Can melatonin, a hormone activated by darkness, suppressed by light, offer long-term benefits to help improve sleep patterns in children and adolescents? The research thus far is scanty, with little evidence of melatonin’s long-term safety or efficacy in treating sleep disorders either in children or in adults. Still, melatonin continues to be used in clinical settings, gaining increased attention in the scientific as well as popular press as a treatment for various types of sleep disorders in children, adolescents and adults.
Exogenous melatonin was first synthesized over twenty years ago. Melatonin is allowed to be sold as an over-the-counter (OTC) dietary supplement in the U.S., since it is synthesized from the amino acid tryptophan which occurs naturally in certain foods, such as turkey, seeds and nuts. One of the major concerns regarding melatonin’s use is that it has not been FDA-reviewed for safety, efficacy or purity.
A 2001 study1 investigated medication use in treating pediatric insomnia among 671 primary care pediatricians in the U.S. Lead investigator Judith A. Owens, M.D., director of the Sleep Disorders Clinic, Hasbro Children’s Hospital, Providence, RI, and colleagues, found that melatonin was reportedly recommended for children and adolescents by approximately 15% of the responding physicians.
Emphasizing that their study only reflects the frequency with which certain treatments are used and not the appropriateness of specific choices in a given clinical situation, Owens and colleagues found that after antihistamines and combination sleep medication/pain relievers, melatonin was the most frequently recommended over-the-counter treatment by the respondents for pediatric insomnia. The relatively high rate of melatonin use (25% of respondents) was “largely because of the increased use in older children and adolescents,” they write. Among toddlers and pre-school children, melatonin was reportedly rarely recommended.
A study2 carried out in the UK investigating the prescribing patterns of melatonin in children by a small group of child psychiatrists found that melatonin was reported to be the third most frequently prescribed agent, after methylphenidate and risperidone, in routine clinical practice, despite its non-licensed status. According to the authors, David Bramble, M.D., of the National Health Service and Cathy Feehan, Child & Family Unit, although melatonin is recognized and recommended by the Royal College of Paediatrics and Child Health as a treatment for pediatric sleep disorders, it is available in the UK only on a “named-patient basis.”
This type of prescribing allows a doctor to prescribe an unlicensed drug to a particular named patient, when the manufacturer is prepared to release the drug on this basis, and must be arranged by the doctor on an individual basis. Guidelines for clinicians on the use of melatonin for treating common sleep disorders were drawn up by the participating clinicians, and are appended to their published study.
In both of these studies, the respondents expressed similar concerns regarding the safety and efficacy of melatonin in treating pediatric sleep disorders, emphasizing the need for empirical data to support its use on a long-term basis.
Current research
Some reports indicate that exogenous melatonin may advance or delay the sleep-wake cycle, depending on the dosage and time of day when it is taken. Melatonin has been used in clinical settings for the treatment of severe and chronic sleep-onset insomnia and night-waking problems, for sleep-phase disorders marked by disturbances in sleep biorhythms, and for sleep disturbance associated with blindness or other visual impairment.
“The use of melatonin is appropriate in children and adolescents with circadian rhythm disorders or disruption,” Owens told CABL. “Especially special needs populations like children with neurodevelopmental delays, blindness, autism spectrum disorders and adolescents with delayed sleep phase syndrome.” Although melatonin also has mild hypnotic properties, its use, she says, “should really be reserved for patients with true circadian-based disorders.”
James E. Jan, M.D., a researcher in the area of melatonin and pediatric sleep disorders, and director of the Visually Impaired Program, British Columbia’s Children’s Hospital, Vancouver, suggests that there is a strong consensus among researchers investigating the therapeutic uses of melatonin in pediatric studies, "that exogenous melatonin is beneficial for treating chronic sleep-wake cycle disorders of children who have neurodevelopmental and neuropsychiatric difficulties."3
There is increasing evidence in the literature, he says, of problematic chronic sleep-wake cycles associated with “disturbed melatonin secretion.” His conclusions are based on the results of 24 pediatric studies on melatonin carried out between 1991 and 1998, and later research investigating melatonin in the treatment of sleep disorders in tuberous sclerosis (O’Callaghan et al., 1999) and sleep disorders in Rett syndrome (Miyamoto et al., 1999).
He cautions, however, that while melatonin therapy is “remarkably safe, this treatment should still be in the hands of skilled physicians who are also familiar with the problems of the disabled.”
