Although migraine is among the most common disabling conditions worldwide, it is rarely accurately diagnosed. This study aimed to categorize and compare patients suffering from migraines without aura (MWA) or other types of headaches in primary health care facilities.
We conducted a prospective, cross-sectional, epidemiological, and non-interventional study at 46 primary health care facilities in Bosnia and Herzegovina. The validated Balkan Migraine Screening Questionnaire (BMSQ) was used to classify patients into MWA or non-MWA groups.
More than half the patients in this study were newly classified as having MWA, indicating a high prevalence of undiagnosed migraine. Categorization of patients with headaches is of crucial importance for appropriate treatment and should be utilized in everyday practice in primary health care settings. HIPPOKRATIA 2023, 27 (2):99-105.
Keywords: Migraine without aura, validated questionnaire, migraine screening, visual analogue scale, Balkan migraine screening questionnaire, migraine predictors
Headache disorders are one of the leading causes of disability in the world 1 , 2 . The majority of headaches are diagnosed at primary medical facilities 3 . Migraines and tension-type headaches are the most common types 4 . Between 1990 and 2010, migraine was the primary headache ailment with a constant increase in disability-adjusted life-years (DALYs) 2 . It is estimated that more than one billion people worldwide were affected by migraine in 2016. In the same year, over 45 million years of life lived with disability were estimated for migraine sufferers worldwide. The predominant impact of migraine is felt in the female workforce, resulting in significant socio-economic consequences 1 . The most prevalent type of migraine is migraine without aura (MWA), accounting for 80 % of all migraines 5 . The attacks are recurring and last from four to 72 hours 6 .
Many people suffering from headaches do not seek medical care or obtain adequate diagnosis or therapy. Approximately 30-40 % of migraine sufferers are unaware of their condition, and self-medication regimens are commonly inadequate 7 . Pharmacists 8 , physicians 9 , and headache specialists 10 are playing a crucial role in preventing, diagnosing, and treating migraine. Health care professionals need tools for migraine diagnostics 7 , 11 . Pharmacists need adequate education and communication with physicians to perform their tasks in migraine management effectively 11 . It is also essential to educate in-depth physicians regarding headaches. Karli et al demonstrated that supplementary education enhances the precision of migraine and tension-type headache diagnosis, and the inclusion of appropriate therapy, from 56.3 % before education to 81 % after education 9 . It has been proven that using validated questionnaires is the most reliable and fastest way to diagnose MWA 12 .
This study aimed to categorize patients suffering from MWA or other types of headaches in primary health care facilities located in Bosnia and Herzegovina. Additionally, it aimed to report the number of newly diagnosed patients and compare their demographic and clinical characteristics, as well as any associated diseases and therapies, with those who were not classified into the MWA group.
This cross-sectional, prospective, epidemiological, and non-interventional study was conducted at 46 primary health care facilities in Bosnia and Herzegovina from December 2020 to September 2021. Forty-six out of 335 available primary health care centers were selected based on the investigators’ expertise and the center’s location to cover the entire territory of Bosnia and Herzegovina. All procedures were governed by the 1964 Helsinki Declaration and its later amendments. Prior to any procedure, all patients signed an informed consent form and the study was approved by the Agency for Medicinal Products and Medical Devices of Bosnia and Herzegovina (decision No 08-07.5-10940-1/20).
The study included consecutive patients of both sexes, aged 18 or older who attended a general practitioner complaining of headaches or any other problems related to migraines or headaches similar to migraines. Refusal to sign an informed consent form stood as an exclusion criterion.
The investigators interviewed the patients using a case record form (CRF) that contained general inquiries regarding the patient and filled out the CRFs based on the information/answers obtained from the patients. Data was collected at the baseline visit, including demographic and clinical characteristics, comorbidity, concurrent diseases, and therapies for each patient enrolled in the study. The Balkan Migraine Screening Questionnaire (BMSQ) was utilized to categorize patients. The BMSQ is a questionnaire designed for screening for MWA in general practice, which was previously developed and validated by our group 13 . The aforementioned questionnaire is based on one of the most commonly utilized questionnaires in clinical practice, namely the Migraine Screening Questionnaire (MS-Q). It was specifically designed to enhance the existing questionnaires and enhance diagnostic accuracy. MS-Q has been proven to be a valid and reliable screening tool in clinical practice, helping general practitioners to easily diagnose MWA based on the International Headache Society (IHS) criteria 14 . The BMSQ development and validation outcomes 13 revealed that if a patient answered affirmatively to four or more questions, the investigator could place this patient in the MWA group, prescribe appropriate treatment, and refer them to a medical professional for further evaluation.
