The relationships between
alprazolam and metabolite concentrations and CNS effects were determined in a double-blind placebo controlled four-way crossover trial in 16 normal male volunteers. Active
drug treatments consisted of 4-day regimens of 4 mg
alprazolam PO daily
as 2 mg bid., 1 mg qid, and 0.25 mg each hour. On days 1 and 4, the kinetics,
sedative and psychomotor effects were evaluated. Plasma concentrations of the 4- and alpha-hydroxy metabolites of
alprazolam were less than 10% of unchanged
alprazolam levels on both days. Accumulation of these metabolites and
alprazolam was dependent on
alprazolam half-life (11.6 h). Acute and chronic tolerance to the
sedative and psychomotor effects was observed with all active
drug treatments. All
alprazolam treatments resulted in significantly greater sedation than placebo on days 1 and 4. However, on day 4, sedation was 16-36% less than observed on day 1, despite plasma concentrations 1.4-2.76 times the day 1 concentrations. Sedation from
alprazolam was reduced in each successive study phase, suggesting a tolerance which was sustained during the 10-day washout between phases. By day 4, psychomotor performance was not different from placebo, indicating more complete development of tolerance than occurred for the
sedative effect. Sedation and
psychomotor impairment on day 1 were greatest with 2 mg
alprazolam bid. During the initiation of
therapy, the patient will likely experience less sedation and
psychomotor impairment with smaller, more frequent doses. Since tolerance develops to these effects, the advantage of more frequent dosing regimen dissipates by the 4th day.