervals, a careful record is done administration, nalorphine precipitated absti- kept of the degree of pain before and at hourly nence signs which exceeded in severity those which intervals after medication. (See Eddy & Lee, 1959.) ensued after abrupt withdrawal of morphine follow- While the coded medication is continued, a record ing long periods of addiction to high doses of that is kept of the individual dose and the total amount drug. These observations implied that physical of narcotic administered per day. From this record dependence on morphine-like substances began to and the weekly pain-relief scores a judgement is TESTS FOR ADDICTION (CHRONIC INTOXICATION) OF MORPHINE TYPE 157 made regarding the development of tolerance to the TABLE 2 analgesic effect of the drug. One must bear in mind CRITERIA FOR PHYSICAL DEPENDENCE, AS USED IN THE CLINICAL TEST FOR THE DEVELOPMENT OF TOLERANCE that advancing disease in these mainly terminal AND PHYSICAL DEPENDENCE cases may cause some increase in pain, and in con- sequence some increase in narcotic consumption Abstinence signs Symbol Numerical value independently of tolerance development. Estimation of the development of physical de- Systolic blood pressure BP 1 point for each 2 mm Hg pendence is based upon the periodic administration maximal rise, total not to of nalorphine, the " allyl test ". This test is per- exceed 10 points formed before coded medication is started and Rectal temperature T I point for each 0.1°C rise every two weeks thereafter. In the alternate weeks Respiratory rate R 1 point for each resp./min. a " placebo test " is carried out in like manner, increase saline solution being injected in place of nalorphine. Yawning Y I point In each instance the test is begun two hours after a Lacrimation La I point dose of narcotic. Blood pressure, rectal temperature, Rhinorrhoea Rh 1 point respiratory rate and pupil size are determined and Sweating S 1 point immediately afterwards 1.0 mg of nalorphine hydro- chloride (or 0.5 ml of saline solution for the placebo Gooseflesh G 3 points test) is injected subcutaneously. At 5-minute Mydriasis My 3 points intervals up to 20 minutes blood pressure, tempera- Tremor Tr 3 points ture, respiratory rate and pupil size are re-determined Restlessness Re 5 points and simultaneously the patient is observed for other Abdominal or other characteristic abstinence signs. Unless the symptoms cramps C 5 points observed are strikingly characteristic or severely Urge to defaecate D 5 points disturbing to the patient, 2.0 mg of nalorphine hydrochloride is injected 25 minutes after the first Nausea Na 3 points Emesis V 5 points for each act of dose and the observations are continued for at least emesis another 20 minutes. Alternatively, each allyl test may be performed with the administration of a After Eddy, Lee & Harris (1959). single dose of 3.0 mg of nalorphine hydrochloride. The decision to employ one or two doses of nalor- phine should be made initially and the procedure blood pressure and respiration may occasionally, remain the same for all patients of a study group. under the conditions of the unusual procedure of The signs looked for in each test and the numerical the allyl test, produce wide non-specific fluctuations. values assigned to them, both modified slightly In all cases a positive allyl test should be confirmed from the Himmelsbach hourly scoring system, are by another test giving the same or a greater score, shown in Table 2. A limit of 10 points is set for two weeks or more later, before a definite con- changes in systolic blood pressure but no limit for clusion of physical dependence is reached. an increase in respiration or rise in temperature. Eddy, Lee & Harris (1959) have reported on the The difference scored for blood pressure, respiration application of the procedures just described to a and temperature is the maximum observed after a study of addiction under clinical conditions. They dose of nalorphine compared with the value before have, by this method, compared oxymorphone and any nalorphine is given. The pupil size may be anileridine with morphine and currently some other determined by comparison with a series of dots old and new drugs are being compared in the same differing one from another by 0.5 mm in diameter way. or, preferably, by photographing the pupil. A score Schrappe and his associates (1959), believing that of 15 (the sum of the values for all signs observed) the Himmelsbach scoring system did not give an is judged to be significantly indicative of the presence adequate quantitative representation of abstinence of physical dependence, provided that the score is phenomena, have devised an alternative classifica- contributed to by some sign in addition to changes tion. They separate the abstinence signs into two in blood pressure and respiratory rate. This condi- groups, specific and non-specific, as shown in the tion or restriction is necessary because lability of tabulation below: 158 H. HALBACH & N. B. EDDY

