International Journal of the Addictions
ISSN: 0020-773X (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/isum19
Methadone Maintenance and Narcotic Blocking Drugs Abraham Wikler To cite this article: Abraham Wikler (1977) Methadone Maintenance and Narcotic Blocking Drugs, International Journal of the Addictions, 12:7, 851-856, DOI: 10.3109/10826087709027254 To link to this article: http://dx.doi.org/10.3109/10826087709027254
Published online: 03 Jul 2009.
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Date: 18 March 2016, At: 15:44
The International Journal of t h e Addictions. 12(7). 851 X5h. I977
Downloaded by [University of California, San Diego] at 15:44 18 March 2016
Methadone Maintenance and Narcotic Blocking Drugs Abraham Wikler, M.D University of Kentucky 1exington, Kentucky 40506
Abstract
Drugs which specifically antagonize ccrtain o f the action5 of opioids are reviewed. These antagonists include nalorphine, 1eva 11orphan . n al ox o ne , n a I t rexo tie. and c yc I azoci ne . Progra m s involving antagonist treatment are discussed. This section deals K i t h ;I class of drugs characterized by the property of . s p o c i f i c d / ~ ~antagonizing certiiin ol‘ the actions of opioid:, (drugs, regardless of their chemical structure. that exert effects siniilar to those of niorphine). Such “opioid antagonists” or “narcotic antagonists“ (Fig. I ) may be relatively “pure” (e.g.. naloxone) or they may be “partial agonists” (e.g.. nalorphine cyclazocine). A pure opioid antagonist exerts no agonistic actions but competes competitively with opioidb. A partial agonist does exert agonistic actions. some of which may resemble those of morphine (analgesia, miosis. respiratory depression) which others may not (psychotomimetic effects); some partial agonists also compete competitively with opioids. If an opioid agonist and an opioid antagonist are given together. the initial cffects w i l l depend on the relative concentration of each and on thc intrinsic activity and affinity of the antagonist i.e.. 851 1077 h! \larccl I k k h r r . Inc. All Right\ Kew-\ccl. Ueitlirr thih u o r k nor UII! he rcprodiiccd oi transmitted in any form or by an! mean\. elcilronic or iiiec1ianic:iI. ~ncludingpli(itocopying, iiiicrotilming. and recording. o r b> ;in! inlorniatioii storage a n d retrieval s>stsm. without pri-mission i n ui-ltmg from the publisher.
C‘op>i-iglit
par I
riiir!
WKLER
852
aH N - CH,
Downloaded by [University of California, San Diego] at 15:44 18 March 2016
morphine
nalorphine
&
N- CH,CH =CH,
&cH=cH2 OH
I eva Ilor p han
naltrexone Fig. I .
na loxone
cyc lazocine Morphine and opioid antagonists.
summation or antagonism of agonistic may be observed, but eventually the characteristic effects of the opioid agonist will emerge (unless the duration of action of the opioid agonist does not exceed the apparent duration of action of the opioid antagonist). The antagonistic actions of opioid antagonists upon opioids take place on the same receptor. In the cases of the partial agonists, the sites of their agonist actions are mootinsofar as they produce effects similar to those of opioids, they may act on the same or on a different receptor; insofar as they produce effects different from those of opioids, it is assumed that they act on a different receptor; yet naloxone (a pure antagonist) antagonizes all agonistic actions of partial agonists as well as of opioid agonists. "Narcotic
Downloaded by [University of California, San Diego] at 15:44 18 March 2016
M E T H A D O N E M A I N T E N A N C E A N D N A R C O T I C BLOCKING DRUGS
853
blocking drugs” (“narcotic antagonists,” “opioid antagonists”) do not include drugs, the antidotal actions of which are not confined to the depressant effects of opioids (e.g., amphetamine. picrotoxin) or drugs, tolerance to which confers cross-tolerance to morphine or heroin (e.g., met had one). These findings (discussed in the Appendix. see pages 869-88 1 ) provide the empirical basis for two clinical applications of narcotic antagonists: ( 1 ) resuscitation of patients with opioid poisoning: and ( 2 ) the diagnosis of physical dependence on opioid agonists (first demonstrated with nalorphine). A third clinical application, namely. in the treatment of detoxified opioid addicts, was suggested later by Martin et al. (1976) in connection with cyclazocine: On the basis of our studies, 4 mg per day of cyclazocine will provide protection against the euphorogenic actions of large doses of narcotics, prevent the development of physical dependence, and will thereby control the pharmacological actions which are held responsible for narcotic addiction. . . . There may be other benefits. Wikler (1965)states that two of the important reasons for relapse of the abstinent narcotic addict are conditioned abstinence which may be evoked by stimuli that have been associated with the addict‘s hustling activity to acquire drugs, and reinforcement of drug-seeking behavior through repeated reductions of abstinence by drug. It is possible that in subjects who attempt to readdict themselves while receiving a narcotic antagonist such as cyclazocine. there may be extinction of physical dependence and drug-seeking behavior. More recently, Martin et al. (1973) reported on another narcotic antagonist, naltrexone, which unlike cyclazocine, is practically devoid of agonistic activity in man and which, in a single daily oral dose of 50 mg, will antagonize the actions of large doses of morphine or heroin for up to 24 hours. Commenting o n future research on the development of narcotic antagonists for clinical use in preventing relapse. Martin et al. (1973) observe that It has been the consensus of opinion of investigators that for a narcotic antagonist to be optimally effective in the treatment of narcotic addicts it must be administered in such a way that its
