Br. J. clin. Pharmac. (1979), 7, 291S-296S
MIXED AGONIST-ANTAGONIST OPIATES AND PHYSICAL DEPENDENCE J.J.C. JACOB, G.M. MICHAUD & E.C. TREMBLAY Laboratory of Pharmacology, Institut Pasteur, Rue du Docteur Roux, F75724 Paris Cedex 15, France
1 General methods (chronic, subacute and acute) for assessing physical dependence potential, abstinence precipitating capacity and abstinence preventing activity are briefly presented. 2 Direct dependence experiments indicate that, in general, mixed agonist-antagonist analgesics have relatively lower physical dependence potentials than pure agonist analgesics. That of buprenorphine seems to be particularly low in various animal species. 3 When substitution techniques are used, the dependence potential of buprenorphine seems to be somewhat more developed than with direct dependence techniques. 4 Among various agonists (morphine, methadone and etorphine), antagonists (naloxone, naltrexone and diprenorphine) and mixed agonist-antagonists (pentazocine, butorphanol and buprenorphine), buprenorphine is the most potent and the longest acting drug in preventing precipitated abstinence in mice, rats and dogs. 5 The low physical dependence potential of buprenorphine may result in part from the very slow dissociation of the complex it forms with opiate receptors. This potential might be underestimated when precipitated abstinence methods are used, as naloxone would displace buprenorphine from its receptors only to a very limited extent. New means of evaluating dependence by more direct means need to be developed. 6 Overall, the properties of mixed agonists in general justify their use as analgesics with lower physical dependence potential than the pure opiates and further, those of buprenorphine seem to indicate its possible utility for the treatment of opiate addiction.
Introduction Two of the principal objectives of the study of mixed agonist-antagonists are the development of potent analgesics with a low dependence potential and agents for the treatment of opiate addiction. The first aim is not a mere speculation. Indeed, nalorphine, the first mixed agonist-antagonist to be studied in man, has satisfactory analgesic properties and a much lower dependence potential than the pure opiates. Drug-seeking behaviour is lacking after withdrawal and physical dependence is moderate and of a type different from that of morphine (see Martin, 1979). However, nalorphine could not be used extensively in clinical practice because of its psychotomimetic properties. Pentazocine was developed later; its dependence potenti,l was definitely lower than that of morphine and its psychotomimetic activity less developed than those of nalorphine. Two major types of addiction therapy exist at present. The first is treatment with some selected agonist such as methadone which 'blocks' the drug0306-5251/79/150291-06 $01.00
seeking behaviour and abstinence signs but maintains or promotes the dependent state. The second type is therapy with antagonists which is still rather experimental; antagonists protect against the euphorigenic effects of opiates and prevent the development of dependence. According to Wikler (1974), they should also be used to extinguish various conditioned reactions which maintain addiction. Their major drawback is that they precipitate abstinence in addicts who for this reason often refuse -to continue the treatment. General methodology of animal experiments In the experimental animal, the dependence potential of narcotic or mixed analgesics is assessed by determining (a) the pattern of their acute effects; (b) the existence and characteristics of self administration (which is considered to be a model for psychic
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dependence); and (c) the occurrence and intensity of withdrawal signs by which physical dependence is manifested. The two first types of experiments will not be dealt with in this report. We will only recall that the pattern of actions of mixed agonistantagonists vary considerably according to the particular drug (for references, see Jacob, 1975a) and that nalorphine promotes little self-administration behaviour in monkeys and rats. Self-administration of pentazocine is also less than that observed with typical agonists. The assessment of physical dependence potential relies classically on two general procedures, 'direct induction' and 'substitution', studies. Direct induction consists of administering the drug to be studied subchronically at doses which might be expected to promote dependence. When the treatment is interrupted by withdrawal of the drug various physical signs develop (withdrawal abstinence), the intensity of which can be measured. Interruption of the treatment can also be achieved by administration of an opiate antagonist which will produce a similar but not quite identical syndrome (precipitated abstinence). The use of an antagonist has some practical advantages. In general the precipitated syndrome is more acute, clearcut and intense than that following the interruption of the treatment. It can be obtained after a few or even after a single injection of an opiate (for references, see Jacob, 1975b). This 'acute' or 'single dose dependence' can be used for the thorough study of dose-response relationships, the time course of the underlying dependence, the precise relationships with other acute (for example, analgesic) effects, the modification of the withdrawal syndrome by various substances and also for comparison of various drugs with regard either to their 'agonist' dependenceinducing properties or to their 'antagonist' precipitating activities. These acute techniques, however, have also drawbacks which have already been discussed (Jacob, 1975b). The created state of dependence is of a relatively low intensity and effects exerted by the antagonist in its own right may obscure the syndrome. Additionally, dependence induced by repeated and (or) prolonged treatments includes additional complex factors such as cumulation of effects, development of tolerance, autopotentiation phenomenon and 'shifts of signs'. As a consequence the withdrawal syndrome after chronic treatment becomes different, quantitatively and qualitatively (that is, varies in its constituents). Chronic direct addiction studies are therefore necessary, in particular if the physical dependence potential of the test drug seems to be lower than expected in the acute tests. However, chronic procedures may also be misleading when inadequate dose regimens are used. Adequate dose regimens are not easy to establish and should be based inter
alia on the results of acute pharmacokinetic studies and substitution experiments. Substitution consists of the administration of a known opiate with a schedule known to induce clearcut dependence. The treatment is then interrupted and the test drug is administered to the withdrawn animal displaying signs of abstinence. If the test substance is an agonist (that is, a dependenceinducing drug), it will abolish all signs of abstinence (with an adequate acute dosage) and its dependence potential will be estimated both from the effective dose, and also from concomitant side-effects. If severe side-effects (for example, convulsions or coma) occur at the effective dose for suppression, the abuse potential can be regarded as low; if no sideeffects are present, the potential is rated high. If the test drug is an antagonist, it will, in general, increase the abstinence signs. If it is a mixed agonistantagonist, its effect will vary according to several factors, in particular the predominance of agonist compared with antagonist properties and the intensity of the dependence state induced with the known agonist (the more intense, the more the antagonist properties would emerge). The activity of an antagonist or of a mixed agonistantagonist in precipitating abstinence is studied by administering it to non-withdrawn animals previously treated with a known opiate. This pretreatment can be acute which allows for the easy assay of a whole range of doses of the test substances, or it can be chronic, which is more sensitive with an adequate dose regimen. Antagonism of the development of dependence can also be assessed with the foregoing general testing procedures but needs some more comments. When administered before an opiate, an antagonist will, in principle, prevent the appearance of withdrawal signs following either the interruption of the treatment or the administration of an antagonist. Thus, naloxone injected before morphine is able to prevent the syndrome it would precipitate itself in morphine-treated animals. This antagonism can also be obtained when the antagonist is injected shortly after the opioid and an injection of naloxone after morphine, whether or not it produces abstinence in its own right, can also inhibit the abstinence syndrome that a second injection of naloxone would precipitate. However, antagonism of abstinence does not necessarily mean antagonism of dependence. As commented above, opiates which themselves produce dependence, abolish the abstinence signs by substituting for morphine in withdrawn animals. They can also inhibit these signs when sufficient doses are administered in non-withdrawn animals at appropriate times because they postpone the withdrawal abstinence, just as they can do in addicts, or oppose the precipitation of abstinence by naloxone.
