Precipitation of abstinence in nordiazepam- and diazepam-dependent dogs

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.