Rr. Griffiths et al., INTRAVENOUS FLUMAZENIL FOLLOWING ACUTE AND REPEATED EXPOSURE TO LORAZEPAM IN HEALTHY-VOLUNTEERS - ANTAGONISM AND PRECIPITATED WITHDRAWAL, The Journal of pharmacology and experimental therapeutics, 265(3), 1993, pp. 1163-1174
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.