Migraine is a prevalent and disabling neurological disorder characterized by recurrent episodes of moderate to severe unilateral headache, frequently accompanied by nausea, vomiting, photophobia, and phonophobia [¹,²]. It is ranked among the leading causes of years lived with disability worldwide, particularly affecting individuals in their most productive years of life [³]. According to recent estimates, migraine affected over 1.1 billion people globally in 2021, representing a 58.15% increase in prevalence since 1990 and underscoring its substantial and growing public health burden [⁴,⁵]. Allergic rhinitis (AR) is an IgE-mediated inflammatory condition of the nasal mucosa triggered by exposure to allergens. While commonly perceived as a localized upper airway disease, AR has been increasingly associated with systemic inflammatory processes and a variety of comorbidities [⁶]. Its prevalence ranges from 10% to 30% in adults, with even higher rates reported in pediatric populations [⁷]. Given the immunological basis of both AR and migraine, a potential pathophysiological link has been proposed. Several shared mechanisms may underpin the relationship between AR and migraine, including mast cell activation, histamine release, and cytokine-mediated neuroinflammation, which can contribute to the sensitization of the trigeminovascular system —a central pathway implicated in migraine pathogenesis [⁸]. However, recent genetic evidence from Mendelian randomization analyses does not support a causal relationship, suggesting that previously reported associations may be confounded by environmental or diagnostic factors [⁹]. Moreover, an association between migraine and other allergic conditions, including atopic dermatitis, was observed [¹⁰]. Given these conflicting observations, a comprehensive synthesis of the available literature is warranted. While previous meta-analyses, such as the one by Yang et al., have explored the association between atopic dermatitis and headache disorders, no prior study has quantitatively assessed the specific relationship between allergic rhinitis (AR) and migraine headaches using pooled odds ratios compared to healthy controls. Therefore, this systematic review and meta-analysis were undertaken to estimate the pooled odds ratio of migraine in individuals with AR and to evaluate the strength and consistency of this association across observational studies.

The link between different atopic conditions and headache has been studied in previous literature, and meta-analyses have investigated the association between atopic conditions and headache. However, to our knowledge, this is the first meta-analysis to focus on studying the prevalence of co-occurrence of allergic rhinitis (AR) and migraine headache. This systematic review and meta-analysis investigated 11 observational studies with a total of 4,704,591 participants. Our primary finding indicated a significant association between AR and migraine headache, with an odds ratio of 2.94. Subgroup analysis demonstrated a stronger association between migraine headache and allergic rhinitis in the hospital setting compared to the general population. Remarkably, the accurate diagnosis of AR appeared to affect the association between the two conditions significantly. Our results also showed comparable associations between both conditions within different age groups and geographical regions.

Although the exact mechanism of the coexistence of migraine headache and AR has not yet been fully determined, previous research suggests common immunological mechanisms [²⁷,²⁸,²⁹,³⁰], as well as responses to the same medications [³¹,³²,³³]. This flowchart summarizes key mediators currently believed to be involved in the development of both conditions . This flowchart illustrates the common mediators activated in both migraine and allergic rhinitis, as well as their roles in both pathways.

The role of histamine in both conditions has been repeatedly studied in previous literature; a study by Lassen et al. showed that histamine infusion provoked migraine attacks, and those attacks could be blocked by pretreatment with pyrilamine maleate but not with placebo [³⁴]. Histamine was hypothesized to modulate hypothalamic function and activity, which may have a major role in migraines and influence the severity of migraine attacks [³⁵]. Moreover, whole blood from migraineurs was found to have significantly elevated levels of histamine compared to the control group [²⁸]. A study by Forcelini et al. on pediatric populations suggests that the inflammatory response associated with AR is believed to contribute to the development and worsening of migraines by activating immune mechanisms [³⁶]. Symptoms such as nasal congestion, discharge, and sneezing in AR involve heightened trigeminal nerve transmission, which is linked to migraine [³⁶]. Suggesting a mutual relationship between both conditions rather than a one-way association. These results indicate a wide area of overlap between the two conditions, both in pathogenesis and management [²⁸,³²,³⁶,³⁷]. A study by Zencir et al. failed to demonstrate a significant association between migraine and allergic rhinitis in pediatric patients [²⁶], highlighting the need for further research to investigate the complex interplay between these conditions.

In addition to the stated common inflammatory mediators between allergic rhinitis and migraine, different confounding factors that affect both conditions have been identified in previous literature. [⁶,⁵] Psychological factors, including anxiety and depression, as well as sleep disturbances, have been repeatedly linked to both migraine and allergic disease. [⁶,⁸,⁷] Additionally, dietary mediators pose a notable confounder; biogenic amines, such as histamine and tyramine, present in aged cheeses, cured meats, fermented products, and certain beverages, are well-documented migraine triggers due to their vasoactive and neuromodulatory properties. [⁴,⁹,⁵] These dietary factors also have the potential to provoke allergic-like responses via mast cell activation and histamine release, thereby confounding migraine–allergy associations. [¹⁰] Considering the divergent selection of the population, our analysis revealed a notable association between hospitals and patients. The odds ratio is 7.32 for hospital patients compared to 2.35 for the general population. This discrepancy may be partly explained by Berkson’s bias, which arises when both the exposure and the disease increase the likelihood of hospitalization, thereby inflating the observed association in hospital-based samples [¹¹]. In this context, patients with more severe disease are more likely to seek or require hospital care, leading to an overrepresentation of severe cases and potentially related comorbid conditions. This is supported by Derebery et al. [¹⁷,²⁵], who observed that patients with moderate to severe rhinitis tend to have more comorbidities than those with mild disease. The following reason could be the cause:

A selection bias that occurs when hospital-based populations are used. People with multiple conditions (e.g., both migraine and AR) are more likely to be hospitalized, making comorbidities seem more common than in the general population. Patients with more severe or complex symptoms are more likely to be referred to tertiary care centers (e.g., specialty clinics or hospitals). This means the population in hospital-based studies isn’t representative of the general population. In tertiary care, patients are often thoroughly evaluated, so multiple conditions are more likely to be diagnosed—this inflates the observed association between two diseases like AR and migraine.

