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The Journal of Headache and Pain logoLink to The Journal of Headache and Pain
. 2021 Jul 14;22(1):71. doi: 10.1186/s10194-021-01281-z

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

Valeria Caponnetto 1,✉,#, Manuela Deodato 2,3,✉,#, Micaela Robotti 4,5, Maria Koutsokera 6, Valeria Pozzilli 7, Cristina Galati 8, Giovanna Nocera 8, Eleonora De Matteis 9, Gioacchino De Vanna 10, Emanuela Fellini 7, Gleni Halili 11, Daniele Martinelli 12,13, Gabriele Nalli 7, Serena Serratore 7, Irene Tramacere 14, Paolo Martelletti 15,16,#, Alberto Raggi 17,#; On behalf of the European Headache Federation School of Advanced Studies (EHF-SAS)
PMCID: PMC8278743  PMID: 34261435

Abstract

Background

Primary headache disorders are common and burdensome conditions. They are associated to several comorbidities, such as cardiovascular or psychiatric ones, which, in turn, contribute to the global burden of headache. The aim of this study is to provide a comprehensive description of the pooled prevalence of comorbidities of primary headache disorders using a meta-analytical approach based on studies published between 2000 and 2020.

Methods

Scopus was searched for primary research (clinical and population studies) in which medical comorbidities were described in adults with primary headache disorders. Comorbidities were extracted using a taxonomy derived from the Global Burden of Disease (GBD) study. We compared prevalence of comorbidities among headache sufferers against general population using GBD-2019 estimates, and compared comorbidities’ proportions in clinical vs. population studies, and by age and gender.

Results

A total of 139 studies reporting information on 4.19 million subjects with primary 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 disorders 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. Associations with average age and female prevalence within studies showed that hypertension was more frequent in studies with higher age and less females, whereas fibromyalgia, restless leg syndrome, and depressive disorders were more frequent in studies with younger age and more female.

Conclusions

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. A joint treatment of headaches and of these comorbidities may positively impact on headache sufferers’ health status and contribute to reduce the impact of a group of highly burdensome diseases.

Supplementary Information

The online version contains supplementary material available at 10.1186/s10194-021-01281-z.

Keywords: Primary headache, Migraine, TTH, CH, Comorbidity, Depression, Obesity, Diabetes, Hypertension, Stroke, Sleep disorders

Introduction

The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 showed that headache disorders ranked third out of 369 conditions in terms of years lived with disability (YLDs) for both sexes, and the first in people aged 15–49 (accounting for 8 % of all-cause YLDs), with migraine ranking second and accounting for 7.3 % of all-cause YLDs [1, 2]. However, GBD estimates are biased by the adjustment for comorbidities, which is based on the assumption of the independent distribution of comorbid conditions. This is particularly critical as headache disorders have comorbidity for a variety of conditions, and headache – at least as a symptom – is a common experience to anyone, with any kind of health condition. The presence of multiple medical conditions, which constitutes part of the multifaceted and fragmented burden of headache disorders, is likely to lead to an increase of headache-related disability and cost for societies [3, 4].

Extensive research has recognized an association between primary headache and various comorbidities, as shown in some literature reviews [3, 510]. Comorbidities of primary headache disorders, include neurological, metabolic and cardiovascular conditions, e.g. stroke, epilepsy, multiple sclerosis, obesity, diabetes, hypertension, sleep disorders. In addition to these, mental health conditions, such as depression or anxiety, have been outlined: however, these comorbidities are sometimes poorly defined and addressed as symptoms of depression or anxiety. The same applies to chronic pain disorders for example fibromyalgia, low back pain or neck pain, and other musculoskeletal disorders [3, 68].

This constellation of comorbidities complicates the clinical management and the outcomes of primary headache, especially in chronic forms, where symptoms overlap [6, 7]. It is still difficult to determine through what mechanisms the conditions become comorbid. Comorbidity may act as risk factor for chronicity or as trigger for headache. Comorbidity may be a consequence of repeated headache attacks or headache treatments or a sequelae of other factors shared with headache [3, 57], and comorbidities are among the main drivers of chronification in migraine sufferers [11, 12]. Most of the available research on comorbidities of primary headaches is focused on migraine, with little appraisal of the comorbidities of tension-type headache (TTH) and cluster headache (CH).

Therefore, 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. In addition, a better knowledge of comorbidity in primary headache could contribute to drive the therapeutic symptomatic and prophylactic approaches, both pharmacological and non-pharmacological [13]. Indeed, non-pharmacological approaches, such as nutraceuticals, non-invasive neurostimulation, behavioral therapies and physical therapy, represent valid complementary options especially for patients with specific comorbidities, for those overusing medication, or for pregnant women [1417]. A major awareness of the role of comorbidity in primary headache may therefore help clinicians in clinical management, improve headache sufferers’ quality of life and reduce impact on societies, defined in terms of disability, cost or reduced work productivity [4, 1822].

Currently, there are no pooled data on comorbidity in primary headache, as research has mostly investigated specific relations, and therefore provided bidirectional information on relations such as migraine-hypertension, TTH-musculoskeletal disorders or CH-bipolar disorder. However, the simultaneous presence of primary headaches disorder and multiple medical conditions has not been subject to a full meta-analytic approach. Therefore, we currently have a partial understanding of the comorbidities that clinicians working with patients suffering from headache disorders may find in daily clinical practice.

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.

Methods

We conducted a literature review with meta-analysis and reported results according to the ‘Preferred Reporting Items for Systematic Reviews and Meta-Analyses’ (PRISMA) [23].

Search strategy

In order to identify suitable keywords for the search strategy, a pilot search was performed in Scopus and PubMed Mesh terms. All detected synonyms of ‘migraine’, ‘tension type headache’, ‘cluster headache’, ‘headache’ and ‘medication overuse headache’ (21 terms in total) were combined with the keywords ‘comorb*’, ‘multimorb*’, and all the keywords described as comorbidities of primary headaches, as described in the literature retrieved through a pilot search (66 terms in total). A search on Scopus covering the period between January 1st 2000 and October 9th, 2020 for primary research papers published in English and with an abstract was performed. Review keywords were searched in titles and abstracts: retrieved results were filtered according to relevant subject area (e.g. material sciences, arts and humanities, veterinary, energy) to exclude studies reporting non pertinent keywords. Extended search string is described in Table 1 of the Supplementary file. Retrieved references were managed with Endnote Web.

Study selection

Retrieved references were equally and randomly assigned to twelve authors who screened titles and abstracts for eligibility. Three authors (VC, MD and VP) performed the double check about titles and abstracts eligibility of 20 % randomly selected references. To be eligible and be evaluated in full texts, titles and abstracts had to focus on primary headache disorders in adults: case reports letters, commentaries, editorials, reviews, and congress proceedings were excluded. In this phase, the agreement among the judgements of the raters (inter-rater reliability) was estimated with Krippendorff’s alpha coefficient (α) ranging from 0 (totally disagree) to 1 (totally agree). Any disagreement was resolved by discussion with a third author (AR) until consensus was reached.

Eligible references were equally and randomly assigned to fourteen authors who screened full texts for inclusion. 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 comorbidities could be referred to the subjects with primary headaches, by “downsizing” the sample accounting only for those with primary headaches). Studies reporting subjects with medication overuse headache were included only if they specified which was the underlying primary headache disorder, such as chronic migraine or chronic TTH, which was then extracted. All authors performed a double check on 50 % of the full texts and Krippendorff’s α was calculated: the choice for such a high rate is due to the large set of co-authors.

Data extraction

Data extraction was performed through an ad hoc electronic spreadsheet of Microsoft Excel for Windows. 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 headaches; 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. If the information was not directly available (e.g. females referred as percentage, or headache frequency on a three-month basis), it was calculated.

For each study, the total number of comorbidities was extracted relying on the total number of subjects included in each study and not on the single primary headaches. The only exception was for those studies in which subjects with both primary and secondary headaches were included, and comorbidities referred to subjects with primary headache could be extracted separately from the other studies’ participants: in this cases, the total sample was “downsized” to that of participants of interest for our review. The choice of referring to the whole sample level (with the aforementioned exception) is due to the fact that in most of the studies comorbidities were reported at the whole sample level only, and not by showing the share of comorbidities by different primary headaches, e.g. by migraine vs. TTH, or by episodic vs. chronic migraine.

In order to extract comorbidities, the classification used by the recent publications of the GBD, which comprises a total of 105 non-communicable diseases, was used (see http://ghdx.healthdata.org/gbd-results-tool). Such a taxonomy included higher-level categories (e.g. Mental health disorders) and lower-level ones (e.g. Depressive disorders, Bipolar disorder, Psychotic disorders, Anxiety disorders) and a “Other” category in which those not included in the main categories are included: for example, “Other mental disorders” might include dissociative disorders or gender dysphoria. Once data were extracted, in case some comorbidities were reported by less than 2.5 % of the studies, then these were reclassified into the “other condition” by main disease type. Once the full set of comorbidities from the pre-defined list was completed, the “other” categories were revised in order to identify possible recurrent conditions that were not included in the GBD-derived list. If a condition was included in more than 2.5 % of the studies, then it was addressed as a stand-alone comorbidity.

Data analysis

We descriptively summarized data reported to provide an overview of the included studies and samples in the studies, using medians and interquartile ranges (IQR) for raw data.

The measure of interest was the proportion of subjects with each single comorbidity among subjects with primary headache. The 95 % Confidence Intervals (95 %CI) were based on Wilson’s procedure [24]. The meta-analytic estimates were derived using random-effects models [25], and the pooled estimates were calculated after Freeman-Tukey Double Arcsine Transformation to stabilize variance [26]. The heterogeneity among studies was assessed relying on the χ2-test [27], and significant heterogeneity was defined when P-value was below 0.10. Inconsistency was quantified using the I2 statistic [28]: I2 below 40 % indicates no or not relevant heterogeneity; I2 comprised between 30 and 60 % indicates moderate heterogeneity: I2 comprised between 50 and 90 % indicates substantial heterogeneity; I2 higher than 75 % indicates considerable heterogeneity [29].

To address whether the pooled comorbidity rates observed among subjects with primary headaches are different from those reported in the general population, we relied on GBD-2019 estimates (available at: http://ghdx.healthdata.org/gbd-results-tool). Estimates herein presented are referred to prevalence ad based on all-age percentages, for both genders and at the global level. We searched for conditions that corresponded to those we extracted here but did not include the residual category “other” as the comparison is performed on different set of conditions: “other conditions” in our set is likely to include some unique causes in GBD list (e.g. aortic aneurysm was moved to “other cardiovascular disease”), and vice versa (e.g. restless leg syndrome was a unique comorbidity in our list but not in GBD one). We considered that prevalence of comorbidities is different among headache sufferers than in the general population if the 95 %CI of the pooled rates derived from our meta-analysis does not overlap with the 95 % Uncertainty Interval (95 %UI) of GBD-2019 estimates. The analytical approach herein described is at first reported considering all studies together.

A set of subgroup analyses was then carried out, namely: by study type, gender and age. Comparison by study type was performed by comparing clinical and population studies whereas for the latter subgroup analysis, the included studies were divided into two groups based on the corresponding median value observed for the percentage of females included in the studies and for the average age of participants. Therefore, we compared studies with a proportion of females ≥ than the median value calculated on all studies against those with proportion of females < than the median value, and studies with average age ≥ than the median average age reported in all studies against those with average age < than the median. For these sub-analyses, we did not include the residual category “other conditions” as the content is variable paper by paper and therefore the comparison by study type, average age and female prevalence is likely performed on different conditions.

Results

The electronic searches in Scopus identified 5698 potentially relevant records. Available full-texts of 588 records were then analyzed and we included 139 studies for the meta-analysis of results [30168]. The PRISMA flow-chart is reported in Fig. 1. At abstract check, Krippendorff’s α was 0.90, at full-text it was 0.91.

Fig. 1.

Fig. 1

Flowchart of studies' selection

Table 1 shows a synthesis of studies’ main features. The total number of respondents to the studies herein included was 4.19 million, with three studies accounting for the vast majority of persons (3.7 millions): most of the studies, 100 out of 139, were on participants with migraine only. Information on average age was reported in 131 studies: median average age was 40.4, IQR 36.9–46.0. Information on the amount of women per study was reported in 134 studies: median percentage of females was 77.8 %, IQR 71.4–90.0 %.

Table 1.

