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; Ping-Tao Tseng; Ming-Kung Wu; Yu-Kang Tu; Yi-Cheng Wu; Dian-Jeng Li; Tien-Yu Chen; Kuan-Pin Su; Brendon Stubbs; Andre F Carvalho; Pao-Yen Lin; Yutaka J Matsuoka; Yen-Wen Chen; Cheuk-Kwan Sun; Yow-Ling Shiue

doi:10.1016/j.smrv.2021.101469

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

Sleep Med Rev. 2021 Jun:57:101469. doi: 10.1016/j.smrv.2021.101469. Epub 2021 Mar 11.

Authors

Yu-Shian Cheng¹, Ping-Tao Tseng², Ming-Kung Wu³, Yu-Kang Tu⁴, Yi-Cheng Wu⁵, Dian-Jeng Li⁶, Tien-Yu Chen⁷, Kuan-Pin Su⁸, Brendon Stubbs⁹, Andre F Carvalho¹⁰, Pao-Yen Lin¹¹, Yutaka J Matsuoka¹², Yen-Wen Chen¹³, Cheuk-Kwan Sun¹⁴, Yow-Ling Shiue¹⁵

Affiliations

¹ Department of Psychiatry, Tsyr-Huey Mental Hospital, Kaohsiung Jen-Ai's Home, Kaohsiung, Taiwan; Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
² Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan; Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung, Taiwan; Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan.
³ Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Chemical Engineering and Institute of Biotechnology and Chemical Engineering, I-Shou University, Kaohsiung, Taiwan.
⁴ Institute of Epidemiology & Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.
⁵ Department of Sports Medicine, Landseed International Hospital, Taoyuan, Taiwan.
⁶ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Addiction Science, Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung, Taiwan.
⁷ Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan; Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.
⁸ Institute of Neural and Cognitive Sciences, China Medical University Hospital, Taichung, Taiwan; Department of Psychiatry & Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan; College of Medicine, China Medical University, Taichung, Taiwan.
⁹ Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London, UK; Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, De Crespigny Park, London, UK; Faculty of Health, Social Care and Education, Anglia Ruskin University, Chelmsford, UK.
¹⁰ Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Centre for Addiction & Mental Health (CAMH), Toronto, ON, Canada.
¹¹ Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
¹² Department of Psychiatry & Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan; Division of Health Care Research, Center for Public Health Sciences, National Cancer Center Japan, Tokyo, Japan.
¹³ Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung, Taiwan.
¹⁴ Department of Emergency Medicine, E-Da Hospital, Kaohsiung, Taiwan; School of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung, Taiwan. Electronic address: lawrence.c.k.sun@gmail.com.
¹⁵ Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan. Electronic address: shirley@imst.nsysu.edu.tw.

PMID: 33836486
DOI: 10.1016/j.smrv.2021.101469

Abstract

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.

Keywords: Efficacy; Menopause; Network meta-analysis; Sleep; Systematic review; Tolerability.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't
Review

MeSH terms

Aged
Female
Humans
Menopause*
Middle Aged
Network Meta-Analysis
Randomized Controlled Trials as Topic
Sleep*