Precipitation of abstinence in nordiazepam- and diazepam-dependent dogs

LF McNicholas, WR Martin, JW Sloan and E Wala

University of Kentucky, Department of Pharmacology, College of Medicine, Lexington.

Dogs were made dependent on p.o. administered diazepam (24 or 36 mg/kg/day) or nordiazepam (18 mg/kg/day). Flumazenil (2, 6 or 18 mg/kg) administered p.o. once a week according to a Latin Square design precipitated abstinence in both groups of dogs. Abstinence was evaluated using a Nordiazepam Precipitated Abstinence Scale (NPAS) of various signs of abstinence and by counting seizure episodes. Flumazenil caused dose-related increases in the NPAS scores of both diazepam- and nordiazepam-dependent dogs; the slopes of the two dose- response lines were not different. Both groups of dogs also had both clonic and tonic-clonic seizures after flumazenil administration. CGS- 8216 (2, 6 or 18 mg/kg) administered p.o. did not cause a dose-related elevation in NPAS scores for either group of dogs but clonic and tonic- clonic seizures were seen. Thus, flumazenil precipitates the benzodiazepine abstinence syndrome, as evidenced by tremors, tachypnea and other signs, including seizures, whereas CGS-8216 may have some selectivity in precipitating seizures without other signs of abstinence.

Volume 245, Issue 1, pp. 221-224, 04/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics