Differential acute psychomotor and cognitive effects of diazepam on long-term benzodiazepine users

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Abstract
The aim of this study is to determine whether long-term use (5-20 years) of therapeutic doses of diazepam (5-20 mg/day) in anxious patients (n = 28) is associated with tolerance to its psychomotor and cognitive effects. Patients were tested at baseline, before and after a 10 mg oral dose of diazepam during chronic use, and at 3 weeks and 10 months after benzodiazepine (BZ) discontinuation. The effects of a single i.v. dose of flumazenil (1 mg administered 5 days before baseline) on reversing tolerance were also assessed. No acute effect of diazepam was observed on the psychomotor performance of patients both under BZ treatment and after short- and long-term discontinuation, suggesting persistence of tolerance. In contrast, acute effects of diazepam were observed in memory measures at all times. Given subjects' very prolonged BZ use, it is possible to predict that tolerance to the memory effects never fully develops. Flumazenil administration did not reverse tolerance. This suggests that neuroadaptative mechanisms, other than benzodiazepine receptor set-point shift, occur after long-term use.

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