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Background: Migraine is a debilitating neurological condition linked to various psychological comorbidities. The aims of our study are: 1) to evaluate potential psychopathological differences between patients in treatment with anti-CGRP monoclonal antibodies (SPECIFIC group) and those with onabotulinumtoxin-A/oral pharmacotherapy (Group NON-SPECIFIC), 2) to compare treatment efficacy over time between groups, and examined whether psychopathological comorbidities can influence it. Methods: This is a post-hoc ambispective study: a retrospective analysis of patient-level real-life data prospectively collected for clinical evaluation. We enrolled 102 patients with chronic migraine (CM), 64 in treatment with erenumab or galcanezumab, and 38 with botulinum toxin or oral pharmacotherapies. Psychopathological variables are assessed at baseline, whereas clinical factors over time. Results: The NON-SPECIFIC group showed more pronounced emotion regulation difficulties (DERS, p = 0.001), alexithymia (TAS-20, p = 0.012), and impulsiveness (BIS-11, p = 0.002) with respect to the SPECIFIC group. Moreover, treatment efficacy overtime was more pronounced in the group with anti-CGRP treatment with a reduction of migraine frequency overtime, pain intensity, and improved quality of life up to six months post-treatment. Psychopathological comorbidity did not influence treatment efficacy. Conclusions: Our study highlighted more pronounced psychopathological comorbidities in patients in treatment with NON-SPECIFIC therapies in terms of impulsivity, alexithymia, and emotion regulation. Moreover, treatment efficacy overtime was more pronounced and stable over time in the SPECIFIC group, and psychopathological comorbidity did not influence it. [ABSTRACT FROM AUTHOR]

Abstract Background Anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies have emerged as promising therapeutic options for the treatment of chronic migraine. However, treatment response varies considerably among individuals, suggesting a potential role for genetic factors. This study aimed to identify genetic variants affecting the efficacy of anti-CGRP monoclonal antibody therapy in chronic migraine among the Han Chinese population in Taiwan to enhance treatment precision and to understand the genetic architecture of migraine. Methods We conducted a quantitative trait locus (QTL) association study in patients with chronic migraines from a tertiary medical center in Taiwan using the Taiwan Precision Medicine Array Chip. The patients received fremanezumab or galcanezumab for at least 12 weeks. Treatment efficacy was assessed based on the improvement rate in monthly migraine days. Genetic variants were identified, and their associations with treatment efficacy were examined through quantitative trait loci analysis, linkage disequilibrium studies, and functional annotations using the Gene Ontology database. Results Six single nucleotide polymorphisms (SNPs) relative variants were significantly associated with anti-CGRP therapy response (p

Background: Anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies have emerged as promising therapeutic options for the treatment of chronic migraine. However, treatment response varies considerably among individuals, suggesting a potential role for genetic factors. This study aimed to identify genetic variants affecting the efficacy of anti-CGRP monoclonal antibody therapy in chronic migraine among the Han Chinese population in Taiwan to enhance treatment precision and to understand the genetic architecture of migraine. Methods: We conducted a quantitative trait locus (QTL) association study in patients with chronic migraines from a tertiary medical center in Taiwan using the Taiwan Precision Medicine Array Chip. The patients received fremanezumab or galcanezumab for at least 12 weeks. Treatment efficacy was assessed based on the improvement rate in monthly migraine days. Genetic variants were identified, and their associations with treatment efficacy were examined through quantitative trait loci analysis, linkage disequilibrium studies, and functional annotations using the Gene Ontology database. Results: Six single nucleotide polymorphisms (SNPs) relative variants were significantly associated with anti-CGRP therapy response (p < 1 × 10− 7): rs116870564, rs75244870, rs56216870, rs12938101, rs74655790, and rs149540851. These variants are located in or near genes, including LRRC4C, ATAD2B, and OXR1, which are involved in neuronal development, DNA-dependent ATPase activity, and oxidation-reduction processes, respectively. The rs116870564 variant in LRRC4C showed the strongest association (β = -0.551, p = 6.65 × 10− 9). The functional impact of these variants is attributed to their regulatory effects on gene expression, which are influenced by intron splicing regulation, transcription factors, and changes in chromatin structure. Conclusion: The identification of key genetic markers associated with response to anti-CGRP therapy emphasizes the importance of genetic variability in treatment efficacy. This could lead to more personalized chronic migraine management strategies and tailored therapeutic approaches based on individual genetic profiles. Further research in larger, diverse populations is warranted to validate these findings and refine our understanding of the role of CGRP in chronic migraine pathophysiology. Trial registration: Not applicable. [ABSTRACT FROM AUTHOR]