WIKLER
854
Downloaded by [University of California, San Diego] at 15:44 18 March 2016
effect would have an appreciable duration of action (one week to one month), that it should be devoid of agonistic activity, and that it should be a highly potent compound to permit its administration in a depot form. Currently, research on depot-form injections of naloxone, naltrexone, and other opioid antagonists is being pursued. In connection with the narcotic antagonist treatment program as proposed by Martin and his associates (see above), Wikler (1965) has pointed out that extinction of conditioned physical dependence and of conditioned drug-seeking behavior requires that the patients ‘‘ . . . attempt to readdict themselves while receiving a narcotic antagonist . . . Should such a patient, while maintained on an opioid antagonist, not attempt to readdict himself to an opioid, “extinction” will not take place, and the probability of relapse after discontinuation of the opioid antagonist will remain the same as after prolonged abstention from opioids in consequence of incarceration in a penal institution (presumably drug-free). Accordingly, Wikler (1 973) has proposed that after “detoxcification” and subsequent stabilization on an opioid-antagonist, and while still in hospital status, such patients be required to self-inject themselves with heroin repeatedly until they refuse to give themselves any more injections. Preferably, this procedure should be carried out under conditions that are likely to evoke “conditioned abstinence,” which should be likewise extinguished through lack of reinforcement-i.e., failure to reestablish physical dependence. After discharge from the hospital, maintenance on the opioid antagonist should be continued for about 1 year in view of the expected duration of “protracted abstinence” which, as Martin and Jasinski (1969) have shown, can last as long as 30 weeks after withdrawal of morphine, and may be an important factor in predisposing to relapse. During this period of maintenance, patients should be readmitted to the hospital from time to time, taken off the opioid antagonist, given an injection of heroin, and then replaced on the opioid antagonist before discharge from the hospital in order to extinguish interoceptively conditioned abstinence and drug-seeking behavior. It should be expected that even after carrying out such extinction procedures (both on exteroceptively and interoceptively conditioned behaviors), the change from inpatient to outpatient status would be likely to evoke attempts to obtain heroin illegally and to self-inject the drug, but such “recovery from extinction” should be short-lived in view of the continued opioid blockade and the history of extinction trials while still in ”
Downloaded by [University of California, San Diego] at 15:44 18 March 2016
METHADONE MAINTENANCE AND NARCOTIC‘ BLOCKING DRUGS
855
the hospital. If unscheduled urinary drug-detection tests are consistently negative during the last 3 months of the year of maintenance, the opioid antagonist may be discontinued and, hopefully, the probability of subsequent relapse will have been greatly reduced. It goes without saying that along with maintenance on an opioid antagonist for about 1 year. appropriate psychotherapeutic and rehabilitative measures should be provided. By “appropriate” is meant such psychotherapy as will alter the “congnitive labeling” of ”craving” for heroin. According to Wikler (1948, 1965). “craving” for heroin is the subjective concomitant of “conditioned abstinence,” not of some archaic “oral need.” Hence psychotherapy should be directed toward reinterpreting “craving” in the light of conditioning processes, both exteroceptive and interoceptive, that transpired in the course of self-administration of opioids in the past. As for rehabilitation, cognizance should be taken of the psychopathy (or sociopathy) of many addicts (Hill et al., 1960, 1962) and attempts should be made, by appropriate behavior modification, to train the patient to emit sustained, socially useful activity for delayed monetary rewards, and with delayed consumption of such rewards. Emotional disturbances and thinking disorders. also common among addicts (Monroe et al., 1971), may have to be dealt with pharmacologically as well as with psychotherapy. Finally, it should be pointed out that the opioid antagonist treatment modality as here outlined cannot extinguish nonopioid drug using behavior, and is therefore most likely to succeed in the cases of addicts who have used opioids mainly or exclusively. Whether or not “polydrug” users may benefit from opioid antagonist treatment remains to be seen. ACKNOWLEDGMENT
Preparation of this article was supported, in part. by Research Grant No. DA 00044 from the National Institute on Drug Abuse with funds made available by the Special Action Office for Drug Abuse Prevention. REFERENCES HILL. H.E., HAERTZEN. C.A.. and DAVIS. H. An MMPI factor analysia of alcoholics. narcotic-addicts and criminals. Q. J . Srucl. Alcohol 7 3 : 41 1-431, 1962. HILL. H.E., HAERTZEN. C.A.. and GLASER. Personality characteristics of narcotic addicts as indicated by the MMPI. J . Grn. Ps,,ccil. 61: 177-139, 1960. MARTIN. W.R.. GORODETSKY. C.W.. and MCCLANE. T.K. A n experimentnl study in
WIKLER
856
the treatment of narcotic addicts with cyclazocine. Clin. Pharmacol. Ther. 7: 455465, 1976.