Overview of selected studies

Main headache disorder by study No. Studies No. Patients % of Females Median (IQR) Average age Median (IQR) Average monthly headaches Median (IQR)
Migraine only a 100 3,455,438 79.7 % (72.6–91.5 %) 39.6 (36.4–46.0) 7.1 (4.9–9.8)
TTH only b 5 14,100 53.0 % (53.0-60.5 %) 42.7 (42.7–42.8) 1.9 (1.5-2.0)
CH only c 5 594 25.8 % (18.2–62.2 %) 49.1 (46.1–53.0) NA
Mixed Studiesd 29 724,072 77.4 % (72.5–89.2 %) 39.9 (37.9–42.9) 9.7 (4.6–13.8)
All studies 139 4,185,906 77.8 % (71.4–90.0 %) 40.4 (36.9–46.0) 7.0 (4.0-10.1)

Note. aAmong patients included in studies on migraine only, 48,650 (1.4 %) had episodic migraine, 4,651 (0.1 %) had chronic migraine, and 3,402,137 (98.5 %) had migraine not otherwise specified. In total, 13,765 (0.4 %) were enrolled in clinical studies and 3,441,673 (99.6 %) were enrolled in population studies

bAmong patients included in studies on TTH only, 1,221 (8.7 %) had episodic TTH, 570 (4.0 %) had chronic TTH, and 12,309 (87.9 %) had TTH not otherwise specified. In total, 81 (0.6 %) were enrolled in clinical studies and 14,019 (99.4 %) were enrolled in population studies

cAmong patients included in studies on CH only, 455 (76.6 %) had episodic CH, and 133 (22.4 %) had chronic CH, 6 (1.0 %) had other TACs. All patients were enrolled in clinical studies

dAmong patients included in studies on mixed headache disorders, 137,118 (18.9 %) had migraine, of whom 132,167 had episodic migraine; 568,986 (78.6 %) had TTH, of whom 568,110 had episodic TTH; 24 (< 0.1 %) had CH or other TACs, of whom 13 had episodic CH; 18,044 (24.9 %) had other primary headache, of whom 339 were patients with both migraine-like and TTH-like headaches and 1667 had chronic daily headache not better specified, 2,337 had other primary headache not better specified and 12,571 had other non-migraine primary headache

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. In total, among the aforementioned 4.19 million subjects, 2.75 million comorbidities were reported, with a median ratio of comorbidities per subject of 0.64 (IQR: 0.32–1.07), with 39 studies reporting a comorbidity ratio per subject higher than 1.0. Table 2 of the Supplementary file shows the whole raw distribution of comorbidities across the different studies.

Table 2 shows a synthesis of the pooled distribution of the main comorbidities across all studies, as well as the contrast to GBD 2019 estimates. The most frequently addressed comorbidities were: depressive disorders, hypertension, anxiety disorders and diabetes, addressed in 51, 48, 40 and 39 studies, respectively. Excluding the conditions referred as “other”, the comorbidities with the highest pooled proportion were oral disorders (67 %, 95 %CI 40–89 %; reported in nine studies); sleep disorders (48 %, 95 %CI 42–54 %; reported in 30 studies); back pain (46 %, 95 %CI 20–72 %; reported in seven studies); anxiety disorders (25 %, 95 %CI 22–28 %; reported in 40 studies). See Supplementary Figures for the forest plot of each comorbidity.

Table 2.

Pooled prevalence of selected comorbidities among patients with primary headaches and comparison with 2019 GBD Estimates

Associated condition category Associated condition No. of studies Pooled proportion (95 % CI) GBD Estimates Mean (95 % UI) Comparison
Cancers Any cancer 4 5 % (0–13 %) 6.5 % (5.6–7.6 %)
Cardiovascular diseases Ischemic heart disease 19 7 % (5–10 %) 2.6 % (2.4–2.9 %) Higher in headaches
Stroke/Cerebrovascular 30 5 % (3–7 %) 1.4 % (1.2–1.5 %) Higher in headaches
Hypertension 48 24 % (22–26 %) Risk factor in GBD
Atrial fibrillation and flutter 6 2 % (1–3 %) 0.80 % (0.61–1.01 %)
Other cardiovascular and circulatory diseases 23 9 % (7–11 %)
Digestive diseases Upper digestive system diseases 4 10 % (4–19 %) 10.5 % (9.4–11.6 %)
Irritable bowel syndrome 4 19 % (1–53 %) 0.07 % (0.06–0.07 %) Higher in headaches
Other digestive diseases 7 14 % (1–37 %)
Metabolic and kidney diseases Diabetes mellitus 39 6 % (5–7 %) 6.2 % (5.7–6.7 %)
Chronic kidney disease 5 3 % (0–10 %) 9.4 % (8.7–10.0 %)
Obesity 26 21 % (17–26 %) Risk factor in GBD
Hyperlipidemia 14 15 % (8–24 %) Not in GBD
Hypercholesterolemia 8 26 % (12–43 %) Risk factor in GBD
Thyroid diseases 9 12 % (8–16 %) Not in GBD
Other Metabolic/Kidney disease 11 15 % (10–22 %)
Musculoskeletal disorders Arthritis 8 12 % (9–16 %) 7.1 % (6.4–7.9 %) Higher in headaches
Back pain 7 46 % (20–72 %) 7.6 % (6.8–8.6 %) Higher in headaches
Fibromyalgia 9 26 % (8–50 %) Not in GBD
Other musculoskeletal disorders 4 27 % (5–52 %)
Neurological disorders Parkinson disease 5 1 % (1–2 %) 0.11 % (0.10–0.13 %) Higher in headaches
Idiopathic epilepsy 7 2 % (1–2 %) 0.34 % (0.26–0.42 %) Higher in headaches
Sleep disorder 30 48 % (42–54 %) Not in GBD
Restless leg syndrome 16 20 % (13–27 %) Not in GBD
Other neurological disorders 19 15 % (10–20 %)
Mental health disorders Depressive disorders 51 23 % (20–26 %) 3.8 % (3.4–4.2 %) Higher in headaches
Bipolar disorder 6 5 % (0–12 %) 0.53 % (0.44–0.63 %)
Anxiety disorders 40 25 % (22–28 %) 4.1 % (3.4–4.8 %) Higher in headaches
Post-Traumatic Stress Disorder 7 15 % (6–28 %) Not in GBD
Other mental disorders 17 25 % (15–36 %)
Respiratory diseases Asthma 8 8 % (3–13 %) 3.5 % (3.0-4.2 %)
Chronic obstructive pulmonary disease 5 6 % (0–17 %) 2.8 % (2.7-3.0 %)
Other chronic respiratory diseases 6 13 % (0–41 %)
Sense organ disease Any sense organ disease 6 26 % (10–47 %) 23.7 % (22.5–24.9 %)
Skin and subcutaneous disease Any skin and subcutaneous disease 4 5 % (3–7 %) 27.2 % (26.5–28.0 %) Higher in GBD
Substance use disorders Any substance use disorder 10 6 % (0–17 %) 2.2 % (1.9–2.4 %)
Other NCDs Oral disorders 9 67 % (40–89 %) 46.8 % (43.0-50.7 %)
Hemoglobinopathies and hemolytic anemias 4 1 % (1–2 %) 28.4 % (27.3–29.6 %) Higher in GBD
Other disorders (Congenital birth defects & Gynecological diseases) 4 28 % (5–60 %)
Allergies 8 22 % (12–34 %) 23.7 % (22.5–24.9 %)

For 23 single comorbidities, a corresponding GBD-2019 estimate was available. As shown in Table 2, for nine of them the pooled proportion derived from the present review was higher than the GBD-produced estimates, and the opposite happened for two of them; in the remaining 12, the 95 % CI of the pooled proportion herein defined overlapped with and the 95 % UI produced by GBD-2019 estimates. Specifically, higher rates were found for ischemic heart disease, stroke/cerebrovascular conditions, irritable bowel syndrome, arthritis, back pain, Parkinson's disease, idiopathic epilepsy, depressive disorders, and anxiety disorders.

Subgroup analyses

Table 3 reports the results of the comparison performed by study type. Higher comorbidity proportions were observed in clinical studies, specifically for thyroid diseases, fibromyalgia, sleep disorder, restless leg syndrome (RLS), depressive disorders, anxiety disorders, post-traumatic stress disorder. On the contrary, higher rates were observed in population studies for arthritis, skin disorders, and allergies. 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).

Table 3.

Pooled comorbidity proportion by study type

Associated condition category Associated condition Population studies (52 studies) Clinical studies (87 studies) Heterogeneity between Groups
Cancers Any cancer 3 % (3–3 %) 2 % (0–5 %) p = .131
Cardiovascular diseases Ischemic heart disease 8 % (5–11 %) 5 % (2–10 %) p = .293
Stroke/Cerebrovascular 4 % (3–7 %) 6 % (3–9 %) p = .241
Hypertension 26 % (24–29 %) 19 % (14–26 %) p = .061
Atrial fibrillation and flutter 1 % (0–2 %) 2 % (0–9 %) p = .479
Digestive diseases Upper digestive system diseases 17 % (16–18 %) 8 % (2–18 %) p = .086
Irritable bowel syndrome 19 % (1–53 %)
Metabolic and kidney diseases Diabetes mellitus 6 % (4–7 %) 7 % (3–12 %) p = .281
Chronic kidney disease 4 % (0–13 %) 0 % (0–1 %) p = .097
Obesity 18 % (13–24 %)  25 % (16–35 %) p = .203
Hyperlipidemia 17 % (8–29 %) 13 % (9–19 %) p = .543
Hypercholesterolemia 29 % (13–49 %) 15 % (9–22 %) p = .137
Thyroid diseases 3 % (3–3 %) 16 % (7–27 %) p < .001
Musculoskeletal disorders Arthritis 19 % (15–23 %) 6 % (0–15 %) p = .028
Back pain 54 % (53–55 %) 48 % (11–86 %) p = .774
Fibromyalgia 1 % (1–1 %) 31 % (20–44 %) p < .001
Neurological disorders Parkinson disease 1 % (1–2 %)
Idiopathic epilepsy 2 % (1–2 %) 2 % (2–3 %) p = .199
Sleep disorder 33 % (25–41 %) 56 % (46–66 %) p = .001
Restless leg syndrome 6 % (2–13 %) 28 % (20–38 %) p < .001
Mental health disorders Depressive disorders 15 % (11–19 %) 31 % (24–38 %) p = .000
Bipolar disorder 5 % (0–17 %) 3 % (2–5 %) p = .799
Anxiety disorders 18 % (16–21 %) 30 % (23–39 %) p = .003
Post-traumatic stress disorder 2 % (2–2 %) 21 % (16–26 %) p < .001
Respiratory diseases Asthma 9 % (3–16 %) 7 % (0–27 %) p = .839
Chronic obstructive pulmonary disease 6 % (0–21 %) 3 % (2–4 %) p = .489
Sense organ disease Any sense organ diseases 26 % (10–47 %)
Skin and subcutaneous disease Any skin and subcutaneous disease 7 % (7–7 %) 1 % (0–3 %) p < .001
Substance use disorders Any substance use disorder 5 % (0–18 %) 7 % (4–10 %) p = .665
Other NCDs Oral disorders 67 % (40–89 %)
Hemoglobinopathies and hemolytic anemias 3 % (3–3 %) 0 % (0–2 %) p = .300
Other disorders (Congenital birth defects & Gynecological diseases) 15 % (10–21 %) 33 % (0–85 %) p = .430
Allergies 33 % (17–51 %) 12 % (8–17 %) p = .012

Table 4 reports the results of the comparison performed by female percentage across studies. Higher comorbidity proportions were observed in studies with a higher percentage of females for fibromyalgia, RLS, depressive disorders, and anxiety disorders. On the contrary, higher rates were observed in studies with a lower percentage of females (i.e. with a higher male percentage) for hypertension, asthma, sense organ diseases, skin disorders, and allergies. 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 studies with higher female percentage; median 0.61, IQR 0.30–1.05 for studies with lower female percentage).

Table 4.

