Tolerance to alprazolam after intravenous bolus and continuous infusion: Psychomotor and EEG effects

A study was undertaken to compare the time course of changes in psychomotor performance and spectral edge (SE) of the EEG and to relate these changes to alprazolam concentrations in a pharmacokinetic/pharmacodynamic tolerance model. Digit symbol substitution (DSS) tests were administered and EEG data were obtained for SE calculation in a four-way crossover study in four normal men. Each treatment consisted of a 2-minute bolus injection followed by an 8-hour infusion. Treatment A, placebo, consisted of a 50% propylene glycol injection followed by a saline infusion. Active drug treatments were: B, 0.5 mg alprazolam plus saline infusion; C, 2.0 mg alprazolam plus saline; and D, 1.0 mg plus 72 micrograms alprazolam/hr for a total dose of 1.576 mg in 8 hours. For both DSS and SE data, three distinct effect-concentration curves result from the three alprazolam treatments, with successive shifts to the right as dose increases. A tolerance rate constant (kt) of 0.15 hr-1 was calculated from the DSS vs. time data during the 8 hour alprazolam infusion. The Hill equation was altered by using kt in an exponential modification of EC50. The resulting tolerance model describes both DSS and SE vs. concentration data from the rapid-injection and continuous-infusion treatments.