MARTIN, W.R., and JASINSKI, D.R. Physiological parameters of morphine dependence in man: Tolerance, early abstinence, protracted abstinence. J . Psychiufr. Res. 7: 9-17,
Downloaded by [University of California, San Diego] at 15:44 18 March 2016
1969.
MARTIN, W.R., JASINSKI, D.R., and MANSKY, P.A. Naltrexone, an antagonist for the treatment of heroin dependence. Arch. Gen. fsychiarry 28: 784791, 1973. MONROE, J.J., ROSS, W.F., and BERZINS, J.J. The decline of the addict as “psychopath”: Implications for community care. fnr. J . Addicr. 6: 601-608, 1971. WIKLER, A. Recent progress in research on the neurophysiologic basis o f morphine addiction. Am. J . Psychiarry 105: 329-338, 1948. WIKLER. A. Conditioning factors in opiate addiction and relapse. In D. I. Wilner and G . G . Kassebaum (eds.) Narcotics. New York: McGraw-Hill, 1965, pp. 85-100. WIKLER, A. Dynamics of drug dependence. Implications of a conditioning theory for research and treatment. Arch. Gen. fsvchiatry 28: 61 1-616, 1973.
ISSN: 0020-773X (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/isum19
Methadone Maintenance and Narcotic Blocking Drugs Abraham Wikler To cite this article: Abraham Wikler (1977) Methadone Maintenance and Narcotic Blocking Drugs, International Journal of the Addictions, 12:7, 851-856, DOI: 10.3109/10826087709027254 To link to this article: http://dx.doi.org/10.3109/10826087709027254
Published online: 03 Jul 2009.
Submit your article to this journal
Article views: 3
View related articles
Citing articles: 2 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=isum19 Download by: [University of California, San Diego]
Date: 18 March 2016, At: 15:44
The International Journal of t h e Addictions. 12(7). 851 X5h. I977
Downloaded by [University of California, San Diego] at 15:44 18 March 2016
Methadone Maintenance and Narcotic Blocking Drugs Abraham Wikler, M.D University of Kentucky 1exington, Kentucky 40506
Abstract
Drugs which specifically antagonize ccrtain o f the action5 of opioids are reviewed. These antagonists include nalorphine, 1eva 11orphan . n al ox o ne , n a I t rexo tie. and c yc I azoci ne . Progra m s involving antagonist treatment are discussed. This section deals K i t h ;I class of drugs characterized by the property of . s p o c i f i c d / ~ ~antagonizing certiiin ol‘ the actions of opioid:, (drugs, regardless of their chemical structure. that exert effects siniilar to those of niorphine). Such “opioid antagonists” or “narcotic antagonists“ (Fig. I ) may be relatively “pure” (e.g.. naloxone) or they may be “partial agonists” (e.g.. nalorphine cyclazocine). A pure opioid antagonist exerts no agonistic actions but competes competitively with opioidb. A partial agonist does exert agonistic actions. some of which may resemble those of morphine (analgesia, miosis. respiratory depression) which others may not (psychotomimetic effects); some partial agonists also compete competitively with opioids. If an opioid agonist and an opioid antagonist are given together. the initial cffects w i l l depend on the relative concentration of each and on thc intrinsic activity and affinity of the antagonist i.e.. 851 1077 h! \larccl I k k h r r . Inc. All Right\ Kew-\ccl. Ueitlirr thih u o r k nor UII! he rcprodiiccd oi transmitted in any form or by an! mean\. elcilronic or iiiec1ianic:iI. ~ncludingpli(itocopying, iiiicrotilming. and recording. o r b> ;in! inlorniatioii storage a n d retrieval s>stsm. without pri-mission i n ui-ltmg from the publisher.
