Gago-Veiga et al. The Journal of Headache and Pain (2021) 22:43 https://doi.org/10.1186/s10194-021-01258-y The Journal of Headache and Pain RESEARCH ARTICLE Open Access InterMiG: international differences in the therapeutic approach to migraine patients in specialized headache centers AB Gago-Veiga1*, J-I Huhn2, N Latysheva3, A Vieira Campos1, M Torres-Ferrus4,5, A Alpuente Ruiz4,5, S Sacco6, I Frattale6, R Ornello6, R Ruscheweyh7, IB Marques8, A Gryglas-Dworak9, C Stark10, VJ Gallardo4,5 and P Pozo-Rosich4,5 Abstract Background: There is currently a wide therapeutic arsenal for migraine patients, without a single first-line preventive drug and we choose the different available alternatives taking into account comorbidities, national guidelines, previous treatments and personal experiences. Our objective was to evaluate the differences in the use of migraine treatments between neurologists from different countries. Methods: This is a multi-centre observational study carried out by neurologists from specialized headache units in seven countries, retrospective with consecutive inclusion of all patients presenting with a migraine diagnosis, over a period of three months. Results: A total of 734 patients were recruited but only 600 were considered in the analysis in order to homogenize the patient cohorts from countries: 200 Spain (ES), 100 Italy (IT), 85 Russia (RUS), 80 Germany (DE), 60 Portugal (PT), 45 Poland (PL) and 30 Australia (AU). 85.4 % of patients were women with a mean age of 42.6 ± 11.8 years. Considering previous and current preventive treatment, the order of use was: antidepressants (69.3 %), antiepileptic drugs (54.7 %), beta-blockers and antihypertensive drugs (49.7 %), OnabotulinumtoxinA (44.0 %) and others (36.2 %). Statistically significant differences were found between all pharmacological classes: antidepressants were commonly used in all countries, with the exception of Poland (AU: 76.7 %, IT: 71.0 %, DE: 60.0 %, PL: 31.1 %, PT: 71.7 %, RUS: 70.6 %, ES: 78.5 %; p < 0.0001); antiepileptic drugs were more frequently prescribed in Portugal, Australia and Spain (AU: 73.3 %, IT: 40.0 %, DE: 37.5 %, PL: 48.9 %, PT: 85.0 %, RUS: 29.4 % and ES: 69.0 %; p < 0.0001); beta-blockers and antihypertensive drugs were frequently used in all countries except Italy (AU: 60.0 %, IT: 14.0 %, DE: 53.8 %, PL: 48.9 %, PT: 68.3 %, RUS: 49.4 % and ES: 59.0 %; p < 0.0001); BTX-A were predominately used in Spain, Italy and Australia (AU:56.7 %, IT:58.0 %, DE:20.0 %, PL: 42.2 %, PT: 26.7 %, RUS: 24.7 % and ES: 58.5 %; p < 0.0001) and others were most frequently used in Poland (AU: 0.0 %, IT: 19.0 %, DE: 42.5 %, PL: 95.6 %, PT: 31.7 %, RUS: 3.5 % and ES: 49.5 %; p < 0.0001). If only patients without comorbidities are considered (200/600), statistically differences between countries persist in all preventive treatments. * Correspondence: dra.anagago@gmail.com 1 Headache Unit, Department of Neurology, La Princesa Research Institute. Hospital Universitario de la Princesa, Madrid, Spain Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Gago-Veiga et al. The Journal of Headache and Pain (2021) 22:43 Page 2 of 10 Conclusions: There is heterogeneity in the choice of preventive treatment between different countries. Prospective comparative studies of the different oral and subcutaneous alternatives would help to create a global therapeutic algorithm that would guarantee the best option for our patients. Keywords: Migraine, Preventive treatment, International, Differences, Antidepressant, Antiepileptic, Beta-blockers, OnabotulinumtoxinA Background Lisboa), Poland (PL) (Private Headache Clinic Wroclaw) Migraine is a chronic disease accounting for a large pro- and Australia (AU) (Austin Health). Each centre was re- portion of disability across all ages, especially in the quired to contribute at least 30 patients, starting data young. In fact, in 2019 migraine was named the first was collection in February 2019 and continuing for a max- named the first disabler under the age of 50 [1]. imum of three months. The inclusion criteria were: pa- It has been estimated that up to 38 % of migraine pa- tients with migraine diagnosed according to the tients need preventive treatment [2]. However, the inter- International Classification of Headache Disorders-3 [7], national guidelines on migraine prophylaxis only contain who were 18 years of age, with no upper age limit. Pa- a list of medications, which have undergone randomized tients were excluded when not enough data was col- clinical trials and show their level of evidence [3, 4]. lected in their medical history. These documents do not give recommendations on the choice of first-line drugs. Methodology of the study More recent guidelines have summed up the real-life Each participating neurologist had to complete a data experience of general practitioners and headache centers sheet, when they evaluated a patient with migraine (both and recommend that the choice of a migraine prophy- first and follow-up visits could be included). The data to lactic drug should be based on the attack frequency (epi- be collected were as follows: age, gender and referring sodic vs. chronic), comorbid diseases and the patient’s physician. The baseline characteristics considered were: individual needs [5, 6]. Differences in national healthcare comorbidities - ischemic cardiac disease, hypertension, systems and reimbursement policies also factor in the (pre) syncope, asthma, nephrolithiasis, gastritis, depres- choice of preventive strategies in different countries. sion/anxiety, and body mass index (BMI). With respect This heterogeneity of treatment practices may also be to current acute treatment, the use of each of the trip- partly explained by the differences in headache care sys- tans, paracetamol, non-steroidal anti-inflammatory drugs tems. Whereas in some countries general practitioners (NSAIDs,) metamizole, opiates and combined drugs was successfully treat most patients with migraine, in others documented. We categorized preventive treatment into countries this is not the case, resulting in a large number five different pharmacological categories, about current of drug-naïve patients referred to third-level headache and previously used drugs, including: antiepileptic drugs centers. Such differences in patient populations and pro- (AEDs) (topiramate (TPM), valproic acid (VPA), prega- portions of refractory headaches seen by specialized cen- balin (PGB), zonisamide (ZNS) and lamotrigine (LMT)), ters may also influence drug choice. antidepressants (amitriptyline (AMT), serotonin re- In consequence, the objective of this study was to uptake inhibitors (SSRI), serotonin and norepinephrine evaluate the differences of preferences of use of acute reuptake inhibitors (SNRI) (duloxetine, venlafaxine), vor- and preventive migraine treatments internationally tioxetine, opipramol and agomelatine), beta-blockers across headache centers in several countries. (BB) and antihypertensive drugs (candesartan and lisino- pril), onabotulinumtoxinA (BTX-A) and “others” (cal- cium Channel Blockers (CCB) (Flunarizine and Methods Cinnarizine), anesthetic blocks, magnesium (Mg) and riboflavin). Study population This study was approved by the Hospital de la Prin- We performed a multicentre retrospective observational cesa´s Ethics Committee (register number: 3477). Patient study with consecutive inclusion of patients, carried out data were anonymized for data analysis. by neurologists from specialized headache units in seven countries: Spain (ES) (La Princesa University Hospital and Vall d´Hebron University Hospital), Germany (DE) Statistical analyses (Praxis Gendolla and Ludwig Maximilians University We report nominal (categorical) variables as frequencies Munich), Russia (RUS) (Sechenov University), Italy (IT) (percentages) and continuous variables as mean ± stand- (University of L´Aquila), Portugal (PT) (Hospital da Luz ard deviation for normally distributed variables (age and Gago-Veiga et al. The Journal of Headache and Pain (2021) 22:43 Page 3 of 10 basal headache frequency). We checked normality as- patients (30 AU, 100 IT, 80 DE, 45 PL, 60 PT, 85 RUS sumption of quantitative variables through visual and 200 ES). 85.4 % (515/600) were females with a mean methods (Q-Q plots). We assessed statistical significance age of 42.6 ± 11.8 years. Mean headache frequency was of comparisons between countries by Pearson’s chi- 17.5 ± 8.5 days/month and 25.5 % (154/600) of patients square test when comparing categorical variables and in had migraines with aura. Chronic migraine (CM) was the case of having an expected count less than 5 in more observed in 63.5 % (381/600) of patients. The median of than 20 % of cells in the contingency table, we used the current and previous preventives used by patient was Fisher’s exact test. One-way ANOVA was used in order 3.0. Regarding the main comorbidities that may influ- to study group mean differences between countries and ence the choice of a migraine preventive treatment, the patient’s age and headache frequency. most prevalent was mood disturbance (anxiety and/or We did not conduct a statistical power calculation depression), followed by, overweight (BMI ≥ 25), arterial prior to the study because the sample size was based on hypertension, gastritis and asthma, in this order. Patients the available data. No missing values were obtained. No were principally referred by general practitioners and adjustment for multiple comparisons were made to the general neurologist. Main demographical data and distri- statistical inferences, but exact P values were reported to bution among countries are shown in Table 1, where allow post adjustments, if desired. P values presented are significant differences can be seen. for a two-tailed test and we considered P values < 0.05 statistically