Justification for the appraisal: there are now sufficient studies published on the efficacy in chronic insomnia (onset problems or other insomnia related problems) in adults and children with different type of chronic conditions (neurodevelopmental or psychiatric disorders, altered cognition…), but until now there are only few studies on the efficacy of exogenous melatonin in healthy children, for the indication of chronic onset insomnia / DSPS. Despite the lack of information the use of melatonin is continuously increasing, even in children. There is now a need to evaluate the efficacy and the proper role of melatonin for this type of sleep disorders in pediatric population.
Validity and scientific rigor: despite the fact that the 4 pRTCs included did not use DSPD as an inclusion criterion, most of the participants however, probably met the definition requirements of this circadian rhythm disorder. In the RCT from Van Geijlswijk, however, the term used in the title properly reflected the inclusion criteria of the study.
For the MA only were analyzed those studies in which it was specifically reported the timing of melatonin administration in relationship to the circadian clock. Some studies excluded could still be valid and might have offered useful information.
Two of the 4 pRCTs in the MA where studies in patients with chronic SOI + comorbid ADHD. Also in the other 2 pRCTs3-4 were enrolled participants with high percentages of ADHD: around 27% and 50% respectively.
The MA did not include the search strategy and the descriptors used. There were important limitations of the MA: the language restriction to English and no attempt to localize unpublished researches.
The number of participants children involved in the MA3-6 was a rather low one (226 patients). Likewise, the number of patients in the RTC of the second paper was also low.
Three out of the 4 pRTCs were performed by the same research group and the first author of 2 of them3-4 was, actually, one of the authors of the meta-analysis. This might indicate a sampling bias.
Although the choice of studies on sleep parameters could be an adequate choice for the initial investigation on the effect of melatonin versus placebo, they still could be considered as subrogate outcomes. The true clinical important effects to investigate should include the investigation of the impact of a better sleeping expressed by improvements in wake hours (cognition, learning progress and school grades; attention; behavior, the general quality of life, disappearance of day-time sleepiness…)
In the 2 RCTs from Smits, that included significantly higher numbers of participants diagnosed with ADHD (most of them medicated with stimulant drugs), it might have been advisable to do a subgroup analysis.
Especially in the RCT of Smits 2003(4) the lack of homogeneity of the groups raises doubt for the generalization of their results. The difference in the percentages of participants with methylphenidate, more than twice higher in the placebo group (PG) than in the melatonin group (MG), could have altered the results, overestimating the effect of melatonin. Something that was truly remarkable is that, in the studies in children with ADHD, the rates of some comorbidities was very high, and because of this, the samples were no representative of the children with ADHD. In the MA, the dose were collected and reported, but, for the analysis of effects, dosages were not accounted for, by mean of a separated assessment.
Assessments of the homogeneity, or a sensibility analysis between studies in the MA, were not reported.
Clinical Importance: children given melatonin, in comparison with those that received placebo, advanced the mean clock hour of sleep onset by 26.9-63 minutes and decreased sleep-onset latency by 8-42 minutes.
However, this relatively small change in clock-hour sleep onset achieved raises questions about its clinical significance.
The two clinically useful sleep parameters are the SO/SOT and the SOL, and only those two are considered valid to answer the clinical question. The DLMO is considered as a laboratory parameter, and the WUT and TST parameters are measures depending more than on the medication, on other external factors, like rigid schedules setting the time to get up.
The results also demonstrated that the beneficial effect of melatonin, in terms of sleep improvements, disappear after finishing short-term periods of treatments (1-4 weeks).
Those results could also be achieved with the usual non pharmacologic measures.
In most cases, the RTCs did not reported in the papers the numerical data of delays in SO time of the participants (only in the RTC from Weiss, a mean of 91.7 minutes of SOL delay, is reported), but presumably, the average otherwise healthy child or adolescent with DSPD / chronic SOI, consulting for these problems, usually shows delays of ≥ 2-3 hours of the SOT during school days. In this sense, melatonin seems to reach a profile, more like an optional “little help”, than like the “ultimate solution” for the problem. In fact, some RTCs even showed a bigger effect for sleep hygiene than for the melatonin intervention. But, on the other hand, the size of the effect showed (even if no more than, for instance, 30 minutes) could still matter a lot for the specific situation of some children.
