Doxepin Demonstrates Effectiveness to Treat Sleep Latency in Insomnia

Andrew Krystal, MD

Data from a meta-analysis of 2, double-blind, placebo-controlled phase 3 trials showed that doxepin, an FDA-approved treatment for insomnia, was an effective option to treat sleep latency in adults with insomnia symptoms. At doses of 3 mg, this medication may be particularly impactful for those with a long latency to persistent sleep (LPS).¹

Doxepin, a compound with potent histamine blocking activity, has long been known to have significant sleep promoting effects. Presented at the 2024 SLEEP Annual Meeting, held June 1-5, in Houston, Texas, data showed that doxepin 3 mg improved latency to sleep onset (LSO) by 12% (rate ratio [RR], 0.88; 95% CI, 0.73-1.05) and LPS by 22% (RR, 0.78; 95% CI, 0.64-0.94) when compared with placebo. Combining the 2 studies, the analysis included 460 patients with insomnia with a mean age of 58.5 years (median, 65 years).

Led by Andrew Krystal, MD, a professor of psychiatry at the University of California San Francisco Weill Institute for Neurosciences, the analysis specifically focused on the 3 mg of doxepin and its effects on sleep latency on night 1/day 2 in patients with insomnia. At baseline, the median LSO was 55 minutes and median LPS was 35 minutes. Overall, 68.5% of the cohort was female, 65.2% were White, and 20.0% were African American.

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Results showed a non-statistically significant 6% improvement in LSO in patients above the median (RR, 0.94) and a 15% non-statistically significant improvement in participants below the median (RR, 0.85). Additionally, a statistically significant 29% improvement in LPS was observed for patients above the median (RR, 0.71; 95% CI, 0.56-0.91) and a non-statistically significant 6% improvement for those below the median (RR, 0.94). All the subgroup data regarding those above or at below median baseline values were consistent with results compared with placebo.

In 2011, investigators published the first parallel-group study of low-dose doxepin in adults, assessing the effects of the medication at 3 mg and 6 mg over a 5-week period of patients with chronic primary insomnia. In the trial, patients were randomized to 35 days of nightly treatment with doxepin 3 mg (n = 75), 6 mg (n = 73), or placebo (n = 73), followed by 2 nights of single-blind placebo to evaluate discontinuation effects. Efficacy was assessed using polysomnography (PSG) and patient reports.

Compared with placebo, results showed that the medication at doses of 3 mg and 6 mg significantly improved wake time after sleep onset (WASO) on night 1 (3 mg and 6 mg; P <.0001), night 15 (3 mg: P = .0025; 6 mg: P = .0009), and night 29 (3 mg: P = .0248; 6 mg: P = .0009). The therapy also demonstrated significant improvements in LPS on night 1 (3 mg: P = .0047; 6 mg: P = .0007), and total sleep time on night 1 (3 mg and 6 mg: P <.0001), night 15 (6 mg P = .0035), and night 29 (3 mg: P = .0261; 6 mg: P <.0001). In terms of early morning awakenings, DXP 3 and 6 mg demonstrated significant improvements in SE in the final quarter of the night on N1, N15, and N29, with the exception of 3 mg on N29 (P = 0.0691).²

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REFERENCES
1. Fisher M, Franks B, Araga M, Rawal K, Kyle M, Krystal A. The effect of doxepin 3 mg on sleep latency: results from a meta-analysis of two phase 3 trials. Presented at: 2024 SLEEP Annual Meeting; June 1-5; Houston, TX. ABSTRACT 0416.
2. Krystal A, Lankford A, Durrence HH, et al. Effect and safety of doxepin 3 and 6 mg in a 35-day sleep laboratory trial in adults with chronic primary insomnia. SLEEP. 2011;34(10):1433-1442. doi:10.5665/SLEEP.1294