Dawn C. Buse, Ph.D.; Richard Lipton, MD
January 06, 2022
Being knowledgeable about comorbidities is essential to the study and management of migraine. Migraine is the second most disabling condition worldwide, and comorbidities contribute to disease burden, decrease health-related quality of life, and add to economic burden. Identification of migraine comorbidities can help determine diagnosis, improve the ability to assess prognosis, inform the development of treatment regimens, and contribute to research on subtypes.
Here, we give an overview of the key aspects of migraine comorbidities that can help bring about the best outcomes for patients.
What Can Comorbidities Tell Us?
An in-depth knowledge of migraine comorbidities is important to the scientific study and effective management of migraine for several reasons. People with migraine and particular comorbidities may represent homogeneous subgroups with shared underlying biological mechanisms. This may help clarify the genetic and pathophysiologic substrates of migraine and lead to the development of treatments targeted to particular subgroups. Moreover, awareness of comorbidities may inform diagnostic thinking. For instance, diagnostic parsimony may lead to underdiagnosis (eg, is it migraine or epilepsy?), but awareness of common comorbidities may increase accurate diagnosis and facilitate treatment and referral. In patients with diagnosed migraine, epilepsy (a common comorbidity) is more likely, not less likely.
Comorbidities are an important guide for the formulation of individualized treatment plans. Migraine comorbidities indicate therapeutic opportunities and limitations. They may complicate diagnosis and limit treatment options, as in the case of the contraindication to triptan use in patients with cardiovascular disease. Gastrointestinal comorbidity may limit the ability to use nonsteroidal anti-inflammatory drugs. There may be opportunities to treat two conditions with a single therapy. In the case of migraine and depression, an antidepressant or behavioral therapies may help both disorders. Finally, migraine comorbidities provide insights into disease natural history and opportunities to modify clinical course. Several migraine comorbidities have been identified as risk factors for disease progression, and for some of them (eg, depression), increase in severity is associated with increased risk for progression.
The comorbidities of migraine fall into several categories, including cardiovascular diseases and events (eg, stroke, myocardial infarction), psychiatric disorders (eg. depression, anxiety, panic disorder, bipolar disorder), neurologic diseases (eg, epilepsy), sleep and related conditions (eg, insomnia, restless leg syndrome, sleep apnea, poor sleep quality and duration), respiratory conditions (eg, allergic rhinitis, asthma), dermatologic diseases, chronic pain conditions (eg, fibromyalgia), and others. The MAST study, an analysis of 15,133 people with migraine and 77,453 without, compared rates of self-reported medical diagnosis of 21 potential comorbidities between the two groups. Multivariable binary logistic regression modeling was performed, adjusting for sociodemographic characteristics, and odds ratios (ORs) and 95% CIs for each condition were calculated for the two groups. Results showed that people with migraine were significantly (P < .001) more likely than those without migraine to report insomnia (OR, 3.79; 95% CI, 3.6-4.0), depression (OR, 3.18; 95% CI, 3.0-3.3), anxiety (OR, 3.18; 95% CI, 3.0-3.3), gastric ulcers/gastrointestinal bleeding (OR, 3.11; 95% CI, 2.8-3.5), angina (OR, 2.64; 95% CI, 2.4-3.0), and epilepsy (OR, 2.33; 95% CI, 2.0-2.8), among other conditions. In the cohort with migraine, modeling was done to examine rates of comorbidities as a function of reported average headache pain intensity, monthly headache day (MHD) frequency, and the combination of these. Increasing MHD frequency was associated with increased risk for nearly all comorbidities, most prominent among patients with gastric ulcers/gastrointestinal bleeding, diabetes, anxiety, depression, insomnia, asthma, and allergies/hay fever. Increasing headache pain intensity was associated with comorbidities related to inflammation (psoriasis, allergy), psychiatric conditions (depression, anxiety), and sleep disorders (insomnia). This is one of several studies demonstrating that rates of comorbidities increase with greater MHD frequency.
A range of comorbidities has also been identified among adolescents and children with migraine; these include psychological conditions (depression, anxiety), functional movement disorders, obesity, epilepsy, atopic disorders (allergic rhinitis, atopic dermatitis, asthma), neurodevelopmental and neurobehavioral issues (attention deficit hyperactivity disorder), sleep disorders, and celiac disease.
