DEVELOPMENT OF ACUTE TOLERANCE AFTER ORAL DOSES OF DIAZEPAM AND FLUNITRAZEPAM

Flunitrazepam (1 and 2 mg), diazepam (10 and 20 mg) or placebo was adm inistered to healthy, male volunteers, and the time course of psychomo tor impairment, as indicated by simple and complex choice reaction tim e and movement time, was studied during a period of 6 h after drug int ake. To examine whether acute tolerance developed, the observed perfor mance during decreasing drug plasma concentration was compared to the predicted performance based on kinetic-dynamic modelling of the observ ed performance during the first 1.5 h after intake when the drug plasm a concentrations were increasing or at peak level. Placebo corrections of the test scores were accomplished to adjust for diurnal variation and the possible influence of learning during the test day. After the flunitrazepam treatments, the predictions overestimated the actual per formance significantly with respect to simple and choice reaction time at the 6-h session after intake. After the diazepam treatments, howev er, no significant deviation was detected between predicted and observ ed performance. The results indicate that acute tolerance develops wit h respect to impairment of attention demanding performance after mediu m to large doses of flunitrazepam, and that tolerance is expressed aft er approximately 4-6 h following intake.