Abstinence symptoms of the first order (specific) degree and rate of development of physical depen- 1. Shivering, feeling of cold, gooseflesh. dence with oral administration of analgesic mixtures 2. Yawning, sneezing, cough, hiccup. is only now being sought by a technique adapted from that described above for parenteral administra- 3. Feeling of warmth, profuse sweating. tion of analgesics. For the first report on this work, 4. Rhinorrhoea, lacrimnation, salivation. see Cass and associates (1961). The following is a 5. Diarrhoea. description of the procedure as modified for a con- 6. Colic, increased peristalsis, borborygmus, urge to tinuation of the study of this problem. defaecate. Hospitalized patients are selected for the study 7. Retching and vomiting. who have persistent mild to moderate pain of a 8. Extreme mydriasis (widening of the pupil by 3 mm degree that warrants and is generally relieved by an or more). oral analgesic mixture such as codeine plus APC 9. Automatic movements, severe anxious turning, (codeine phosphate 32.5 mg, aspirin 227.5 mg, psychomotor unrest. acetophenetidin 162.5 mg, caffeine 32.5 mg) or its 10. Muscular discomfort and pain. equivalent. Background information is entered on a 11. Burning sensations. special record sheet (see Annex 5) and the patient Abstinence symptoms of the second order (non-specific) begins a control period of eight days, during which 1. Increase in body temperature of 0.3°C or more. his analgesic medication, whatever it was previously, to five three cr four 2. Increase in respiratory frequency of three per minute is changed grains of aspirin times or more. a day. A record sheet (see Annex 6) is filled out for 1 each of the control days to provide a baseline for 3. Mydriasis (widening of the pupil by only or 2 mm). the degree of relief afforded by aspirin, the patient's 4. Increase of systolic blood pressure of 10 mm or daily complaints, etc. Also during this period a more. screening allyl test is carried out and, if this test is 5. Anxiety, inner unrest. negative, the patient is assigned to a drug group. 6. Nausea. The assignment is based on the background informa- 7. Headache, heart pain, palpitation, faintness. tion and the data obtained on the control days and is Each of the non-specific signs is given a value of intended to make the several drug groups as homo- one point; the specific signs are given a cumulative geneous as possible, since a number of drug mixtures value based on 10 for the first to be observed. The will be compared. The objective will be drug groups emphasis on the various abstinence phenomena each comprising about 25 persons, half males and differs in the Schrappe and Himmelsbach systems half females. The medication is supplied in capsules, and the former does not use a simple summation to under code number, of course, to make the study arrive at the total abstinence score. Schrappe and double-blind, and is administered on a routine four- his associates used successive doses of nalorphine to times-a-day schedule to those patients who get precipitate abstinence signs during continuing adequate pain relief on such a schedule and on a narcotic administration and compared the syndromes patient demand (p.r.n.) schedule to all others. In thus produced with those occurring spontaneously the latter group, the number of capsules per dose, after abrupt withdrawal of morphine or methadone. the interval between doses and the total number of capsules per day are adjusted to the patient's need Oral administration of analgesic mixtures or demand, thus further simulating usual clinical Himmelsbach et al. (1940) showed that codeine conditions and allowing psychic dependence and administered either subcutaneously or orally sup- tolerance, if they develop, to play their roles in ported previously established physical dependence total drug consumption. The medication for a to morphine. Himmelsbach reviewed the literature particular patient remains the same, but the code is on addiction to codeine, cases of which continue to changed with the consumption of each 100 dosage appear occasionally. Even the oral preparations of units. A record is kept for each patient each day codeine of relatively low concentration are subject (see Annex 7), showing total medication (number and to some abuse, and abuse of dihydrocodeinone oral time of administration of dose units taken), whether preparations is comparatively common (United pain was present or absent at three interviews States Bureau of Narcotics-personal communica- during the day, and patient's complaints (side- tion, 1960). However, specific information on the effects), if any. TESTS FOR ADDICTION (CHRONIC INTOXICATION) OF MORPHINE TYPE 159