C‘op>i-iglit
par I
riiir!
WKLER
852
aH N - CH,
Downloaded by [University of California, San Diego] at 15:44 18 March 2016
morphine
nalorphine
&
N- CH,CH =CH,
&cH=cH2 OH
I eva Ilor p han
naltrexone Fig. I .
na loxone
cyc lazocine Morphine and opioid antagonists.
summation or antagonism of agonistic may be observed, but eventually the characteristic effects of the opioid agonist will emerge (unless the duration of action of the opioid agonist does not exceed the apparent duration of action of the opioid antagonist). The antagonistic actions of opioid antagonists upon opioids take place on the same receptor. In the cases of the partial agonists, the sites of their agonist actions are mootinsofar as they produce effects similar to those of opioids, they may act on the same or on a different receptor; insofar as they produce effects different from those of opioids, it is assumed that they act on a different receptor; yet naloxone (a pure antagonist) antagonizes all agonistic actions of partial agonists as well as of opioid agonists. "Narcotic
Downloaded by [University of California, San Diego] at 15:44 18 March 2016
M E T H A D O N E M A I N T E N A N C E A N D N A R C O T I C BLOCKING DRUGS
853
blocking drugs” (“narcotic antagonists,” “opioid antagonists”) do not include drugs, the antidotal actions of which are not confined to the depressant effects of opioids (e.g., amphetamine. picrotoxin) or drugs, tolerance to which confers cross-tolerance to morphine or heroin (e.g., met had one). These findings (discussed in the Appendix. see pages 869-88 1 ) provide the empirical basis for two clinical applications of narcotic antagonists: ( 1 ) resuscitation of patients with opioid poisoning: and ( 2 ) the diagnosis of physical dependence on opioid agonists (first demonstrated with nalorphine). A third clinical application, namely. in the treatment of detoxified opioid addicts, was suggested later by Martin et al. (1976) in connection with cyclazocine: On the basis of our studies, 4 mg per day of cyclazocine will provide protection against the euphorogenic actions of large doses of narcotics, prevent the development of physical dependence, and will thereby control the pharmacological actions which are held responsible for narcotic addiction. . . . There may be other benefits. Wikler (1965)states that two of the important reasons for relapse of the abstinent narcotic addict are conditioned abstinence which may be evoked by stimuli that have been associated with the addict‘s hustling activity to acquire drugs, and reinforcement of drug-seeking behavior through repeated reductions of abstinence by drug. It is possible that in subjects who attempt to readdict themselves while receiving a narcotic antagonist such as cyclazocine. there may be extinction of physical dependence and drug-seeking behavior. More recently, Martin et al. (1973) reported on another narcotic antagonist, naltrexone, which unlike cyclazocine, is practically devoid of agonistic activity in man and which, in a single daily oral dose of 50 mg, will antagonize the actions of large doses of morphine or heroin for up to 24 hours. Commenting o n future research on the development of narcotic antagonists for clinical use in preventing relapse. Martin et al. (1973) observe that It has been the consensus of opinion of investigators that for a narcotic antagonist to be optimally effective in the treatment of narcotic addicts it must be administered in such a way that its
WIKLER
854
Downloaded by [University of California, San Diego] at 15:44 18 March 2016
effect would have an appreciable duration of action (one week to one month), that it should be devoid of agonistic activity, and that it should be a highly potent compound to permit its administration in a depot form. Currently, research on depot-form injections of naloxone, naltrexone, and other opioid antagonists is being pursued. In connection with the narcotic antagonist treatment program as proposed by Martin and his associates (see above), Wikler (1965) has pointed out that extinction of conditioned physical dependence and of conditioned drug-seeking behavior requires that the patients ‘‘ . . . attempt to readdict themselves while receiving a narcotic antagonist . . . Should such a patient, while maintained on an opioid antagonist, not attempt to readdict himself to an opioid, “extinction” will not take place, and the probability of relapse after discontinuation of the opioid antagonist will remain the same as after prolonged abstention from opioids in consequence of incarceration in a penal institution (presumably drug-free). Accordingly, Wikler (1 973) has proposed that after “detoxcification” and subsequent stabilization on an opioid-antagonist, and while still in hospital status, such patients be required to self-inject themselves with heroin repeatedly until they refuse to give themselves any more injections. Preferably, this procedure