Central effects during the continuous osmotic infusion of a benzodiazepine (triazolam)

The effects of relatively constant plasma levels of a rapidly eliminated benzodiazepine (triazolam) were studied in young healthy males to determine whether tolerance to certain effects may develop over a relatively short period of time. The drug was given over a period of 30 h (2 days and 1 night) at zero-order rate using a rectal osmotic pump. Performance was measured at 2 hourly intervals during the day and was continuously impaired during the infusion, though there was a rapid recovery when the infusion ceased. All tasks were affected, in particular mental arithmetic and letter cancellation, but there was some improvement in performance during the second day. The normal circadian improvement in performance may have contributed to this effect, but some degree of tolerance to the effect of the drug cannot be excluded. Overnight there was a marked reduction in wakefulness, suppression of slow wave sleep, and delay to the onset and reduction in the duration of rapid eye movement sleep. During the night after infusion there was less slow wave sleep and increased wakefulness. The experimental design may prove useful in the study of tolerance to drugs.