To check for the development of physical de- TESTS FOR DETECTION OF DRUG USE AND RECIDIVISM pendence an allyl test (nalorphine hydrochloride, The diagnosis of addiction or of return to drugs 3 mg subcutaneously) will be carried out once a by an individual who has undergone treatment or month, also on a double-blind basis. To effect this, incarceration for violation of the narcotic laws is nalorphine and saline solution are provided in not easy in the absence of definite signs of abstinence. identically appearing ampoules, each ampoule This problem has been discussed at length in a carrying a different code number, and tests are report, entitled " What to do with a drug addict? ", carried out on successive days using two coded by Isbell (1952) to the Council on Pharmacy and ampoules, one of which contains nalorphine and Chemistry of the American Medical Association. the other saline. The tests are carried out as des- The report points out that there are no pathogno- cribed in the section on parenteral administration monic physical signs of addiction and comments and the data are recorded (see Annex 8) and evalu- on various aspects of the situation and devices ated by the modified Himmelsbach score (Table 2). employed by addicts that need to be borne in The daily record sheets and the allyl or placebo mind if one is not to be misled. Since complete or test results are reviewed by a person not directly partial tolerance to many of the effects of morphine associated with the patients, so that the narcotic and allied drugs develops during the course of medication can be stopped and a withdrawal period addiction, addicts will not show the same effects as instituted, by substitution of APC capsules under might be expected in persons not addicted. Constric- code number for the specific analgesic mixture, as tion of the pupil and signs of sedation are not likely soon as a significant degree of physical dependence to appear unless a dose of the addicting drug has is demonstrated. During this withdrawal period been received recently. Superficially tolerant addicts observations will be made three times a day for the will appear to be physically and mentally normal first three days and then daily through ten days for unless they have been without drugs for some time the spontaneous appearance of withdrawal signs, and signs of abstinence are beginning to appear. according to the Kolb & Himmelsbach daily scoring The most important findings are the presence of system (Table 1). old and recent needle marks. These should be sought In the initial study by Cass and his associates, over the veins in the antecubital spaces, the deltoid results were reported on 63 patients who received region, the abdomen, the anterior surfaces of the their medication on a rigid four-times-a-day sche- thighs and along the veins of the legs and hands. dule. The drugs employed were codeine plus APC, Long scars or tattooing over superficial veins is ethoheptazine plus aspirin, oxycodone plus a modi- extremely suggestive, especially if fresh needle marks fied APC, and dextropropoxyphene. The experiment are present. Also suggestive are multiple abscesses was terminated in each case after not more than or old abscess scars. Addicts using either pethidine 90 days of specific medication followed by a 10-day or methadone are likely to have induration and withdrawal period. The authors said: inflammation of large areas of the skin, particularly " On periodic administration of Nalline (nalorphine), over the deltoid region and the anterior surface of some signs of addiction were demonstrated with all the thigh. An important feature may be that no products, but these symptoms were neither consistent, physical findings are present which satisfactorily progressive or clear-cut. Upon withdrawal, some symp- explain the serious symptoms detailed by the pa- toms suggestive at least of physical dependence were tient. A complete physical examination as part of observed with all drugs except ethoheptazine. All four drugs demonstrated analgesic effectiveness." the diagnostic procedure is imperative. A definitive diagnosis of addiction to morphine or In the current continuation of the study the similar drugs depends upon the demonstration of medications are APC alone, codeine phosphate plus the characteristic signs of abstinence following com- APC, methadone hydrochloride plus APC, and plete and abrupt withdrawal of drugs. To prove the levorphanol tartrate plus APC. These were deli- presence of physical dependence, the addict must be berately selected on the basis of previous experience isolated in an environment so well controlled that to provide a range in the development of physical there is no possibility of his obtaining any narcotic dependence as a background for inclusion in the drugs other than those prescribed. If such an en- study later of new substances, concerning which vironment is available, isolation of the addict and nothing is known of their addictiveness when withholding of all narcotics will prove the presence administered orally under clinical conditions. or absence of dependence on these drugs. Detection 160 1H.: HALBACH & N. B. EDDY requires, of course, familiarity with the signs of sional doses of narcotics, nor does it prove that he abstinence and at best the procedure is prolonged was not actively addicted a week before the test was and difficult for patient, physician and attendants. done. A positive test, as just described, can have but The precipitation of an abstinence syndrome by one meaning. However, efforts have been made to nalorphine or another specific opiate antagonist and use a much milder reaction, even dilatation of the the utility of such a procedure in experimental pupil alone, as presumptive evidence of the use of clinical designs have been described above. As narcotics and this aspect of the procedure requires early as the report to the Council that has been further discussion. quoted above, the possibility of the use of nalor- Terry & Braumoeller (1956) reported upon the phine for diagnosis was suggested and a little later use of nalorphine for the detection of addiction, its use for this purpose was described more explicitly relying upon changes in pupil size for a definitive (Isbell, 1953). As mentioned later, however, there result. They mentioned other withdrawal symptoms, are certain basic requirements for the safety and but said: interpretation of this test. " The observation of gross withdrawal symptoms should When these requirements have been met, a 3-mg not be depended upon for a diagnosis but should be dose of nalorphine is given subcutaneously. If avoided if possible. To some degree patients themselves signs of abstinence have not appeared in 20 minutes, can control withdrawal symptoms. The pupillary res- an additional 5-mg dose is given and, if a definite ponse alone is an accurate, sufficient, and sensitive index abstinence syndrome does not appear after 20 more of narcotic addiction or of occasional use, or of the minutes, a final dose of 8 mg is administered. If absence of narcotics." abstinence has not become evident within 20 minutes The authors reported upon the use of the nalor- after the final injection, the patient is not addicted phine test in 454 patients suspected of taking an and can be released after the direct effects of nalor- opiate. They used a single dose of 3 mg. A card with phine have worn off, usually in less than six hours. black dots was used to measure the size of the pupil, If signs of abstinence appear after any of the doses of the authors believing this to be accurate to 0.5 mm nalorphine the individual has been taking morphine of diameter. According to the authors' interpreta- or an allied drug at sufficiently short intervals and in tion, sufficient amounts