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

Abstract

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.

Midazolam and nitrazepam in the maternity ward: milk concentrations and clinical effects.

“…The choice of drug dosage and the battery of sleep variables will influence the hypnotic effect measured. In contrast to a previous study (Godtlibsen et al, 1986) using the same standard doses in volunteers we demonstrated a higher number of awakenings with midazolam compared with nitrazepam. Rebound insomnia, considered to be a problem with short-acting benzodiazepines (Bixler et al, 1985), was not assessed in our study.…”

“…A total sleep index was calculated for each patient based on four sleep variables (onset, awakenings, quality, morning condition) scored by a self-report questionnaire (Godtlibsen et al, 1986;Hindmarch et al, 1984). Sedation and side effects were also evaluated.…”

“…Thus, a shorter acting hypnotic may be preferable for use in the maternity ward. Midazolam, having a mean half-life of 2.5 h, has very little residual effect (Dundee et al, 1984;Godtlibsen et al, 1986), but there is no information on its transfer into breast milk.…”

Hypnotics and antihistamines : effects ono cognitive functions and driving performance

“…Most failed to find significant residual effects 8 hours or more after bedtime administration, yet two studies demonstrated minor, but significant, residual effects on driving and divided attention at 8 and 9 hours after administration (Moskowitz et al, 1990;Riedel et al, 1988). At 10 hours after ingestion the only significant impairment found was on memory (Godtlibsen et al, 1986;Jackson et al, 1993). It may therefore be concluded that the risk for residual effects 8 hours or more after bedtime use of midazolam 15 mg is low, but not absent.…”

“…Meta-analysis confirmed that nitrazepam 10 mg is likely to impair performance the entire day after bedtime administration and experts rated the effects initially as severe and declining to moderate (Berghaus, 1998;Wolschrijn et al, 1991). Nitrazepam 5 mg was occasionally found to produce significant residual impairment between 8 and 12 hours after the administration (e.g., Bourin et al, 1987;Godtlibsen et al, 1986;Laurell and Tornros, 1986;Morgan, 1985;Subhan and Hindmarch, 1984a), but not on performance in the driving test (Volkerts and O'Hanlon, 1986). There was no consensus among experts with respect to the severity of residual effects of nitrazepam 5 mg.…”