Doxepin for insomnia: a systematic review of randomized placebo-controlled trials

Sleep Med Rev. 2015 Feb:19:75-83. doi: 10.1016/j.smrv.2014.06.001. Epub 2014 Jun 19.


Doxepin, a sedating tricyclic drug, at 3 mg and 6 mg doses was recently approved by the U.S. food and drug administration (FDA) for the treatment of insomnia. The objective of this systematic review was to obtain a precise summary of the efficacy and safety of doxepin as a hypnotic. We searched key databases and trial registers up to March 2014 and contacted pharmaceutical companies and the FDA for unpublished data. A total of nine randomized placebo-controlled trials were analyzed. Six studies were on doxepin 1-6 mg/d, two on doxepin 25-300 mg/d, and one on ramelteon 8 mg and doxepin 3 mg combined. All low-dose studies were industry-sponsored. We found that low-dose doxepin had a small to medium effect size against placebo for sleep maintenance and sleep duration but not for sleep initiation at both immediate and short-term posttreatment. There was no significant next-day residual effect with low-dose doxepin. Headache and somnolence were the most common side effects. We concluded that low-dose doxepin for 1-2 nights appeared to be safe and effective in improving sleep. However, a clear conclusion on its short-term benefits and risks as well as withdrawal effects was not possible due to the small number of studies.

Keywords: Antidepressants; Doxepin; Insomnia; Randomized controlled trials; Systematic review.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Dose-Response Relationship, Drug
  • Doxepin / adverse effects
  • Doxepin / therapeutic use*
  • Drug Therapy, Combination
  • Female
  • Humans
  • Indenes / adverse effects
  • Indenes / therapeutic use
  • Male
  • Middle Aged
  • Randomized Controlled Trials as Topic
  • Sleep Initiation and Maintenance Disorders / diagnosis
  • Sleep Initiation and Maintenance Disorders / drug therapy*
  • Treatment Outcome
  • United States
  • United States Food and Drug Administration
  • Young Adult


  • Indenes
  • Doxepin
  • ramelteon