More recently, Dutch researcher Kristiaan B. van der Heijden, M.D., and colleagues, presented an analysis4 based on data combined from two previously published randomized, double-blind, placebo-controlled trials. The studies investigated the efficacy of pretreatment dim light melatonin onset (DLMO), a phase marker in the circadian system, in 110 Dutch children (ages 6 to 12 years) with idiopathic sleep onset insomnia (SOI). Following a 4-week treatment period of melatonin 5 mg or placebo, given at 6 or 7 pm, melatonin advanced DLMO by 1:12 h (p<0.001), sleep onset (by 0:42 min (p=0.004), and reduced sleep latency by 25 min (p=0.019).
Commenting on the study by van der Heijden and colleagues, Owens told CABL: “This is an interesting study. The implication is that melatonin worked best in those children with sleep onset insomnia who truly had a circadian phase delay as measured by the DLMO; this makes perfect sense. It also emphasized the timing of administration is critical. Third, it pointed out that we do not have good data regarding long-term safety, so caution should be exercised.”
Van der Heijden and colleagues are presently investigating the possibility of replacing melatonin after a few weeks of treatment with early morning light therapy.
Adverse events
To date, adverse events associated with melatonin have not been systematically evaluated. Some short-term side effects have included nocturnal worsening of asthma (Sutherland et al., 2003), seizures (Sheldon 1998), depression in adults (Carman et al., 1976), and effects on fertility and onset of puberty (Weaver 1997).
The National Sleep Foundation website cautions that some animal studies have shown that melatonin may increase blood pressure and possibly affect fertility. This might be risky for people with heart-related problems, hypertension and stroke, kidney disease and sleep apnea, as well as for women of child-bearing age.
According to Owens, melatonin is generally thought to be safe and well-tolerated. Nevertheless, she points out that it may interact with the hypothalamic-gonadal axis, and “abrupt withdrawal after long-term use could theoretically result in triggering precocious puberty.” She also indicates that there is the potential for melatonin to lower the seizure threshold.
Conclusions
In the absence of official recommendations on the use of treatments in pediatric insomnia, Owens and colleagues5 suggest that a child’s specific history about sleep quality be an integral part of the evaluation and care of children with chronic medical and mental health problems. Consultation with a sleep specialist, developmental behavioral pediatrician or pediatric neurologist, is often warranted.
“A very evident gap is emerging between the common, and probably growing use of melatonin on the one hand and the supportive clinical evidence and clear funding streams to support such practice on the other,” conclude Bramble and Feehan. Taken together, they say, these factors indicate a pressing need to carry out large-scale qualitative and quantitative clinical trials, focusing particularly on using “supra-physiological” doses of melatonin over long periods of time in patients with neurodisabilities.
About melatonin
Melatonin is secreted nocturnally by the pineal gland, which is located in the hypothalamus above the optic chiasm. During daylight hours when the pineal is inactive, or exposure to bright artificial indoor lighting, melatonin is suppressed. As light passes through the retina to the supra chiasmatic nucleus of the hypothalamus, plasma levels drop to where they are barely discernible during the day. With the onset of darkness, plasma levels rise sharply and drowsiness begins to set in. Thus, melatonin’s chronobiotic properties are associated with circadian rhythm which regulates sleep-wake cycles.
References:
1. Owens JA, Rosen CL, Mindell JA: Medication use in the treatment of pediatric insomnia: results of a survey of community-based pediatricians. Pediatrics 2003; 111(5):628-635.
2. Bramble D, Feehan C. Psychiatrists’ use of melatonin with children. CAMH 2005; 10(3):145-149.
3. Jan JE, Hamilton D, Seward N, et al.: Clinical trials of controlled-release melatonin in children with sleep-wake cycle disorders. J Pineal Res 2000; 29(1):34-39.
4. van der Heijden KB, Smits MG, van Someren EJW, et al.: Prediction of melatonin efficacy by pretreatment dim light melatonin onset in children with idiopathic chronic sleep onset insomnia. J Sleep Re 2005; 14(2):187-194.
5. Owens JA, Babcock D, Blumer J, et al.: The use of pharmacotherapy in the treatment of pediatric insomnia in primary care: rational approaches. a consensus meeting summary. J Clin Sleep Med 2005; 1(1):1-11.
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