Emmanouil V. Dermitzakis

Aim: This prospective real-world study aimed to evaluate the effectiveness of escalating eptinezumab to 300 mg in difficult-to-treat migraine patients with a partial response after two 100 mg cycles. Methods: We included adults with high-frequency episodic or chronic migraine who achieved a partial response (30% to < 50% reduction in monthly headache days (MHD)) after two 100 mg eptinezumab cycles and escalated to 300 mg for two consecutive quarterly cycles. The primary outcome was the proportion of patients achieving a ≥ 50% MHD reduction from baseline after each 300 mg cycle. Secondary outcomes evaluated changes in MHDs with peak intensity > 4, monthly acute medication intake, Migraine Disability Assessment (i.e. MIDAS), and Headache Impact Test-6 (i.e. HIT-6) scores. Logistic regression assessed predictors of response. Results: We analyzed 57 patients (87.7% female, mean ± SD age of 48.2 ± 10.8 years). Following dose escalation, 57.9% and 64.9% of partial responders achieved ≥ 50% MHD reduction after the first and second 300 mg cycles, respectively. Using generalized estimating equations models, estimated marginal mean MHDs (95% confidence interval) dropped from a baseline of 18.65 (16.93–20.37) days/month to 13.33 (11.76–14.91) days/month after two 100 mg cycles, 10.02 (8.15–11.88) days/month after one 300 mg cycle, and 8.84 (6.77–10.91) days/month after two 300 mg cycles (all p < 0.05 vs baseline). Across all secondary outcomes, significant cumulative improvements occurred. Multivariable analysis showed that greater MHD reduction during the 100 mg phase (odds ratio = 0.920, p = 0.008) and no prior erenumab exposure (odds ratio = 0.145, p = 0.012) independently predicted a ≥ 50% response. Conclusions: Escalation to eptinezumab 300 mg was associated with improved population-averaged outcomes in this selected cohort of difficult-to-treat partial responders to 100 mg, supporting, as such, dose escalation over switching therapy.

Objective: To evaluate whether the conventional ≥50% reduction in monthly migraine days (MMDs) accurately reflects clinically meaningful benefit compared with IHS-aspired migraine control definitions in difficult-to-treat high-frequency episodic migraine (HFEM). Methods: In this post-hoc analysis of a prospective, real-world registry, conducted by the Greek Research Alliance for the Study of Headache and Pain (GRASP), 114 HFEM patients who had failed ≥3 preventive therapies and achieved a sustained ≥50% reduction in MMDs with monthly fremanezumab over 24 months, were included. Treatment response (≥50% and ≥75% MMD reduction) and IHS-defined control states (freedom, optimal, modest, insufficient control) were assessed using headache diaries at baseline (T0), month 12 (T1), and month 24 (T2). Secondary outcomes included headache intensity, analgesic use, and migraine-related disability. Results: At T1, fremanezumab significantly improved all efficacy and disability outcomes (p < 0.001), with mean MMDs reduced from 11.9 at baseline to 5.1 at T1. While 78.1% achieved ≥50% MMD reduction, only 19.3% reached optimal control (<4 MMDs), highlighting a mismatch between relative response and true disease control. At T2, MMDs further declined to 4.3, while optimal control increased to 29.8% and insufficient control declined to 7.8%. Overall, most patients remained moderately controlled (60.6%) with residual 4–6 MMDs. Non-prior exposure to other anti-CGRP therapies emerged as the only independent predictor of optimal long-term control (OR:2.1; p = 0.03). Conclusion: Achieving a ≥ 50% MMD reduction with CGRP-targeted therapies may not always correspond to clinically-meaningful benefit. More ambitious outcome measures are essential for more accurately evaluating treatment effectiveness and achieving clinically-meaningful reduction of migraine's disability.

Trigeminal neuralgia (TN) ranks among the most excruciating neuropathic pain syndromes, characterized clinically by multiple daily episodes of unilateral, paroxysmal, electric shock-like facial pain. The daily activities and quality of life of affected patients are profoundly diminished. First-line pharmacological agents, such as carbamazepine and oxcarbazepine, provide initial relief for many patients. However, a significant proportion eventually develops refractory symptoms or experience intolerable adverse effects, leading to the discontinuation of traditional oral medications. For these patients with complex clinical phenotypes who fail to respond or are intolerant to these therapies, alternative pharmacological strategies are required before considering invasive surgical procedures. Over the past two decades, botulinumtoxin type-A (BoNTA) has become an effective and safe, minimally invasive therapeutic option for refractory TN. This review provides a practical framework for BoNTA use in the clinical setting of refractory TN. To connect the pathophysiological background with clinical patient care, we summarize the current understanding of TN pathophysiology, the proposed mechanisms by which BoNTA exerts its antinociceptive effects and the evolving clinical evidence supporting its efficacy and safety. We also critically examine dosing protocols, injection techniques, long-term outcomes and the integration of BoNTA into the management algorithm of refractory TN.

