Cluster headache and migraine were linked to the circadian system, data from a meta-analysis and other research showed.

Across 16 studies, cluster headache had a prominent circadian pattern of attacks in 70.5% of 4,953 participants, with a clear peak between 21:00 and 03:00 and circannual peaks in the spring and autumn, reported Mark Joseph Burish, MD, PhD, of the University of Texas Health Science Center at Houston, and colleagues.

Migraine had a circadian pattern of attacks in 50.1% of 5,385 participants in eight studies, with a clear trough between 23:00 and 07:00 and a circannual peak from April to October, the researchers wrote in Neurology.

“These data suggest that both headache disorders are highly circadian at multiple levels, especially cluster headache,” Burish said in a statement.

“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,” he said. “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.”

The results also raise the potential for using circadian-based treatments for headache disorders, Burish noted. “This could include both treatments based on the circadian rhythm — such as taking medications at certain times of the day – and treatments that cause circadian changes, which certain medications can do,” he said.

While the percentage of patients with a circadian pattern was not as high in migraine as it was in cluster headache, it was notable in a “disorder for which timing is not considered a prominent feature,” Burish and colleagues wrote.

Chronotype was highly variable in both cluster and migraine headaches. Cluster headache was associated with lower melatonin and higher cortisol levels compared with controls. It also was associated with two core circadian genes, CLOCK and REV-ERBα. Five of the nine cluster headache susceptibility genes were clock-controlled genes (CCGs) which have a circadian pattern of expression.

Migraine patients also had lower urinary melatonin levels, which declined even further during an attack. Migraine was associated with two core circadian genes, CK1δ and RORα, and 110 of the 168 migraine susceptibility genes were CCGs.

A better understanding of the chronobiological factors at play in cluster headaches and migraine may influence treatment approaches, said Heidi Sutherland, PhD, and Lyn Griffiths, PhD, both of the Queensland University of Technology in Australia. in an accompanying editorial.

Interventions known to regulate sleep — like melatonin or cognitive behavioral therapy — may be useful for some patients susceptible to circadian misalignment or sleep disorders, the editorialists noted. In addition, treatment of comorbidities that result in sleep disturbances, like insomnia, may help manage headache. Moreover, the potential chronobiological effects of headache and migraine drugs should also be considered, Sutherland and Griffiths suggested.

The observation of circadian features of cluster headache “is perhaps unsurprising” in that it confirmed previous research, the researchers noted. “However, migraine has separate lines of research that suggest it too is strongly associated with the circadian system,” Burish and co-authors observed. Many common migraine triggers — bright light, exercise, skipping meals, and sleep-wake changes like undersleeping and oversleeping — are also variables that can act as circadian time cues, they pointed out.

The researchers evaluated all available studies on cluster headache and migraine that had information on the timing of headaches during the day and during the year, and performed a separate analysis of genome-wide association studies.

A limitation was that many studies did not define what a “circadian pattern” was, the researchers acknowledged. Some did not report medications, other disorders such as bipolar disorder, or circadian rhythm issues including shift work, they added.

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