Asthma is a chronic inflammatory disorder of the airways characterized by clusters of clinical respiratory symptoms. Many cells and cellular elements, such as mast cells, macrophages, and T lymphocytes, play a significant role in asthma (1). Reversible airway obstruction, airway inflammation, and airway hyperresponsiveness are the main features of asthma. Patients with asthma generally experience recurrent episodes of wheezing, coughing, dyspnea, and chest tightness, especially early in the morning and at night. Asthma is a serious global health problem affecting 1–18% of the population in different countries, estimates have indicated that 8% of adults aged 18 and over in the United States currently have asthma (2, 3). The global asthma prevalence is continuing to rise over the last decades (4). In addition, asthma is associated with many mental health disorders, such as major depressive disorder, bipolar disorder, and anxiety disorder (5).

Migraine is a severe neurobiological headache disorder characterized by various combinations of neurological, gastrointestinal, and autonomic changes (6). People with migraines may experience paroxysmal unilateral headache, vomiting, nausea, and severe sensitivity to light and sound, resulting in poor quality of life. Hours to days before a migraine attack, 20–60% of patients with migraine can experience premonitory symptoms, such as depression and cognitive dysfunction (7). Migraine is considered one of the most disabling medical diseases in the world. According to the findings of the Global Burden of Disease 2019, migraine ranked second among the global causes of disability, affecting an estimated 1.04 billion people worldwide (8).

Asthma is hypothesized to be an “acephalgic migraine” or a “pulmonary migraine” (9, 10). Previous studies have indicated that asthma and migraine share similar pathophysiology (11). Both asthma and migraine are characterized by inflammation and activation of smooth muscles in the airway or blood vessels. In addition, the shared environmental or genetic factors between asthma and migraine could induce subsequent diseases. Previous studies have demonstrated that long-term exposure to multiple air pollutants (such as air pollution, volatile organic compounds, oil, and gas wells, etc.) is a potential role for the occurrence or aggravation of asthma and migraine (12, 13). The polymorphisms of transient receptor potential receptors located on the trigeminal nerve and sensory afferents in the lungs are an example of genetic factors that account for the association between asthma and migraine (14). A previous systematic review and meta-analysis reported an association between asthma and migraine (15). However, the strength of the findings was limited by the lack of clear differentiation between migraines and general headaches. This study aimed to specifically explore the association between asthma and migraine while considering multiple confounders.

To our knowledge, our study is not the first meta-analysis to examine the association between asthma and migraine. The previous meta-analysis by Sayyah et al. (15) indicated the bidirectional association between asthma and migraine. But they mistakenly considered headache the same as migraine and included studies both on headache and migraine in the meta-analysis, which may reduce the accuracy and validity of the outcome. In addition, both children and adults with asthma were included in their meta-analysis without an appropriate acknowledgment that the pathogenesis and manifestations may differ between the age groups. In addition, the comorbidities and medication use in asthma or migraine may account for their relationship, but this systemic review and meta-analysis did not mention that. Whereas, our study made a clear distinction between migraine and headache, and only included adults for the meta-analysis, which may increase the quality of evidence for the outcome. In addition, we added more recent studies (two cross-sectional studies and one cohort study) and analyzed the data separately according to study design and multiple confounders, thus providing more rationality evidence on the association between asthma and migraine than previous studies.

Our study showed that asthma was associated with a moderately increased risk of migraines. Similar results were found in the subgroup meta-analyses according to age, methodological quality, and adjustment for confounding factors. When analyzing only cohort studies, this association remained significant, suggesting asthma as a potential risk factor for migraines. Nevertheless, owing to the limited number and quality of cohort studies included in the meta-analysis, the general conclusion is far from definitive at this stage.

The mechanisms underlying the association between asthma and migraine could be thought of from the perspective of inflammation, immune dysfunction, and environmental triggers. Atopy, parasympathetic hyperactivity, and elevated neuropeptide release are the main pathophysiological factors of inflammation and immune dysfunction that play a crucial role in the pathogenesis of asthma and migraine. For patients with asthma, exposure to allergens, such as grass, pollen, and animal hair, may trigger an airway hypersensitivity response mediated by mast cells. Plasma cells produce allergen-specific immunoglobulin E antibodies due to the hypersensitivity response, which can stimulate mast cells to release a variety of inflammatory mediators (e.g., histamine, prostaglandins, chymase, tryptase, etc.) and cytokines (TGFβ1, TSLP, IL-33, IL-23, etc.) (27, 28). In migraines, meningeal mast cells are in proximity to meningeal blood vessels and nociceptive axons. When meningeal mast cells are activated by allergens, they degranulate and secrete large numbers of inflammatory cytokines [e.g., Tumor necrosis factor (TNF)], leading to neurogenic inflammation, which activates or sensitizes nociceptors and neurons and influences the reactivity of signal nociceptors to the brain, thereby triggering the genesis of migraine (29). A previous study has shown that allergy shots can reduce the frequency of migraine by up to 48% in young patients with atopic migraine; a finding which strongly supports that atopy is a potential mechanism of migraine (30). In addition, a previous study had shown that exposure to tobacco smoke appeared to skew immune responses mainly by altering the immune functions of varieties of immune cells and aggravating allergic inflammation and sensitization, which is implicated in the pathogenesis of asthma and migraine (31, 32).

