Chapter 13 - Therapeutic role of melatonin in migraine prophylaxis: Is there a link between sleep and migraine?

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Abstract

Melatonin is a ubiquitously distributed molecule that possesses diverse functions. Melatonin plays a key role in the endogenous circadian rhythms of humans via light stimulation in the hypothalamus. In addition, melatonin has roles in the opioid system, the nitric oxide pathway, free radical scavenging, inflammation, and antinociception. Melatonin is nontoxic and relatively safe. Recently, exogenous melatonin has been shown to have significant effects in the treatment of migraine. Further, it has demonstrated efficacy in the treatment of sleep disorders, including insomnia, circadian rhythm sleep-wake disorders, parasomnias, and sleep breathing disorders. Sleep disorders are commonly reported by those who experience migraine, and migraine and sleep disorders have been reported to be closely associated in cross-sectional studies. Longitudinal studies have shown that some sleep disorders and migraine show bidirectional comorbidities. Therefore, the identification and treatment of sleep disorders is important when treating migraine. Melatonin represents a promising treatment strategy for both disorders, especially when these conditions are combined.

Introduction

Melatonin (N-acetyl-5-methoxytryptamine) is a prevalent molecule found in almost all living organisms, including bacteria, algae, fungi, plants, insects, and vertebrates (Reiter et al., 2010). In vertebrates, melatonin is produced in the pineal gland and released in the blood. In humans, it is associated with a variety of functions, including circadian regulation, immune function, tumor inhibition, antioxidant activity, free radical scavenging, and antinociception (Blask et al., 2002; Dubocovich et al., 1999; Malpaux et al., 2001). Lower than normal levels of melatonin have been reported in cases of Parkinson's disease, Alzheimer's disease, insomnia, epilepsy, ischemic injury, and various psychiatric disorders (Shimozuma et al., 2011; Wehr et al., 2001), suggesting that it may play important roles in these disorders. Melatonin is known to exert antioxidative, anxiolytic, analgesic, antihypertensive, anti-inflammatory, and oncostatic effects (Wilhelmsen et al., 2011).

Recently, it has been shown that melatonin plays a key role in the endogenous circadian rhythm of humans, via light stimulation in the hypothalamus. Sleep is controlled by a circadian rhythm and normally occurs at night, usually coinciding with nocturnal melatonin secretion (Rodenbeck et al., 1999). Thus, melatonin is a facilitator of sleep in humans and may be useful for treating sleep disorders. There is evidence that melatonin administration can induce sleep in cases with an insufficient sleep drive and can be used to induce phase shifts in the circadian clock to desired times. An antinociceptive role of melatonin also has been reported: exogenous melatonin is effective in relieving chronic pain and treating migraine (Kaur and Shyu, 2018; Wilhelmsen et al., 2011). In this chapter, we describe the latest findings related to melatonin with respect to the physiology of migraine and sleep and discuss the potential utility of melatonin in the treatment of migraine and sleep disorders.

Section snippets

Migraine and sleep disorders

Sleep is a major issue in the lives of people affected by migraine, and sleep disturbances are generally regarded as a trigger factor of a migraine attack. Various symptoms and circumstances can serve as such a trigger: insufficient sleep, disturbed sleep, oversleeping, keeping late hours, rising earlier than usual, irregular sleep cycles due to shift working, or jet lag. Indeed, a meta-analysis revealed that sleep was the second most common trigger factor (after stress) in primary headache

Pathophysiology of comorbidity between migraine and sleep disorders

A complex relationship between migraine and sleep has been reported. Migraine shows a bidirectional comorbidity with insomnia, suggesting shared pathophysiologic mechanisms (Odegard et al., 2011, Odegard et al., 2013). Although the relationship between migraine and sleep problems vary, anatomical locations and roles of signaling molecules (neurotransmitters, neuropeptides and hormones) are common (Vgontzas and Pavlovic, 2018).

Melatonin could play an important role in the significant association

Melatonin synthesis and release

Melatonin is mainly synthesized by pinealocytes, which are cells in the pineal gland that are under the control of the suprachiasmatic (SCN) nucleus of the hypothalamus. Melatonin synthesis begins from tryptophan, which is transformed to 5-hydroxytryptophan by the enzyme tryptophan hydroxylase. After transformation, it is converted into serotonin by the action of aromatic l-amino acid decarboxylase. Serotonin is then converted into N-acetyl serotonin by N-acetyltransferase (AANAT), which is

Safety and adverse effects of melatonin

Melatonin is a relatively safe and nontoxic molecule safe for short-term use (Buscemi et al., 2006). Animal studies have reported no adverse effects or death at a dose of 200 mg/kg in pregnant rats and 800 mg/kg in mice (Makay, 2009). In clinical studies, daily administration of 1000 mg/day melatonin for 1 month led to minor side effects including drowsiness, headache, dizziness, and nausea. Administration of high melatonin doses in healthy volunteers did not impair memory or visual sensitivity.

Melatonin in migraine pathophysiology

Melatonin may play a role in migraine pathophysiology in several ways. Neurogenic inflammation is an important process in the development of migraine (Ramachandran, 2018). Melatonin has anti-inflammatory effects.

Melatonin exerts anti-inflammatory actions in various ways. It inhibits the synthesis of prostaglandin E, decreasing inflammation in the trigeminovascular system (Gimeno et al., 1980). It prevents the translocation of nuclear factor kappa B to the nucleus, which reduces the upregulation

Effects of exogenous melatonin on migraine

To date, seven studies have investigated the effects of exogenous melatonin in the treatment of migraine, including four randomized controlled studies (Alstadhaug et al., 2010; Ebrahimi-Monfared et al., 2017; Fallah et al., 2018; Goncalves et al., 2016) and three observational studies (Bougea et al., 2016; Miano et al., 2008; Peres et al., 2004). Among the four controlled trials, three were double-blinded studies and one was a single-blinded study. One double-blind study evaluated adjunctive

Conclusions and future directions

Melatonin plays important roles in the pathophysiology of migraine and sleep disorders. Migraine and sleep disorders have shown significant associations in clinical and epidemiological studies. Recent studies have shown that exogenous melatonin may be effective at treating both disorders. Therefore, melatonin has promising therapeutic potential for the treatment of these disorders, especially when they are combined. Nevertheless, there are several points that need to be clarified with further

Source of funding/support

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2019R1F1A1053841).

Disclosure

TJS and BSK declare that there are no conflicts of interest regarding this submission. MKC is a site investigator for a multi-center trial sponsored by Otsuka Korea, Novartis International AG, and Eli Lilly and Company. He has served as an advisory member for Teva and received lecture honoraria from Allergan Korea, Handok-Teva, and Yuyu Pharmaceutical Company in the past 24 months. He received grants from Yonsei University College of Medicine (2018-32-0037) and National Research Foundation of

Authors' contributions

T.J.S. and B.S.K. acquired and analyzed the data and drafted the manuscript; M.K.C. conceptualized the study, analyzed the data, and revised the manuscript.

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