Precipitation of abstinence in nordiazepam- and diazepam-dependent dogs

J Pharmacol Exp Ther. 1988 Apr;245(1):221-4.


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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analysis of Variance
  • Animals
  • Diazepam* / analogs & derivatives
  • Diazepam* / blood
  • Dogs
  • Flumazenil / pharmacology
  • Nordazepam* / blood
  • Oxazepam / blood
  • Pyrazoles / pharmacology
  • Seizures / chemically induced
  • Substance Withdrawal Syndrome / physiopathology*
  • Substance-Related Disorders / physiopathology*


  • Pyrazoles
  • Flumazenil
  • Nordazepam
  • Oxazepam
  • 2-phenylpyrazolo(4,3-c)quinolin-3(5H)-one
  • Diazepam