The effects of midazolam and flumazenil on psychomotor function

Abstract

To determine the effects of midazolam and its antagonism with flumazenil on psychomotor function as assessed by the perceptive accuracy test (PAT) and choice reaction time (CRT). Double-blind, cross-over, randomized, placebo-controlled study. Department of Anaesthesiology, University Hospital, Linköping, Sweden. 11 healthy volunteers (6 females, 5 males, mean age 32 years). Midazolam 0.1 mg/kg (Group MH), midazolam 0.035 mg/kg (Group ML), or placebo (Group PL) were injected intravenously (IV) in a cross-over design. Flumazenil 0.5 mg was injected after 60 minutes. Plasma concentrations of midazolam were measured at 3, 30, 60 and 75 minutes. Baseline values were first obtained on psychomotor tests including the PAT and CRT. These tests were then repeated 30 and 60 minutes after the IV injection of midazolam or placebo, and repeated 15 and 30 minutes following the injection of flumazenil. A dose-dependent effect of midazolam was seen on the PAT and CRT. Flumazenil completely reversed the psychomotor effects of midazolam in Group ML at 60 minutes but not in Group MH, and this action was clearly detected by the PAT. Psychomotor tests had returned to baseline values when the plasma concentration of midazolam was below 33 ng/ml. A marked inter-individual variation was seen on the PAT, CRT, and in the correlation between the plasma concentration and the results on the PAT. There was a dose-dependent deterioration in psychomotor performance in subjects given midazolam. The PAT was sensitive in the detection of these residual effects, but a large inter-individual variation in the psychomotor effects of midazolam was evident that could be due to pharmacodynamic and pharmacokinetic variability between individuals. Flumazenil in a dose of 0.5 mg IV completely reversed the effects of low-dose, but not high-dose, midazolam.