Headache in Men

Migraine and cluster headache are the two most important primary headache disorders in terms of their prevalence and associated disability. Each encompasses a family of diagnostic variants that are distinguished from each other by temporal pattern (episodic vs chronic) and, in the case of migraine, by the presence or absence of certain associated symptoms (migraine without aura vs migraine with aura, the latter of which is subdivided by aura type). These variants are defined in the International Headache Society’s third edition of the International Classification of Headache Disorders.¹ Diagnostic criteria for migraine without aura and cluster headache are listed in Tables 1 and 2, respectively.

Worldwide, the 1-year prevalence of migraine is approximately 15%, and the lifetime prevalence of cluster headache is approximately 0.1%.^2,3 Migraine often is thought of as a disease primarily prevalent among women and cluster headache as primarily prevalent among men. Nevertheless, migraine is more prevalent than cluster headache in men by at least an order of magnitude. This article addresses important topics in this conversation, focusing primarily on the ways in which the migraine experience of men is distinct from that of women, and on the description and management of cluster headache, the most severe primary headache disorder, which is more common in men than women.

The terms “sex,” “men,” and “women” are used in this article because they are the primary terms used in the sources that informed the content. In the primary sources, these terms generally refer to biologic sex assigned at birth based on morphology of the external reproductive organs. These terms are not adequate to capture all the nuances of sex and gender in the human population, and what is said here about men therefore cannot be applied to all individuals identifying as male.

Migraine in Men: Distinctive Features

Several important differences have been observed between the presentation of migraine in men and women. Studies assessing the prevalence of migraine both worldwide and in the United States have found that migraine is between 2 and 3 times more prevalent in women than men.^2,4-6 Multiple studies evaluating for sex-related differences in headache and migraine attack characteristics have shown tendencies toward lower attack frequency, shorter duration of attacks, lesser pain intensity and headache unpleasantness, lower likelihood of disability related to attacks, and shorter duration of disability in men than women.^5,7-10 Symptoms of photophobia, phonophobia, nausea, vomiting, visual and sensorimotor aura, and cutaneous allodynia may be less common in men than women.^5,7,8,11 Men may be less likely to have impairment in household productivity, miss time at work or school, and miss family or social events because of migraine.^7,8 Sex differences were not found for all of these characteristics in all of the studies that investigated them, however.

Various physiologic and social elements have been considered as factors in the sex differences seen in the phenotype of migraine. One study reported interictal differences in brain structure as well as functional differences between people with and without migraine.¹⁰ A structural MRI analysis identified increased cortical thickness in the posterior insula and the precuneus in the migraine group compared with healthy controls that was unique to women as well as decreased volume of the parahippocampal gyrus in the migraine group compared with healthy men that was unique to men.¹⁰ Functional MRI analyses demonstrated stronger deactivation responses and negative functional connectivity involving regions such as the amygdala and parahippocampal gyrus in women vs men.¹⁰ These differences may contribute to a higher degree of headache unpleasantness experienced by women independent of pain intensity.¹⁰

Another important factor is the influence of sex hormones. Evidence of increased sensitization of the trigeminal system during the stages of the rat estrous cycle that correspond to abrupt declines in ovarian hormone levels points to a possible pathophysiologic role of sex hormones in menstrual cycle–related fluctuations in migraine burden observed in many women with migraine.¹² Strong clinical evidence of the role of sex hormones in migraine burden among women was reported in a study that showed that a high proportion of women with chronic migraine and menstrual-related migraine experienced reversion to an episodic migraine pattern after successful treatment of their menstrual-related migraine.¹³

Comorbidities also may play a role. A large population-based study evaluating for comorbidity between migraine and somatic medical diseases showed that fewer diseases are comorbid with migraine in men than in women and that there were no comorbidities unique to men.¹⁴ Thyroid diseases and musculoskeletal disease, such as osteoarthritis and fibromyalgia, accounted for the majority of the comorbidities unique to women.¹⁴ Furthermore, data suggest lower rates of clinical depression and anxiety in men with migraine.⁷

