Rationale: Pharmacokinetics of melatonin in children might differ from that in adults. Objectives: This study aims to establish a dose-response relationship for melatonin in advancing dim light melatonin onset (DLMO), sleep onset (SO), and reducing sleep onset latency (SOL) in children between 6 and 12 years with chronic sleep onset insomnia (CSOI). Methods: The method used for this study is the randomized, placebo-controlled double-blind trial. Children with CSOI (n=72) received either melatonin 0.05, 0.1, and 0.15 mg/kg or placebo during 1 week. Sleep was assessed with log and actigraphy during this week and the week before. Outcomes were the shifts in DLMO, SO, and SOL. Results: Treatment with melatonin significantly advanced SO and DLMO by approximately 1 h and decreased SOL by 35 min. Within the three melatonin groups, effect size was not different, but the circadian time of administration (TOA) correlated significantly with treatment effect on DLMO (r s=-0.33, p=0.022) and SO (r s=-0.38, p=0.004), whereas clock TOA was correlated with SO shift (r=-0.35, p=0.006) and not with DLMO shift. Conclusions: No dose-response relationship of melatonin with SO, SOL, and DLMO is found within a dosage range of 0.05-0.15 mg/kg. The effect of exogenous melatonin on SO, SOL, and DLMO increases with an earlier circadian TOA. The soporific effects of melatonin enhance the SO shift. This study demonstrates that melatonin for treatment of CSOI in children is effective in a dosage of 0.05 mg/kg given at least 1 to 2 h before DLMO and before desired bedtime. © 2010 The Author(s).

Sleep disturbance is a common problem in children with developmental disabilities. Effective pharmacologic interventions are needed to ameliorate sleep problems that persist when behavior therapy alone is insufficient. The aim of the present study was to provide an overview of the quantity and quality of pharmacologic research targeting sleep in children with developmental disabilities. Efficacy studies of medications most likely to be prescribed to children are reviewed in detail. Medline and PsychInfo searches were performed to identify relevant clinical trials and case reports, published between 1975 and 2009. Key search terms included sleep, children, antihistamines, alpha adrenergic agonists, antidepressants, antipsychotics, melatonin, ramelteon, benzodiazepines, and nonbenzodiazepines. The literature search identified 58 articles that met the inclusion criteria. Well-controlled studies employing both objective polysomnography and subjective sleep measures are needed to determine the efficacy and safety of currently prescribed pediatric sleep medicines. Melatonin appears to be the most widely assessed agent and safest choice for children with developmental disabilities. Trazodone, mirtazapine, and ramelteon hold promise but require further study.

OBJECTIVE:

A large proportion of paediatric patients with attention-deficit/hyperactivity disorder (ADHD) have associated sleep problems which not only affect the child's wellbeing but also impact family functioning. Management of sleep problems is consequently an important aspect of overall ADHD management in paediatric patients. Although some drugs are being used off-label for the management of paediatric insomnia, there is scant clinical evidence supporting their use. Our aim was to identify and assess the quality of published studies reporting the safety, tolerability and efficacy of drugs used for treating behavioural insomnia in children with ADHD.

METHODS:

After an initial screen to determine which drugs were most commonly used, we conducted a systematic review of English-language publications from searches of PubMed, EMBASE, PsycINFO and two trial register databases to February 2017, using keywords 'clonidine', 'melatonin', 'zolpidem', 'eszopiclone', 'L-theanine', 'guanfacine', 'ADHD', 'sleep disorder' and 'children'. For quality assessment of included studies, we used the CONSORT checklist for randomised control trials (RCTs) and the Downs and Black checklist for non-RCTs.

RESULTS:

Twelve studies were included. Two case series for clonidine, two RCTs and four observational studies for melatonin and one RCT each for zolpidem, eszopiclone, L-theanine and guanfacine. Of the 12 included studies, only one on eszopiclone scored excellent for quality. The quality of the rest of the studies varied from moderate to low. For clonidine, melatonin and L-theanine, improvements in sleep-onset latency and total sleep duration were reported; however, zolpidem, eszopiclone and guanfacine failed to show any improvement when compared with placebo. Clonidine, melatonin, L-theanine, eszopiclone and guanfacine were well tolerated with mild to moderate adverse events; zolpidem was associated with neuropsychiatric adverse effects.

CONCLUSION:

There is generally poor evidence for prescribing drugs for behavioural insomnia in children with ADHD. Further controlled studies are warranted.

OBJECTIVE:

To investigate the effect of melatonin treatment on sleep, behavior, cognition, and quality of life in children with attention-deficit/hyperactivity disorder (ADHD) and chronic sleep onset insomnia.

METHOD:

A total of 105 medication-free children, ages 6 to 12 years, with rigorously diagnosed ADHD and chronic sleep onset insomnia participated in a randomized, double-blind, placebo-controlled trial using 3 or 6 mg melatonin (depending on body weight), or placebo for 4 weeks. Primary outcome parameters were actigraphy-derived sleep onset, total time asleep, and salivary dim light melatonin onset.

