Effectiveness and safety of monthly versus quarterly fremanezumab for migraine prevention: An Italian, multicenter, real-life study.

BACKGROUND AND PURPOSE: Fremanezumab, a monoclonal antibody targeting the calcitonin gene-related peptide for migraine prevention, is available in monthly (225 mg) and quarterly (675 mg) doses. Previous studies showed efficacy and safety for both regimens, but a real-life comparison is lacking. This study aimed to compare the effectiveness and safety of monthly and quarterly fremanezumab in a real-life setting. METHODS: This Italian, prospective, multicenter study enrolled 95 migraine patients. During a 3-month treatment period, patients received either monthly or quarterly fremanezumab (49 monthly, 46 quarterly). A 6-month treatment period involved 79 patients (43 monthly, 36 quarterly). Monthly headache (MHD) and migraine days (MMD), number of days (AMD) and pills (AMP) of acute medication intake, and Headache Impact Test (HIT-6), Migraine Disability Assessment (MIDAS) test, and Numeric Rating Scale (NRS) scores were recorded at baseline and after 3 and 6 months of treatment. Adverse events (AEs), responder rates, and medication overuse were also investigated. RESULTS: Both monthly and quarterly treatments led to significant reductions in MMD, MHD, AMP, AMD, HIT-6, MIDAS, and NRS scores after 3 and 6 months. The monthly regimen exhibited a slightly greater reduction in MMD and MHD after the first quarter, with no significant difference observed after 6 months. The most common AE was transient injection-site reaction, without between-group differences. Responder rates and resolution of medication overuse did not significantly differ between the groups. CONCLUSIONS: Both monthly and quarterly regimens were effective and safe, with a tendency for an advantage of the monthly regimen only in the first quarter of treatment.

Is physiotherapy in migraines known to sufferers? A cross-sectional study.

BACKGROUND: Migraine, a prevalent neurological condition, often impairs daily functioning and quality of life. While medications are the primary treatment, the potential of physiotherapy as an integrative approach remains underexplored. The aim of the study was to explore the awareness and experience of migraine patients regarding physiotherapy as a complementary treatment. METHODS: A comprehensive survey was conducted on 200 migraine patients. Data collected included demographics, diagnosis, Migraine Disability Assessment Score Questionnaire (MIDAS) scores, and perceptions and experiences related to physiotherapy. RESULTS: The average age of participants was 47.7 ± 13.2 years, with a predominance of females, 149 out of 200 (74.5%). The mean MIDAS score was 36.7 ± 45.3, indicating a significant impact on daily life. While 39 out of 200 (19.5%) had undergone physiotherapy for their headache, 161 out of 200 (80.5%) had not. Of those who had, 22 out of 39 (56.4%) reported benefits, including reduced attack intensity and frequency. Interestingly, 145 out of 161 (90.1%) expressed interest in physiotherapy, with many expecting it to reduce attack intensity, 57 out of 200 (28.5%) and frequency, 77 out of 200 (38.5%). CONCLUSIONS: The study highlights the substantial burden of migraines and the potential of physiotherapy as an adjunctive treatment. Increasing awareness and accessibility to physiotherapy could offer migraine patients a more holistic treatment approach; however, randomized controlled trials are mandatory in order to confirm its efficacy.

Blood pressure monitoring in elderly migraineurs starting an anti-CGRP monoclonal antibody: a real-world prospective study.

BACKGROUND: While monoclonal antibodies (mAbs) targeting the CGRP pathway have revolutionized migraine management due to their improved tolerance and adherence, concerns remain about their potential impact on blood pressure (BP), especially in older patients, due to CGRP-mediated vasodilation blockade. Given the growing use of these therapies in older populations, assessing their cardiovascular (CV) safety is of paramount importance. METHODS: This multicentric observational prospective study focused on migraine sufferers aged ≥ 60 who began erenumab, galcanezumab, or fremanezumab for prevention. Baseline, three-month, and twelve-month BP measurements were collected. Changes in antihypertensive medication and "Newly or Worsened Hypertensive" patients (NWHP) were assessed. RESULTS: Among 155 patients receiving anti-CGRP mAbs (40 Erenumab, 47 Galcanezumab, 68 Fremanezumab), 42.5% had hypertension history and 39% were on antihypertensive treatment. No significant systolic or diastolic BP changes occurred at any time point compared to baseline (all p > 0.05), with no differences between the three groups. After one year, 20/155 (12.9%) patients were considered NWHP; 11/20 had prior hypertension, and 5/11 adjusted antihypertensive therapy. Among 9/20 newly hypertensive patients, 5/9 had a single measurement above the normal threshold with no requirement for new pharmacological therapy. A higher baseline BP value was associated with increased BP (p = 0.002). CONCLUSIONS: The study concludes that treatment with anti-CGRP mAbs over one year does not significantly affect BP in patients aged ≥ 60, nor does it increase the incidence of hypertension compared to general population trends. Nonetheless, continuous monitoring and further long-term studies are necessary to fullya scertain the cardiovascular safety of these medications in the elderly.

