BACKGROUND Melatonin is widely available either on prescription for the treatment of sleep disorders or as an over-the-counter dietary supplement. Melatonin has also recently been licensed in the UK for the short-term treatment of jetlag. Little is known about the potential for adverse events (AEs), in particular AEs resulting from long-term use. Concern has been raised over the possible risks of exposure in certain populations including pre-adolescent children and patients with epilepsy or asthma. OBJECTIVES The aim of this systematic review was to assess the evidence for AEs associated with short-term and longer-term melatonin treatment for sleep disorders. METHODS A literature search of the PubMed/Medline database and Google Scholar was conducted to identify randomised, placebo-controlled trials (RCTs) of exogenous melatonin administered for primary or secondary sleep disorders. Studies were included if they reported on both the types and frequencies of AEs. Studies of pre-term infants, studies of < 1 week in duration or involving single doses of melatonin and studies in languages other than English were excluded. Findings from open-label studies that raised concerns relating to AE reports in patients were also examined. Studies were assessed for quality of reporting against the Consolidated Standards of Reporting Trials (CONSORT) checklist and for risk of bias against the Cochrane Collaboration risk-of-bias criteria. RESULTS 37 RCTs met criteria for inclusion. Daily melatonin doses ranged from 0.15 mg to 12 mg. Subjects were monitored for up to 29 weeks, but most studies were of much shorter duration (4 weeks or less). The most frequently reported AEs were daytime sleepiness (1.66%), headache (0.74%), other sleep-related AEs (0.74%), dizziness (0.74%) and hypothermia (0.62%). Very few AEs considered to be serious or of clinical significance were reported. These included agitation, fatigue, mood swings, nightmares, skin irritation and palpitations. Most AEs either resolved spontaneously within a few days with no adjustment in melatonin, or immediately upon withdrawal of treatment. Melatonin was generally regarded as safe and well tolerated. Many studies predated publication of the CONSORT checklist and consequently did not conform closely to the guidelines. Similarly, only eight studies were judged 'good' overall with respect to the Cochrane risk-of-bias criteria. Of the remaining papers, 16 were considered 'fair' and 13 'poor' but publication of almost half of the papers preceded that of the earliest version of the guidelines. CONCLUSION Few, generally mild to moderate, AEs were associated with exogenous melatonin. No AEs that were life threatening or of major clinical significance were identified. The scarcity of evidence from long-term RCTs, however, limits the conclusions regarding the safety of continuous melatonin therapy over extended periods. There are insufficient robust data to allow a meaningful appraisal of concerns that melatonin may result in more clinically significant adverse effects in potentially at-risk populations. Future studies should be designed to comply with appropriate quality standards for RCTs, which most past studies have not.

