Effect of midazolam on development of acute tolerance to alfentanil: the role of pharmacokinetic interactions.

Abstract

This study in rats was performed to explore whether the inhibitory effect of midazolam on the development of acute tolerance to the analgesic effect of alfentanil is due to pharmacokinetic mechanisms. Analgesia was determined with tail-compression and hot-plate tests. Alfentanil and midazolam concentrations in plasma and the brain were measured using a radioimmunoassay and chromatographic technique, respectively. After the 4-h period of alfentanil administration (155 microg x kg(-1) x h(-1) after a 50-microg/kg bolus), when acute tolerance had already developed, midazolam (2-mg/kg bolus) enhanced the alfentanil-induced analgesia by 120% (P < 0.001) with the tail-compression test and 76% (P < 0.01) with the hot-plate test. At the height of midazolam-induced enhancement of the analgesic effect of alfentanil, the measurements of the alfentanil and midazolam plasma and brain concentrations did not demonstrate any significant changes in the drugs' concentrations. The results confirm that midazolam attenuates the development of acute tolerance to the analgesic effect of alfentanil and indicate that this interaction is not pharmacokinetic.