Pooled comorbidity proportion by female percentage within studies

Associated condition category Associated condition Female percentage ≥ 77.8 % (67 studies) Female percentage < 77.8 % (67 studies) Heterogeneity between Groups
Cancers Any cancer 2 % (2–5 %) 2 % (2–3 %) p = .077
Cardiovascular diseases Ischemic heart disease 5 % (1–10 %) 8 % (5–12 %) p = .261
Stroke/Cerebrovascular 3 % (2–4 %) 5 % (2–10 %) p = .447
Hypertension 18 % (15–21 %) 29 % (24–34 %) p < .001
Atrial fibrillation and flutter 1 % (1–1 %) 2 % (0–6 %) p = .193
Digestive diseases Upper digestive system diseases 12 % (5–22 %) 6 % (5–8 %) p = .111
Irritable bowel syndrome 7 % (4–9 %) 11 % (7–18 %) p = .090
Metabolic and kidney diseases Diabetes mellitus 5 % (3–8 %) 7 % (5–9 %) p = .650
Chronic kidney disease 3 % (0–10 %)
Obesity 21 % (18–24 %) 21 % (12–32 %) p = .924
Hyperlipidemia 12 % (7–19 %) 17 % (8–29 %) p = .419
Hypercholesterolemia 22 % (8–41 %) 28 % (12–48 %) p = .659
Thyroid diseases 13 % (2–31 %) 11 % (7–16 %) p = .638
Musculoskeletal disorders Arthritis 11 % (0–30 %) 15 % (10–21 %) p = .772
Back pain 39 % (4–83 %) 66 % (65–67 %) p = .234
Fibromyalgia 31 % (25–36 %) 2 % (2–2 %) p < .001
Neurological disorders Parkinson disease 1 % (1–2 %)
Idiopathic epilepsy 1 % (1–1 %) 2 % (1–3 %) p = .112
Sleep disorder 48 % (27–69 %) 47 % (41–53 %) p = .950
Restless leg syndrome 35 % (24–48 %) 9 % (4–16 %) p < .001
Mental health disorders Depressive disorders 29 % (23–36 %) 19 % (16–21 %) p = .001
Bipolar disorder 1 % (1–1 %) 7 % (0–21 %) p = .147
Anxiety disorders 32 % (24–40 %) 20 % (22–28 %) p = .004
Post-traumatic stress disorder 17 % (3–40 %) 10 % (8–13 %) p = .491
Respiratory diseases Asthma 2 % (2–3 %) 8 % (4–12 %) p = .002
Chronic obstructive pulmonary disease 2 (2–3 %) 7 % (0–22 %) p = .342
Sense organ disease Any sense organ diseases 7 % (4–10 %) 51 % (37–64 %) p < .001
Skin and subcutaneous disease Any skin and subcutaneous disease 1 % (0–3 %) 7 % (7–7 %) p < .001
Substance use disorders Any substance use disorder 7 % (0–27 %) 4 % (2–5 %) p = .622
Other NCDs Oral disorders 66 % (17–100 %) 69 % (53–82 %) p = .898
Hemoglobinopathies and hemolytic anemias 0 % (0–2 %) 3 % (3–3 %) p = .300
Other disorders (Congenital birth defects & Gynecological diseases) 33 % (0–85 %) 15 % (10–21 %) p = .430
Allergies 12 % (6–20 %) 29 % (15–45 %) p = .043

Table 5 reports the results of the comparison performed by average age across studies. Higher comorbidity proportions were observed in studies with older subjects for hypertension, irritable bowel syndrome, chronic kidney disease, hypercholesterolemia, and chronic obstructive pulmonary disease. On the contrary, higher rates were observed in studies with younger subjects for sleep disorder, RLS, depressive disorders, and other disorders (congenital birth defects & gynecological diseases). Taken as a whole, it can be concluded that difference in average has a limited effect on total comorbidity rates, as the median and interquartile ranges were largely overlapping (median 0.63, IQR 0.34–0.97 for studies with younger participants; median 0.65, IQR 0.32–1.05 for studies with older participants).

Table 5.

Pooled comorbidity proportion by average age of participants

Associated condition category Associated condition Average age ≤ 40.3 (65 studies) Average age ≥ 40.4 (66 studies) Heterogeneity between groups
Cancers Any cancer 2 % (2–3 %) 2 % (0–5 %) p = .077
Cardiovascular diseases Ischemic heart disease 6 % (3–9 %) 6 % (3–10 %) p = .908
Stroke/Cerebrovascular 3 % (2–5 %) 4 % (1–8 %) p = .591
Hypertension 13 % (9–17 %) 30 % (27–32 %) p < .001
Atrial fibrillation and flutter 2 % (1–3 %) 1 % (0–3 %) p = .813
Digestive diseases Upper digestive system diseases 14 % (6–24 %) 3 % (1–7 %) p = .010
Irritable bowel syndrome 6 % (4–8 %) 19 % (13–28 %) p < .001
Metabolic and kidney diseases Diabetes mellitus 5 % (4–7 %) 6 % (4–8 %) p = .709
Chronic kidney disease 0 % (0–0 %) 5 % (1–11 %) p = .007
Obesity 21 % (15–29 %) 19 % (14–26 %) p = .681
Hyperlipidemia 10 % (3–20 %) 15 % (9–21 %) p = .359
Hypercholesterolemia 9 % (2–22 %) 38 % (30–36 %) p < .001
Thyroid diseases 13 % (4–24 %) 12 % (2–26 %) p = .937
Musculoskeletal disorders Arthritis 14 % (12–15 %) 10 % (6–16 %) p = .470
Back pain 67 % (60–74 %) 41 % (5–84 %) p = .259
Fibromyalgia 29 % (20–38 %) 13 % (0–48 %) p = .382
Neurological disorders Parkinson disease 1 % (1–2 %)
Idiopathic epilepsy 2 %  (1–4 %) 2 % (1–3 %) p = .852
Sleep disorder 60 % (40–79 %) 34 % (28–39 %) p = .013
Restless leg syndrome 32 % (19–46 %) 11 % (6–19 %) p = .005
Mental health disorders Depressive disorders 31 % (22–41) 19 % (15–22 %) p = .011
Bipolar disorder 1 % (1–2 %) 6 % (0–18 %) p = .132
Anxiety disorders 25 % (18–34 %) 24 % (21–28 %) p = .841
Post-traumatic stress disorder 12 % (10–14 %) 14 % (1–36 %) p = .809
Respiratory diseases Asthma 4 % (2–7 %) 9 % (4–14 %) p = .056
Chronic obstructive pulmonary disease 2 % (1–3 %) 12 % (12–13 %) p < .001
Sense organ disease Any sense organ diseases 49 % (38–60 %) 29 % (5–62 %) p = .266
Skin and subcutaneous disease Any skin and subcutaneous disease 5 % (3–7 %)
Substance use disorders Any substance use disorder 2 % (0–5 %) 8 (1–22 %) p = .164
Other NCDs Oral disorders 66 % (57–74 %) 71 % (0-100 %) p = .931
Hemoglobinopathies and hemolytic anemias 1 % (1–2 %)
Other disorders (Congenital birth defects & Gynecological diseases) 58 % (48–68 %) 6 % (4–9 %) p < .001
Allergies 32 % (30–34 %) 19 % (7–34 %) p = .085

Discussion

The results of this literature review with meta-analysis show that out of 4.19 million headache sufferers, 3.70 million comorbidities were reported (median 0.64, interquartile range 0.32–1.07). For many conditions, prevalence among subjects with primary headache disorders were higher than what can be estimated in the general population, with some conditions – in particular, depression, anxiety and back pain – showing pooled prevalence higher than 20 % in the lower bound. In addition to them, there are other comorbidities with a considerably high prevalence among headache sufferers, such as hypertension, sleep disorders and oral disorders: however, for the first two, no GBD estimates were available, whereas for the third, the estimates generated by our review overlapped with those referred to the general population. Data derived from clinical studies included a higher prevalence in some conditions, and a globally higher raw rate of comorbidity per subject, likely owing to a higher precision in comorbidities identification. Minor differences were instead retrieved from the age and gender comparison, but some specific associations could be observed for some of the most relevant comorbidities. Hypertension was mostly associated to older age and lower females’ prevalence; fibromyalgia, restless leg syndrome, and depressive disorders were mostly associate to younger age and higher females’ prevalence.

Our findings show that the most frequent psychiatric comorbidities in subjects with primary headaches were anxiety and depression, followed by post-traumatic stress disorder: these comorbidities were found, respectively, in 25 % (95 %CI: 22–28 %), 23 % (95 %CI: 20–26 %) and 15 % (95 %CI: 6–28 %) of the subjects. Several studies in literature confirmed the coexistence of these conditions in subjects with headaches and particularly in those with migraine [169171].

Understanding psychiatric comorbidities in subjects suffering from headache disorders, and migraine in particular, is important in reason of the bidirectional relationship between the two [10]: in fact, anxiety and depression can determine the onset of headache, but they can be a consequence of frequent headache attacks [171]. These considerations are essential in clinical practice: comorbidity to anxiety and depression seems to have limited influence on the use and overuse of medications, but subjects with these comorbidities perceived a lower treatment satisfaction and effectiveness [172]. Regarding prophylactic treatment for chronic migraine (CM), there is an important overlap between drugs that are prescribed for CM, anxiety and mood disorders: in fact, antidepressants such as amitriptyline and anxiolytics such as bromazepam are commonly used in CM prophylaxis. As migraine, anxiety and depression share common neurobiological pathophysiology (e.g. derangement in central monoaminergic systems and abnormalities in the metabolism of glutamate and gamma-aminobutyric acid [173]), when present simultaneously should be treated with a single medication [174].

Screening for comorbid psychiatric disorders in headache sufferers, and among those with migraine in particular, is therefore of great importance for management, treatment and prognosis. Important alternative interventions that are worth adding to pharmacological treatment include non-pharmacological ones. In particular, behavioral therapies, such as cognitive behavioral therapy or mindfulness-based approaches, have shown to be useful in treating symptoms related to headache, but also anxiety and depression [15, 175, 176].

Prior studies have described a close correlation between headache and sleep disorders [177, 178], and such knowledge was enriched by our presentation of the pooled prevalence of sleep disorder (48 %, 95 %CI: 42–54 %) and RLS (20 %, 95 %CI: 13–27 %) in primary headaches. The relationships between primary headache and sleep disorders is poorly understood [178]: sleep disturbances may act as a trigger for headache, but headache may promote sleep disturbances which, in turn, may also be related to depressed mood. The comorbidity between headache disorders, anxiety and depression, and sleep-related disturbances is a driver for worse health outcomes [179]. These three comorbidities have a pivot role in pain modulation. Primary headaches are influenced by sleep wake cycle, with a probable involvement of the hypothalamus, which does not only regulate the sleep-wake cycle, but is also involved in pain modulation [177, 178, 180, 181]. In addition to this, a dysfunction of serotoninergic and dopaminergic pathways seems to explain the simultaneous presence of headache and sleep disorder: impairments of serotoninergic system are common among headache, sleep and psychiatric disorder, whereas impairments of dopaminergic system is common in headache, sleep disorders and RLS [177, 180, 181].

These findings have several implications for clinical practice: first, the evaluation of the sleep habits is of great relevance as they may be considered prognostic factors for primary headache development and a risk factor for shift to chronic headache; second, the combined multimodal approaches may be effective in improving headache parameters thought the joint treatment of sleep comorbidities.

There are conflicting results about the coexistence of migraine and diabetes. In our review, prevalence of diabetes among persons with headache was 6 % (95 %CI: 5–7 %), but few reports on such a relation exist. A recent study observed no significant differences in prevalence of migraine between patients with diabetes mellitus and healthy controls [182], whereas another study has shown that insulin resistance seems to exist in individuals with both migraine and prediabetes [183]. Besides specific treatment needed for diabetes, behavioral indications should be provided to headache patients for weight control, such as engaging in regular exercise and following a balanced daily dietary intake, considering the fact that diabetes often presents together with obesity [184], which in our review was found in 21 % (95 %CI: 17–26 %) of subjects. Topiramate, which has an appetite-suppressive effect and whose utilization has been associated to weight loss, may be considered as a prophylactic agent [185].

The association between headache disorders, most of all migraine, and Cardiovascular Diseases (CVDs) is well known since more than 40 years. A wide range of studies have revealed a link between migraine and hypertension, stroke, ischemic heart disease, patent foramen ovale and other cardiovascular diseases, as well as the role of migraine as a risk factors for several CVDs [36, 50]. Females aged 45 or less suffering from migraine with aura are exposed to an increased risk of stroke, particularly if smokers and if under oral contraceptives [186], and to an increased incidence of major CVD events, particularly if smokers and if they have comorbidities with hypertension and diabetes [35]. However, a relation between migraine and major CVD events has been shown also among men [117]. What is important to notice here, is that the association between migraine and stroke is stronger among young subjects than among older ones [77].

Evidence on the association between CVD and headache disorders other than migraine has been little reported. A recent study has shown that migraine sufferers undergoing pharmacologic treatment have a lower hazard of aneurysmal subarachnoid hemorrhage than subjects with TTH [141]. Our data, however, do not enable to address such a kind of relation as CVD comorbidities were addressed in their pooled prevalence to the entire group of headache sufferers.