Objective: The objective of this systematic review and meta-analysis was to determine whether patients with episodic (EM) or chronic migraine (CM), who were treated with anti-CGRP antibodies, showed a reversal from medication overuse (MO) or medication overuse headache (MOH) status at their baseline to non-overuse status. Furthermore, this study aimed to establish which acute headache medication (AHM) categories responded more effectively to anti-CGRP antibodies. Methods: A systematic search was conducted in the PubMed database for relevant studies from January 2013 to September 2023. We included phase three randomized controlled trials to examine the role of anti-CGRP antibodies in patients with EM or CM and their MO status. A meta-analysis was conducted to find the association between anti-CGRP antibodies and the number of EM and CM patients with MO or MOH at baseline that reverted to non-MO status or below the MOH threshold. Results: The initial search yielded a total of 345 studies. After removing duplicates and screening with inclusion criteria, 5 studies fulfilled our conditions. Each study reviewed the response to changes in the MO status of patients after receiving anti-CGRP antibodies, including eptinezumab, fremanezumab, galcanezumab, and erenumab, compared to placebo. Our study analyzed three AHM categories: triptans, simple analgesics, and multiple drugs. The overall relative risk (RR) was 1.44 (95% CI, 1.31 to 1.59; p < 0.001). The RRs for triptans, simple analgesics, and multi-drug groups were 1.71 (95% CI, 1.53 to 1.91; p < 0.001), 1.10 (95% CI, 0.83 to 1.47; p = 0.5), and 1.29 (95%CI 1.14 to 1.46; p < 0.001) respectively. Conclusion: The meta-analysis has shown that anti-CGRP antibodies were statistically significant in transitioning from MO or MOH status to non-MO status or below the MOH threshold (RR = 1.44) for all included studies and all AHM categories except for simple analgesics. Patients from the triptan group had the highest RR of 1.71 with a p-value < 0.001, while the simple analgesics group had an RR of 1.10, however, with a p-value > 0.05. Interestingly, this analysis can be interpreted as that anti-CGRP antibodies might not be effective in reducing simple analgesics use in EM or CM patients. Further studies are needed to investigate these matters. [ABSTRACT FROM AUTHOR]

Background: the aim of this study was to investigate the neurophysiological effect of anti-CGRP monoclonal antibodies on central and peripheral levels in migraine patients. Methods: An observational cohort study in patients with migraine was performed. All subjects underwent Single-Pulse and Paired-Pulse Transcranial Magnetic Stimulation, as well as a Pressure Pain Threshold assessment. The same protocol was repeated three and four months after the first injection of anti-CGRP monoclonal antibodies. Results: A total of 11 patients with a diagnosis of migraine and 11 healthy controls were enrolled. The main findings of this study are the significant effects of anti-CGRP mAb treatment on the TMS parameters of intracortical inhibition and the rise in the resting motor threshold in our group of patients affected by resistant migraine. The clinical effect of therapy on migraine is associated with the increase in short-interval intracortical inhibition (SICI), resting motor threshold (RMT), and Pressure Pain Threshold (PPT). In all patients, all clinical headache parameters improved significantly 3 months after the first injection of mAbs and the improvement was maintained at the 1-month follow-up. At baseline, migraineurs and HCs had significant differences in all TMS parameters and in PPT, while at follow-up assessment, no differences were observed on RMT, SICI, and PPT between the two groups. After anti-CGRP monoclonal antibody injection, a significant increase in the intracortical inhibition, in the motor threshold, and in the Pressure Pain Threshold in critical head areas was observed in patients with migraine, which was related to significant clinical benefits. Conclusions: Anti-CGRP monoclonal antibodies improved clinical and neurophysiological outcomes, reflecting a normalization of cortical excitability and peripheral and central sensitization. By directly acting on the thalamus or hypothalamus and indirectly on the trigeminocervical complex, treatment with anti-CGRP monoclonal antibodies may modulate central sensorimotor excitability and peripheral sensitization pain. [ABSTRACT FROM AUTHOR]