to produce physical dependence, " If the person tested has not been using opiates the and therefore is addicted. Obviously this method of diameter of the pupil is reduced by 0.5 mm. In a person diagnosing addiction requires familiarity with the who has been using opiates occasionally but who is not signs and symptoms of nalorphine-induced abstin- addicted, the pupils will remain unchanged in size. In a ence. Within two or three minutes after the adminis- person who is addicted the diameter of the pupils will tration of nalorphine an addicted person experiences increase by from 0.5 to 2 mm, the amount of increase a sensation of heat in the back or abdomen spreading depending upon the degree of addiction." over the body. There follow abdominal cramps and Other localities in the USA have been employing frequently defaecation. The patient becomes appre- the nalorphine test for the detection of addiction hensive and restless, perspires profusely and yawns and in some it has been made a condition of proba- frequently. Lacrimation and rhinorrhoea appear tion that the individual report periodically for such and increase in degree. The patient complains of a test to determine whether or not there has been chilly sensations and recurring waves of gooseflesh a return to drugs. It is now generally believed that are observed. Vomiting is likely to occur. The the dose of nalorphine in these tests should not patient may become quite hostile and antagonistic. exceed 3 mg, but there is not general agreement on Respiratory rate and minute volume increase and the reliance to be placed on pupillary changes alone the blood pressure is sharply elevated. The pupils or on the desirability or necessity for other evidence. are dilated. These symptoms constitute a full- There is a strong feeling that a positive finding- blown abstinence syndrome, which may begin in definite pupillary dilatation-could be used as a five minutes, reach peak intensity in 20, start to presumptive basis for holding an individual, but decline in 60 minutes and disappear after three that confirmation of such results should be sought hours. The symptoms are relieved, but not easily, by immediate urinalysis. Urinalysis should be done by the administration of morphine. in the cases showing equivocal results (slight dilata- A negative nalorphine test does not exclude the tion or no change in pupil size) after nalorphine. possibility that the person has been taking occa- Such analysis is cumbersome and time-consuming TESTS FOR ADDICTION (CHRONIC INTOXICATION) OF MORPHINE TYPE 161 and attention is being given to simplification. Public Health, which has published a guide explain- Cochin & Daly (1962), for example, have described ing the purpose and application of the test, the a method employing thin-layer chromatography that manner in which it is to be carried out and the cri- is rapid and accurate in its differentiation of opiates teria for determining that the test is positive (State in the urine and attention is being given to the of California Department of Public Health, 1961). application of gas chromatography to this problem. This guide says with respect to the test: The proponents of the nalorphine test for detecting " The procedure recommended here is intended to serve drug addiction and relapse are strongly of the only as a guide to physicians performing the synthetic opinion that it is a deterrent to relapse where it has opiate-antagonist test as an adjunct to the diagnosis of been used as a condition of probation. The test opiate usage. The procedure is not recommended as an has value and me-rits wider application, but it needs aid in detection of obvious addiction to opiates. As in any clinical circumstance, the results of a single test or to be carried out under better conditions and with procedure do not constitute a diagnosis." precautions which have not always been observed. Isbell (personal communication, 1961) has outlined This is a statement worthy of emphasis, because the requisite conditions for the nalorphine test as often the impression has been given that the nalor- follows: It should always be performed by a phy- phine test or even a small degree of pupillary dilata- sician who has studied the technique, is aware of the tion occurring in the test is all that is needed for a observations to be made, the precautions to be positive diagnosis, whereas the test may give some followed and the interpretation of the reaction. false positives and false negatives when checked by Before the test is done the patient should be given a urinalysis and other evidence. Mason & Shepherd complete physical and mental examination, which (1962) have reviewed tests performed on 154 cases will yield information on the history of addiction, in Illinois, USA, one of the States that authorizes the presence or absence of needle marks, miosis, etc., the use of the nalorphine test as a check on return to the presence or absence of serious organic disease drug use of individuals on probation. They reported and the patient's competence to sign a consent form. that in 59.1 % of the cases the result of the test was The test is contra-indicated in any person who has unequivocal, 37.0% negative and 22.1 % positive. serious organic disease, whatever the nature of that In 28.6% the test was equivocal, 11.7% negative disease may be. The consent of the patient should be and 16.9% positive according to further analysis. obtained in writing, after the test and its purpose There were 15 (9.6%) false positives and 4 (2.6%) have been explained to him. This explanation should false negatives. All of the nalorphine tests were include the possibility of severe reactions, their checked by urinalyses, but in these only morphine hazards and possible medico-legal implications. If (by indirection heroin and codeine also) was looked the pa:ient is under legal age or is mentally incom- for. Very probably this raised the number of appa- petent, c)nsent must be obtained from a parent or rent false positives, since the nalorphine test is legal guardian. The test should be done in a clinic strongly positive when methadone is the drug used or hospital where there are adequate facilities for and may be positive when the individual has been care of the patient in the case of a severe reaction taking pethidine or a related addicting substance. and it should not be done unless there are facilities for putting the patient to bed before, during and DISCUSSION AND SUMMARY after the test and resuscitative equipment is at hand, The many procedures which have been described, including epinephrine and/or other stimulants, both laboratory and clinical, have been devised infusion sets with normal saline and plasma ex- partly to learn more about the phenomena of toler- panders, mechanical respirators and aspirators and ance and physical dependence and partly as attempts injectable forms of morphine and barbiturates. The at predicting the risks or relative safety for clinical dose of nalorphine should not exceed 3 mg initially practice of new agents possessing in some degree and additional doses should not be given except by one or more of morphine's clinically useful proper- persons with considerable experience. There should ties. Undoubtedly much has been and can be learned always be present two professional observers-two by these methods that is pertinent to their first pur- physicians or a physician and a nurse-each of pose. Some comments are in order with respect to whom will make observations independently. the degree of attainment of the second objective. Isbell's recommendations have been in large part What happens in man is, of course, our real accepted by the State of California Department of concorn, but human material for abuse and addic- 162 H. HALBACH & N. B. EDDY

