Melatonin in paediatric sleep disorders

Melatonin (N-acetyl-5-methoxytryptamin) is synthesized in the pineal body exclusively during periods of darkness. It plays an important role in initiating and maintaining sleep (1)

• physiological increase in melatonin secretion during the night has a peak around 2 am and night-time values usually at least three times greater than daytime values
  • pineal melatonin production is powerfully suppressed by light acting through the retinohypothalamic tract
  • in addition to light, and consequently seasonal affects, pineal melatonin secretion can also be influenced by endogenous factors including sex, age and pubertal stage
• melatonin is sometimes used in the treatment of paediatric sleep disorder - melatonin can effect the circadian system, and shift the sleep-wake cycle; and that there are situations in which this can be desirable (2): (3)
  • paediatric insomnia is a widespread problem, with an overall prevalence of 1% to 6%, but rising to 50% to 75% in children with neurodevelopmental or psychiatric comorbidities, and specifically ASD and neurogenetic disorders (e.g. Rett syndrome, Tuberous Sclerosis, Smith-Magenis syndrome and Angelman syndrome) (1)
    
    
  • in a study by Gringras et al, children with neurodevelopmental disorders and sleep problems, immediate-release melatonin was found to be more effective than placebo in increasing total sleep time and reducing sleep onset latency
    • adverse effects were few, mild in degree, and distributed equally between the two groups with no increase in, or new onset of, epileptic seizures
    • total sleep time increased by an average of 23 minutes and sleep onset latency reduced by an average of 38 minutes
    • the study authors concluded that "..children gained little additional sleep on melatonin; though they fell asleep significantly faster, waking times became earlier. Child behaviour and family functioning outcomes did not significantly improve. Melatonin was tolerable over this three month period. Comparisons with slow release melatonin preparations or melatonin analogues are required..."
      
      
  • the same lead author (Gringras P) undertook a 13-week study in which 125 children with insomnia and ASD (96.8%)/ neurogenetic disorders (3.2% SMS) were randomised to prolonged-release melatonin, PRM, (2mg -5mg) or placebo. After 13 weeks of treatment with PRM, children slept on average 57.5 minutes more per night and went to sleep on average 39.6 minutes earlier. Importantly, and unlike IR melatonin, PRM did not result in earlier waking
    • the study authors concluded that as PRM was ".. efficacious and safe for treatment of insomnia in children and adolescents with ASD with/without ADHD and NGD. The acceptability of this pediatric formulation in a population who usually experience significant difficulties in swallowing was remarkably high.."
      
      
  • a meta-synthesis of published studies on the effectiveness of sleep-based interventions for children with ASD, concluded that melatonin, behavioural interventions and parent education/interventions appear the most effective at ameliorating multiple domains of sleep problems (4)
    
    
• institutionalized children, and those with severe learning disorders, often have irregular sleep-wake patterns, and there is evidence that melatonin can result in improvement to the benefit of both the child and the carers. The affected children can become less irritable, calmer, happier, and content. Also they may socialize better and become more attentive, with an improvement in their cognitive abilities
• another group of children who are likely to suffer from disturbed sleep are those who are visually handicapped. Melatonin given in the evening can improve their sleep patterns, and often their performance
  
  
• all forms of sleep disorders are more common in children with learning and behavioural difficulties, autism, Attention Deficit Hyperactivity Disorder (ADHD) and sensory impairments (particularly visual). Although behavioural interventions should be the primary intervention and has robust evidence base, exogenous melatonin is the 'first-line' medication prescribed for childhood insomnia and sleep disorders (5)
  
  
• the British Association for Psychopharmacology have noted (6):
  • "... paediatric mini-pill sustained release melatonin at a dose of 2–10 mg was well-tolerated, efficacious and safe compared to placebo for treatment of insomnia in children with autistic spectrum disorder (ASD)... showed clinically meaningful improvements in total sleep time (TST), duration of uninterrupted sleep (longest sleep episode) and sleep latency (SL) with corresponding behavioural improvements for the children, and improved quality of life measures in their parents over a two-year period..."
  • and have recommended (6):
    • Behavioural strategies should be tried first in children with disturbed sleep
    • Melatonin improves sleep in children with autistic spectrum disorder (ASD)
    • Melatonin administration can be used to advance sleep onset to normal values in children with ADHD who are not on stimulant medication
      

The Summary of Products Characteristics (SPC) must be consulted before prescribing melatonin.

Reference:

1. Lerchi A, Reiter RJ.Treatment of sleep disorders with melatonin BMJ 2012;345:e6968
2. Gringras P et al. Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial BMJ 2012;345:e6664
3. Gringras P et al. Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children With Autism Spectrum Disorder. J Am Acad Child Adolesc Psychiatry. 2017 Nov;56(11):948-957
4. Cuomo BM et al. Effectiveness of sleep-based interventions for children with autism spectrum disorder: a meta-synthesis. Pharmacotherapy 2017; 37: 555-578
5. NHS Black Country Foundation Trust. CAMHS - Melatonin Prescribing (Accessed 22/4/2020)
6. Wilson S et al. British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders: An update. J Psychopharmacol. 2019 Aug;33(8):923-947