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Claudia Altamura,1,2 Nicoletta Brunelli,1,2 Marilena Marcosano,1,2 Alessandro Alesina,1,2 Luisa Fofi,1,2 Fabrizio Vernieri1,2 1Fondazione Policlinico Universitario Campus Bio-Medico, Roma, 00128, Italy; 2Unit of Headache and Neurosonology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, ItalyCorrespondence: Claudia Altamura, Unit of Headache and Neurosonology, Department of Medicine and Surgery, Fondazione Policlinico Campus Bio-Medico, Via Alvaro del Portillo, 200, Roma, 00128, Italy, Tel +3906225411270, Fax +3906225411936, Email c.altamura@policlinicocampus.itAbstract: The new Calcitonin Gene-Related Peptide (CGRP)-targeted therapies have proven high efficacy and tolerability in episodic and chronic migraine. Eptinezumab is a humanized monoclonal antibody that selectively binds CGRP with high affinity. Eptinezumab was approved by the Food and Drug Administration on February 21st, 2020, for the preventive treatment of migraine in adults. It is administered intravenously over 30 minutes with a standard dose of 100 mg and has a T-max of 30 minutes-1 hour and a half-life of 27 days. These pharmacological properties allow for a very rapid onset of effect and a quarterly administration. It is the first time that a preventive treatment for migraine can be offered as an intravenous administration. As the range of therapeutic possibilities in migraine is expanding, the treatment process must include common decision-making, where physicians should explain in detail to patients the different characteristics of treatment options beyond efficacy and side effects. Patients can now express a preference on a range of opportunities: pharmacological versus non-pharmacological approaches, route of administration, frequency of administration, efficacy, rapidity, side effects, costs, the possibility of titration or dosing, and durability of effectiveness at suspension. Also, patient preferences can be influenced by age, country, migraine severity, and earlier experience with CGRP-targeted therapies. Besides, adherence may be influenced by several factors, including route and the schedule of administration. This narrative review describes a new perspective from the patient’s point of view. Clinicians should ally with patients to select treatments that meet each patient’s needs and thus apply a tailored approach, addressing not only headaches. In this way, physicians would care for the patients globally and stand out their preferences on different aspects of treatment. Besides, healthcare professionals shall be aware that patients’ beliefs about therapies are subject to change with increasing experience with new therapeutic approaches.Keywords: eptinezumab, CGRP, preference, adherence

The calcitonin gene-related peptide (CGRP) is a neuropeptide widely distributed throughout the human body. While primarily recognized as a nociceptive mediator, CGRP antagonists are currently utilized for migraine treatment. However, its role extends far beyond this, acting as a regulator of numerous biological processes. Indeed, CGRP plays a crucial role in vasodilation, inflammation, intestinal motility, and apoptosis. In this review, we explore the non-nociceptive effects of CGRP in various body systems, revealing actions that can be contradictory at times. In the cardiovascular system, it functions as a potent vasodilator, yet its antagonists do not induce arterial hypertension, suggesting concurrent modulation by other molecules. As an immunomodulator, CGRP exhibits intriguing complexity, displaying both anti-inflammatory and pro-inflammatory effects. Furthermore, CGRP appears to be involved in obesity development while paradoxically reducing appetite. A thorough investigation of CGRP's biological effects is crucial for anticipating potential side effects associated with its antagonists' use and for developing novel therapies in other medical fields. In summary, CGRP represents a neuropeptide with a complex systemic impact, extending well beyond nociception, thus offering new perspectives in medical research and therapeutics.

