Results of a Web-Based Survey on 2105 Greek Migraine Patients—Second Part: Efficacy of Acute and Prophylactic Migraine Treatments and Corresponding Patients’ Reported Satisfaction

Background and Objectives: The Greek Society of Migraine and Headache Patients conducted, in 2020, its second online survey, titled “Migraine in Greece—2020”, after publication of the first similar online survey conducted in 2018. To compare the current findings with the corresponding data obtained in 2018, we herein release the second part of results obtained from the 2020 survey on the efficacy of preventive and symptomatic anti-migraine medications and the patients’ reported satisfaction with these treatments. Materials and Methods: We surveyed 2105 migraine patients from all over Greece with the use of a 151-questions specific migraine-focused questionnaire in Greek language, which was distributed through the online research software “SurveyMonkey”. Results: Triptans were mostly used with efficacy for the symptomatic relief of migraine attacks. About 2 of 3 surveyed patients had received various prophylactic oral medications and the majority of them discontinued these prophylactic medications as a result of inefficacy/safety issues. BoNTA was reported to be effective only when administration was commenced by a trained neurologist/headache specialist, while our current findings are generally comparable to those obtained in our 2018 pre-COVID-19 survey and the pandemic has not imposed any significant attitudes on migraine therapies and corresponding patients’ satisfaction. Conclusion: Although a market change is anticipated with the evolving widespread use of anti-CGRPs monoclonal antibodies or gepants in the symptomatic and prophylactic treatment of migraine, it is of great interest to review published results of larger longitudinal population-based studies to further ascertain the satisfaction of patients to migraine therapies.


Introduction
Migraine, clinically classified as either episodic (low frequency episodic: 4-7 days monthly; high frequency episodic: 8-14 days monthly) or chronic migraine (more than 15 headache days monthly, of which at least 8 are of migrainous type for more than 3 months), is a common primary headache disorder imposing a significant burden on patients [1]. Despite chronic migraine (CM) being considered to be much more disabling compared to episodic migraine (EM) [2], there is evidence from a study collecting data from American Migraine Foundation's (AMF) American Registry for Migraine Research (ARMR) that the current definition of migraine, based on the number of monthly headache days, may not reflect the exact differences in burden and disability among EM and CM

Materials and Methods
The data collection occurred over a period of two months from June 1 to July 31 2020. The methods for conducting this survey are described in detail in our recent publication containing the first part of its results concerning the demographic and clinical characteristics of participants, the severity and effects of migraine on their quality of life, and the effects of the coronavirus pandemic on the course of migraine [16]. The same methods were used in the current second part of results on the efficacy of preventive and symptomatic anti-migraine medications and the patients' reported satisfaction with these treatments.
Briefly, candidate participants from all over Greece (all 13 regions) were randomly called to reply to a 151-questions specific migraine-focused questionnaire in Greek language, which was distributed through the online research software "SurveyMonkey". The target group included GSMHP members (personal email invitation), but not exclusively, as the survey was promoted through GSMHP's social media accounts (Facebook, Instagram, and Twitter). In 2020, GSMHP formally had 1812 members and 10,000 followers in its social media accounts. Eventually, this survey included adult patients with a definite diagnosis of migraine in a two-stage procedure, i.e., (i) the screening interview (first stage), wherein demographics and residency were first collected and then participants had to reply to a screening question expressed as "do you have a definite diagnosis of migraine established by a physician or do you have clinical symptoms resembling migraine but not formally diagnosed by a physician?", whereas afterwards, they completed key clinical questions to ascertain whether the diagnostic criteria for a definite migraine diagnosis were fulfilled [18]; (ii) participants failing to fulfil the migraine diagnostic criteria were not allowed to proceed further in the online survey (second stage), in which only definite migraineurs were able to continue and complete all primary questions in relation to the efficacy of preventive and symptomatic anti-migraine medications as well as the patients' reported satisfaction to these treatments. At the end of the procedure, patients were allocated in two groups: those with a diagnosis of migraine established by a physician (Group A), and cases with clinical migraine symptoms who had not been diagnosed by a medical professional (Group B). The flow diagram of participants remained the same as previously presented [16].
The study was performed in accordance with the principles of the Declaration of Helsinki, while its protocol was approved from the ethics committee of Euromedica General Clinic, Thessaloniki, Greece. At the beginning of the study procedure, each patient had to read a mandatory consent form so as to be informed about the objectives, which was in agreement with regulations of data protection, and clearly note her/his agreement in order to be further allowed to anonymously complete the web-based survey.

