INTRAVENOUS FLUMAZENIL FOLLOWING ACUTE AND REPEATED EXPOSURE TO LORAZEPAM IN HEALTHY-VOLUNTEERS - ANTAGONISM AND PRECIPITATED WITHDRAWAL

The effects of i.v. administered flumazenil (3.0 mg) were studied in h ealthy male subjects who received pretreatment with p.o. placebo or lo razepam. The duration of placebo or lorazepam (3.0 mg single p.o. dail y dose) pretreatment before a flumazenil or placebo injection was 1, 3 , 7 or 14 days in four sequential groups of subjects. Initial administ ration of lorazepam produced a classic sedative profile of effects on various psychomotor/behavioral performance, observer-rated and subject -rated measures. Tolerance to repeated daily administration of lorazep am was suggested by a progressive diminution of performance disrupting effects. In subjects pretreated with placebo, flumazenil increased su bject-ratings of dizziness over preinjection ratings. Flumazenil produ ced an immediate reversal of lorazepam effects in subjects who were no t tolerant to lorazepam (1- and 3-day pretreatment groups). Flumazenil did not precipitate withdrawal symptoms in subjects who received a si ngle administration of lorazepam. Precipitated withdrawal symptoms wer e evident after 3 and 7 days of lorazepam pretreatment, and there was a tendency toward precipitated withdrawal symptoms (that included one panic attack) after 14 days of lorazepam pretreatment. Precipitated wi thdrawal was characterized by an elevation in subject-rated symptoms i ncluding dizziness, tenseness, tachycardia, perceptual disturbance and sweating. Symptoms were maximal immediately after injection, usually mild in severity and usually resolved within 1 hr. There was no eviden ce of precipitated withdrawal on psychomotor/behavioral performance or observer ratings. The present study provides the strongest human expe rimental evidence to date that flumazenil can precipitate withdrawal s ymptoms after a history of repeated benzodiazepine exposure.