Lack of effect of a small dose of flumazenil in reversing short-term tolerance to benzodiazepines in normal subjects

Abstract

Twelve normal volunteers received two courses of 7 days of either lorazepam (2 mg every morning; six subjects) or oxazepam (30 mg every morning; six subjects). After one of the courses, 0.2 mg of flumazenil was injected, after the other placebo, using a balanced design and double-blind procedures. A test dose of the lorazepam or oxazepam was administered the day after the flumazenil or placebo. A battery of physiological and psychological tests was applied before and after the dose of benzodiazepine on days 1, 4, 8 and 10. The benzodiazepines had the expected effects on the EEG, and event-related potentials (ERP), impaired several psychological tests and induced drowsiness and relaxation. Some tolerance was seen with respect to anxiolytic effects, some EEG and ERP variables and some psychological tests, but not those of memory. Tolerance tended to be more apparent in the subjects given lorazepam than in the oxazepam-treated subjects. No effects of the small dose of flumazenil in reversing tolerance were apparent.