Statistical Analysis
Descriptive statistics, performed with the SPSS for Windows (release 27.0; SPSS Inc., Chicago, IL), generated categorical variables (observed counts and weighted percentages) and continuous variables (mean or median with the corresponding standard error or range), depending on their nature. The Mann-Whitney U test for two samples was used for nonparametric comparisons, whereas the Chi-square one-sample test and Chi-square with Yates corrected p-value were used to compare proportions. Significance was set at the p < 0.05 level.

Results
As previously mentioned, the study enrolled 2105 patients who after completion of the first diagnostic part of the questionnaire fulfilled the diagnostic criteria for migraine, according to both the ICHD-3 symptom criteria [18] and physician diagnostic criteria. The baseline epidemiological and clinical characteristics of participants were previously described in detail [16]. Briefly, we surveyed 159 males (7.6%) and 1946 females (92.4%) with a mean age of 32.5 ± 14.3 (range: 18-60) years, who failed to a median number of 3 (range: 0-7) previous prophylactic medications. Most common comorbidities included various chronic pain syndromes (N = 286; 58.8%), followed by hypo/hyperthyroidism (N = 211; 43.4%). A total of 1248 (83.5%) participants had EM, either very low, low or high frequency, while 247 (16.5%) were with CM. Among the total of 2105 participants, 1550 of them had been diagnosed by a physician (group A), and 555 cases were allocated to group B as they were at baseline with clinical migraine symptoms but lacked a formal migraine diagnosis established by a medical professional. Group B patients were without any other evidence of suffering from another type of headache disorder.
We obtained the following data regarding the efficacy of preventive and symptomatic anti-migraine medications and the patients' reported satisfaction to these treatments.

Prophylactic Anti-Migraine Treatments (Group A Only)
Among patients with established migraine diagnosis by a physician, 815 patients (57.23%) had received various prophylactic treatments. The answers to the multiple-choice question "Which prophylactic treatment(s) have you received at least once are shown (drug class)?" is described in Figure 1. them had been diagnosed by a physician (group A), and 555 cases were allocated to group B as they were at baseline with clinical migraine symptoms but lacked a formal migraine diagnosis established by a medical professional. Group B patients were without any other evidence of suffering from another type of headache disorder.
We obtained the following data regarding the efficacy of preventive and symptomatic anti-migraine medications and the patients' reported satisfaction to these treatments.

Prophylactic Anti-Migraine Treatments (Group A Only)
Among patients with established migraine diagnosis by a physician, 815 patients (57.23%) had received various prophylactic treatments. The answers to the multiplechoice question "Which prophylactic treatment(s) have you received at least once are shown (drug class)?" is described in Figure 1. Nonetheless, the majority of participants (64.2%) prioritized safety over effectiveness in medications prescribed for their migraine prophylaxis.

Beta Blockers or Calcium Channel Blockers
Prophylactic treatments with either beta blockers (propranolol) or calcium channel blockers (flunarizine) were commenced in 221 (27.07%) and 329 (40.42%) patients, respectively. The vast majority (90%) of propranolol-treated patients discontinued treatment due to side effects, such as bradycardia, irritability, and mood disorders, while ineffectiveness was the main cause of flunarizine intake, coupled with weight gain as a side effect.

OnabotulinumtoxinA (BoNTA)
Among the 158 (19.41%) responders with CM who had been treated with BoNTA, only 99 (62.65%) answered that their treatment was performed with the approved fixed sitefixed dose PREEMPT protocol by a trained neurologist. The remaining 59 patients received BoNTA by dermatologists or ENT physicians at arbitrary and unapproved injection sites, i.e., just in forehead, and dosage. To the question "How happy are you with the effect of BoNTA treatment in migraine prophylaxis", 42 (26.58%) were not happy at all (37 of them were treated by a non-neurologist physician), 57 (36.07%) were modestly happy, 30 (18.98%) were fairly happy, 15 (9.49%) were very happy, and 12 (7.59%) were extremely happy. The question "Have you stopped your treatment with BoNTA for any reason?" was answered positively by 87 (55.06%) of the responders. When asked (multiple choice) "Why did you stop your treatment with BoNTA?", 83 (95.4%) responded "due to ineffectiveness" and 4 (4.6%) responded "due to side effects", including neck pain and eyelid ptosis.

Acute Migraine Treatment (Group A and B)
In the sample, 1428 (95.71%) participants from group A and 450 (90.36%) from group B systematically used symptomatic treatment. (Question "Do you receive symptomatic treatment (painkillers) during crisis?"). The answers to the multiple-choice question "During migraine attacks, what symptomatic treatment do you receive?" are shown in Figure 2.