Migraine chronification as an allostatic disorder: a proof-of-concept study.

OBJECTIVE: The underpinning biologics of migraine chronification are not well understood. We aim to investigate the role of the cumulative burden of stress, namely the allostatic load, in migraine chronification. METHODS: This was a cross-sectional study. The allostatic load was measured with a composite multi-system score (BALI: Bologna Allostatic Load Index), evaluating 20 biomarkers representing four physiological systems: immune, metabolic, cardiovascular, and neuroendocrinological systems. BALI score was subdivided into high score and low score based on the distribution in controls. Migraine patients were included and subclassified into low-frequency episodic migraine group (low-EM group), high-frequency episodic migraine group (high-EM group), and chronic migraine group (CM group). RESULTS: The distribution of BALI high-score increased in parallel with headache attacks monthly frequency: 16% in low-EM group (n = 10), 24% in high-EM group (n = 12), and 40% in CM group (n = 21) (p = 0.017). In a multivariable analysis, the odds ratio of having a high-score BALI in CM patients (vs. low-EM patients) was 2.78 (95% CI 1.07-7.22; p = 0.036). Individual BALI biomarkers values which were significantly different among migraine subgroups included systolic blood pressure (p = 0.018), diastolic blood pressure (p < 0.001), and heart rate (p = 0.019). CONCLUSION: Our study substantiates this emerging concept of migraine chronification as an allostatic disorder.

Gender-related stress factors and emotional perception in migraine: a structured online questionnaire in migraine patients and controls.

BACKGROUND: While migraine is markedly prevalent in women, gender-related phenotype differences were rarely assessed. For this reason, we investigated, through a multicenter observational cross-sectional study, based on an online questionnaire, gender-related differences in stress factors, emotions, and pain perception in migraine patients and controls and their impact on migraine severity. METHODS: The study was designed as an online questionnaire. The link was emailed to healthy subjects (C) and migraine patients (MIG) (age 18-75, education ≥ 13 years) recruited during the first visit in 8 Italian Headache Centers adhering to Italian Society for Headache Study (SISC). The questionnaire included personal/social/work information, the Perceived Stress Scale, the Romance Quality Scale, the Emotion Regulation Questionnaire, the Beck Anxiety Inventory, the Body Perception Questionnaire, the pain perception, and a self-assessment of migraine severity in the last 3 months. RESULTS: 202 MIG and 202 C completed the survey. Independently from gender, migraine was characterized by higher pain sensitivity and more severe partner relationships. The female gender, in MIG, exhibited higher anxiety scores, body awareness, and reduced emotional suppression. Body awareness and emotional suppression were discriminating factors between genders in control and migraine groups without relevant influence on disease features. Perceived perception of migraine severity was similar between genders. CONCLUSION: Gender-related emotional and stress factors did not contribute to delineate a distinct phenotype in migraine men and women. The possible impact of emotional and stress factors characterizing genders could be considered for a single case-tailored therapeutic approach.

Profiling iNPH features through cluster analysis: an aid for clinical suspicion and diagnosis.

PURPOSE: Idiopathic Normal Pressure Hydrocephalus (iNPH) is a neurological syndrome defined by gait disturbance, cognitive impairment and urinary incontinence. However, its clinical presentation can vary widely due to overlapping syndromes and common comorbidities in older adults. This study aims to provide practical guidance to aid in the clinical suspicion and support the diagnostic and therapeutic processes for these patients. METHODS: Six quantitative variables regarding clinical, functional, and demographic aspects were considered for a large sample of patients with diagnosed iNPH. Principal component analysis (PCA) was adopted to define the main dimensions explaining the variability of the phenomenon. Then, two clusters of iNPH patients were described. RESULTS: 178 patients were included in the analysis. The PCA produced two dimensions covering 61.8% of the total variability. The first one relied mainly on both clinical (mRS, iNPHGs) and functional (TUG, Tinetti) variables, while the second one was represented mainly on the demographic pattern (age and education). Cluster analysis depicted two main groups of patients. Cluster n.1 is composed of individuals who are older, more disabled, with poor functional performances, and highly symptomatic. Cluster n.2 patients are slightly younger, more educated, fitter, and with more nuanced clinical aspects. CONCLUSIONS: Profiling iNPH patients using quantitative variables and cluster analysis can help identify distinct characteristics of these patients, aiding in the guidance of both medical and surgical interventions.

