Melatonin administration for sleep disorders in traumatic brain injury: A review of the literature

Christina Barton; Christopher Falco

doi:10.4103/jisprm.JISPRM-000153

REVIEW ARTICLE

Year : 2022 | Volume : 5 | Issue : 2 | Page : 46-50

Melatonin administration for sleep disorders in traumatic brain injury: A review of the literature

Christina Barton¹, Christopher Falco²
¹ Department of Physical Medicine and Rehabilitation, The University of Texas Health Science Center John P. and Katherine G. McGovern Medical School, Texas, USA
² Department of Physical Medicine and Rehabilitation, The University of Texas Health Science Center John P. and Katherine G. McGovern Medical School, Texas, USA; TIRR Memorial Hermann Hospital Houston, Texas, USA

Date of Submission	08-Nov-2021
Date of Decision	13-Jan-2022
Date of Acceptance	25-Jan-2022
Date of Web Publication	04-Jun-2022

Correspondence Address:
Dr. Christopher Falco
The University of Texas Health Science Center, Houston John P and Katherine G McGovern Medical School, 1333 Moursund Avenue, Houston, Texas
USA

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jisprm.JISPRM-000153

Abstract

Melatonin is a neurohormone that acts at the suprachiasmatic nucleus to diminish the wake-promoting signal of the circadian clock and induce sleepiness. Exogenous melatonin is available as an over-the-counter supplement to induce sleepiness with 1.3% of adults reporting melatonin use in the past 30 days in 2012. Melatonin is also a frequently used treatment for sleep disturbances in the traumatic brain injury (TBI) population, however, evidence of melatonin efficacy for disordered sleep in this population is scarce. This article reviews the evidence regarding melatonin or melatonin receptor agonists used for sleep disorders in the TBI population. A literature search was performed using PubMed, Embase, Ovid MEDLINE, Cochrane Library, and Google Scholar. In total, four clinical randomized controlled trials were summarized and graded based on the American Academy of Neurology clinical practice guidelines. The evidence that exists suggests melatonin or melatonin receptor agonists improve some aspects of sleep in the TBI population. Additional high-quality studies investigating how melatonin affects the sleep and functional recovery of individuals with TBIs are needed.

Keywords: Melatonin, ramelteon, sleep disorder, traumatic brain injury

How to cite this article:
Barton C, Falco C. Melatonin administration for sleep disorders in traumatic brain injury: A review of the literature. J Int Soc Phys Rehabil Med 2022;5:46-50

How to cite this URL:
Barton C, Falco C. Melatonin administration for sleep disorders in traumatic brain injury: A review of the literature. J Int Soc Phys Rehabil Med [serial online] 2022 [cited 2023 May 28];5:46-50. Available from: https://www.jisprm.org/text.asp?2022/5/2/46/346569

Introduction

Disordered sleep is common after traumatic brain injury (TBI) with 30%–70% of persons with TBI reporting difficulty sleeping.^[1] The negative consequences of poor sleep in TBI populations include ongoing cognitive dysfunction, poorer rehabilitation outcomes, poorer functional status, increased anxiety, depression, and fatigue.^[1],[2] The prevalence and harmful consequences of poor sleep in TBI populations make its treatment of the utmost importance.^[3],[4] Melatonin supplementation has an excellent side effect profile,^[4],[5] is available over the counter, and has been shown to have beneficial effects such as reduced secondary injury (apoptosis, inflammation, and oxidative stress) and reduced symptoms related to impaired memory, learning, and motor function in preclinical studies in several other central nervous system disorders.^[5] Furthermore, melatonin supplementation works best when endogenous levels of melatonin are low, and studies indicate that melatonin levels after TBI may remain depressed chronically.^[5] A recent study showed a 42% decrease in overnight melatonin production in individuals with TBI compared to healthy controls.^[6]

While evidence exists supporting the use of exogenous melatonin for secondary sleep disorders,^[7] literature investigating its use for sleep disorders specifically after TBI is lacking. Previously published reviews explore the use of melatonin as therapy for TBI but do not focus on melatonin's effect on sleep, are largely limited to preclinical studies, and are generally outdated.^[5],[8] The purpose of this review is to provide an updated critical assessment of the available evidence regarding treatment of disordered sleep in the TBI population with exogenous melatonin or melatonin receptor agonists.

