The theoretical basis of narcotic addiction treatment with narcotic antagonists was well stated by Martin et al. (). Briefly, outpatient maintenance of a previously detoxified opioid addict on a daily oral opioid-blocking dose of a narcotic antagonist is expected to accomplish two objectives: (a) to remove the incentive for seeking and using opioid drugs; and (b), to extinguish conditioned abstinence (including “craving”) should this phenomenon occur as a response to environmental stimuli to which unconditioned abstinence had previously become conditioned (). Needless to add, such a period of out-patient maintenance on a narcotic antagonist should be used to “rehabilitate” the patient – i.e., to train him in the skills necessary for holding a socially useful job. to form new, mutually supportive relationships with non-drug using persons, and to persuade him to give up the illegal “hustling” activities which had become self-reinforcing during previous periods of opioid addiction.
Such a period of out-patient maintenance on a narcotic antagonist would have advantages over detoxification followed by enforced abstention from opioids (by prison sentences with or without a subsequent probationary period) in that it would permit the patient to expose himself to conditional environmental stimuli which evoke “craving” and possibly other conditioned abstinence phenomena, without the danger of their reinforcement by the pharmacological actions of opioid drugs. Eventually, if the patient so exposes himself frequently enough, such conditioned abstinence phenomena should become extinguished through repeated non-reinforcement.
Emphasizing the importance of extinction of conditioned abstinence and of drug-seeking behavior for minimizing the probability of relapse after out-patient maintenance on the narcotic antagonist has been discontinued, Wikler () proposed a program of ” active extinction,” to be carried out initially while the patient is still an in-patient at the hospital (where he was detoxified) and subsequently as an out-patient on narcotic antagonist maintenance. Along the lines of the models used to extinguish conditioned responses and behavior in animal experimentation, it was suggested that as in-patients, previously detoxified patients blocked by a narcotic antagonist be exposed to conditioned stimuli that evoke “craving” and perhaps other conditioned abstinence phenomena and be permitted to self-inject themselves with heroin repeatedly ad libitum: hopefully, under narcotic-antagonist blockade, self-injection of heroin-would ultimately cease. Appropriate conditioned stimuli might consist of heroin-related pictures () or the presence of previously detoxified patients self-injecting themselves with heroin in the unblocked condition. After completion of such active extinction under narcotic antagonist blockade as an in-patient, the patient may go on out-patient status, still receiving his daily oral blocking dose of the narcotic antagonist. It was assumed that under the different conditions of outpatient status, the patient would again display opioid-seeking behavior, which should not be discouraged, as further extinction of this behavior under “natural” conditions is to be desired. The progress of such patient-regulated “hustling” for and extinction of opioid-seeking behavior could be monitored by frequent, though unscheduled urine-testing for morphine. It was suggested that maintenance on a narcotic antagonist should be continued for about 10 months to one year (beyond the duration of protracted abstinence, which lasts about 30 weeks, Martin and Jasinski) and if urine screen remains negative for morphine, the narcotic antagonist could then be discontinued. Conditioned abstinence and opioid-seeking behavior having been extinguished, and the patient having been “rehabilitated,” the probability of relapse would be greatly reduced.
That in the rat well-established intravenous morphine self-injection can be extinguished by pre-treatment with naloxone and presentation of a conditioned reinforcer in the operant chamber has been demonstrated by Davis and Smith (). There is some question of whether in this study the decline in lever-pressing for morphine was not due to aversive conditioning, rather than to extinction, inasmuch as after pre-treatment with naloxone, no transient increase in lever pressing rate was observed prior to the rapid fall in lever-pressing rate. Naloxone may have precipitated a grossly undetectable abstinence syndrome, inasmuch as the rats had been self-injecting morphine, albeit in a very small unit dose, 60 mcg/kg, for 3 days prior to naloxone pre-treatment. However! in other intravenous morphine self-injecting rats, apparent extinction was accomplished by substituting saline for morphine solution in the operant chamber and presentation of the conditioned reinforcer; no transient increase in lever-pressing rate was observed under these conditions either.
As might have been anticipated, however, carrying out active extinction in man presents special problems because of his cognitive ability to perceive the experimental arrangements and alternative courses of action open to him which even the experimenter could not foresee. From as yet unpublished reports, it appears that these are two major problems connected with attempts at in-patient extinction with the aid of narcotic antagonists: (a) the patient simply refuses to self-inject himself with heroin or another opioid while he is blockaded by a narcotic antagonist, on the grounds that he “knows that he will not get high;” and (b) the patient reports that the narcotic antagonist “took all my craving” away – i.e. , the narcotic antagonist seems to have a “satiating” effect.
