Melatonin and Migraine

By Lynn Keegan, RN, PhD, HNC-BC, FAAN Director, Holistic Nursing Consultants, Port Angeles, WA. Dr. Keegan reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.

Many things affect quality of life; among the most difficult to deal with are migraine headaches. Each year we learn more about the triggers and methods of treatment. We now know that if one parent suffers from migraines, the child has a 50% chance of developing migraine headaches.

Primary headache classifications include migraine, tension, cluster, paroxysmal hemicrania, and miscellaneous headaches unassociated with structural lesions.1 Chronic migraine is a frequent headache disorder that affects 2-3% of the general population. Analgesic overuse, insomnia, depression, and anxiety are disorders that often are comorbid with this condition.2 Of the nearly 32 million Americans who suffer with migraine, approximately 24 million are women. Prior to puberty, girls are afflicted with migraine at approximately the same rate as boys, but after puberty there is an emerging female predominance. Although hormones do not entirely explain the epidemiological variation seen in migraine, estrogen plays an important role.3

Relationship Between Melatonin and Headache

Discovered approximately 40 years ago, melatonin has been called the "darkness" hormone. Production rises at night, falls by day, and affects the internal body clock and sleep cycles.4 There is increasing evidence that headache disorders are connected with melatonin secretion and pineal function. Some headaches, such as cluster headaches, have a clear-cut seasonal and circadian pattern. Melatonin levels have been found to be decreased in patients suffering both migraine and cluster headaches.5 It is interesting to note that the supportive data for use of melatonin seem to be consistent for the past decade.

Melatonin is a human hormone secreted by the pineal gland, a pea-size structure at the center of the brain. Melatonin is produced at night to help the body regulate sleep-wake cycles. The amount produced in the body seems to decrease with aging.

Treatment with Melatonin

Interest in melatonin is increasing as a result of new discoveries about its role in the biological regulation of circadian rhythm, sleep, mood, aging, tumor growth, and reproduction. Perhaps these processes have led to its use in the treatment of many current problems such as migraine and the control of epileptic seizures.6 Melatonin may play an important therapeutic role in the treatment of migraines and other types of headaches, particularly those related to delayed sleep phase syndrome.7 Although a multitude of pharmaceutical agents are available for the treatment of mood disorders, anxiety, and insomnia, many patients have difficulty tolerating the side effects, do not respond adequately, or eventually lose their response. Many therapeutic herbs and nutrients have far fewer side effects and may provide an alternative treatment or can be used to enhance the effect of prescription medications. Melatonin is one of these alternative choices and migraine is one of the disorders.8 The cornerstone of allopathic maintenance prophylaxis for cluster headache (often masquerading as migraine) is verapamil, yet methysergide, lithium, and divalproex sodium also may be employed. In some patients, melatonin or topiramate may be found useful as adjunctive therapies.9

Probable Causes of Migraine

There are a variety of hypothesized causes of migraines, some better documented than others. When seeking an etiology, one might consider the role of the retino-hypothalamic-pineal axis in the pathophysiology of primary headaches in terms of (1) retinal dysfunction, (2) hypothalamic dysfunction and human circadian desynchrony, (3) pineal melatonin dysfunction, and (4) rostral limbic dysfunction mediating the human stress response.1

Some think that migraine is caused by a primary biochemical disorder of the central nervous system involving neurotransmitters, specifically serotonin. The pathogenetic mechanism triggered by external and internal stimuli is not well explained or understood. There is a likelihood that the pineal gland, a primary source of central serotonin and melatonin, contributes significantly to migraine attacks.10

Another theory suggests that since environmental stimuli are known to trigger migraine headaches, the pineal gland may be involved in migraine etiology. Specifically, a pineal gland irregularity may be the physical origin of migraine headaches, with subsequent physiological changes being secondary. Research has found the pineal hormone melatonin is low in migraine patients.7