Methods

The following literature databases were searched initially between July 2020 and September 2020 and again in December 2021 for any new articles: PubMed, Embase, Ovid MEDLINE, Cochrane Library, and Google Scholar. The search terms used were “melatonin” or “ramelteon” and “TBI,” “concussion,” “brain injury,” “brain trauma,” or “TBI.” Studies were included in the review if they were clinical studies of participants with a confirmed TBI, assessed for sleep disorder post TBI, assessed treatment with melatonin or a melatonin receptor agonist, and included human participants. Studies were excluded if they were review articles, participants had premorbid sleep disorders, sleep disturbance was not a primary outcome measure, or participants had a significant loss of vision as a result of TBI. Titles and abstracts were screened for inclusion followed by a full-text assessment for eligibility of the remaining articles. The American Academy of Neurology (AAN) criteria were utilized to evaluate the articles.

Results

The initial search yielded 160 articles. After duplicates were removed, 121 titles and abstracts were screened for inclusion. Of the 121 records screened, 114 were excluded due to review article, lack of sleep disorder, melatonin not a pharmacologic treatment, animal studies, primary outcome measure was not sleep related, or lack of TBI. Of the seven full-text articles assessed, one randomized controlled trial (RCT) was excluded because sleep was not a primary outcome, and three case reports were excluded for the following reasons: subject with non-TBI, subject with unconfirmed TBI, and subject with bilateral vision loss. The three remaining studies were all RCTs with crossover designs. Two studies were placebo controlled, and one used a best-available-therapy control group. A repeat search for more recent articles yielded one additional RCT published in April 2021. This study is a secondary analysis of a previously published study that focused on melatonin as a treatment of persistent postconcussion symptoms (PPCS). The four studies ultimately included in this review are summarized in [Table 1].

Table 1: Characteristics and American Academy of Neurology grade of studies included in review

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Ramelteon compared to placebo

Lequerica et al. assessed the effect of the melatonin receptor agonist ramelteon on sleep and daytime functioning among individuals with TBI. The study utilized a randomized, double-blind, placebo-controlled crossover design that ran from June 2010 through June 2013. The primary outcome measures were total sleep time, sleep onset latency, and cognitive function. Actigraphy was used to measure objective total sleep time, sleep onset latency, number of awakenings, and wake time after sleep onset. A sleep log was also used to assess patient-reported bedtime, wake-up time, number of awakenings, subjective sleep quality, and levels of pain and anxiety experienced overnight. Cognitive function was assessed using the CNS Vital Signs, a computer-administered program that measures neurocognitive function across multiple domains. Participants were required to have a confirmed diagnosis of TBI at least 1 month before enrollment and a Pittsburgh Sleep Quality Index (PSQI) score greater than 5. The final total sample size for this study was 13 persons. The intervention included 1 week of baseline evaluations followed by 3 weeks of either 8 mg of ramelteon or placebo with a 2-week washout period between treatment arms. A significant increase in objective total sleep time of approximately 1 h was observed in the treatment group (approximately 470 min versus approximately 410 min in the placebo group; P = 0.007).^[1] A small but statistically significant increase of approximately 5 min in objective sleep onset latency was observed after 3 weeks of treatment with ramelteon compared to placebo, a finding not seen in previous studies. There was no significant effect on subjective total sleep time or subjective sleep onset latency. Significant improvement in cognitive function was also observed in the treatment group, specifically in the areas of executive function and in the Neurocognitive Index (a composite of multiple cognitive domains). Based on AAN criteria, this was graded a Class II level study with a major limitation being <80% completion rate.

