Cluster, Migraine Headache Strongly Linked to Circadian Rhythm

Cluster headache and migraine have strong ties to the circadian system at multiple levels, new findings that could have significant treatment implications.

A meta-analysis of 16 studies showed a circadian pattern in 71% of cluster headache attacks (3490 of 4953), with a clear circadian peak between 9:00 PM and 3:00 AM.

Migraine was also associated with a circadian pattern in 50% of cases (2698 of 5385) across eight studies, with a clear circadian trough between 11:00 PM and 7:00 AM.

Seasonal peaks were also evident for cluster headache (spring and autumn) and migraine (April to October).

“In the short-term, these findings help us explain the timing to patients — for example it is possible that a headache at 8 AM is due to their internal body clock instead of their pillow, or breakfast food, or morning medications,” lead investigator Mark Burish, MD, PhD, associate professor, Department of Neurosurgery, McGovern Medical School at UTHealth Houston, told Medscape Medical News.

“In the long-term, these findings do suggest that medications that target the circadian system could be effective in migraine and headache patients,” Burish added.

The study was published online March 29 in Neurology.

Treatment Implications?

Across studies, chronotype was “highly variable” for both cluster headache and migraine, the investigators report.

Cluster headache was associated with lower melatonin and higher cortisol levels compared with non–cluster headache controls.

On a genetic level, cluster headache was associated with two core circadian genes (CLOCK and REV-ERB–alpha), and five of the nine genes that increase the likelihood of having cluster headache are genes with a circadian pattern of expression.

Migraine headache was associated with lower urinary melatonin levels and with the core circadian genes, CK1-delta and ROR-alpha, and 110 of the 168 genes associated with migraine were clock-controlled genes.

“The data suggest that both of these headache disorders are highly circadian at multiple levels, especially cluster headache,” Burish said in a release.

“This reinforces the importance of the hypothalamus – the area of the brain that houses the primary biological clock – and its role in cluster headache and migraine. It also raises the question of the genetics of triggers such as sleep changes that are known triggers for migraine and are cues for the body’s circadian rhythm,” Burish said.

“We hope that future research will look into circadian medications as a new treatment option for migraine and cluster headache patients,” Burish told Medscape Medical News.

Importance of Sleep Regulation

The authors of an accompanying editorial note that the even though the study doesn’t have immediate clinical implications, it offers a better understanding of the way chronobiologic factors may influence treatment.

“At a minimum, interventions known to regulate and improve sleep (e.g. melatonin, cognitive behavioral therapy), and which are safe and straightforward to introduce, may be useful in some individuals susceptible to circadian misalignment or sleep disorders,” write Heidi Sutherland, PhD, and Lyn Griffiths, PhD, with Queensland University of Technology, Australia.

“Treatment of co-morbidities (e.g. insomnia) that result in sleep disturbances may also help headache management. Furthermore, chronobiological aspects of any pharmacological interventions should be considered, as some frequently used headache and migraine drugs can modulate circadian cycles and influence the expression of circadian genes (e.g. verapamil),10 or have sleep-related side effects,” they add.

A limitation of the study was the lack of information on factors that could influence the circadian cycle, such as medications; other disorders, such as bipolar disorder; or circadian rhythm issues, such as night-shift work.

The study was supported by grants from the Japan Society for the Promotion of Science, the National Institutes of Health, The Welch Foundation, and The Will Erwin Headache Research Foundation. Burish is an unpaid member of the medical advisory board of Clusterbusters, and a site investigator for a cluster headache clinical trial funded by Lundbeck. Sutherland has received grant funding from the US Migraine Research Foundation, and received institute support from Queensland University of Technology for genetics research. Griffiths has received grant funding from the Australian NHMRC, US Department of Defense (DOD), and the US Migraine Research Foundation, and consultancy funding from TEVA.

Neurology. Published online March 29, 2023. Article; Editorial

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