title: Meta-analyses of hypnotics and infections: eszopiclone, ramelteon, zaleplon, and zolpidem.
abstract: OBJECTIVE
  Recent meta-analyses raising concern about risks of hypnotics suggest a need for more clarification of these risks.
  
  
  METHODS
  Because of preliminary suggestions that eszopiclone causes infections, we studied US Food and Drug Administration files on the 4 most-recently approved hypnotics, combined with published studies, to compile the risk ratios of infections for groups randomly assigned to receive hypnotics versus those assigned to receive placebos in controlled trials. Parallel controlled clinical trials of eszopiclone, ramelteon, zaleplon, and zolpidem were included when data on subjects, duration of exposure, and adverse effects were available. Results of trials were combined by meta-analyses.
  
  
  RESULTS
  Of 8828 participants assigned to the 4 hypnotics and 4383 participants who randomly received placebos, 606 in the hypnotics groups and 200 in the placebo groups were reported to develop some kind of infection (risk ratio = 1.44, 95% confidence interval 1.25-1.64, p < 0.00001). Most infections were apparently mild and did not lead to dropouts. Subanalyses for individual drugs indicated that eszopiclone and zolpidem individually were associated with reported infections. There were insufficient data concerning individual studies of zaleplon and ramelteon for valid secondary meta-analyses of zaleplon or ramelteon by themselves.
  
  
  CONCLUSIONS
  Research is needed to objectively determine whether the use of hypnotics increases the risk of infections. Immune compromise or esophageal reflux and aspiration should be studied as possible mechanisms.
authors.affiliation: Scripps Clinic Sleep Center, La Jolla, CA 92037, USA.
authors.forename: Florendo L
authors.initials: FL
authors.lastname: Joya
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Kripke
authors.forename: Richard T
authors.initials: RT
authors.lastname: Loving
authors.forename: Arthur
authors.initials: A
authors.lastname: Dawson
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Kline
mesh_terms: D000081:Acetamides / Q000009:adverse effects; D053961:Azabicyclo Compounds / Q000009:adverse effects; D000069582:Eszopiclone; D006801:Humans; D006993:Hypnotics and Sedatives / Q000009:adverse effects*; D007192:Indenes / Q000009:adverse effects; D007239:Infections / Q000139:chemically induced*; D010879:Piperazines / Q000009:adverse effects; D011725:Pyridines / Q000009:adverse effects; D011743:Pyrimidines / Q000009:adverse effects; D016032:Randomized Controlled Trials as Topic; D012306:Risk; D000077334:Zolpidem
chemical_list: D000081:Acetamides; D053961:Azabicyclo Compounds; D006993:Hypnotics and Sedatives; D007192:Indenes; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D000077334:Zolpidem; C495910:ramelteon; C085665:zaleplon; D000069582:Eszopiclone