The evolutionary meaning of migraine.

INTRODUCTION: Migraine's astonishing prevalence and preserved genetic background contrast with the definition of a disease and the biological meaning of experiencing recurrent, severe headache attacks is still puzzling. METHODS: To provide a comprehensive explanation of the migraine evolutionary meaning, we review (i) the putative role of the autonomic nervous system in migraine attacks, (ii) the inter-ictal autonomic, functional, and metabolic signature of migraine patients, (iii) the bio-behavioral perspective of pain, and (iv) the allostatic perception of migraine chronification. RESULTS: Migraineurs have inter-ictal cortical hyperexcitability and metabolic dysfunction that predisposes to brain energetic imbalance. Multiple precipitating factors may lead to brain energy consumption over the migraine attack generation threshold. In response, the brain engenders adaptive, evolutionary conserved, autonomic-behavior responses through the antidromic activation of the trigeminovascular system. The sickness behavior and severe pain experienced during migraine attacks result in avoiding mental and physical activity, allowing brain energy restoration. Chronic exposure to stressors may result in an allostatic overload, leading to maladaptive chronic activation of these responses. In this bio-behavioral perspective, the chronification of migraine should be envisioned as a pathological process, whereas the migraine itself should not. CONCLUSION: Migraine has an evolutionary (Darwinian) meaning.

Prevalence, natural history and dynamic nature of chronic headache and medication overuse headache in Italy: The SPARTACUS study.

BACKGROUND: Chronic headaches and medication overuse headache are common and burdening conditions. No studies have evaluated the prevalence of chronic headache and medication overuse headache in an unselected Italian population. METHODS: We performed a three-year cross-sectional and longitudinal population-based study to investigate prevalence, natural history, and prognostic factors of chronic headache. We delivered a self-administered questionnaire to 25,163 subjects. Chronic headache patients were interviewed by General Practitioners. After three years, medication overuse headache patients were invited to undergo a neurological evaluation at our Center. RESULTS: 16,577 individuals completed the questionnaire; 6878 (41,5%) were episodic headache sufferers and 636 (3.8%) were chronic headache subjects. 239 (1.4%) patients were acute medication over-users. All medication overuse headache patients had migraine or headache with migrainous features. At the three-year follow-up of 98 patients, we observed conversion to episodic headaches in 53 (54.1%) patients. 27 (50.9%) patients remitted spontaneously. CONCLUSIONS: We present the first prevalence data on chronic headache and medication overuse headache in an unselected Italian population and a high rate of spontaneous remission. These data support the interpretation of medication overuse headache as a specific migraine-related disorder that may reflect chronic migraine's dynamic nature, the need for more specific medication overuse headache diagnostic criteria, and highlight the priority of targeted public health policies.

Maintenance of response and predictive factors of 1-year GalcanezumAb treatment in real-life migraine patients in Italy: The multicenter prospective cohort GARLIT study.

BACKGROUND AND PURPOSE: To evaluate the 1-year effectiveness and tolerability of galcanezumab in real life and the prognostic indicators of persistent response. METHODS: High-frequency episodic migraine (HFEM) and chronic migraine (CM) patients treated with galcanezumab who completed a 1-year observation were enrolled. The primary outcomes assessed during the 12 months (V1-V12) were the change in monthly migraine days (MMDs) from baseline and the response rates ≥50% in MMDs (MMD ≥50% RR). The secondary outcomes were changes in pain intensity (numerical rating scale [NRS]) and in monthly acute medication intake (MAMI). RESULTS: We enrolled 191 patients (77.5% CM). Twenty-three patients (12%) dropped out, two for nonserious adverse events. At least 40% of patients took add-on standard preventives from baseline to V12. At V12, MMDs were reduced by 6.0 days in HFEM and by 11.9 days in CM patients (both p < 0.00001); NRS and MAMI were also decreased in both groups (p < 0.00001). One-hundred eight (56.5%) patients presented MMD ≥50% RR for 9 cumulative months (interquartile range=8): we defined this value as the cutoff for a persistent response. Persistent responders were less likely to have a higher body mass index (BMI) (p = 0.007) but more frequently had a good response to triptans (p = 0.005) and MMD ≥50% RR at V1 (p < 0.0000001). Patients without a persistent response were on add-on therapy for longer periods of time (p < 0.001). CONCLUSIONS: Galcanezumab was effective and well-tolerated in the 1-year term, with most patients presenting MMD ≥50% RR for at least 9 months. Triptan response, lower BMI, and MMD ≥50% RR in the first month emerged as predictive factors for a persistent response.

