Physical dependence capacity of brotizolam in rhesus monkeys. 1st communication: primary dependence studies

Abstinence symptoms of doses acutely equi-effective on motocoordination of brotizolam (2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno [3,2-f]-1,2,4-triazolo[4,3-a]-1,4-diazepine, We 941, Lendormin) and diazepam in rhesus monkeys were evaluated in a primary dependence study of 61 days. After termination of oral treatment with 3 X 5.4 mg/kg/d brotizolam and 3 X 13.5 mg/kg/d diazepam the duration of withdrawal symptoms varied. Most symptoms of brotizolam abstinence disappeared within 24 h of withdrawal, while the withdrawal symptoms following diazepam were more pronounced between the second and fifth day after termination of administration. Regularly during the whole study, determinations of the serum levels of brotizolam and diazepam were performed. Two days after termination of brotizolam treatment the substance could scarcely be detected in the serum. Diazepam serum levels, in contrast, declined more slowly. The physical dependence capacity of lower daily doses of brotizolam, 3 X 0.2, 3 X 0.6, and 3 X 1.8 mg/kg/d was tested in experiments with chronic administration for 4 weeks. 3 X 1.8 mg/kg/d was the lowest oral dose inducing physical dependence. Taking into consideration the great difference in human therapeutic single dosages, brotizolam is thought to have a very low physical dependence capacity in man, compared with diazepam.