(1) Background: Randomized controlled trials and real-life studies demonstrated the efficacy of OnabotulinumtoxinA (OBT-A) for CM prevention. However, no studies specifically addressed its effect on pain's quantitative intensity and qualitative characteristics. (2) Methods: This is an ambispective study: a post-hoc retrospective analysis of real-life prospectively collected data from two Italian headache centers on CM patients treated with OBT-A over one year (i.e., Cy1-4). The primary endpoint was the changes in pain intensity (Numeric Rating Scale, NRS; the Present Pain Intensity (PPI) scale, the 6-point Behavioral Rating Scale (BRS-6)) and quality scale (the short-form McGill Pain Questionnaire (SF-MPQ)) scores. We also assessed the relationship between changes in intensity and quality of pain and disability scale (MIDAS; HIT-6) scores, monthly headache days (MHDs), and monthly acute medication intake (MAMI) (3) Results: We retrieved 152 cases (51.5 years SD 11.3, 80.3% females). From baseline to Cy-4, MHDs, MAMI, NRS, PPI, and BRS-6 scores decreased (consistently p < 0.001). Only the throbbing ( p = 0.004), splitting ( p = 0.018), and sickening ( p = 0.017) qualities of pain collected in the SF-MPQ were reduced. Score variations in MIDAS related to those in PPI scales ( p = 0.035), in the BRS-6 ( p = 0.001), and in the NRS ( p = 0.003). Similarly, HIT-6 score changes related to PPI score modifications ( p = 0.027), in BRS-6 ( p = 0.001) and NRS ( p = 0.006). Conversely, MAMI variation was not associated with qualitative or quantitative pain score modifications except BRS-6 ( p = 0.018). (4) Conclusions: Our study shows that OBT-A alleviates migraine by reducing its impact on multiple aspects, such as frequency, disability, and pain intensity. The beneficial effect on pain intensity seems specific to pain characteristics related to C-fiber transmission and is associated with a reduction in migraine-related disability.

Background: The clinical benefit of galcanezumab, demonstrated in randomized clinical trials (RCTs), remains to be quantified in real life. This study aimed at evaluating the effectiveness, safety and tolerability of galcanezumab in the prevention of high-frequency episodic migraine (HFEM) and chronic migraine (CM) in a real-life setting., Methods: This multicenter prospective observational cohort study was conducted between November 2019 and January 2021 at 13 Italian headache centers. Consecutive adult HFEM and CM patients clinically eligible were enrolled and treated with galcanezumab subcutaneous injection 120 mg monthly with the first loading dose of 240 mg. The primary endpoint was the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM patients after 6 months of therapy (V6). Secondary endpoints were the Numerical Rating Scale (NRS), monthly painkiller intake (MPI), HIT-6 and MIDAS scores changes, ≥50% responder rates (RR), the conversion rate from CM to episodic migraine (EM) and Medication Overuse (MO) discontinuation., Results: One hundred sixty-three patients (80.5% female, 47.1 ± 11.7 years, 79.8% CM) were included. At V6, MMDs reduced by 8 days in HFEM and MHDs by 13 days in CM patients (both p < .001). NRS, MPI, HIT-6 and MIDAS scores significantly decreased (p < .001). Ten patients (6.1%) dropped out for inefficacy and classified as non-responders. Patients with ≥50%RRs, i.e. responders, were 76.5% in the HFEM and 63.5% in the CM group at V6. Among CM patients, the V6 responders presented a lower body mass index (p = .018) and had failed a lower number of preventive treatments (p = .013) than non-responders. At V6, 77.2% of CM patients converted to EM, and 82.0% ceased MO. Adverse events, none serious, were reported in up to 10.3% of patients during evaluation times., Conclusions: Galcanezumab in real life was safe, well tolerated and seemed more effective than in RCTs. Normal weight and a low number of failed preventives were positively associated with galcanezumab effectiveness in CM patients., Trial Registration: ClinicalTrials.gov NCT04803513 .

Botulinum neurotoxin is widely used for the treatment of central and peripherical neurological conditions. Initially used to treat strabismus, over the years its use has been expanded also to spasticity and other neurological disorders. This review summarizes the evidence from the published literature regarding its effect on neuropathic pain. Almost all investigations were performed using onabotulinum toxin type A (BoNT/A). Most studies provided positive results, even though toxin formulation, dose, dilution, injection techniques, and sites are heterogeneous across studies. Future larger, high-quality, specifically designed clinical trials are warranted to confirm botulinum neurotoxin efficacy in neuropathic pain., (Copyright © 2020 Egeo, Fofi and Barbanti.)