Vessel-wall MRI in primary headaches: The role of neurogenic inflammation.

OBJECTIVE: The purpose of this study was to investigate if vessel-wall magnetic resonance imaging (VW-MRI) could differentiate among primary headaches disorders, such as migraine and cluster headache (CH), and detect the presence of neurogenic inflammation. BACKGROUND: The pathophysiology of primary headaches disorders is complex and not completely clarified. The activation of nociceptive trigeminal afferents through the release of vasoactive neuropeptides, termed "neurogenic inflammation," has been hypothesized. VW-MRI can identify vessel wall changes, reflecting the inflammatory remodeling of the vessel walls despite different etiologies. METHODS: In this case series, we enrolled seven patients with migraine and eight patients with CH. They underwent a VW-MRI study before and after the intravenous administration of contrast medium, during and outside a migraine attack or cluster period. Two expert neuroradiologists analyzed the magnetic resonance imaging (MRI) studies to identify the presence of vessel wall enhancement or other vascular abnormalities. RESULTS: Fourteen out of 15 patients had no enhancement. One out of 15, with migraine, showed a focal parietal enhancement in the intracranial portion of a vertebral artery, unmodified during and outside the attack, thus attributable to atherosclerosis. No contrast enhancement attributable to neurogenic inflammation was observed in VW-MRI, both during and outside the attack/cluster in all patients. Moreover, MRI angiography registered slight diffuse vasoconstriction in one of seven patients with migraine during the attack and in one of eight patients with cluster headache during the cluster period; both patients had taken triptans as symptomatic therapy for pain. CONCLUSIONS: These preliminary results suggest that VW-MRI studies are negative in patients with primary headache disorders even during migraine attacks or cluster periods. The VW-MRI studies did not detect signs of neurogenic inflammation in the intracranial intradural vessels of patients with migraine or CH.

Detoxification vs non-detoxification before starting an anti-CGRP monoclonal antibody in medication overuse headache.

BACKGROUND: Medication overuse headache significantly contributes to the chronification process and treatment refractoriness of migraine. Currently, abrupt discontinuation of the overused medication still represents the best management strategy for these patients, challenging public health system resources. METHODS: In this prospective study, chronic migraine and medication overuse headache sufferers with at least 28 days of analgesic consumption per month were included. Assessment of efficacy outcomes at three months were compared among patients who underwent in-hospital abrupt discontinuation of overused acute medication (YES-DETOX group) and patients who did not (NO-DETOX group) before starting an anti-CGRP monoclonal antibody. RESULTS: Of 401 patients who received either erenumab or galcanezumab, 28% (n = 111) satisfied inclusion criteria (YES-DETOX n = 28; NO-DETOX n = 83). After three months of treatment, 59% (n = 65; 47/83 YES-DETOX; 18/28 NO-DETOX) patients reverted from medication overuse headache and 51% (n = 57; 42/83 YES-DETOX; 15/28 NO-DEOTX) achieved ≥50% reduction in monthly headache days; yet no statistical differences were observed between the two groups (p = 0.4788 and p = 0.8393, respectively). Monthly consumption of pain medication was the only baseline prognostic factor in multivariate analysis in the overall cohort (p = 0.016). CONCLUSION: Our results support the emerging evidence that anti-CGRP monoclonal antibodies may be effective in medication overuse headache patients irrespective of detoxification, yet further studies are needed to draw definitive conclusions.

Self-administered subcutaneous diclofenac sodium in acute migraine attack: A randomized, double-blind, placebo-controlled dose-finding pilot study.

