Background
Sleep disturbances are commonly reported following traumatic brain injury (TBI), occurring across the spectrum of severity and persisting years following injury [
1,
2]. Insomnia and hypersomnia are among the most prevalent sleep disorders in TBI patients [
2,
3]. Despite a high prevalence, sleep disturbances are often overlooked in the TBI population and evidence-based treatments are lacking [
3]. Consequently, untreated sleep disturbances following TBI contribute to ongoing cognitive dysfunction [
4], poorer rehabilitation outcomes [
5], lower productivity [
6] and poorer functional status [
7].
Although numerous mechanisms may contribute to sleep disturbance in TBI [
1], our research demonstrates that TBI is associated with attenuated and delayed melatonin profiles [
8,
9]. Specifically, we observed reduced evening [
9] and overnight melatonin [
8] production in TBI patients compared to age and sex matched controls, with evening melatonin production positively correlated with REM sleep [
9]. As endogenous melatonin has sleep-promoting effects and is involved in the circadian control of the sleep–wake cycle, attenuated melatonin profiles may contribute to sleep-related disturbances following TBI. Thus, restoring melatonin with supplementation may help to alleviate sleep disturbances in individuals with TBI. The aim of the current study was to evaluate the effect of melatonin supplementation (2 mg/d) on sleep quality in patients with TBI reporting sleep disturbances.
Discussion
The aim of the current study was to investigate the efficacy of melatonin in alleviating sleep disturbance in patients with TBI and insomnia. We found that melatonin improved subjective sleep quality and actigraphic sleep efficiency. Melatonin also reduced self-reported anxiety symptomatology and fatigue, whilst improving self-perceived vitality and mental functioning as assessed by the SF-36 v1 health survey. No improvement was observed for daytime sleepiness, depressive symptomatology or the six remaining SF-36 v1 domains. The present results, therefore, suggest that melatonin may be useful in treating sleep disturbances in patients with TBI.
Our study is limited by the following factors. Firstly, the sample recruited was smaller than intended. Due to the poor recruitment of stroke patients, we cannot determine whether melatonin can improve sleep following a stroke. Secondly, we did not determine endogenous melatonin concentrations and circadian phase in all participants. In a subset of TBI participants (
n = 9), we demonstrated a 42% reduction in overnight salivary melatonin production (
d = 0.87;
p = .034) and delayed circadian phase (
d = 1.23;
p = .003) relative to age and-gender matched controls with similar sleep schedules [
8]. As melatonin concentrations and phase were not captured, we are unable to determine the extent to which changes in sleep quality were mitigated by alterations in circadian phase. The aim of the present study was to demonstrate the efficacy of melatonin supplementation in TBI regardless of melatonin production and circadian phase, given that such information is not measured in the clinical setting. The current study was designed to exploit the sleep-promoting effects of melatonin, which have been previously characterised [
22], utilising a prolonged-release preparation that mimics the endogenous profile and targets sleep maintenance problems. Therefore, timing of treatment was selected to harness the sleep prompting effects, with time of administration consistent with directions for use as indicated by the manufacturer. Although additional information regarding endogenous melatonin profiles would have been useful, melatonin supplementation was found to be therapeutic. Phenotyping circadian phase (e.g., dim light melatonin onset (DLMO)) would be an important step for future studies by informing the treatment approach by targeting underlying circadian misalignment for maximal benefit. Furthermore, recent discussions regarding the therapeutic outcomes between short-acting vs. long-acting melatonin preparations [
23] suggest comparative studies are needed for evidence-based recommendations.
We implemented a 48-hour washout period between consecutive treatments. Although the terminal half-life for melatonin is relatively short (3.5–4 hours) [
24], it is possible that melatonin administered in the first treatment period could have induced a circadian phase advance, which could have persisted for up to several days in the following (placebo) treatment period [
10‐
12]. We confirmed that there were no treatment order effects across all outcome measures, and we limited most of the assessment treatment outcomes (except sleep diary and actigraphy) to the end of each treatment condition, when circadian phase would have re-established after melatonin treatment had ceased.
The rationale of using a crossover design over a parallel design was to minimise confounding covariates such as TBI characteristics and factors underpinning sleep disturbance, such as depression, anxiety and pain, which were inherently controlled by each participant serving as their own control. The implementation of a crossover design reduced the number of participants required, and it guaranteed all participants received the active treatment.
