Melatonin or ramelteon for the prevention of postoperative delirium in elderly patients: A systematic review and meta-analysis of randomized clinical trials

IF 6 2区医学 Q1 ANESTHESIOLOGY

Journal of Clinical Anesthesia Pub Date : 2026-03-01 Epub Date: 2026-02-16 DOI:10.1016/j.jclinane.2026.112151

João Mário Mira Furquim Borges MD , Raphaela Gomes Mendes MD , Rafaela Pereira Silva , Henrique Baggio Pivetta , Rafael Lopes Miranda , Isabela Alles , Tatiana Souza Nascimento MD

{"title":"Melatonin or ramelteon for the prevention of postoperative delirium in elderly patients: A systematic review and meta-analysis of randomized clinical trials","authors":"João Mário Mira Furquim Borges MD , Raphaela Gomes Mendes MD , Rafaela Pereira Silva , Henrique Baggio Pivetta , Rafael Lopes Miranda , Isabela Alles , Tatiana Souza Nascimento MD","doi":"10.1016/j.jclinane.2026.112151","DOIUrl":null,"url":null,"abstract":"<div><h3>Introduction</h3><div>Postoperative delirium (POD)—an acute, fluctuating disturbance in attention and awareness—is common among elderly surgical patients and is associated with morbidity, mortality, prolonged hospitalization, and increased costs. Melatonin has been investigated for POD prevention, but its perioperative effectiveness and safety remain uncertain. We conducted a systematic review and meta-analysis to assess whether perioperative melatonin or ramelteon reduces POD incidence in elderly surgical patients.</div></div><div><h3>Methods</h3><div>This meta-analysis included randomized controlled trials (RCTs) of elderly patients (>60 years) undergoing surgery, comparing perioperative melatonin or ramelteon (a melatonin receptor agonist) with placebo or non-pharmacological interventions for the prevention and treatment of POD. Secondary outcomes included sedation, pain, and length of hospital stay. A comprehensive search was conducted across PubMed, Embase, and Cochrane databases. We utilized a random-effects model with 95% Confidence Intervals. Pooled-effect sizes were measured with Mean Difference (MD) or Standardized Mean Difference (SMD) for continuous outcomes and Risk Ratio (RR) for binary outcomes. Heterogeneity was assessed with I2 statistics. Statistical analyses were performed using R v4.5.0.</div></div><div><h3>Results</h3><div>Sixteen RCTs (<em>n</em> = 2115; 48.7% intervention) were included; 12 evaluated melatonin and 4 ramelteon. Overall, postoperative delirium occurred in 188/895 patients (21.0%) receiving melatonergic agents and 254/893 patients (28.4%) in control groups, corresponding to a significant reduction in POD (RR 0.72; 95% CI 0.56–0.92; <em>p</em> = 0.009). In melatonin-only trials, delirium incidence was 163/729 (22.4%) versus 230/732 (31.4%) in controls (RR 0.67; 95% CI 0.52–0.88; <em>p</em> = 0.004), whereas ramelteon showed no significant effect (25/166 [15.1%] vs 24/161 [14.9%]; RR 0.98; 95% CI 0.47–2.01; <em>p</em> = 0.948). Trials using melatonin doses ≥5 mg demonstrated a greater reduction in POD, with delirium occurring in 57/314 patients (18.2%) in the melatonin group compared with 113/308 patients (36.7%) in control groups (RR 0.52; 95% CI 0.40–0.68; <em>p</em> < 0.001). No significant differences were found for pain, Ramsay Sedation Score, or length of stay. Heterogeneity was moderate to high for several analyses, and the certainty of evidence for POD was rated low.</div></div><div><h3>Conclusion</h3><div>Perioperative melatonin was associated with reduced POD in elderly surgical patients, with an apparent dose-response at ≥5 mg. Ramelteon did not demonstrate benefit in the available trials. Given heterogeneity and low certainty, findings—especially dose effects—should be interpreted cautiously.</div></div>","PeriodicalId":15506,"journal":{"name":"Journal of Clinical Anesthesia","volume":"110 ","pages":"Article 112151"},"PeriodicalIF":6.0000,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Clinical Anesthesia","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0952818026000292","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/2/16 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"ANESTHESIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Introduction

Postoperative delirium (POD)—an acute, fluctuating disturbance in attention and awareness—is common among elderly surgical patients and is associated with morbidity, mortality, prolonged hospitalization, and increased costs. Melatonin has been investigated for POD prevention, but its perioperative effectiveness and safety remain uncertain. We conducted a systematic review and meta-analysis to assess whether perioperative melatonin or ramelteon reduces POD incidence in elderly surgical patients.

Methods

This meta-analysis included randomized controlled trials (RCTs) of elderly patients (>60 years) undergoing surgery, comparing perioperative melatonin or ramelteon (a melatonin receptor agonist) with placebo or non-pharmacological interventions for the prevention and treatment of POD. Secondary outcomes included sedation, pain, and length of hospital stay. A comprehensive search was conducted across PubMed, Embase, and Cochrane databases. We utilized a random-effects model with 95% Confidence Intervals. Pooled-effect sizes were measured with Mean Difference (MD) or Standardized Mean Difference (SMD) for continuous outcomes and Risk Ratio (RR) for binary outcomes. Heterogeneity was assessed with I2 statistics. Statistical analyses were performed using R v4.5.0.

