Efficacy of melatonin and ramelteon for the acute and long‐term management of insomnia disorder in adults: A systematic review and meta‐analysis

Melatonin has gained growing interest as a treatment of insomnia, despite contradictory findings, and a low level of evidence. A systematic review and meta-analysis was conducted following PRISMA criteria, to assess the efficacy of melatonin and ramelteon compared with placebo on sleep quantity and quality in insomnia disorder, while also considering factors that may impact their efficacy. This review included 22 studies, with 4875 participants, including 925 patients treated with melatonin, 1804 treated with ramelteon and 2297 receiving a placebo. Most studies evaluated the acute efficacy of prolonged release (PR) melatonin in insomnia disorder. Compared with placebo, PR melatonin appears efficacious with a small to medium effect size on subjective sleep onset latency (sSOL) (p = 0.031; weighted difference = -6.30 min), objective sleep onset latency (oSOL) (p < 0.001; weighted difference = -5.05 min), and objective sleep efficiency (oSE) (p = 0.043; weighted difference = 1.91%). For the subgroup mean age of patients ≥55, PR melatonin was efficacious on oSE with a large effect size (p < 0.001; weighted difference = 2.95%). Ramelteon was efficacious with a large effect size at 4 weeks on objective total sleep time (oTST) (p = 0.010; weighted difference = 17.9 min), subjective total sleep time (sTST) (p = 0.006; weighted difference = 11.7 min), sSOL (p = 0.009; weighted difference = -8.74 min), and oSOL (p = 0.017; weighted difference = -14 min). Regarding long-term effects, ramelteon has a large effect size on oTST (p < 0.001; weighted difference = 2.02 min) and sTST (p < 0.001; weighted difference = 14.5 min). PR melatonin and ramelteon appear efficacious compared with placebo for insomnia symptoms with PR melatonin showing mostly small to medium effect sizes. PR melatonin for individuals with a mean age ≥ 55 and ramelteon show larger effect sizes.