A controlled study of flumazenil-precipitated withdrawal in chronic low- dose benzodiazepine users

Rationale: Preclinical studies of the benzodiazepine antagonist flumazenil (Romazicon®) have contributed to the understanding of the physical dependence associated with chronic benzodiazepine use; when administered to animals chronically pretreated with benzodiazepines, flumazenil precipitates a withdrawal syndrome. However, few controlled clinical studies have been conducted. Objectives: The objective was to characterize the effects of flumazenil in long-term users of therapeutic doses of benzodiazepines. Methods: The acute physiological, participant- rated, and observer-rated effects of intravenously administered flumazenil (1 mg/70 kg) and caffeine (300 mg/70 kg; active drug control) were evaluated in an experimental group of 13 long-term users (mean 4.6 years) of low therapeutic doses (mean 11.2 mg/day diazepam equivalent) relative to a matched group of 13 volunteers without prior exposure to benzodiazepines in a double-blind, placebo-controlled, mixed design. Results: Whereas the experimental group did not differ from the control group with respect to the effects of placebo, and both groups showed some changes in response to caffeine (e.g., increased blood pressure and anxiety scores), only the experimental group showed considerable changes in physiological measures, participant ratings (e.g., increased ratings of dizziness, blurred vision, heart pounding, feelings of unreality, pins and needles, nausea, sweatiness, noises louder than usual, jitteriness, things moving, sensitivity to touch), and observer ratings in response to flumazenil; in addition, four participants developed panic attacks. Conclusions: This study clearly demonstrates that flumazenil can precipitate symptoms commonly associated with benzodiazepine withdrawal in chronic low-dose benzodiazepine users.