The well-known and close relationship between migraine and CVD has many therapeutic implications. Among those for whom triptans are contraindicated, Gepants [187] as well as Lasmiditan, which showed a good safety profile in those with CVD [188], could be considered for acute migraine treatment. Migraine with aura should be considered as “red flag” risk factor for stroke, especially in young women who smoke and take oral contraceptives: thus, contraceptive therapies should be used with caution, if not avoided, among women suffering from migraine with aura, and specific advice for smoke cessation provided. Anyway, a thrombophilic assessment panel should be considered.

Prescription of prophylactic treatment should take into account the presence of cardiovascular comorbidities, leading to the exclusion of some preventive therapies (β-blockers in cardiac insufficiency, amitriptyline and calcium antagonists in arrhythmia, pizotifen in hypertension and angina), and some acute treatments (triptans in previous ischemic heart disease or hypertension, ergot-derivates in hypertension and vasculopathy). On the contrary, the use of β-blockers could be suggested as prevention therapy in headache sufferers with comorbidity to hypertension or angina, together with calcium antagonists and angiotensin inhibitors. Considering the new migraine-specific treatments, data emerging from trials with Calcitonin Gene-Related Peptide (CGRP) antibodies suggest that this specific blockade has shown no relevant cardiovascular side effects [189, 190]. Anti-CGRP and anti-CGRP receptor monoclonal antibodies, in addition to ditans and small molecule CGRP receptor antagonists (Second-Generation Gepants), have so far demonstrated efficacy and cardiovascular safety, further supporting the pathophysiological underpinnings of migraine as a primarily neuronal process.

The clinical vs. population subgroup analysis showed the existence of significant differences in comorbidities with high prevalence, such as anxiety and depressive disorders, which likely reflects different methodological approaches concerning the subject inclusion criteria, as well as the identification of such comorbidities. Participants enrolled in clinical studies might in fact undergo a clinical evaluation for such diseases or be stratified based on response to questionnaires for the evaluation of symptoms of depression or anxiety, such as the Major Depression Inventory or the Patient Health Questionnaire-9 [191, 192]. On the contrary, the identification of anxiety or depression cases in population studies, in addition to questionnaires’ use, likely relies on participants’ self-identification as depression or anxiety sufferers, a procedure that has a lower reliability [193]. Other differences favoring clinical studies deal with comorbidities which showed high prevalence only in clinical studies, such as fibromyalgia and RLS: in these cases, precise clinical criteria have to be applied, which makes it difficult to address them in population studies.

The sub-analyses carried out by age and gender group did not reveal unexpected findings. The association we produced here do not really reflect age and gender differences, but differences observed on the average age of subjects enrolled in the studies, above or below the age of 40.4, as well as on the prevalence of females in the single studies, above or below 77.8 %. In the case of age-based groups, the median age observed in the studies with younger participants was 36.9 (IQR: 33.7–38.8), and that in the studies with older participants was 46.8 (IQR: 42.2–52.8). In the case of gender-based groups, the median female percentage observed in the studies with less female participants was 71.2 % (IQR: 64.6–74.4 %), and that in the studies with more female participants was 89.6 % (IQR: 82.5–100 %). 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 fibromyalgia, RLS, and depressive disorders are likely to be found as comorbidities in studies whose participants are younger and with higher female presence. These results are largely consistent with the available evidence that hypertension is more common in men and in older subjects, especially in high-income countries [194], and that depressive disorders are more common among younger females [195]. With regard to fibromyalgia and RLS, an association with female gender is known [196, 197], whereas the association with age is, on the contrary, debatable. Fibromyalgia is in fact more often diagnosed early in life and some evidence of rising prevalence with age exist [198]: however, among older subjects with chronic widespread pain, osteoarthritis rather than fibromyalgia is often diagnosed [196]. For RLS too an association with increasing age has been observed [197], which apparently contrasts with our analysis. A previous literature review addressing the comorbidity between migraine and RLS found significant differences between migraine and healthy controls with regard to RLS prevalence (17.6 % vs. 7.1 %): this suggested a specific pattern of association, which also include shared mechanisms of action involving the dopaminergic nucleus of the dorsalposterior hypothalamus [199]. 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.

In order to address whether headache disorders are associated to a higher prevalence in the selected comorbidities, we contrasted such rates with the estimates generated by the GBD-2019 study. Such a choice was considered as the only viable since GBD estimates are referred to the global level, and we have global-level studies, and enable to produce age-standardized percentages [1]. In order to make the information referred to the estimates comparable to our results we would have to select, for each specific comorbidity, a different year of GBD estimates: in fact, our analysis span between 2000 and 2020, a period in which estimates for some conditions have significantly changed, and regional variation might be different. Moreover, publication year and data collection year are not identical. We therefore decided to rely on the last available ones. The comparison was made between the 95 %CI of our pooled prevalence and the 95 %UI of GBD-2019 estimates, with the latter being the results of a meta-analytic simulation performed in GBD studies.

Our results show that for some conditions, prevalence among headache sufferers was higher than in GBD-2019 estimates, which leads to concluding that headaches might be both a cause or a consequence of these comorbidities. For example, migraine can be a risk factor for several CVDs [36, 50]: thus it is not surprising that the pooled proportion of ischemic heart disease and of stroke/cerebrovascular conditions was higher among headache sufferers than among the general population. Another note can be made for comorbidities with conditions with a relevant pain component, such as back pain. Such an association has already been observed [200, 201] and might be due to the role of shared nociceptive ways, in particular dealing with the central sensitization, and cephalic and extracephalic allodynia [201].

The added value of the present literature review is that it enables a broader appreciation of the comorbidities of headache disorders. Most of available research, if not addressed in a meta-analytic way, point out few comorbidities or groups of conditions, and most of available knowledge was based on migraine only, with the result of excluding the recognition of a large set of comorbidities and of headache sufferers. The results herein presented reflect in part such a situation, and the reason for this is that the majority of the studies herein presented (100 out of 139) were on migraine only. However, we were able to produce new insights on minor conditions because we used the broadest possible approach, as we did not select a specific primary headache, we decided not to pre-select the main (and most known) comorbidities, and we included both clinical and population studies.

The comorbidities that have been identified in the present review are leading burdensome conditions in terms of disability-adjusted life years (DALYs) as shown in the last published estimates produced by the GBD study [1]. If all age groups are taken into account, ischemic heart disease ranked 2nd (accounting for 7.2 % of all-cause DALYs), stroke ranked 3rd (accounting for 5.7 % of all-cause DALYs), diabetes ranked 8th (accounting for 2.8 % of all-cause DALYs), and depressive disorders ranked 13th (accounting for 1.8 % of all-cause DALYs). If the 14–49 age group, where headache disorders are mostly prevalent, is instead taken into account, ischemic heart disease ranked again 2nd (accounting for 4.7 % of all-cause DALYs), depressive disorders ranked 6th (accounting for 3.5 % of all-cause DALYs), stroke ranked 9th (accounting for 3.2 % of all-cause DALYs), diabetes ranked 14th (accounting for 2.2 % of all-cause DALYs) and anxiety disorders ranked 15th (accounting for 2.0 % of all-cause DALYs). Therefore, addressing comorbidities of headache disorders with appropriate treatment, either pharmacological, behavioral or lifestyle-directed, may positively impact towards reducing the impact of some of the most burdensome diseases.

Some limitations have to be taken into account. First, we relied on Scopus only, rather than on a wider set of search engines, which might have caused a loss in studies’ identification. Second, we were unable to locate some studies, despite requests were sent to the corresponding authors. Third, we were unable to further address analyses by headache frequency, despite the relevance of comorbidities for the process of headache chronification: the reason for this is that only a minority of selected studies reported comorbidities by chronic vs. episodic headache or average headache frequency. Similarly, as very few studies presented comorbidity information on TTH and TACs, we were unable to present a comorbidity profile by primary headache. Fourth, around a fifth of studies included subjects with mixed populations, which makes it complex to understand the relation between headaches and comorbidities. Fifth, we used a taxonomy based on that employed by the GBD study consortium, which includes very broad labels for each comorbidity, with an unavoidable precision loss. Last, if on one side clinical studies have high reliability with the identification of specific headache disorders, on the basis of the second or third version of the International Classification of Headache Disorders, population studies are reasonably expected to be less precise.

Conclusions

In conclusion, 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, ischemic 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 common: 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. Therefore, addressing and treating the most relevant comorbidities of headache disorders not only positively impacts on the health status of headache sufferers, but it may also positively contribute towards reducing the impact of a group of high-burden conditions.

Supplementary Information

10194_2021_1281_MOESM1_ESM.docx (1.2MB, docx)

Additional file 1: Supplementary Table 1. Search strategy. Supplementary Table 2. Distribution of comorbidities in all included studies and by main condition (raw mean and min-max percentage). Supplementary figures, first set: Sub-analysis by study type, clinical vs. population studies (the overall pooled proportion correspond to the overall proportion of headache sufferers with each specific comorbidity as described in table 2 of main text). Supplementary figures, second set: Sub-analysis by female proportion, < 77.8% vs. ≥ 77.8%. Supplementary figures, third set: Sub-analysis by average age, < 40.4 vs. ≥ 40.4 years.

Acknowledgements

Alberto Raggi is supported by a grant from the Italian Ministry of Health (Ricerca Corrente, Fondazione Istituto Neurologico C. Besta, Linea 4—Outcome Research: dagli Indicatori alle Raccomandazioni Cliniche).

Abbreviations

CGRP

Calcitonin Gene-Related Peptide

CH

Cluster Headache

CM

Chronic Migraine

CVD

Cardiovascular Diseases

DALYs

Disability-Adjusted Life Years

GBD

Global Burden of Diseases, Injuries, and Risk Factors Study

IQR

Interquartile Range

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

RLS

Restless Leg Syndrome

TTH

Tension-Type Headache

TACs

Trigeminal Autonomic Cephalalgias

YLDs

Years Lived with Disability

95%CI

95% Confidence Intervals

95%UI

95% Uncertainty Interval

Authors’ contributions

VC, MD and AR led the manuscript preparation, selected studies, extracted data and drafted part of the manuscript; MR, MK, VP, CG and GNo selected studies, extracted data and drafted part of the manuscript; EDM, GDV, EF, GH, DM, GNa and SS selected studies, extracted data and revised the manuscript; IT ran the analyses and drafted part of the manuscript; PM supervised the entire process and revised the manuscript. All authors approved the final version.

Funding

Not applicable.

Availability of data and materials

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Valeria Caponnetto and Manuela Deodato contributed equally.

Paolo Martelletti and Alberto Raggi contributed equally.

Paolo Martelletti and Alberto Raggi are senior fellows of EHF-SAS

Contributor Information

Valeria Caponnetto, Email: valeria.caponnetto@univaq.it.

Manuela Deodato, Email: mdeodato@units.it.