Background Every year, 15% of the global population suffers from migraines, making it a substantial social burden with a significant negative impact on quality of life. This systematic review aims to evaluate the comparative efficacy, safety profiles, cost-effectiveness, and additional dimensions of two prominent chronic migraine (CM) prophylactics: OnabotulinumtoxinA (BoNT-A) and calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs). Methods Using specific keywords related to onabotulinumtoxinA and anti-CGRP treatments for migraines, we conducted a comprehensive search of electronic databases, including PubMed and the Cochrane Library, spanning from 2015 to 2024. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results Our analysis included 13 publications that revealed notable decreases in migraine frequency and severity with both treatment modalities. While CGRP mAbs demonstrated significant reductions in migraine days with minimal adverse effects, BoNT-A emerged as a superior option due to its cost-efficiency and higher patient satisfaction. Both treatments exhibited mild short-term side effects; however, CGRP mAbs were occasionally associated with extended periods of constipation. The simplicity of adherence, with either monthly self-administered injections of CGRP mAbs or quarterly physician-administered BoNT-A injections, further distinguished these treatments. BoNT-A, in particular, was recognized for enhancing overall quality of life and performance metrics. Conclusions BoNT-A stands out as a low-cost intervention effective across various migraine categories, including chronic, episodic, unilateral, and vestibular types, significantly alleviating pain severity and reducing migraine episode frequency. The findings underscore that both CGRP mAbs and BoNT-A are comparably effective for CM prophylaxis. However, BoNT-A is especially beneficial for patients ineligible for CGRP mAb therapy or those requiring localized treatment with minimal systemic exposure risk. For patients resistant or refractory to BoNT-A, combining it with CGRP mAbs may maximize therapeutic benefits due to their distinct modes of action. The efficacy, safety, and cost-benefit analyses of these medications may help clinicians make more informed treatment decisions based on the study's findings.

Introduction: Limited clinical evidence is available regarding the potential effectiveness of anti‐CGRP monoclonal antibodies for the preventive treatment of migraine with aura. Aim of the Study: This observational study involved a series of migraine patients affected by either migraine with or without aura, who were investigated for any changes in their frequencies and their migraine aura attack characteristics observed during treatment with anti‐CGRP Mabs over a 1‐year period. Patients and Methods: Twelve migraine patients were included, seven of whom were treated with erenumab, 2 with fremanezumab, and 3 with galcanezumab. Clinical data were collected at baseline, which were defined as 3 months prior to the initiation of treatment, and thereafter at each trimester, over the 1‐year treatment period. The parameters included the number of headache and migraine days/month, the frequency of aura episodes, the number of days with acute drug intakes/month, and the scores from the migraine disability status scale (MIDAS), and the Headache Impact Test 6 (HIT‐6). Results: Anti‐CGRP Mbs antibodies induced significant decreases in mean headache and migraine without aura days per month, the number of days with medication intake, as well as MIDAS and HIT‐6 scores (p < 0.0001). In contrast, the anti‐CGRP Mab treatment did not appear to impact the frequency of migraine with aura attacks but seemed to reduce both the intensity and the duration of headache phases of migraine aura. Furthermore, some migraine patients referred to having aura attacks without headache over the course of the treatment period. Conclusions: Based on the above findings, we hypothesize that anti‐CGRP Mabs did not influence neuronal and vascular events related to cortical spreading depression (CSD) which is considered the pathophysiological substrate of aura. Conversely, these antibodies are able to counteract, via their peripheral mechanisms of action, the sensitization of the trigemino‐vascular pathway which is triggered by CSD. This aforementioned might explain why in our patients, migraine aura attacks remained unchanged in their frequencies, but the headache phases were either reduced or absent. [ABSTRACT FROM AUTHOR]