should be carried out under conditions that are likely to evoke “conditioned abstinence,” which should be likewise extinguished through lack of reinforcement-i.e., failure to reestablish physical dependence. After discharge from the hospital, maintenance on the opioid antagonist should be continued for about 1 year in view of the expected duration of “protracted abstinence” which, as Martin and Jasinski (1969) have shown, can last as long as 30 weeks after withdrawal of morphine, and may be an important factor in predisposing to relapse. During this period of maintenance, patients should be readmitted to the hospital from time to time, taken off the opioid antagonist, given an injection of heroin, and then replaced on the opioid antagonist before discharge from the hospital in order to extinguish interoceptively conditioned abstinence and drug-seeking behavior. It should be expected that even after carrying out such extinction procedures (both on exteroceptively and interoceptively conditioned behaviors), the change from inpatient to outpatient status would be likely to evoke attempts to obtain heroin illegally and to self-inject the drug, but such “recovery from extinction” should be short-lived in view of the continued opioid blockade and the history of extinction trials while still in ”
Downloaded by [University of California, San Diego] at 15:44 18 March 2016
METHADONE MAINTENANCE AND NARCOTIC‘ BLOCKING DRUGS
855
the hospital. If unscheduled urinary drug-detection tests are consistently negative during the last 3 months of the year of maintenance, the opioid antagonist may be discontinued and, hopefully, the probability of subsequent relapse will have been greatly reduced. It goes without saying that along with maintenance on an opioid antagonist for about 1 year. appropriate psychotherapeutic and rehabilitative measures should be provided. By “appropriate” is meant such psychotherapy as will alter the “congnitive labeling” of ”craving” for heroin. According to Wikler (1948, 1965). “craving” for heroin is the subjective concomitant of “conditioned abstinence,” not of some archaic “oral need.” Hence psychotherapy should be directed toward reinterpreting “craving” in the light of conditioning processes, both exteroceptive and interoceptive, that transpired in the course of self-administration of opioids in the past. As for rehabilitation, cognizance should be taken of the psychopathy (or sociopathy) of many addicts (Hill et al., 1960, 1962) and attempts should be made, by appropriate behavior modification, to train the patient to emit sustained, socially useful activity for delayed monetary rewards, and with delayed consumption of such rewards. Emotional disturbances and thinking disorders. also common among addicts (Monroe et al., 1971), may have to be dealt with pharmacologically as well as with psychotherapy. Finally, it should be pointed out that the opioid antagonist treatment modality as here outlined cannot extinguish nonopioid drug using behavior, and is therefore most likely to succeed in the cases of addicts who have used opioids mainly or exclusively. Whether or not “polydrug” users may benefit from opioid antagonist treatment remains to be seen. ACKNOWLEDGMENT
Preparation of this article was supported, in part. by Research Grant No. DA 00044 from the National Institute on Drug Abuse with funds made available by the Special Action Office for Drug Abuse Prevention. REFERENCES HILL. H.E., HAERTZEN. C.A.. and DAVIS. H. An MMPI factor analysia of alcoholics. narcotic-addicts and criminals. Q. J . Srucl. Alcohol 7 3 : 41 1-431, 1962. HILL. H.E., HAERTZEN. C.A.. and GLASER. Personality characteristics of narcotic addicts as indicated by the MMPI. J . Grn. Ps,,ccil. 61: 177-139, 1960. MARTIN. W.R.. GORODETSKY. C.W.. and MCCLANE. T.K. A n experimentnl study in
WIKLER
856
the treatment of narcotic addicts with cyclazocine. Clin. Pharmacol. Ther. 7: 455465, 1976.
MARTIN, W.R., and JASINSKI, D.R. Physiological parameters of morphine dependence in man: Tolerance, early abstinence, protracted abstinence. J . Psychiufr. Res. 7: 9-17,
Downloaded by [University of California, San Diego] at 15:44 18 March 2016
1969.
MARTIN, W.R., JASINSKI, D.R., and MANSKY, P.A. Naltrexone, an antagonist for the treatment of heroin dependence. Arch. Gen. fsychiarry 28: 784791, 1973. MONROE, J.J., ROSS, W.F., and BERZINS, J.J. The decline of the addict as “psychopath”: Implications for community care. fnr. J . Addicr. 6: 601-608, 1971. WIKLER, A. Recent progress in research on the neurophysiologic basis o f morphine addiction. Am. J . Psychiarry 105: 329-338, 1948. WIKLER. A. Conditioning factors in opiate addiction and relapse. In D. I. Wilner and G . G . Kassebaum (eds.) Narcotics. New York: McGraw-Hill, 1965, pp. 85-100. WIKLER, A. Dynamics of drug dependence. Implications of a conditioning theory for research and treatment. Arch. Gen. fsvchiatry 28: 61 1-616, 1973.