References

  • 1.GBD 2019 Diseases and Injuries Collaborators Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396:1204–1222. doi: 10.1016/S0140-6736(20)30925-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Steiner TJ, Stovner LJ, Jensen R, et al. Migraine remains second among the world’s causes of disability, and first among young women: findings from GBD2019. J Headache Pain. 2020;21:137. doi: 10.1186/s10194-020-01208-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Jensen R, Stovner LJ. Epidemiology and comorbidity of headache. Lancet Neurol. 2008;7:354–61. doi: 10.1016/S1474-4422(08)70062-0. [DOI] [PubMed] [Google Scholar]
  • 4.Leonardi M, Raggi A. A narrative review on the burden of migraine: when the burden is the impact on people’s life. J Headache Pain. 2019;20:41. doi: 10.1186/s10194-019-0993-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Scher AI, Bigal ME, Lipton RB. Comorbidity of migraine. Curr Opin Neurol. 2005;18:305–310. doi: 10.1097/01.wco.0000169750.52406.a2. [DOI] [PubMed] [Google Scholar]
  • 6.Tietjen GE, Herial NA, Hardgrove J, et al. Migraine comorbidity constellations. Headache. 2007;47:857–865. doi: 10.1111/j.1526-4610.2007.00814.x. [DOI] [PubMed] [Google Scholar]
  • 7.Buse DC, Manack A, Serrano D, et al. Sociodemographic and comorbidity profiles of chronic migraine and episodic migraine sufferers. J Neurol Neurosurg Psychiatry. 2010;81:428–432. doi: 10.1136/jnnp.2009.192492. [DOI] [PubMed] [Google Scholar]
  • 8.Patel UK, Malik P, Sheth R, et al. Fibromyalgia and Myositis Linked to Higher Burden and Disability in Patients with Migraine. SN Compr Clin Med. 2019;1:882–890. doi: 10.1007/s42399-019-00129-7. [DOI] [Google Scholar]
  • 9.Tiseo C, Vacca A, Felbush A, et al. Migraine and sleep disorders: a systematic review. J Headache Pain. 2020;21:126. doi: 10.1186/s10194-020-01192-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Dresler T, Caratozzolo S, Guldolf K, et al. Understanding the nature of psychiatric comorbidity in migraine: a systematic review focused on interactions and treatment implications. J Headache Pain. 2019;20:51. doi: 10.1186/s10194-019-0988-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Torres-Ferrús M, Ursitti F, Alpuente A, et al. From transformation to chronification of migraine: pathophysiological and clinical aspects. J Headache Pain. 2020;21:42. doi: 10.1186/s10194-020-01111-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Buse DC, Reed ML, Fanning KM, et al. 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. J Headache Pain. 2020;21:23. doi: 10.1186/s10194-020-1084-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Sarchielli P, Granella F, Prudenzano MP, et al. Italian guidelines for primary headaches: 2012 revised version. J Headache Pain. 2012;13:31–70. doi: 10.1007/s10194-012-0437-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Schoenen J, Roberta B, Magis D, Coppola G. Noninvasive neurostimulation methods for migraine therapy: The available evidence. Cephalalgia. 2016;36:1170–1180. doi: 10.1177/0333102416636022. [DOI] [PubMed] [Google Scholar]
  • 15.Raggi A, Grignani E, Leonardi M, et al. Behavioral Approaches for Primary Headaches: Recent Advances. Headache. 2018;58(6):913–925. doi: 10.1111/head.13337. [DOI] [PubMed] [Google Scholar]
  • 16.Lemmens J, De Pauw J, Van Soom T, et al. The effect of aerobic exercise on the number of migraine days, duration and pain intensity in migraine: a systematic literature review and meta-analysis. J Headache Pain. 2019;20:16. doi: 10.1186/s10194-019-0961-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Lee HJ, Lee JH, Cho EY, et al. Efficacy of psychological treatment for headache disorder: a systematic review and meta-analysis. J Headache Pain. 2019;20:17. doi: 10.1186/s10194-019-0965-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Wong LP, Alias H, Bhoo-Pathy N, et al. Impact of migraine on workplace productivity and monetary loss: a study of employees in banking sector in Malaysia. J Headache Pain. 2020;21:68. doi: 10.1186/s10194-020-01144-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Raggi A, Leonardi M, Sansone E, et al. The cost and the value of treatment of medication overuse headache in Italy: a longitudinal study based on patient-derived data. Eur J Neurol. 2020;27:62–61. doi: 10.1111/ene.14034. [DOI] [PubMed] [Google Scholar]
  • 20.Linde M, Gustavsson A, Stovner LJ, et al. The cost of headache disorders in Europe: the Eurolight project. Eur J Neurol. 2012;19:703–711. doi: 10.1111/j.1468-1331.2011.03612.x. [DOI] [PubMed] [Google Scholar]
  • 21.Berra E, Sances G, De Icco R, et al. Cost of chronic and episodic migraine. A pilot study from a tertiary headache centre in northern Italy. J Headache Pain. 2015;16:532. doi: 10.1186/s10194-015-0532-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Baker VB, Sowers CB, Hack NK. Lost productivity associated with headache and depression: a quality improvement project identifying a patient population at risk. J Headache Pain. 2020;21:50. doi: 10.1186/s10194-020-01107-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Inter Med. 2009;151:264–269. doi: 10.7326/0003-4819-151-4-200908180-00135. [DOI] [PubMed] [Google Scholar]
  • 24.Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat Med. 1998;17:857–872. doi: 10.1002/(SICI)1097-0258(19980430)17:8&#x0003c;857::AID-SIM777&#x0003e;3.0.CO;2-E. [DOI] [PubMed] [Google Scholar]
  • 25.DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188. doi: 10.1016/0197-2456(86)90046-2. [DOI] [PubMed] [Google Scholar]
  • 26.Freeman MF, Tukey JW. Transformations related to the angular and the square root. Ann Math Stats. 1950;21:607–611. doi: 10.1214/aoms/1177729756. [DOI] [Google Scholar]
  • 27.Greenland S. Qualitative methods in the review of epidemiologic literature. Epidemiol Rev. 1987;9:1–30. doi: 10.1093/oxfordjournals.epirev.a036298. [DOI] [PubMed] [Google Scholar]
  • 28.Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–560. doi: 10.1136/bmj.327.7414.557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Higgins JPT, Green S (eds) (2011) Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0. Cochrane, Available from https://handbook-5-1.cochrane.org/front_page.htm, last access 12 Dec 2020
  • 30.Aldemir A, Yucel K, Güven H, et al. Structural neuroimaging findings in migraine patients with restless legs syndrome. Neuroradiology. 2020;62:1301–1313. doi: 10.1007/s00234-020-02451-7. [DOI] [PubMed] [Google Scholar]
  • 31.Al-Hashel JY, Ismail II. Impact of coronavirus disease 2019 (COVID-19) pandemic on patients with migraine: a web-based survey study. J Headache Pain. 2020;21:115. doi: 10.1186/s10194-020-01183-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Chu HT, Liang CS, Lee JT, et al. Subjective cognitive complaints and migraine characteristics: A cross-sectional study. Acta Neurol Scand. 2020;141:319–327. doi: 10.1111/ane.13204. [DOI] [PubMed] [Google Scholar]
  • 33.Haggiag A, Speciali JG. A new biofeedback approach for the control of awake bruxism and chronic migraine headache: utilization of an awake posterior interocclusal device. Arq Neuropsiquiatr. 2020;78:397–402. doi: 10.1590/0004-282x20200031. [DOI] [PubMed] [Google Scholar]
  • 34.Khan FA, Mohammed AE, Poongkunran M, et al. Wearing Off Effect of OnabotulinumtoxinA Near the End of Treatment Cycle for Chronic Migraine: A 4-Year Clinical Experience. Headache. 2020;60:430–440. doi: 10.1111/head.13713. [DOI] [PubMed] [Google Scholar]
  • 35.Kurth T, Rist PM, Ridker PM, et al. Association of Migraine with Aura and Other Risk Factors with Incident Cardiovascular Disease in Women. JAMA. 2020;323:2281–2289. doi: 10.1001/jama.2020.7172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Kuybu O, Amireh A, Davis D, et al. Prevalence of ischemic stroke and atrial fibrillation in young patients with migraine national inpatient sample analysis. J Stroke Cerebrovasc Dis. 2020;29:104972. doi: 10.1016/j.jstrokecerebrovasdis.2020.104972. [DOI] [PubMed] [Google Scholar]
  • 37.Lin GY, Lin YK, Liang CS, et al. Association of genetic variants in migraineurs with and without restless legs syndrome. Ann Clin Transl Neurol. 2020;7:1942–1950. doi: 10.1002/acn3.51186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Oğuz Akarsu E, Baykan B, Ertaş M, et al. Sex differences of migraine: Results of a nationwide home-based study in Turkey. Noropsikiyatri Arsivi. 2020;57:126–130. doi: 10.29399/npa.23240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Onder H, Ulusoy EK, Aslanyavrusu M, et al. The prevalence of papilledema in patients with migraine: a crucial cooccurrence of migraine and idiopathic intracranial hypertension. Neurol Sci. 2020;41:2613–2620. doi: 10.1007/s10072-020-04473-8. [DOI] [PubMed] [Google Scholar]
  • 40.Cai X, Xu X, Zhang A, et al. Cognitive Decline in Chronic Migraine with Nonsteroid Anti-inflammation Drug Overuse: a Cross-Sectional Study. Pain Res Manag. 2019;2019:7307198. doi: 10.1155/2019/7307198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Gur-Ozmen S, Karahan-Ozcan R. Factors Associated with Insulin Resistance in Women with Migraine: A Cross-Sectional Study. Pain Med. 2019;20:2043–2050. doi: 10.1093/pm/pnz055. [DOI] [PubMed] [Google Scholar]
  • 42.Kim KM, Lee DH, Lee EJ, et al. Self-reported insomnia as a marker for anxiety and depression among migraineurs: a population-based cross-sectional study. Sci Rep. 2019;9:19608. doi: 10.1038/s41598-019-55928-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Kim SK, Hong SM, Park IS, Choi HG. Association between Migraine and Benign Paroxysmal Positional Vertigo among Adults in South Korea. JAMA Otolaryngol Head Neck Surg. 2019;145:307–312. doi: 10.1001/jamaoto.2018.4016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Kulkarni AR, Kulkarni VA. Study of prevalence of migraine associated with cardio-vascular diseases in women of maharashtra population. Indian Journal of Public Health Research Development. 2019;10:164–166. doi: 10.5958/0976-5506.2019.01871.0. [DOI] [Google Scholar]
  • 45.Lee SH, Kang Y, Sohn JH, Cho SJ. Dizziness Handicap and Its Contributing Factors in Patients With Migraine. Pain Pract. 2019;19:484–490. doi: 10.1111/papr.12767. [DOI] [PubMed] [Google Scholar]
  • 46.Lin YK, Liang CS, Lee JT, et al. Association of Suicide Risk With Headache Frequency Among Migraine Patients With and Without Aura. Front Neurol. 2019;10:228. doi: 10.3389/fneur.2019.00228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Onder H, Hamamci M, Alpua M, Ulusoy EK. Comorbid fibromyalgia in migraine patients: clinical significance and impact on daily life. Neurol Res. 2019;41:909–915. doi: 10.1080/01616412.2019.1630164. [DOI] [PubMed] [Google Scholar]
  • 48.Rubino E, Rainero I, Garino F, et al. Subclinical hypothyroidism is associated with migraine: A case-control study. Cephalalgia. 2019;39:15–20. doi: 10.1177/0333102418769917. [DOI] [PubMed] [Google Scholar]
  • 49.Song TJ, Cho SJ, Kim WJ, et al. Sex Differences in Prevalence, Symptoms, Impact, and Psychiatric Comorbidities in Migraine and Probable Migraine: A Population-Based Study. Headache. 2019;59:215–223. doi: 10.1111/head.13470. [DOI] [PubMed] [Google Scholar]
  • 50.Adelborg K, Szépligeti SK, Holland-Bill L, et al. Migraine and risk of cardiovascular diseases: Danish population based matched cohort study. BMJ. 2018;360:k96. doi: 10.1136/bmj.k96. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Akdag Uzun Z, Kurt S, Karaer Unaldi H. The relationship with restless legs syndrome, fibromyalgia, and depressive symptoms in migraine patients. Neurol Sci. 2018;39:1409–1414. doi: 10.1007/s10072-018-3438-7. [DOI] [PubMed] [Google Scholar]
  • 52.D’Amico D, Sansone E, Grazzi L, et al. Multimorbidity in patients with chronic migraine and medication overuse headache. Acta Neurol Scand. 2018;138:515–522. doi: 10.1111/ane.13014. [DOI] [PubMed] [Google Scholar]
