Comorbidities of primary headache disorders: a literature review with meta-analysis

DOI: https://doi.org/10.1186/s10194- 021- 01281- z

Abstract-Summary The aim of this study is to provide a comprehensive description of the pooled preva- lence of comorbidities of primary headache disorders using a meta-analytical approach based on studies published between 2000 and 2020.

Scopus was searched for primary research (clinical and population studies) in which medical comorbidities were described in adults with primary headache disorders.

310

2 Mechanisms

We compared prevalence of comorbidities among headache sufferers against general population using GBD-2019 estimates, and compared comorbidities’ pro- portions in clinical vs. population studies, and by age and gender.

A total of 139 studies reporting information on 4.19 million subjects with pri- mary headaches were included: in total 2.75 million comorbidities were reported (median per subject 0.64, interquartile range 0.32–1.07).

The most frequently addressed comorbidities were: depressive disorders, addressed in 51 studies (pooled proportion 23%, 95% CI 20–26%); hypertension, addressed in 48 studies (pooled proportion 24%, 95% CI 22–26%); anxiety disor- ders addressed in 40 studies (pooled proportion 25%, 95% CI 22–28%).

For conditions such as anxiety, depression and back pain, prevalence among

headache sufferers was higher than in GBD-2109 estimates.

Some of the most relevant comorbidities of primary headache disorders – back pain, anxiety and depression, diabetes, ischemic heart disease and stroke  – are among the most burdensome conditions, together with headache themselves, according to the GBD study.

Extended: The aim of present study is to provide a comprehensive description of the main comorbidities of primary headaches, i.e. migraine, TTH and CH, using a meta-analytical approach based on clinical studies and population surveys carried out between 2000 and 2020.

A total of 33 main comorbidities, including five large-group categories referred as “any” (e.g. Any cancer, Any substance use disorder) and seven additional groups referred as “others” (e.g. Other cancers, Other neurological disorders), were reported in more than 2.5% of the studies.

The most frequently addressed comorbidities were: depressive disorders, hyper- tension, anxiety disorders and diabetes, addressed in 51, 48, 40 and 39 studies, respectively.

Introduction Comorbidities of primary headache disorders, include neurological, metabolic and cardiovascular conditions, e.g. stroke, epilepsy, multiple sclerosis, obesity, diabetes, hypertension, sleep disorders.

This constellation of comorbidities complicates the clinical management and the outcomes of primary headache, especially in chronic forms, where symptoms over- lap [337, 338].

Understanding the bidirectional relationships between primary headaches and presence of specific comorbidities may provide epidemiological and clinical clues concerning the pathophysiological mechanisms, the progression from episodic to chronic form, the appropriate diagnosis and treatments.

There are no pooled data on comorbidity in primary headache, as research has mostly investigated specific relations, and therefore provided bidirectional informa- tion on relations such as migraine-hypertension, TTH-musculoskeletal disorders or CH-bipolar disorder.

The aim of present study is to provide a comprehensive description of the main comorbidities of primary headaches, i.e. migraine, TTH and CH, using a

2.3 Comorbidities

311

meta- analytical approach based on clinical studies and population surveys carried out between 2000 and 2020.

Methods For full texts evaluation, studies had to: (a) be available in full text; (b) be published on peer-reviewed journals in English; (c) include primary research (i.e. case reports letters, commentaries, editorials, reviews, and congress proceedings were excluded); (d) include adult subjects; (e) include subjects with primary headache disorders only, or studies with both primary and secondary headache disorders if the different group of subjects could be addressed separately for frequency of comorbidities (i.e. we included studies on both primary and secondary headache disorders if comor- bidities could be referred to the subjects with primary headaches, by “downsizing” the sample accounting only for those with primary headaches).

Included studies were equally and randomly assigned to fourteen authors who extracted the following information: study type, i.e. clinical study vs. population survey; number of involved subjects for each type of primary headache, i.e. migraine, TTH, CH and trigeminal autonomic cephalalgias (TACs), and other primary head- aches; when available, the total number of subjects and number of females, the average age (mean or median as available), the number of employed subjects, and the frequency of headache reported as monthly headaches were extracted too.

Results Higher comorbidity proportions were observed in clinical studies, specifically for thyroid diseases, fibromyalgia, sleep disorder, restless leg syndrome (RLS), depres- sive disorders, anxiety disorders, post-traumatic stress disorder.

Taken as a whole, it can be concluded that higher comorbidity rates are observed among samples enrolled in clinical studies (median comorbidity per subject 0.70, IQR 0.40–1.09) than among samples from population studies (median 0.50, IQR 0.29–0.97).

Higher comorbidity proportions were observed in studies with a higher percent- age of females for fibromyalgia, RLS, depressive disorders, and anxiety disorders.

Taken as a whole, it can be concluded that difference in females’ prevalence across sample has a limited effect on total comorbidity rates, as the median and interquartile ranges were largely overlapping (median 0.66, IQR 0.34–1.03 for stud- ies with higher female percentage; median 0.61, IQR 0.30–1.05 for studies with lower female percentage).

Discussion With these caveats in mind, it can be concluded that specific age and gender-based association can be found: hypertension is likely to be found as a comorbidity in studies whose participants are older and with higher men presence, whereas fibro- myalgia, RLS, and depressive disorders are likely to be found as comorbidities in studies whose participants are younger and with higher female presence.

In consideration of migraine epidemiology, which mostly affects younger females, and of the research design herein employed (i.e. the fact that we looked for comorbidities among headache disorders), our result showing an association with younger age in addition to female gender can be justified.

312

2 Mechanisms

In order to address whether headache disorders are associated to a higher preva- lence in the selected comorbidities, we contrasted such rates with the estimates generated by the GBD-2019 study.

Conclusions The results of this literature review with meta-analysis of comorbidities of primary headache disorders show that some of the most prevalent comorbidities of headache disorders – such as hypertension, back pain, anxiety and depression, diabetes, isch- emic heart disease and stroke—are among the most burdensome conditions and relevant risk factors according to the GBD study together with headache disorders themselves.

Many comorbidities could merely reflect coincidence of diseases that are com- mon: however, the prevalence rate of some of them (e.g. back pain, sleep disorders, anxiety and depression) was higher when addressed as comorbidities of headaches compared to the general population estimates produced by GBD-2019.

Acknowledgement A machine generated summary based on the work of Caponnetto, Valeria; Deodato, Manuela; Robotti, Micaela; Koutsokera, Maria; Pozzilli, Valeria; Galati, Cristina; Nocera, Giovanna; De Matteis, Eleonora; De Vanna, Gioacchino; Fellini, Emanuela; Halili, Gleni; Martinelli, Daniele; Nalli, Gabriele; Serratore, Serena; Tramacere, Irene; Martelletti, Paolo; Raggi, Alberto; 2021  in The Journal of Headache and Pain.

Comorbid and co-occurring conditions in migraine and associated risk of increasing headache pain intensity and headache frequency: results of the migraine in America symptoms and treatment (MAST) study