Melatonin use for sleep disturbance in children with cerebral palsy: a narrative review
Review Article

Melatonin use for sleep disturbance in children with cerebral palsy: a narrative review

Sarah Millershaski1, Teresa Bailey1, Mariam Ischander2, Dilip R. Patel2

1Ferris State University College of Pharmacy, Big Rapids, MI, USA; 2Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI, USA

Contributions: (I) Conception and design: All authors (II) Administrative support: DR Patel; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final Approval of manuscript: All authors.

Correspondence to: Dilip R. Patel. Department of Pediatric and Adolescent Medicine, Western Michigan University Homer Stryker MD School of Medicine, 1000 Oakland Drive, Kalamazoo, MI, USA. Email: Dilip.patel@med.wmich.edu.

Background and Objective: Current evidence on melatonin use for sleep disturbances in children with cerebral palsy is, limited; however, in clinical practice, melatonin is used to treat different types of sleep disturbances in children with cerebral palsy. Studies suggest that between 20% and 80% of patients with cerebral palsy and other neurological disorders report sleep disturbances. Our objective in conducting this literature review was to identify evidence supporting the use of melatonin to treat sleep problems in children with cerebral palsy.

Methods: We conducted a literature search using online database PubMed, specifically for studies related to the use of melatonin in cerebral palsy and neurodevelopmental disabilities in children and adolescents from 1996 to 2020. Our search was limited to English language publications. In addition to PubMed, we also consulted standard textbooks. We included original research as well as systematic reviews and meta-analysis type of articles. The key search terms included cerebral palsy, sleep disorders, melatonin, and neurodevelopmental disorders.

Key Content and Findings: Studies suggest that sleep latency may be decreased in patients who have cerebral palsy. Significant limitations of the studies exist that include: cerebral palsy was not the sole disorder in the randomized controlled studies, the lack of oversight in the dietary supplement market, as well as an unestablished pediatric dose of melatonin. Overall, minimal adverse effects were reported with use of melatonin, although this could be explained by the small sample sizes. The studies propose that patients with severe brain injury, or who are prone to seizures, may experience adverse events from melatonin use.

Conclusions: Due to the variance in the product, minimal number of studies, adverse effect potential, and lack of data on doses in children, melatonin should be used with caution in children with cerebral palsy. Additional research is needed on the use of melatonin in the treatment of sleep disorders, specifically in children who have cerebral palsy.

Keywords: Cerebral palsy; melatonin; insomnia

Received: 21 October 2020; Accepted: 06 November 2020; Published: 30 November 2020.

doi: 10.21037/pm-20-92

Introduction

Cerebral palsy (CP) is reported to occur in 1.5 to 2.5 children per 1,000 live births in developed countries (1,2). Cerebral palsy (CP) is a neurological disorder that leads to varying degrees of motor dysfunction (1,2). In addition to the motor dysfunction these individuals may also have seizures, vision disorders, sleep disturbance, and intellectual disability (1,2). CP is defined as a group of disorders of movement and posture associated with a variable degree of activity limitations (2). There are many ways that a child can develop CP, with each cause centering on an injury inflicted upon the child’s developing brain in a congenital or acquired manner (2). Different types of sleep disturbances have been described in individuals with cerebral palsy (Table 1) (3-9).

Table 1

Sleep disturbances in cerebral palsy

Disorders of sleep initiation
Disorders of sleep maintenance
Sleep-wake transition disorders
Parasomnias
Obstructive sleep apnea
Central sleep apnea

A thorough clinical evaluation should be performed to identify and characterize any underlying specific cause for sleep disturbance in these patients. Sleep disturbance in patients with cerebral palsy can be attributed to multiple causes (Table 2) (3-9).

Table 2

Reasons for sleep disturbances in patients with cerebral palsy

Muscle spasms
Decreased ability to change position
Seizures
Side effects of some anti-epileptic drugs
Cortical visual impairment
Gastroesophageal reflux
Excessive salivation
Pain from unrecognized trauma such as dislocated hip
Pain from unrecognized infections such as urinary infection
Circadian rhythm disturbance

Sleep disorders in this population have numerous hypotheses, including diminished melatonin secretion, higher diurnal and lower nocturnal melatonin content, vision impairment, and severe motor impairment (3-10). Vision impairment is believed to be the most likely cause of sleep difficulty due to a disturbance of melatonin secretion (9).

We present the following article in accordance with the Narrative Review Checklist (available at http://dx.doi.org/10.21037/pm-20-92).

Objective

Although the evidence on the use of melatonin for the treatment of sleep disorders in children with cerebral palsy is limited, it is commonly used in clinical practice. Our main objective was to review relevant literature on the use of melatonin in children with cerebral palsy.