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Experimental studies
Induction ofdependence Various opiates or mixed agonist-antagonists were compared with morphine in mice and rats using single dose procedures (Jacob & Tremblay, unpublished observations). In mice, naloxone 1 mg/kg subcutaneously precipitated jumping in 660/ of mice 2 h after administration of morphine 15 mg/kg subcutaneously, in 50% and 80% 1 and 2 h after methadone 3 and 10 mg/kg subcutaneously, respectively, in 75% 1 h after etorphine 0.1 mg/kg subcutaneously, and in 35% 1 h after pentazocine 100 mg/kg subcutaneously. Thus, methadone and morphine seem to be almost equipotent in inducing acute dependence and are much less active than etorphine; pentazocine is least effective. This rank order correlates well with the analgesic potencies of these drugs. The dependence produced by them with the test doses was of short duration as naloxone was much less effective or inactive when injected 4-8 h after the opiate. Buprenorphine gave quite different results, as naloxone 1 or 10 mg/kg subcutaneously or diprenorphine 1 or 10 mg/kg subcutaneously did not precipitate jumping when administered at various time intervals (up to 1 d) after various doses of buprenorphine (from 0.1-10 mg/kg subcutaneously). Irregular jumping was observed when the time interval between the administration of buprenorphine and that of naloxone or diprenorphine was 1 or 2 days. In rats, naloxone 1-10 mg/kg subcutaneously and diprenorphine 1 mg/kg subcutaneously which precipitated several signs of abstinence after morphine 15-50 or 100 mg/kg subcutaneously, produced only few and feeble withdrawal signs when injected at different times after buprenorphine 0.1 or 1 mg/kg subcutaneously. In unanaesthetized dogs, naloxone 1 mg/kg administered subcutaneously 2 h after either morphine 6 mg/kg intravenously or buprenorphine 0.1 mg/kg intravenously antagonized the sedation, myosis and bradycardia induced by either drug but produced an overshoot phenomenon characteristic of physical dependence, intense and typical agitation, mydriasis and tachycardia, only in the morphinetreated animals. When a higher dose of buprenorphine (1 mg/kg intravenously) was used, naloxone did not antagonize the morphinomimetic effects of the drug (Michaud & Jacob, 1978; Jacob & Michaud, unpublished observations). Using subacute techniques, pentazocine (Saelens et al., 1971) and buprenorphine (Cowan et al., 1977) have been shown to induce little dependence, as manifested by naloxone precipitation. Classical chronic procedures have supported the same conclusion for pentazocine, and with similar
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procedures the dependence potential of buprenorphine has been shown to be low in the dog (Martin et al., 1976) and absent in monkeys, in which no abstinence was observed either after interruption of treatment in rhesus monkeys (Swain & Seevers, 1975) or after administration of naloxone to patas monkeys (Cowan, 1974; Cowan et al., 1977).