Since the high burden of chronic migraine (CM), it is challenging to identify the best prevention treatment. Based on the preclinical evidence about the different therapeutic targets of onabotulinumtoxinA (BT-A), acting on C-fibers, and anti-CGRP monoclonal antibodies (mAbs), acting on Aδ-fibers, the rationale of using alternative or combining therapies has been hypothesized. Until now, the association of BT-A and mAbs has been poorly investigated. This study evaluated whether mAbs are effective and safe in CM patients previously treated with BT-A, either as an alternative or add-on treatment. We enrolled 47 patients: according to the response to BT-A treatment, patients were defined as non-responder (NR) and partial-responder (PR). NR were shifted to mAbs. PR were randomly divided into those who added mAbs therapy (PR-P) and those who shifted treatment (PR-S), interrupting BT-A. Clinical variables were collected at baseline, after three and six months. Study results evidenced the efficacy of mAbs in improving clinical outcomes in CM patients, with a better response in the PR group. No statistically significant differences in clinical changes were observed between PR-P and PR-S groups. No safety concerns were raised in combined treatments. Preventive prophylaxis with mAbs is effective, even in difficult to treat CM patients. Further studies, with larger samples, are needed to highlight a potential additive effect of combined therapies. [ABSTRACT FROM AUTHOR]

The aim of the present study was to evaluate whether previous preventive treatment with onabotulinumtoxin-A might influence subsequent clinical response following a switch to anti-CGRP monoclonal antibodies (mAbs). The present retrospective study was conducted at the Headache Centre—Neurology Clinic at the Spedali Civili Hospital of Brescia between November 2018 and May 2023. The primary objective was to assess clinical outcome (monthly headache days (MHDs), monthly migraine days (MMDs), mean analgesics consumption, and clinical disability according to Migraine Disability Assessment (MIDAS)) following three months (T3) of preventive treatment with anti-CGRP mAbs comparing patients who did and those who did not previously receive treatment with Onabotulinumtoxin-A. Moreover, we aimed to evaluate whether the clinical response to anti-CGRP mAbs was affected by the number of previous Onabotulinumtoxin-A administrations. At T3, compared to Onabotulinumtoxin-A naïve patients, patients who previously received Onabotulinumtoxin-A documented fewer MMDs (3.3 ± 3.7 versus 5.2 ± 5.0; p = 0.017) and a lower MIDAS score (23.2 ± 20.9 versus 37.4 ± 39.6; p = 0.013). Patients who received at least 3 onabotulinumtoxin-A administrations documented, at T3, lower MMDs compared to those who received fewer cycles (respectively, 2.1 ± 2.7 vs. 6.5 ± 4.4; p = 0.024). In conclusion, according to our data, previous treatment with onabotulinumtoxin-A might improve subsequent response to anti-CGRP mAbs preventive treatment. [ABSTRACT FROM AUTHOR]

Chronic migraine is a disabling neurovascular disorder that ranks amongst the top causes of years lived with disability worldwide. The duration and the frequency of migraine affect cognitive and affective domains, inducing worsening of memory, executive functions, orientation and causing anxiety. Population-based studies report a worrying level of resistance to treatments. Therefore, this study aims: 1) to assess efficacy of monoclonal antibodies (mAbs) directed towards the calcitonin gene-related peptide (CGRP) or its receptor (CGRP-R) for chronic migraine resistant to current preventatives; 2) to design a clinical trial protocol to evaluate the efficacy and safety of combination therapy utilizing anti-CGRP/CGRP-R together with onabotulinumtoxin A in patients suffering from resistant chronic migraine; 3) to provide a molecular rationale for combination therapy. A controlled trial is warranted as pooled analysis of real-world data from our group highlighted that combined treatment provides ≥50% reduction vs. baseline (onabotulinumtoxin A) of monthly headache days (MHDs) in up to 58.8% of patients, but there has been only sparse application of this combined therapy to date. The mAbs chosen are: erenumab, because its combination effect with onabotulinumtoxin A improved symptoms in 65% of patients; eptinezumab, due to its faster action. The results highlight that early diagnosis of migraine improves therapeutic outcomes with mAbs alone, confirming their effectiveness and the need for an adequately powered clinical trial evaluating the safety and potential superior effectiveness of eptinezumab/erenumab and onabotulinumtoxin A together.

