Theories Related to Physical Dependence

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Abstract
Except for the “dual action” theory of physical dependence on morphine proposed by Tatum, Seevers, and Collins in 1929, 1 (the original form of which has been discarded by Seevers and Deneau 2 ) theories related to physical dependence not only on opioids, but also on barbiturates, certain nonbarbiturate sedatives, “minor tranquilizers,” and on ethanol, generally postulate one or another sort of “counter-adaptation” to the agonistic actions of these drugs, which results in the development of “latent hyperexcitability” of the central nervous system that becomes manifest as an abstinence syndrome when the drug in question is withdrawn abruptly. At least in the case of dependence on morphine or other opioids, such a hypothesis is strongly suggested by the fact that in general, the direction of change in directly observable physiological variables during the “primary” (or “early” or “acute”) abstinence syndrome is opposite to that produced by the drug in the nontolerant state. Thus, in nontolerant human subjects, morphine constricts the pupil and depresses respiratory rate; while little, if any tolerance develops to the miotic effect of morphine during chronic administration of the drug, partial tolerance to the respiratory-depressant effect does supervene. However, in the “primary” abstinence syndrome, miosis gives way to mydriasis, and bradypnea to tachypnea. To 360account for such, and other autonomic changes during cycles of morphine addiction, Himmelsbach 3 proposed a “homeostatic” counter-adaptive theory of morphine tolerance and physical dependence. According to this theory, through its actions on hypothalamic centers, morphine disturbs homeostasis in the nontolerant subject. In response to this “stress,” autonomic adjustments take place which partially restore homeostasis. With repeated administration of morphine, such adjustments gain strength “disproportionately,” so that continued presence of the drug is required to maintain a new level of homeostasis. When the drug is withdrawn abruptly, the “equilibrium” which had been achieved is lost, and the unchecked, counter-adaptive changes in autonomic function become manifest as the abstinence syndrome. That such counter-adaptive changes are associated with “latent hyperexcitability” of the autonomic nervous system is indicated by Himmelsbach’s 4 observation that vasopressor responses to a standard cold stimulus were greater, and recovery after removal of the stimulus was slower in morphine-tolerant subjects than in normal subjects.

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