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Authors' conclusions: melatonin demonstrated efficacy (sleep parameters) in school aged children and adolescents with delayed sleep phase disorders: advancing sleep onset time, shortening latencies, and others. An earlier time of administration could increase the effect. The adverse events rates were low (none serious). Results in waking hours (cognition, general health, mood…): few improvements.
Reviewers' commentary: the results evidenced that melatonin did better than placebo. It could be used in selected cases of chronic sleep onset insomnia. Small benefit (doubtful clinical significance) that disappears after short-term treatment periods. Remain unproved: prolonged treatments (safety…); benefits in waking hours; recommendation of an earlier time of administration. Patients with longer times of delay: not specifically investigated.
Evidences coming from few studies of small sample sizes, most of them not from healthy children (high percentages of: ADHD, comorbidities and stimulants drugs).
Barroso Espadero D, Ugarte Libano R. Therapy with melatonin in school aged children and adolescents whit sleep onset insomnia. Evid Pediatr. 2012;8:3.
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AE: adverse effects.
DLMO: dim light melatonin onset.
DSPS/DSPD: delayed sleep phase disorder or syndrome.
MA: meta-analysis.
MD: mean differences.
MG: melatonin group.
PG: placebo group.
RCTs: clinical randomized trials.
pRCTs: pediatric RTCs.
SO: clock hour of sleep onset.
SOI: sleep onset insomnia.
SOL: sleep onset latency.
SOT: sleep onset time.
SOT: sleep onset time.
TOA: time of administration.
TST: total sleep time (amount of time between SOT and WUT).
WUT: wake-up time.
The parents of a 12 years old boy tell us that their son doesn’t fall asleep at the expected time (22:00) but around 01:00 am. He is a healthy sport boy that is getting good grades and do not have behavioral problems or significant marks in his medical history (adenoidectomy at the age of 3 years). Nothing remarkable in the physical examination: normal blood pressure, body mass index in the 45th percentile. Tanner P2-3/G3. We assessed schedules and personal/familiar habits related to sleep, sleep hygiene and activities in the last hours of the day (questionnaires and a 3 week follow-up period with sleep diaries). The child fails to get asleep when expected, but once he falls asleep he gets uninterrupted overnight sleep. He needs to get up at 6:30 am every morning (school is 70 km away from home), being somewhat sleepy in the early hours of the day (never at weekends or holidays). He spends 2 hours a day in extracurricular evening activities (including basket training 2 days a week, from 18:30 to 20:00). He spends the hours before falling asleep browsing the Internet. The parents believe that their son “needs medications to help him to fall asleep”. They heard about melatonin, did some “research” in the Internet, and found that melatonin “is being used increasingly for the insomnia in children”.
We considered, after checking over the references retrieved, that 2 papers were appropriate to answer the raised clinical question1-2.
Objective: to assess the efficacy and safety of exogenous melatonin in advancing sleep-wake rhythm in patients with delayed sleep phase disorder.
Study design: meta-analysis (MA) of controlled clinical randomized trials (RCTs).
Sources of data and bibliographic databases: PubMED, Embase and the abstracts of sleep and chronobiologic societies (1990 – September, 2009). Language restriction: English only. Reference list of the papers found were checked. The authors did not look for additional unpublished papers.
Study selection: published articles that were randomized, placebo-controlled, double-blind, clinical trials.
Inclusion criteria: eligible RCTs had to involve individuals who had DSPD / DSPS (delayed sleep phase disorder) and: a) had to compare melatonin to a placebo; b) had to report 1 or more of the following sleep parameters: dim light melatonin onset (DLMO), sleep onset time (SOT / SO), wake-up time (WUT), sleep onset latency (SOL, i.e., amount of time between lying down to sleep at light-off time, and the onset of sleep), and TST (i.e., amount of time between SOT and WUT); c) only those studies where the timing of melatonin treatment in relationship to the circadian clock was mentioned. They excluded studies in populations with other medical problems (but they did not exclude studies with patients diagnosed of ADHD).
They also excluded studies using other clinical outcomes, and studies with biochemical measurements alone.
Other interventions, like sleep hygiene, were possible, but other medications for the treatment of insomnia were not allowed. Nine studies were included out of an initial amount of 182.
Extraction and processing of data: were done by some authors and checked later by other different authors. Internal validity was evaluated with the Jadad (quick scan) and the QA scores (Down & Black checklist). The authors extracted from every paper, in addition to the type o study and number of patients in the placebo and treatment groups, data corresponding to variations after the intervention (set as endpoints) for the following sleep parameters: (DLMO), clock hour of sleep onset (SO), WUT, SOL, and TST. The mean differences (MD) and the 95% confidence intervals (95% CI) extracted for each parameter were shown in graphics in the MA. Other data selected: adverse effects, melatonin doses, duration of melatonin treatment, and time of medication administration.
The primary outcome was the measurement of changes before/after treatment (using several valid methods of measurements) of 1 or more of the above mentioned parameters. For each parameter the overall pooled mean difference, and the 95% confidence interval (95%CI) were calculated. A random-effects method was used for the pooling of results. In all cases results were considered as changes from baseline, either these results came from the parallel studies or from the crossover ones.