Background: Clinical trials on anti-calcitonin gene-related peptide monoclonal antibodies poorly investigated their impact on migraine accompanying symptoms. Objective: To evaluate the impact of basal accompanying symptoms on anti-CGRP monoclonal antibodies treatment response and their evolution after six months of treatment in migraine patients. Methods: Patients with migraine diagnosis seen in the Headache Clinic and treated with erenumab, galcanezumab or fremanezumab were prospectively recruited. They completed a daily eDiary which provided data on headache frequency and the following accompanying symptoms of each day: photophobia, phonophobia, nausea, dizziness, and aura. Patients were classified as responders or non-responders based on 50% or greater reduction in headache days per month at month 6 (≥50% response rate). Accompanying symptoms ratios based on headache days per month were assessed per patient at baseline and after three and six months. Comparisons for basal characteristics, basal accompanying symptoms ratios and their evolution after six months between responders and non-responders were performed. Results: One hundred and fifty-eight patients were included, 44% (69/158) showed ≥50% response rate after six months. A significant reduction in headache days per month in both groups was found at month 6 (−9.4 days/month in ≥50% response rate group; p < 0.001, −2.2 days/month in <50% response rate group; p = 0.004). Additionally, significant decreases in photophobia (−19.5%, p < 0.001), phonophobia (−12.1%, p = 0.010) and aura ratios (−25.1%, p = 0.008) were found in ≥50% response rate group. No statistically significant reductions were found in nausea and dizziness in any group since their reduction was correlated with the decrease in headache days per month. Higher photophobia ratios at baseline were predictive of an increased response between months 3 and 6 (Incidence Risk Ratio = 0.928, p = 0.040). Conclusions: The days per month with photophobia, phonophobia and aura decreased at a higher rate than headache days per month after six months in the ≥50% response group. Higher photophobia ratios were associated with higher response rates between three and six months. It could indicate an involvement of peripheral CGRP in photophobia as well as a central modulation of migraine through these treatments which mainly act on the periphery. [ABSTRACT FROM AUTHOR]

Headache is one of the most common neurological symptoms associated with coronavirus disease 19 (COVID-19), which can mimic primary headache phenotypes. COVID-19 and quarantine have affected both the course of primary headache and patient care strategies. The safety of migraine treatment with anti-CGRP (calcitonin gene-related peptides) monoclonal drugs has become important. Another challenge posed by the introduction of mass vaccination is vaccine-related headache, the most common neurological adverse event, and a less common complication, cerebral venous thrombosis. The article provides a brief overview of COVID-19 induced headache and its features, vaccination-induced headache, the impact of COVID-19 and quarantine on primary headache, the safety of anti-CGRP monoclonals, and the advantages and disadvantages of remote consultations on primary headaches.

Objective: To report the effcacy of different anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) on headache frequency, intensity, and duration. Background: Blockade of CGRP receptors or neuropeptide with anti-CGRPmAbs have been successfully used for several years for the prevention of chronic and episodic migraine. The response is usually assessed by improvement seen in the number of days with headache per month. However, clinical praxis indicates that sole reliance on the frequency of headaches might be insuffcient to interpret the effcacy of these treatments. Methods: Retrospective review of a case with a meticulous headache diary who has tried three different anti-CGRP mAbs for chronic migraine prevention. Results: The patient has been diagnosed with chronic migraine and was first treated with erenumab, followed by fremanezumab and thereafter galcanezumab due to several reasons. In addition to significant improvement in all three parameters analyzed with anti-CGRP mAb treatment, the most important and valuable effect on the patient's quality of life was decreased duration and frequency of headaches. At present, the patient is receiving fremanezumab treatment with an excellent tolerability. Conclusion: There is a clear need for careful follow-up and detailed daily records of headaches showing the frequency, duration, and severity for the evaluation of anti-CGRP mAbs treatment. This study shows the importance of this information in order formedical professionals tomake an informed decision regarding the best course of anti-CGRP mAbs treatment in cases of side effects or lack of effcacy. [ABSTRACT FROM AUTHOR]

