A Theory of Opioid
Dependence

Abraham Wikler, M.D.

Psychoanalytical theories of addiction virtually ignored the specific pharmacological actions of the drug of addiction but stressed the importance of alleged intrapsychic "impulses" and "archaic longings." Thus, Rado (1933) stated, ". . . not the toxic agent, but the impulse to use it, makes an addict out of a given individual." Fenichel (1945) wrote, "... the origin and nature of addiction are not determined by the chemical effect of the drug but by the psychological structure of the patient." Be this as it may, the author is not aware of any data on the results of psychoanalytical therapy in the treatment of addicts; indeed, apart from the prohibitive cost of such therapy, it would seem that in view of the prevalence of psychopathy (sociopathy) and thinking disorder among detoxified opioid addicts (Hill et al. 1960; Monroe et al. 1971), psychoanalytical therapy would be futile. Furthermore, the fact that rats and monkeys, equipped with intravenous cannulas for self-injection, will readily take and maintain themselves on morphine, amphetamines, cocaine, and pentobarbital (Schuster and Thompson 1969) casts some doubt on the necessity of such psychoanalytical variables for the genesis of addiction.

Regardless of theoretical speculations about the role of personality, most writers have agreed that it is the "euphoria" produced by morphine that impels the user to repeat the experience and to relapse after long periods of abstention, for whatever reason. "Euphoria" is defined by McAuliffe and Gordon (1974) as "a subjectively pleasurable feeling produced by taking an opiate drug," and may be assigned a numerical rating on the Hill-Haertzen MBG scale (feeling happy, clear-headed, less discouraged, full of energy, etc.--cited by Jasinski [1973]). However, on the basis of interviews of 60 to 70 opioid addicts, Lindesmith

This paper is reprinted with permission from Dr. Wikler's "Opioid Antagonists and Deconditioning in Addiction Treatment," in Drug Dependence-Treatment and Treatment Evaluation, Skandia International Symposia, eds. H. Bostrom, T. Larsson, and N. Ljungstedt (Stockholm: Almqvist & Wiksell International, 1975), pp. 157-182.

(1947) contended that "euphoria" disappears once the subject has become physically dependent, and that the user becomes an addict, and regards himself as such, when he makes a cognitive connection between administration of the drug and relief of withdrawal distress. This has been contested recently by McAuliffe and Gordon (1974), who reported that 98 percent of 64 opioid addicts stated they experienced "euphoria" (initial "rush," followed by "on the nod") after each selfinjection of opioid drug (usually heroin) despite long-continued daily use, and claim they have demonstrated that "despite the development of tolerance chronic opioid addicts do experience euphoria following injections, and that their desire for euphoria appears to be a major factor in the explanation of their behavior." (Presumably, "behavior" includes relapse.) It may be questioned just how tolerant (and physically dependent) McAuliffe and Gordon's subjects were, since the amounts of drug they took were estimated in street terms and dependence was judged merely by asking other addicts about the individual, looking for extensive old and new scarring ("needle tracks") and asking the addicts themselves. Furthermore, Wikler (1952) observed that there was often a wide discrepancy between subjective reports made by an addict and his objective behavior. Thus, after intravenous injection of 30 mg of morphine, the subject reported he was full of "pep," then went "on the nod" and had to be aroused to explain what he meant by "pep." After several days on multiple, escalating doses of morphine (given on demand), reports of "pep" decreased markedly (though the "thrill" or "rush" persisted) and the subject became increasingly dysphoric (guilt, hostility). Although the subject was at liberty to discontinue taking morphine at any time (with appropriate treatment to minimize withdrawal distress) he continued to escalate the dose and frequency of injections and developed a high degree of tolerance and physical dependence. Wikler (1952) concluded that with the development of physical dependence, a new, pharmacological need was acquired, the gratification of which (by injection of morphine) served to maintain addiction despite the waning of initial "euphoria." It should be noted that this need is appetitive (gratification of it is accomplished by getting more and more of the reinforcer, morphine), not aversive (gratification of it is accomplished by getting less and less of the reinforcer, e.g., electric shock). Dysphoria (hypochondriasis) in opioid-tolerant and physically dependent subjects has also been observed by Haertzen and Hooks (1969) and by Martin et al. (1973). In an experimental study on six ex-addicts involving a tenday period of self-injection of heroin (earned by operating a counter), Mirin et al. (1976) observed that initially increased scores on "elated mood" as well as decreased scores on "anxiety" and "somatic concern" tended to return to baseline with continued self-administration of heroin, while concomitantly, belligerence and negativism increased over baseline. Babor et al. (1976) found that the patients showed a tendency to express more hostility after higher doses of heroin. It appears, therefore, that the commonsense interpretation of relapse, namely the quest for "euphoria," is open to question.

