Efficacy of Melatonin in Children With Postconcussive Symptoms: A Randomized Clinical Trial

Abstract

BACKGROUND: Approximately 25% of children with concussion have persistent postconcussive symptoms (PPCS) with resultant significant impacts on quality of life. Melatonin has significant neuroprotective properties, and promising preclinical data suggest its potential to improve outcomes after traumatic brain injury. We hypothesized that treatment with melatonin would result in a greater decrease in PPCS symptoms when compared with a placebo. METHODS: We conducted a randomized, double-blind trial of 3 or 10 mg of melatonin compared with a placebo (NCT01874847). We included youth (ages 8–18 years) with PPCS at 4 to 6 weeks after mild traumatic brain injury. Those with significant medical or psychiatric histories or a previous concussion within the last 3 months were excluded. The primary outcome was change in the total youth self-reported Post-Concussion Symptom Inventory score measured after 28 days of treatment. Secondary outcomes included change in health-related quality of life, cognition, and sleep. RESULTS: Ninety-nine children (mean age: 13.8 years; SD = 2.6 years; 58% girls) were randomly assigned. Symptoms improved over time with a median Post-Concussion Symptom Inventory change score of −21 (95% confidence interval [CI]: −16 to −27). There was no significant effect of melatonin when compared with a placebo in the intention-to-treat analysis (3 mg melatonin, −2 [95% CI: −13 to 6]; 10 mg melatonin, 4 [95% CI: −7 to 14]). No significant group differences in secondary outcomes were observed. Side effects were mild and similar to the placebo. CONCLUSIONS: Children with PPCS had significant impairment in their quality of life. Seventy-eight percent demonstrated significant recovery between 1 and 3 months postinjury. This clinical trial does not support the use of melatonin for the treatment of pediatric PPCS.

Evaluation of Posttraumatic Headache Phenotype and Recovery Time After Youth Concussion

“…A retrospective study of youth with PTH found that melatonin was as effective as prescription preventive medications, which may explain the recommendation of melatonin to 30% of participants. 18 Unfortunately, a 2020 randomized clinical trial of melatonin 24 did not support its use for postconcussive symptoms. It is interesting that nutraceuticals were recommended to over 37% of both groups while preventive medications were not commonly prescribed.…”

Melatonin Attenuates Sepsis-Induced Acute Lung Injury Through Improvement of Epithelial Sodium Channel-Mediated Alveolar Fluid Clearance Via Activation of SIRT1/SGK1/Nedd4-2 Signaling Pathway

“…activation of SIRT1/SGK1/Nedd4-2 signaling pathway. In addition, melatonin is safe being devoid of clinically significant side effects (Barlow et al, 2020). These studies suggest that melatonin treatment may be a potential therapy for sepsis-induced acute lung injury.…”

Neural correlates of sleep recovery following melatonin treatment for pediatric concussion: a randomized control trial

“…This study was a single-center, randomized, double-blind, placebo-controlled trial of melatonin administered in children (ages 8 to 18 years) with PPCS at 4 to 6 weeks post-injury, conducted at Alberta Children’s Hospital (NCT01874847) and has been reported previously. 25 The clinical trial was conducted in accordance with Good Clinical Practice guidelines and enrollment occurred between February 2014 and April 2017. Participants were excluded if (1) they had had a previous concussion within 3-months; (2) a Glasgow Coma Scale (GCS) scores less than 13; (3) significant medical history including any subjects taking medications that were likely to affect neuroimaging and/or sleep; and (4) inability to complete questionnaires and/or neuropsychological evaluation.…”

“…26 These domains include physical, cognitive, emotional and sleep/fatigue. As reported elsewhere, 25 participants were considered to have recovered if the post-treatment total PCSI score returned to preinjury levels or below (assessed at enrollment using pre-injury PCSI) and they had returned to normal activities.…”

“…Analyses of structural and functional MRI were performed in a randomized, double-blind, placebo-controlled clinical trial of melatonin in a pediatric PPCS cohort over a 4-week period, with neuroimaging obtained before and after treatment. 25 A whole-brain connectomics approach was employed to ascertain treatment effects in conjunction with change in sleep parameters. This study hypothesized that, following melatonin treatment, associated changes in whole-brain grey matter and functional connectivity would enhance compensatory functions of the DMN and be positively associated with improvement in sleep parameters and overall recovery.…”