Complementary and Alternative Medicine (CAM) as Acute Treatment of Migraine Attacks
The use of CAM was reported by 1427 group A and 474 group B patients. The answers of the two groups to the multiple-choice question "What alternative symptomatic treatment do you use to relieve your migraine attack in case that you do not use conventional medical treatment?" are shown in Figure 3.

Associations
When we examined potential associations of demographic and baseline clinical characteristics with both acute and prophylactic treatment preferences, we found gender effects with males favoring CAM approaches three times more than females (odds ratio (OR) 2.9, p < 0.001), compared to pharmacological approaches. Age effects were also noted in relation to the acute and prophylactic pharmacological medication intake, which was much lower in the 18-35 age group, compared to older patients, especially to those in the 45-59 age group (OR 1.5, p = 0.01). We were not able to detect any other notable effect of

Associations
When we examined potential associations of demographic and baseline clinical characteristics with both acute and prophylactic treatment preferences, we found gender effects with males favoring CAM approaches three times more than females (odds ratio (OR) 2.9, p < 0.001), compared to pharmacological approaches. Age effects were also noted in relation to the acute and prophylactic pharmacological medication intake, which was much lower in the 18-35 age group, compared to older patients, especially to those in the 45-59 age group (OR 1.5, p = 0.01). We were not able to detect any other notable effect of demographic and baseline clinical characteristics on treatment preferences.