Calculation of sample size was performed taking into consideration that migraine prevalence is about 6.4% [95 % confidence interval (CI) 6-6.8 %] in Bosnia and Herzegovina 1 , with maximal marginal error 1.5 % with 95 % CI resulting in a total of 1,023 (963-1,082) patients that need to be included. When 20 % were added, the required number totaled 1,298 patients. The normal distribution of variables was established by examining visual representations of histograms, box-plots and Q-Q plots, as well as using the Kolmogorov-Smirnov test. We present the numerical variables with a normal distribution as means ± standard deviation while the numerical variables with a non-normal distribution are presented as medians and interquartile range. The t-test and the Mann-Whitney U test, respectively, were employed for analysis. The categorical variables are presented as absolute numbers and percentages, and Pearson’s chi-square test was used for analysis.
The binary logistic regression model was used to predict the classification of patients by BMSQ into one of defined groups (MWA or non-MWA). The forward Stepwise Wald model was applied. Age, sex, smoking, alcohol consumption, body mass index (BMI), education, headache intensity, number of headache attacks in the preceding six months, frequency of headache therapy, family history of migraine, and mental comorbidities were included in the logistics analysis model. The collinearity among predictors was evaluated by linear regression. Cook’s D index evaluated influential cases. Outcome predictors are presented as odds ratio (OR) and a 95 % CI. The significance level was set at p =0.05. All tests were two-tailed. All statistical analyses were performed with the statistical package IBM SPSS Statistics for Windows, Version 26.0 (IBM Corp., Armonk, NY, USA).
The study included 1,366 patients with migraine or migraine-like headaches and 1,198 patients had not been previously diagnosed with migraine ( Table 1 ). The BMSQ questionnaire was utilized to classify patients into two groups: MWA if the BMSQ score was ≥4 (n =896, 65.6 %) and non-MWA if the BMSQ score was below four (n =470, 34.4 %). Seven hundred thirty-four (53.7 %) patients were newly detected as having MWA by the BMSQ. Out of the 168 patients with previously confirmed diagnoses of migraines, 162 (96.4 %) were correctly classified by BMSQ, while six (3.6 %) had a score below four (Table 1).
Demographic and clinical characteristics, comorbidity, concurrent diseases, and therapies of the 1,366 patients enrolled from 46 primary health care facilities in Bosnia and Herzegovina and classified according to the Balkan Migraine Screening Questionnaire to patients suffering from migraines without aura (MWA) and non-MWA patients.
Values are presented for numerical variables as means ± standard deviation (normal distribution), median and interquartile range in brackets (non-normal distribution) and for categorical variables as absolute numbers with percentages in brackets. BMI: Body mass index, BMSQ: Balkan Migraine Screening Questionnaire, MWA: Migraine without aura, NSAID: Non-steroidal anti-inflammatory drugs, VAS: Visual-analogue scale.
The majority of patients in the MWA group reported experiencing a headache with a pulsating nature (n =791, 88.3 %), whereas the majority of patients in the non-MWA group reported experiencing a headache that intensified during physical activity (n =237, 50.4 %) (Table 1).
Patients were significantly younger in the MWA (49.9 ± 13.7 years) group compared to the non-MWA (52.0 ± 14.4 years) group (p =0.008). In female patients, no significant age difference was observed between the MWA and non-MWA groups, while male patients in the MWA group were significantly younger compared to male patients in the non-MWA group (Table 1).
Among the 1,366 patients, 425 (31.1 %) reported one or more mental comorbidities. Both groups had a similar percentage of patients with mental problems (p =0.105) (Table 1). The most frequently reported mental comorbidities were F41: Other anxiety disorders reported in 154 (11.3 %) patients, F32: Depression reported by 134 (9.8 %) patients, and F43: Reaction to severe stress and adjustment disorders reported in 57 (4.2 %) patients.
Predictors of classification into the MWA or non-MWA group
A binary logistic regression model was used to predict classification of patients by BMSQ into the MWA or non-MWA group. The collinearity among the predictors was excluded. Cook’s D index was below 0.09 for all variables. The final model included alcohol consumption, family history of migraine, and headache intensity. The model was significant, with a Nagelkerke R-square value of 0.213, a Cox & Snell R-square value of 0.154, and a Hosmer and Lemeshow goodness of fit with a Chi-square value of 12.800 and a p value of 0.119. This model’s specificity was 49.4 %, sensitivity 86.6 %, and accuracy 73.6 %. Family history of migraine (OR: 1.694, 95 % CI: 1.285-2.231) and headache intensity (OR: 1.596, 95 % CI: 1.472-1.730) were significantly positively associated with the classification of patients as having MWA. The consumption of alcohol was significantly negatively associated with the designation of patients as having MWA (OR: 0.583, 95 % CI: 0.408-0.834). Although female sex was positively associated with the model, it did not reach statistical significance (p =0.102).