Nitric oxide supersensitivity is another hypothesis. Its role in causing migraine headaches and chronic morning headaches can be triggered both by normal and abnormal characteristics of the sleep cycle and more specifically by the release of nitric oxide that occurs toward the end of the sleep cycle. Stress and the age-related loss of sleep continuity, together with the corresponding increase in cortisol levels, potentiate delta rebound. Delta rebound results in deeper sleep intensity. It is associated with increased nitric oxide production. Increased delta rebound then causes an increase in the amount and duration of nitric oxide release at night. Migraineurs are susceptible to migraine headaches because they are supersensitive to nitric oxide. The diurnal pattern of the incidence of sleep-related headaches in a subset of the general population is caused by the effect of nitric oxide supersensitivity during the sleep cycle.11

Mechanism of Action

Melatonin mechanisms of action are related to headache pathophysiology in many ways, including its anti-inflammatory effect, toxic free radical scavenging, reduction of proinflammatory cytokine up-regulation, nitric oxide synthase activity and dopamine release inhibition, membrane stabilization, GABA and opioid analgesia potentiation, glutamate neurotoxicity protection, neurovascular regulation, serotonin modulation, and the similarity of chemical structure to that of indomethacin.5,12 Melatonin is involved in the regulation of seasonal and circadian fluctuations of other hormones and in the synchronization of many different aspects of circadian rhythmicity to the light-dark cycle. In addition to these receptor-mediated functions, melatonin may act as a modulator of intracellular signal transduction to enhance or suppress the responses of many different cells to other incoming signals. This hormone also is a potent scavenger of reactive oxygen species and thus may protect cells and tissues against radical-mediated damage. The production of melatonin declines with increasing age, and circulating melatonin levels are affected by certain pharmacological or physiological manipulations, notably food restriction which increases melatonin levels and prevents its age-related decline.13

Clinical Trials

One proposed treatment for both sleep-related migraine headaches and chronic morning headaches consists of melatonin and moclobemide taken at night.11 Both melatonin and moclobemide affect three important aspects of sleep-related headaches: nitric oxide supersensitivity, stress system dysfunction, and sleep pathology. Both melatonin and moclobemide have demonstrated effectiveness in preventing migraine headaches. Additionally, both melatonin and moclobemide are compatible with most of the other therapeutic agents used to prevent migraine headaches and with at least one therapeutic agent that is used to treat migraine headaches.

A Norwegian university research team investigated potential seasonal variation of migraine and other headaches in an Arctic population where light conditions are extreme during both winter and summer.14 Because of the immense seasonal variation in sunlight, focus on seasonal migraine variation in a population living in an Arctic area is interesting even from a theoretical point of view. Northern Norway comprises the three Norwegian counties north of the Arctic Circle. There are three neurology centers in this region, which provide service for approximately half a million people. During a two-year period, 1,403 patients (0.3% of the population) were referred to these centers for a specialist assessment of their headaches. A questionnaire was mailed to all of these patients (with a 75% response rate). The questionnaire included questions on headache characteristics to make it possible to identify migraine according to the International Headache Society criteria. Questions on seasonal variation of headache also were included. Nineteen percent reported that their headaches clearly did vary with season; 11% experienced more headache during polar night, while 7% had more symptoms during midnight sun season. When the migraine and non-migraine groups were compared, significant differences were demonstrated. Patients with nonmigrainous headache were more likely to have increased headaches during the dark winter season, while patients with migraine experienced more headache during the summer (P = 0.002). These findings support the increased light sensitivity and recently demonstrated cortical hyperexcitability in patients with migraine, and may perhaps suggest a role of the hypothalamus and/or melatonin secretion in migraine pathophysiology.

