EFFECT OF MIDAZOLAM ON DEVELOPMENT OF ACUTE TOLERANCE TO ALFENTANIL -THE ROLE OF PHARMACOKINETIC INTERACTIONS

This study in rats was performed to explore whether the inhibitory eff ect of midazolam on the development of acute tolerance to the analgesi c 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 usi ng a radioimmunoassay and chromatographic technique, respectively. Aft er the 4-h period of alfentanil administration (155 mu g.kg(-1).h(-1) after a 50-mu g/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) wi th the hot-plate test. At the height of midazolam-induced enhancement of the analgesic effect of alfentanil, the measurements of the alfenta nil and midazolam plasma and brain concentrations did not demonstrate any significant changes in the drugs' concentrations. The results conf irm that midazolam attenuates the development of acute tolerance to th e analgesic effect of alfentanil and indicate that this interaction is not pharmacokinetic.