significant. All analysis was done using SPSS Use of migraine acute medication statistical package, v21.0 for Windows (IBM Corp. Re- The most commonly used acute drugs were triptans, es- leased 2012. Armonk, NY: IBM Corp.) pecially sumatriptan, followed by NSAIDs and, much less frequently, paracetamol, combined treatments meta- Results mizole and opioids (Table 2). Statistically significant dif- Participants ferences between countries were found in the use of A total of 734 patients were included but there were sta- each acute treatment (Table 2). Triptans were more fre- tistically significant differences in age and gender be- quently used in Poland and Russia but in general by at tween countries. In order to obtain a homogeneous least half of patients in all countries. The use of NSAIDs population, we randomly selected age- and gender- predominates in countries like Poland and Italy although matched patients considering the same age-range (20– their use is not as frequent in countries like Australia. In 70 years old) and gender distribution with a similar relation to the rest of analgesic medication, their use was equally proportional effect between countries. Patients drastically reduced compared to the previous two, except who had not tried any preventive treatment (8.4 %; 62/ for paracetamol in Poland or Australia. 734) and pregnant patients (or those hoping to be) We set out to study if acute medication prescription in (3.1 %; 23/734) were not included. Hence, the final sam- countries was influenced by patient diagnosis or the type ple size considered for the following analysis was 600 of medical referral. For that reason, we only performed Table 1 Demographics, migraine characteristics, main comorbidities and medical referral according to each country Bold font in the P values column indicates statistically significant. †Significance assessed with chi-square test. ‡Significance assessed with the one-way ANOVA. SD standard deviation; CM chronic migraine; d/mo days per month. Gago-Veiga et al. The Journal of Headache and Pain (2021) 22:43 Page 4 of 10 Table 2 General use (%) of acute treatment according to each country Bold font in the P values column indicates statistically significant. †Significance assessed with chi-square test or Fisher’s exact test. NSAIDs non-steroidal anti-inflammatory drug the same comparative analysis in CM patients, and thus, Portugal, Australia and Spain; beta-blockers and antihy- homogenized the sample. Once again, triptans (74.0 %, pertensive drugs were frequently used in all countries 282/381) and NSAIDs (66.7 %, 254/381) were the most except Italy; BTX-A were predominately used in Spain, common treatments. Moreover, the same statistically sig- Italy and Australia and the group of “others” were nificant differences were observed between countries: mainly used in Poland. while triptans were predominately used in Poland Since the selection of the best preventive treatment ac- (93.5 %), Russia (84.6 %) and Portugal (74.0 %), NSAIDs cording to their pharmacological class mainly depends on were also more frequently used in Poland (96.8 %) and patient comorbidities, we repeated the same analysis in Italy (87.8 %). Regarding medical referral, if we only se- patients without comorbidities (33.3 %; 200/600) (Fig. 2): lected patients referred by general neurologists (38.8 %, antidepressants were most frequently prescribed in 233/600): triptans (73.4 %, 171/233) and NSAIDS (53.6 %, Australia, Spain, Italy and Portugal; AEDs were more 125/233) were also the standard treatments and non- popular in Australia, Spain and Portugal; beta-blockers statistically significant differences were found in triptan and antihypertensive drugs were scarcely used in Italy and prescription between countries (AU: 66.7 %, IT: 79.5 %, Poland; BTX-A was more habitual used in Australia, Spain DE: 62.5 %, PL: 80.0 %, PT: 76.9 %, RUS: 84.8 %, ES: and Italy and “others” were predominately used in Poland. 74.0 %; p = 0.178). However, when we focus the analysis on patients referred by general practitioners (175/600, 29.2 %), differences are observed between countries, both Use of migraine preventive medication: antidepressants in the use of triptans (AU: 53.8 %, IT: 51.0 %, DE: 91.3 %, We specifically analyzed antidepressants (AMT, SSRI, PL: 80.0 %, PT: 55.6 %, RUS: 100.0 %, ES: 36.4 %; p = 0.012) SNRI, vortioxetine, opipramol and agomelatine). The and NSAIDs (AU: 34.6 %, IT: 84.0 %, DE: 73.9 %, PL: most commonly used medications in this pharmaco- 100.0 %, PT: 55.6 %, RUS: 0.0 %, ES: 63.6 %; p < 0.0001). logical category were AMT (54.8 %, 329/600), SSRI (30.0 %, 180/600) and SNRI (14.2 %, 85/600). The rest of Use of preventive migraine medication: pharmacological medications (vortioxetine, opipramol, agomelatine) were classes only used in 5.2 % (31/600) of participants. In this section, we have analyzed the most used treat- Statistically significant