Substitution As already stated, mixed agonist-antagonists substitute for morphine when the test animal has been pretreated with relatively low doses of the agonist and precipitate abstinence when these doses are high. Buprenorphine substituted for morphine in withdrawn mice having received high doses of morphine for 3 days. Thus, the physical dependence potential seems in the same animal species to be greater with this technique than with the direct dependence method. Buprenorphine substituted partly for morphine in withdrawn subacutely morphine-treated rats, the substitution attenuating only some signs of abstinence (head shakes, teeth chattering and abnormal posture; Jacob & Tremblay, unpublished observations). As reported by Martin at this symposium, it also substitutes for morphine in dogs but with a flatter dose-response curve than that obtained with pure agonists. Prevention of abstinence Precipitated abstinence In acute experiments in mice, abstinence precipitated by naloxone can be prevented by both agonists and antagonists given before the precipitating dose of naloxone and either before or after the priming dose of morphine. This has been demonstrated for morphine and naloxone in experiments of our laboratory (Tremblay et al., 1976a). The effect of morphine is comparable to its effect in substitution experiments, except that the use of naloxone, which also antagonizes this action of morphine, renders it necessary to use rather high doses of the agonist. As observed in substitution experiments also, the agonist in this test situation does not really antagonize but rather postpones the abstinence. Antagonists are thought to antagonize dependence itself but their mechanism of action, as well as that of buprenorphine, is probably more complex (see later). In extending these studies to other agonists, antagonists and mixed agonist-antagonists, we have found that methadone was more effective than morphine in the prevention of acute abstinence. Etorphine is the most potent agonist in the abstinence prevention test to date (Jacob et al., 1976). Among antagonists, diprenorphine is more effective than naltrexone which in turn is more effective than naloxone (Tremblay et al., 1976b). Among mixed
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agonist-antagonists, buprenorphine is much more effective than butorphanol which itself is much more effective than pentazocine (Jacob et al., 1976). Not only was buprenorphine effective at very low doses (5-20 jig/kg depending on the doses of morphine and of naloxone used), but also its action was much more sustained than that of all other studied drugs. For these latter compounds, the activity decreases considerably within 3 h, whereas for buprenorphine it was maintained for a 4-h period. The activity of buprenorphine was also much less dependent than that of the other drugs on the doses of morphine or naloxone used in the experiment. Similar results were obtained in rats in which several signs of precipitated abstinence could be measured or quoted. The studied antagonists and mixed agonists-antagonists were able to antagonize all abstinence signs, a characteristic which contrasts with the partial action of drugs like parasympatholytics, neuroleptics, and so on. Among antagonists, the rank order of effectiveness is again naltrexone, diprenorphine, naloxone (Tremblay et al., 1976b). Etorphine is not effective in the tolerated dose range. Buprenorphine is extremely potent with a relatively long duration of action (Jacob et al., 1976). In dogs, buprenorphine was again very effective: 0.1 mg/kg given intravenously 2 h after morphine 6 mg/kg intravenously, almost completely prevented the tachycardia, mydriasis and hyperthermia produced by naloxone injected 24 h later (Michaud & Jacob, 1978; Jacob & Michaud, unpublished observations). Buprenorphine and diprenorphine were also able to prevent abstinence in mice following the interruption, of a subacute treatment with morphine, when they were administered each day before the first daily injection of the test agonist. The necessary doses were rather high, due probably in part to the fact that a duration of action of at least 8 h was then necessary. Buprenorphine is somewhat more potent than diprenorphine in this situation (Jacob & Tremblay, unpublished observations). Precipitation of abstinence in non-withdrawn animals The effectiveness of antagonists such as naloxone, naltrexone and diprenorphine in classical chronic experiments is well established and need not be commented upon here. Similarly, the low efficacy of pentazocine is also well established. Our acute experiments in mice and rats have compared the effectiveness of naloxone, naltrexone, diprenorphine and buprenorphine in acute and in some subacute experiments. In mice 4 h after morphine 100 mg/kg subcutaneously, naloxone, diprenorphine and naltrexone ranked in order of decreasing efficacy,
had ED,0 values of 0.30, 0.03 and 0.006 mg/kg, respectively (Tremblay et al., 1976b). In the same conditions, buprenorphine with doses ranging from 1 g.g-10 mg/kg subcutaneously did not precipitate any jumping. In rats, following morphine 50 mg/kg subcutaneously, 1 mg/kg subcutaneously of either naloxone, naltrexone of diprenorphine produced an intense syndrome in 75%0 of the animals but buprenorphine was quite ineffective (Jacob & unpublished observations). Tremblay, Buprenorphine also had a low efficacy in mice and rats following subacute treatment with morphine (Cowan, 1976). In dogs having received a single dose of morphine 2 h before, buprenorphine 0.1 and 1 mg/kg increased rather than decreased the antinociceptive effect .of morphine but antagonized its sedative, myotic and bradycardic actions (Michaud & Jacob, 1978; Jacob & Michaud, unpublished observations). It did not produce any overshoot, which is characteristic of abstinence precipitated by naloxone, except that the higher dose of buprenorphine produced some transient tachycardia. In chronically spinalized dogs following a chronic treatment with morphine, buprenorphine precipitated a mild abstinence (Martin et al., 1976). A mild syndrome was also observed in patas monkeys (Cowan, 1974; Cowan et al., 1977) and a more severe one in rhesus monkeys (Swain & Seevers, 1975). Discussion and conclusions In general, the 'classical' experimental animal procedures have shown that the physical dependence potential of the mixed agonist-antagonists is rather lower than that of the opiates, a conclusion which is also obtained using acute techniques. Buprenorphine seems to have an exceptionally low physical dependence potential in several animal species (mice, rats, dogs and monkeys). This characteristic may result, at least in part, from the unusual kinetics of its binding with the opiate receptors. As Rance (1979) has commented in this symposium, the complex formed by buprenorphine and the opiate receptors is very stable and dissociates very slowly. This would account not only for the protracted character of the abstinence as observed in mice (see above) and in man (Jasinski et al., 1978) but also for the fact that the abstinence syndromes, when observed, are very partial and of low intensity. The slowness of the disappearance of buprenorphine (or of its displacement by naloxone) would give time for at least partial maintenance of homeostasis and thus limit the imbalances produced by withdrawal of the inhibitory effects of the opiate. The dependence potential of buprenorphine is probably underestimated when naloxone is used to precipitate abstinence, as naloxone displaces