Assessment of the internal validity: all nine studies selected scored over the cutoff point of 3 in the Jadad scale. The mean quality score for the 9 RCTs included in the meta-analysis was 4.0 out of 5 (range 3–5) on the Jadad scale, and 26 out of 32 (range 19–31) on the Dwon and Black checklist. Punctuations in the QA score (Dwon & Black) for the pediatric studies were always ≥ 28 (range: 28-31).
Main results: five RCTs had been conducted in adults only; the other 4 were pediatric studies (pRCTs).
The 4 studies with children3-6 involved 226 patients aged 6 to 14 years. Sample sizes ranged between 19 and 105. The rates of losses in the pRTCs ranged between 0% and 5% for three of them; the other4 showed 11.4% of losses.
Four studies in adults and one pediatric study were crossover studies. The other four studies were parallel-group RCTs. In the pediatric RCT with a crossover design, the participants received melatonin / placebo for 2 ten-day periods, separated by a 5 days washout period. The 3 remaining studies in children were parallel-group RCTs, and the duration of the treatments in all three was of 4 weeks. The total amount of children whit ADHD was ≥160 out of the 226. The range of timing for the administration of the intervention was very broad, and different dosages of melatonin were used.
All the four RCTs in children found that melatonin did better than placebo.
For the combination of the pRCTs all the results were statistically significant, but for the case of the WUT parameter (for the combination of the studies in adults the results for the following parameters were statistically insignificant: WUT, SOL and TST). The average results for each parameter in the MA (combination of all the nine RCTs) were the following: DLMO: shortening of 1.18 h; SOT: shortening of 0.67 h; WUT: shortening of 0.28 h; SOL: shortening of 23.27 min, and TST: increase of 16.23 min (table 2).
Table 1. *The authors present the time period results expressed as decimal hours. Mostrar/ocultar
The analysis of the studies in children showed that melatonin treatment advanced mean clock hour of sleep onset by 38.4 minutes (95% CI: 28.8 to 59.9 minutes). Melatonin decreased sleep-onset latency by 23.27 minutes (95% CI: 4.83 – 41.72 min).
The main adverse effects (AE): headaches (6% or 7% of subjects). Other adverse events were decrease in appetite and dizziness4-5.
Conclusion of the authors of the MA: melatonin is effective in advancing sleep-wake rhythm and endogenous melatonin rhythm in delayed sleep phase disorder.
Conflict of interest / Funding: the author stated that the MA was not industry supported. The authors plead no financial conflicts of interest.
Objectives: to establish, in children with chronic sleep onset insomnia (SOI), a dose–response relationship between melatonin administration and sleep onset (SO) advance / SOL reduction.
Design: Randomized, placebo-controlled double-blind trial.
Location of the study: The Netherlands. Third level center specialized in sleep–wake disorders and disorders of the chronobiology of the sleep. Referral center placed in a hospital.
Study population: n = 72 (children with an age range of 6–12 years and chronic SOI).
The patients included were referred patients from local practices of pediatricians and psychiatrists. There was no detailed explanation on the selection procedure.
Intervention: placebo versus melatonin. Length of the treatment period: one week (RCT of parallel design).
Measurements of the outcome variables: the outcome assessed was the improvement in the SOI measured with the advances in SO, and the shortening of the SOL.
Additional information on repercussion in mood was reported.
Results: SO advanced in all three melatonin groups; the SO shift difference with placebo was: 42–56 min (p < 0.001).
SOL (difference melatonin vs. placebo): 31–42 min of shortening (35 minutes when melatonin was given 2 hours before desired bedtime), the reduction was significant with all the different doses used (p = 0.007, p = 0.001, and p < 0.001).
Drug-holiday breaks during 1 week resulted in return of the former sleep pattern in more than 90% of the users.
Conclusions of authors: the size of the effect of exogenous melatonin, advancing SO and SOL, increases with an earlier circadian TOA.
Serious short term adverse events did not occur.
Funding / Conflict of interest / Disclosure: the authors of the paper state that Pharma Nord, Denmark supplied the melatonin.
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:
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.
We recommend them to apply most of the following non pharmacologic measures: a) to avoid light exposure before going to bed [turning off bright lights, computers, TV sets, cell phones, game consoles, etc.]; b) to avoid exercise late in the evening; c) relaxation techniques before sleep time; d) to drop some non essential extracurricular activities (overscheduled); e) to avoid caffeine containing beverages in the evening and night.
Basket-ball and some of the extracurricular classes will end in the next week (school year ending). For the next year, they agree in significantly reduce the extracurricular activities, all before 19:00 h. A closer center, or an earlier scheduled starting time in the morning, could significantly change the situation. We inform the parents about the size of benefit that could be expected from the use of melatonin, about the unsolved questions, and about the fact that, currently, melatonin is not available in Spain as a prescription medication.
The parents decide that, in the current situation, they could be interested in adding an 1 month melatonin treatment period to the recommended non pharmacologic measures, if their son still fails to get asleep before 23:30 after a trial period (because now is the final exams time of the course), even if at the end of the treatment, the pretreatment situation reappears, and 30 minutes of advance could still matter, meaning an increase of 10 % in total night sleep time. We schedule the following visits.
Barroso Espadero D, Ugarte Libano R. Therapy with melatonin in school aged children and adolescents whit sleep onset insomnia. Evid Pediatr. 2012;8:3.
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