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

Int Clin Psychopharmacol. 1999 Sep;14(5):287-303.


Differences in development of tolerance and occurrence of rebound insomnia have been well established between rapidly and slowly eliminated benzodiazepine hypnotics. Based on meta-analytic methodology, this study assesses whether there are such differences among the rapidly eliminated benzodiazepine and benzodiazepine-like hypnotics (brotizolam, midazolam, triazolam, zolpidem and zopiclone). All sleep laboratory studies of these drugs (n = 137) published from 1966 to 1997 were obtained, mainly through a MEDLINE search. Rigorous selection criteria resulted in the inclusion of 75 studies employing 1276 individuals (804 insomniacs and 472 healthy volunteers). Using a mixed effects regression model, reliable estimation of the effects on insomniacs of the recommended dose of each drug could be obtained. All five rapidly eliminated hypnotics showed statistically significant initial efficacy. Tolerance with intermediate and long-term use was clearly developed with triazolam and was only marginal with midazolam and zolpidem; it could not be estimated for brotizolam or zopiclone because of insufficient data. Rebound insomnia on the first withdrawal night was intense with triazolam and mild with zolpidem; data were unavailable for brotizolam and inadequate for midazolam and zopiclone. In conclusion, there are differences among the rapidly eliminated hypnotics with respect to tolerance and rebound insomnia suggesting that, in addition to short elimination half-life, other pharmacological properties are implicated in the mechanisms underlying these side-effects.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Anxiety Agents / pharmacokinetics
  • Anti-Anxiety Agents / pharmacology*
  • Benzodiazepines
  • Half-Life
  • Humans
  • Hypnotics and Sedatives / pharmacokinetics
  • Hypnotics and Sedatives / pharmacology*
  • Recurrence
  • Sleep Initiation and Maintenance Disorders / drug therapy*
  • Substance Withdrawal Syndrome


  • Anti-Anxiety Agents
  • Hypnotics and Sedatives
  • Benzodiazepines