Background

Behavioural, cognitive, and pharmacological interventions can all be effective for insomnia. However, because of inadequate resources, medications are more frequently used worldwide. We aimed to estimate the comparative effectiveness of pharmacological treatments for the acute and long-term treatment of adults with insomnia disorder.

Methods

In this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, PsycINFO, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and websites of regulatory agencies from database inception to Nov 25, 2021, to identify published and unpublished randomised controlled trials. We included studies comparing pharmacological treatments or placebo as monotherapy for the treatment of adults (≥18 year) with insomnia disorder. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. Primary outcomes were efficacy (ie, quality of sleep measured by any self-rated scale), treatment discontinuation for any reason and due to side-effects specifically, and safety (ie, number of patients with at least one adverse event) both for acute and long-term treatment. We estimated summary standardised mean differences (SMDs) and odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with Open Science Framework, https://doi.org/10.17605/OSF.IO/PU4QJ.

Findings

We included 170 trials (36 interventions and 47 950 participants) in the systematic review and 154 double-blind, randomised controlled trials (30 interventions and 44 089 participants) were eligible for the network meta-analysis. In terms of acute treatment, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more efficacious than placebo (SMD range: 0·36–0·83 [CINeMA estimates of certainty: high to moderate]). Benzodiazepines, eszopiclone, zolpidem, and zopiclone were more efficacious than melatonin, ramelteon, and zaleplon (SMD 0·27–0·71 [moderate to very low]). Intermediate-acting benzodiazepines, long-acting benzodiazepines, and eszopiclone had fewer discontinuations due to any cause than ramelteon (OR 0·72 [95% CI 0·52–0·99; moderate], 0·70 [0·51–0·95; moderate] and 0·71 [0·52–0·98; moderate], respectively). Zopiclone and zolpidem caused more dropouts due to adverse events than did placebo (zopiclone: OR 2·00 [95% CI 1·28–3·13; very low]; zolpidem: 1·79 [1·25–2·50; moderate]); and zopiclone caused more dropouts than did eszopiclone (OR 1·82 [95% CI 1·01–3·33; low]), daridorexant (3·45 [1·41–8·33; low), and suvorexant (3·13 [1·47–6·67; low]). For the number of individuals with side-effects at study endpoint, benzodiazepines, eszopiclone, zolpidem, and zopiclone were worse than placebo, doxepin, seltorexant, and zaleplon (OR range 1·27–2·78 [high to very low]). 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: 0·41 [0·04–0·78; very low]) and eszopiclone was more effective than ramelteon (0.63 [0·16–1·10; very low]) and zolpidem (0·60 [0·00–1·20; very low]). Compared with ramelteon, eszopiclone and zolpidem had a lower rate of all-cause discontinuations (eszopiclone: OR 0·43 [95% CI 0·20–0·93; very low]; zolpidem: 0·43 [0·19–0·95; very low]); however, zolpidem was associated with a higher number of dropouts due to side-effects than placebo (OR 2·00 [95% CI 1·11–3·70; very low]).

Interpretation

Overall, eszopiclone and lemborexant had a favorable profile, but eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce and do not allow firm conclusions. Many licensed drugs (including benzodiazepines, daridorexant, suvorexant, and trazodone) can be effective in the acute treatment of insomnia but are associated with poor tolerability, or information about long-term effects is not available. Melatonin, ramelteon, and non-licensed drugs did not show overall material benefits. These results should serve evidence-based clinical practice.

Funding

UK National Institute for Health Research Oxford Health Biomedical Research Centre.