  • 53.Friedman LE, Zhong QY, Gelaye B, et al. Association Between Migraine and Suicidal Behaviors: A Nationwide Study in the USA. Headache. 2018;58:371–380. doi: 10.1111/head.13235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Kocaman G, Kahraman N, Gürkan Köseoğlu B, et al. Evaluation of onabotulinumtoxina treatment in patients with concomitant chronic migraine and temporomandibular disorders. Noropsikiyatri Arsivi. 2018;55:330–336. doi: 10.5152/npa.2017.19257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Serdaroğlu Beyazal M, Tüfekçi A, Kirbaş S, Topaloğlu MS. The impact of fibromyalgia on disability, anxiety, depression, sleep disturbance, and quality of life in patients with migraine. Noropsikiyatri Arsivi. 2018;55:140–145. doi: 10.5152/npa.2016.12691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Song TJ, Chu MK, Sohn JH, et al. Effect of vitamin D deficiency on the frequency of headaches in migraine. J Clin Neurol. 2018;14:366–373. doi: 10.3988/jcn.2018.14.3.366. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Yang FC, Chou KH, Hsu AL, et al. Altered brain functional connectome in migraine with and without restless legs syndrome: A resting-state functional MRI study. Front Neurol. 2018;9:25. doi: 10.3389/fneur.2018.00025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Zaproudina N, Rissanen APE, Lipponen JA, et al. Tooth clenching induces abnormal cerebrovascular responses in migraineurs. Fronti Neurol. 2018;9:1112. doi: 10.3389/fneur.2018.01112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Gajria K, Lee LK, Flores NM, et al. Humanistic and economic burden of nausea and vomiting among migraine sufferers. J Pain Res. 2017;10:689–698. doi: 10.2147/JPR.S124683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Güngen B, Yildirim A, Aras YG, et al. Effect of maternal migraine on Children’s quality of sleep. Ideggyogyaszati Szemle. 2017;70:417–423. doi: 10.18071/isz.70.0417. [DOI] [PubMed] [Google Scholar]
  • 61.Harnod T, Wang YC, Lin CL, Tseng CH. Association between use of short-acting benzodiazepines and migraine occurrence: a nationwide population-based case–control study. Curr Med Res Opin. 2017;33:511–517. doi: 10.1080/03007995.2016.1266313. [DOI] [PubMed] [Google Scholar]
  • 62.Ibrahim NK, Alotaibi AK, Alhazmi AM, et al. Prevalence, predictors and triggers of migraine headache among medical students and interns in King Abdulaziz University, Jeddah, Saudi Arabia. Pak J Med Sci. 2017;33:270–275. doi: 10.12669/pjms.332.12139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Lantz M, Sieurin J, Sjölander A, et al. Migraine and risk of stroke: A national population-based twin study. Brain. 2017;140:2653–2662. doi: 10.1093/brain/awx223. [DOI] [PubMed] [Google Scholar]
  • 64.Lee SH, Kang Y, Cho SJ. Subjective cognitive decline in patients with migraine and its relationship with depression, anxiety, and sleep quality. J Headache Pain. 2017;18:77. doi: 10.1186/s10194-017-0779-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Streel S, Donneau AF, Dardenne N, et al. Screening for the metabolic syndrome in subjects with migraine. Cephalalgia. 2017;37:1180–1188. doi: 10.1177/0333102416672494. [DOI] [PubMed] [Google Scholar]
  • 66.Sun W, Guo P, Ren T, Wang W. Magnetic resonance imaging of intratympanic gadolinium helps differentiate vestibular migraine from Ménière disease. Laryngoscope. 2017;127:2382–2388. doi: 10.1002/lary.26518. [DOI] [PubMed] [Google Scholar]
  • 67.Fuh JL, Chung MY, Yao SC, et al. Susceptible genes of restless legs syndrome in migraine. Cephalalgia. 2016;36:1028–1037. doi: 10.1177/0333102415620907. [DOI] [PubMed] [Google Scholar]
  • 68.Kim J, Cho SJ, Kim WJ, et al. Insomnia in probable migraine: a population-based study. J Headache Pain. 2016;17:92. doi: 10.1186/s10194-016-0681-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Lin GY, Lin YK, Lee JT, et al. Prevalence of restless legs syndrome in migraine patients with and without aura: a cross-sectional, case-controlled study. J Headache Pain. 2016;17:97. doi: 10.1186/s10194-016-0691-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Palacios-Ceña M, Florencio LL, Ferracini GN, et al. Women with chronic and episodic migraine exhibit similar widespread pressure pain sensitivity. Pain Med. 2016;17:2127–2133. doi: 10.1093/pm/pnw056. [DOI] [PubMed] [Google Scholar]
  • 71.Peşkersoy C, Peker Ş, Kaya A, et al. Evaluation of the relationship between migraine disorder and oral comorbidities: Multicenter randomized clinical trial. Turk J Medi Sci. 2016;46:712–718. doi: 10.3906/sag-1412-71. [DOI] [PubMed] [Google Scholar]
  • 72.Wang HI, Ho YC, Huang YP, Pan SL. Migraine is related to an increased risk of Parkinson’s disease: A population-based, propensity score-matched, longitudinal follow-up study. Cephalalgia. 2016;36:1316–1323. doi: 10.1177/0333102416630577. [DOI] [PubMed] [Google Scholar]
  • 73.Yang FC, Lin TY, Chen HJ, et al. Increased risk of restless legs syndrome in patients with migraine a nationwide population-based cohort study. Med (Baltim) 2016;95:e2646. doi: 10.1097/MD.0000000000002646. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Chen PK, Fuh JL, Wang SJ. Bidirectional triggering association between migraine and restless legs syndrome: A diary study. Cephalalgia. 2015;36:431–436. doi: 10.1177/0333102415596444. [DOI] [PubMed] [Google Scholar]
  • 75.He Z, Dong L, Zhang Y, et al. Metabolic syndrome in female migraine patients is associated with medication overuse headache: A clinic-based study in China. Eur J Neurol. 2015;22:1228–1234. doi: 10.1111/ene.12732. [DOI] [PubMed] [Google Scholar]
  • 76.Law HZ, Amirlak B, Cheng J, Sammer DM. An association between carpal tunnel syndrome and migraine headaches - National health interview survey, 2010. last Reconstr Surg Glob Open. 2015;3:e333. doi: 10.1097/GOX.0000000000000257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Monteith TS, Gardener H, Rundek T, et al. Migraine and risk of stroke in older adults: Northern Manhattan Study. Neurology. 2015;85:715–721. doi: 10.1212/WNL.0000000000001854. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Qiu C, Frederick IO, Sorensen T, et al. Sleep disturbances among pregnant women with history of migraines: A cross-sectional study. Cephalalgia. 2015;35:1092–1102. doi: 10.1177/0333102415570493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Sani SHD, Etemadi M, Shahri B, et al. Association between size of patent foramen ovale and migraine with aura in comparison with migraine without aura. Int Med J. 2015;22:27–29. [Google Scholar]
  • 80.Sinnige J, Korevaar JC, Westert GP, et al. Multimorbidity patterns in a primary care population aged 55 years and over. Fam Pract. 2015;32:505–513. doi: 10.1093/fampra/cmv037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Vij B, Whipple MO, Tepper SJ, et al. Frequency of migraine headaches in patients with fibromyalgia. Headache. 2015;55:860–865. doi: 10.1111/head.12590. [DOI] [PubMed] [Google Scholar]
  • 82.Yalinay Dikmen P, Yavuz BG, Aydinlar EI. The relationships between migraine, depression, anxiety, stress, and sleep disturbances. Acta Neurol Belg. 2015;115:117–122. doi: 10.1007/s13760-014-0312-0. [DOI] [PubMed] [Google Scholar]
  • 83.Cioffi I, Perrotta S, Ammendola L, et al. Social impairment of individuals suffering from different types of chronic orofacial pain. Prog Orthod. 2014;15:27. doi: 10.1186/s40510-014-0027-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Fava A, Pirritano D, Consoli D, et al. Chronic migraine in women is associated with insulin resistance: A cross-sectional study. Eur J Neurol. 2014;21:267–272. doi: 10.1111/ene.12289. [DOI] [PubMed] [Google Scholar]
  • 85.Ghajarzadeh M, Jalilian R, Togha M, et al. Depression, poor sleep, and sexual dysfunction in migraineurs women. Int J Prev Med. 2014;5:1113–1118. [PMC free article] [PubMed] [Google Scholar]
  • 86.Goulart AC, Santos IS, Brunoni AR, et al. Migraine headaches and Mood/Anxiety disorders in the ELSA Brazil. Headache. 2014;54:1310–1319. doi: 10.1111/head.12397. [DOI] [PubMed] [Google Scholar]
  • 87.Gürkov R, Kantner C, Strupp M, et al. Endolymphatic hydrops in patients with vestibular migraine and auditory symptoms. Eur Archf Otorhinolaryngol. 2014;271:2661–2667. doi: 10.1007/s00405-013-2751-2. [DOI] [PubMed] [Google Scholar]
  • 88.Jalilian R, Ghajarzadeh M, Fateh R, et al. Comparison of sleep quality in women with migraine moreover, multiple sclerosis. Acta Med Irani. 2014;52:690–693. [PubMed] [Google Scholar]
  • 89.Lin KH, Chen YT, Fuh JL, et al. Migraine is associated with a higher risk of transient global amnesia: A nationwide cohort study. Eur J Neurol. 2014;21:718–724. doi: 10.1111/ene.12346. [DOI] [PubMed] [Google Scholar]
  • 90.Monteith T, Gardener H, Rundek T, et al. Migraine, white matter hyperintensities, and subclinical brain infarction in a diverse community: The northern manhattan study. Stroke. 2014;45:1830–1832. doi: 10.1161/STROKEAHA.114.005447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91.Turan B, Siva ZO, Uluduz D, et al. The impact of depression and ghrelin on body weight in migraineurs. J Headache Pain. 2014;15:23. doi: 10.1186/1129-2377-15-23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92.Walters AB, Hamer JD, Smitherman TA. Sleep disturbance and affective comorbidity among episodic migraineurs. Headache. 2014;54:116–124. doi: 10.1111/head.12168. [DOI] [PubMed] [Google Scholar]
  • 93.Ofte HK, Berg DH, Bekkelund SI, Alstadhaug KB. Insomnia and periodicity of headache in an arctic cluster headache population. Headache. 2013;53:1602–1612. doi: 10.1111/head.12241. [DOI] [PubMed] [Google Scholar]
  • 94.Shin JE, Kim CH, Park HJ. Vestibular abnormality in patients with Meniere’s disease and migrainous vertigo. Acta Otolaryngol. 2013;133:154–158. doi: 10.3109/00016489.2012.727469. [DOI] [PubMed] [Google Scholar]
  • 95.Stam AH, Weller CM, Janssens ACJW, et al. Migraine is not associated with enhanced atherosclerosis. Cephalalgia. 2013;33:228–235. doi: 10.1177/0333102412466966. [DOI] [PubMed] [Google Scholar]
  • 96.Zhu Z, Fan X, Li X, et al. Prevalence and predictive factors for poor sleep quality among migraineurs in a tertiary hospital headache clinic. Acta Neurol Belg. 2013;113:229–235. doi: 10.1007/s13760-012-0159-1. [DOI] [PubMed] [Google Scholar]
  • 97.Chen YC, Tang CH, Ng K, Wang SJ. Comorbidity profiles of chronic migraine sufferers in a national database in Taiwan. J Headache Pain. 2012;13:311–319. doi: 10.1007/s10194-012-0447-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Curone M, Tullo V, Mea E, et al. Psychopathological profile of patients with chronic migraine and medication overuse: Study and findings in 50 cases. Neurol Sci. 2011;32:S177–S179. doi: 10.1007/s10072-011-0527-2. [DOI] [PubMed] [Google Scholar]
  • 99.Kurth T, Diener HC, Buring JE. Migraine and cardiovascular disease in women and the role of aspirin: Subgroup analyses in the Women’s Health Study. Cephalalgia. 2011;31:1106–1115. doi: 10.1177/0333102411412628. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100.Le H, Tfelt-Hansen P, Russell MB, et al. Co-morbidity of migraine with somatic disease in a large population-based study. Cephalalgia. 2011;31:43–64. doi: 10.1177/0333102410373159. [DOI] [PubMed] [Google Scholar]
  • 101.Mancia G, Rosei EA, Ambrosioni E, et al. Hypertension and migraine comorbidity: Prevalence and risk of cerebrovascular events: Evidence from a large, multicenter, cross-sectional survey in Italy (MIRACLES study) J Hypertens. 2011;29:309–318. doi: 10.1097/HJH.0b013e3283410404. [DOI] [PubMed] [Google Scholar]