Melatonin compared to placebo

Grima et al. investigated the efficacy of melatonin supplementation for sleep disturbance associated with TBI by conducting a randomized, double-blind, placebo-controlled crossover study from August 2011 to November 2016. The primary endpoints were sleep quality as measured by PSQI global score and sleep onset latency measured by actigraphy. Thirty-three adults with mild-to-severe TBI and PSQI score of at least 8 were included in this study. The intervention included a 2-week baseline evaluation followed by 4 weeks of 2 mg of prolonged-release melatonin or placebo with a 48-h washout period between treatment arms. They found that melatonin supplementation significantly reduced global PSQI scores (melatonin 7.68 vs. placebo 9.47; P < 0.0001). No significant effect on actigraphic sleep onset latency was noted. The secondary outcomes suggested an association between melatonin supplementation and increased sleep efficiency, increased self-reported vitality and mental health, and decreased anxiety and fatigue. No significant effect on daytime sleepiness or depression was noted. Based on AAN criteria, this study was graded as Class I and was among the stronger studies reviewed.

Melatonin compared to amitriptyline

The third study by Kemp et al. investigated the efficacy of melatonin supplementation compared to amitriptyline in treating sleep disorders post TBI. This amitriptyline-controlled crossover RCT assessed four variables using a sleep diary: sleep latency, sleep duration, sleep quality, and daytime alertness. Seven male adults recruited between January and March 2002 who experienced a TBI at least 6 months prior and subsequently developed a sleep disturbance were included in this study. No formal criteria were noted to diagnose the sleep disturbance. The intervention included a 1-month baseline evaluation followed by 1 month of 5-mg melatonin or 25-mg amitriptyline and a 2-week washout period between treatment arms. While melatonin supplementation was found to have no improvement on the tested variables using significance testing, effect sizes were calculated due to the small sample size and showed improvement in all four variables for both melatonin and amitriptyline groups compared to baseline.^[9] This was graded a Class III study as no carryover effects were examined and baseline characteristics of treatment order groups were not presented.

Melatonin compared to placebo in children with persistent postconcussion symptoms

In April 2021, Barlow et al. published a secondary analysis of the PlayGame Trial conducted between February 2014 and October 2017. The secondary analysis focused specifically on sleep disturbance rather than PPCS. The primary outcome of this randomized, double-blind, placebo-controlled study was change in sleep-related problems (SRPs) measured using the postconcussion symptom inventory (PCSI) after 2 weeks of treatment. The secondary outcomes included change in actigraphic sleep efficiency, total sleep time, sleep onset latency, and wake after sleep onset (WASO). Seventy-two youths (8–18 years of age) who suffered a mild TBI with PPCS and significant sleep disturbance (defined as a three-point or greater increase in the sleep disturbance domain of the PCSI when compared to pre-injury) were included in this analysis. Participants were randomized to placebo (n = 22), melatonin 3 mg (n = 25), or melatonin 10 mg (n = 25). The melatonin formulation was a sustained-release sublingual preparation taken one hour before night-time sleep for 28 days and continued even if symptoms resolved. SRPs decreased across all three groups, and there was a small but significant decrease with melatonin 3 mg compared to placebo (3-mg melatonin 3.7 vs. placebo 7.4; P = 0.043). Actigraphy data were available for 64 participants and found a significant increase in mean total sleep time of 43 min in the melatonin 3-mg group and 55 min in the melatonin 10-mg group (P = 0.003). There was no significant effect of the treatment group on sleep efficiency by mixed-model analysis, however, after accounting for noncompliance, melatonin 10 mg was found to have a significant effect of 7% improved sleep efficiency compared to placebo (P = 0.039).^[10] There was no significant effect of the treatment group on sleep onset latency or WASO. Based on AAN criteria, this was graded a Class I study and among the stronger studies reviewed.

