Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis.
Level 1 - systematic review of randomized trials
Systematic review and network meta-analysis of randomized controlled trials
PubMed 35843245 · doi:10.1016/S0140-6736(22)00878-9
What was done
A systematic review and random-effects network meta-analysis evaluated published and unpublished randomized controlled trials of monotherapy pharmacological treatments versus placebo or active comparators for adult insomnia disorder (searched through November 25, 2021). The systematic review analyzed 170 trials (36 interventions, 47,950 participants), with 154 double-blind RCTs (30 interventions, 44,089 participants) eligible for network meta-analysis. Primary outcomes were self-rated sleep quality, all-cause and adverse-event-related treatment discontinuation, and safety (proportion experiencing at least one adverse event) for acute and long-term treatment, with certainty evaluated using the CINeMA framework.
What was found
For acute treatment, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more efficacious than placebo (SMD 0.36 to 0.83; high-to-moderate certainty). Benzodiazepines, eszopiclone, zolpidem, and zopiclone were more efficacious than melatonin, ramelteon, and zaleplon (SMD 0.27 to 0.71; moderate-to-very-low certainty). Intermediate-acting benzodiazepines, long-acting benzodiazepines, and eszopiclone had fewer all-cause dropouts than ramelteon (OR 0.70 to 0.72; moderate certainty). Zopiclone and zolpidem caused more adverse event dropouts than placebo (zopiclone OR 2.00 [95% CI 1.28–3.13; very low certainty]; zolpidem OR 1.79 [95% CI 1.25–2.50; moderate certainty]). For long-term treatment, eszopiclone and lemborexant were more effective than placebo (eszopiclone SMD 0.63 [95% CI 0.36–0.90; very low]; lemborexant SMD 0.41 [95% CI 0.04–0.78; very low]). Eszopiclone and zolpidem had lower all-cause discontinuations than ramelteon (OR 0.43 for both; very low), but long-term zolpidem increased dropouts due to side-effects versus placebo (OR 2.00 [95% CI 1.11–3.70; very low]).
Why it matters
Eszopiclone and lemborexant demonstrated the most favorable risk-benefit profiles for insomnia management, but high-quality evidence is restricted to acute use as long-term trial data remain sparse.
Limits
Long-term evidence was universally rated very low certainty. Safety data for lemborexant were inconclusive, and data for doxepin, seltorexant, and zaleplon were too scarce to draw firm conclusions. Melatonin and ramelteon demonstrated no material benefits over placebo.
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