The question of whether or not the opioid antagonists exert a hitherto unknown agonistic, “satiating” effect on opioid-deprived receptors is very important from both the theoretical and practical standpoints. If a placebo can be found which produces an unpleasant after- taste similar to that produced by naltrexone, then a double-blind experiment on initiation of self-injection with heroin or hydromorphone may answer this question. If affirmed, a “satiation” effect of an opioid antagonist would render extinction trials both impractical and useless. Then reliance will have to be made on prolonged, though limited maintenance on an opioid-antagonist with, of course, efforts at re-education and social rehabilitation (which would be necessary in any case). However, should the results of such an experiment be negative – i.e., naltrexone does not have a “satiating” effect, then perhaps it may be possible to modify the extinction procedure in such a way as to make experimental extinction possible, despite the addict’s learned discrimination (his prior knowledge that naltrexone will block heroin effects, including “euphoria”). For example, an addict may be admitted to the hospital and “detoxified.” Then he may be allowed to work for and self-inject “earned” heroin (amounts subject to specified limits) on one day. Three or four days later, a “naloxone test” is made to determine if there is any residual physical dependence, and if the results are positive, “naloxone tests” are repeated every three days until the results are negative. Then naltrexone placebo (with the metallic after-taste) is administered by mouth and again the addict is permitted or persuaded (by monetary reinforcement, if necessary) to work for and self-inject “earned” heroin. Following this, “naloxone tests” are made as before until the results are negative (or, the data from the previous “naloxone tests” may be accepted as an estimate of the time required for physical dependence to dissipate). Then a full 24-hour blocking dose of naltrexone is administered by month and the subject is again permitted or persuaded (by monetary reinforcement, if necessary) to work for and self-inject “earned” heroin. Thereafter the full 24-hour blocking dose of naltrexone is administered by mouth every day and the extinction procedure is repeated until the addict no longer works for and self-injects heroin. For other addicts, the naltrexone placebo day should be omitted, attempted extinction (by monetary reinforcement , if necessary) being carried out under full 24-hour blocking doses of naltrexone. This is necessary to insure that addicts will not be able to anticipate whether or not the oral medication on the first day will block the effects of self-injected heroin. Or, another method may be tried. On the first day, the “detoxified” addict is given a partial blocking dose of naltrexone p.o., and he is permitted to work for and receive heroin on that day. At intervals determined by negative “naloxone tests” for physical dependence that may have been acquired by self-injection of heroin, the procedure is repeated with progressively increasing doses of naltrexone p.o., up to and including the day (or days) on which a full 24-hour blocking dose of naltrexone is administered and the addict finally ceases to self-inject himself with heroin [despite monetary reinforcement). It may be expected that the proposed program will have to be modified to nullify unforeseen, ingenious methods which the addicts may employ to “decode” the oral medication conditions. At any rate, by going “Beyond Skinner” (anticipating what the addict may do to discriminate naltrexone placebo from naltrexone) it should be possible to achieve experimental extinction of heroin-seeking behavior under hospital conditions.
Flexibility and ingenuity is also necessary in the maintenance of a patient on a narcotic antagonist in out-patient status. A close personal relationship between the patient and therapist is essential. The elements of conditioning theory, conditioned abstinence and “craving” as well as conditioned “hustling” should be explained to the patient, so that he could recognize these phenomena for what they are, rather than ascribe them to the “flu.” After out-patient extinction has proceeded, the relationship between the therapist and the patient should be such that the therapist can furnish positive reinforcement for socially acceptable behaviors. Quitting naltrexone or other narcotic antagonist should be expected, but the relationship between therapist and patient should be maintained nevertheless-and every effort should be made to brine the patient back into the narcotic antagonist-extinction treatment program without prejudice. In short, it should be remembered that a clinic is very different from an animal operant chamber and that in man, unlike the rat and monkey, the experimenter has met his match. Nevertheless, the principles of conditioning and extinction still hold – it is up to the experimenter to modify the animal paradigm of active extinction in a manner that will resolve the difficulties created by the patient’s powers of discrimination of the stimulus and reinforcement conditions set up by the experimenter.
Addendum: If it is proven that narcotic antagonists do have a “satiating” effect, then extinction of conditioned abstinence may be carried out as follows. Admit a group of detoxified addicts to the hospital and have them sign a contract (with monetary rewards) to stay in the hospital at least one month regardless of whether or not they are permitted to self- inject heroin. Do not administer any opioid antagonist. Allow some of the subjects to self-inject heroin without narcotic antagonist-blockade, while the others are not permitted to self-inject anything. Watching fellow-subjects self-inject heroin without being able to do likewise is likely to evoke strong “craving” and other signs and/or symptoms of conditioned abstinence which, on daily repetition should gradually wane and eventually extinguish. Then these subjects should be placed on full blocking doses of naltrexone and discharged to out-patient status where extinction of heroin-seeking behavior may take place if daily naltrexone medication is maintained and the subject “hustles” for heroin or other opioids. New detoxified addicts should now be admitted to reform the hospital in-patient group and permitted to self-inject heroin without narcotic antagonist blockade, while those who had been allowed previously to self-inject heroin without blockade are now detoxified and then carried through the conditioned abstinence extinction procedure, signing another contract if necessary. After these subjects are discharged to outpatient status on naltrexone, the in-patient group can be re-formed again by admission of new detoxified addicts, and the extinction and discharge sequence can be repeated indefinitely. For controls, some of the subjects who had been permitted to self-inject heroin without blockade may be detoxified and discharged to out-patient status on naltrexone without going through the conditioned abstinence extinction procedure.
Selections from the book: “Narcotic Antagonists: Naltrexone”. Editors: Demetrios Julius, M.D., and Pierre Renault, M.D. Progress report of development, pre-clinical and clinical studies of naltrexone, a new drug for treatment of narcotic addiction. National Institute on Drug Abuse Research Monograph 9. September 1976.