differences were found in the pre- ments considering those that the patient was currently scription of these medications between countries (Fig. 3 a): taking as well those that had been prescribed in the past. AMT was more frequently used in Spain, Portugal and If we evaluate all the patients as a whole, the order of Australia; SSRIs were more popular in Portugal, Italy and use would be as follows: antidepressants (69.3 %, 416/ Russia and SNRIs were predominately used in Russia and 600), AEDs (54.7 %, 328/600), beta-blockers and antihy- Spain. The rest are hardly used: vortioxetine (AU: 0.0 %, IT: pertensive drugs (49.7 %, 298/600), BTX-A (44.0 %, 264/ 2.0 %, DE: 0.0 %, PL: 0.0 %, PT: 1.7 %, RUS: 8.2 %, ES: 1.0 %; 600) and others (36.2 %, 217/600). Statistically significant p = 0.014); Opipramol only in Germany and Poland (AU: differences were found between all pharmacological clas- 0.0 %, IT: 0.0 %, DE: 11.3 %, PL: 2.2 %, PT: 0.0 %, RUS: 0.0 %, ses and countries (Fig. 1): antidepressants were com- ES: 0.0 %; p < 0.0001) and agomelatine in Portugal, Russia monly used in all countries, with the exception of and Germany (AU: 0.0 %, IT: 0.0 %, DE: 3.8 %, PL: 0.0 %, PT: Poland; AEDs were more frequently prescribed in 8.3 %, RUS: 1.2 %, ES: 0.0 %; p = 0.001). Gago-Veiga et al. The Journal of Headache and Pain (2021) 22:43 Page 5 of 10 Fig. 1 General use (%) of pharmacological classes of preventive treatment according to each country. All treatment classes use between countries resulted statistically significantly different (p<0.0001). AU: Australia; IT: Italy; DE: Germany; PL: Poland; PT: Portugal; RUS: Russia; ES: Spain; AD: antidepressants; AEDs: anti-epileptic drugs; BB&AHT: beta-blockers and antihypertensive drugs; BTX-A: Onabotulinumtoxin A. We found that patients included presented differences (AU: 53.8 %, IT: 40.0 %, DE: 79.2 %, PL: 30.8 %, PT: in the percentage of anxiety-depression as a comorbidity 69.6 %, RUS: 43.8 % and ES: 79.8 %; p < 0.0001); SSRIs depending on the country. Hence, we analyzed whether were predominately used in Italy (AU: 23.1 %, IT: 92.5 %, countries prescribed differently these treatments in these DE: 45.8 %, PL: 61.5 %, PT: 63.0 %, RUS: 60.4 % and ES: patients (44.7 %, 268/600). Once again, the most fre- 46.4 %; p < 0.0001) and SNRIs were scarcely used in quently used treatments were AMT (61.9 %, 166/268), Germany, Portugal and Italy (AU: 23.1 %, IT: 2.5 %, DE: SSRI (58.2 %, 156/268) and SNRI (19.4 %, 52/268). Pa- 0.0 %, PL: 30.8 %, PT: 0.0 %, RUS: 6.7 % and ES: 9.7 %; tients with comorbid anxiety and/or depression were p < 0.0001). treated differently according to their home country: Finally, we studied the prescription of antidepres- AMT is mostly used in Spain, Germany and Portugal sants in patients without comorbidities (Fig. 4 a) Fig. 2 General use (%) of pharmacological classes of preventive treatment according to each country in patients without comorbidities (200/600). All treatment classes use between countries resulted statistically significantly different (p<0.0001). AU: Australia; IT: Italy; DE: Germany; PL: Poland; PT: Portugal; RUS: Russia; ES: Spain; AD: antidepressants; AEDs: anti-epileptic drugs; BB&AHT: beta-blockers and antihypertensive drugs; BTX-A: Onabotulinumtoxin A. Gago-Veiga et al. The Journal of Headache and Pain (2021) 22:43 Page 6 of 10 Fig. 3 General use (%) of preventive treatment according to each country. AU: Australia; IT: Italy; DE: Germany; PL: Poland; PT: Portugal; RUS: Russia; ES: Spain; AMT: amitriptyline; SSRI: Selective Serotonin Reuptake Inhibitors, SNRI: Serotonine-Norepinephrine Reuptake Inhibitors; TPM: Topiramate; VPA: valproic acid; BTX-A: Onabotulinum Toxin A; PGB: pregabaline; ZNS: zonisamide; BB: beta-blockers; CCB: Calciumchannel blockers. between different countries: AMT was the main Use of migraine preventive medication: beta-blockers and medication used and their prescription remained sta- antihypertensive drugs tistically significantly different between countries. Here we studied the distinctive use of BB, candesartan and lisinopril in different countries. In this pharmaco- logical subgroup (Fig. 3 c), BBs were the most popular Use of migraine preventive medication: antiepileptic treatment (45.3 %, 272/600) followed by candesartan drugs (AEDs) (8.5 %, 51/600) and lisinopril (2.7 %, 16/600). BBs and In this section, we particularly analyzed the different candesartan were commonly used in all countries, with neuromodulator treatments. The most widely use the exception of Italy. Lisinopril was hardly used except neuromodulator treatment used was TPM (50.8 %, in Spain (AU: 0.0 %, IT: 0.0 %, DE: 1.3 %, PL: 0.0 %, PT: 305/600) followed by VPA (10.8 %, 65/600), PGB 0.0 %, RUS: 0.0 %, ES: 7.5 %; p < 0.0001). (8.2 %, 49/600), ZNS (7.8 %, 47/600) and LMT (2.8 %, The prescription of beta-blockers and antihypertensive 17/600). Statistically significant differences between drugs