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In the central nervous system (CNS), excitatory neurons fire regularly, and inhibitory neurons inhibit the transmission of these impulses. Whenever action is required, the inhibitory tone diminishes, permitting the excitatory nerve impulses to travel to their end organs. Thus, all action in human neurophysiology can be considered to result from disinhibition.

Tonic inhibition (sustained, as opposed to phasic or transient inhibition) triggered by the constant presence of a xenobiotic produces an adaptive change in the affected neuron such that the constant presence of that xenobiotic is required to prevent dysfunction. A withdrawal syndrome occurs when the constant presence of this xenobiotic is removed or reduced and the adaptive changes persist. Withdrawal is a dysfunctional condition in which tonic inhibitory neurotransmission is significantly reduced, essentially producing excitation (Fig. 15–1). Every withdrawal syndrome has two characteristics: (1) a preexisting physiologic adaptation to a xenobiotic, the continuous presence of which prevents withdrawal, and (2) decreasing concentrations of that xenobiotic. In contrast, simple tolerance to a xenobiotic is characterized as a physiologic adaptation that shifts the dose–response curve to the right; that is, greater amounts of a xenobiotic are required to achieve a given effect. Physiologic dependence, generally simply called dependence, occurs when the absence of the xenobiotic leads to the development of a specific withdrawal syndrome. Dependence needs to be distinguished from addiction, which is compulsive drug-seeking behavior. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), uses the term substance use to combine the DSM-IV disorders of substance abuse and substance dependence.3

FIGURE 15–1.

Alcohol intoxication, tolerance, and withdrawal. Alcohol consumption in an alcohol-naïve person produces intoxication and sedation by simultaneous agonism at the γ-aminobutyric acid (GABA) receptor–chloride channel complex and antagonism at the N-methyl-d-aspartate (NMDA)-glutamate receptor. Continuous alcohol consumption leads to the development of tolerance through changes in both the GABA receptor–chloride channel complex (a subunit shift from α1 to α4, resulting in reduced sensitivity to the sedating effects of alcohol) and the NMDA subtype of glutamate receptor (upregulation in number, resulting in enhanced wakefulness). There is conceptually a concentration at which the tolerant patient may appear clinically normal despite having an elevated blood alcohol concentration. Tolerant patients who are abstinent lose the tonic effects of alcohol on these receptors, resulting in withdrawal.

Withdrawal is manifested by either of the following: (1) a characteristic withdrawal syndrome for the substance, or (2) the same (or a closely related) substance is taken to relieve withdrawal symptoms. Note that either criterion fulfills this definition. Logically, all syndromes have the first criterion, so it is the presence of the second criterion that is critical to understanding physiology and therapy.

For the purposes of defining a unifying pathophysiologic pattern of withdrawal syndromes, this chapter considers syndromes in which both features are present. An analysis ...

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