In 1948, Wikler proposed that in man relapse is due to evocation by drug-related environmental stimuli ("bad associates," neighborhoods where opioids are illegally available) of fragments of the opioidabstinence syndrome that had become classically conditioned to such stimuli during previous episodes of addiction. As elaborated further over the years (Wikler 1961, 1965, 1973a,b,c) and presented in figure 1, this hypothesis may be stated as follows. Reinforcement of opioid self-administration and of physiological events immediately preceding such self-administration is contingent upon the prior existence of

In

"needs" (or "sources of reinforcement") which are reduced by the pharmacological effects of the drug (e.g., heroin). The processes of addiction and relapse may be divided into two successive phases, namely, "primary" and "secondary" pharmacological reinforcement. the cases of young persons with prevailing moods of hypophoria and anxiety and with strong needs to belong to some identifiable group, self-administration of heroin is often practiced in response to the pressure of a heroin-using peer group in a social environment in which such a peer group exists. In primary pharmacological reinforcement, the pharmacological effects of heroin (miosis, respiratory depression, analgesia, etc.) are conceived as reflex responses to the receptor actions of the drug, but its "direct" reinforcing properties are ascribed to acceptance by the peer groups and reduction of hypophoria and anxiety.

With repetition of self-administration of heroin, tolerance develops rapidly to the direct pharmacological effects of the drug and physical dependence begins (demonstrable by administration of narcotic antagonists after only a few doses of morphine, heroin, or methadone; see Wikler et al. 1953). The prevailing mood of the heroin user is now predominantly dysphoric, and withholding of heroin now has as its reflex consequence the appearance of signs of heroin abstinence (mydriasis, hyperpnea, hyperalgesia, etc.), which generate a new need, experienced as abstinence distress. Because of previous reinforcement of heroin self-administration, the heroin user engaged in "hustling" for opioids-i.e., seeking "connections," earning or stealing money, attempting to outwit the law--which eventually becomes self-reinforcing, though initially at least, it is maintained by acquiring heroin for selfadministration. In this stage, the "indirect" reinforcing properties of heroin are attributed to its efficacy in suppressing abstinence distress. "On the street," the heroin user who is both tolerant and physically dependent frequently undergoes abstinence phenomena before he is able to obtain and self-administer the next dose. Given certain more or less constant exteroceptive stimuli (street associates, neighborhood characteristics, "strung out" addicts or leaders, "dope" talk) that are temporally contiguous with such episodes, the cycle of heroin abstinence and its termination can become classically conditioned to such stimuli, while heroin-seeking behavior is operantly conditioned. Sooner or later, the heroin user is detoxified, either in a hospital or in a jail. The well-known "acute" heroin-abstinence syndrome which is of relatively short duration (about two to four weeks) is followed by the "protracted" abstinence syndrome which, in the case of morphine addiction, has been found to last about 30 weeks (Martin 1972). At least during this period, the detoxified heroin user may be said to have still another new need. If, then, he is returned to his home environment, he is exposed to the phase of secondary pharmacological reinforcement. In response to the conditioned exteroceptive stimuli already described, he may exhibit transient conditioned abstinence changes, experienced as yet another new need, namely "narcotic hunger" or "craving." Previously reinforced "hustling" is also likely to appear now as a conditioned response (self-reinforcing) to these same exteroceptive stimuli and lead to acquisition and self-administration of heroin. The reinforcing properties of heroin, ascribed to its efficacy in suppressing conditioned abstinence distress, generate further selfadminstration of the drug with reestablishment of physical dependence as in the "indirect" stage of primary pharmacological reinforcement, and the cycle of renewed conditioning, detoxification, and secondary pharmacological reinforcement with relapse is repeated again. Also, in

the phase of primary pharmacological reinforcement, certain of the interoceptive actions of opioids, not involved in the suppression of abstinence phenomena, can acquire conditioned properties, inasmuch as in a tolerant and physically dependent individual, they are often followed by abstinence phenomena before termination of the latter by the next dose. Hence, in the phase of secondary pharmacological reinforcement, the usual effects of an opioid, administered for whatever reason, may be followed by conditioned abstinence phenomena, conditioned abstinence distress, and conditioned hustling leading to selfadministration of heroin (relapse). Other interoceptive events can likewise acquire the property of evoking conditioned self-administration of opioids. For example, anxiety is frequently associated with the opioid-abstinence syndrome, and probably the two phenomena are mediated, in part, by the same central nervous system pathways. Hence, the occurrence of anxiety for whatever reason long after detoxification may result in relapse.

If it is accepted that conditioning factors (classical and operant) and protracted abstinence play an important role in relapse, then addiction must be regarded as a disease sui generis, and regardless of antecedent etiological variables (e.g., premorbid personality), its specific features must be eliminated by appropriate procedures. As Wikler (1965) pointed out, mere detoxification, with or without conventional psychotherapy and enforced abstention from self-administration of opioids, will not prevent relapse when the former addict returns to his home environment or other environments where the conditioned stimuli are present (drugs readily available; "pushers" and active addicts). What is needed in treatment after "detoxification" is active extinction of both classically conditioned abstinence and operantly conditioned opioid self-administration. This would require repeated elicitation of conditioned abstinence and repeated self-administration of opioids under conditions that prevent the reinforcing effects of opioids (production of "euphoria," reestablishment of physical dependence). Under such conditions, conditioned abstinence should eventually disappear and self-administration of opioids should eventually cease. With the introduction of the orally effective, long-acting opioid antagonist, cyclazocine, by Martin et al. (1966), it became possible to prevent the reinforcing effects of opioids by daily administration of cyclazocine. If former addicts are maintained on blocking doses of an antagonist for a sufficient length of time (e.g., over 30 weeks) to permit disappearance of protracted abstinence, and if active extinction procedures are carried out during this period (Wikler 1973d), then administration of the antagonist may be discontinued, with the expectation that relapse will be much less likely to recur.