Discussion
With the release of the second part of results from the current population web-based survey conducted by GSMHP in 2020, we primarily aimed to trace potential treatment differences of patients with migraine in Greece, according to study groups (group A: migraine diagnosed by a physician; group B: with clinical migraine symptoms at baseline but lacked a formal migraine diagnosis established by a medical professional), focusing on the assessment of efficacy of preventive and symptomatic anti-migraine medications as also the satisfaction of patients to these treatments, in terms of safety/efficacy. In addition, we sought to compare the relevant results of the 2020 survey with those previously obtained in 2018 [17].
Our results, overall, point towards the view that patients whose migraine was diagnosed by a neurologist/headache expert (group A) had higher disability and were more difficult to treat than patients belonging to group B, a fact which most likely contributed to ask specialized consultation. Amongst formally diagnosed migraine patients (group A), 815 (57.23%) have received prophylactic anti-migraine treatment with orally and/or injectable-administered medications, a percentage that is comparable to the corresponding findings of the 2018 survey in which 58.2% of participants received various prophylactic treatments [17]. This consistency in percentages of patients under anti-migraine prophylaxis between timepoints (2018 vs. 2020) shows that about 40% of migraineurs remain untreated, despite the current raised awareness and improved migraine care; however, it should be mentioned that a small percentage of them was with very low frequency episodic migraine and no need for prophylaxis. Nonetheless, it is also evident that more than 50% of patients experience migraine intensification during the course of the disease, in terms of both frequency and intensity, which is significant enough to impose disability such that patients seek consultation by a neurologist/headache expert and are eventually treated with available prophylactic treatments.
Specifically for migraine prophylaxis with the use of antiepileptic or antidepressant medications, it was evident that about 60% of 815 participants from group A had received either topiramate/valproic acid or SSRIs/SNRIs/tricyclics, with modest efficacy/safety as the majority of them (61%) remained null to minimally satisfied from these medications due to inefficacy (about 70%) or evidence of side effects (about 55%). Very or quite satisfied from antiepileptics/antidepressants only represented 15% of our interviewed patients. About 65% (2 out of 3) of our participants discontinued these prophylactic medications as a result of inefficacy/safety issues, findings which are in close agreement with data demonstrating that up to 55% of migraine patients discontinue oral pharmacological preventive approaches after 12 months of treatment [19], because of modest response, poor adherence, and compliance to more than one line of such prophylactic therapies [20]. Interestingly, amitriptyline was associated with the higher rates of satisfaction due to efficacy among antidepressants, thoroughly demonstrating that it either has direct antimigraine prophylactic properties by increasing the concentration of the neurotransmitters serotonin and norepinephrine or indirectly acting against the overlapping tension-type headache to migraine [21].
Only a small percentage of group A participants was treated with BoNTA (19.4%) and even fewer patients with anti-CGRP MAbs (3%). The satisfaction with these treatments was rather modest, although tellingly, these findings were strongly biased to allow generalization. Specifically, for BoNTA, it was evident that about 40% of exposed patients were treated by other medical specialties, instead of neurologists/headache experts, with schemes not adhering to the approved fixed-site, fixed-dose (155-195 UI) PREEMPT pro-tocol [22]. As such, it is strongly advised that experienced BoNTA injectors are required to guide and plan the therapeutic protocol for each patient with CM to optimize good and safe outcomes, based on widely acknowledged guidelines of BoNTA infusion for CM efficient prophylaxis [23]. Additionally, our findings on the efficacy and satisfaction of participants to anti-CGRP MAbs are not reliable and cannot be discussed because of strong bias imposed by the very limited use of this new category of prophylactic injectable medications in 2020, attributable to the un-approved use and lack of reimbursement for anti-CGRPs from the National Health System (NHS) and social services at that year. The formal market reimbursed release of anti-CGRPs after 2021 is expected to dramatically change the satisfaction of migraine patients to this modern prophylactic treatment. The exposure to external neurostimulation devices was also very limited (6.3%), in agreement with evidence supporting that generally Greek migraineurs seem to prefer oral medication to injection or stimulation devices for both prophylactic and symptomatic treatment of their migraine [24].
The findings on the exposure in CAMT are rather surprising to us, as it was evident that a rather high percentage (about 45%) of our participants received nutrients or was treated with homeopathy or acupuncture, although 80% of them discontinued these unapproved approaches due to ineffectiveness.
Regarding the use of acute treatments for the symptomatic relief of migraine attacks, it was evident that the majority of patients who were diagnosed and regularly followed by a neurologist/headache expert (group A) used triptans, as opposed to the much lower percentage of triptans use in group B patients (61.06% in group A vs. 18.08% in group B). Moreover, group A patients seem to have comprehended the clinical benefits of early triptan use for the adequate symptomatic relief of migraine attack [25] as a significant percentage of them took triptans (62.5%) within 20 min after its onset.
As previously reported, although the data for this survey were collected during the COVID-19 pandemic, the majority of participants mentioned that they did not experience any effect on their migraine, including in treatment attitudes [16]. This is an intriguing finding given that an exacerbation in migraine severity was potentially anticipated as a result of SARS-CoV2 infection and vaccinations, which may cause a change in the nature or severity of headaches [26][27][28]. Indeed, there is evidence to support that anti-SARS-CoV2 vaccines are associated to a two-fold risk of developing headache with migraine-like features within 7 days from injection, likely due to systemic immunological reaction than to a vaccine-type specific reaction [29,30]. Post-vaccination headache incidence is considered to be higher in patients with a history of headache, including migraine, compared to naïve patients [31], while atypical phenomenology and course of migraine attacks may occasionally occur during COVID-19 infection [32]. Nonetheless, the intake of over-the-counter simple analgesics or NSAIDs, such as paracetamol, ibuprofen, and acetylsalicylic acid, might effectively alleviate the burden, which is associated with this temporary exacerbation of headache, particularly post-vaccination [33].
We should acknowledge as a limitation of our study the sampling process we applied to target advocacy group members with diagnosed migraine (group A) via a web-based survey and a questionnaire which is not validated or subjected to any form of psychometric evaluation, instead of a prospective follow up in our headache outpatients' clinics. This approach restricted us from collecting more objective data. Moreover, the cross-sectional study design and the inclusion of participants with a tentative diagnosis of migraine at baseline (group B) may also further bias the interpretation of our findings.

Conclusions
Taken together, our results overall demonstrate that about 2 of 3 surveyed patients had received various prophylactic oral medications and the majority of them discontinued these prophylactic medications as a result of inefficacy/safety issues. BoNTA was reported to be effective only when administration was commenced by a trained neurologist/headache specialist, while our current findings are generally comparable to those obtained in our 2018 pre-COVID-19 survey [17] and the pandemic has not imposed any significant attitudes on migraine therapies and corresponding patients' satisfaction. The pandemic and its restrictive measures imposed few barriers in health services access requiring a headache specialist or clinic, such as BoNTA injections for CM. Although a market change is anticipated with the evolving widespread use of anti-CGRPs MAbs or gepants in the symptomatic and prophylactic treatment of migraine, it is of great interest to review published results of larger longitudinal population-based studies to further ascertain the satisfaction of patients to migraine therapies both in our country and abroad.

Informed Consent Statement:
A mandatory consent question was included in the beginning of the web-based survey and the participants were informed about the purpose of the survey, how the data will be used, that the data are anonymous, and they had to read and provide informed consent.

Data Availability Statement:
The corresponding author has full control of all primary data and agrees to allow the journal to review our data upon reasonable request.

Conflicts of Interest:
The authors declare no conflict of interest.