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Thirty-five years ago, apparent interactions between intensities of morphine withdrawal phenomena in patients and presence or absence of the physician on the ward raised the question of the “organicity‘’ or “psychogenicity‘’ of the opioid abstinence syndrome. Operationally, “psychic‘’ was equated with “conditionable,‘’ requiring the integrity of the cerebral cortex, according to Pavlov. Evidence of tolerance to morphine and methadone and of severe abstinence syndromes was obtained in studies on long surviving deneocorticated dogs, chronic spinal dogs, and in a chronic spinal man. While the deneocorticated dogs could not acquire visual or auditory conditioned defense reflexes, surprisingly they did so with tactile conditioned stimuli after several hundred pairings of the tactile stimulus with the unconditioned stimulus, electric shock to a hindlimb, indicating the persistence of a rudimentary “psyche.‘’ However, in chronic spinal dogs, no conditioned reflex appeared after more than 1000 pairings of a tactile stimulus (applied to the tail) and electric shock to a hindlimb, evoking flexion. Hence, the opioid abstinence syndrome is organic, though that it may also become psychic given proper stimulus and reinforcement conditions, was not excluded. Indeed, anecdotal evidence of classical conditioning of the opioid abstinence syndrome and operant conditioning of opioid-seeking behavior was obtained in interviews with addicts and reports of other observers. Such conditioning could be an important factor in relapse long after opioid withdrawal when ex-addicts return to their drug-ridden home environment. In rats, a morphine abstinence sign, increased frequency of “wet dog shakes,‘’ could be classically conditioned to a specific environment and such conditioning persisted up to 155 days following permanent morhpine withdrawal. Also, ex-addict rats drank more of an opioid (etonitazene, 5μg/ml) than naïve rats in choice tests (etonitazene vs. water) at intervals for up to 1 year. That such “relapse‘’ may be due to conditioned reinforcing properties of etonitazene in rats that had previously undergone repeated cycles of morphine abstinence and its suppression was indicated in another study in which rats, while dependent on morphine, were repeatedly permitted to drink anise-flavored etonitazene which suppressed their morphine abstinence syndromes, while other morphine-dependent rats drank anise-flavored water. For 137 days following permanent morphine withdrawal, the previous anise-flavored etonitazene-drinking group drank more anise-flavored water than plain water compared to the other group or two groups of naïve rats treated similarly. Experimental extinction of such conditioned (psychic) responses may help prevent relapse of ex-addicts.

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