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buprenorphine from its complex less effectively in vivo than in vitro because it is itself rapidly eliminated from the brain. Substitution experiments in mice and rats, in which naloxone is not used, point seemingly to a greater (but still low) dependence potential than the direct induction experiments using precipitated abstinence. The ineffectiveness of naloxone in precipitating abstinence is itself not entirely accounted for by its inability to gain access to the receptors because, in acute experiments, we have shown that naloxone exerts some antagonistic effect in buprenorphine-treated mice or dogs and thus must bind with receptors and displace some buprenorphine without precipitating abstinence. Indeed, the existence of drugs like buprenorphine poses the problem of developing new means of evaluating dependence. These include, for instance, the determination of the modalities of occupation of receptors by buprenorphine in vivo (in other words, does it bind mainly as an agonist or as an antagonist; with what classes of opiate receptors; and how does this binding change with time?) and of various biochemical events which are thought to be related to dependence (hypersensitivity of some biogenic amine receptors, variation in ion flux or adenylate cyclase activity). Despite such important theoretical uncertainties, mixed agonist-antagonists seem to have great potential in therapy. In general, experiments in man have confirmed that, with very few exceptions, they have lower dependence potential than the agonists. This also seems to be the case for buprenorphine (Jasinski, 1979; Robbie, 1979). With regard to their use as analgesics, it is well known that their patterns of antinociceptive actions are, in animals, very different from those of agonist analgesics and that most of them, including buprenorphine, show ceiling phenomena in some test situations. Thus, the
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animal pharmacologist cannot establish a single ratio of antinociceptive activity/dependence potential. For example, this ratio is for buprenorphine greater than 1000 in mice when moderate effectiveness in the hotplate test and precipitated abstinence are considered but nearly zero in dogs when depression of skin reflexes are used. It is therefore the burden of the clinician to estimate the efficacy of these drugs on various types of pain, so as to determine finally in what instances the mixed agonist-antagonists are useful and safer than the opiates. With regard to the treatment of addiction, buprenorphine seems to have uniquely favourable characteristics. Among the various agonists, antagonists and mixed agonist-antagonists that we have studied, it is by far the most effective in preventing abstinence and, perhaps more important, in affording a protection of long duration. As already commented its physical dependence potential seems to be lower than that of methadone, and further, its potency in precipitating abstinence is much lower in several animal species than those of naloxone, naltrexone and diprenorphine. Thus, buprenorphine deserves consideration for therapeutic trials in opiate addiction, especially because, as will be commented in other reports in this symposium, other relevant properties in man (psychic dependence, tolerance and cross tolerance) seem at this time to be acceptable in such an indication. Needless to say, much theoretical and clinical work is still necessary but the results to date are indicative that buprenorphine may prove to be a partial agonist drug of some significance. The work of the laboratory has been supported by grants from the INSERM (contract AT 76-71) and the DRET (contract 77/443).
References COWAN, A. (1974). Evaluation of the physical dependence capacities of oripavine-thebaine partial agonists in patas monkeys. In Narcotic Antagonists. Advances in Biochemical Psychopharmacology, 8. Ed. Braude, M.C. et al. Pp. 427-438. New York: Raven Press. COWAN, A. (1976). Use of the mouse jumping test for estimating antagonistic potencies of morphine antagonists. J. Pharm. Pharmac., 28, 177-182. COWAN, A., DOXEY, J.C. & HARRY, E.J.R. (1977). The animal pharmacology of buprenorphine, an oripavine analgesic agent. Br. J. Pharmac., 60, 547-554. COWAN, A., LEWIS, J.W. & MACFARLANE, I.R. (1977). Agonist and antagonist properties of buprenorphine, a new antinociceptive agent. Br. J. Pharmac., 60, 537-545. JACOB, J. (1975a). Pharmacologic des antagonistes de la morphine. La Revue de Medecine, n° 7, 7 fevrier 1975, 431-444.
JACOB, J.C. (1975b). The problems of acute physical dependence on opioids. In Neuropsychopharmacology. Proc. ninth Congr. CINP. Ed. Hippius, Boissier, J.R. & Pichot, P. Pp. 279-286. Amsterdam: Excerpta Medica International Congress. JACOB, J., TREMBLAY, E. & MICHAUD, G. (1976).
Antagonism of precipitated abstinence by narcotics, narcotic antagonists and mixed agonist-antagonists. In Opiates and Endogenous Opioid Peptides. Ed. Kosterlitz, H. W. Amsterdam: North-Holland. JASINSKI, D.R. (1979). Human pharmacology of narcotic antagonists. Br. J. clin. Pharmac. 17, 287S-290S.
MARTIN, W.R., EADES, C.G., THOMPSON, J.A., HUPPLER, R.E. & GILBERT, P.E. (1976). The effects of morphine and nalorphine-like drugs in the non-dependent and morphine-dependent chronic spinal dog. J. Pharmac.
exp. Therap., 197, 517-532.
298S J.J.C. JACOB, G.M. MICHAUD & E.C. TREMBLAY MARTIN, W.R. (1979). History and development of narcotic antagonists. Br. J. clin. Pharmac. 7, 273S-279S. MICHAUD, G. & JACOB, J. (1978). Interactions between
buprenorphine, morphine and naloxone. Antagonism by buprenorphine of precipitated abstinence in dogs acutely dependent on morphine. Seventh Int. Congr. Pharmac. Paris, 16-21 July, abstracts, 460, p. 179. RANCE, M.J. (1979). Animal and molecular pharmacology of mixed agonist-antagonist drugs. Br. J. clin. Pharmac. 7, 281S-286S. ROBBIE, D.S. (1979). Sublingual buprenorphine in cancer pain. Br. J. clin. Pharmac. 7, 315S-317S. SAELENS, J.K., GRANAT, J.R. & SAWYER, W.K. (1971). The mouse jumping test. A simple screening method to estimate the physical dependence capacity of analgesics. Arch. Int. Pharmacodyn., 190,213-218. SWAIN, H.H. & SEEVERS, M.H. (1975). Evaluation of new compounds for morphine-like physical dependence in the
rhesus-Monkey. In Proc. 37th Ann. Sci. Meet of Comm. Problems Drug Dependence, pp. 773-795. Washington: Natn. Acad. Sci. natn. Research Council. TREMBLAY, E., COLOMBEL, Mc. & JACOB, J. (1976a). Effets de la morphine et de la naloxone sur l'abstinence pr6cipitee chez la Souris en 6tat de dependance aigue a la morphine. J. Pharmacol. Paris, 7, 103-114. TREMBLAY, E., COLOMBEL, MC. & JACOB, J. (1976b). Precipitation et pr6vention de l'abstinence chez le Rat et la Souris en etat de dependance aigue. Comparaison de la naloxone, de la naltrexone et de la dipr6norphine. Psychopharmacology, 49, 41-48. WIKLER, A. (1974). Requirements for extinction of relapse. Facilitating variables and for rehabilitation in a narcotic antagonist Treatment program. In Narcotic Antagonists. Advances in Biomedical Psychopharmacology, S. Ed. Braude, M.C. et al. Pp. 399.414. New York: Raven Press.
