Original Article
Prolonged-Release Melatonin for Children With Neurodevelopmental Disorders

https://doi.org/10.1016/j.pediatrneurol.2011.02.001Get rights and content

Abstract

Previous studies demonstrated the efficacy and safety of prolonged-release melatonin in children and adolescents with neurodevelopmental and behavioral disorders. The long-term effectiveness and safety of prolonged-release melatonin treatment were assessed in 88 children (42 girls and 46 boys) with neurodevelopmental disorders. These patients participated in a compassionate-use program with the drug Circadin (2 mg; Neurim Pharmaceuticals, Tel Aviv, Israel) in France, and received treatment in the context of regular care by a specialized physician. The study involved a structured questionnaire for the parents, comprising a combination of multiple-choice and numeric questions addressing sleep onset/offset, sleep quality problems, and mood. The dose of melatonin ranged from 4-6 mg, and treatment duration ranged from 6-72 months. Within 3 months, sleep latency with prolonged-release melatonin decreased by 44.0% (P < 0.001), sleep duration increased by 10.1% (P < 0.001), the number of awakenings decreased by 75% (P < 0.001), and sleep quality improved by 75%, compared with baseline (P < 0.001). No serious adverse events or treatment-related comorbidities were reported. Prolonged-release melatonin remains a safe, effective therapy for the long-term treatment of sleep disorders in children with neurodevelopmental disorders.

Introduction

Sleep disturbances are reported in 75-80% of children with autism spectrum disorder, psychomotor retardation, or other developmental delays, and are among the most common complaints in this population [1], [2], [3]. Sleep disorders exert a profound impact on the physical and mental health of a child and create distress for the families of these children [4]. Long-term sleep disorders and the resulting day and night care difficulties are among the main factors affecting parental decisions on whether and when to institutionalize their child as they grow older.

Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone involved in the regulation of the sleep-wake cycle [5]. It is produced in the pineal gland during the night. Its levels begin to rise at nightfall, with peak serum concentrations typically occurring between 2-4 AM in adults. The secretion of melatonin is inhibited by light, and its level during daytime is minimal.

Melatonin is hepatically metabolized, with 80-90% converted to 6-sulphatoxymelatonin, an inactive compound excreted in urine. The average elimination half-life of melatonin in adults is 20-50 minutes. After an oral administration of exogenous fast-release melatonin, peak concentrations are achieved within 60 minutes, and decline rapidly occurs afterward [6]. The administration of exogenous melatonin does not appear to affect endogenous production or secretion.

Melatonin promotes sleep through its regulation of the activity of the suprachiasmatic nucleus [7] and other sleep-related brain networks, such as the precuneus in the rostromedial aspect of the occipital cortex [8]. A growing body of evidence on abnormal melatonin secretion in children with neurodevelopmental disorders has prompted the use of melatonin to treat sleep disorders in these populations [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19].

Several exploratory studies and case reports have led to the strong consensus among researchers that exogenous melatonin is beneficial for treating chronic sleep disturbances in children with neurodevelopmental and neuropsychiatric difficulties [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19]. Headache, excessive sedation, and transient depression were reported, most often at doses greater than 8 mg/day. Isolated cases of rash, psychotic episodes, gynecomastia, and autoimmune hepatitis were also reported after the use of melatonin, but in none of these cases was melatonin identified as the cause [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19]. In most instances, fast-release melatonin preparations available as food supplements in the United States were used. Fast-release melatonin facilitates sleep but does not work throughout the night, and midnight awakenings remain frequent in these diseases. Parents of children with sleep maintenance difficulties expressed their wish for a commercially available, prolonged-release melatonin product that would promote sleep for 8-10 hours [15], [19], [20].

Circadin (Neurim Pharmaceuticals, Tel Aviv, Israel) is a 2 mg prolonged-release melatonin formulation that mimics the physiologic secretion profile of melatonin, and can offer more sustained blood levels of melatonin through the night. After an oral administration of prolonged-release melatonin, melatonin levels rapidly peaked, were maintained for 3-4 hours, and slowly decreased, thus working throughout the night. Circadin is the first fully developed melatonin pharmaceutical product, and was approved for marketing in the European Union for the treatment of primary insomnia in patients aged 55 years and older in 2007 [21], [22].

Several studies involved the use of this drug for sleep-wake cycle disturbances in children with neurodevelopmental disabilities [18], [19]. Initially, a randomized, double-blinded, crossover design was used in 16 children, comparing the effectiveness of fast-release and prolonged-release melatonin.

The average final prolonged-release dose of melatonin in patients was 5.7 mg (range, 2-12 mg). In other patients, prolonged-release melatonin was studied on a clinical basis. The effectiveness of treatment was assessed by sleep charts and clinical follow-up. Emphasis was placed on the judgment of the parents, who received guidance from physicians. These studies indicated that fast-release melatonin was most effective when only delayed sleep onset was present, but the prolonged-release formulation was more useful for sleep maintenance.

In cases of Smith-Magenis syndrome, a genetic disorder involving mental retardation and extremely severe sleep disorder, patients manifest a severe phase shift of their circadian melatonin rhythm with the diurnal secretion of this hormone. These patients thus received a β-blocker (acebutolol, 10 mg/kg/day) in a single morning dose to reduce the production of this hormone during the day, and prolonged-release melatonin (Circadin®, 6 mg/day) in a single evening dose to restore circadian timing. Adding Circadin in the evening reset the patients’ circadian rhythm: plasma melatonin remained low during the day, exogenous melatonin rose at 10 PM and remained high until 2 AM, and decreased until 6 AM. Actigraph recordings were correlated with sleep diaries, and indicated that the mean onset of sleep was delayed; the children slept all night, with a mean sleep duration of 10 hours. A constant improvement of the patients’ sleep disorders was observed, with no treatment-related adverse events [11], [12], [13].

Little evidence is available regarding melatonin’s long-term safety profile in children. Most studies reported on its use in children for a short period of time (up to 3 months).

Here, we assessed the long-term (up to 6 years) effectiveness and safety of this drug in children with neurodevelopmental disorders, including Smith-Magenis syndrome.

Section snippets

Patients and Methods

The participants comprised 88 children (42 girls and 46 boys) who were followed in a neurodevelopmental clinic specializing in genetic and neurodevelopmental disorders. They presented with Smith-Magenis syndrome (47 patients), mental retardation (14 patients), encephalopathy (seven patients), autism (seven patients), Angelman syndrome (five patients) , Rett syndrome (five patients), Bourneville syndrome (one patient), blindness (one patient), and delayed sleep-phase syndrome (one patient),

Results

Eighty-eight parents gave permission for their children to participate in this study. The follow-up time (mean ± S.D.) of this study was 33.5 ± 21.2 months. The mean age (± S.D.) of patients at the initiation of treatment with prolonged-release melatonin was 10.2 ± 4.4 years (range, 5-20 years).

Sixty-two (70.5%) children still used melatonin daily at the time of follow-up. The duration of melatonin use ranged from 6-72 months (mean ± S.D., 39.23 ± 21.33 months). Twenty-six (29.5%) children

Discussion

This retrospective study indicates the long-term effectiveness of prolonged-release melatonin at a maximal dose of 6 mg in children (aged 5-15 years) with different neurodevelopmental pathologies. Evaluated on an open-label basis in a clinical setting, treatment gains were maintained for up to 72 months of follow-up. The beneficial effects of prolonged-release melatonin treatment on the initiation, duration, and quality of sleep, as reported by the parents in a 3-month follow-up, further

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