Effects of Prazosin on Provoked Alcohol Craving and Autonomic and Neuroendocrine Response to Stress in Alcohol Use Disorder.

Abstract

Chronic alcohol use results in changes to stress biology and autonomic arousal contributing to acute alcohol withdrawal symptoms, neuroendocrine tolerance of the hypothalamic-pituitary-adrenal axis responses, high stress-induced craving, and risk of alcohol relapse. Thus, stress coping and recovery from alcohol during early abstinence may be jeopardized by such stress system dysfunction. Significant preclinical evidence suggests that noradrenergic disruption may contribute to these alcohol-related stress arousal changes and that alpha-1 adrenergic antagonists, such as prazosin, may normalize these stress system adaptations and reduce alcohol intake. Thus, we hypothesized that prazosin would reduce stress-induced craving and improve neuroendocrine and autonomic response to stress and alcohol cue exposure during early abstinence. We secondarily also assessed the role of lifetime anxiety disorders on these prazosin effects. Forty inpatient treatment-seeking alcohol-dependent individuals were randomly assigned to receive placebo (n=18) or 16mg/d, T.I.D., prazosin (n=22) in a double-blind manner, titrated over 2weeks. In weeks 3 to 4 after achieving full dose, patients were exposed to 3 5-minute personalized guided imagery conditions (stress cue, alcohol cue, neutral/relaxing cue), on 3 consecutive days in a random, counterbalanced order. Alcohol craving, anxiety, heart rate, cortisol, and adrenocorticotropic hormone (ACTH) levels were assessed at baseline, following imagery and at repeated recovery timepoints. Prazosin reduced stress cue-induced alcohol craving (p<0.05) and stress- and alcohol cue-induced anxiety (p<0.05) and increased heart rate responses in all imagery conditions (p<0.05). Prazosin lowered basal cortisol and ACTH (p's<0.05) and attenuated stress cue-induced rises in cortisol (p<0.05) versus placebo. Finally, in those without lifetime anxiety disorder, the placebo group showed stress- and alcohol cue-induced increases in cortisol (p's<0.05), while the prazosin group did not. Prazosin may attenuate stress cue-induced alcohol craving and anxiety during early abstinence while improving adrenergic and stress system function, effects which are independent of a history of lifetime anxiety disorders.