We categorized patients having MWA or other headaches in primary health care centers and compared their demographic and clinical characteristics, concomitant diseases, and therapies. The patients in the MWA group were significantly younger, had a higher proportion of women, and consumed less alcohol compared to the non-MWA group. Also, patients in the MWA group experienced more severe headaches, and more frequent headache attacks, used more headache therapy, and had a positive family history of migraine. The binomial regression model identified two positive predictors (family history of migraines and headache intensity) and one negative predictor (alcohol consumption) for the BMSQ classification of patients into the MWA group.
More patients were in the MWA arm (n =896, 65.6 %) than in the non-MWA arm (n =470, 34.4 %). Even though migraine is less common than tension-type headaches, it has a higher number of years lived with disability 4 . It has been demonstrated that patients who are classified as having MWA are more likely to utilize headache therapy (Table 1). With frequent use of symptomatic treatment, there is a high risk of accelerating MWA 6 and developing medication overuse headache (MOH) 2 . This disorder is frequent, and its recognition is meaningful in clinical settings 6 . It is correlated with an increase in the intensity of headache pain 15 . Patients with chronic headache often develop MOH, which can be improved by discontinuation of the overused drug 6 . Limmroth et al found that various treatments have different impacts on the MOH. They reported that triptans led to MOH faster and at lower doses than ergotamines 16 . In our study, there was no difference between the classes of medicines used in the groups. Most patients used NSAIDs and analgesics. However, MWA patients used more classes of drugs simultaneously, increasing their risk of MOH development.
If a migraine attack is occurring for more than three months with a duration of more than 15 days a month, and at least eight of those days have characteristics of a migraine, this clinical entity is classified as a chronic migraine 6 . Although this study did not measure the headache duration, the longer duration of headache therapy may indicate that the MWA group had a longer symptom duration. Overuse of medication is among the risk factors for the development of chronic migraine 17 . In a study involving 6,491 adults, it was found that migraine patients commonly experience 12 attacks per year, with a quarter of them experiencing at least two attacks per month 18 . In our study, we found that the MWA group compared to non-MWA had a significantly higher percentage of patients with more than six headache attacks in the preceding six months. In the MWA group, approximately half of the patients had fewer than six attacks, and half had more than six attacks in the previous six months. In a retrospective study analyzing data from a headache smartphone application, Cronin et al found that the number of headache attacks per month was lower in migraine compared to patients with other headaches 19 . This disparity may be attributed to the fact that Cronin et al conducted a comprehensive analysis of all types of migraine, as well as to possible variations in the characteristics of patients belonging to non-migraine group.
In addition to the frequency and duration of headache attacks, pain intensity is vital to consider. The median intensity of headache on the VAS was higher among patients in the MWA group, as evidenced in Table 1. Other studies have reported similar results. Cronin et al found that pain intensity was higher in migraine compared to non-migraine headache 19 while Gil-Gouveia et al found significantly higher pain on the VAS scale in migraine compared to tension-type headache patients 15 . Patients who experience cluster headaches have identified migraine as a condition that presents with intense pain, along with fibromyalgia, bone fracture, myocardial infarction, and lumbar radiculopathy. Although the same patients identified cluster headache as the most painful condition, they stated that migraine pain was less intense but had a longer duration 20 . The perception of pain varies among individuals, as well as concerning the same individual, depending on various factors. Numerous studies have demonstrated that the pain threshold decreases while the pain perception intensity increases during migraine attacks 21 , 22 . Kim et al discovered that pain-related anxiety was a contributing factor to disability resulting from migraine 22 .
Smoking and alcohol consumption are among the factors that have the potential to influence the likelihood of developing migraine 23 . In our study, there was no difference in the percentage of smokers between groups, but significantly fewer MWA patients consumed alcohol compared to the non-MWA group. Alcohol is among the ten most common migraine triggers 24 and there is a possibility that patients in the MWA group avoided alcohol consumption because of migraine attacks afterwards, although most of them were not previously diagnosed as migraineurs. Yuan et al discovered that the consumption of alcohol based on genetic predictions was negatively associated with the risk of migraine 23 . Migraine is defined as a disorder of brain excitability that is genetically determined 21 and various studies have shown that inheritance can influence susceptibility and clinical symptoms of migraine 25 , 26 . Genome-wide association studies (GWAS) have identified more than 40 genetic loci associated with migraine to date 25 , 26 . In our study, there was a significantly higher percentage of patients with a positive family history of migraine in the MWA compared to the non-MWA group.