may vary in patients with cardiovascular risk. In our AEDs used were also found between countries (Fig. 3 study, we wanted to analyse the differential use of this b): TPM was predominately used in Portugal, pharmacological subgroup in patients with overweight, Australia and Spain; VPA and PGB were more popu- hypertension and/or cardiac ischemia (26.3 %, 158/600) lar in Portugal, Spain and Poland and ZNS was prac- between countries. In this subgroup, most frequently tically only used in Spain. No statistically significant treatments were also BBs (51.3 %, 81/158) and candesartan differences were found in the use of LMT between (13.9 %, 22/158). While no differences were found in can- countries. desartan prescription between countries (p = 0.113), the Finally, we studied the prescription of AEDs be- similar statistically significant use was found with BBs tween countries in patients without comorbidities (AU: 40.0 %, IT: 13.9 %, DE: 65.5 %, PL: 60.0 %, PT: 65.4 %, (Fig. 4 b): TPM was the main medication used and RUS: 63.6 % and ES: 61.0 %; p < 0.0001). their prescription remained statistically significantly Finally, the prescription of BBs in patients without co- different between countries. morbidities was also statistically significantly different Gago-Veiga et al. The Journal of Headache and Pain (2021) 22:43 Page 7 of 10 Fig. 4 General use (%) of preventive treatment according to each country in patients without comorbidities (200/600). AU: Australia; IT: Italy; DE: Germany; PL: Poland; PT: Portugal; RUS: Russia; ES: Spain; AMT: amitriptyline; SSRI: Selective Serotonin Reuptake Inhibitors, SNRI: Serotonine- Norepinephrine Reuptake Inhibitors; TPM: Topiramate; VPA: valproic acid; BTX-A: Onabotulinum Toxin A; PGB: pregabaline; ZNS: zonisamide; BB: beta-blockers; CCB: Calciumchannel blockers. between countries (Fig. 4 c). No differences were found presence: 61.6 %; p = 0.002) and BTX-A (absence: 38.3 % in the use of candesartan and lisinopril between coun- vs. presence: 51.1 %; p = 0.003). Popular pharmacological tries in this subset of patients. categories in overweight patients were antidepressants (absence: 67.5 % vs. presence: 77.5 %; p = 0.041) and Use of migraine preventive medication: other treatments AEDs (absence: 52.1 % vs. presence: 65.8 %; p = 0.011). In this group, the most commonly used treatments were Specifically, the use of TPM is higher 60.4 % (67/111 CCB (21.7 %, 130/600) followed by Mg (19.8 %, 119/ subgroup of overweight patients) vs. 50.8 % (305/600 600), anaesthetic blocks (9.2 %, 55/600) and riboflavin total sample) and the use of CCB is slightly lower 20.7 % (6.2 %, 37/600). In relation to other countries (Fig. 3 d), (23/111) vs. 21 % (130/600), and this is even less if both CCB has a statistically significant higher use in Spain but comorbidities are present, being overweight and experi- Mg, anaesthetic blocks and riboflavin were predomin- encing mood alteration (16.1 % (9/56) vs. 21 %). Surpris- ately used in Poland. ingly, the use of VPA in overweight patients is slightly The same proportional use between countries was ob- higher 11.7 % (13/111) vs. 10.8 % (65/600). Regarding served in patients without comorbidities (Fig. 4 d). hypertension, patients were more commonly treated with beta-blockers/antihypertensive drugs (absence: Migraine treatment use according to patient comorbidity 47.6 % vs. presence: 63.0 %; p = 0.012) and BTX-A (ab- Statistically significant differences were found in the glo- sence: 42.2 % vs. presence: 55.6 %; p = 0.030). The use of bal set of all patients in the use of preventive treatments BB was lower in patients with asthma (absence: 46.1 vs. considering the patient´s previous pathology. Thus, we presence: 37.3 % p = 0.243). Finally, patients with gastritis finally studied the differential prescription of pharmaco- were more commonly prescribed alternative treatments logical subgroups and the presence/absence of frequent (absence: 34.8 % vs. presence: 48.4 %; p = 0.037). comorbidities in our cohort (presence ≥ 10 %). In this context, patients with presence of anxiety and/or depres- Discussion sion were statistically significantly more frequently pre- There are multiple reviews on the best preventive treat- scribed with antidepressants (absence: 53.3 % vs. ments for patients with migraine [7–11], as well as Euro- presence: 89.2 %; p < 0.0001), AEDs (absence: 49.1 % vs. pean and American recommendations [3, 4, 12] and Gago-Veiga et al. The Journal of Headache and Pain (2021) 22:43 Page 8 of 10 national guidelines in each country [5, 6, 13, 14], how- the next ones in use are the SSRIs, especially in coun- ever there is no consensus on which the drug of first tries such as Portugal, Italy or Russia. SNRIs are less choice is, due to the limitations of comparative studies used in general, with Russia and Spain as exceptions. carried out to date, with few head to head comparisons AMT was also the