Results

Sixteen RCTs (n = 2115; 48.7% intervention) were included; 12 evaluated melatonin and 4 ramelteon. Overall, postoperative delirium occurred in 188/895 patients (21.0%) receiving melatonergic agents and 254/893 patients (28.4%) in control groups, corresponding to a significant reduction in POD (RR 0.72; 95% CI 0.56–0.92; p = 0.009). In melatonin-only trials, delirium incidence was 163/729 (22.4%) versus 230/732 (31.4%) in controls (RR 0.67; 95% CI 0.52–0.88; p = 0.004), whereas ramelteon showed no significant effect (25/166 [15.1%] vs 24/161 [14.9%]; RR 0.98; 95% CI 0.47–2.01; p = 0.948). Trials using melatonin doses ≥5 mg demonstrated a greater reduction in POD, with delirium occurring in 57/314 patients (18.2%) in the melatonin group compared with 113/308 patients (36.7%) in control groups (RR 0.52; 95% CI 0.40–0.68; p < 0.001). No significant differences were found for pain, Ramsay Sedation Score, or length of stay. Heterogeneity was moderate to high for several analyses, and the certainty of evidence for POD was rated low.

Conclusion

Perioperative melatonin was associated with reduced POD in elderly surgical patients, with an apparent dose-response at ≥5 mg. Ramelteon did not demonstrate benefit in the available trials. Given heterogeneity and low certainty, findings—especially dose effects—should be interpreted cautiously.

查看原文本刊更多论文

褪黑素或拉美替恩预防老年患者术后谵妄：随机临床试验的系统回顾和荟萃分析

术后谵妄（POD）是一种急性的、波动的注意力和意识障碍，在老年外科患者中很常见，与发病率、死亡率、住院时间延长和费用增加有关。褪黑素已被研究用于预防POD，但其围手术期的有效性和安全性仍不确定。我们进行了一项系统回顾和荟萃分析，以评估围手术期褪黑素或拉美替龙是否能降低老年外科患者POD的发病率。方法：本荟萃分析纳入了接受手术的老年患者（bb0 - 60岁）的随机对照试验（RCTs），比较围手术期褪黑激素或拉美替恩（褪黑激素受体激动剂）与安慰剂或非药物干预措施对POD的预防和治疗。次要结局包括镇静、疼痛和住院时间。在PubMed、Embase和Cochrane数据库中进行了全面的搜索。我们采用随机效应模型，置信区间为95%。用连续结局的平均差异（MD）或标准化平均差异（SMD）和二元结局的风险比（RR）测量合并效应大小。采用I2统计量评估异质性。使用R v4.5.0进行统计分析。结果：纳入16项rct (n = 2115，干预率48.7%)；12人评估褪黑素，4人评估拉梅尔肽。总体而言，接受褪黑激素药物治疗的患者中，术后谵妄发生率为181 /895例（21.0%），对照组为254/893例（28.4%），POD显著降低（RR 0.72; 95% CI 0.56-0.92; p = 0.009）。在仅褪黑激素的试验中，谵妄发生率为163/729(22.4%)，对照组为230/732 (31.4%)(RR 0.67; 95% CI 0.52-0.88; p = 0.004)，而拉梅尔替恩无显著影响（25/166[15.1%]对24/161 [14.9%];RR 0.98; 95% CI 0.47-2.01; p = 0.948）。使用褪黑素剂量≥5mg的试验显示，与对照组的112 /308例患者（36.7%）相比，褪黑素组的57/314例患者（18.2%）出现谵妄（RR 0.52; 95% CI 0.40-0.68; p）， POD的减少更大。结论：围手术期褪黑素与老年手术患者POD的减少相关，且≥5mg时存在明显的剂量反应。在现有的试验中，Ramelteon没有显示出益处。考虑到异质性和低确定性，研究结果——尤其是剂量效应——应谨慎解释。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Journal of Clinical Anesthesia 医学-麻醉学

CiteScore

7.40

自引率

4.50%

发文量

346

审稿时长

23 days

期刊介绍： The Journal of Clinical Anesthesia (JCA) addresses all aspects of anesthesia practice, including anesthetic administration, pharmacokinetics, preoperative and postoperative considerations, coexisting disease and other complicating factors, cost issues, and similar concerns anesthesiologists contend with daily. Exceptionally high standards of presentation and accuracy are maintained. The core of the journal is original contributions on subjects relevant to clinical practice, and rigorously peer-reviewed. Highly respected international experts have joined together to form the Editorial Board, sharing their years of experience and clinical expertise. Specialized section editors cover the various subspecialties within the field. To keep your practical clinical skills current, the journal bridges the gap between the laboratory and the clinical practice of anesthesiology and critical care to clarify how new insights can improve daily practice.