tion liability testing is not readily available. The full development of physical dependence and quan- Addiction Research Center at Lexington is the only titative comparisons, whatever the experimental place in the world where tests of this nature are subject, small or large animal (Seevers, 1958). going on and very few studies (to our knowledge less The investigators at the Addiction Research than half a dozen) of the development of tolerance Center in Lexington have pointed out similarities in and physical dependence in man under carefully the behaviour of dog and man during chronic controlled conditions are in progress. An animal administration and withdrawal of morphine, and method, therefore, which could be relied upon not particularly the comparability of results with similar to give false positive results would be very valuable. administration and withdrawal of pethidine and its Negative results in animal experiments may be derivatives. They have reported that the demonstra- encouraging but are at present not conclusive and tion of physical dependence can be made more are not likely to be. rapidly and definitely by the use of nalorphine to The method of Shemano & Wendel for predicting precipitate abstinence signs and Martin & Eades the probability of addiction on the basis of a relation- (1961) claim.d very recently that a single intravenous ship between the dose producing a Straub tail- infusion of morphine brought about, in a matter of reaction and the dose with a lethal effect in the hours, reproducible and measurable tolerance and mouse is simple and economical of time and material, physical dependence. Spinal dogs, too, have been particularly since it does not require any period of shown to exhibit characteristic and reproducible repeated administration. However, a Straub tail- withdrawal signs spontaneously and after the use of reaction has been described in the action of sub- nalorphine. However, these various procedures as stances which are not at all morphine-like and are applied to the dog have not yet been investigated known not to produce tolerance or physical depend- systematically by extending the observations to a ence. The authors report the highest Straub index large number of morphine-like substances of known for apomorphine, though they point out that its addiction potential in man to determine their pre- ability to produce physical dependence has never dictive value in screening. In addition, maintenance been tested. The practicability and reliability of the of spinal dogs in good physical condition is beset by method with respect to other false positives, if the major technical difficulties. apomorphine result is a false positive, will need La Barre's method of measuring motor activity confirmation through extension to a much wider in the dog during addiction to morphine or a test series of compounds to establish confidence in its substance and withdrawal or substitution of a predictive value as a screening procedure. potentially addicting agent is relatively simple and The several procedures which have been developed objective. The limited number of substances in experiments on the rat have demonstrated that studied so far by this method does not allow ex- this animal can become physically dependent on tensive comparison to be made with the results morphine and related substances. Also an abstin- obtained by other methods and in other species, ence syndrome, not unrelated to that seen in man, including man. Also the limitation that has been can appear after abrupt withdrawal of chronically imposed on dosage in direct addictions and in administered morphine and, more particularly and substitutions may increase very greatly the likelihood more characteristically, following administration of of false negatives in comparison with tests in the nalorphine or another opiate antagonist during monkey or man. In both of these species the ten- chronic morphinization. Attempts have been made dency has been to push dosages upward until the to quantify the components of the nalorphine- appearance of signs of toxicity, unless positive precipitated syndrome. Confirmation and refine- results have been obtained at lower dose levels. It ment of this quantitative evaluation may yield a should be advantageous to include in La Barre's preliminary screening test for substances with method the nalorphine abstinence precipitation physical dependence liability of morphine type, at technique and to attempt determination of dosage least for positive results. Again negative results equivalence in terms of intensity of withdrawal cannot be considered more than suggestive. Also phenomena and completeness of substitution of it should be borne in mind that continuity of admi- one agent for another, as well as to remove the nistration, seven days a week without interruption, at limitation on dosage increase. an around-the-clock interval consonant with the Seevers and his associates have demonstrated duration of action of the drug, is essential for the repeatedly the qualitative similarity in the results TESTS FOR ADDICTION (CHRONIC INTOXICATION) OF MORPHINE TYPE 163 obtained in suppression of the morphine abstinence over design, and to determine the likelihood of these syndrome in the monkey and in man and have individuals using the drug if it were available to warned of the hazard of quantitative predictions. them. In other words, these tests determine the In the single-dose abstinence suppression tests the patient's ability to identify the compound tested as monkey is more sensitive than man to pethidine " dope " (morphine- or heroin-like) or as being derivatives and less sensitive than man to benzo- like some other agent of his experience, the subject's morphan derivatives (substances related to phena- liking for or attitude towards the new drug, and, if a zocine). Nevertheless, observations in the monkey direct addiction experiment is done, the rate and have now been extended to the largest series of degree of development of tolerance and physical compounds of related and diverse structure and the dependence, again in comparison with morphine results are subject to the greatest number of com- and perhaps other known agents. The tests at least parisons with the results in man. The single-dose provide direct evidence on the likelihood of abuse, abstinence suppression technique in the monkey is one of the criteria for narcotics control, and may proving of practical value in that it discourages the measure directly addiction liability. It is significant continuation of work with new compounds which that predictions made as a result of work at Lex- show high physical dependence capacity and en- ington have been confirmed whenever the agent in courages the development of compounds which have question has entered into extensive clinical use. low physical dependence capacity, and demons- The more recent additions to the series of tests trates the presence or absence of morphine-like pro- devised at the Addiction Research Center merit a perties in new agents not yet sufficiently well known final word. Reference is made particularly to (a) the for trial in man. 24-hour substitution procedure, which reduces the From the work in monkeys and the study of discomfort to which the subject may be exposed and addiction liability in man no substance has yet been permits extensive cross-over observations with found which will significantly suppress (to the extent positive and negative controls; (b) the short-term, that codeine does, for example) morphine abstin- 20-day, direct addiction experiment, which is time- ence phenomena, or which will substitute for mor- saving and again permits cross-over observations; phine in an established addiction, maintaining the and (c) the very short, 7-day, intravenous drug addiction and preventing the appearance of abstin- administration, which gives an opportunity for the ence symptoms, which will not itself produce ad- patient to express his likes or dislikes and his pre- diction (physical dependence). Therefore, ability to ference for one drug over another. substitute for morphine, suppressing the abstinence The final test in which the physician is likely to syndrome and sustaining the addiction, defines a have the most confidence is the experience of clinical compound as addictingjust as certainly as producing practice. Before nalorphine, this was so tima- an addiction. consuming and impressionistic as to be of no im- All of the observations at the Addiction Research mediate value. The working out of techniques for Center in Lexington are made on individuals who monitoring, by periodic nalorphine injection, have been or are currently addicted to an opiate, narcotic analgesic medication for chronic pain and the question must arise of the validity for clinical without seriously disturbing the patient, makes practice of conclusions and predictions based on possible the accumulation of data on tolerance and work with such a population. All of the procedures physical dependence and comparison of one agent at Lexington are designed to push the dosage if with another in the same environment. The method necessary to the limits of safety, to determine the requires painstaking and long-continued observa- subjective and objective reactions of the subjects to tion, but where groups of suitable patients are the agent tested in comparison with their reactions available results of practical importance for the to known drugs given to the same subject in a cross- physician's guidance can be obtained.