BACKGROUND: A novel formulation of diclofenac, complexed with hydroxypropyl-ß-cyclodextrin (HPßCD) as a solubility enhancer, in a prefilled syringe for self-administered subcutaneous injection may overcome the limitations of acute migraine treatments administered by oral, rectal, intramuscular, or intravenous routes. METHODS: This multicentre, phase 2, double-blind, randomized, placebo-controlled, dose-finding pilot study evaluated the efficacy, safety and tolerability of three different doses (25/50/75 mg/1 mL) of subcutaneous diclofenac sodium in the treatment of an acute migraine attack in 122 subjects. The primary efficacy endpoint was the percentage of patients pain-free at 2 hours after the study drug injection. RESULTS: A significantly higher percentage of patients in the 50 mg diclofenac group 14 (46.7%) were pain-free at 2 hours when compared with placebo: 9 (29.0%) (p = 0.01). The 50 mg dose proved superior to placebo also in the majority of the secondary endpoints. The overall global impression favoured diclofenac vs placebo. There were no adverse events leading to study withdrawal. The majority of treatment-emergent adverse events were mild. CONCLUSIONS: The 50 mg dose of this novel formulation of diclofenac represents a valuable self-administered option for the acute treatment of migraine attacks.Trial registration: EudraCT Registration No. 2017-004828-29.

Rapid response to galcanezumab and predictive factors in chronic migraine patients: A 3-month observational, longitudinal, cohort, multicenter, Italian real-life study.

BACKGROUND AND PURPOSE: A rapid response to preventive therapy is of pivotal importance in severely disabled patients with chronic migraine (CM) and diverse preventive treatment failures. This prospective, observational, multicenter real-life study aimed at investigating the effectiveness of galcanezumab in the first 3 months of treatment of CM patients at 14 Italian headache centers. METHODS: All consecutive adult patients with CM diagnosis with the clinical indication for galcanezumab were considered. We collected patients' baseline characteristics, monthly headache days, monthly painkiller intake, migraine clinical characteristics, and disability scale scores during a 1-month run-in period (baseline) and the first 3 months of therapy. Possible predictive factors of treatment were considered. RESULTS: A total of 156 patients (82.4% female, aged 47.3 ± 12.3 years) were enrolled. The 65 (41.7%) patients with a consecutive ≥50% response rate (RR) in the 3 months of therapy presented a lower body mass index (p = 0.004) and more frequently presented unilateral migraine pain (p = 0.002) and good response to triptans (p = 0.003). Persistent conversion from CM to episodic migraine was observed in 55.8% (87/156) of patients. They more frequently presented a good response to triptans (p = 0.003) and unilateral pain (p = 0.046). At baseline, 131 of 156 (83.9%) patients presented medication overuse (MO). Of these, 61.8% (81/131) no longer displayed MO consistently during the 3 months. These patients were more frequently responders to triptans (p = 0.002) and less frequently suffered from gastrointestinal comorbidity (p = 0.007). CONCLUSIONS: Unilateral pain, good response to triptans, and normal weight may be associated with a persistent positive response in the first 3 months of therapy with galcanezumab in CM patients.

The ultimate guide to the anti-CGRP monoclonal antibodies galaxy.

BACKGROUND: Anti-CGRP monoclonal antibodies have represented a real revolution in the field of headaches, being the result of an extraordinary process of translation of new pathophysiological discoveries into successful therapies. Nonetheless, clinical practice is far more complex than pivotal trials setting, and real-world studies are blooming to deepen knowledge of these revolutionary medications. OBJECTIVE: To provide an updated guide for evidence-based clinical practice. METHODS: Pivotal phase 3 randomised clinical trials for each anti-CGRP(-R) monoclonal antibody were considered. We evaluated prospective real-world studies and summarised evidence on anti-CGRP mAbs use beyond episodic and chronic migraine. RESULTS: All phase 3 RCTs showed an unprecedented profile of efficacy and safety in migraine prevention for the four anti-CGRP mAbs. However, plenty of questions remained open after the approval process. Real-world studies filled the gap and effectiveness results equalled or unexpectedly outperformed RCTs figures in most cases; safety results showed a lower incidence of adverse events, but a higher frequency of reported constipation compared to RCTs. Almost all studies displayed a rapid and progressive headache worsening following treatment suspension. Several positive response predictors were suggested, such as unilateral pain, allodynia in episodic migraineurs, response to triptans, and a lower number of failed prophylaxes. Comparable effectiveness was observed in resistant/refractory patients. In medication overuse headache patients, a clear clinical benefit was observed irrespective of any possible detoxification program. CONCLUSIONS: Our narrative review restates the remarkable efficacy, effectiveness, and safety profile in both RCTs and real-world settings and provides scientific evidence for clinical practice.