In a Global Burden of Disease Study 2016, the most affected by migraine were female persons aged between 15 and 49 years 1 . Sex-related differences in migraine patients are mainly due to interactions of different hormones with neurological and vascular systems 27 . In our study, we found that the MWA group had a significantly higher percentage of female individuals, and patients were significantly younger, with a mean age of 49.9 years, compared to the non-MWA group, with a mean age of 52 years. It is noteworthy that in the female sex, no significant disparity was observed in age between MWA and non-MWA groups, whereas in the male sex, the MWA group was significantly younger. Finocchi et al reported that the peak age for migraine in female patients is between 30 and 40 years and that it decreases gradually after menopause 28 . A study that included 62,959 women had similar results where women with self-reported migraine tended to be older than women who did not experience migraine 29 . Further evaluation of these findings is warranted.
Female sex is often associated with migraines, but male patients can also be affected 18 , 27 , 28 . In our analysis, the female sex was positively associated with classifying patients into the MWA group, but it was not statistically significant. However, two positive predictors (family history of migraine and headache intensity) and one negative predictor (alcohol consumption) of the BMSQ classification of patients into the MWA group were identified based on the binomial regression model. All identified predictors of MWA are according to a strong correlation with the disease 15 , 19 , 20 , 21 , 23 - 26 .
Patients were grouped into MWA or non-MWA groups using BMSQ, a reliable and easy-to-use tool significant in overcoming problems with unrecognized MWA in the Balkan region 13 . By utilizing BMSQ, the MWA was determined in a total of 734 new patients, indicating that more than half of the patients enrolled in the study (53.7 %) were newly classified into the MWA group. This percentage was comparable to the one obtained through validation of BMSQ, wherein 49.4 % of patients were newly diagnosed with MWA 13 . Furthermore, MWA was confirmed in 162 patients with a prior diagnosis of migraine. Only six out of 168 (3.6 %) patients with a previously confirmed diagnosis of migraine had a BMSQ score below 4, so were not correctly classified into the group with migraine. This is in accordance with the results obtained through validation of the BMSQ, where 4.3 % of patients met the International Classification of Headache Disorders 3 rd edition criteria for MWA but had a BMSQ score below four and were not classified as having MWA 13 . BMSQ provides a valuable resource to overcome the problem of undiagnosed migraine. Campaigns to raise awareness of undiagnosed migraine among the general public can be successful and beneficial 7 . An accurate diagnosis of migraine is crucial for appropriate treatment and improvement of quality of life in affected individuals. Screening tools such as BMSQ could be used to overcome the lack of time and education in primary health care settings. It can be used to identify new potential cases of migraine and to alleviate problems associated with undiagnosed migraine, such as overuse of medications 2 . Risks associated with self-medication could be mitigated by the involvement of community pharmacies 11 and primary care physicians 7 .
The strengths of this study were the large number of subjects that were screened and the use of a validated questionnaire that can be used in other countries where the same language is spoken. Limitations included the convenience sampling of participating primary health care centers based on the expertise of the investigator. However, locations of centers were selected with the aim of covering the entire territory of Bosnia and Herzegovina. Also, there was a lack of final confirmation of migraine headache and the diagnosis of headaches in non-MWA patients. The use of additional instruments to measure other aspects related to MWA, such as quality of life, would bring additional benefits. Furthermore, laboratory analyses would provide significant information about the patients included. Additional studies should be applied in neighboring countries, using the same questionnaire and approach to screen patients for the presence of MWA.
This study classified patients who visited a general practitioner or family physician for headache-related issues into MWA and non-MWA groups. More than half of the patients were newly classified as having MWA, indicating a significant proportion of patients with undiagnosed migraine. The specific characteristics of patients with MWA were elucidated and compared with those who did not suffer from MWA and who were experiencing headaches. The results offer valuable information for everyday practice, indicating the importance of MWA diagnosis in primary health care centers.
Meliha Mehić, MD; Amna Tanović, MD; Aziz Šukalo, MD; Una Glamočlija, PhD; disclose the following relationships: employees of Bosnalijek d.d., a pharmaceutical company producing ergotamine combination drug for the treatment of migraine. Bosnalijek d.d. had a role in the study’s design, collection, analysis, and interpretation of data, writing the manuscript, and deciding to publish the results.
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