Similarly, Aamodt et al. observed that the frequency of migraine attacks was positively correlated with the association with all types of asthma-related disorders [¹⁶], further contributing to the differential representation in hospital settings.

Another reason for the higher association observed in hospital-based populations is what Aamodt et al. described as “personality trait”, which means that patients who report their AR symptoms are more likely to report headache symptoms once they develop it [¹⁶]. Also, the fact that most studies on the general population relied on self-report or previous diagnosis of one or more conditions may question the accuracy of the diagnosis [³⁸].

Furthermore, considering the effect of diagnostic accuracy, we analyzed the results according to the diagnostic system used in each study for both AR and migraine. Interestingly, when the skin prick test (SPT) was used for diagnosing AR, the results showed a significant association with migraine, with an odds ratio of 6.93, compared to 2.59 and 2.06 for previous diagnosis and self-report, respectively. SPT is believed to be the gold standard in AR diagnosis [³⁵], likely contributing to more accurate assessment and higher diagnostic rates [³⁶,³⁹], thereby amplifying the observed association. This finding underscores the importance of diagnostic precision in elucidating the relationship between migraine and AR. It also underlines the necessity of utilizing standardized diagnostic procedures in future research to ensure consistency and reliability.

Notably, different diagnostic methods of migraine showed statistically significant results that are consistent across variables. However, whereas many studies relied on self-report or previous migraine diagnosis, it is of fundamental importance to note that applying the International Headache Society (IHS) classification system had a pivotal role in the results. Eross et al. concluded in their study that 86% of patients with a self-diagnosis and/or physician diagnosis of “sinus headache” have migraine (63%) or probable migraine (23%) as defined by the IHS Classification Criteria [⁴⁰]. A finding replicated by Cady and Schreiber, who found in their study that 90% of physicians and/or self-diagnosed sinus headaches meet IHS criteria for migraine [⁴⁰]. Another study by Schreiber assessed more than 2000 patients with reported sinus headaches and found that 80% had migraine [⁴¹]. These findings indicate that the actual number of migraine cases is significantly underestimated in existing records, and further prospective studies are needed to assess the effect of using the IHS criteria as a standard of migraine diagnosis and its impact on the results of future research. Subgroup analysis within different age groups, geographic regions, and study designs demonstrated a statistically significant relationship between AR and migraine. However, it is important to note that the consistently elevated odds ratios associated with these factors reinforce the robustness of the association between the two conditions and may reflect an underlying biological link. Overall, the subgroup analysis enhances our understanding of the complex dynamics of AR and migraine headache, considering the accuracy of diagnosis, the selection of population, and the sample size as important factors affecting their co-occurrence.

In this systematic review, we conducted a meta-analysis based on a systematic evaluation of previous research results, resulting in a relatively large sample size and confirming the link between AR and migraine. This meta-analysis also explored more precise connections between migraine and AR by considering age, regional variations, distinctions in study populations, and diverse diagnostic approaches for AR and migraine. The results of this investigation need further validation and exploration. Despite its limitations, the study results still provide preliminary clues about the potential connection between AR and migraine.

Several reasons contribute to the strength of this study. First, as a comprehensive analysis, we applied systematic review and meta-analysis methods, integrating data from 11 studies that encompassed more than 4 million participants, to investigate the association between AR and migraine. Second, extensive subgroup analysis has enabled a deeper understanding of the nuanced dynamics between the two conditions and a better understanding of the variable association between the AR and migraine in different populations. Third, it highlighted the potential effect of diagnostic accuracy and questioned the need for standardized diagnostic systems, thereby providing direction for future research. The study also has certain limitations. First, the study’s limited causality is a result of its observational design; therefore, it can only determine the association between the two conditions, rather than assessing the causal effect or determining the pathogenesis of both conditions. Second, substantial heterogeneity was observed among studies, likely reflecting variability in sample demographics, diagnostic methods of both conditions, and study designs. This limits the generalizability of our findings and underscores the need for more uniform study designs and diagnostic methods in future research. Additionally, tests for publication bias are underpowered when based on fewer than 10 studies and should be interpreted with caution. Despite the heterogeneity between the two cohort prospective studies, which can be attributed to differences in population characteristics, age groups, diagnostic coding, and sample size, both studies contributed to a pooled risk ratio of 2.27 (95% CI: 1.10–4.65, p = 0.026). This suggests a statistically significant association between AR and the development of migraine. As prospective studies, these findings imply that AR can be a contributing risk factor for migraine rather than being only a co-existing condition. Additionally, higher effect sizes observed in smaller studies may indicate potential small-study bias, which warrants cautious interpretation of the findings and highlights the need for larger, high-quality investigations. Also, many included studies relied on self-reported or historical diagnoses, introducing potential misclassification bias

Our findings demonstrate a significant association between allergic rhinitis (AR) and migraine. This relationship appears particularly relevant in cases where sinus headache symptoms persist or are resistant to typical explanations. Further research is warranted to clarify the nature of this association, ideally through prospective cohort studies with consistent diagnostic criteria and better control of confounding variables. Further high-quality prospective research is required before changes to screening or management practices can be recommended. In addition, the causal relationship between both conditions and the potential response of AR and migraine to the same management protocol is an insightful area that requires future research.