Methods

We conducted a literature search using online database PubMed, specifically for studies related to the use of melatonin in cerebral palsy and neurodevelopmental disabilities in children and adolescents from 1996 to 2020. Our search was limited to English language publications. In addition to PubMed, we also consulted standard textbooks. We included original research as well as systematic reviews and meta-analysis type of articles. The key search terms included cerebral palsy, sleep disorders, melatonin, and neurodevelopmental disorders.

Discussion

Key findings

Numerous studies have described the use of melatonin in a wide range of sleep problems in children and adolescents, including in children with neurodevelopmental disorders (11-34). Melatonin has had increasing use for sleep disorders such as jet lag, and children with attention deficit hyperactivity disorder (ADHD). In addition to these indications, melatonin has been used for sleep in children and adolescents with neurodevelopmental disabilities such as cerebral palsy and traumatic brain injuries (15-40). Melatonin (N-acetyl-5-methoxytryptamine) is a chronobiologic agent that is essential for the appropriate regulation of sleep-wake cycle in humans (41-44). Generally, melatonin secretion begins in the evening and peaks between 2 AM and 4 AM (9,41). Exposure to natural light is the most important inhibitor of melatonin secretion. Exogenous melatonin is appealing because of its rapid onset of action (30–60 minutes) and its short elimination half-life (30–50 minutes for immediate release formulations) (20).

According to Wasdell et al. (2008), approximately 13–85% of patients with cerebral palsy and other neurological injuries have a sleep disorder (34). Difficulties sleeping can lead to numerous other difficulties and strain on the child’s family. Sleep detriments are typically something that can be avoided; however, there is limited research performed on interventions for sleep disorders in children with cerebral palsy (3,6,8,35,37).

Systematic reviews, clinical reviews and meta-analysis have been published regarding the use of melatonin for impaired sleep in children with neurodevelopmental or developmental disabilities (12-22). However, the terms neurodevelopmental disabilities or developmental disabilities were used in studies to describe a variety of disabilities including cerebral palsy. Disabilities could include intellectual disability, learning disabilities, communication disorders, autism spectrum disorders, neural tube defects, cerebral palsy, and ADHD. Of the studies on the use of melatonin in children with neurodevelopmental or developmental disabilities, seven studies reported the number of patients with cerebral palsy included in their studies (14,29-31,33-35), and reviewed studies on interventions for insomnia in children with cerebral palsy or a post-traumatic brain injury (23). There are no studies or guidelines published exclusively on the use of melatonin to treat sleep disorders in children with cerebral palsy (37). Two studies had 50% or more of their subjects with a diagnosis of cerebral palsy listed in the baseline characteristics (34,35).

Wasdell et al. (2008), performed a randomized, placebo-controlled, double-blind, crossover trial to measure total sleep time in fifty children aged 2-18 with neurodevelopmental disabilities (34). In addition, the secondary outcomes included, sleep latency, sleep efficiency, and number of nighttime awakenings. Twenty-six of the participants had cerebral palsy. Participants were required to have delayed sleep phase syndrome (>30 minutes delay) or impaired sleep maintenance (>2 prolonged awakenings during the night and daytime symptoms are present). Results were observed through a caregiver-completed somnolog (sleep log), as well as nightly actigraph wrist watch readings. Subjects received 10 days of 5 mg controlled release (CR) melatonin or placebo (20–30 min before bed), followed by 3–5 days of washout, then 10 days of the other treatment. Following this, the caregivers of the subjects were made aware of the treatment and were given the option to participate in a 3-month open label study; the melatonin could be increased in 5 mg increments, with a maximum dose of 15 mg.

A 31-minute difference in total sleep time between melatonin and placebo groups was found, based on somnolog (P value <0.01). Sleep latency was also found to improve in the melatonin group, with a time difference of 32.7 minutes, P value <0.01. Actigraph reading showed improvements in total sleep time (23.7 minutes) and latency (24.3 minutes). The caregivers were surveyed via Parents’ Global Assessment Scale (PGAS) and Family Stress Scale, and reported statistically significant improvements in severity and family stress. Parents reported 0.31 score decrease in impairment and a 0.1 score decrease in family stress (P<0.01 and <0.05, respectively). Adverse events reported included seizures, flulike symptoms, agitation, and headache. Adverse events were determined to coincide with the patient’s baseline medical history and were therefore not attributed to melatonin. The study achieved an effect size of 0.4 for total sleep time (P<0.01) and 0.9 for sleep latency (P<0.01).

There have not been dosage studies of melatonin use in children; however, a review recommends 2-10 mg once daily (23,34,41). While benefit is shown in the small sample, the specific benefit in patients with cerebral palsy was not evaluated. Adverse effects were reported as minimal, although seizures were observed in eleven patients. Due to its crossover design, the 3–5-day washout period may not have been a proper length of time. Additional limitations include the subjective nature of the caregiver-completed somnolog, Global Assessment Scale, and the Family Stress Scale. Additionally, while the effect size does show a large magnitude of effect, this test was done against placebo and not a standard treatment.

