2025 Highlights in comorbidities and headache

Headache disorders, such as migraine, are very prevalent and frequently co-exist with other comorbidities. When we discuss this phenomenon, we often think about the interaction between different medical conditions. In many cases, considering the management of headache disorders within the broader context of comorbid and co-existing conditions can lead to improved clinical outcomes. Understanding headache comorbidities could enable timely intervention for associated conditions and provide a deeper insight into the nature of headache disorders. The headache community strives to set ambitious goals in headache and migraine management. It might be possible to aim for a migraine freedom and address any residual disease burden (1). Learning about headache comorbidities can be helpful as we search for optimal diagnostic and treatment paradigms. In this editorial, we highlight the papers published in 2025 that addressed headache and migraine comorbidities, such as hormonal imbalances, chronic pain syndromes, psychiatric disorders and different neurological conditions.

Endocrine and reproductive comorbidities: Endometriosis

A recent paper by Lee et al. (2) examined the potential role of prolactin, a neurohormone secreted by the anterior pituitary, in the association between migraine and endometriosis. The study revealed that in a mouse model of endometriosis, prolactin circulating in the bloodstream heightened migraine vulnerability, likely through trigeminal neuron sensitization. This suggests that reducing prolactin may help prevent migraine in women with endometriosis in some cases. There could be a potential role for novel monoclonal antibodies that are directed at prolactin signaling or clinically available dopamine receptor agonists.

An editor's choice article tackles the complex issue of hypothalamic-pituitary-adrenal (HPA) axis, expanding our understanding of stress, a common migraine trigger, and sparking discussion about the role of post-stress modulation (3).

Pain syndrome comorbidities: Fibromyalgia and temporomandibular disorders

Stress has been known to play a part in multiple other headache and migraine comorbidities, for example, potentially contributing to muscle tension and jaw clenching. Migraine frequently overlaps with temporomandibular disorders (TMD), raising the question of whether treatment protocols could be developed to address both conditions simultaneously. In their paper, Romero-Reyes et al. (4) highlighted the need for integrated care involving both medicine and dentistry when managing patients with coexisting migraine and TMD. They reported that calcitonin gene-related peptide (CGRP), a key player in migraine pathophysiology, is also involved in TMD. This shared mechanism suggests that CGRP-targeting therapies may offer a promising pharmacological monotherapy for addressing this comorbidity.

Fibromyalgia, another complex pain condition, has been reported to have associations with migraine. In a study involving over 2000 participants with migraine, Liao et al. (5) found that individuals with a higher frequency of migraine attacks were at increased risk of fibromyalgia and potentially experienced more severe fibromyalgia symptoms. This highlights the importance of routinely assessing individuals with migraine, especially those with high headache frequency, for possible fibromyalgia symptoms. In another study, Ling et al. (6) showed that patients with both chronic migraine and fibromyalgia experience poorer outcomes for both conditions. Taken together, these findings underscore the importance of routinely assessing for fibromyalgia in patients with migraine, and of adopting a multidisciplinary approach when both conditions are present (6).

Neurologic comorbidities: Epilepsy

In a study conducted by Chen et al. (7), the researchers investigated the prevalence of headache among people with epilepsy and found that about 46% experienced headache, either after seizures (postictal) or between them (interictal). Notably, in those with interictal headache, the presence of migraine was linked to a marked reduction in daily functioning and psychological health. Furthermore, certain genes linked to a rare subtype of migraine known as familial hemiplegic migraine—specifically protein-altering variants in CACNA1A, ATP1A2, and SCN1A—have also been reported to overlap with epilepsy. A study by Staehr et al. (8) looks into the genes that are associated with migraine and epilepsy, which contributes to a better understanding of the possibilities for developing more precise and individualized treatments for both conditions.

Psychiatric comorbidities: Depression

Migraine has been shown to be associated with depression. Several studies have evaluated the presence of depression among individuals with migraine. In their review, Asheer et al. (9) highlighted the importance of using appropriate diagnostic tools in migraine research to minimize bias. They emphasized the need for further validation of depression screening tools in migraine population and recommended the development of guidelines for their use. This would enable more accurate and reliable assessment of comorbidity between migraine and depression. Lipton et al. (10) published results of clinical trial that suggested that migraine specific CGRP antibody may improve migraine and depressive symptoms in people living with both conditions.

In summary, the 2025 publications have significantly advanced our understanding of headache comorbidities, reinforcing that migraine and other headache disorders rarely exist in isolation. From hormonal and pain-related mechanisms to genetic and psychological overlaps, these studies highlight the intricate connections between migraine and conditions such as endometriosis, fibromyalgia, TMD, epilepsy, and depression. Collectively, the findings emphasize that recognizing and managing these comorbidities is essential for improving patient outcomes. As the field moves forward, multidisciplinary care and precision medicine approaches will be key to addressing the full complexity of headache disorders and their associated conditions.