Asthma and migraine are characterized by parasympathetic hyperactivity. Parasympathetic nerves innervate the lungs and control the symptoms of asthma through peripheral muscarinic receptor signaling. Activated by inflammatory mediators, the parasympathetic nerves signal the airway smooth muscles and secretory glands, mediating airway stenosis and increased mucus secretion, which are the key features of an asthmatic response (33). Similarly, the parasympathetic nerves supply meningeal vessels via the sphenopalatine ganglion. Many neurotransmitters, such as acetylcholine, vasoactive intestinal polypeptide, and pituitary adenylate cyclase-activating polypeptide, are released from parasympathetic nerves, which play important roles in the mechanism of migraine (34). A previous study demonstrated that the blood velocity in the middle cerebral artery slowed during a migraine attack, reflecting the vasodilation of cerebral vessels, which is a result of increased parasympathetic tone (35). Thus, we hypothesized that the generalized parasympathetic hyperactivity observed in patients with asthma might contribute to their increased susceptibility to migraines.

Both asthma and migraine are also characterized by elevated neuropeptide release. Activated by endogenous or inhaled irritants, the airway C-fiber sensory nerves release various neuropeptides, such as calcitonin gene-related peptide, neurokinins, and tachykinins, inducing mucus secretion, inflammation, and constriction and hyperactivity of the airway, all of which are key features in the pathophysiology of asthma (36). Similarly, neuropeptides may initiate neurogenic inflammation and participate in the sensitization of the trigeminal system, both of which play key roles in the initiation of migraines.

It is also possible that migraines are not directly caused by asthma; shared environmental triggers may be responsible for the association between them. Studies have shown that air pollution, such as high concentrations of PM2.5, PM10, and NO₂, can induce asthma and even aggravate its symptoms (37). Similarly, the rate of emergency treatments for migraines increases due to exposure to air pollution (38). Considering that asthma is diagnosed earlier than migraine, we hypothesized that the impact of environmental triggers on asthma precede their impact on migraine. Psychological factors also account for the association between asthma and migraine. The findings of previous studies suggest that asthma and mental health disorders share genetic risk factors (5). Asthma is associated with a 1.81-fold increased risk for mental health disorders (39). Depression and stressful events are the main risk factors for migraine or the progression of acute migraine to chronic migraine (40). Thus, effective control of environmental and psychological factors may reduce the occurrence of asthma and migraine.

Additionally, sleep-related disorders could be a latent confounder account for the relationship between the two diseases. In asthmatic patients, poor quality sleep and sleep disturbance are highly prevalent, the symptoms of increased sleep latency, a reduction in slow-wave sleep, and reduced sleep efficiency can be seen in asthmatic patients and have been objectively demonstrated in the previous studies (41). In migraines, poor sleep has been consistently reported both in precipitating and during attacks and physicians regularly consider sleep as a treatment for migraine (such as selecting medications with sedative sides effects) (42, 43). Many studies have reported that the prevalence of migraine is higher in patients with sleep disorders (such as insomnia, parasomnias, sleep-related movement disorders) compared with those without (44).

The medication use in asthmatic patients may account for the relationship between asthma and migraine. Theβ₂-adrenoceptor agonists (such as salbutamol, salmeterol) are the most effective and widely used drugs that rapidly reverse bronchoconstriction and have become standard bronchodilators for the emergency room treatment of asthma, and as a day-to-day reliever medication (45). A study conducted in a United Kingdom cohort of 15,407 patients found that headache was associated with the use of salmeterol and was one of the most common adverse reactions to salmeterol (46). Hence, we hypothesized that the series of drugs to treat asthma may be a risk factor for migraines. Moreover, β-blockers are the most widely used class of drugs in prophylactic migraine treatment (47). However, previous studies indicated that the administration of β-blockers could increase airway hyperresponsiveness and airflow limitation which could induce asthma symptoms or exacerbations in people with asthma (48). Therefore, the lack of administration of β-blockers in asthmatic patients may aggravate the symptoms of migraine. In addition, asthma is often associated with numerous comorbidities which may mediate its relationship with migraine. A nationwide case-control study (N = 40,477,745) conducted in Germany found that more than 50% of patients with asthma had mental diseases and every fourth patient had a diagnosis of depressive episode and every fifth patient had sleep disorders (49). And these diseases have been confirmed to have a link with migraines, historically (44, 50, 51). Our subgroup meta-analysis according to the adjustment of medication use and comorbidities found that the association between asthma and migraine was lower than the whole group meta-analysis, which could provide evidence for our hypothesis.

The findings of this study suggest that a relationship exists between asthma and migraine. Clinicians should be aware that patients with asthma show an increased incidence of migraines. Although asthma and migraine may have similar pathogeneses, it is difficult to determine whether there is a direct relationship between them. More large-scale prospective studies are warranted to verify the findings of this study and to provide more information on the association between asthma and migraine.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

L-LK made great contributions to data acquisition, analysis and interpretation, and manuscript writing. P-EC has done lots of work on data acquisition and manuscript revision. T-HT and C-WC made substantial contributions to the design and conception of the study and revised the manuscript. All authors have read and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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