Clinical Applicability: many of the unanswered questions about exogenous melatonin as a medication are related to long-term treatments (AE, duration of the effect, etc.), but in short-term periods of treatment there are, also, some unsolved doubts:
The demonstrated effect of melatonin cannot be sustained over time. It seems that the effect wears off when finishing short periods of treatment (< 1 month)2 A recent study (not placebo-controlled) finds that again7.
In the MA is hypothesized that the right timing of administration of melatonin (the right clock TOA) correlates whit a better effect of the medication in terms of sleep parameters (but not demonstrated). In the RTC from Van Geijlswijk, this correlation is demonstrated. As a consequence, the authors advocated for an early administration of the medication. This proposal of administration in the early evening hours raises concerns about the possible interference of the soporific effects of melatonin with the capacity of concentration of children and adolescents in the late evening hours, when many children are expected to dedicate to self-learning activities and homework. This is not, until now, ruled out. In children diagnosed of ADHD and treatment with methylphenidate, this advance postulated in the TOA could result in overlapping of the time of action of both medications.
Another unanswered question is if melatonin achieves the same size of the effect in children/adolescents with small delays, than in those with larger delays. To shed light on this point could imply very important consequences, because we really need to know how melatonin does in the subgroup of patients with larger delays (children whit “the real problem”), since these are the patients that are to be visiting our offices asking for medications. In the pediatric RCTs appraised here, the inclusion criteria placed the cutoff point in levels of delays of >30 minutes, but, do those patients who advanced their SOT with correctly applied non-pharmacologic strategies, (but still get asleep 30 minutes later than desired) have, really, a problem that needs to be treated with drugs?
Further RCTs need to investigate the performance of melatonin in children with real large delays (by placing the cutoff point of the inclusion criteria somewhere higher, or by doing a subgroup analysis).
The diagnosis of DSPD remains a point of discussion. The fact that its description includes an external factor, not depending of the individual and having to do with environmental exigencies (“inability to fall asleep at times established, so as to adapt to societal demands, and difficulty to wake early in the morning”) leads to controversy if that represents a real medical condition, based on a biological alteration, or could only be the manifestation of the difficulty of, otherwise perfectly healthy children, to catch up with the body’s sleep requirements under imposed conditions of chronic sleep deprivation. In the puberty there is a physiological phase delay, and lifestyle-related phase delays are also common during adolescence.
In the published literature, the estimate prevalence of children (>6 years of age) and adolescents with problems to go to bed at expected time vary, and could be as higher as 27 %, presenting SOL > 30 minutes at least 11% of them8. Other authors report estimations around 7-10%9. The relative lack of data reported and the discrepancy in the numbers of adolescents and SOI probably reflects the confusion and overlapping of different problems and concepts (simple chronic SOI, physiological phase delay of adolescents, true chronobiologic DSPD, imposed sleep deprivation…).
There is a need of further rigorously designed and well-performed trials, conducted in healthy children, without any medications, and with adequate sample sizes. Thus, there could be solved the many unanswered questions about the use of melatonin in healthy children: which children could get benefits, how long could those treatment be maintained, what would be the right time of administration or the optimal dosage, etc.
The results support the possibility of using melatonin, as a complementary therapeutic tool, in school aged children and adolescents with primary chronic SOI / DSPD. The possibility of its use could arise in some cases, for a short term period of less than a month, and provided that the usual non-pharmacologic measures, correctly applied, had been insufficient. It is mandatory to inform about the relatively small size of effect demonstrated. This approach should restrict the use of melatonin, for otherwise healthy children and adolescents with this kind of sleep problems, to a very specific subset of them. The generalized use of melatonin for these patients seems to be unjustified. Melatonin is a hormone of multisystemic effects; it is advisable that this medication be classed as a prescription drug of mandatory indication by physicians. The treatments with melatonin should be kept under strict control and supervision by primary care pediatricians and medical experts of specialties related with sleep.