Discussion

Based on these studies, exogenous melatonin or melatonin receptor agonists can improve some aspects of sleep in individuals with TBI. Two of the studies included in this review specifically investigated the effect of melatonin or melatonin receptor agonists on objective total sleep time, and both studies revealed a significant increase in this measure.^[1],[10] These findings are consistent with prior studies in the non-TBI population including a meta-analysis investigating exogenous melatonin use for secondary sleep disorders^[7] and a meta-analysis investigating exogenous melatonin use for primary sleep disorders,^[11] both of which found melatonin to improve total sleep time. Additionally, melatonin administration was found to improve overall sleep quality in one of the studies reviewed,^[2] a finding consistent with previous studies investigating the treatment of primary sleep disorders.^[11] However, while prior studies have suggested melatonin may lower sleep onset latency,^[7],[11] none of the studies in this review observed such a finding. In fact, the use of ramelteon was associated with a small but statistically significant increase in objective sleep onset latency of approximately 5 min in the study by Lequerica et al. Although it is unclear why ramelteon would have this effect on sleep onset latency, the authors note that this small increase in time to fall asleep is likely of minimal clinical significance. The study by Kemp et al. did not find any significant effect on subjective total sleep time, sleep onset latency, sleep quality, or daytime alertness, however, it should be noted that this was a particularly small study of only seven subjects, and a trend toward improvement in all four sleep variables was noted after calculating effect sizes.

An interesting secondary finding in the Lequerica et al. study was the treatment group's improvement in cognitive function on neuropsychological testing, in particular within the domain of executive function. This raises the question of whether these effects on cognitive functioning were related to improved sleep or rather an actual change in the underlying pathophysiology of the injured brain. In light of the current evidence that exists regarding the possible neuroprotective effect of melatonin,^[5] this is an important finding that warrants further investigation, especially given the challenges experienced by TBI patients with persistent executive dysfunction.

The studies in this review used several different methods for sleep detection. Three studies used both subjective and objective sleep detection methods,^[1],[2],[10] while one used only subjective methods of sleep assessment.^[9] Subjective methods such as sleep diaries and questionnaires are often thought of as unreliable, however, evidence indicates their sensitivity is often above 90% and their specificity ranges between 73% and 97.7%.^[4] Alternatively, while objective methods such as actigraphy are considered more accurate due to their high sensitivity, their specificity is between 20% and 52%.^[4] Therefore, it seems appropriate to utilize a combination of both subjective and objective methods in assessing the treatment of sleep disorders.

Although the results of these studies suggest benefit in the use of melatonin or melatonin receptor agonists in the treatment of sleep disorder after TBI, translating these findings to clinical practice is fraught with potential pitfalls. First and foremost, there is no clear evidence available regarding the optimal dosing of exogenous melatonin, not just for individuals with TBI, but in the general population as well. As a result, there are wide variations in dosing recommendations^[12] and practice patterns among providers.^[13] This is further confounded by the unregulated nature of over-the-counter medications and the potential for large discrepancies between formulations.^[14] Such a concern does not exist for ramelteon of course, however, the use of ramelteon may be limited by its cost and risk of not being covered by many insurance plans.

Limitations

This review has a few limitations worth noting. Although all RCTs, the majority of these studies include a small number of subjects. Only articles published in English or with an English translation were included in this review. Furthermore, unpublished data were not included in this review and the gray literature was not searched. Additionally, no formal guidelines for a systematic review (e.g., the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines) were followed.

Future directions

Although helpful conclusions can be drawn from this review, perhaps the primary point of emphasis from this work should be the true dearth of literature that exists regarding the administration of melatonin for the treatment of sleep disturbance after TBI. It is likely that the results of this review will not alarm anyone that regularly works with this patient population, nor would they be expected to lead to dramatic changes in clinician practice patterns. Some clinicians, however, may be surprised to know that an extensive search of the literature using the methods described above yields only four RCTs. For a medication so commonly used in this patient population to have only a handful of studies supporting its use underscores the need for additional research moving forward.

Ample opportunities exist to gain better knowledge of the potential benefits of melatonin in the TBI population. What is the optimal dosing, timing, and duration of therapy? How does an immediate-release formulation compare to extended-release? Does the early use of melatonin in acute TBI reduce sleep/wake dysfunction, and could this lead to increased cognitive functioning and overall functional gains? Shorter hospital stays? Better overall outcomes? If we can build on the studies that currently exist and strive to answer these questions and more, the closer we will be in establishing a true best practice for the use of melatonin in TBI patients.

Conclusions

Although limited to only a few small studies, the available evidence suggests that the use of melatonin or melatonin receptor agonists improves sleep quality, increases total sleep time, and potentially improves cognitive functioning in individuals with history of sleep disorder due TBI. This existing literature should be used as a foundation to inform future larger studies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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