ReSUMI Pendant longtemps. seules des observations de cas l'animal et a l'homme, permettant d'estimer le risque de reels de toxicomanie permettaient de se rendre compte toxicomanie qu'implique l'emploi de ces substances. des effets toxicomanogenes des opiaces ainsi que des Le critere sur lequel sont fondes les tests est la depen- substances analgesiques a effet morphinique. Actuelle- dance physique (toxicomanie). Les animaux de choix, ment, des methodes ont ete elaborees, applicables A pour ces epreuves, par ordre croissant d'analogie avec les 164 H. HALBACH & N. B. EDDY

r6actions de 1'homme, sont le rat, le chien et surtout le et a beaucoup accelere l'obtention des resultats. L'utilisa- singe. Les auteurs evaluent les divers tests et esquissent tion de ces antagonistes, en particulier, a permis l'observa- certains developpements ou perfectionnements possibles. tion clinique de l'apparition de 1'effet toxicomanogene, et Mais pour etablir de fa9on certaine le pouvoir toxico- de la tolerance, au cours de traitements prolonges par des manogene de produits inconnus, l'observation sur substances morphinomimetiques. l'homme reste indispensable. On trouve dans cet article le Les travaux sur les singes, de meme que les observations detail des modalites d'observation, et des tentatives sur l'homme, ont montre qu'une substance qui supprime d'evaluation quantitative approximative de l'effet des le syndrome d'abstinence du au retrait de la morphine, ou substances a 1'etude. qui, substituee a la morphine, entretient la toxicomanie, La mise au point d'antagonistes specifiques de la mor- est elle-meme toxicomanogene. C'est pourquoi, la capa- phine (du type de la nalorphine) grace auxquels le syn- cite d'une substance de remplacer la morphine en drome d'abstinence peut etre precocement decele a supprimant le syndrome d'abstinence ou d'entretenir contribue pour une large part 'a la precision des tests per- la toxicomanie, permet de la qualifier de toxico- mettant de mettre en evidence le pouvoir toxicomanogene, manogene.

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Annex I

SINGLE-DOSE ATTITUDE QUESTIONNAIRE (PATIENTS' RATINGS)

Name: ...... No...... Date:

Medication: .. Dose: ...... Time: Questions to be answered by you about the effects of this drug. In answering all questions check only sensations which you have experienced since your last examination by the aide. If the words listed are not satisfactory for describing your feelings, please write in other words or make comments.

Hour: 1 2 3 4 5 6 7 8 9 10

No No No No No No No No No No 1. Do you feel the medicine? Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

2. This drug is most like what drug listed below (check one)?

(a) A blank (water) ...... (d) Marihuana (reefer)

(b) " Dope" (opiates) (e)" Goof balls " (barbiturate-like)..

(c) Cocaine ...... (f) Benzedrine (" Benny ") ...... Other(g) (please name) ......

3. Check each sensation which you feel:

(a) Normal (no change) ...... (g) "Pleasant sick"

(b) "urningTof stomach ...... (h) " Drive " ......

(c) Skin itchy ...... (i) Sleepy ...... (d) Relaxed ....Nerv...... ) N

(e) " Coasting " ...... (k) Drunken .. (f) " Soap-box" (loquacious; tendency to brag) Otherdescribe)...... (please

4. Your liking for this drug is most nearly described by which of the following?

(a ot) N a ...... (d) A lot ......

(b) Slight ...... (e) An awful lot ......

Moderate(c) ...... (f) ther (pleasedescribe).

ments: ...... TESTS FOR ADDICTION (CHRONIC INTOXICATION) OF MORPHINE TYPE 167

Annex 2

SINGLE-DOSE ATTITUDE QUESTIONNAIRE (OBSERVERS' RATINGS)

...... No..... Date:

Medication: ...... Dose: .. Time:. In answering all questions check only the items of behaviour observed since your last examination. If the words listed are not satisfactory, please insert others which you consider more appropriate or make comments.