  • 102.Vo M, Ainalem A, Qiu C, et al. Body mass index and adult weight gain among reproductive age women with migraine. Headache. 2011;51:559–569. doi: 10.1111/j.1526-4610.2010.01833.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 103.Buse DC, Manack A, Serrano D. Sociodemographic and comorbidity profiles of chronic migraine and episodic migraine sufferers. J Neurol Neurosurge Psychiatry. 2010;81:428–432. doi: 10.1136/jnnp.2009.192492. [DOI] [PubMed] [Google Scholar]
  • 104.Calhoun AH, Ford S, Millen C, et al. The prevalence of neck pain in migraine. Headache. 2010;50:1273–1277. doi: 10.1111/j.1526-4610.2009.01608.x. [DOI] [PubMed] [Google Scholar]
  • 105.Gruber HJ, Bernecker C, Pailer S, et al. Lipid profile in normal weight migraineurs - Evidence for cardiovascular risk. Eur J Neurol. 2010;17:419–425. doi: 10.1111/j.1468-1331.2009.02861.x. [DOI] [PubMed] [Google Scholar]
  • 106.Schürks M, Buring JE, Kurth T. Migraine, migraine features, and cardiovascular disease. Headache. 2010;50:1031–1040. doi: 10.1111/j.1526-4610.2009.01609.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 107.Allam M, Fathi S, Elfayomy N, et al. When can migraine alert for cerebral stroke? Egypt J Neurol Psychiat Neurosurg. 2009;46:517–529. [Google Scholar]
  • 108.Fatini C, Poli D, Sticchi E, et al. Lipoprotein (a) [Lp(a)]: a possible link between migraine and stroke. Transl Res. 2009;153:44–47. doi: 10.1016/j.trsl.2008.11.001. [DOI] [PubMed] [Google Scholar]
  • 109.Kurth T, Schürks M, Logroscino G, Buring JE. Migraine frequency and risk of cardiovascular disease in women. Neurology. 2009;73:581–588. doi: 10.1212/WNL.0b013e3181ab2c20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 110.Kurth T, Schürks M, Logroscino G, et al. Migraine, vascular risk, and cardiovascular events in women: Prospective cohort study. BMJ. 2008;337:383–387. doi: 10.1136/bmj.a636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 111.Peterlin BL, Tietjen G, Meng S, et al. Post-traumatic stress disorder in episodic and chronic migraine. Headache. 2008;48:517–522. doi: 10.1111/j.1526-4610.2008.00917.x. [DOI] [PubMed] [Google Scholar]
  • 112.Rundek T, Elkind MSV, Di Tullio MR, et al. Patent foramen ovale and migraine: A cross-sectional study from the Northern Manhattan Study (NOMAS) Circulation. 2008;118:1419–1424. doi: 10.1161/CIRCULATIONAHA.108.771303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 113.Schürks M, Zee RYL, Buring JE, Kurth T. Interrelationships among the MTHFR 677 C > T polymorphism, migraine, and cardiovascular disease. Neurology. 2008;71:505–513. doi: 10.1212/01.wnl.0000316198.34558.e5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 114.Schwaiger J, Kiechl S, Stockner H, et al. Burden of atherosclerosis and risk of venous thromboembolism in patients with migraine. Neurology. 2008;71:937–943. doi: 10.1212/01.wnl.0000325918.48056.75. [DOI] [PubMed] [Google Scholar]
  • 115.Vgontzas A, Cui L, Merikangas KR. Are sleep difficulties associated with migraine attributable to anxiety and depression? Headache. 2008;48:1451–9. doi: 10.1111/j.1526-4610.2008.01175.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 116.Barbanti P, Fabbrini G, Aurilia C, et al. A case-control study on excessive daytime sleepiness in episodic migraine. Cephalalgia. 2007;27:1115–1119. doi: 10.1111/j.1468-2982.2007.01399.x. [DOI] [PubMed] [Google Scholar]
  • 117.Kurth T, Gaziano JM, Cook NR, et al. Migraine and risk of cardiovascular disease in men. Arch Intern Med. 2007;167:795–801. doi: 10.1001/archinte.167.8.795. [DOI] [PubMed] [Google Scholar]
  • 118.Rhode AM, Hösing VG, Happe S, et al. Comorbidity of migraine and restless legs syndrome - A case-control study. Cephalalgia. 2007;27:1255–1260. doi: 10.1111/j.1468-2982.2007.01453.x. [DOI] [PubMed] [Google Scholar]
  • 119.Tietjen GE, Peterlin BL, Brandes JL, et al. Depression and anxiety: Effect on the migraine-obesity relationship. Headache. 2007;47:866–875. doi: 10.1111/j.1526-4610.2007.00810.x. [DOI] [PubMed] [Google Scholar]
  • 120.Artto V, Wessman M, Nissilä M, et al. Comorbidity in finnish migraine families. J Headache Pain. 2006;7:324–330. doi: 10.1007/s10194-006-0319-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 121.Corchs F, Mercante JP, Guendler VZ, et al. Phobias, other psychiatric comorbidities and chronic migraine. Arq Neuropsiquiatr. 2006;64:950–953. doi: 10.1590/S0004-282X2006000600012. [DOI] [PubMed] [Google Scholar]
  • 122.Kurth T, Gaziano JM, Cook NR, et al. Migraine and risk of cardiovascular disease in women. JAMA. 2006;296:283–291. doi: 10.1001/jama.296.3.283. [DOI] [PubMed] [Google Scholar]
  • 123.Neuhauser HK, Radtke A, Von Brevern M, et al. Migrainous vertigo: Prevalence and impact on quality of life. Neurology. 2006;67:1028–1033. doi: 10.1212/01.wnl.0000237539.09942.06. [DOI] [PubMed] [Google Scholar]
  • 124.Tietjen GE, Conway A, Utley C, et al. Migraine is associated with menorrhagia and endometriosis. Headache. 2006;46:422–428. doi: 10.1111/j.1526-4610.2006.00290.x. [DOI] [PubMed] [Google Scholar]
  • 125.Kruit MC, Van Buchem MA, Hofman PAM, et al. Migraine as a Risk Factor for Subclinical Brain Lesions. JAMA. 2004;291:427–434. doi: 10.1001/jama.291.4.427. [DOI] [PubMed] [Google Scholar]
  • 126.Carerj S, Narbone MC, Zito C, et al. Prevalence of atrial septal aneurysm in patients with migraine: An echocardiographic study. Headache. 2003;43:725–728. doi: 10.1046/j.1526-4610.2003.03129.x. [DOI] [PubMed] [Google Scholar]
  • 127.Cook NR, Benseñor IM, Lotufo PA, et al. Migraine and coronary heart disease in women and men. Headache. 2002;42:715–727. doi: 10.1046/j.1526-4610.2002.02173.x. [DOI] [PubMed] [Google Scholar]
  • 128.Tietjen GE, Al-Qasmi MM, Shukairy MS. Livedo reticularis and migraine: a marker for stroke risk? Headache. 2002;42:352–5. doi: 10.1046/j.1526-4610.2002.02106.x. [DOI] [PubMed] [Google Scholar]
  • 129.Breslau N, Schultz LR, Stewart WF, et al. Headache types and panic disorder: Directionality and specificity. Neurology. 2001;56:350–354. doi: 10.1212/WNL.56.3.350. [DOI] [PubMed] [Google Scholar]
  • 130.Kim KM, Kim J, Cho SJ, et al. Excessive Daytime Sleepiness in Tension-Type Headache: A Population Study. Front Neurol. 2019;10:1282. doi: 10.3389/fneur.2019.01282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 131.Wagner BA, Moreira Filho PF, Bernardo VG. Association of bruxism and anxiety symptoms among military firefighters with frequent episodic tension type headache and temporomandibular disorders. Arq Neuropsiquiatr. 2019;77:478–484. doi: 10.1590/0004-282x20190069. [DOI] [PubMed] [Google Scholar]
  • 132.Yang FC, Chen HJ, Lee JT, et al. Increased risk of Parkinson’s disease following tension-type headache: A nationwide population-based cohort study. Oncotarget. 2018;9:2148–2157. doi: 10.18632/oncotarget.23298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 133.Chung PW, Cho SJ, Kim WJ, et al. Restless legs syndrome and tension-type headache: a population-based study. J Headache Pain. 2017;18:47. doi: 10.1186/s10194-017-0754-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 134.Kim J, Cho SJ, Kim WJ, et al. Insomnia in tension-type headache: a population-based study. J Headache Pain. 2017;18:95. doi: 10.1186/s10194-017-0805-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 135.Hryvenko I, Cervantes-Chavarría AR, Law AS, Nixdorf DR. Hemicrania continua: Case series presenting in an orofacial pain clinic. Cephalalgia. 2018;38:1950–1959. doi: 10.1177/0333102418764895. [DOI] [PubMed] [Google Scholar]
  • 136.Piacentini SHMJ, Draghi L, Cecchini AP, Leone M. Personality disorders in cluster headache: a study using the Millon Clinical Multiaxial Inventory-III. Neurol Sci. 2017;38:181–184. doi: 10.1007/s10072-017-2929-2. [DOI] [PubMed] [Google Scholar]
  • 137.Louter MA, Wilbrink LA, Haan J, et al. Cluster headache and depression. Neurology. 2016;87:1899–1906. doi: 10.1212/WNL.0000000000003282. [DOI] [PubMed] [Google Scholar]
  • 138.Sadeghniiat K, Rajabzadeh A, Ghajarzadeh M, Ghafarpour M. Sleep quality and depression among patients with migraine. Acta Med Iran. 2013;51:784–788. [PubMed] [Google Scholar]
  • 139.Graff-Radford SB, Newman A. Obstructive sleep apnea and cluster headache. Headache. 2004;44:607–610. doi: 10.1111/j.1526-4610.2004.446010.x. [DOI] [PubMed] [Google Scholar]
  • 140.Abou Elmaaty AA, Flifel ME, Belal T, Zarad CA. Migraine and tension headache comorbidity with hypothyroidism in Egypt. Egypt J Neurol Psychiat Neurosurg. 2020;56:78. doi: 10.1186/s41983-020-00208-w. [DOI] [Google Scholar]
  • 141.Lamsam L, Bhambhvani HP, Thomas A, et al. Aneurysmal subarachnoid hemorrhage in patients with migraine and tension headache: A cohort comparison study. J Clin Neurosci. 2020;79:90–94. doi: 10.1016/j.jocn.2020.07.017. [DOI] [PubMed] [Google Scholar]
  • 142.Lee DH, Kim KM, Cho SJ, et al. Impacts of migraine on the prevalence and clinical presentation of depression: A population-based study. J Affect Dis. 2020;272:215–222. doi: 10.1016/j.jad.2020.03.102. [DOI] [PubMed] [Google Scholar]
  • 143.Saha FJ, Pulla A, Ostermann T, et al. Effects of occlusal splint therapy in patients with migraine or tension-type headache and comorbid temporomandibular disorder: A randomized controlled trial. Med (Baltim) 2019;98:e16805. doi: 10.1097/MD.0000000000016805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 144.Suzuki K, Suzuki S, Haruyama Y, et al. Restless legs syndrome is associated with headache-related disabilities in patients with migraine: a prospective 7-year follow-up study. Eur J Neurol. 2019;26:238–245. doi: 10.1111/ene.13796. [DOI] [PubMed] [Google Scholar]
  • 145.Martami F, Ghorbani Z, Abolhasani M, et al. Comorbidity of gastrointestinal disorders, migraine, and tension-type headache: a cross-sectional study in Iran. Neurol Sci. 2018;39:63–70. doi: 10.1007/s10072-017-3141-0. [DOI] [PubMed] [Google Scholar]
  • 146.Norton J, Portet F, Gabelle A, et al. Are migraine and non-migrainous headache risk factors for stroke in the elderly? Findings from a 12-year cohort follow-up. Eur J Neurol. 2016;23:1463–1470. doi: 10.1111/ene.13060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 147.Zarei MR, Shabani M, Chamani G, et al. Migraine patients have a higher prevalence of PTSD symptoms in comparison to chronic tension-type headache and healthy subjects: a case–control study. Acta Odontol Scand. 2016;74:633–635. doi: 10.1080/00016357.2016.1232435. [DOI] [PubMed] [Google Scholar]
  • 148.Cho SJ, Chung YK, Kim JM, Chu MK. Migraine and restless legs syndrome are associated in adults under age fifty but not in adults over fifty: a population-based study. J Headache Pain. 2015;16:554. doi: 10.1186/s10194-015-0554-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 149.Khan HB, Shah PA, Bhat MH, Imran A. Association of hypothyroidism in patients with migraine and tension-type headache disorders in Kashmir, North India. Neurology Asia. 2015;20:257–261. [Google Scholar]
  • 150.Wang Y, Xie J, Yang F, et al. Comorbidity of poor sleep and primary headaches among nursing staff in north China. J Headache Pain. 2015;16:88. doi: 10.1186/s10194-015-0571-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 151.Yang FC, Lin TY, Chen HJ, et al. Risk of restless legs syndrome following tension-type headache a nationwide population-based cohort study. Med (Baltim) 2015;94:e2109. doi: 10.1097/MD.0000000000002109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 152.De Angeli F, Lovati C, Giani L et al (2014) Negative emotions in migraineurs dreams: the increased prevalence of oneiric fear and anguish, unrelated to mood disorders. Behav Neurol. 2014:919627 [DOI] [PMC free article] [PubMed]
