Residual effect of single and repeated doses of midazolam and nitrazepam in relation to their plasma concentrations

Twelve healthy volunteers were given either midazolam 15 mg or nitrazepam 5 mg for 7 consecutive days in a randomized cross-over trial. Self-assessment of sleep, mood or condition on awakening and adverse effects was performed, and the volunteers underwent evaluation of psychomotor performance. Hypnotic effect, judged by the classical sleep variables, showed that the drugs were more or less equal and were superior to placebo. Nitrazepam consistently produced an impaired condition on awakening and also clearly displayed a spectrum of adverse motor effects. Motor tests revealed impairment induced by both drugs, but, in the midazolam group the effect subsided during the trial period. Both drugs had a significant effect on memory, midazolam appearing to perturb certain memory functions to a greater extent than did nitrazepam. The residual plasma concentration of midazolam 11 h after treatment correlated well with the scores obtained in several of the psychomotor tests, whereas plasma nitrazepam levels were not related to performance in any subtest. When discontinued neither drugs, induced any rebound phenomenon. However, the adverse effects of nitrazepam appeared to be carried over into the adjacent placebo period.