Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
Health Technol Assess. 2012;16(40):i-239. doi: 10.3310/hta16400.
Difficulties in initiating and maintaining sleep are common in children with neurodevelopmental disorders. Melatonin is unlicensed in children yet widely prescribed for sleep problems.
To determine whether or not immediate-release melatonin is beneficial compared with placebo in improving total duration of night-time sleep in children with neurodevelopmental problems.
Randomised, double-blind, placebo-controlled, parallel study.
Hospitals throughout England and Wales recruited patients referred by community paediatricians and other clinical colleagues.
Children with neurodevelopmental problems aged from 3 years to 15 years 8 months who did not fall asleep within 1 hour of lights out or who had < 6 hours of continuous sleep. Before randomisation, patients meeting eligibility criteria entered a 4- to 6-week behaviour therapy period in which a behaviour therapy advice booklet was provided. Sleep was measured using sleep diaries and actigraphy. After this period the sleep diaries were reviewed to determine if the sleep problem fulfilled the eligibility criteria. Eligible participants were randomised and followed for 12 weeks.
Melatonin or placebo capsules in doses of 0.5 mg, 2 mg, 6 mg and 12 mg for a period of 12 weeks. The starting dose was 0.5 mg and the dose could be escalated through 2 mg and 6 mg to 12 mg during the first 4 weeks, at the end of which the child was maintained on that dose.
The primary outcome was total night-time sleep time (TST) calculated using sleep diaries at 12 weeks compared with baseline. Secondary outcome measures included TST calculated using actigraphy data, sleep-onset latency (SOL) (time taken to fall asleep), sleep efficiency, Composite Sleep Disturbance Index score, global measure of child's sleep quality, Aberrant Behaviour Checklist, Family Impact Module of the Pediatric Quality of Life Inventory (PedsQL™), the Epworth Sleepiness Scale, number and severity of seizures and adverse events. Salivary melatonin concentrations and association of genetic variants with abnormal melatonin production were also investigated.
A total of 275 children were screened to enter the trial; 263 (96%) children were registered and completed the 4- to 6-week behaviour therapy period and 146 (56%) children were randomised, of whom 110 (75%) contributed data for the primary outcome. The difference in TST time between the melatonin and placebo groups adjusted for baseline was 22.43 minutes [95% confidence interval (CI) 0.52 to 44.34 minutes; p = 0.04] measured using sleep diaries. A reduction in SOL, adjusted for baseline, was seen for melatonin compared with placebo when measured by sleep diaries (-37.49 minutes, 95% CI -55.27 to -19.71 minutes; p < 0.0001) and actigraphy (-45.34 minutes, 95% CI -68.75 to -21.93 minutes; p = 0.0003). There were no significant differences between the two groups in terms of the reporting of adverse events. The results of other secondary outcomes favoured melatonin but were not statistically significant.
On average, the children treated with melatonin slept 23 minutes longer than those in the placebo group; however, the upper limit of the confidence interval was less than 1 hour, the minimum clinically worthwhile difference specified at the outset of the trial. Melatonin is effective in reducing SOL in children with neurodevelopmental delay by a mean of 45 minutes; a value of 30 minutes was specified a priori to be clinically important. Future studies should be conducted over longer periods and directly compare different formulations of melatonin with conventional hypnotic and sedative medications. It would also be important to study groups of children with specific neurological disorders.
Current Controlled Trials ISRCTN05534585.
This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 40. See the HTA programme website for further project information.
在患有神经发育障碍的儿童中，入睡困难和维持睡眠困难很常见。褪黑素在儿童中未获得许可，但广泛开处用于治疗睡眠问题。
确定即时释放型褪黑素与安慰剂相比，是否能改善神经发育问题儿童夜间总睡眠时间。
随机、双盲、安慰剂对照、平行研究。
英格兰和威尔士的医院通过社区儿科医生和其他临床同事招募患者。
年龄在 3 岁至 15 岁 8 个月之间的神经发育问题儿童，入睡时间不到 1 小时或连续睡眠时间不足 6 小时。在随机分组之前，符合入选标准的患者进入为期 4 至 6 周的行为治疗期，期间提供行为治疗建议手册。使用睡眠日记和活动记录仪测量睡眠。在这段时间之后，审查睡眠日记以确定睡眠问题是否符合入选标准。符合条件的参与者被随机分组并随访 12 周。
褪黑素或安慰剂胶囊，剂量为 0.5mg、2mg、6mg 和 12mg，持续 12 周。起始剂量为 0.5mg，在第 4 周内可以通过 2mg 和 6mg 逐步增加剂量，达到 12mg，此时孩子维持该剂量。
主要结局指标为使用睡眠日记在 12 周时与基线相比的总夜间睡眠时间（TST）。次要结局指标包括使用活动记录仪数据计算的 TST、睡眠潜伏期（SOL）（入睡所需时间）、睡眠效率、综合睡眠障碍指数评分、儿童睡眠质量总体测量、异常行为检查表、儿科生活质量量表（PedsQL）的家庭影响模块、嗜睡量表、癫痫发作次数和严重程度以及不良反应。还研究了唾液褪黑素浓度和遗传变异与异常褪黑素生成的关系。
共有 275 名儿童接受了筛选以进入试验；263 名（96%）儿童登记并完成了 4 至 6 周的行为治疗期，146 名（56%）儿童被随机分组，其中 110 名（75%）为主要结局提供了数据。褪黑素组与安慰剂组相比，调整基线后的 TST 时间差异为 22.43 分钟[95%置信区间（CI）为 0.52 分钟至 44.34 分钟；p = 0.04]，使用睡眠日记测量。与安慰剂相比，褪黑素组的 SOL 减少，调整基线后，使用睡眠日记测量时减少了-37.49 分钟[95%CI-55.27 分钟至-19.71 分钟；p<0.0001]，使用活动记录仪测量时减少了-45.34 分钟[95%CI-68.75 分钟至-21.93 分钟；p = 0.0003]。两组在不良反应报告方面没有显著差异。其他次要结局的结果有利于褪黑素，但没有统计学意义。
平均而言，接受褪黑素治疗的儿童比安慰剂组多睡 23 分钟；然而，置信区间的上限小于 1 小时，这是试验开始时规定的最小临床有意义差异。褪黑素可有效减少神经发育迟缓儿童的 SOL，平均减少 45 分钟；预先指定 30 分钟为临床重要值。未来的研究应进行更长时间，并直接比较褪黑素与传统催眠和镇静药物的不同制剂。研究具有特定神经障碍的儿童群体也很重要。
当前对照试验 ISRCTN05534585。
本项目由英国国家卫生与保健优化研究所健康技术评估计划资助，将在《健康技术评估》杂志全文发表；第 16 卷，第 40 期。请访问 HTA 计划网站以获取更多项目信息。
