Melatonin and its use in children
Melatonin, a hormone secreted by the pineal gland in a circadian manner, promotes sleep through its regulation of the activity of the suprachiasmatic nucleus and other sleep-related brain networks. Its production is suppressed by light and stimulated by darkness, with a rise of serum levels preceding the onset of sleep by about 90 minutes.
There is a growing body of evidence describing abnormal melatonin secretion in children with neurodevelopmental disorders, and this has prompted the use of exogenous melatonin to treat sleep disorders in these populations.1,2
Sleep disorders have been identified in children across the neurodevelopmental disorder spectrum, including in attention deficit-hyperactivity disorder (ADHD), Rett syndrome, autism, intellectual deficits, visual impairment, epilepsy and brain damage. They affect approximately 80 per cent of children with moderate to severe neurodevelopmental disorders, and warrant special attention for several reasons, including their prevalence, severity and adverse impact on carers. Indeed, sleep disorders represent one of the most common reasons parents or caregivers of children with a neurodevelopmental disorder seek medical attention.3,4
The main characteristics of insomnia associated with neurodevelopmental disorders in children are:
- Delayed sleep onset
- Frequent night time arousals (for minutes or hours)
- Early morning awakenings
There is currently only one formulation of UK licensed melatonin: a prolonged-release 2mg tablet (Circadin). However, this is only licensed for the short-term treatment of primary insomnia, characterised by poor quality of sleep, in adults 55 years of age and over so its use in children is off-label.
In 2008, the London New Drugs Group reported at least 50 unlicensed melatonin preparations, either being imported into or manufactured in the UK, and available on a “named patient” basis. These products are available as immediate release capsules and tablets, sustained release capsules and tablets, and as a liquid formulation.5
In terms of risk hierarchy for the prescribing of unlicensed medicines, the Medicines and Healthcare Products Regulatory Agency has published a guide to prescribers for the preferential order in which products should be prescribed.6 In short, it is important to ensure that a licensed product is used wherever possible. This includes off-label use of the licensed product, if seemed suitable by the prescriber, although the overall prescribing decision should be based on meeting the individual patient’s clinical needs.7
Much of the melatonin prescribed to this patient population is under shared care agreements between child and adolescent mental health services (CAMHS) specialists and the patient’s GP, with the GP prescribing the recommended melatonin product for dispensing in primary care. The BNF for Children recommends that the manufacturer should be specified in the shared-care guideline because of variability of unlicensed formulations.
Is there a clinical rationale for the use of melatonin in children with sleep disorders secondary to a neurodevelopmental disorder? There are a large number of small, often poorly controlled studies with heterogeneous populations, efficacy criteria and outcome measures examining the effects of various formulations of unlicensed immediate release melatonin on children with neurodevelopmental disorders and sleep disorders. Consequently, data from meta-analyses and systematic reviews where available may be more reliable to test efficacy.
In one systematic review and meta-analysis, the authors concluded that immediate release melatonin produces a significant reduction in sleep onset latency and sleep duration but with variable effects on the number of night time awakenings.2
In children with ADHD, specifically those who are experiencing sleep onset insomnia, there is limited evidence from two small randomised controlled trials8,9 and one small, long-term follow-up study10 suggesting that short-term treatment with melatonin taken just before bedtime may improve sleep onset, sleep onset latency and sleep duration. (Mean time to follow up was 3.7 years.)
There have also been studies with prolonged release melatonin. Jan et al, in a double blind, randomised, cross over study, compared the effectiveness of immediate release with prolonged release melatonin in 16 children with severe neurodevelopmental disorders and chronic sleep-wake cycle disorders.11 They concluded that immediate release melatonin was more effective when there was only delayed sleep onset, but the prolonged formulation was more useful for sleep maintenance. The authors also hypothesised that some patients with marked sleep onset delay and early morning awakening may benefit from the combination of immediate release and prolonged release formulations of melatonin.
- About 80 per cent of children with neurodevelopmental disorders, including ADHD, experience insomnia and there is growing evidence describing abnormal melatonin secretion in these children.
- Short-term melatonin is being prescribed either off-label or unlicensed for these children, at doses of up to 10mg before bedtime, where non-pharmacological interventions have been unsuccessful.
- Licensed prolonged release melatonin should be prescribed as first-line therapy for these children based on the published evidence, consideration of cost and patient safety guidance around the use of licensed and unlicensed medicines.