Machine learning (ML) is largely used to develop automatic predictors in migraine classification but automatic predictors for medication overuse (MO) in migraine are still in their infancy. Thus, to understand the benefits of ML in MO prediction, we explored an automated predictor to estimate MO risk in migraine. To achieve this objective, a study was designed to analyze the performance of a customized ML-based decision support system that combines support vector machines and Random Optimization (RO-MO). We used RO-MO to extract prognostic information from demographic, clinical and biochemical data. Using a dataset of 777 consecutive migraine patients we derived a set of predictors with discriminatory power for MO higher than that observed for baseline SVM. The best four were incorporated into the final RO-MO decision support system and risk evaluation on a five-level stratification was performed. ROC analysis resulted in a c-statistic of 0.83 with a sensitivity and specificity of 0.69 and 0.87, respectively, and an accuracy of 0.87 when MO was predicted by at least three RO-MO models. Logistic regression analysis confirmed that the derived RO-MO system could effectively predict MO with ORs of 5.7 and 21.0 for patients classified as probably (3 predictors positive), or definitely at risk of MO (4 predictors positive), respectively. In conclusion, a combination of ML and RO - taking into consideration clinical/biochemical features, drug exposure and lifestyle - might represent a valuable approach to MO prediction in migraine and holds the potential for improving model precision through weighting the relative importance of attributes., Competing Interests: Piero Barbanti has received consultancy fees from Allergan, Bayer, electroCore, Lusofarmaco, Merck, Visufarma, and advisory fees from TEVA, Novartis and Eli-Lilly. Gabriella Egeo received travel grants and honoraria from Eli-Lilly, Novartis, New Penta and Ecupharma; Luisa Fofi received travel grants and honoraria from Teva, Eli-Lilly and Novartis; Patrizia Ferroni, Fabio M. Zanzotto, Noemi Scarpato, Antonella Spila, Alessandro Rullo, Raffaele Palmirotta and Fiorella Guadagni report no conflict of interest., (© 2020 The Author(s).)

Background: The study of COMT gene polymorphisms in migraine could be of particular interest since impaired catecholaminergic neurotransmission, namely chronic dopaminergic and noradrenergic hypofunction, is a peculiar migraine trait. In this study, for the first time, we focused on the role of COMT rs4818 genetic variant, the polymorphism most strongly affecting COMT activity, in migraine. This study was conducted in a cohort of carefully clinical characterized Caucasian migraineurs recruited in a specifically dedicated migraine biobank, providing also a replication study on rs4680 polymorphism., Findings: Genotyping of rs4680 and rs4818 Catechol-O-Methyltransferase gene polymorphisms was performed on 380 unrelated migraine patients, and 132 healthy subjects matched for age, gender and race-ethnicity, with no clinical evidence or family history of migraine or other neurological diseases. The rs4680 and rs4818 genotypic frequencies did not deviate from those expected for a population in Hardy-Weinberg equilibrium and did not correlate with demographics or clinical migraine features, even when considering migraine subtypes such as dopaminergic migraine, menstrual migraine, and menstrually related migraine ., Conclusions: COMT genotype does not influence migraine susceptibility or phenotype, even considering rs4818 polymorphism and peculiar clinical subtypes. This finding prompts to go over COMT to explain catecholamine derangement in migraine, exploring enzymes involved in catecholamines synthesis and catabolism, such as monoamine-oxidase, dopamine beta-hydroxylase, tyrosine-hydroxylase or tyrosine-decarboxylase, among others.

The objective and background is to confirm in a double-blind, placebo-controlled study the high triptan response rates we had previously reported in an open study in migraine patients with unilateral cranial autonomic symptoms. In this randomized, double-blind, placebo-controlled study 80 migraineurs with unilateral cranial autonomic symptoms were assigned to receive rizatriptan 10 mg wafer or placebo (ratio 1:1) and treated for a single moderate or severe migraine attack. The primary endpoints were pain freedom at 2 h and total migraine freedom at 2 h. Secondary endpoints included pain relief, no associated symptoms and sustained pain freedom or relief. Significantly more patients reported pain freedom at 2 h after taking rizatriptan (54 %) than after placebo (8 %) (therapeutic gain 46 % [28 %; 64 %]; P < 0.001). Similarly, significantly more patients reported total migraine freedom at 2 h after rizatriptan (51 %) than after placebo (8 %) (therapeutic gain 43 % [26 %; 61 %]; P < 0.001). Rizatriptan was also more effective than placebo on most secondary endpoints. We confirm in a placebo-controlled study our previous data suggesting that the presence of unilateral cranial autonomic symptoms in migraineurs predicts a positive response to triptans, probably owing to intense trigeminal peripheral afferent activation which strongly recruits peripheral neurovascular 5-HT1B/1D receptors. Acute and preventive pharmacological trials in migraine should focus also on this subset of migraine patients.