title: Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Systematic review and meta-analysis.
  
  
  METHODS
  US Food and Drug Administration (FDA).
  
  
  METHODS
  Randomised double blind parallel placebo controlled trials of currently approved Z drugs (eszopiclone, zaleplon, and zolpidem).
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Allied Health Sciences, University of Connecticut, 358 Mansfield Road U-2101, Storrs, CT 06269-2101, USA.
authors.forename: Tania B
authors.initials: TB
authors.lastname: Huedo-Medina
authors.forename: Irving
authors.initials: I
authors.lastname: Kirsch
authors.forename: Jo
authors.initials: J
authors.lastname: Middlemass
authors.forename: Markos
authors.initials: M
authors.lastname: Klonizakis
authors.forename: A Niroshan
authors.initials: AN
authors.lastname: Siriwardena
mesh_terms: D000081:Acetamides / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D053961:Azabicyclo Compounds / Q000627:therapeutic use; D016001:Confidence Intervals; D000069582:Eszopiclone; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use; D017286:Polysomnography; D011725:Pyridines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*; D016896:Treatment Outcome; D014481:United States; D014486:United States Food and Drug Administration; D000077334:Zolpidem
chemical_list: D000081:Acetamides; D053961:Azabicyclo Compounds; D006993:Hypnotics and Sedatives; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D000077334:Zolpidem; C085665:zaleplon; D000069582:Eszopiclone