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Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration

BMJ 2012; 345 doi: (Published 17 December 2012) Cite this as: BMJ 2012;345:e8343
  1. Tania B Huedo-Medina, assistant professor1,
  2. Irving Kirsch, associate director of program in placebo studies (PiPS), lecturer in medicine2, professor of psychology3,
  3. Jo Middlemass, research assistant4,
  4. Markos Klonizakis, research fellow4,
  5. A Niroshan Siriwardena, professor of primary and prehospital health care4
  1. 1Department of Allied Health Sciences, University of Connecticut, 358 Mansfield Road U-2101, Storrs, CT 06269-2101, USA
  2. 2Harvard Medical School, Beth Israel Deaconess Medical Center, USA,
  3. 3School of Psychology, Plymouth University, Plymouth, UK
  4. 4Community and Health Research Unit, Lincoln School of Health and Social Care, University of Lincoln, Lincoln LN6 7TS, UK
  1. Correspondence to: A N Siriwardena nsiriwardena{at}
  • Accepted 30 November 2012


Objectives To investigate the effectiveness of non-benzodiazepine hypnotics (Z drugs) and associated placebo responses in adults and to evaluate potential moderators of effectiveness in a dataset used to approve these drugs.

Design Systematic review and meta-analysis.

Data source US Food and Drug Administration (FDA).

Study selection Randomised double blind parallel placebo controlled trials of currently approved Z drugs (eszopiclone, zaleplon, and zolpidem).

Data extraction Change score from baseline to post-test for drug and placebo groups; drug efficacy analysed as the difference of both change scores. Weighted raw and standardised mean differences with their confidence intervals under random effects assumptions for polysomnographic and subjective sleep latency, as primary outcomes. Secondary outcomes included waking after sleep onset, number of awakenings, total sleep time, sleep efficiency, and subjective sleep quality. Weighted least square regression analysis was used to explain heterogeneity of drug effects.

Data synthesis 13 studies containing 65 separate drug-placebo comparisons by type of outcome, type of drug, and dose were included. Studies included 4378 participants from different countries and varying drug doses, lengths of treatment, and study years. Z drugs showed significant, albeit small, improvements (reductions) in our primary outcomes: polysomnographic sleep latency (weighted standardised mean difference, 95% confidence interval −0.57 to −0.16) and subjective sleep latency (−0.33, −0.62 to −0.04) compared with placebo. Analyses of weighted mean raw differences showed that Z drugs decreased polysomnographic sleep latency by 22 minutes (−33 to −11 minutes) compared with placebo. Although no significant effects were found in secondary outcomes, there were insufficient studies reporting these outcomes to allow firm conclusions. Moderator analyses indicated that sleep latency was more likely to be reduced in studies published earlier, with larger drug doses, with longer duration of treatment, with a greater proportion of younger and/or female patients, and with zolpidem.

Conclusion Compared with placebo, Z drugs produce slight improvements in subjective and polysomnographic sleep latency, especially with larger doses and regardless of type of drug. Although the drug effect and the placebo response were rather small and of questionable clinical importance, the two together produced to a reasonably large clinical response.


  • Contributors: ANS and IK had the original idea for the study. All authors were involved in the design of the review, developed the search strategy, performed the study selection, interpreted and discussed results, and contributed to the writing and review of the various drafts of the report. JM, MK, and ANS extracted data from included studies. TBH-M, IK, and ANS were involved in data analysis. ANS is guarantor.

  • Funding: This study was funded by the College of Social Science Research Fund at the University of Lincoln. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Not required.

  • Data sharing: No additional data available.

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