Review articleCurrent role of melatonin in pediatric neurology: Clinical recommendations
Introduction
Melatonin is an endogenously produced indoleamine secreted by the pineal gland. It is usually secreted during darkness and its secretion is suppressed by light. It plays a key role in regulating the circadian rhythm.1, 2 Melatonin has many other biological functions including chronobiotic and antioxidant properties, anti-inflammatory effects, and free radical scavenging.3 It is critically involved in early development through its direct effects on placenta, developing neurons and glia, and its role in the ontogenetic establishment of diurnal rhythms.4, 5 Furthermore melatonin regulates the vigilance states depending on the activated melatonin receptors (MT1, MT2 or both); MT2 and MT1 receptors are mainly involved in NREM and REM sleep, respectively.6
Several studies have demonstrated the key chronobiotic role of melatonin as a modulator of the sleep–wake rhythm; it has both chronobiotic and hypnotic properties7 that influence circadian rhythmicity and affect circadian rhythm sleep disorders.8, 9, 10 Because of these strong chronobiotic and hypnotic properties, melatonin can improve sleep–wake rhythm disturbances and decrease sleep latency in children with sleep disorders, when it is administered at the right time and in the right dose.7, 9, 10, 11, 12 As a result, it is one of the most commonly used drugs by pediatricians for infants, children and adolescents with sleep problems.13, 14, 15, 16 A recent study carried out in Norway showed that hypnotic drug use in young people 0–17 years old increased during the period 2004–2011, from 8.9 to 12.3 per 1000, mainly owing to doubling of melatonin use. The hypnotic drug use peaked at 15 per 1000 among those aged 1–2 years and melatonin use increased steadily from 6 to 12 years of age. Summarising the results of this study, the authors reported that melatonin was dispensed more frequently than any of the other hypnotic drugs.16
Melatonin is prescribed by pediatricians mainly for sleep onset insomnia (89%), delayed sleep phase syndrome (66%) and night-time awakenings (30%). It is prescribed both for typically-developing children and for children with developmental disorders, including autism, developmental delay, ADHD, and behavioral disorders.17 Although melatonin is widely used in children and is currently recommended by many practitioners as a ‘‘natural sleeping aid’’ due to its endogenous origin,17 there are no clinical guidelines on how to prescribe melatonin in children with different neurological disorders.
A European consensus conference was held in Rome on October 4th 2014 with the aims of assessing the current role of melatonin in childhood sleep disturbances and answering some key questions, including those relating to the correct dosage in infants, children and adolescents, timing of administration, duration of the treatment, benefits and pitfalls of immediate compared to controlled release, and predictors of response to melatonin treatment. This paper reports the main points discussed at this conference, starting with the physiology and pharmacokinetics of melatonin, followed by a review of the use of melatonin in the most relevant neuropsychiatric disorders based on meta-analyses/systematic reviews or individual studies. Finally, we provide consensus recommendations for the use of melatonin in both typically developing children and those with neuropsychiatric disorders in daily clinical practice.
Section snippets
Physiology
Night-time melatonin production during pregnancy increases after 24 weeks gestation until term. The fetus receives melatonin by rapid trans-placental transfer depending on maternal circadian secretion.18 In 1997 Sadeh studied 20 normal, healthy infants for 1 week with actigraphy and determined the levels of 6-sulphatoxymelatonin (aMT6s), a melatonin metabolite.19 He identified two groups of infants: 1) infants with “mature” secretion patterns (rise of aMT6s during the evening hours and
Pharmacokinetics
As an exogenous compound, melatonin advances sleep onset in patients with circadian rhythm sleep disorders i.e. delayed sleep phase disorder, improving health status and decreasing parental stress.7, 9, 27, 28 Long term treatment is usually needed.29, 30
Melatonin is a peculiar drug because timing of its administration plays a critical role in the results of treatment. According to the melatonin phase-response curve of 0.5 mg melatonin in adults, phase advances occur with from ±8 h before DLMO
Delayed sleep phase syndrome and chronic sleep onset insomnia
Delayed sleep phase syndrome (DSPS) is a circadian rhythm sleep disorder characterized by a rigid delay in the timing of the major sleep period in relation to desired sleep–wake times. It is associated with a delayed 24-h melatonin rhythm, possibly linked to a PER3 polymorphism.37, 38, 39 The etiology is likely to be heterogeneous, including delayed circadian timing, longer than normal circadian rhythm period, slower accumulation in homeostatic sleep drive, increased sensitivity to
Attention-deficit/hyperactivity disorder (ADHD)
As many as 70% of children with ADHD have been reported as having mild to severe sleep problems. The most recent meta-analysis of sleep disturbances in ADHD, focused on children and adolescents, found significantly more sleep problems in children with ADHD than a normal comparison group, based upon subjectively-rated sleep items, including bedtime resistance, sleep onset difficulties, night awakenings, difficulties with morning awakenings, sleep disordered breathing, and daytime sleepiness.50
Epilepsy
Because a high proportion of children with neurodevelopmental disorders have sleep problems and either have or develop epilepsy, there is great interest in determining whether melatonin is liable to exacerbate or precipitate seizures. The increased prevalence of sleep disorders in children with NDD has been discussed earlier. The prevalence of epilepsy in NDD depends on the type of the disorder and the severity of any intellectual disability. For example, in ASD, the prevalence of epilepsy is
Neuroprotective effects of melatonin
Birth asphyxia in term newborn infants remains a significant problem throughout the world, contributing to 510,000–717,000 neonatal deaths, 1.15 million new cases of neonatal encephalopathy and 413,000 impaired survivors,98 which may suffer from long-term neurological consequences such as cerebral palsy, mental retardation and epilepsy. To date, therapeutic hypothermia is the only clinical intervention that has shown to be effective in reducing brain damage in asphyxiated babies; however
Melatonin as pre-medication for neurologic diagnostic procedures
Melatonin has been used as a sleep inducing agent in neurophysiological and neuroimaging procedures in child neurology. Obtaining sleep to record EEG in childhood is of major importance because sleep can activate epileptiform abnormalities, thus helping clinicians to achieve a more accurate electroclinical assessment.105 However, sleep deprivation, which is usually necessary to make the child fall asleep in the EEG laboratory, can be difficult and burdensome for the family, especially in the
Adverse effects of melatonin
No serious safety concerns have been attributed to melatonin use in children. Systematic reviews showed that for sleep disorders such as jet lag and shift work, melatonin appears to be is safe for short-term and long-term use.42, 49 Rossignol and Frye (2011) stated that no adverse effects were reported with the use of melatonin in children with ASD in 7 of the 12 studies included in their meta-analysis.67
The most frequently reported side effects associated with melatonin use in children include
Clinical recommendations
As evident from the previous sections, the dose, timing and modalities of administration of melatonin vary considerably across studies. Table 2 presents the consensus of the authors regarding the use of melatonin in infants and children with sleep–wake rhythm disorders or sleep onset insomnia. It must be emphasized that these represent general recommendations that need to be tailored to each individual.
So far, the best evidence for the indication of melatonin treatment in children is for
Conclusions and future directions
Melatonin can be effective not only for primary sleep disorders but also for sleep disorders associated with several neurological conditions. Controlled studies on melatonin for sleep disturbance in children are needed since melatonin is very commonly prescribed in infants, children and adolescents, and there is a lack of certainty about dosing regimens. The dose of melatonin should be individualized according to multiple factors, including not only the severity and type of sleep problem, but
Conflict of interest
None.
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