Migraine in Men: Disparities in Care

Whereas the evidence suggests a somewhat lower degree of morbidity from migraine for men than women, medical care patterns are dramatically different in men. While the rates are low for both sexes, men have been found to be much less likely to use preventive medication and prescription acute medication for treatment of migraine.¹⁵ Elucidation of the reasons for this discrepancy requires consideration of the 2 action steps that generally are prerequisite for appropriate treatment of migraine: 1) consultation with a health care professional and 2) diagnosis of migraine.¹⁶ Among people who report any kind of headache as well as those who meet diagnostic criteria for migraine, men have been found to be less likely than women to consult a health care provider for these problems.^17-19 It can be theorized that stigma attached to migraine as well as the perception that it is a disease of women may play a role in the hesitancy of men to seek treatment. One source of this perception is the feminized representation of the person with migraine by the pharmaceutical industry in its marketing efforts which appear to target a largely female consumer base.²⁰ Among people with migraine who consult a health care professional, men are less likely than women to be diagnosed with migraine, suggesting the possibility of sex or gender bias in migraine diagnosis.^16,19 Consultation and diagnosis have been found to influence the likelihood of appropriate migraine treatment independently, indicating that failures of both of these events are important barriers to appropriate migraine treatment for men.¹⁶ There does not appear to be a bias against treatment of migraine in men when it has been diagnosed.^16,21 Stigma must be confronted to ensure that men with migraine take the steps necessary to receive care.

In addition to clinical management, men are thought to be underrepresented in migraine research in areas such as neuroimaging and treatment.²² Because they reflect the actual migraine population, migraine clinical trials have enlisted mostly female participants.²² Because sex has the potential to influence many pharmacologic responses, however, more attention to sex is needed in trials to ensure that effective treatments for both men and women are brought to market.²²

Overview of Cluster Headache

In contrast to migraine, which bears the reputation of being a disease of women, cluster headache is cast as a disease of men. Cluster headache is the most common of a group of related disorders called “trigeminal autonomic cephalalgias”. Cluster headache is characterized by attacks of intense unilateral headache accompanied by ipsilateral cranial autonomic symptoms or restlessness or agitation.¹ The duration of cluster attacks ranges from 15 minutes to 3 hours.¹ The disorder is named for the fact that in episodic cluster headache, the attacks occur on a daily basis for a continuous period of time, typically between 2 weeks and 3 months, and remit completely between these cluster periods.¹

The inverse of migraine, a marked sex-related difference in cluster headache prevalence has been demonstrated consistently, with a meta-analysis of population-based studies reporting a pooled male-to-female prevalence ratio of 4.3 to 1.³ Multiple studies analyzing samples of individuals with cluster headache who received care at particular institutions over several decades identified a decline in the male:female preponderance.^23,24 Another study that sampled more broadly found the ratio to be stable, however, and the authors speculated that the decline observed in the other studies was an artifact of referral patterns at those particular institutions.²⁵ In addition to male sex, risk factors include family history of cluster headache and tobacco and alcohol use.²⁵

Treatment of cluster headache can be categorized into strategies that are used to eliminate individual headache attacks, referred to as “acute treatments”, and ones that are used to terminate cluster periods and bring about remission, referred to as “preventive treatments”. The most effective acute treatments in use are rapidly acting injectable and nasal preparations of sumatriptan, zolmitriptan, and dihydroergotamine, as well as high-flow inhaled oxygen. Widely used preventive treatments include verapamil, topiramate, lithium, corticosteroids, greater occipital nerve blocks, and recently galcanezumab. A phase 3 clinical trial (ALLEVIATE [Eptinezumab in Participants With Episodic Cluster Headache]; Unique Identifier: NCT04688775) investigating the use of a different calcitonin gene-related peptide antibody, eptinezumab, is ongoing.

Conclusion

Migraine and cluster headache illustrate the varied and important considerations pertaining to headache disorders in men. Further exploration of these concepts stands to improve the experience of headache in this population.