Chronic migraine evolution after 3 months from erenumab suspension: real-world-evidence-life data.

BACKGROUND: Erenumab is a monoclonal antibody acting against calcitonin gene-related peptide receptor which has been found effective even for the treatment of chronic migraine (CM) complicated with medication overuse headache (MOH). According to the present guidelines, the treatment with erenumab should continue for up to 1 year. The aim of the present study is to explore the evolution of patients affected by CM and MOH at the baseline, after erenumab discontinuation. METHODS: One hundred and eighty-five patients affected by CM and MOH were recruited and followed up after erenumab discontinuation. The number of migraine days per month, the number of painkillers taken per month, the number of days in which one medication was used for a month were collected every 30 days for the 3 months following erenumab suspension. RESULTS: At the 3rd month after suspension, patients displayed a significantly higher number of migraine days per month, a significantly higher painkiller consumption, and a significantly higher migraine-related disability. A high body mass index and the presence of aura were positively correlated with the relapse of CM and MOH. CONCLUSION: Patients affected by CM and MOH at the baseline displayed a significant worsening of their headaches after erenumab discontinuation.

Real-life assessment of erenumab in refractory chronic migraine with medication overuse headache.

OBJECTIVE: To determine whether erenumab is effective and safe in refractory chronic migraine with medication overuse headache. METHODS: In this prospective, multicentric, real-life study, chronic migraine with medication overuse headache patients who received erenumab were recruited. Study inclusion was limited to patients who previously failed onabotulinumtoxinA in addition to at least three other pharmacological commonly used migraine preventive medication classes. RESULTS: Of 396 patients who received erenumab, 38% (n = 149) met inclusion criteria. After 3 months, 51% (n = 76) and 20% (n = 30) patients achieved ≥ 50% and ≥ 75% reduction in monthly headache days, respectively. Monthly pain medications intake decreased from 46.1 ± 35.3 to 16.8 ± 13.9 (p < 0.001), while monthly headache days decreased from 25.4 ± 5.4 to 14.1 ± 8.6 (p < 0.001). Increasing efficacy of erenumab over the study period was observed. Allodynia was a negative predictive factor of erenumab response (odds ratio = 0.47; p = 0.03). Clinical conversion to episodic migraine with no medication overuse was observed in 64% (n = 96) patients. No serious adverse events were observed. CONCLUSIONS: Erenumab reduced significantly migraine frequency and pain medication intake in refractory chronic migraine with MOH patients.

Predictors of response to anti-CGRP monoclonal antibodies: a 24-week, multicenter, prospective study on 864 migraine patients.

BACKGROUND AND OBJECTIVES: The identification of predictors of response to antiCGRP mAbs could favor tailored therapies and personalized treatment plans. This study is aimed at investigating predictors of ≥ 50%, ≥ 75% and 100% response at 24 weeks in patients with high-frequency episodic (HFEM: 8-14 days/month) or chronic migraine (CM). METHODS: This is a large, multicenter, cohort, real-life study. We considered all consecutive adult patients affected by HFEM or CM who were prescribed antiCGRP mAbs for ≥ 24 weeks in 20 headache centers. Patients were interviewed face-to-face using a shared semi-structured questionnaire carefully exploring socio-demographic and clinical characteristics. Patients received subcutaneous erenumab (70 mg or140 mg, monthly), galcanezumab (120 mg monthly, following a 240 mg loading dose), or fremanezumab (225 mg, monthly or 675 mg, quarterly) according to drug market availability, physician's choice, or patient's preference. The primary endpoint of the study was the assessment of ≥ 50% response predictors at 24 weeks. Secondary endpoints included ≥ 75% and 100% response predictors at 24 weeks. RESULTS: Eight hundred sixty-four migraine patients had been treated with antiCGRP mAbs for ≥ 24 weeks (erenumab: 639 pts; galcanezumab: 173 pts; fremanezumab: 55 pts). The ≥50% response (primary endpoint) in HFEM was positively associated with unilateral pain (UP) + unilateral cranial autonomic symptoms (UAs) (OR:4.23, 95%CI:1.57-11.4; p = 0.004), while in CM was positively associated with UAs (OR:1.49, 95%CI:1.05-2.11; p = 0.026), UP + UAs (OR:1.90, 95%CI:1.15-3.16; p = 0.012), UP + allodynia (OR:1.71, 95%CI:1.04-2.83; p = 0.034), and negatively associated with obesity (OR:0.21, 95%CI:0.07-0.64; p = 0.006). The 75% response (secondary endpoint) was positively associated with UP + UAs in HFEM (OR:3.44, 95%CI:1.42-8.31; p = 0.006) and with UP + UAs (OR:1.78, 95%CI:1.14-2.80; p = 0.012) and UP + allodynia (OR:1.92, 95%CI:1.22-3.06; p = 0.005) in CM. No predictor of 100% response emerged in patients with HFEM or CM. CONCLUSIONS: A critical evaluation of headache characteristics indicating peripheral or central sensitization may help in predicting responsiveness to antiCGRP mAbs in HFEM and CM. A more precise pain profiling may represent a steppingstone for a mechanism-based approach and personalized treatment of migraine with compounds targeting specific molecular mechanisms.