Abstract Background Resistant chronic migraine is a highly disabling condition which is very difficult to treat. The majority of the treatments for migraine prophylaxis are nonspecific and present weak safety profiles, leading to low adherence and discontinuation. Currently, monoclonal antibodies (mAb) targeting the trigeminal sensory neuropeptide, calcitonin gene-related peptide (CGRP), are available for migraine prophylaxis being the first drugs developed specifically to target migraine pathogenesis. The main objective of the current work is to carry out a systematic review of randomised controlled trials that specifically analyse the effectivity and safety of anti-CGRP mAb, comparatively to placebo, in patients with resistant chronic migraine and possibly fill the literature gap or be a source of information to health professionals. Additionally the current knowledge on migraine, particularly resistant chronic migraine, was revisited and summarised. Methods Literature search was carried out on MEDLINE, Scopus, Science Direct and ClinicalTrials.gov database, from inception to December 2021. Articles were selected according to prespecified criteria of inclusion and exclusion. Efficacy and safety outcomes included were: change from baseline in monthly migraine days (MMD); ≥50% reduction of MMD values from baseline; change from baseline in monthly acute migraine-specific medication days (MAMD); Migraine-specific Quality of Life Questionnaire (MSQ); and registered adverse events. Additionally, we used the Cochrane risk of bias tool (RoB 2) to assess the risk of bias of the included studies. Results Four studies were included in this systematic review, involving 2811 resistant chronic migraine patients, 667 in a study using erenumab, 838 in a study using fremanezumab and 1306 in two studies using galcanezumab. When compared to placebo, all investigated anti-CGRP mAb and respective doses demonstrate effectiveness in decreasing MMD, reducing acute medication use and improving the MSQ scores, including, sometimes, reversion of chronic to episodic migraine (efficacy outcomes). Regarding the safety outcomes, the number and type of adverse events did not differ between anti-CGRP mAb-treated and placebo groups. Conclusions Anti-CGRP or anti-CGRP receptor monoclonal antibodies are a promising preventive migraine therapy which can be particularly useful for resistant chronic migraine patients.

ObjectiveTo report the efficacy of different anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) on headache frequency, intensity, and duration.BackgroundBlockade of CGRP receptors or neuropeptide with anti-CGRP mAbs have been successfully used for several years for the prevention of chronic and episodic migraine. The response is usually assessed by improvement seen in the number of days with headache per month. However, clinical praxis indicates that sole reliance on the frequency of headaches might be insufficient to interpret the efficacy of these treatments.MethodsRetrospective review of a case with a meticulous headache diary who has tried three different anti-CGRP mAbs for chronic migraine prevention.ResultsThe patient has been diagnosed with chronic migraine and was first treated with erenumab, followed by fremanezumab and thereafter galcanezumab due to several reasons. In addition to significant improvement in all three parameters analyzed with anti-CGRP mAb treatment, the most important and valuable effect on the patient's quality of life was decreased duration and frequency of headaches. At present, the patient is receiving fremanezumab treatment with an excellent tolerability.ConclusionThere is a clear need for careful follow-up and detailed daily records of headaches showing the frequency, duration, and severity for the evaluation of anti-CGRP mAbs treatment. This study shows the importance of this information in order for medical professionals to make an informed decision regarding the best course of anti-CGRP mAbs treatment in cases of side effects or lack of efficacy.

We sought to assess the effectiveness of combining dual therapy with onabotulinumtoxinA (BTX) add-on to anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (anti-CGRP MAbs) in treatment-refractory patients with chronic migraine (CM). We retrospectively reviewed the medical files of 19 treatment-refractory patients with CM who had failed to two oral migraine preventatives, at least three consecutive BTX cycles (less than 30% response rate), at least three consecutive sessions with either fremanezumab or erenumab (less than 30% response rate), and were eventually switched to dual therapy with BTX add-on to any of the already-given anti-CGRP MAbs. We then assessed from baseline to each monotherapy or dual intervention predefined efficacy follow-up the changes in the following efficacy outcomes: (i) monthly headache days (MHD), (ii) monthly days with moderate/severe peak headache intensity, and (iii) monthly days with intake of any acute headache medication. Response (50% reduction in MHD) rates, safety, and tolerability were also determined. In the majority of cases (n = 14), dual targeting proved effective and was associated with clinically meaningful improvement in all efficacy variables; 50% response rates (also disability and QOL outcomes) coupled with favorable safety/tolerability. Our results advocate in favor of the view that dual therapy is effective and should be considered in difficult-to-treat CM patients who have failed all available monotherapies. [ABSTRACT FROM AUTHOR]

