Effect of the chronic dose of diazepam on the intensity and characteristics of the precipitated abstinence syndrome in the dog.
The ability of different chronic doses of diazepam to produce dependence was studied in groups of six dogs who received diazepam p.o. (0.05625, 0.225, 0.5625, 4.5, 9 or 36 mg/kg/day) every 8 hr. After 5 to 6 weeks of stabilization, the intensity of precipitated abstinence was measured by benzodiazepine-precipitated abstinence scores (BPAS) after the p.o. administration of graded doses of the benzodiazepine antagonist, flumazenil (0.66, 2, 6, 18, 36 and 72 mg/kg or a placebo). A modified Latin square design was used. Dogs receiving the two lowest stabilization doses of diazepam showed only liminal signs of precipitated abstinence even with 72 mg/kg of flumazenil. The intensity of the precipitated abstinence syndrome increased with the stabilization dose of diazepam. There was also a dose-related increase in BPAS for increasing doses of flumazenil for all doses of diazepam except the 9-mg/kg/day dose. Not only were quantitative differences observed in precipitated abstinence signs for different levels of diazepam dependence, but the pattern of abstinence signs differed also. Dogs dependent on high doses of diazepam were more sensitive to flumazenil than those dependent on lower doses. Furthermore, seizure activity was seen only in dogs dependent on 9 and 36 mg/kg/day of diazepam. BPAS increased linearly with plasma and brain total and free levels of the sum of diazepam and its metabolites (oxazepam and nordiazepam), but not with free plasma and brain levels of diazepam.
Department of Anesthesiology, University of Kentucky College of Medicine, Lexington.
J W
JW
Sloan
W R
WR
Martin
E
E
Wala
D000818:Animals; D003975:Diazepam / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005442:Flumazenil / Q000494:pharmacology; D013375:Substance Withdrawal Syndrome
D005442:Flumazenil; D003975:Diazepam