In a retrospective, open-label study ranging from six to 72 months De Leersnyder et al examined the use of UK licensed prolonged release melatonin in 88 children with neurodevelopmental disorders and sleep disturbances.12 The study reported reductions in sleep onset latency, the number of night-time awakenings and improvements in sleep duration and quality. Quality of family life was noted to be significantly improved and a driver for continued treatment outside the period of study. The same authors noted that a single evening dose of licensed prolonged release melatonin (6mg) restored circadian timing in 34 patients with Smith-Magenis syndrome.13
The licensed prolonged release melatonin is formulated to circumvent the fast clearance of melatonin from the body and mimic the physiological pattern of endogenous melatonin release: an intact tablet releases melatonin in a controlled and prolonged manner over at least eight hours but there is a component of immediate release, with approximately 40 per cent of total dose being released within the first hour.
The in vitro release from a crushed tablet might be expected to provide a bioavailability profile similar to that of an unlicensed immediate release tablet or oral liquid and as such, crushing the licensed product may be an alternative option to either of these formulations. Use of licensed prolonged release melatonin in this way (ie, outside the terms of its licence) may be preferable to use of an unlicensed product as outlined in the MHRA risk hierarchy.
Melatonin is well tolerated with the most commonly reported side effects of headache, dizziness, nausea and drowsiness having a similar frequency in placebo treated groups.14
There is some uncertainty over the long-term effects of melatonin. For example, this hormone may, theoretically, effect other circadian rhythms, such as endocrine or reproductive hormone secretion.
Studies have tended to look at short-term treatment (eg, 10 days or four weeks) and Circadin is licensed for use in adults for up to 13 weeks. The BNFC recommends that the need to continue therapy should be reviewed every six months.
In terms of both spending and prescribing volume, unlicensed special order melatonin products are listed among the top five of all special order products prescribed from July to September 2012. Prescription cost analysis in England (primary care) shows that between July 2011 and June 2012 in general practice, licensed prolonged-release melatonin accounted for around 44 per cent of the total melatonin prescribed items (for all indications) and around 16 per cent of the cost (£2,850,038), whereas the 56 per cent of unlicensed melatonin accounted for around 84 per cent of the cost (£17,295,385). These data suggest potential savings to the NHS if the licensed prolonged release melatonin preparation is prescribed first-line instead of the unlicensed melatonin products, where clinically appropriate.
Guidance and evidence summaries
The BNFC states that melatonin may be of value in treating sleep onset insomnia and delayed sleep phase syndrome in children with conditions such as visual impairment, cerebral palsy, ADHD, autism and learning difficulties, when appropriate behavioural sleep interventions (eg, behavioural therapy and sleep hygiene measures) fail.15 Doses of melatonin of up to 10mg daily, given at bed time, have been reported to treat sleep disorders in children with neurodevelopmental disorders. However, in my experience of clinical practice, daily doses in the range of 2 to 6mg are more often observed.
In its guideline, “Assessment, diagnosis and clinical interventions for children and young people with autism spectrum disorders”, the Scottish Intercollegiate Guidelines Network16 recommends that melatonin may be considered for treatment of sleep problems which have persisted despite behavioural interventions.
Most recently, the National Institute for Health and Clinical Excellence (NICE) published an evidence summary (see Panel), “Use of unlicensed or off-label medicines; melatonin in sleep disorders in children and young people with ADHD”.17 This states that immediate release melatonin may reduce sleep onset latency in children with ADHD by about 20 minutes although it also states that the evidence was limited and not of high quality. Use of melatonin in children with sleep disorders secondary to neurodevelopmental disorders was outside the scope of the NICE review. Published guidelines indicate that some UK NHS trusts already implement this as best practice guidance,18,19 but many do not.
NICE evidence summaries
Produced by NICE’s Medicines and Prescribing Centre, evidence summaries present the published evidence for selected unlicensed or off-label medicines considered significant to the NHS where there are no clinically appropriate licensed alternatives.
They provide information for clinicians and patients to inform decision-making and support the construction and updating of local formularies. The strengths and weaknesses of the relevant evidence of a drug’s efficacy, safety and cost are critically reviewed but these summaries do not constitute formal NICE guidance.
A UK national consensus and consistency of approach on this would be welcome.
A patient information leaflet is available from the Medicines for Children website, which is a partnership of the Royal College of Paediatrics and Child Health, the Neonatal and Paediatric Pharmacists Group and the WellChild charity.20
DECLARATION OF INTEREST
The author has undertaken consultancy work for Nycomed and Flynn Pharma, which market or hold licences for Circadin.
About the author
Raymond J Bunn, MBA, MRPharmS, is a community pharmacist and medical writer
Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2013.11116406
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