Objective: Cranial autonomic symptoms (CAS), including conjunctival injection, tearing, nasal congestion or rhinorrhea, eyelid edema, miosis or ptosis, and forehead or facial sweating ipsilateral to headache, are often reported by patients with migraine during headache attacks. CAS is a consequence of the activation of the trigeminovascular system, which is the target of monoclonal antibodies acting on the CGRP pathway. Therefore, we hypothesized that patients with CAS might have higher trigeminovascular activation than those without CAS leading to a better response to anti-CGRP treatments. Methods: We performed a prospective analysis including patients with episodic or chronic migraine treated with anti-CGRP monoclonal antibodies (i.e., erenumab, fremanezumab, and galcanezumab) between 2019 and 2021. The observation period included a 12-week baseline before treatment with anti-CGRP antibodies and a 12-week treatment follow-up. We evaluated the prevalence of CAS in our cohort and compared disease characteristics and treatment response (i.e., 12-week monthly headache days and 0-29, 30-49, 50-74, 75-99, and 100% monthly headache days reduction from baseline) among patients with and without CAS using the X² test, Kruskal-Wallis test, and Mann-Whitney U-test. Results: Out of 136 patients, 88 (65%) had CAS. Both patients with and without CAS reported a significant decrease in monthly headache days from baseline. During the 12-week follow-up, the median difference in monthly headache days from baseline was higher in patients with CAS (-10, IQR-15 to-6) than in those without CAS (6, IQR 12 to 3; P = 0.009). However, the proportions of patients with 0 to 29, 30 to 49, 50 to 74, 75 to 99, and 100% response rates did not differ between the two groups. Conclusions: In our cohort, the presence of CAS was associated with a greater response tomonoclonal antibodies targeting the CGRP pathway. CAS could be a clinical marker of trigeminovascular activation and thus be related to a better response to CGRP treatments. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Chronic migraine (CM) is a great challenge for physicians dealing with headaches. Despite the introduction of the monoclonal antibodies (mAbs) acting against the calcitonin gene-related peptide (CGRP) that has revolutionized the treatment of CM, some patients still experience an incomplete relief. So, the association of two preventive treatments may be a reliable option for these patients. So, onabotulinumtoxinA (BT-A) and anti-CGRP mAbs may be used together, and some pre-clinical and clinical evidence of an additive action of the 2 drugs is emerging. In particular, since BT-A acts mainly on C-fibers and anti-CGRP mAbs on Aδ ones, their association may prevent the wearing-off phenomenon of BT-A, thus giving an additional benefit in those patients experiencing an incomplete response to BT-A alone. Despite this, the clinical studies available in the literature have a small sample size, often a retrospective design, and are heterogeneous in terms of the outcomes chosen. Considering this, the evidence of a favorable effect of the association between BT-A and anti-CGRP mAbs is still scarce. Furthermore, this association is explicitly forbidden by many National regulatory agencies, due to the high costs of both treatments. Anyway, their association could help in reducing the burden associated with the most severe cases of CM, thus relieving the direct and indirect costs of this condition. More well-designed studies with big samples are needed to unveil the real therapeutic gain of this association. Moreover, pharmacoeconomics studies should be performed, to assess the economic suitability of this association. [ABSTRACT FROM AUTHOR]