To our knowledge, only one other study has examined the therapeutic benefit of melatonin on sleep disturbance in TBI. Kemp and colleagues did not find any statistically significant benefits of melatonin on sleep latency, duration, quality or daytime alertness [
25]. However, this study was limited to seven males and melatonin was compared to amitriptyline rather than a placebo. With a rigorous study design involving a placebo control and larger sample size, we found melatonin to be efficacious in improving sleep relative to a non-active control.
Previous clinical trials have shown melatonin’s sleep-promoting properties in patients with insomnia [
16‐
19] and tetraplegia [
26]. Trials that have utilised Circadin (2 mg), the melatonin formulation used in the current study, have shown that this melatonin preparation improves sleep quality [
17‐
19] and sleep efficiency, [
16,
27] in people over the age of 55 with insomnia. A similar melatonin formulation has been shown to be effective in improving sleep quality in patients with tetraplegia [
26,
28] for whom melatonin profiles are abolished [
29,
30]. Our study extends these findings by showing that a prolonged-release melatonin formation, Circadin, is efficacious in improving sleep quality and sleep efficiency in patients with TBI.
The current study found that melatonin improved subjective sleep quality. Such findings may be attributed to the sleep-promoting properties of melatonin [
22]. The temporal association between the nocturnal rise in melatonin and increase in sleep propensity suggests that onset of nocturnal melatonin secretion facilitates the transition from wake to sleep by inhibiting the wake-alerting system [
31,
32]. Melatonin may act as a sleep-promoting agent by attenuating wake-promoting signals from the suprachiasmatic nucleus, primarily via the melatonin MT1 receptor [
33]. Melatonin’s sleep-promoting properties may also be mediated by the hypothermic response based on the temporal and causal relationship between increases in endogenous melatonin concentrations and subsequent decline in core body temperature [
34,
35]. It has also been hypothesised that melatonin may act as a muscle relaxant, [
36] and this may explain the apparent impact of melatonin on anxiety symptoms in the present study. The anxiolytic properties of melatonin have been demonstrated in rodents [
37,
38] and paediatric populations [
39]. The improvement in sleep quality also appeared to have a flow-on effect to reduce the subjective impact of fatigue in daily life and improve vitality. Although no clinical global impression was obtained in the current study, a large majority of the outcome measures were based on self-reports by the participants and thus, the current findings are clinically meaningful because changes were perceived by the participants themselves.
The present study required participants to consume treatment approximately 2 hours prior to habitual bedtime and after their evening meal. These instructions are in line with previous studies utilising Circadin [
16‐
18,
40] and are based on the pharmacokinetic profile of Circadin (
Tmax = 1.6 hours) [
41]. As a large majority of participants consumed their treatment as prescribed, the translation of the current findings into clinical practice is dependent on appropriately timed melatonin administration.
Various pharmacological treatments exist for the management of sleep disturbance. Hypnotics such as benzodiazepines and non-benzodiazepines are frequently prescribed to patients with TBI experiencing sleep disturbance [
42]. Whereas benzodiazepines and non-benzodiazepines are equally effective in treating insomnia in patients with TBI over 7 days [
43], the efficacy and safety of long-term use in patients with TBI is unknown. Hypnotics are only indicated for short-term use and prolonged use can result in dependence, especially in vulnerable populations, such as patients with TBI [
44]. Conversely, the safety and tolerance profile of melatonin observed in the current study is consistent with previous studies in non-TBI populations [
17]. Thus, based on the current findings, melatonin affords TBI patients an alternative treatment to alleviate sleep disturbance with minimal side effects.
In the current study, melatonin had a moderate effect size for improving sleep quality (
d = 0.46). This magnitude of improvement in sleep quality is double that of amitriptyline (a tricyclic antidepressant) relative to no treatment, when administered to patients with TBI over the same time period (
d = 0.21) [
25]. As melatonin was well tolerated in the current study, with no serious adverse events reported, melatonin offers clinicians an alternative treatment to that of conventional sleeping medications.
While melatonin was found to be effective in alleviating sleep disturbances, it is acknowledged that the mechanisms underpinning sleep disturbances in TBI involve multiple biological and psychological systems, such as alterations in monoaminergic neurons [
45,
46] and wake-promoting hypocretin-1 neurons [
47], and alterations in melatonin levels [
8,
9], as well as pain [
48,
49] and mood disturbance [
50]. This suggests that while melatonin supplementation may alleviate sleep disturbance in individuals with TBI, melatonin is unlikely to address all sleep problems. Cognitive behavioural therapy for insomnia (CBT-I) has been shown efficacious in TBI populations [
51]. Due to the multi-factorial nature of sleep disturbances following TBI, complementing melatonin supplementation with CBT-I may prove beneficial.