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Insomnia From Drug Treatments

Evidence From Meta-analyses of Randomized Trials and Concordance With Prescribing Information
  • Anthony G. Doufas
    Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA

    Outcomes Research Consortium, Cleveland, OH
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  • Orestis A. Panagiotou
    Department of Health Services, Policy, and Practice, Brown University School of Public Health, Providence, RI

    Center for Gerontology and Healthcare Research, Brown University School of Public Health, Providence, RI
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  • Periklis Panousis
    Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA
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  • Shane Shucheng Wong
    MD Program, Stanford University School of Medicine, Stanford, CA
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  • John P.A. Ioannidis
    Correspondence: Address to John P.A. Ioannidis, MD, DSc, Stanford Prevention Research Center, Stanford University School of Medicine, MSOB X306, 1265 Welch Rd, Stanford, CA 94305.
    Stanford Prevention Research Center, Department of Medicine, Stanford University School of Medicine, Stanford, CA

    Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA

    Meta-Research Innovation Center at Stanford, Stanford University School of Medicine, Stanford, CA

    Department of Statistics, Stanford University School of Humanities and Sciences, Stanford, CA
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Published:November 11, 2016DOI:



      To determine whether drugs used to treat diverse conditions cause insomnia symptoms and whether their prescription information is concordant with this evidence.


      We conducted a survey of meta-analyses (Cochrane Database of Systematic Reviews) and comparisons with package inserts compiled in the Physicians' Desk Reference (PDR). We identified randomized controlled trials (RCTs) in which any drug had been evaluated vs placebo and sleep had been assessed. We collectively referred to insomnia-related outcomes as sleep disturbance. We also searched the PDR to identify any insomnia symptoms listed for drugs with RCT evidence available.


      Seventy-four Cochrane systematic reviews corresponding to 274 RCTs assessed 88 drugs in 27 different conditions, providing evidence on 109 drug-condition pairs. Of these 88 drugs, 5 decreased sleep problems and 19 increased sleep problems; 64 drugs had no nominally statistically significant effect on sleep. Acetylcholinesterase inhibitors, dopamine agonists, and selective serotonin reuptake inhibitors were the drug classes most importantly associated with sleep disturbance. Of 35 drugs that included disturbed sleep as an adverse effect in the PDR, only 14 had RCT evidence supporting such effect, and 2 had evidence of increasing and decreasing sleep problems in RCTs, although this was not shown in the PDR. We identified weak concordance between the PDR and RCTs (weighted κ=0.31; P<.001).


      The RCTs offer substantial evidence about the common effects of drugs on the risk of sleep disturbance; currently, prescription information only partially agrees with the available randomized evidence.

      Abbreviations and Acronyms:

      AE (adverse event), CDSR (Cochrane Database of Systematic Reviews), COMTI (catechol-O-methyltransferase inhibitor), DOPA (dopamine), FDA (Food and Drug Administration), GABA (γ-aminobutyric acid), GnRH (gonadotropin-releasing hormone), IQR (interquartile range), MAOI (monoamine oxidase inhibitor), NA (number of events is not applicable because the outcome is continuous), NL (drug is not listed in the PDR), NMDA (N-methyl-d-aspartic acid), NSAID (nonsteroidal anti-inflammatory drug), OR (odds ratio), PDR (Physicians' Desk Reference), RCT (randomized controlled trial), SNRI (serotonin-norepinephrine reuptake inhibitor), SSRI (selective serotonin reuptake inhibitor), TCA (tricyclic antidepressant)
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