Objective: This retrospective, intention-to-treat real-world study, designed by the Greek Research Alliance for the Study of headache and Pain (GRASP) sought to compare the effectiveness and safety of anti-CGRP monoclonal antibodies (anti-CGRP Mabs) to topiramate in preventing migraine. Patients and methods: Patients received either fremanezumab, erenumab, galcanezumab, eptinezumab, or topiramate for at least six months. Outcomes included reductions in monthly headache days (MHDs), ≥50% and ≥75% responder rates, monthly acute medication intake (MAI), MHDs with peak headache intensity ≥5 on VAS, migraine-related disability (MIDAS, HIT-6), quality of life (EQ-VAS), discontinuation rates and safety. Results: We included 409 migraine patients (median age 45.2 years), predominantly female (80%) and mostly with long-standing disease and high baseline burden. After six months, all treatments reduced MHDs. Mean MHDs decreased by −7.8 days with anti-CGRP Mabs versus −3.8 days with topiramate (p < 0.001). Higher ≥50% and ≥75% responder rates were observed across all anti-CGRP agents, compared to topiramate. Anti-CGRP Mabs also achieved greater reductions in moderate/severe MHDs, MAI, disability metrics, and superior QOL gains. Among the CGRP-targeted therapies, slight differences in effectiveness outcomes were present, though failing to demonstrate any specific superiority. Safety was favorable for anti-CGRP Mabs, whereas topiramate showed substantially higher adverse events and discontinuations. Conclusions: Anti-CGRP Mabs were more effective, produced greater reductions in disability and higher improvements quality-of-life metrics and were better tolerated than topiramate. Differences among individual anti-CGRP agents were modest and unlikely to represent a clinically meaningful superiority, supporting a class-wide benefit vs. topiramate in migraine prevention both in terms of effectiveness and safety.

The objective of this multicenter, real-world study, designed by the Greek Research Alliance for the Study of headache and Pain (GRASP), was to prospective

Objectives: This prospective, real-world study, designed by the Greek Research Alliance for Studying headache and Pain (GRASP), primarily aimed to examine whether a single administration of eptinezumab 100 mg can provide early therapeutic benefits over weeks 1–4 in preventing high-frequency chronic migraine (HFCM). Methods: We enrolled adults with HFCM (>23 monthly headache days—MHD) who had failed at least three preventive therapies and received a single infusion of 100 mg IV eptinezumab. Its efficacy was assessed using daily headache diaries over weeks 1–4 and at week 12, as well as with the Patients’ Global Impression of Change (PGIC) scale at week 4. Primary outcomes included ≥50% reduction in monthly headache days (MHD) through week 4 and early response at week 1. Secondary outcomes included changes in migraine severity, acute medication use, and incidence of most bothersome symptoms (MBS) accompanying headache. Results: A total of 39 HFCM patients were analyzed. Their mean age was 48.1 years, and most were female. More than half (n = 22; 56%) were fast-responders, showing >50% reduction in MHD at week 1. Early 50% response rates at week 1 favored CGRP-naïve patients, compared to prior non-responders. Likewise, significant improvement was observed early across all other efficacy domains through week 4, with sustained benefits through month 3. MBS, like photophobia and nausea, decreased notably, while osmophobia and allodynia improved less over weeks 1–4, post-eptinezumab. At week 4, 64.1% of patients reported meaningful overall improvement on PGIC. Conclusions: Eptinezumab rapidly prevented HFCM with clinically meaningful benefits seen early at week 1. Patients experienced sustained improvement in all measured clinical domains through week 4 and onward to month 3.

Background: This study, designed by the Greek Research Alliance for the Study of Headache and Pain (GRASP), sought to prospectively examine whether the treatment with two consecutive OnabotulinumtoxinA (BoNTA) cycles might improve the frequency and severity of chronic migraine (CM) with comorbid bruxism. We also explored whether the potential BoNTA-related alleviation of bruxism can directly influence the improvements in migraine efficacy outcomes. Methods: A total of 58 CM patients with comorbid bruxism at baseline, attaining two consecutive (quarterly given) BoNTA cycles, were studied. The changes in bruxism-related pain were assessed with the 0–10 numeric scale PI-NRS. Bruxism was clinically diagnosed using the self-report Bruxscreen-Q questionnaire. Any phenotypic changes in bruxism, according to Bruxscreen-Q, from baseline (T0) to the last efficacy evaluation follow-up (T1), were analyzed and then compared. Migraine-related efficacy and disability outcomes, mostly mean headache days (MHD), were also compared between T0 and T1. Results: BoNTA exerted significant improvements in bruxism-related pain, with PI-NRS median scores being significantly reduced from 7 at T0 to 3 at T1 (p < 0.001). The rates of masseter hypertrophy at T1 significantly dropped, compared to T0 (chi-square: 16; p < 0.001). Patients also self-reported significant improvements in the Bruxscreen-Q items at T1, compared to T0. At T1, 41/58 (70.7%) patients responded to BoNTA. The significant decrease in MHD frequency at T1 was positively correlated with improvements in bruxism-related pain severity (Pearson’s correlation: 0.710; p < 0.001). Conclusions: BoNTA exerts dual beneficial effects towards both the reduction of migraine frequency and the alleviation of bruxism-related pain and disability. Both of these effects seem closely interrelated in our study.