Dodge et al. (2001), performed a randomized, double-blind, placebo controlled trial to observe total sleep time, sleep latency, and number of night time awakenings in 20 children age 1–12 years of age, with moderate to severe developmental disability; 15 subjects had cerebral palsy (35). Subjects received 5 mg melatonin or placebo at bedtime for 2 weeks. Results were obtained through a caregiver-conducted sleep log. The study required 30 patients to achieve a power of 74%. A significant difference in sleep latency was shown between the two groups, P<0.05 (0.7 vs. 1.2 hours). There was a difference in total sleep time from baseline in the melatonin group; however, this was not significant between the treatment and placebo groups. Adverse effects were mild, with two parents reporting moodiness or hyperactivity. Sixteen of the twenty participants were reported to have improved sleep by their parents.

Limitations included that being a supplement, the melatonin formulations may vary. This study had a small sample size and the method used for data collection was subject to the subjectivity of the caregivers. Additionally, melatonin was compared to placebo and not a standard treatment. Data on total sleep time sleep latency, and number of nighttime awakenings was not reported.

Sheldon (1998) performed an observational study in six children with severe neurological deficits and sleep disturbances given 5 mg of melatonin orally at bedtime (36). Five of the six patients did show improvements in total sleep time, and sleep latency. In four of the six patients new or increased seizure activity was observed, which returned to baseline after discontinuing the melatonin.

Besag et al. (2019) systematically reviewed adverse events associated with melatonin (0.15 to 12 mg daily) for the treatment of primary or secondary sleep disorders (38). The most commonly reported adverse events were daytime sleepiness, headache, dizziness and hypothermia; all occurring at a rate of less than 1% with the exception of daytime sleepiness (1.66%). However, the data collected suggests that melatonin is safe. Melatonin should be used with caution in patients with epilepsy and neurological deficits due to the observed seizure activity. It is unknown whether this event may be due to patient history or due to potential antiepileptic effects of melatonin. Boafo, et al. (2019) reported on the effect of melatonin on pubertal development (39). They noted that long-term, high-dose use of melatonin might contribute to delayed onset of puberty. Melatonin plays a role on the physiological progression of puberty. Melatonin receptors are present in the adrenal glands and ovaries and melatonin may suppress the gonadotropin-releasing hormone from the hypothalamus.

Jan et al. (2004) recommended that in children with multiple disabilities the dose of melatonin might start at 1–2 mg and gradually increase to optimal response (40). As the severity of the disabilities increase, so may the melatonin dose, with a maximum reported dose of 15 mg. Tolerance to melatonin does not seem to develop.

Limitations

Research is limited on the use of melatonin in the treatment of sleep disorders in children with cerebral palsy. Most studies include many other disorders in which melatonin is used. Most studies report small sample size. Another limiting factor is the variability of different formulations of melatonin being used. Melatonin products are not regulated as drugs and it is difficult to ascertain the quality of each product. No large-scale studies are available to provide guidance on the use of melatonin specifically in children with cerebral palsy.

Future research

Larger prospective studies on the use of melatonin to treat sleep disorders in children with cerebral palsy will be useful in guiding clinical decisions on such use.

Summary

While melatonin is commonly used to decrease sleep onset latency and improve sleep maintenance, there is little evidence or specific clinical guidelines on its effectiveness and recommended dose in the treatment of sleep disorders in patients with cerebral palsy. Each of the studies used a melatonin dose of 5 mg at bedtime. Quality of melatonin products in the US remains a concern. Erland et al. (2017) found more than 70% of the 31 melatonin supplements were tested outside the acceptable range of 90–110% of the label claim (42). Furthermore, serotonin was identified in eight of the supplements at levels of 1 to 75 µg. The United States Food and Drug Administration (FDA) states that the responsibility to ensure, safety, and content of the products is on the manufacturers of dietary supplements (43). The FDA does not currently approve dietary supplements for safety; it only review reports of serious adverse events. While the FDA does not currently regulate dietary supplements, such as melatonin, United States Pharmacopeia (USP) verified products provides information on the safest products to use (18). The USP aims to standardize dietary supplements and improve their quality (44) USP-verified is defined as meeting USP-NF standards for quality, purity, potency, performance, consistency, and good manufacturing practice (44).

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Pediatric Medicine. The article was sent for external peer review organized by the editorial office.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at http://dx.doi.org/10.21037/pm-20-92

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/pm-20-92).The authors have no conflict of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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doi: 10.21037/pm-20-92
Cite this article as: Millershaski S, Bailey T, Ischander M, Patel DR. Melatonin use for sleep disturbance in children with cerebral palsy: a narrative review. Pediatr Med 2020;3:26.

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