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Pharmacologic and hormonal treatments for menopausal sleep disturbances: A network meta-analysis of 43 randomized controlled trials and 32,271 menopausal women

Yu-Shian Cheng  1 , Ping-Tao Tseng  2 , Ming-Kung Wu  3 , Yu-Kang Tu  4 , Yi-Cheng Wu  5 , Dian-Jeng Li, et al.

Sleep Med Rev. 2021 Mar 11;57:101469.doi: 10.1016/j.smrv.2021.101469. Online ahead of print

This network meta-analysis aimed at investigating efficacy/tolerability of pharmacologic/hormonal interventions for menopausal sleep disturbances. Major databases were searched for randomized controlled trials (RCTs) examining pharmacologic or hormonal interventions with either placebo or active controlled designs. Primary outcomes were improvements in sleep disturbance severity/tolerability (i.e., overall dropout rates), whereas secondary outcome was adverse event-related discontinuation rates. Analysis of 43 RCTs with 25 treatment arms involving 32,271 women during/after menopausal transition (age: 61.24 ± 4.23, duration: 90.83 ± 66.29 wks) showed therapeutic effect of melatonin-fluoxetine [SMD = -2.47 (95% CI:-4.19-0.74)] against sleep disturbances compared to placebo. Subgroup analysis of 15 RCTs on vasomotor symptoms demonstrated superior benefits of gabapentin [SMD = -1.04 (95% CI:-1.90-0.18)], oral combined hormone therapy [SMD = -0.62 (95% CI:-1.06-0.18)], and bazedoxifene-conjugated estrogens [SMD = -0.50 (95% CI:-0.96-0.04)] to placebo/control. Despite benefits of raloxifene-only [SMD = -1.86 (95% CI:-3.09-0.63)] and raloxifene-oral estrogen [SMD = -2.64 (95% CI:-4.64-0.63)], patient selection may be a confounder. Dropout rates were comparable between interventions and placebo/control. Eszopiclone [RR = 3.84 (95% CI: 1.14-12.87)] and oral combined hormone therapy [RR = 2.51 (95% CI: 1.04-6.07)] were associated with higher rates of adverse event-related discontinuation. The results support combined estrogen-progesterone therapy for menopausal sleep disturbances associated with vasomotor symptoms but showed no significant effects of hypnotics in this clinical setting.