Melatonin works better than you'd think in kids

Author: Omar Mesarwi, MD
Date: April 3, 2019

Melatonin is the neurohormone that serves as the major regulator of the circadian drive for wakefulness. It’s released primarily by the pineal gland, resulting from light stimulus to the retina, via the retinohypothalamic tract, the suprachiasmatic nucleus, and the superior cervical ganglion. Melatonin isn’t regulated by the FDA; instead it’s considered a supplement. It is probably one of the most widely used substances for sleep in the United States, because it does not require a prescription, and because it is perceived to be relatively benign. However, a major drawback is that the available data suggest that melatonin isn’t all that effective either. One recent meta-analysis showed that melatonin reduced sleep latency by around 7 minutes relative to placebo, and increased total sleep time by around 8 minutes. In fact, when only studies that considered objective measures of sleep time were analyzed, melatonin had no effect on total sleep time at all (mean difference 0.33 minutes, p=0.95!). Not exactly much to brag about. For the sake of comparison, another meta-analysis regarding the efficacy of so-called Z-drugs (eszopiclone, zolpidem, and zaleplon, the non-benzodiazopene hypnotics) showed a reduction in sleep latency of around 33 minutes. Interestingly, in that analysis, the authors noted that placebo reduced sleep latency by 11 minutes. It’s hard to compare across analyses, but with the available evidence, melatonin hardly looks like a winner.

So here comes a new meta-analysis from Wei and colleagues in Sleep Medicine, this time looking at the impact of melatonin in children and adolescents. This is an intriguing group to investigate, since most practitioners are reluctant to use hypnotics in kids. As the authors note too, sleep loss in kids is associated with cognitive and behavioral issues that can have long-term ramifications. Although chronotherapy, light therapy, and sleep hygiene are often used to treat insomnia in children, there is very little evidence to support any of these approaches. There have been mixed data about the efficacy of melatonin in children, and so the authors sought to apply a random-effects model to determine mean differences between melatonin and placebo groups in a meta-analysis of available studies.

In the end, seven studies of the 596 evaluated were included in the analysis. In total, there were 387 participants (mean study size of 55 participants). Six of the seven studies enrolled children with a mean age of 9 years, and the other study enrolled adolescents. For unclear reasons, more than two thirds of the participants were boys, and most of the studies enrolled kids with comorbid ADHD. The melatonin dose varied from 1-6 mg nightly, and for the most part it was administered before 7:30 pm. Treatment duration was 1-4 weeks in the seven studies (mean 2.7 weeks). Four of the studies used actigraphy to determine sleep onset and total sleep time, and the authors used these objective measures when possible.

The authors found that sleep onset time (the primary outcome in the meta-analysis) was advanced by a little over 37 minutes in the melatonin group relative to placebo. Concomitantly, dim light melatonin onset (a measure of circadian timing) was advanced by just over 49 minutes. Total sleep time increased by almost 23 minutes.

These sound like pretty low numbers, and again, comparison between trials or analyses is fraught with uncertainty, but if you look just for a moment at the raw numbers in comparison with some of the other drugs we use routinely for sleep, this looks like a huge winner. Why would we expect melatonin to be so effective in the pediatric population? Perhaps the study participants were enriched for efficacy of melatonin by virtue of so many of them having comorbid ADHD, or perhaps the prevalence of delayed sleep phase is higher in this group relative to the adults studied. After all, most of the benefit of melatonin here seemed to come due to advanced sleep onset time. Of course, the usual cautions apply: There may be a publication bias in the included studies, the overall numbers were relatively low, demographics aren’t considered in this meta-analysis, and recording of sleep parameters wasn’t uniform.

Pediatric sleep physicians, any comments? Will this change how you approach insomnia in your patients diagnosed with ADHD? Or in other patients?