Development of acute tolerance after oral doses of diazepam and flunitrazepam

Flunitrazepam (1 and 2 mg), diazepam (10 and 20 mg) or placebo was administered to healthy, male volunteers, and the time course of psychomotor impairment, as indicated by simple and complex choice reaction time and movement time, was studied during a period of 6 h after drug intake. To examine whether acute tolerance developed, the observed performance during decreasing drug plasma concentration was compared to the predicted performance based on kinetic-dynamic modelling of the observed performance during the first 1.5 h after intake when the drug plasma 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 performance significantly with respect to simple and choice reaction time at the 6-h session after intake. After the diazepam treatments, however, no significant deviation was detected between predicted and observed performance. The results indicate that acute tolerance develops with respect to impairment of attention demanding performance after medium to large doses of flunitrazepam, and that tolerance is expressed after approximately 4-6 h following intake.