MIXED AGONIST-ANTAGONIST OPIATES AND PHYSICAL DEPENDENCE J.J.C. JACOB, G.M. MICHAUD & E.C. TREMBLAY Laboratory of Pharmacology, Institut Pasteur, Rue du Docteur Roux, F75724 Paris Cedex 15, France
1 General methods (chronic, subacute and acute) for assessing physical dependence potential, abstinence precipitating capacity and abstinence preventing activity are briefly presented. 2 Direct dependence experiments indicate that, in general, mixed agonist-antagonist analgesics have relatively lower physical dependence potentials than pure agonist analgesics. That of buprenorphine seems to be particularly low in various animal species. 3 When substitution techniques are used, the dependence potential of buprenorphine seems to be somewhat more developed than with direct dependence techniques. 4 Among various agonists (morphine, methadone and etorphine), antagonists (naloxone, naltrexone and diprenorphine) and mixed agonist-antagonists (pentazocine, butorphanol and buprenorphine), buprenorphine is the most potent and the longest acting drug in preventing precipitated abstinence in mice, rats and dogs. 5 The low physical dependence potential of buprenorphine may result in part from the very slow dissociation of the complex it forms with opiate receptors. This potential might be underestimated when precipitated abstinence methods are used, as naloxone would displace buprenorphine from its receptors only to a very limited extent. New means of evaluating dependence by more direct means need to be developed. 6 Overall, the properties of mixed agonists in general justify their use as analgesics with lower physical dependence potential than the pure opiates and further, those of buprenorphine seem to indicate its possible utility for the treatment of opiate addiction.
Introduction Two of the principal objectives of the study of mixed agonist-antagonists are the development of potent analgesics with a low dependence potential and agents for the treatment of opiate addiction. The first aim is not a mere speculation. Indeed, nalorphine, the first mixed agonist-antagonist to be studied in man, has satisfactory analgesic properties and a much lower dependence potential than the pure opiates. Drug-seeking behaviour is lacking after withdrawal and physical dependence is moderate and of a type different from that of morphine (see Martin, 1979). However, nalorphine could not be used extensively in clinical practice because of its psychotomimetic properties. Pentazocine was developed later; its dependence potenti,l was definitely lower than that of morphine and its psychotomimetic activity less developed than those of nalorphine. Two major types of addiction therapy exist at present. The first is treatment with some selected agonist such as methadone which 'blocks' the drug0306-5251/79/150291-06 $01.00
seeking behaviour and abstinence signs but maintains or promotes the dependent state. The second type is therapy with antagonists which is still rather experimental; antagonists protect against the euphorigenic effects of opiates and prevent the development of dependence. According to Wikler (1974), they should also be used to extinguish various conditioned reactions which maintain addiction. Their major drawback is that they precipitate abstinence in addicts who for this reason often refuse -to continue the treatment. General methodology of animal experiments In the experimental animal, the dependence potential of narcotic or mixed analgesics is assessed by determining (a) the pattern of their acute effects; (b) the existence and characteristics of self administration (which is considered to be a model for psychic
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dependence); and (c) the occurrence and intensity of withdrawal signs by which physical dependence is manifested. The two first types of experiments will not be dealt with in this report. We will only recall that the pattern of actions of mixed agonistantagonists vary considerably according to the particular drug (for references, see Jacob, 1975a) and that nalorphine promotes little self-administration behaviour in monkeys and rats. Self-administration of pentazocine is also less than that observed with typical agonists. The assessment of physical dependence potential relies classically on two general procedures, 'direct induction' and 'substitution', studies. Direct induction consists of administering the drug to be studied subchronically at doses which might be expected to promote dependence. When the treatment is interrupted by withdrawal of the drug various physical signs develop (withdrawal abstinence), the intensity of which can be measured. Interruption of the treatment can also be achieved by administration of an opiate antagonist which will produce a similar but not quite identical syndrome (precipitated abstinence). The use of an antagonist has some practical advantages. In general the precipitated syndrome is more acute, clearcut and intense than that following the interruption of the treatment. It can be obtained after a few or even after a single injection of an opiate (for references, see Jacob, 1975b). This 'acute' or 'single dose dependence' can be used for the thorough study of dose-response relationships, the time course of the underlying dependence, the precise relationships with other acute (for example, analgesic) effects, the modification of the withdrawal syndrome by various substances and also for comparison of various drugs with regard either to their 'agonist' dependenceinducing properties or to their 'antagonist' precipitating activities. These acute techniques, however, have also drawbacks which have already been discussed (Jacob, 1975b). The created state of dependence is of a relatively low intensity and effects exerted by the antagonist in its own right may obscure the syndrome. Additionally, dependence induced by repeated and (or) prolonged treatments includes additional complex factors such as cumulation of effects, development of tolerance, autopotentiation phenomenon and 'shifts of signs'. As a consequence the withdrawal syndrome after chronic treatment becomes different, quantitatively and qualitatively (that is, varies in its constituents). Chronic direct addiction studies are therefore necessary, in particular if the physical dependence potential of the test drug seems to be lower than expected in the acute tests. However, chronic procedures may also be misleading when inadequate dose regimens are used. Adequate dose regimens are not easy to establish and should be based inter
