Many a time in life when stress hormones are flying, our patients experience the unfortunate experience of insomnia and disrputed sleep. The experience of insomnia is not uncommon, with about one-third to two-thirds of adults in cross-sectional surveys describing insomnia symptoms of any severity, with 10 to 15% of individuals describing chronic insomnia which bleeds into daytime difficulties as well.Sleep difficulties are more common in women, individuals who are single (widowed, divorced, or separated), and often coexist with psychiatric disorders such as depression, or more commonly, an anxiety disorder. Insomnia and disrupted sleep can also be due to a medication including those used to treat anxiety and depression, so this should not be neglected in assessing for the possible cause. Many individuals who experience insomnia never have a diagnosis, and self-medication with substances such as alcohol or over-the-counter medications is not uncommon.However, alcohol can be a contributing factor to poor sleep quality, and negatively affects the body’s circadian rhythm when consumed chronically, obliterating the perceived benefits one may attribute to its use.
Melatonin – The Body’s Natural Sleep Regulator
Melatonin, primarily produced in the body by the pineal gland, is the body’s natural sleep promoting hormone. Melatonin levels have a circadian rhythm, and rise at night, and are low during the day, nearly opposite in profile to the diurnal cortisol pattern. Light is one factor which mediates melatonin secretion, and bright light can be used to shift its circadian pattern. Decreased melatonin production and altered rhythms have been seen with increasing age, in individuals who experience conditions including depression, visual impairment, and neurodevelopmental disorders.The receptors MT1 and MT2 which are activated by melatonin play not only a role in sleep, but also in mood disorders, learning and memory, drug abuse, and cancer.
Melatonin also has importance in the body as a neuroprotective antioxidant, and not only has antioxidant action on its own, but also stimulates the body’s production of other antioxidants including superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase through the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway.
Clinical Studies and Meta-Analysis Support the Use of Melatonin
Melatonin has been studied clinically as a sleep-supportive agent in populations ranging from 2 to 84 years of age. In these studies, serious medication-related adverse events have not been observed. Typical adverse events included morning drowsiness, headache, or night-time awakening. Occasionally, a loss of therapeutic effect was seen with time and continued nightly melatonin use. In some studies, melatonin was even combined with multiple other psychotropic medications in the very young and elderly without any adverse events. In clinical studies, the duration of treatment ranged from days to as long as 4 years.Dosages in studies for the purpose of supporting sleep range from 0.75 to 15 mg, and often if higher the dosages were used, the dose was titrated gradually over time.
Several meta-analysis have been performed looking at the effectivity of melatonin for various types of sleep disorders. In children with neurodevelopment disorders, melatonin was found to significantly improve total sleep time as well as sleep onset latency, although no difference was seen in nocturnal awakenings. In adults and children with delayed phase sleep disorders, melatonin was found to advance the sleep-wake rhythm as well as the endogenous melatonin onset. In patients with sleep disorders associated with dementia, a meta-analysis of seven clinical studies found that melatonin significantly prolonged total sleep time and marginally improved sleep efficacy, although no significant changes were seen in cognitive function. In neurodegenerative disease including Parkinson’s disease and Alzheimer’s, melatonin was found to positively impact certain markers of sleep as evaluated by the Pittsburgh Sleep Quality Index (PSQI), as well as clinical and neurophysiological aspects of rapid eye movement sleep behavior disorder. The largest meta-analysis considered 19 studies involving 1683 individuals with primary sleep disorders, and found that melatonin improved several measurements of healthy sleep (sleep onset latency, total sleep time and overall sleep quality) and that the effects did not dissipate with continued use. The authors conclude with the statement, “Although the absolute benefit of melatonin compared to placebo is smaller than other pharmacological treatments for insomnia, melatonin may have a role in the treatment of insomnia given its relatively benign side-effect profile compared to these agents,” which fairly well summarizes the majority of research surrounding melatonin.
Outside of these selected meta-analyses which broadly assess the impact of melatonin on common conditions associated with altered sleep, melatonin has also been studied in the setting of traumatic brain injury (TBI). Many individuals who experience a TBI subsequently have fragmented or disrupted sleep, which can further negatively impact neuropsychiatric, physical and cognitive outcomes. Altered sleep is in part due to a dramatic decline in the nocturnal melatonin production, but also may be due to oxidative stress and a disrupted blood-brain barrier. In a randomized, double-blind, placebo-controlled cross-over study of patients with sleep disturbances subsequent to a mild to severe TBI, prolonged-release melatonin was found to significantly improve the primary outcome of PSQI scores as well as secondary outcomes of sleep efficiency, vitality, and mental health. Again, no serious adverse events were reported, and additionally, patients did not experience increased daytime sleepiness. It has been suggested that melatonin also be considered for other events of trauma leading to intensive care hospitalization, as these conditions also are associated with declines in melatonin secretion.
Consideration for an Extended-Release Format
Although hereunto not discussed specifically, at times, an extended-release format of melatonin was used within some of these studies which were referenced explicitly or existed within the meta-analysis reviews. Prolonged-release formats may more closely mimic the endogenous release of melatonin, thus enabling lower dosing and reduced residual daytime sleepiness. For the melatonin-naïve, children, elderly, and individuals who are sensitive to medications and supplemental therapies, this may be beneficial.
In many of these clinical settings, melatonin is not only indicated to support sub-optimal endogenous melatonin levels, but also for the antioxidant action it also delivers. Adequacy of melatonin is one critically important thing to consider when supporting a normal, healthy sleep cycle, and volumes of clinical research support its use in a range of healthy and challenged individuals.