EVALUATION OF THE DEVELOPMENT OF ACUTE TOLERANCE TO THE PSYCHOMOTOR EFFECTS OF MIDAZOLAM FOLLOWING INTRAVENOUS INFUSIONS IN HEALTHY-VOLUNTEERS

The effect on digit-symbol substitution (DSST) of duration and extent of exposure to midazolam was studied in seven healthy male volunteers. Individual pharmacokinetic and pharmacodynamic parameters were estima ted after a 7.5 mg intravenous bolus dose of midazolam. Subjects then received, in a double-blind crossover design, loading doses of midazol am and steady-dose infusions to provide (A) 25 per cent of maximal eff ect (E(max)) for 6 h, (B) 50 per cent of E(max) for 3 h, (C) 75 per ce nt of E(max) for 2 h, and (D) 0 per cent of E(max) (placebo). Infusion s A-C were designed to yield a similar area under the effect curve (AU EC) during the infusion. DSST was assessed during the infusion and aft er a 3.75 mg IV midazolam challenge dose given at 6 h after infusion s tart. Actual decrements in DSST scores during infusions were 40.2 per cent, 60.7 per cent, and 86.8 per cent at 1 h for infusions A-C, respe ctively The degree of tolerance was assessed by calculating an effect ratio: ER = peak challenge dose DSST decrement/challenge dose C-max. E R's for treatments A-C and were 69.9 per cent, 79.3 per cent, and 68.4 per cent, respectively, of the control value; treatment A and CER's w ere significantly different from control. There were no significant di fferences among infusions A-C in ER or AUEC. These results show that, in subjects who are relatively sensitive to the effects of midazolam, tolerance develops acutely to the effects of midazolam and suggest tha t tolerance is dependent on both the time and extent of exposure.