alia on the results of acute pharmacokinetic studies and substitution experiments. Substitution consists of the administration of a known opiate with a schedule known to induce clearcut dependence. The treatment is then interrupted and the test drug is administered to the withdrawn animal displaying signs of abstinence. If the test substance is an agonist (that is, a dependenceinducing drug), it will abolish all signs of abstinence (with an adequate acute dosage) and its dependence potential will be estimated both from the effective dose, and also from concomitant side-effects. If severe side-effects (for example, convulsions or coma) occur at the effective dose for suppression, the abuse potential can be regarded as low; if no sideeffects are present, the potential is rated high. If the test drug is an antagonist, it will, in general, increase the abstinence signs. If it is a mixed agonistantagonist, its effect will vary according to several factors, in particular the predominance of agonist compared with antagonist properties and the intensity of the dependence state induced with the known agonist (the more intense, the more the antagonist properties would emerge). The activity of an antagonist or of a mixed agonistantagonist in precipitating abstinence is studied by administering it to non-withdrawn animals previously treated with a known opiate. This pretreatment can be acute which allows for the easy assay of a whole range of doses of the test substances, or it can be chronic, which is more sensitive with an adequate dose regimen. Antagonism of the development of dependence can also be assessed with the foregoing general testing procedures but needs some more comments. When administered before an opiate, an antagonist will, in principle, prevent the appearance of withdrawal signs following either the interruption of the treatment or the administration of an antagonist. Thus, naloxone injected before morphine is able to prevent the syndrome it would precipitate itself in morphine-treated animals. This antagonism can also be obtained when the antagonist is injected shortly after the opioid and an injection of naloxone after morphine, whether or not it produces abstinence in its own right, can also inhibit the abstinence syndrome that a second injection of naloxone would precipitate. However, antagonism of abstinence does not necessarily mean antagonism of dependence. As commented above, opiates which themselves produce dependence, abolish the abstinence signs by substituting for morphine in withdrawn animals. They can also inhibit these signs when sufficient doses are administered in non-withdrawn animals at appropriate times because they postpone the withdrawal abstinence, just as they can do in addicts, or oppose the precipitation of abstinence by naloxone.
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Experimental studies
Induction ofdependence Various opiates or mixed agonist-antagonists were compared with morphine in mice and rats using single dose procedures (Jacob & Tremblay, unpublished observations). In mice, naloxone 1 mg/kg subcutaneously precipitated jumping in 660/ of mice 2 h after administration of morphine 15 mg/kg subcutaneously, in 50% and 80% 1 and 2 h after methadone 3 and 10 mg/kg subcutaneously, respectively, in 75% 1 h after etorphine 0.1 mg/kg subcutaneously, and in 35% 1 h after pentazocine 100 mg/kg subcutaneously. Thus, methadone and morphine seem to be almost equipotent in inducing acute dependence and are much less active than etorphine; pentazocine is least effective. This rank order correlates well with the analgesic potencies of these drugs. The dependence produced by them with the test doses was of short duration as naloxone was much less effective or inactive when injected 4-8 h after the opiate. Buprenorphine gave quite different results, as naloxone 1 or 10 mg/kg subcutaneously or diprenorphine 1 or 10 mg/kg subcutaneously did not precipitate jumping when administered at various time intervals (up to 1 d) after various doses of buprenorphine (from 0.1-10 mg/kg subcutaneously). Irregular jumping was observed when the time interval between the administration of buprenorphine and that of naloxone or diprenorphine was 1 or 2 days. In rats, naloxone 1-10 mg/kg subcutaneously and diprenorphine 1 mg/kg subcutaneously which precipitated several signs of abstinence after morphine 15-50 or 100 mg/kg subcutaneously, produced only few and feeble withdrawal signs when injected at different times after buprenorphine 0.1 or 1 mg/kg subcutaneously. In unanaesthetized dogs, naloxone 1 mg/kg administered subcutaneously 2 h after either morphine 6 mg/kg intravenously or buprenorphine 0.1 mg/kg intravenously antagonized the sedation, myosis and bradycardia induced by either drug but produced an overshoot phenomenon characteristic of physical dependence, intense and typical agitation, mydriasis and tachycardia, only in the morphinetreated animals. When a higher dose of buprenorphine (1 mg/kg intravenously) was used, naloxone did not antagonize the morphinomimetic effects of the drug (Michaud & Jacob, 1978; Jacob & Michaud, unpublished observations). Using subacute techniques, pentazocine (Saelens et al., 1971) and buprenorphine (Cowan et al., 1977) have been shown to induce little dependence, as manifested by naloxone precipitation. Classical chronic procedures have supported the same conclusion for pentazocine, and with similar
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procedures the dependence potential of buprenorphine has been shown to be low in the dog (Martin et al., 1976) and absent in monkeys, in which no abstinence was observed either after interruption of treatment in rhesus monkeys (Swain & Seevers, 1975) or after administration of naloxone to patas monkeys (Cowan, 1974; Cowan et al., 1977).