most used drug, both in the subgroup [15, 16], where there is only one study which also in- of patients with anxiety and/or depression, whereas in cludes non-oral treatments [17]. countries like Portugal it represents a very high percent- This is the first international multicentre study with age, and in the subgroup without comorbidities. the aim of comparing whether there are differences in Secondly, the most widely used neuromodulator treat- the use of acute and preventive migraine treatments ment was TPM, also in patients without comorbidities, when analyzing the drugs prescribed in seven countries. however countries like Russia use it significantly less, ap- It can be seen that there is no single first-line drug of proximately in 1/4 patients, compared to others such as choice as preventive treatment, and significant differ- Portugal or Australia, where it has been prescribed in 3/ ences can be observed between countries and there is a 4 or Spain in 2/3. In a much smaller percentage, VPA wide arsenal of drugs used, opting for one or the other and PGB were more popular in Portugal, Spain and according to the patient´s profile and their comorbidi- Poland. ties, but there are also differences in relation to the na- BB were the most used preventive treatment within tionality of the prescribing physician. the group of antihypertensives. BB and candesartan were In our study, we have analyzed a total of 734 patients commonly prescribed in all countries, with the exception from seven different countries (Australia, Italy, Germany, of Italy. Poland, Portugal, Russia and Spain), from specialized BTX-A, a first-line drug together with TPM in chronic headache units, which implies a more complex patient migraine [21], is widely used, also considering that they profile, often with a long pharmacological history. The are patients in specialized units, especially in Spain, Italy mean number of days of pain per month was almost 20, and Australia. with a high percentage of drugs tested by each patient, In relation to anaesthetic blocks, their use is much less over all in Spain, Portugal and Poland. common, except in Poland (40 %), where the use of In relation to acute treatment, given the patient’s pro- nutraceuticals also predominates. Here, almost all pa- file and being monitored in a specialized unit, it is not tients have tried Riboflavine or Mg (the latter is used surprising to find that the percentage of use of triptans more by the rest of the countries except for Australia, is generally high in all countries. Sumatriptan is the most Italy and Russia). widely used of these, possibly because it has the longest In the use of CCB, important differences appear, such therapeutic course and naratriptan and frovatriptan was as its use in Spain of almost 40 % vs. in countries such the least used, perhaps because these are usually consid- as Australia or Russia, where no prescriptions were ered to be more tolerable but a bit slower and with lon- made. ger half-lives [18]. However, there are also differences Drugs like pregabalin, LMT, vortioxetine, agomela- between countries; sumatriptan is used much more in tine are hardly used. There are drugs such as ZNS countries like Poland (93.3 %) or Russia (75.3 %) com- and lisinopril, which were prescribed almost exclu- pared to others such as Italy, which only accounts for sively in Spain or Opipramol in Germany. Possibly 3 % or Portugal 6.4 %. Nevertheless, when we separate due to low scientific evidence [22, 23] except in the this aspect in relation to the referring physician, it be- case of lisinopril [24]. comes clear that this difference is possibly due more to The findings in relation to the use of preventive treat- whether the patient had been referred by primary care ments and patient comorbidity are consistent with our or general neurology, than actually to nationality. NSAI usual clinical practice. Therefore, in those patients with Ds are also widely used, in contrast to other analgesics previous cardiac ischemia or who have hypertension, BB such as paracetamol, metamizole, opioids and combined, or antihypertensives such as candesartan for their dual in line with international recommendations [19, 20]. effect are commonly used; and, we avoid them in pa- Regarding migraine preventive treatment, the most tients with asthma in the case of non-selective BB [25]. commonly used drugs were antidepressants (69.3 %), Another key point, looking for synergistic effects is also AEDs (54.7 %) and beta-blockers (49.7 %), in this order. mood comorbidity. In these patients we use drugs with However, at this point we found significant differences double effect, such as AMT, SSRI, SNRI or drugs that between countries. do not worsen it, such as antihypertensives and we reject Firstly, in relation to the use of antidepressants, AMT CCB [26], which also lead to weight gain. Some do the was used in all countries in more than 1/3 of