INTRAVENOUS FLUMAZENIL FOLLOWING PROLONGED EXPOSURE TO LORMETAZEPAM IN HUMANS - LACK OF PRECIPITATED WITHDRAWAL

The capacity of flumazenil to reverse benzodiazepine agonist effects h as been widely demonstrated. In contrast, the role of flumazenil in pr ecipitating withdrawal symptoms is unclear in humans: the inability of RO 15-1788 to induce benzodiazepine withdrawal seems to be related to the duration of exposure to the GABAergic drugs. In the present exper iment we evaluated the effects of intravenous flumazenil or placebo in 36 healthy volunteers pretreated with lormetazepam for 30 days (2 mg/ day) and 18 lormetazepam-dependent subjects (6-8 mg/day). Measurements of a balance task, subject- and observer-rated symptoms shelved a rev ersal of lormetazepam effects induced by flumazenil without any signif icant withdrawal symptoms. Slight anxiety, increase in heart rate and perspiration were observed in a few subjects. Independent of benzodiaz epine doses, long-term treatment seems to be responsible for tolerance development with consistent changes in GABA-benzodiazepine receptor s ensitivity. Flumazenil could be able to normalize benzodiazepine recep tor sensitivity and exert its weak agonist activity.