Hour: 1 2 3 4 5 6 7 8 9 10

No No No No No No No No No No 1. Any evidence of drug effects? Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

2. Behaviour is most like that seen after (check one):

(a) A blank ...... (d) Marihuana (reefer) ...... (b) " Dope " (opiates or potent synthetic (e) " Goof balls" (barbiturates) b analgesics) ..(f).Benzedrine Benny ")...... (f).Benzedrine.(".Benn (c) Cocaine ...... (g) Other (please name).

3. Check each item which you think the patient shows:

(a) Norm al (no change) ...... (g) Vomiting ......

(b) Scratching ...... (h) "Nodding. . Red(c) eyes ...... (...... Sleepy ...... (d) Relaxed ...... (j)N ervous

Coasting" " (e) ...... ( k)Drun ken ...... (f) " Soap-box " (loquacious; tendency to brag) ...... (/) Other (please describe)

4. How much do you think the patient liked the effects of this drug during the past hour?

(a (d A lot ......

(b) Slightly ...... (e) An awful lot ..

(c) Moderately . ... (f) Other (please describe) . .

5. Pupils: ......

. o ents: ......

...... I...... i......

Initials of aide: ...... 168 H. HALBACH & N. B. EDDY

Annex 3

CHRONIC DOSAGE ATTITUDE QUESTIONNAIRE FOR OPIATES (PATIENTS' RATINGS)

Nameof patient: ...... Date:. Answer all questions according to how this drug is affecting you today.

drug1.Hasproducedthis any effect on you? Yes ...... Noo.....

Does2. this drug feel like an opiate (" dope ") ? Yes ...... No ...... If so, which of the drugs given below is this drug most nearly like, and how strong do you think it is ? It Is most nearly like (check one):

(a) Heroin ...... (c) Codeine ...... Morphine(b) ...... (d) Other "dope"-like drug ease(plname) I think the strength of this drug is (check one):

(a) No effect ...... (d) Average ...... (b) Very weak ...... (e) Strong ......

(c) Weak...... (f) Very strong ...... (g) Overdose......

3. Is the feeling from this drug like that from one of the drugs given below? Yes .No . It is most nearly like (check one):

blank(a)(water)A ...... (d) "Goof balls"(barbiturate-like) ......

Marihuana(b) (reefer) ...... (e) Alcohol (whiskeyor beer) ......

Cocaine(c) ...... (f) Benzedrine ("Benny") Other(g)(please name) ...... I think the strength of this drug Is (check one): Noeffect(a) ...... (d) Average Very weak ...... (e) Strong

Weak(c) ...... (f) Very strong...... (g) Overdose ......

Would4. you like to take this drug every day? Yes ...... No...... Don't care ......

drugmakethis5.Does you feel bad? Yes ...... If so, does it make you feel so badly that you would stop taking it if you were not on a test? Yes . No

cr. brieflyies be themost important effects of this drug on you:

...... I...... I......

7 Are you "1 kicking a habit " ? Yes No TESTS FOR ADDICTION (CHRONIC INTOXICATION) OF MORPHINE TYPE 169

Annex 4

CHRONIC DOSAGE ATTITUDE QUESTIONNAIRE FOR OPIATES (OBSERVERS' RATINGS)

Name of patient ...... at ...... Answer all questions according to how this drug Is affecting this patient today.

1. Is this drug affecting the behaviour of this patient in any way? Yes .No

Doesthis2. patient show behaviour resembling that seen after opiates? Yes ...... No...... If so, indicate from your observations of the patient's behaviour the drug listed below which induces behaviour most nearly resembling that of the patient. Also describe the potency of this drug in inducing opiate-like behaviour. Behaviour is most nearly like that seen after (check one): (a) Heroin ...... Codeine(c).

(b) Morphine . . . (d) Other opiate (please name)...... The potency of this drug In Inducing behavioural changes Is (check one): (a) No effect ...... (d) Average . (b) Very weak ...... (e) Strong . (c) Weak ...... (f) Very strong . (g) Overdose.

3 Is the behaviour after this drug like that after one of the drugs listed below? Yes .No. Behaviour is most nearly like that seen after (check one): A blank(a) ...... ((d)"olGoof ballsa" (barbiturates)b..... Marihuana(b) (reefer) ...... (f) Alcohol...... (c) Cocaine ...... (f) Benzedrinee(("Bennyy"). Other(g) (please name) ...... The potency of this drug In inducing behavioural changes Is (check one): (a) No effect ...... (d) Average . (b) Very weak ...... (e) Strong . (c) Weak ...... (f) Very strong . (g) Overdose.

4. Do you think this patient would like to take this drug every day?

.NoYes .Doesn't care .

5. Do you think this drug makes this patient uncomfortable? YesY.No.. If the answer is " yes " to this question, do you think he dislikes it sufficiently to voluntarily stop taking it if he were not on an experi- mental test? YesY.No..

briefly6. Describemostimportantthe effects of this drug in this patient: ......

7. Is this patient " kicking a habit " ? Yes .. No. Initials of aide: ...... 170 H. HALBACH & N. B. EDDY

Annex S

PATIENT'S INITIAL DATA SHEET

Name: ...... Hosp. No...... Date: ......