Later research conducted in France examined the sensitivity to light of melatonin secretion in familial migraine during a headache-free interval.15 Twelve female patients and 12 healthy controls were included in the trial. All subjects were studied twice. In each session, light exposure (300 lx) or placebo was randomly administered for 30 min between 00:30 and 01:00 h. Blood was sampled hourly between 20:00 and 24:00 h, and 02:00 and 04:00 h and every 15 min between 00:30 and 01:30 h. Plasma melatonin levels were determined by radioimmunoassay. Melatonin suppression was more marked in the migraine group than in the control group. These findings show a clear hypersensitivity to light in young female migraineurs during the headache-free period.

Hypothalamic dysfunction has been implicated in the pathogenesis of migraine, but it has never been studied in patients with chronic migraines. A Brazilian study analyzed the hypothalamic involvement in this group by measurement of melatonin, prolactin, growth hormone, and cortisol nocturnal secretion.2 A total of 338 blood samples (13 per patient) from 17 patients with chronic migraines and nine age- and sex-matched healthy volunteers were taken. Melatonin, prolactin, growth hormone, and cortisol concentrations were determined every hour for 12 hours. The presence of comorbid disorders also was evaluated. The results discovered an abnormal pattern of hypothalamic hormonal secretion in those with chronic migraines. This included: (1) a decreased nocturnal prolactin peak, (2) increased cortisol concentrations, (3) a delayed nocturnal melatonin peak in patients with chronic migraine, and (4) lower melatonin concentrations in migraine patients with insomnia. Growth hormone secretion did not differ from controls. These results support hypothalamic involvement in chronic migraine sufferers, shown by a chronobiologic dysregulation, and a possible hyperdopaminergic.

Safety Concerns

In a Canadian study of 13 electronic databases and reference lists of relevant reviews and included studies, results indicated that there is evidence that melatonin is safe with short-term use.16

Dosage

The recommended dose is 3 mg, taken within 30 minutes before bedtime.17 Melatonin is sold in 1.5 and 3 mg tablets. The appropriate dose can vary from person to person. It is suggested that one start with a 1.5 mg tablet each night before bedtime, working up to larger doses of 3 mg if needed.18

Conclusion

Frequent and recurrent migraine headaches can, over time, pose the additional risks of stroke, brain damage, heart failure, and attention deficit. This is why prevention should always be a part of the treatment.11 There is evidence that melatonin may play a role in the biological regulation of circadian rhythms, sleep, mood, and aging. Altered melatonin levels in cluster headache and migraine sufferers have been documented.12

Current research supports the hypothesis that migraines are a response to a pineal circadian irregularity in which the administration of melatonin normalizes this circadian cycle; i.e., melatonin may play a role in resynchronizing biological rhythms to lifestyle and subsequently relieve migraines and other forms of headaches. In addition, research testing the administration of melatonin found it safe in migraine sufferers, with few or no side effects.7 For melatonin to become as a more standardized therapy, larger, randomized control trials are needed to confirm that its use to migraine patients is effective.

References

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11. Eli R, Fasciano JA. A chronopharmacological preventive treatment for sleep-related migraine headaches and chronic morning headaches: Nitric oxide supersensitivity can cause sleep-related headaches in a subset of patients. Med Hypotheses 2006;66:461-465.

12. Peres MF. Melatonin, the pineal gland and their implications for headache disorders. Cephalalgia 2005;25:403-411.

13. Huether G. Melatonin as an antiaging drug: Between facts and fantasy. Gerontology 1996;42:87-96.

14. Salvesen R, Bekkelund SI. Migraine, as compared to other headaches, is worse during midnight-sun summer than during polar night. A questionnaire study in an Arctic population. Headache 2000;40:824-829.

15. Claustrat B, et al. Melatonin secretion is supersensitive to light in migraine. Cephalalgia 2004;24:128-133.

16. Buscemi N, et al. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: Meta-analysis. BMJ 2006;332:385-393. Epub 2006 Feb 10.

17. Peres MF, et al. Melatonin, 3 mg, is effective for migraine prevention. Neurology 2004;63:757.

18. Melatonin. Available at: www.melatonin.com/melatonin-faq.php#DOSAGE. Accessed May 1, 2006.