Evaluation of the development of acute tolerance to the psychomotor effects of midazolam following intravenous infusions in healthy volunteers

Abstract

AbstractThe 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 estimated after a 7·5 mg intravenous bolus dose of midazolam. Subjects then received, in a double‐blind crossover design, loading doses of midazolam and steady‐dose infusions to provide (A) 25 per cent of maximal effect (Emax) for 6h, (B) 50 per cent of Emax for 3 h, (C) 75 per cent of Emax for 2 h, and (D) 0 per cent of Emax (placebo). Infusions A‐C were designed to yield a similar area under the effect curve (AUEC) during the infusion. DSST was assessed during the infusion and after a 3·75 mg IV midazolam challenge dose given at 6 h after infusion start. 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, respectively. The degree of tolerance was assessed by calculating an effect ratio: ER = peak challenge dose DSST decrement/challenge dose Cmax. ER'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 were significantly different from control. There were no significant differences 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 that tolerance is dependent on both the time and extent of exposure.