  • 153.Desai SD, Pandya RH. Study of psychiatric comorbidity in patients with headache using a short structured clinical interview in a rural neurology clinic in Western India. J Neurosci Rural Pract. 2014;5:S39–S42. doi: 10.4103/0976-3147.145199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 154.Scher AI, Ross GW, Sigurdsson S, et al. Midlife migraine and late-life parkinsonism: AGES-Reykjavik study. Neurology. 2014;83:1246–1252. doi: 10.1212/WNL.0000000000000840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 155.De Tommaso M, Federici A, Serpino C, et al. Clinical features of headache patients with fibromyalgia comorbidity. J Headache Pain. 2011;12:629–638. doi: 10.1007/s10194-011-0377-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 156.Mehlsteibl D, Schankin C, Hering P, et al. Anxiety disorders in headache patients in a specialised clinic: Prevalence and symptoms in comparison to patients in a general neurological clinic. J Headache Pain. 2011;12:323–329. doi: 10.1007/s10194-011-0293-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 157.Peterlin BL, Rosso AL, Sheftell FD, et al. Post-traumatic stress disorder, drug abuse and migraine: new findings from the National Comorbidity Survey Replication (NCS-R) Cephalalgia. 2011;31:235–244. doi: 10.1177/0333102410378051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 158.Winsvold BS, Hagen K, Aamodt AH, et al. Headache, migraine and cardiovascular risk factors: The HUNT study. Eur J Neurol. 2011;18:504–511. doi: 10.1111/j.1468-1331.2010.03199.x. [DOI] [PubMed] [Google Scholar]
  • 159.Beghi E, Bussone G, D’Amico D, et al. Headache, anxiety and depressive disorders: The HADAS study. J Headache Pain. 2010;11:141–150. doi: 10.1007/s10194-010-0187-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 160.Gipponi S, Venturelli E, Rao R, et al. Hypertension is a factor associated with chronic daily headache. Neurol Sci. 2010;31:S171–S173. doi: 10.1007/s10072-010-0322-5. [DOI] [PubMed] [Google Scholar]
  • 161.Sancisi E, Cevoli S, Vignatelli L, et al. Increased prevalence of sleep disorders in chronic headache: A case-control study. Headache. 2010;50:1464–1472. doi: 10.1111/j.1526-4610.2010.01711.x. [DOI] [PubMed] [Google Scholar]
  • 162.Tietjen GE, Brandes JL, Peterlin BL, et al. Childhood maltreatment and migraine (part II). Emotional abuse as a risk factor for headache chronification. Headache. 2010;50:32–41. doi: 10.1111/j.1526-4610.2009.01557.x. [DOI] [PubMed] [Google Scholar]
  • 163.Katsnelson MJ, Peterlin BL, Rosso AL, et al. Self-reported vs measured body mass indices in migraineurs. Headache. 2009;49:663–668. doi: 10.1111/j.1526-4610.2009.01400.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 164.Peterlin BL, Tietjen GE, Brandes JL, et al. Posttraumatic stress disorder in migraine. Headache. 2009;49:541–551. doi: 10.1111/j.1526-4610.2009.01368.x. [DOI] [PubMed] [Google Scholar]
  • 165.Seidel S, Hartl T, Weber M, et al. Quality of sleep, fatigue and daytime sleepiness in migraine - A controlled study. Cephalalgia. 2009;29:662–669. doi: 10.1111/j.1468-2982.2008.01784.x. [DOI] [PubMed] [Google Scholar]
  • 166.Cologno D, Cicarelli G, Petretta V, et al. High prevalence of Dopaminergic Premonitory Symptoms in migraine patients with Restless Legs Syndrome: A pathogenetic link? Neurolo Sci. 2008;29:S166–S168. doi: 10.1007/s10072-008-0915-4. [DOI] [PubMed] [Google Scholar]
  • 167.Beghi E, Allais G, Cortelli P, et al. Headache and anxiety-depressive disorder comorbidity: The HADAS study. Neurol Sci. 2007;28:S217–S219. doi: 10.1007/s10072-007-0780-6. [DOI] [PubMed] [Google Scholar]
  • 168.Scher AI, Stewart WF, Ricci JA, Lipton RB. Factors associated with the onset and remission of chronic daily headache in a population-based study. Pain. 2003;106:81–89. doi: 10.1016/S0304-3959(03)00293-8. [DOI] [PubMed] [Google Scholar]
  • 169.Breslau N. Psychiatric comorbidity in migraine. Cephalalgia 18 Suppl. 1998;22:56–61. doi: 10.1177/0333102498018S2210. [DOI] [PubMed] [Google Scholar]
  • 170.Lampl C, Thomas H, Tassorelli C, et al. Headache, depression and anxiety: associations in the Eurolight project. J Headache Pain. 2016;17:59. doi: 10.1186/s10194-016-0649-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 171.Chu H, Te, Liang CS, Lee JT, et al. Associations Between Depression/Anxiety and Headache Frequency in Migraineurs: A Cross-Sectional Study. Headache. 2018;58(3):407–415. doi: 10.1111/head.13215. [DOI] [PubMed] [Google Scholar]
  • 172.Lantéri-Minet M, Radat F, Chautard MH, Lucas C. Anxiety and depression associated with migraine: Influence on migraine subjects’ disability and quality of life, and acute migraine management. Pain. 2005;118:319–326. doi: 10.1016/j.pain.2005.09.010. [DOI] [PubMed] [Google Scholar]
  • 173.Casucci G, Villani V, Finocchi C. Therapeutic strategies in migraine patients with mood and anxiety disorders: physiopathological basis. Neurol Sci. 2010;31:S99–S101. doi: 10.1007/s10072-010-0296-3. [DOI] [PubMed] [Google Scholar]
  • 174.Finocchi C, Villani V, Casucci G. Therapeutic strategies in migraine patients with mood and anxiety disorders: clinical evidence. Neurol Sci. 2010;31:S95–S98. doi: 10.1007/s10072-010-0297-2. [DOI] [PubMed] [Google Scholar]
  • 175.Andrasik F, Grazzi L, D’Amico D, et al. Mindfulness and headache: A “new” old treatment, with new findings. Cephalalgia. 2016;36:1192–1205. doi: 10.1177/0333102416667023. [DOI] [PubMed] [Google Scholar]
  • 176.Grazzi L, Toppo C, D’Amico D, et al. Non-Pharmacological Approaches to Headaches: Non-Invasive Neuromodulation, Nutraceuticals, and Behavioral Approaches. Int J Environ Res Public Health. 2021;18:1503. doi: 10.3390/ijerph18041503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 177.Dosi C, Figura M, Ferri R, Bruni O. Sleep and Headache. Semin Pediatr Neurol. 2015;22:105–112. doi: 10.1016/j.spen.2015.04.005. [DOI] [PubMed] [Google Scholar]
  • 178.Ferini-Strambi L, Galbiati A, Combi R. Sleep disorder-related headaches. Neurol Sci. 2019;40:S107–S113. doi: 10.1007/s10072-019-03837-z. [DOI] [PubMed] [Google Scholar]
  • 179.Yeung W-F, Chung K-F, Wong C-Y. Relationship between insomnia and headache in community-based middle-aged Hong Kong Chinese women. J Headache Pain. 2010;11:187–195. doi: 10.1007/s10194-010-0199-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 180.Vgontzas A, Pavlović JM. Sleep Disorders and Migraine: Review of Literature and Potential Pathophysiology Mechanisms. Headache. 2018;58:1030–1039. doi: 10.1111/head.13358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 181.Freedom T. Headaches and sleep disorders. Dis Mon. 2015;61:240–248. doi: 10.1016/j.disamonth.2015.03.008. [DOI] [PubMed] [Google Scholar]
  • 182.Haghighi FS, Rahmanian M, Namiranian N, et al. Migraine and type 2 diabetes; is there any association? J Diabetes Metab Disord. 2016;15:37. doi: 10.1186/s40200-016-0241-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 183.Wang X, Li X, Diao Y, Meng S, et al. Are Glucose and Insulin Metabolism and Diabetes Associated with Migraine? A Community-Based, Case-Control Study. J Oral Facial Pain Headache. 2017;31:240–250. doi: 10.11607/ofph.1843. [DOI] [PubMed] [Google Scholar]
  • 184.Schmidt MI, Duncan BB. Diabesity: an inflammatory metabolic condition. Clin Chem Lab Med. 2003;41:1120–1130. doi: 10.1515/CCLM.2003.174. [DOI] [PubMed] [Google Scholar]
  • 185.Khalil NY, AlRabiah HK, Al Rashoud SS, et al. Topiramate: Comprehensive profile. Profiles Drug Subst Excip Relat Methodol. 2019;44:333–378. doi: 10.1016/bs.podrm.2018.11.005. [DOI] [PubMed] [Google Scholar]
  • 186.MacClellan LR, Giles W, Cole J, et al. Probable migraine with visual aura and risk of ischemic stroke: the stroke prevention in young women study. Stroke. 2007;38:2438–2445. doi: 10.1161/STROKEAHA.107.488395. [DOI] [PubMed] [Google Scholar]
  • 187.Mathew PG, Klein BC. Getting to the Heart of the Matter: Migraine, Triptans, DHE, Ditans, CGRP Antibodies, First/Second-Generation Gepants, and Cardiovascular Risk. Headache. 2019;59:1421–1426. doi: 10.1111/head.13601. [DOI] [PubMed] [Google Scholar]
  • 188.Goasby PJ, Wietecha LA, Dennehy EB, et al. Phase 3 randomized, placebo controlled, double blind study of Lasmiditan for acute treatment of migraine. Brain. 2019;142:1894–1904. doi: 10.1093/brain/awz134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 189.Favoni V, Giani L, Al-Hassany A, et al. CGRP and migraine from a cardiovascular point of view: what do we expect from blocking CGRP? J Headache Pain. 2019;20:27. doi: 10.1186/s10194-019-0979-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 190.Kudrow D, Pascual J, Winner PK, et al. Vascular safety of erenumab for migraine prevention. Neurology. 2020;94:e497–e510. doi: 10.1212/WNL.0000000000008743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 191.Christensen KS, Oernboel E, Nielsen MG, Bech P. Diagnosing depression in primary care: a Rasch analysis of the Major Depression Inventory. Scand J Prim Health Care. 2019;37(2):256–263. doi: 10.1080/02813432.2019.1608039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 192.Dejesus RS, Vickers KS, Melin GJ, Williams MD. A system-based approach to depression management in primary care using the Patient Health Questionnaire-9. Mayo Clin Proc. 2007;82(11):1395–402. doi: 10.4065/82.11.1395. [DOI] [PubMed] [Google Scholar]
  • 193.Stuart AL, Pasco JA, Jacka FN, et al. Comparison of self-report and structured clinical interview in the identification of depression. Compr Psychiatry. 2014;55(4):866–869. doi: 10.1016/j.comppsych.2013.12.019. [DOI] [PubMed] [Google Scholar]
  • 194.Mills KT, Bundy JD, Kelly TN. Global Disparities of Hypertension Prevalence and Control: A Systematic Analysis of Population-Based Studies From 90 Countries. Circulation. 2016;134(6):441–450. doi: 10.1161/CIRCULATIONAHA.115.018912. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 195.Malhi GS, Mann JJ. Depression Lancet. 2018;392:2299–2312. doi: 10.1016/S0140-6736(18)31948-2. [DOI] [PubMed] [Google Scholar]
  • 196.Rahman A, Underwood M, Carnes D. Fibromyalgia . BMJ. 2014;348:g1224. doi: 10.1136/bmj.g1224. [DOI] [PubMed] [Google Scholar]
  • 197.Allen RP, Bharmal M, Calloway M. Prevalence and disease burden of primary restless legs syndrome: results of a general population survey in the United States. Mov Disord. 2011;26(1):114–120. doi: 10.1002/mds.23430. [DOI] [PubMed] [Google Scholar]
  • 198.Vincent A, Lahr BD, Wolfe F, et al. Prevalence of fibromyalgia: a population-based study in Olmsted County, Minnesota, utilizing the Rochester epidemiology project. Arthritis Care Res. 2013;65:786–792. doi: 10.1002/acr.21896. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 199.Yang X, Liu B, Yang B, et al. Prevalence of restless legs syndrome in individuals with migraine: a systematic review and meta-analysis of observational studies. Neurol Sci. 2018;39:1927–1934. doi: 10.1007/s10072-018-3527-7. [DOI] [PubMed] [Google Scholar]
  • 200.Yoon MS, Manack A, Schramm S, et al. Chronic migraine and chronic tension-type headache are associated with concomitant low back pain: results of the German Headache Consortium study. Pain. 2013;154(3):484–492. doi: 10.1016/j.pain.2012.12.010. [DOI] [PubMed] [Google Scholar]
  • 201.Ashina S, Lipton RB, Bendtsen L, et al. Increased pain sensitivity in migraine and tension-type headache coexistent with low back pain: A cross-sectional population study. Eur J Pain. 2018;22(5):904–914. doi: 10.1002/ejp.1176. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

10194_2021_1281_MOESM1_ESM.docx (1.2MB, docx)

Additional file 1: Supplementary Table 1. Search strategy. Supplementary Table 2. Distribution of comorbidities in all included studies and by main condition (raw mean and min-max percentage). Supplementary figures, first set: Sub-analysis by study type, clinical vs. population studies (the overall pooled proportion correspond to the overall proportion of headache sufferers with each specific comorbidity as described in table 2 of main text). Supplementary figures, second set: Sub-analysis by female proportion, < 77.8% vs. ≥ 77.8%. Supplementary figures, third set: Sub-analysis by average age, < 40.4 vs. ≥ 40.4 years.

Data Availability Statement

Not applicable.


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