Disease Progression
Many single comorbidities have been identified as risk factors for progression from episodic migraine (EM) (defined as < 15 MHDs) to chronic migraine (CM) (defined as ≥ 15 MHDs). Various combinations of comorbidities or multimorbidity are also associated with medication overuse and new onset of CM. Approximately 2.5% of persons with EM progress to CM over the course of one year, although rates are higher for individuals with some comorbidities and multimorbidities. In a study of 6657 participants with EM, progression to CM after 1 year was significantly related to both the presence and severity of depression. In analyses adjusted for multiple covariates, depression was a significant predictor of CM onset (OR, 1.65; 95% CI, 1.12-2.45). There was also a depression-dose effect. Relative to participants with no depression or mild depression, those with moderate (OR, 1.77; 95% CI, 1.25-2.52), moderately severe (OR, 2.35; 95% CI, 1.53-3.62), or severe depression (OR, 2.53; 95% CI, 1.52-4.21) were at increased risk for CM.
Although depression has been indicated as a risk factor for migraine progression, having a psychiatric comorbidity does not always predict poor treatment outcomes. A trial of 177 participants compared three preventive migraine therapies: beta-blocker, behavioral migraine management, or the two combined. Headache disability was assessed using the Migraine Specific Quality of Life Questionnaire and Headache Disability Inventory. Persons with a mood and/or anxiety disorder recorded larger reductions in migraine days (P < .05) and improvements on the Migraine-Specific Quality of Life Questionnaire (P < .001) and Headache Disability Inventory (P < .01) than did participants with neither diagnosis.
In addition to individual comorbidities, multiple comorbidities have been associated with an increased risk for new-onset CM. Latent class analysis exploring data from the CaMEO study identified eight naturally occurring subgroups of migraine based on comorbidity clusters that exhibited distinct headache features. All comorbidity classes had significantly elevated hazard ratios for risk for progression to CM from EM relative to the “fewest comorbidities” group. Hazard ratios for CM onset ranged from 5.34 (95% CI, 3.89-7.33; P ≤ .001) for the “most comorbidities” group to 1.53 (95% CI, 1.17-2.01; P < .05) for the “respiratory” group.
The Connection Between Migraine and Comorbidities
Several processes have been proposed that account for the link between migraine and comorbid conditions. One possibility is that one disease may directly or indirectly cause the other (unidirectional causality). For example, migrainous infarction could cause epilepsy and create a cortical seizure focus. Alternatively, each condition may predispose to the other (bidirectional causality). A bidirectional relationship has been demonstrated for migraine and depression. Research following people with depression found an OR of 3.4 (95% CI, 1.4-8.7) for developing migraine within 2 years, whereas those with migraine had an OR of 5.8 (95% CI, 2.7-12.3) for developing depression over 2 years.
A third possibility is that an underlying environmental risk factor may account for the linkage. For example, traumatic brain injury predisposes to both migraine and epilepsy and accounts for part of the comorbidity. A fourth possibility is that a shared genetic risk factor may contribute to comorbidity. The genes for family hemiplegic migraine also contribute to the development of epilepsy. The fact that both environmental and genetic risk factors contribute to the links between migraine and epilepsy lead to the hypothesis suggesting that either environmental or genetic risk factors may predispose to a brain state that contributes to the expression of two comorbid disorders. For migraine and epilepsy, that may be a brain state of neuronal hyperexcitability.
Additional research is required to characterize the mechanistic links between migraine and many comorbidities. Nevertheless, having knowledge of prevalent comorbidities can increase diagnostic vigilance. The following clinical recommendations may enhance disease management:
- Screen patients with migraine for common comorbidities. Similarly, suspect migraine in persons with such conditions as depression, anxiety, or epilepsy.
- Educate patients about comorbidities and normalize the experience to reduce stigma.
- Monitor and track changes over time in both migraine and comorbid conditions.
- Treat comorbidities to the extent of personal comfort level and/or refer for treatment (may include pharmacologic, behavioral and lifestyle approaches, or a combination) as appropriate.
Comorbidities in migraine contribute to disease burden, both on an individual level where it is associated with increased disability and reduced health related quality of life, and on a societal level, where it is associated with greater economic impact and burden. Exploration of the pathways that drive these comorbidities in migraine may lead to insights that further illuminate pathophysiology and improve treatment. Whereas it has been established that treating migraine improves some of these comorbidities (eg, depression and anxiety), it is less well known whether treating various comorbidities improves or reduces migraine frequency, severity, or associated disability.
Continued exploration of these questions is necessary for improving patient care and outcomes. In the meantime, healthcare professionals should remain vigilant for comorbidities in their patients with migraine and actively assess, treat, and/or refer as appropriate in order to obtain the best outcomes possible.
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