Acute Tolerance and Reversal of the Motor Control Effects of Midazolam

Abstract The purpose of this study was to determine whether acute tolerance develops to the motor control effects of the short-acting benzodiazepine, midazolam. Using a bolus and constant infusion scheme, 40 healthy adults received a 70-min intravenous infusion of either saline ( n = 20) or 6.1 (SE = 0.2) mg midazolam ( n = 20). Following the 70-min infusion period, half of the subjects in each group ( n = 10) received a 25-min intravenous infusion of flumazenil (benzodiazepine antagonist); the remainder of the subjects ( n = 10/group) received a 25-min infusion of saline. Drug administration during both infusion periods was double blind. Prior to the infusions, subjects were trained in a motor control assessment battery. Throughout both infusions, repeated motor control testing and blood sampling were performed. The initial (10 min) midazolam plasma concentration was 52.0 (SE = 2.2) ng/ml. Plasma midazolam concentration rose gradually to 60.7 (SE = 2.1) ng/ml at the end of the infusion (70 min). Midazolam initially impaired performance on the motor control tasks. However, performance improved in subjects receiving midazolam despite the gradual increase in midazolam concentrations. This suggests that the recovery of motor task performance may be attributable to the development of acute tolerance rather than to waning drug concentrations. Flumazenil immediately reversed midazolam’s effects on the visual tracking task. However, there was little evidence for precipitation of muscle force rebound, which has been hypothesized to result from the same underlying mechanism that is responsible for acute tolerance development.