Tolerance and rebound insomnia with rapidly eliminated hypnotics: a meta-analysis of sleep laboratory studies

Differences in development of tolerance and occurrence of rebound insomnia have been well established between rapidly and slowly eliminated benzodiaze pine hypnotics. Based on meta-analytic methodology this study assesses whet her there are such differences among the rapidly eliminated benzodiazepine and benzodiazepine like hypnotics (brotizolam, midazolam, triazolam, zolpid em and zopiclone). All sleep laboratory studies of these drugs (n = 137) pu blished from 1966 to 1997 were obtained, mainly through a MEDLINE search. R igorous selection criteria resulted in the inclusion of 75 studies employin g 1276 individuals (804 insomniacs and 472 healthy volunteers). Using a mix ed effects regression model, reliable estimation of the effects on insomnia cs of the recommended dose of each drug could be obtained. All five rapidly eliminated hypnotics showed statistically significant initial efficacy. To lerance with intermediate and long-term use was clearly developed with tria zolam and was only marginal with midazolam and zolpidem; it could not be es timated for brotizolam or zopiclone because of insufficient data. Rebound i nsomnia on the first withdrawal night was intense with triazolam and mild,v ith zolpidem; data were unavailable for brotizolam and inadequate for midaz olam and zopiclone. In conclusion, there are differences among the rapidly eliminated hypnotics with respect to tolerance and rebound insomnia suggest ing that, in addition to short elimination half-life, other pharmacological properties are implicated in the mechanisms underlying these side effects. Int Clin Psychopharmacol 14:287-303 (C) 1999 Lippincott Williams & Wilkins .