Patient No Med. Code Card No..

Age: . Sex: .Weight:.

andDiagnosisgeneral condition: ......

Mental state: ......

......

Nature or origin of pain:,

......

Current treatment for pain: Kind: ......

Dose: .....F...... Fr...... Frequency: ......

Has codeine or other narcotic analgesic been used for this patient within

three months? Yes No

If yes, give details:

......

Does this patient require laxative medication? Yes No

If yes, give details :

......

Does this patient require any other regular medication? Yes No ......

If yes, give details:

...... TESTS FOR ADDICTION (CHRONIC INTOXICATION) OF MORPHINE TYPE 171

Annex 6

DAILY RECORD: CONTROL PERIOD

..Name:...... Date: ......

Patient No...... Control day:.

Analgesic medication:

Aspirin Dose: 5 grisins Time:

Aspirin 5 grn ains Time: ......

Aspirin 5 grn ains Time: ......

Pain relief ' (circle figure which applies): Morning: 8 a.m. 0 1 2 3 4 Afternoon: 12 noon 0 1 2 3 4 Average ...... Evening: 4 p.m. 0 1 2 3 4

Side-effects (complaints) 2 (circle figure which applies): 8 a.m. 12 noon 4 p.m. Nausea 0 1 2 3 0 1 2 3 0 1 2 3 Vomiting 0 1 2 3 0 1 2 3 0 1 2 3 Nervousness 0 1 2 3 0 1 2 3 0 1 2 3 Drowsiness 0 1 2 3 0 1 2 3 0 1 2 3 Mental dullness 0 1 2 3 0 1 2 3 0 1 2 3 Lightheadedness, faintness 0 1 2 3 0 1 2 3 0 1 2 3 Unsteadiness 0 1 2 3 0 1 2 3 0 1 2 3 Dizziness 0 1 2 3 0 1 2 3 0 1 2 3 Euphoria 0 1 2 3 0 1 2 3 0 1 2 3 Other (explain) 0 1 2 3 0 1 2 3 0 1 2 3 Constipation 0 + Bowel movement 0 + Laxative required 0 +

0 = moderately severe pain; patient claims no relief from medication. 1 very little relief from medication. 2 = slight to moderate pain; moderate relief attributed to medication. 3= very little paln. 4 = no pain; comfortable in this respect, whether or not on account of medication. '0 = not present; I = slight; 2 = moderate; 3 = severe. 172 H. HALBACH & N. B. EDDY

Annex 7

DAILY RECORD: STUDY PERIOD

Name:...... Date:. Coded med.No..

Patient No.. Studyday Analgesic medication:

Units: Time: Units:. Time: ... ..

Pain relief I (circle figure which applies): Morning: 8 a.m. 0 1 2 3 4 Afternoon:12 noon 0 1 2 3 4 Average ...... Evening: 4 p.m. 0 1 2 3 4

Side-effects (complaints) 2 (circle figure which applies): 8 a.m. 12 noon 4 p.m. Nausea 0 1 2 3 0 1 2 3 0 1 2 3 Vomiting 0 1 2 3 0 1 2 3 0 1 2 3 Nervousness 0 1 2 3 0 1 2 3 0 1 2 3 Drowsiness 0 1 2 3 0 1 2 3 0 1 2 3 Mental dullness 0 1 2 3 0 1 2 3 0 1 2 3 Lightheadedness, faintness 0 1 2 3 0 1 2 3 0 1 2 3 Unsteadiness 0 1 2 3 0 1 2 3 0 1 2 3 Dizziness 0 1 2 3 0 1 2 3 0 1 2 3 Euphoria 0 1 2 3 0 1 2 3 0 1 2 3 Other (explain) 0 1 2 3 0 1 2 3 0 1 2 3 Constipation 0 + Bowel movement 0 + Laxative required 0 +

' 0= moderately severe pain; patient claims no relief from medication. I = very little relief from medication. 2 = slight to moderate pain; moderate relief attributed to medication. 3= very little pain. 4 = no pain; comfortable in this respect, whether or not on account of medication. ' 0 = not present; I = slight; 2- moderate; 3 = severe. TESTS FOR ADDICTION (CHRONIC INTOXICATION) OF MORPHINE TYPE 173

Annex 8

ALLYL OR PLACEBO TEST RECORD SHEET

Nam e: Date:.. Code No. of solution injected:

Patient No...... Study day: ...... Test No...... Time: Time of last preceding coded drug given:

Blood pressure: Pupll size:

Control ...... Control ......

10 min...... 10 min......

20 min...... 20 min......

30 min...... 30 in. ...

40 min. .... Points 40 min...... Points ....

Respiratory rate: Other signs (circle as observed):

Control ..... Yawning +

Lacrimation 0 10 min...... Rhinorrhoea 0 20 min. Sweating 0 -...I...... I...... + 30 min...... Gooseflesh 0

Tremor 0 40 min-. Po ints Restlessness 0

Rectal temperature: Abdominal or other cramps 0

Control ....-...... Urge to defaecate 0

Nausea 0 10 min...... Emesis 0 20 m in....

30 min......

40 min...... Points

Total score:

Remarks: