Melatonin improves sleep in children with epilepsy: a randomized, double-blind, crossover study

Abstract

Objective: Insomnia, especially maintenance insomnia, is widely prevalent in epilepsy. Although melatonin is commonly used, limited data address its efficacy. We performed a randomized, double-blind, placebo-controlled, crossover study to identify the effects of melatonin on sleep and seizure control in children with epilepsy.

Methods: Eleven prepubertal, developmentally normal children aged 6-11 years with epilepsy were randomized by a software algorithm to receive placebo or a 9-mg sustained release (SR) melatonin formulation for four weeks, followed by a one-week washout and a four-week crossover condition. The pharmacy performed blinding; patients, parents, and study staff other than a statistician were blinded. The primary outcomes were sleep onset latency and wakefulness after sleep onset (WASO) measured on polysomnography. The secondary outcomes included seizure frequency, epileptiform spike density per hour of sleep on electroencephalogram (EEG), and reaction time (RT) measures on psychomotor vigilance task (PVT). Statistical tests appropriate for crossover designs were used for the analysis.

Results: Data were analyzed from 10 subjects who completed the study. Melatonin decreased sleep latency (mean difference, MD, of 11.4 min and p = 0.02) and WASO (MD of 22 min and p = 0.04) as compared to placebo. No worsening of spike density or seizure frequency was seen. Additionally, slow-wave sleep duration and rapid eye movement (REM) latency were increased with melatonin and REM sleep duration was decreased. These changes were statistically significant. Worsening of headache was noted in one subject with migraine on melatonin.

Conclusion: SR melatonin resulted in statistically significant decreases in sleep latency and WASO. No clear effects on seizures were observed, but the study was too small to allow any conclusions to be drawn in this regard.

Keywords: EEG spikes; Natural supplement; Seizure frequency; Sleep architecture; Sleep latency; WASO.

Conflict of interest statement

Disclosure of conflict of interest: We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Sejal V Jain is funded by CTSA and CReFF, interprets neurophysiological studies and sleep studies, participates in epilepsy monitoring unit in her clinical practice (60% effort) and bills for the procedures. She does not receive industry support.

Paul Horn has nothing to disclose.

Katherine Holland is funded by NIH grants R01 NS062756, R01 NS062806, and R01 NS065020. She does not receive industry support. She co-directs the Clinical Neurophysiology Laboratory Service through the Division of Neurology at Cincinnati Children’s Hospital, interprets neurophysiological studies, participates in epilepsy monitoring unit in her clinical practice (30% effort) and bills for the procedures.

Narong Simakajornboon is funded by NIH U01DK072493, Shriners Hospital for Children Research Grant, and Jazz Pharmaceuticals, Investigator Initiated Research on behalf of Sleep Research Network (SRN).

Dean Beebe is funded by NIH grants R01 HL092149, R01 NR012734, and UL1 RR026314, American Diabetes Association grant ADA 7-13-CE-32 and Lupus Foundation of America grant 013-02. He does not receive industry support. He directs the Neuropsychology Service through the Division of Behavioral Medicine and Clinical Psychology at Cincinnati Children’s, providing and overseeing provision of clinical services to patients with neurological conditions, including epilepsy.

Anna Byars is funded by NIH grants 1R01-NS082320-01, 1P20-NS080199-01, and 1R01-NS065840 and contract HHSN275200900018C and TS Alliance/Simonds Foundation/Novartis. She spends approximately 60% effort in clinical neuropsychological practice.

Tracy Glauser is funded by NIH grants 2U01-NS045911, U10-NS077311, R01-NS053998, R01-NS062756, R01-NS043209, R01-LM011124, and R01-NS065840. He has received consulting fees from Supernus, Sunovion, Eisai, UCB, Upsher-Smith, Lundbeck, and Questcor and is on the speaker’s bureau of Supernus. He also serves as an expert consultant for the US Department of Justice and has received compensation for work as an expert on medico-legal cases. He receives royalties from a patent license from AssureRx Health.

Copyright © 2015 Elsevier B.V. All rights reserved.

Figures

Figure 1

CONSORT diagram

Figure 2

Study design V: study visits, Diaries- Sleep diary, Seizure diary; Qs: questionnaires- BASC-PRS and SBQ and QOLCE; PVT: psychomotor vigilance task; EEG: electroencephalogram; PSG: polysomnography, SML: salivary melatonin level, Rnd: randomization, Blind: blinding

Figure 3

Mean salivary melatonin levels with standard error bars The time points for collection were 1: at the time of the admission (mean 1705), 2: 30 min before sleep onset (mean 2112) and 3: upon awakening in the morning (mean 0732)