Substitution As already stated, mixed agonist-antagonists substitute for morphine when the test animal has been pretreated with relatively low doses of the agonist and precipitate abstinence when these doses are high. Buprenorphine substituted for morphine in withdrawn mice having received high doses of morphine for 3 days. Thus, the physical dependence potential seems in the same animal species to be greater with this technique than with the direct dependence method. Buprenorphine substituted partly for morphine in withdrawn subacutely morphine-treated rats, the substitution attenuating only some signs of abstinence (head shakes, teeth chattering and abnormal posture; Jacob & Tremblay, unpublished observations). As reported by Martin at this symposium, it also substitutes for morphine in dogs but with a flatter dose-response curve than that obtained with pure agonists. Prevention of abstinence Precipitated abstinence In acute experiments in mice, abstinence precipitated by naloxone can be prevented by both agonists and antagonists given before the precipitating dose of naloxone and either before or after the priming dose of morphine. This has been demonstrated for morphine and naloxone in experiments of our laboratory (Tremblay et al., 1976a). The effect of morphine is comparable to its effect in substitution experiments, except that the use of naloxone, which also antagonizes this action of morphine, renders it necessary to use rather high doses of the agonist. As observed in substitution experiments also, the agonist in this test situation does not really antagonize but rather postpones the abstinence. Antagonists are thought to antagonize dependence itself but their mechanism of action, as well as that of buprenorphine, is probably more complex (see later). In extending these studies to other agonists, antagonists and mixed agonist-antagonists, we have found that methadone was more effective than morphine in the prevention of acute abstinence. Etorphine is the most potent agonist in the abstinence prevention test to date (Jacob et al., 1976). Among antagonists, diprenorphine is more effective than naltrexone which in turn is more effective than naloxone (Tremblay et al., 1976b). Among mixed
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agonist-antagonists, buprenorphine is much more effective than butorphanol which itself is much more effective than pentazocine (Jacob et al., 1976). Not only was buprenorphine effective at very low doses (5-20 jig/kg depending on the doses of morphine and of naloxone used), but also its action was much more sustained than that of all other studied drugs. For these latter compounds, the activity decreases considerably within 3 h, whereas for buprenorphine it was maintained for a 4-h period. The activity of buprenorphine was also much less dependent than that of the other drugs on the doses of morphine or naloxone used in the experiment. Similar results were obtained in rats in which several signs of precipitated abstinence could be measured or quoted. The studied antagonists and mixed agonists-antagonists were able to antagonize all abstinence signs, a characteristic which contrasts with the partial action of drugs like parasympatholytics, neuroleptics, and so on. Among antagonists, the rank order of effectiveness is again naltrexone, diprenorphine, naloxone (Tremblay et al., 1976b). Etorphine is not effective in the tolerated dose range. Buprenorphine is extremely potent with a relatively long duration of action (Jacob et al., 1976). In dogs, buprenorphine was again very effective: 0.1 mg/kg given intravenously 2 h after morphine 6 mg/kg intravenously, almost completely prevented the tachycardia, mydriasis and hyperthermia produced by naloxone injected 24 h later (Michaud & Jacob, 1978; Jacob & Michaud, unpublished observations). Buprenorphine and diprenorphine were also able to prevent abstinence in mice following the interruption, of a subacute treatment with morphine, when they were administered each day before the first daily injection of the test agonist. The necessary doses were rather high, due probably in part to the fact that a duration of action of at least 8 h was then necessary. Buprenorphine is somewhat more potent than diprenorphine in this situation (Jacob & Tremblay, unpublished observations). Precipitation of abstinence in non-withdrawn animals The effectiveness of antagonists such as naloxone, naltrexone and diprenorphine in classical chronic experiments is well established and need not be commented upon here. Similarly, the low efficacy of pentazocine is also well established. Our acute experiments in mice and rats have compared the effectiveness of naloxone, naltrexone, diprenorphine and buprenorphine in acute and in some subacute experiments. In mice 4 h after morphine 100 mg/kg subcutaneously, naloxone, diprenorphine and naltrexone ranked in order of decreasing efficacy,
had ED,0 values of 0.30, 0.03 and 0.006 mg/kg, respectively (Tremblay et al., 1976b). In the same conditions, buprenorphine with doses ranging from 1 g.g-10 mg/kg subcutaneously did not precipitate any jumping. In rats, following morphine 50 mg/kg subcutaneously, 1 mg/kg subcutaneously of either naloxone, naltrexone of diprenorphine produced an intense syndrome in 75%0 of the animals but buprenorphine was quite ineffective (Jacob & unpublished observations). Tremblay, Buprenorphine also had a low efficacy in mice and rats following subacute treatment with morphine (Cowan, 1976). In dogs having received a single dose of morphine 2 h before, buprenorphine 0.1 and 1 mg/kg increased rather than decreased the antinociceptive effect .of morphine but antagonized its sedative, myotic and bradycardic actions (Michaud & Jacob, 1978; Jacob & Michaud, unpublished observations). It did not produce any overshoot, which is characteristic of abstinence precipitated by naloxone, except that the higher dose of buprenorphine produced some transient tachycardia. In chronically spinalized dogs following a chronic treatment with morphine, buprenorphine precipitated a mild abstinence (Martin et al., 1976). A mild syndrome was also observed in patas monkeys (Cowan, 1974; Cowan et al., 1977) and a more severe one in rhesus monkeys (Swain & Seevers, 1975). Discussion and conclusions In general, the 'classical' experimental animal procedures have shown that the physical dependence potential of the mixed agonist-antagonists is rather lower than that of the opiates, a conclusion which is also obtained using acute techniques. Buprenorphine seems to have an exceptionally low physical dependence potential in several animal species (mice, rats, dogs and monkeys). This characteristic may result, at least in part, from the unusual kinetics of its binding with the opiate receptors. As Rance (1979) has commented in this symposium, the complex formed by buprenorphine and the opiate receptors is very stable and dissociates very slowly. This would account not only for the protracted character of the abstinence as observed in mice (see above) and in man (Jasinski et al., 1978) but also for the fact that the abstinence syndromes, when observed, are very partial and of low intensity. The slowness of the disappearance of buprenorphine (or of its displacement by naloxone) would give time for at least partial maintenance of homeostasis and thus limit the imbalances produced by withdrawal of the inhibitory effects of the opiate. The dependence potential of buprenorphine is probably underestimated when naloxone is used to precipitate abstinence, as naloxone displaces