Objectives: The present open-label multicenter pilot study sought to prospectively evaluate the efficacy and safety of rimegepant in treating migraine attacks. Methods: The primary endpoint was pain freedom at two hours post-dose, while the co-primary efficacy endpoints included a reduction in the headache intensity and freedom from the most bothersome symptoms (MBS) associated with migraine at the same time point. To test the potential efficacy of rimegepant, patients were asked to record in a questionnaire all the relevant changes with each migraine attack treated with rimegepant at two hours post-dose vs. two hours before. The attending neurologists provided information on the basic demographics, medical anamnesis, and migraine history as well as the triptan use history. Results: A total of 54 patients (32 with episodic and 22 with chronic migraine) received rimegepant 75 mg at least once during a single migraine attack (overall, 140 dosage intakes). Pain freedom at 2 h was achieved in 45/140 (32.1%) intakes. Regarding the efficacy of the first rimegepant dose (n = 54), significant reductions in the headache intensity were observed between the pre- and 2 h post-treatment average VAS scores (−4.8 ± 2.8 mean; p < 0.001). Likewise, the same mean reductions in the average VAS scores occurred when the 2 h response to all 140 doses was analyzed (−5 ± 2.8; p < 0.001). Freedom from MBS at 2 h post-dose was achieved for photophobia in 43%, for phonophobia in 53%, and for nausea in 57%. The ability to fully return to everyday activities at 2 h post-dose was achieved in 83/140 instances (59%). We only recorded mild adverse events in 24/140 dosages. Conclusions: Our preliminary results demonstrate that rimegepant is effective, safe, and well tolerated in treating acute migraine attacks.

Objective: The Greek Society of Migraine and Headache Patients conducted its third in-line population web-based survey in 2023 to ascertain if the burden of the disease and the patients’ satisfaction with conventional and novel migraine therapies are changing compared to our previous findings from 2018 and 2020. Methods: The sampling process was based on a random call to participants to reply to a specific migraine-focused self-administered questionnaire, including 83 questions in Greek, which was distributed nationwide through the online research software SurveyMonkey. Results: We eventually enrolled 2565 patients, the majority of which were females. Our findings clearly demonstrate that migraine is still a burdensome condition. The degree of its impact on all aspects of productivity depends on the monthly frequency of migraine and the response rates to acute and prophylactic treatments. A total of 1029 (42.4%) of the patients had visited the emergency room mainly for unresponsiveness to acute treatments or aura-related symptoms. Triptans seem to be partly effective as acute therapies. OnabotulinumtoxinA seems to be effective for almost half of chronic migraine patients (43.9%) to report adequate satisfaction with this treatment (27.8% were “fairly happy”, 10.6% were “very happy”, and 5.5% were “extremely happy”). Due to their high rates of preventative effectiveness, most respondents treated with anti-CGRP Mabs expressed their optimism concerning their future while living with their migraine (88.25%), as well as towards further improvements in their quality of life (82.8%) status, mostly with fremanezumab. Conclusions: The patients recognize the usefulness of anti-CGRP Mabs in migraine prevention and consequently seem to be more optimistic than before about living with migraine. Considering the market change that is anticipated with the use of gepants and ditans, larger longitudinal population-based studies are warranted to further explore if the new era of migraine therapeutics might further lessen the burden of the disease.

Objective: Phase II/III randomized clinical trials (RCTs) are vulnerable to many types of bias beyond randomization. Insights into the reporting quality of RCTs involving migraine patients treated with monoclonal antibodies targeting the calcitonin gene-related peptide system (anti-CGRP MAbs) are currently lacking. Our aim was to analyze the reporting quality of phase II/III RCTs involving migraine patients treated with anti-CGRP MAbs. Methods: A systematic search was performed on the PubMed and EMBASE databases, according to PRISMA guidelines, for relevant RCTs in either episodic or chronic migraine prevention. Additionally, an adapted version of the 2010 CONSORT statement checklist was utilized. The ROBvis online tool was used to document the risk of bias. Results: From the initially identified 179 articles, we finally found 31 RCTs that were eligible for evaluation. The average CONSORT compliance was 88.7% (69.7–100%), while 93.5% (N = 29) of the articles had a compliance greater than 75%. Twenty-eight CONSORT items were reported in more than 75% of the articles. The average compliance of the analyzed RCTs was 93.9% for Galcanezumab, 91.3% for Fremanezumab, followed by 85.4% for Erenumab and Eptinezumab studies. Implementation of the ROB2 tool showed some concerning “missing information” arising from the inadequate reporting. Specifically, 50% of the studies (N = 16) were categorized as having inadequate information regarding the randomization process. Conclusions: Adequate reporting quality was disclosed in the evaluated RCTs with anti-CGRP MAbs in migraine prevention. However, some methodological issues need to be highlighted to be addressed in future studies assessing the efficacy of new molecules targeting CGRP or other candidate pathways implicated in migraine pathophysiology.