RESULTS:

Sleep onset advanced by 26.9 +/- 47.8 minutes with melatonin and delayed by 10.5 +/- 37.4 minutes with placebo (p < .0001). There was an advance in dim light melatonin onset of 44.4 +/- 67.9 minutes in melatonin and a delay of 12.8 +/- 60.0 minutes in placebo (p < .0001). Total time asleep increased with melatonin (19.8 +/- 61.9 minutes) as compared to placebo (-13.6 +/- 50.6 minutes; p = .01). There was no significant effect on behavior, cognition, and quality of life, and significant adverse events did not occur.

CONCLUSION:

Melatonin advanced circadian rhythms of sleep-wake and endogenous melatonin and enhanced total time asleep in children with ADHD and chronic sleep onset insomnia; however, no effect was found on problem behavior, cognitive performance, or quality of life.

Abstract: Background: Treatment of sleep disorders in visually impaired children is complicated by a complex pathophysiology, a high incidence of sleep disorders in this population, and a dearth of management options. The significant impact on the health of these children and distress to their caregivers warrant a systematic assessment of the published literature on therapeutic approaches. Objective: This systematic review aims to assess the current therapeutic options in the management of sleep disorders in visually impaired children to identify knowledge gaps and guide future research. Methods: A search of primary literature was conducted using the bibliographic databases PubMed (1980–August 2010), EMBASE (1990–August 2010), Science Citation Index Expanded (1990–August 2010), and CINHAL (1992–August 2010) and the Cochrane Central Register of Controlled Trials (CENTRAL). Additional studies were identified through snowballing search techniques (manually by searching retrieved references and electronically by using citation-tracking software). Search terms included behavioral treatment, children, circadian rhythm, hypnosedatives, intellectual disability, light therapy, melatonin, phototherapy, random allocation, randomized controlled trial (RCT), sleep disorder, and visual impairment. Randomized and quasi-randomized clinical trials of therapeutic options (behavioral treatment, light therapy, melatonin, or hypnosedatives) used in participants aged 3 months to 18 years who had both a visual impairment and a sleep disorder were included. Independent extraction of articles was performed by 2 authors using predefined data fields, including quality of the therapeutic options, based on the Strength of Recommendation Taxonomy evidence-rating system. Results: Two RCTs were retrieved for melatonin, with improved effect on sleep latency (P = 0.019 and P < 0.05, respectively). However, separate analysis for visual impairment was not conducted. No RCTs were retrieved for behavioral intervention, light therapy, or hypnosedatives. Three studies using behavioral therapy (2 case reports and 1 case series) anecdotally showed improvement in sleep habit. No improvement in sleep rhythm was observed with a case series applying light therapy as an intervention. Conclusions: Children with visual impairment and sleep disorders are a heterogeneous patient group, making diagnosis and treatment difficult. RCTs on treatment options remain in their infancy, with a lack of evidence for appropriate therapeutic strategies. Trials across a range of selected diagnoses need to be conducted with adequate sample populations to differentiate the efficacy of 4 different treatment modalities (behavioral therapy, light therapy, melatonin, and hypnosedatives) as agents for improving sleep.

BACKGROUND:

By the age of sixteen, one in five children will sustain a mild traumatic brain injury also known as concussion. Our research found that one in seven school children with mild traumatic brain injury suffer post-concussion syndrome symptoms for three months or longer. Post-concussion syndrome is associated with significant disability in the child and his/her family and yet there are no evidence-based medical treatments available. Melatonin has several potential mechanisms of action that could be useful following mild traumatic brain injury, including neuroprotective effects. The aim of this study is to determine if treatment with melatonin improves post-concussion syndrome in youths following mild traumatic brain injury. Our hypothesis is that treatment of post-concussion syndrome following mild traumatic brain injury with 3 or 10 mg of sublingual melatonin for 28 days will result in a decrease in post-concussion syndrome symptoms compared with placebo.

METHODS/DESIGN:

Ninety-nine youths with mild traumatic brain injury, aged between 13 and 18 years, who are symptomatic at 30 days post-injury will be recruited. This study will be conducted as a randomized, double blind, placebo-controlled superiority trial of melatonin. Three parallel treatment groups will be examined with a 1:1:1 allocation: sublingual melatonin 3 mg, sublingual melatonin 10 mg, and sublingual placebo. Participants will receive treatment for 28 days. The primary outcome is a change on the Post-Concussion Symptom Inventory (Parent and Youth). The secondary outcomes will include neurobehavioral function, health-related quality of life and sleep. Neurophysiological and structural markers of change, using magnetic resonance imaging techniques and transcranial magnetic stimulation, will also be investigated.

DISCUSSION:

Melatonin is a safe and well-tolerated agent that has many biological properties that may be useful following a traumatic brain injury. This study will determine whether it is a useful treatment for children with post-concussion syndrome. Recruitment commenced on 4 December 2014.

TRIAL REGISTRATION:

This trial was registered on 6 June 2013 at ClinicalTrials.gov.

REGISTRATION NUMBER:

NCT01874847.