MIXED AGONIST-ANTAGONIST OPIATES
buprenorphine from its complex less effectively in vivo than in vitro because it is itself rapidly eliminated from the brain. Substitution experiments in mice and rats, in which naloxone is not used, point seemingly to a greater (but still low) dependence potential than the direct induction experiments using precipitated abstinence. The ineffectiveness of naloxone in precipitating abstinence is itself not entirely accounted for by its inability to gain access to the receptors because, in acute experiments, we have shown that naloxone exerts some antagonistic effect in buprenorphine-treated mice or dogs and thus must bind with receptors and displace some buprenorphine without precipitating abstinence. Indeed, the existence of drugs like buprenorphine poses the problem of developing new means of evaluating dependence. These include, for instance, the determination of the modalities of occupation of receptors by buprenorphine in vivo (in other words, does it bind mainly as an agonist or as an antagonist; with what classes of opiate receptors; and how does this binding change with time?) and of various biochemical events which are thought to be related to dependence (hypersensitivity of some biogenic amine receptors, variation in ion flux or adenylate cyclase activity). Despite such important theoretical uncertainties, mixed agonist-antagonists seem to have great potential in therapy. In general, experiments in man have confirmed that, with very few exceptions, they have lower dependence potential than the agonists. This also seems to be the case for buprenorphine (Jasinski, 1979; Robbie, 1979). With regard to their use as analgesics, it is well known that their patterns of antinociceptive actions are, in animals, very different from those of agonist analgesics and that most of them, including buprenorphine, show ceiling phenomena in some test situations. Thus, the
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animal pharmacologist cannot establish a single ratio of antinociceptive activity/dependence potential. For example, this ratio is for buprenorphine greater than 1000 in mice when moderate effectiveness in the hotplate test and precipitated abstinence are considered but nearly zero in dogs when depression of skin reflexes are used. It is therefore the burden of the clinician to estimate the efficacy of these drugs on various types of pain, so as to determine finally in what instances the mixed agonist-antagonists are useful and safer than the opiates. With regard to the treatment of addiction, buprenorphine seems to have uniquely favourable characteristics. Among the various agonists, antagonists and mixed agonist-antagonists that we have studied, it is by far the most effective in preventing abstinence and, perhaps more important, in affording a protection of long duration. As already commented its physical dependence potential seems to be lower than that of methadone, and further, its potency in precipitating abstinence is much lower in several animal species than those of naloxone, naltrexone and diprenorphine. Thus, buprenorphine deserves consideration for therapeutic trials in opiate addiction, especially because, as will be commented in other reports in this symposium, other relevant properties in man (psychic dependence, tolerance and cross tolerance) seem at this time to be acceptable in such an indication. Needless to say, much theoretical and clinical work is still necessary but the results to date are indicative that buprenorphine may prove to be a partial agonist drug of some significance. The work of the laboratory has been supported by grants from the INSERM (contract AT 76-71) and the DRET (contract 77/443).
References COWAN, A. (1974). Evaluation of the physical dependence capacities of oripavine-thebaine partial agonists in patas monkeys. In Narcotic Antagonists. Advances in Biochemical Psychopharmacology, 8. Ed. Braude, M.C. et al. Pp. 427-438. New York: Raven Press. COWAN, A. (1976). Use of the mouse jumping test for estimating antagonistic potencies of morphine antagonists. J. Pharm. Pharmac., 28, 177-182. COWAN, A., DOXEY, J.C. & HARRY, E.J.R. (1977). The animal pharmacology of buprenorphine, an oripavine analgesic agent. Br. J. Pharmac., 60, 547-554. COWAN, A., LEWIS, J.W. & MACFARLANE, I.R. (1977). Agonist and antagonist properties of buprenorphine, a new antinociceptive agent. Br. J. Pharmac., 60, 537-545. JACOB, J. (1975a). Pharmacologic des antagonistes de la morphine. La Revue de Medecine, n° 7, 7 fevrier 1975, 431-444.
JACOB, J.C. (1975b). The problems of acute physical dependence on opioids. In Neuropsychopharmacology. Proc. ninth Congr. CINP. Ed. Hippius, Boissier, J.R. & Pichot, P. Pp. 279-286. Amsterdam: Excerpta Medica International Congress. JACOB, J., TREMBLAY, E. & MICHAUD, G. (1976).
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MARTIN, W.R., EADES, C.G., THOMPSON, J.A., HUPPLER, R.E. & GILBERT, P.E. (1976). The effects of morphine and nalorphine-like drugs in the non-dependent and morphine-dependent chronic spinal dog. J. Pharmac.
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buprenorphine, morphine and naloxone. Antagonism by buprenorphine of precipitated abstinence in dogs acutely dependent on morphine. Seventh Int. Congr. Pharmac. Paris, 16-21 July, abstracts, 460, p. 179. RANCE, M.J. (1979). Animal and molecular pharmacology of mixed agonist-antagonist drugs. Br. J. clin. Pharmac. 7, 281S-286S. ROBBIE, D.S. (1979). Sublingual buprenorphine in cancer pain. Br. J. clin. Pharmac. 7, 315S-317S. SAELENS, J.K., GRANAT, J.R. & SAWYER, W.K. (1971). The mouse jumping test. A simple screening method to estimate the physical dependence capacity of analgesics. Arch. Int. Pharmacodyn., 190,213-218. SWAIN, H.H. & SEEVERS, M.H. (1975). Evaluation of new compounds for morphine-like physical dependence in the
rhesus-Monkey. In Proc. 37th Ann. Sci. Meet of Comm. Problems Drug Dependence, pp. 773-795. Washington: Natn. Acad. Sci. natn. Research Council. TREMBLAY, E., COLOMBEL, Mc. & JACOB, J. (1976a). Effets de la morphine et de la naloxone sur l'abstinence pr6cipitee chez la Souris en 6tat de dependance aigue a la morphine. J. Pharmacol. Paris, 7, 103-114. TREMBLAY, E., COLOMBEL, MC. & JACOB, J. (1976b). Precipitation et pr6vention de l'abstinence chez le Rat et la Souris en etat de dependance aigue. Comparaison de la naloxone, de la naltrexone et de la dipr6norphine. Psychopharmacology, 49, 41-48. WIKLER, A. (1974). Requirements for extinction of relapse. Facilitating variables and for rehabilitation in a narcotic antagonist Treatment program. In Narcotic Antagonists. Advances in Biomedical Psychopharmacology, S. Ed. Braude, M.C. et al. Pp. 399.414. New York: Raven Press.