patients opposite such as TPM, while others have no effect on (especially in Spain, Portugal and Australia), except in weight such as BTX-A and this is also observed in the Poland (16 %). In relation to the other antidepressants, choice of preventive treatment [27]. Gago-Veiga et al. The Journal of Headache and Pain (2021) 22:43 Page 9 of 10 Nevertheless, when only analyzing patients without comor- Abbreviations bidities - in order not to affect the choice of treatment - sig- AMT: Amitriptyline; AU: Australia; BB: Beta-Blokers; BMI: Body mass index; BTX- A: Onabotulinumtoxin A; CCB: calcium channel blockers; CGRP: calcitonin nificant differences persist in all pharmacological groups. gene related peptide; ES: Spain; DE: Germany; IT: Italy; LMT: Lamotrigine; This study presents a number of considerations that Mg: Magnesium; PL: Poland; PT: Portugal; PGB: Pregabalin; RUS: Russia; must be taken into account. The main limitation of our SNRI: Serotonin and Norepinephrine reuptake inhibitors; SSRI: Serotonin reuptake inhibitors; TPM: Topiramate; VPA: Valproic acid; ZNS: Zonisamide study is that for each country only one or two centres par- ticipated, so it must not be inferred that it is a representa- Acknowledgements tion of the global prescribing trends of each country, but AbbVie-Allergan supported the publication fees. rather it is based on the opinion of neurologists of differ- Authors' contributions ent nationalities. However, in relation to this point, it is AGV, JH, NL and PPR participated in the design of the study. AGV, JH, NL, important to consider that all participating physicians AVC, MTF, AAR, SS, IF, RO, RR, IM, AG and CS collaborated in the data collection. AGV and VJG contributed to analysis and interpretation of data. work in specific headache units and all of them have been AGV wrote first draft. All the author critically revised the final draft and trained in line with the guidelines of each country and approved the final manuscript. they follow their national recommendations. It should also be noted that the number of patients included in some Funding This work did not receive any funds. countries is low in relation to others, which means that perhaps if the size of patients analyzed were increased, the Availability of data and materials differences could be greater. We have not divided the uses Study material and supplementary material are available upon request to the corresponding author. in episodic or chronic migraine due to the fact that all drugs prescribed to the patient are analyzed, where it is Declarations not possible to know whether a drug was prescribed in a Ethics approval and consent to participate period with a lower or higher frequency of attacks. More- This study was approved by Hospital de la Princesa´s Ethics Committee over, in the list of preventive treatments taken by the pa- (register number: 3477). Patient data were anonymised for data analysis. tient, it was not indicated who had made the prescription Consent for publication and it is possible that some of the first treatments used All authors gave their consent for publication. were not prescribed in the specialized headache centre, ra- ther by the primary care physician or the general neurolo- Competing interests gist, although these patients usually have an early referral Gago-Veiga AB has received honoraria as a consultant and speaker for: AbbVie-Allergan, Chiesi, Exeltis, Novartis, Eli Lilly and Teva. due to their complexity and, likewise, there is an the over- Huhn J-I has received honaria as speaker or travel grants for: AbbVie- all trend in the country. Lastly, with regard to treatment Allergan, Novartis, Teva, Eli-Lilly and md-hoizonte. with anti-CGRP monoclonal antibodies, the results are Latysheva N has received honoraria as a consultant and speaker for: AbbVie- Allergan and Novartis. not included because in many of the countries included in Torres-Ferrus M has received honoraria as consultant or speaker for Allergan- the study at the time when this study was carried out, they Abbvie, Almirall, Chiesi, Eli Lilly, Novartis and Teva. were not approved by their National Healthcare Service. Alpuente A has received honoraria as speaker for Allergan-Abbvie, Eli Lilly and eductation for Chiesi, Novartis and Teva. Sacco S has received honoraria as a consultant and speaker for: Abbot, Conclusions Allergan-Abbvie, AstraZeneca, Eli Lilly, Novartis and Teva. Her research group In the process of choosing the most appropriate acute has received research grants from Allergan-Abbvie and Novartis and has re- ceived funding for clinical trials from Allergan-Abbvie, Novartis and Teva. She or preventive migraine treatment, comorbidities, the is a member of the Council of the European Headache Society and co-chair patient’s opinion [28], and of course, that of the neur- of the guideline board of the European Stroke Organization. She is the Spe- ologist must always