中文翻译：

---

与褪黑素相关的不良事件，用于治疗原发性或继发性睡眠障碍：系统评价。

背景技术褪黑素可广泛用于治疗睡眠障碍的处方药或作为非处方饮食补充剂。褪黑激素最近还获得了英国对时差的短期治疗的许可。关于不良事件（AE）的潜在可能性知之甚少，特别是长期使用引起的不良事件。人们对某些人群（包括青春期前儿童和癫痫或哮喘患者）的暴露风险表示了担忧。目的本系统综述的目的是评估与短期和长期褪黑激素治疗睡眠障碍相关的不良事件的证据。方法对PubMed / Medline数据库和Google Scholar进行文献检索，以鉴定随机分组，对原发性或继发性睡眠障碍进行外源性褪黑激素的安慰剂对照试验（RCT）。如果研究报告了不良事件的类型和频率，则将其包括在内。不包括早产儿研究，持续时间<1周或单次服用褪黑激素的研究以及英语以外的其他语言的研究。还检查了开放式研究的发现，这些发现引起了患者对不良事件报告的关注。根据《综合报告标准》（CONSORT）清单评估研究的报告质量，并评估对Cochrane协作偏见风险标准的偏见风险。结果37个RCT符合纳入标准。褪黑激素的每日剂量为0.15毫克至12毫克。监测对象长达29周，但大多数研究的持续时间要短得多（4周或更短）。报告最频繁的AE是白天嗜睡（1.66％），头痛（0.74％），其他与睡眠有关的AE（0.74％），头晕（0.74％）和体温过低（0.62％）。很少有被认为是严重的或具有临床意义的不良事件。这些包括躁动，疲劳，情绪波动，噩梦，皮肤刺激和心。大多数AE要么在几天之内自发消退，而褪黑激素没有调节，要么在停药后立即消失。褪黑激素通常被认为是安全且耐受性良好的。许多研究早于CONSORT清单的发布，因此与指南不符。同样，就Cochrane偏倚风险标准而言，只有8项研究总体被评为“良好”。在其余的论文中，16篇被认为是“一般”，13篇被认为是“差”，但是几乎一半的论文发表于该指南的最早版本之前。结论外来褪黑激素很少与一般的AE有关。没有发现危及生命或具有重大临床意义的不良事件。然而，长期随机对照试验缺乏证据，这限制了关于长期连续褪黑激素治疗安全性的结论。没有足够的可靠数据，无法对潜在的危险人群中的褪黑激素可能在临床上产生更大的不良影响进行有意义的评估。未来的研究应设计为符合RCT的适当质量标准，而过去的大多数研究都没有这样做。但是几乎有一半的论文发表在该指南的最早版本之前。结论外来褪黑激素很少与一般的AE有关。没有发现危及生命或具有重大临床意义的不良事件。然而，长期随机对照试验缺乏证据，这限制了关于长期连续褪黑激素治疗安全性的结论。没有足够的可靠数据，无法对潜在的危险人群中的褪黑激素可能在临床上产生更大的不良影响进行有意义的评估。未来的研究应设计为符合RCT的适当质量标准，而过去的大多数研究都没有这样做。但是几乎有一半的论文发表在该指南的最早版本之前。结论外来褪黑激素很少与一般的AE有关。没有发现危及生命或具有重大临床意义的不良事件。然而，长期随机对照试验缺乏证据，这限制了关于长期连续褪黑激素治疗安全性的结论。没有足够的可靠数据，无法对潜在的危险人群中的褪黑激素可能在临床上产生更大的不良影响进行有意义的评估。未来的研究应设计为符合RCT的适当质量标准，而过去的大多数研究都没有这样做。一般而言，轻度至中度的AE与外源性褪黑激素有关。没有发现危及生命或具有重大临床意义的不良事件。然而，长期随机对照试验缺乏证据，这限制了关于长期连续褪黑激素治疗安全性的结论。没有足够的可靠数据，无法对潜在的危险人群中的褪黑激素可能在临床上产生更大的不良影响进行有意义的评估。未来的研究应设计为符合RCT的适当质量标准，而过去的大多数研究都没有这样做。一般而言，轻度至中度的AE与外源性褪黑激素有关。没有发现危及生命或具有重大临床意义的不良事件。然而，长期随机对照试验缺乏证据，这限制了关于长期连续褪黑激素治疗安全性的结论。没有足够的可靠数据，无法对潜在的危险人群中的褪黑激素可能在临床上产生更大的不良影响进行有意义的评估。未来的研究应设计成符合RCT的适当质量标准，而过去的大多数研究都没有这样做。限制了关于长期连续褪黑激素治疗安全性的结论。没有足够的可靠数据，无法对潜在的危险人群中的褪黑激素可能在临床上产生更大的不良影响进行有意义的评估。未来的研究应设计成符合RCT的适当质量标准，而过去的大多数研究都没有这样做。限制了关于长期连续褪黑激素治疗安全性的结论。没有足够的可靠数据，无法对潜在的危险人群中的褪黑激素可能在临床上产生更大的不良影响进行有意义的评估。未来的研究应设计成符合RCT的适当质量标准，而过去的大多数研究都没有这样做。