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

Doxepin, a sedating tricyclic drug, at 3mg and 6mg 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 We searched key databases and trial registers up to March 2014 and contacted pharmaceutical companies and the FDA for unpublished data.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 1-6mg/d, two on doxepin 25-300mg/d, and one on ramelteon 8mg and doxepin 3mg 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.