Comparing the relative and absolute effect of erenumab: is a 50% response enough? Results from the ESTEEMen study.

BACKGROUND: Monoclonal antibodies acting on the calcitonin gene-related peptide (CGRP) or its receptor have changed migraine preventive treatment. Those treatments have led to reconsidering the outcomes of migraine prevention. Available data mostly considered benefits in terms of relative efficacy (percent or absolute decrease in monthly migraine days [MMDs] or headache days compared with baseline). However, not enough attention has been paid to residual MMDs and/or migraine-related disability in treated patients. In the present study, we aimed at comparing the relative and absolute efficacy of erenumab. METHODS: ESTEEMen was a collaborative project among 16 European headache centers which already performed real-life data collections on patients treated with erenumab for at least 12 weeks. For the present study, we performed a subgroup analysis on patients with complete data on MMDs at baseline and at weeks 9-12 of treatment. Starting from efficacy thresholds proposed by previous literature, we classified patients into 0-29%, 30-49%, 50-74%, and ≥75% responders according to MMD decrease from baseline to weeks 9-12 of treatment. For each response category, we reported the median MMDs and Headache Impact test-6 (HIT-6) scores at baseline and at weeks 9-12. We categorized the number of residual MMDs at weeks 9-12 as follows: 0-3, 4-7, 8-14, ≥15. We classified HIT-6 score into four categories: ≤49, 50-55, 56-59, and ≥60. To keep in line with the original scope of the ESTEEMen study, calculations were performed in men and women. RESULTS: Out of 1215 patients, at weeks 9-12, 381 (31.4%) had a 0-29% response, 186 (15.3%) a 30-49% response, 396 (32.6%) a 50-74% response, and 252 (20.7%) a ≥75% response; 246 patients (20.2%) had 0-3 residual MMDs, 443 (36.5%) had 4-7 MMDs, 299 (24.6%) had 8-14 MMDs, and 227 (18.7%) had ≥15 MMDs. Among patients with 50-74% response, 246 (62.1%) had 4-7 and 94 (23.7%) 8-14 residual MMDs, while among patients with ≥75% response 187 (74.2%) had 0-3 and 65 (25.8%) had 4-7 residual MMDs. CONCLUSIONS: The present study shows that even patients with good relative response to erenumab may have a clinically non-negligible residual migraine burden. Relative measures of efficacy cannot be enough to thoroughly consider the efficacy of migraine prevention.

Clinical features, disease progression, and use of healthcare resources in a large sample of 866 patients from 24 headache centers: A real-life perspective from the Italian chROnic migraiNe (IRON) project.

OBJECTIVE: To develop a dedicated Italian chronic migraine (CM) database (IRON project) to overcome disease misconceptions, improve clinical administration, reduce patients' burden, and rationalize economic resource allotment. BACKGROUND: Proper CM management requires a comprehensive appraisal of its full clinical, social, and economic complexity. METHODS: In this cross-sectional study, CM patients were screened in 24 certified headache centers with face-to-face interviews. Information on sociodemographic factors, medical history, characteristics of CM, and of prior episodic migraine (EM), and healthcare resource use was gathered using a semistructured web-based questionnaire. RESULTS: A total of 866 CM patients were enrolled. CM started ~20 years after EM onset (age at EM onset 17.4 ± 9.1 vs. age at CM onset 35.3 ± 12.5 [mean ± SD]). CM prophylaxis, used by 430/866 (49.6%) of the patients, was often ineffective, not tolerated, and prematurely discontinued. Medications and diagnostic workup, frequently inappropriate, were mostly subsidized by the Italian national health service. CM patients with ≥25 headache days/month revealed substantial clinical differences and heavier disability and economic burden compared with those with <25 headache days/month. CONCLUSIONS: CM is a heterogeneous headache disorder deserving more in-depth clinical characterization, sharper diagnostic criteria, and tailored treatments. CM registries are expected to improve clinical management, resulting in increased disease awareness, better healthcare resource allocation, and reduced economic burden.