be assessed, but as we have ob- cialty Chief Editor in Headache Medicine and Facial Pain in Frontiers in Neur- ology, associate editor for The Journal of Headache and Pain and for Stroke served in this first international study, this may differ in Frontiers in Neurology, assistant editor for Stroke and member of the edi- depending on the country where the treatment is torial board of Neurological Sciences, International Journal of Stroke, Euro- prescribed. pean Stroke Journal. Ornello R has received personal fees from Novartis and Ei Lilly, funding for In fact, the European guidelines to dictate the new publication fees from Allergan and Novartis, and travel grants from Novartis monoclonal treatments against CGRP [29] indicate that and Teva. at least two oral treatments must be prescribed (and Ruscheweyh R has received honoraria for talks and/or advisory boards from Allergan, Hormosan, Lilly, Novartis and Teva. BTX-A in the case of chronic migraine), however, it is Marques IB has received honoraria as speaker and/or advisory board for: not specified which should be the two first options. AbbVie-Allergan, Sanofi and Novartis. This investigation shows the need for a larger multi- Gryglas-Dworak A. has received honoraria as a consultant or speaker for AbbVie-Allergan and Novartis. centre study to verify these results and to continue with Pozo-Rosich P has received honoraria as a consultant and speaker for: comparative clinical trials between the first line treat- Allergan-Abbvie, Almirall, Amgen, Biohaven, Chiesi, Eli Lilly, Medscape, Neuro- ments, in order to create global international algorithms diem, Novartis and Teva. Her research group has received research grants from Allergan, and has received funding for clinical trials from Alder, that guarantee the best therapeutic option for our Allergan-Abbvie, Electrocore, Eli Lilly, Novartis and Teva. She is a trustee patients. member of the board of the International Headache Society, member of the Gago-Veiga et al. The Journal of Headache and Pain (2021) 22:43 Page 10 of 10 Council of the European Headache Society. She is in the editorial board of migraine patients: medication overuse headache and chronic migraine. Revista de Neurologia, associate editor for Cephalalgia, Headache, Neurolo- French guidelines. Rev Neurol (Paris) 170:162–176 gia, Frontiers of Neurology and The Journal of Headache and Pain. She is a 15. Jackson J, Cogbill E, Santana-Davila R, Eldredge C, Collier W, Gradall A, member of the Clinical Trials Guidelines Committee of the International Sehgal N, Kuester J (2015) A comparative effectiveness meta-analysis of Headache Society. She has edited the Guidelines for the Diagnosis and Treat- drugs for prophylaxis of migraine. PloS One 10:e0130733 ment of Headache of the Spanish Neurological Society. She is the founder of 16. Ashtari F, Shaygannejad V, Akbari M (2008) A double-blind, randomized trial www.midolordecabeza.org. Pozo-Rosich P does not own stocks from any of low-dose topiramate vs propanolol in migraine prophylaxis. Acta Neurol pharmaceutical company. Scand 118:301–305 Vieira-Campos A, Frattale I, Stark C and Gallardo VJ report no disclosures 17. Rothrock JF, Adams AM, Lipton RB, Silberstein SD, Jo E, Zhao X, Blumenfeld AM (2019) FORWARD Study investigative group. FORWARD Study: Author details Evaluating the Comparative Effectiveness of OnabotulinumtoxinA and 1 Headache Unit, Department of Neurology, La Princesa Research Institute. Topiramate for Headache Prevention in Adults with Chronic Migraine. Hospital Universitario de la Princesa, Madrid, Spain. 2Praxis Gendolla. Zentrum Headache 59:1700–1713 für Neurologie und Schmerztherapie, Essen, Germany. 3Department of 18. Ferrari MD, Roon KI, Lipton RB, Goadsby PJ (2001) Oral triptans (serotonin 5- Neurology, Institute for Professional Education, I.M.Sechenov First Moscow HT (1b/1d) agonist) in acute migraine treatment: a meta-analysis of 53 trials. State Medical University (Sechenov University), Moscow, Russia. 4Headache Lancet 358:1668–1675 Unit, Neurology Department, Hospital Universitari Vall d’Hebron, Barcelona, 19. Marmura MJ, Silberstein S, Schwedt T (2015) The acute treatment of Spain. 5Headache and Neurological Pain Research Group, Vall d’Hebron migraine in adults: the american headache society evidence assessment of Research Institute, Departament de Medicina, Universitat Autònoma de migraine pharmacotherapies. Headache 55:3–20 Barcelona, Barcelona, Spain. 6Neuroscience Section, Department of Applied 20. Cameron C, Kelly S, Hsieh SC, Murphy M, Chen L, Kotb A, Peterson J, Coyle Clinical Sciences and Biotechnology, University of L’Aquila, L´Aquila, Italy. D, Skidmore B, Gomes T, Clifford T, Wells G (2015) Triptans in the acute 7 Department of Neurology, Ludwig Maximilians University Munich, Munich, theatment of migraine: A systematic Review and Network Meta-analysis. 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