中文翻译：

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药物干预对成人失眠症急性和长期管理的比较效果：系统评价和网络荟萃分析

背景

行为、认知和药物干预都可以有效治疗失眠。然而，由于资源不足，药物在世界范围内的使用更为频繁。我们的目的是评估药物治疗对成人失眠症的急性和长期治疗的比较有效性。

方法

在此系统评价和网络荟萃分析中，我们搜索了 Cochrane 对照试验中央注册中心、MEDLINE、PubMed、Embase、PsycINFO、WHO 国际临床试验注册平台、ClinicalTrials.gov 和监管机构网站，从数据库开始到 11 月 25 日, 2021, 以确定已发表和未发表的随机对照试验。我们纳入了比较药物治疗或安慰剂作为成人（≥18 岁）失眠症单一疗法的研究。我们使用网络荟萃分析 (CINeMA) 框架的置信度评估了证据的确定性。主要结果是疗效（即，通过任何自评量表测量的睡眠质量）、因任何原因和特别是由于副作用而停止治疗，以及安全性（即，有至少一种不良事件的患者人数）用于急性和长期治疗。我们使用具有随机效应的成对和网络荟萃分析估计了汇总标准化均值差 (SMD) 和比值比 (OR)。本研究已在开放科学框架中注册，https://doi.org/10.17605/OSF.IO/PU4QJ。

发现

我们在系统评价中纳入了 170 项试验（36 项干预措施和 47 950 名参与者），并且 154 项双盲、随机对照试验（30 项干预措施和 44 089 名参与者）符合网络荟萃分析的条件。在急性治疗方面，苯二氮卓类药物、多西拉敏、依佐匹克隆、柠檬黄、seltorexant、唑吡坦和佐匹克隆比安慰剂更有效（SMD 范围：0·36–0·83 [CINeMA 确定性估计：高到中]）。苯二氮卓类药物、依佐匹克隆、唑吡坦和佐匹克隆比褪黑激素、雷美替胺和扎来普隆更有效 (SMD 0·27–0·71 [中度至极低])。与雷美替尼相比，中效苯二氮卓类、长效苯二氮卓类和右佐匹克隆因任何原因停药的次数更少（OR 0·72 [95% CI 0·52–0·99；中等]，0·70 [0·51–0 ·95；中等] 和 0·71 [0·52–0·98；中等]，分别）。与安慰剂相比，佐匹克隆和唑吡坦因不良事件导致更多的退出（佐匹克隆：OR 2·00 [95% CI 1·28–3·13；极低]；唑吡坦：1·79 [1·25–2·50；缓和]）; 佐匹克隆比右佐匹克隆（OR 1·82 [95% CI 1·01–3·33；低]）、daridorexant（3·45 [1·41–8·33；低]）和 suvorexant（3 ·13 [1·47–6·67；低])。对于在研究终点出现副作用的个体数量，苯二氮卓类药物、依佐匹克隆、唑吡坦和佐匹克隆比安慰剂、多虑平、seltorexant 和扎来普隆更差（OR 范围 1·27–2·78 [高到极低]）。对于长期治疗，右佐匹克隆和柠檬黄比安慰剂更有效（右佐匹克隆：SMD 0·63 [95% CI 0·36–0·90；极低]；柠檬黄：0·41 [0·04–0·78 ; 非常低]) 并且右佐匹克隆比雷美替胺更有效 (0.63 [0·16–1·10; 非常低]) 和唑吡坦 (0·60 [0·00–1·20; 非常低])。与雷美替尼相比，右佐匹克隆和唑吡坦的全因停药率较低（右佐匹克隆：OR 0·43 [95% CI 0·20–0·93；非常低]；唑吡坦：0·43 [0·19–0 ·95; 非常低]); 然而，与安慰剂相比，唑吡坦与更多因副作用而退出的人数相关（OR 2·00 [95% CI 1·11–3·70；非常低]）。

解释

总的来说，右佐匹克隆和柠檬黄具有良好的疗效，但右佐匹克隆可能会导致大量不良事件，而且柠檬黄的安全性数据尚无定论。多虑平、seltorexant 和扎来普隆的耐受性良好，但疗效和其他重要结果的数据很少，因此无法得出明确的结论。许多获得许可的药物（包括苯二氮卓类药物、daridorexant、suvorexant 和曲唑酮）可有效治疗失眠的急性期，但耐受性较差，或者无法获得有关长期影响的信息。褪黑激素、雷美替胺和非许可药物并没有显示出整体的物质利益。这些结果应该服务于循证临床实践。

资金

英国国家健康研究所牛津健康生物医学研究中心。