Long-term (48 weeks) effectiveness, safety, and tolerability of erenumab in the prevention of high-frequency episodic and chronic migraine in a real world: Results of the EARLY 2 study.

OBJECTIVE: To evaluate the long-term effectiveness, safety, and tolerability of erenumab in a real-world migraine population, looking for putative predictors of responsiveness. BACKGROUND: Erenumab proved to be effective, safe, and well tolerated in the prevention of episodic migraine (EM) and chronic migraine (CM) in long-term extension studies of double-blind, placebo-controlled trials in patients with no more than two (EM) or three (CM) prior preventive treatment failures. METHODS: A 48-week, multicenter, longitudinal cohort real-life study was conducted at 15 headache centers across eight Italian regions between December 20, 2018 and July 31, 2020. We considered all consecutive patients with high-frequency episodic migraine (HFEM) or CM aged 18-65 years. Each patient was treated with erenumab 70 mg, administered monthly. The dose was switched to 140 mg in nonresponders and in responders who had become nonresponders for at least 4 weeks. Change in monthly migraine days (MMDs) or monthly headache days (MHDs) at Weeks 45-48 compared with baseline was the primary efficacy endpoint. Secondary endpoints encompassed variation in monthly analgesic intake, achievement of a ≥50%, ≥75%, or 100% reduction in migraine or headache days, and any change in the Visual Analogue Scale (VAS) and Headache Impact Test-6 scores (HIT-6) during the same time interval. RESULTS: A total of 242 patients with migraine received at least one dose of erenumab 70 mg and were considered for safety analysis, whereas 221 received a monthly erenumab dose for ≥48 weeks and were included in the effectiveness and safety analysis set. All patients had previously been treated unsuccessfully with ≥3 migraine-preventive medication classes. From baseline to Weeks 45-48, erenumab treatment reduced MMD by 4.3 ± 5.3 (mean ± SD) in patients with HFEM, and MHD by 12.8 ± 8.9 (mean ± SD) in subjects with CM. VAS and HIT-6 scores were decreased by 1.8 ± 1.9 (mean ± SD) and 12.3 ± 11 (mean ± SD) in HFEM, and by 3.0 ± 2.2 (mean ± SD) and 13.1 ± 11.2 (mean ± SD) in CM. Median monthly analgesic intake passed from 11.0 (interquartile range [IQR] 10.0-13.0) to 5 (IQR 2.0-8.0) in HFEM and from 20.0 (IQR 15.0-30.0) to 6.0 (IQR 3.8-10.0) in CM. The ≥50% responders were 56.1% (32/57) in HFEM and 75.6% (124/164) in CM; ≥75% responders were 31.6% (18/57) and 44.5% (73/164); and 100% responders were 8.8% (5/57) and 1.2% (2/164), respectively. At Week 48, 83.6% (137/164) of patients with CM had reverted to EM. Erenumab was safe and well tolerated. Responsiveness to erenumab was positively associated with cutaneous allodynia (OR: 5.44, 95% CI: 1.52-19.41; p = 0.009) in HFEM. In patients with CM, ≥50% responsiveness was positively associated with male sex (OR: 2.99, 95% CI: 1.03-8.7; p = 0.044) and baseline migraine frequency (OR: 1.12, 95% CI: 1.05-1.20; p = 0.001) and negatively associated with psychiatric comorbidities (OR: 0.37, 95% CI: 0.15-0.87; p = 0.023) and prior treatment failures (OR: 0.77, 95% CI: 0.64-0.92; p = 0.004). CONCLUSIONS: Long-term (48-week) erenumab treatment provides sustained effectiveness, safety, and tolerability in real-life patients with HFEM or CM with ≥3 prior preventive treatment failures. The dose of 140 mg was required in most patients along the study and should be taken into consideration as the starting dose. Allodynia (in HFEM), male sex, and baseline migraine frequency (in CM) might represent positive responsiveness predictors. Conversely, psychiatric comorbidities and multiple prior preventive treatment failures could be negative predictors in patients with CM.