Melatonin use in the Pediatric Realm

Melatonin is mainly used in as a regulatory agent, which helps to promote and regulate the sleep–wake cycle. In healthy, well-regulated individuals, melatonin is secreted in high levels at night and low levels during the day. During the last few years, the use of Melatonin has significantly increased; however, variability exists in its application and dosages. While melatonin use has been widely documented in adults for sleep regulation support, similar application in children is still being explored.

Monin and colleagues conducted a retrospective review of 516 children who received melatonin at a children’s hospital during a ten-year period. They found that the number of children given melatonin increased each year from 3.7% in 2004 to 21.9% in 2013. ¹ The most common diagnosis in the study population was developmental delay or intellectual disability (46.5%), followed by seizure disorder (37.4%). Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD) were documented in 10.3% and 10.5% of these patients respectively.¹  As the prevalence of these diagnoses increase, it becomes increasingly important to explore the role of melatonin in these populations.

Several studies have found benefit to melatonin therapy in children, with the main finding being moderate improvements in sleep. During early childhood there are significant changes in the duration and timing of sleep for most children. A study by Akacem and colleagues examined differences in circadian phase and sleep between napping and non-napping toddlers. They found that napping influenced individual variability in melatonin secretion in early childhood. For napping children, melatonin onset was 38 min later and sleep onset time was 59 min later than that of non-napping children.² The delayed bedtime of napping toddlers most likely permits later light exposure in the evening, which can contribute to a change in the melatonin secretion and circadian rhythm generation.

Melatonin also helps stimulate sleep in children with disrupted circadian rhythms, and has therefore been found to be beneficial and safe in children with ASD-associated sleep latency and maintenance. Additionally, melatonin pathways have been found to be abnormal in children with ADHD.³ It is hypothesized that children with ADHD do not have adequate melatonin production, contributing to nighttime hyperactivity.

There is still no consensus on the dosing of melatonin for children. In one review researchers found that melatonin given in doses ranging from 3mg to 6 mg/night, significantly reduced sleep onset delay and increased total sleep duration, but did not significantly impact daytime ADHD core symptoms.³ In relation to genetic syndromes, researchers found that the melatonin dose should be kept low, around 0.3 mg, especially due to the prevalence of slow metabolic breakdown found in children with Angelman syndrome.⁴ In practice, melatonin is commonly prescribed to children with neurodevelopmental disorders at doses ranging from 1 to 10 mg before bedtime, with variable efficacy reported by parents and caregivers.⁵ The sleep onset effects of oral melatonin has been reported to be around 30 min after ingestion.^{6,7,8, 9} As this information can provide guidelines in prescription, it is important to remember that dosing will be dependent upon the individual case.

Recently, researches have been exploring the use of melatonin for children who are undergoing anesthesia. One study was conducted comparing oral melatonin (0.5 mg/kg) versus another oral sedative. Researchers found that oral administration of melatonin significantly reduced doses of the anesthetic and was significantly superior to the oral medication, supporting the use of melatonin as a premedicant in pediatric surgical patients. ⁸ Another study demonstrated that premedication with oral melatonin decreases anxiety and pain levels in pediatric patients undergoing surgical procedures.⁹ Researchers hypothesized that this may even be applicable for practitioners performing minor surgeries or blood draws on pediatric patients.

The most frequently reported side effects associated with melatonin use in children include morning drowsiness, increased enuresis, headache, dizziness, diarrhea, rash, and hypothermia.^{6, 7} No study of antenatal or postnatal melatonin treatment has shown any serious side effects, nor were any serious adverse events identified in a study observing 3000 children taking melatonin for an extended period of time (six years).^{4, 10} The safety of melatonin has also been addressed in a few neonatal studies. In these small neonatal clinical studies, melatonin was found to improve outcomes in sepsis, prematurity and perinatal asphyxia.^{10, 11, 12}

Melatonin is most commonly utilized for sleep onset insomnia, delayed sleep phase syndrome, and nighttime awakenings. Furthermore, melatonin is prescribed both for normally developing children and children with developmental disorders, including autism, developmental delay, ADHD, and behavioral disorders.¹³ Of the available sleep aids in the pediatric population, melatonin is a safe and beneficial choice.

References:

1. Monin, J., and N. Wood. “Use Of Melatonin In A Tertiary Children’s Hospital: A 10 Year Review.” Journal of Paediatrics and Child Health J Paediatr Child Health 51 (2015): 9.
2. Akacem, Lameese D., Charles T. Simpkin, Mary A. Carskadon, Kenneth P. Wright, Oskar G. Jenni, Peter Achermann, and Monique K. Lebourgeois. “The Timing of the Circadian Clock and Sleep Differ between Napping and Non-Napping Toddlers.” PLoS ONE 10.4 (2015).
3. Owens J, Gruber R, Brown T, et al. Future research directions in sleep and ADHD: report of a consensus working group. J Atten Disord 2013;17:550-64. 58.
4. Buscemi N, Vandermeer B, Hooton N, et al. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. BMJ 2006;332:385–93.
5. Wasdell MB, Jan JE, Bomben MM, et al. A randomized, placebo-controlled trial of controlled release melatonin treatment of delayed sleep phase syndrome and impaired sleep maintenance in children with neurodevelopmental disabilities. J Pineal Res 2008;44:57–64.
6. Andersen IM, Kaczmarska J, McGrew SG, Malow BA. Melatonin for insomnia in children with autism spectrum disorders. J Child Neurol 2008;23:482-5.
7. Wasdell MB, Jan JE, Bomben MM, et al. A randomized, placebo-controlled trial of controlled release melatonin treatment of delayed sleep phase syndrome and impaired sleep maintenance in children with neurodevelopmental disabilities. J Pineal Res 2008;44:57-64.
8. Melatonin versus midazolam premedication in children undergoing surgery: A pilot study Andersen LP, Werner MU, Rosenberg J, Gögenur I. A systematic review of peri-operative melatonin. Anaesthesia 2014; 69: 1163–71.
9. Stefani LC, Muller S, Torres IL et al. A phase II, randomized, double-blind, placebo controlled, dose–response trial of the melatonin effect on the pain threshold of healthy subjects. PLoS ONE 2013;
10. Gitto E, Karbownik M, Reiter RJ, et al. Effects of melatonin treatment in septic newborns. Pediatr Res 2001;50:756–60.
11. Gitto E, Reiter RJ, Cordaro SP, et al. Oxidative and inflammatory parameters in respiratory distress syndrome of preterm newborns: beneficial effects of melatonin. Am J Perinatol 2004;21:209–16.
12. Fulia F, Gitto E, Cuzzocrea S, et al. Increased levels of malondialdehyde and nitrite/nitrate in the blood of asphyxiated newborns: reduction by melatonin. J Pineal Res 2001;31:343–9.
13. Heussler H, Chan P, Price AM, et al. Pharmacological and non-pharmacological management of sleep disturbance in children: an Australian paediatric research network survey. Sleep Med 2013;14:189-94