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The Comparative Effectiveness and Safety of Insomnia Drugs: A Systematic Review and Network Meta-Analysis of 153 Randomized Trials

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Abstract

Background

Pharmacological treatment is common in practice and widely used for the management of insomnia. However, evidence comparing the relative effectiveness, safety, and certainty of evidence among drug classes and individual drugs for insomnia are still lacking. This study aimed to determine the relative effectiveness, safety, and tolerability of drugs for insomnia.

Methods

In this systematic review and network meta-analysis we systematically searched PubMed, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, and ClinicalTrials.gov, from inception to January 10, 2022 to identify randomized controlled trials that compared insomnia drugs with placebo or an active comparator in adults with insomnia. We conducted random-effects frequentist network meta-analyses to summarize the evidence, and used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty, categorize interventionsand present the findings.

Results

A total of 148 articles met our eligibility criteria; these included 153 trials which enrolled 46,412 participants and assessed 36 individual drugs from eight drug classes. Compared with placebo, both subjectively and objectively measured total sleep time were significantly improved with non-benzodiazepine (subjective: mean difference [MD] 25.07, 95% confidence interval [CI] 15.49–34.64, low certainty; objective: MD 22.34, 95% CI 7.64–37.05, high certainty), antidepressants (subjective: MD 54.40, 95% CI 34.96–75.83, low certainty; objective: MD 35.64, 95% CI 13.05–58.24, high certainty), and orexin receptor antagonists (subjective: MD 21.62, 95% CI 0.84–42.40, high certainty; objective: MD 31.81, 95% CI 2.66–60.95, high certainty); of which doxepin, almorexant, suvorexant, and lemborexant were among the relatively effective drugs with relatively good tolerability and lower risks of any adverse events (AEs). Both subjectively and objectively measured sleep onset latency were significantly shortened with non-benzodiazepines (subjective: MD − 10.12, 95% CI − 13.84 to − 6.40, moderate certainty; objective: MD − 12.11, 95% CI − 19.31 to − 4.90, moderate certainty) and melatonin receptor agonists (subjective: MD − 7.73, 95% CI − 15.21 to − 0.26, high certainty; objective: MD − 7.04, 95% CI − 12.12 to − 1.95, moderate certainty); in particular, zopiclone was among the most effective drugs with a lower risk of any AEs but worse tolerability. Non-benzodiazepines could significantly decrease both subjective and objective measured wake time after sleep onset (subjective: MD − 16.67, 95% CI − 21.79 to − 11.56, moderate certainty; objective: MD − 13.92, 95% CI − 22.71 to − 5.14, moderate certainty).

Conclusions

Non-benzodiazepines probably improve total sleep time, sleep onset latency, and wake time after sleep onset. Other insomnia drug classes and individual drugs also showed potential benefits in improving insomnia symptoms. However, the choice of insomnia drugs should be based on the phenotype of insomnia presented, as well as each drug’s safety and tolerability.

Protocol registration PROSPERO (CRD42019138790).

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Authors and Affiliations

  1. Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, No. 199 Donggang West Road, Chengguan District, Lanzhou, 730000, China

    Bei Pan, Liangying Hou, Ming Liu, Jinhui Tian & Kehu Yang

  2. Evidence-Based Social Science Research Center, School of Public Health, Lanzhou University, No. 199 Donggang West Road, Chengguan District, Lanzhou, 730000, China

    Bei Pan, Long Ge, Honghao Lai, Liangying Hou, Chen Tian, Yao Lu, Hongfei Zhu, Mengting Li, Xiuxia Li, Guowu Ding & Kehu Yang

  3. Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China

    Bei Pan, Long Ge, Liangying Hou, Xiuxia Li, Jinhui Tian & Kehu Yang

  4. Department of Epidemiology, School of Public Health, Shandong University, Jinan, China

    Qi Wang

  5. Department of Public Health and Primary Care, Academic Centre for Nursing and Midwifery, KU Leuven-University of Leuven, Leuven, Belgium

    Kelu Yang

  6. Department of Neurology, West China Hospital, Sichuan University, Chengdu, China

    Deren Wang

  7. Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

    Yuqing Zhang

  8. Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada

    Ya Gao

Authors
  1. Bei Pan
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  2. Long Ge
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  3. Honghao Lai
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  15. Ming Liu
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  18. Kehu Yang
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Corresponding authors

Correspondence to Long Ge or Kehu Yang.

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Funding

This research received no specific grant from any funding agency.

Conflict of interest

BP, LG, JHT, GWD, XXL, YQZ, DRW, KHY, LYH, HHL, KLY, CT, YL, QW, HFZ, YG, ML, and JYL declare no competing interests.

Ethics approval

Not applicable.

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Not applicable.

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Not applicable.

Availability of data and materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable.

Author contributions

BP, LG, JHT, GWD, XXL, YQZ, DRW, and KHY conceived and designed the study. BP, LYH, HHL, KLY, CT, YL, QW, HFZ, YG, and ML screened and selected the articles. BP, LYH, HHL, KLY, JYL, QW, HFZ, YG, and ML extracted the data. BP, LYH, CT, YL, and QW assessed the risk of bias. BP, HHL, CT, and LYH analyzed the data. LG and KHY supervised the data analyses. BP, YL, QW, and LYH rated the certainty of evidence. BP, LG, JHT, GWD, and KHY interpreted the data. BP, LG, XXL, YQZ, and KHY drafted the manuscript. All authors had full access to all the data in the study, had read and approved the final version of the manuscript, and agree to be accountable for the work.

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Pan, B., Ge, L., Lai, H. et al. The Comparative Effectiveness and Safety of Insomnia Drugs: A Systematic Review and Network Meta-Analysis of 153 Randomized Trials. Drugs 83, 587–619 (2023). https://doi.org/10.1007/s40265-023-01859-8

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