Drug anticipation and the treatment of dependence.

Results of much research demonstrate that tolerance is not the inevitable consequence of repeated drug exposure: the drug-experienced organism often demonstrates tolerance when the drug is administered in the context of the usual predrug cues, but not in the context of alternative cues. Such findings raise the importance of learning factors above that of the purely physiological factors in substance abuse. Incorporated in a model of tolerance that emphasizes the Pavlovian conditioning of an association between predrug cues and the systemic effect of the drug are findings that learned tolerance leads to death by overdose. A history of association results in drug-compensatory conditional responses, and these conditional pharmacological responses may be displayed as "withdrawal symptoms" and craving when the organism with a history of drug administration is confronted with the usual predrug cues without the usual pharmacological consequences. An implication of the conditioning analysis is that successful treatment of drug addiction should acknowledge not only pharmacodynamic and pharmacokinetic principles, but also the powerful evocative effects of drug-predictive environmental cues. Permanent abstinence is most likely if the treated addict is either protected from reexposure to these predrug cues (for example, by residence relocation), or treated with a protocol which incorporates extinction of the association between these cues and the drug. As Hamlet suggested to his mother (Act III, Scene 4): Assume a virtue if you have it not ... refrain tonight; And that shall lend a kind of easiness To the next abstinence: the next more easy; For use almost can change the stamp of nature And master ev'n the devil or throw him out With wondrous potency.