OnabotulinumtoxinA, targeting the CGRP machinery, has been approved for the last two decades for chronic migraine prevention. The recently approved monoclonal antibodies (mAbs) directed towards the calcitonin gene-related peptide (CGRP) pathway open a new age for chronic migraine control. However, some 40% patients suffering from chronic migraine is still resistant to treatment. The aim of this work is to answer the following PICOS (participants intervention comparator outcome study design) question: Is there evidence of efficacy and safety of the combined administration of anti-CGRP mAbs and onabotulinumtoxinA in chronic migraine? A systematic review and meta-analysis [Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 recommendations] was made up to 19 April 2022. The results are encouraging: the combined treatment proved to afford ≥50% monthly headache days (MHDs)/frequency reduction respect to baseline in up to 58.8% of patients; in comparison, anti-CGRP mAbs reduce MHDs of 1.94 days from baseline and botulinum toxin of 1.86 days. Our study demonstrates for the first time that the combination therapy of onabotulinumtoxinA with anti-CGRP mAbs affords a reduction of 2.67 MHDs with respect to onabotulinumtoxinA alone, with moderate certainty of evidence. Adequately powered, good-quality studies are needed to confirm the response to combination therapy in terms of efficacy and safety. PROSPERO registration: CRD42022313640. [ABSTRACT FROM AUTHOR]

Headache is one of the most common neurological symptoms as-sociated with coronavirus disease 19 (COVID-19), which can mimic primary headache phenotypes. COVID-19 and quarantine have affected both the course of primary headache and patient care strategies. The safety of migraine treatment with anti-CGRP (calcitonin gene-related peptides) monoclonal drugs has become important. Another challenge posed by the introduction of mass vaccination is vaccine-related headache, the most common neu-rological adverse event, and a less common complication, cere-bra1 venous thrombosis. The article provides a brief overview of COVID-19 induced headache and its features, vaccination-in-duced headache, the impact of COVID-19 and quarantine on pri-mary headache, the safety of anti-CGRP monoclonals, and the advantages and disadvantages of remote consultations on pri-mary headaches. [ABSTRACT FROM AUTHOR]

ObjectiveCranial autonomic symptoms (CAS), including conjunctival injection, tearing, nasal congestion or rhinorrhea, eyelid edema, miosis or ptosis, and forehead or facial sweating ipsilateral to headache, are often reported by patients with migraine during headache attacks. CAS is a consequence of the activation of the trigeminovascular system, which is the target of monoclonal antibodies acting on the CGRP pathway. Therefore, we hypothesized that patients with CAS might have higher trigeminovascular activation than those without CAS leading to a better response to anti-CGRP treatments.MethodsWe performed a prospective analysis including patients with episodic or chronic migraine treated with anti-CGRP monoclonal antibodies (i.e., erenumab, fremanezumab, and galcanezumab) between 2019 and 2021. The observation period included a 12-week baseline before treatment with anti-CGRP antibodies and a 12-week treatment follow-up. We evaluated the prevalence of CAS in our cohort and compared disease characteristics and treatment response (i.e., 12-week monthly headache days and 0–29, 30–49, 50–74, 75–99, and 100% monthly headache days reduction from baseline) among patients with and without CAS using the χ2 test, Kruskal–Wallis test, and Mann–Whitney U-test.ResultsOut of 136 patients, 88 (65%) had CAS. Both patients with and without CAS reported a significant decrease in monthly headache days from baseline. During the 12-week follow-up, the median difference in monthly headache days from baseline was higher in patients with CAS (-10, IQR−15 to−6) than in those without CAS (6, IQR 12 to 3; P = 0.009). However, the proportions of patients with 0 to 29, 30 to 49, 50 to 74, 75 to 99, and 100% response rates did not differ between the two groups.ConclusionsIn our cohort, the presence of CAS was associated with a greater response to monoclonal antibodies targeting the CGRP pathway. CAS could be a clinical marker of trigeminovascular activation and thus be related to a better response to CGRP treatments.

Background: Resistant chronic migraine is a highly disabling condition which is very difficult to treat. The majority of the treatments for migraine prophylaxis are nonspecific and present weak safety profiles, leading to low adherence and discontinuation. Currently, monoclonal antibodies (mAb) targeting the trigeminal sensory neuropeptide, calcitonin gene-related peptide (CGRP), are available for migraine prophylaxis being the first drugs developed specifically to target migraine pathogenesis. The main objective of the current work is to carry out a systematic review of randomised controlled trials that specifically analyse the effectivity and safety of anti-CGRP mAb, comparatively to placebo, in patients with resistant chronic migraine and possibly fill the literature gap or be a source of information to health professionals. Additionally the current knowledge on migraine, particularly resistant chronic migraine, was revisited and summarised. Methods: Literature search was carried out on MEDLINE, Scopus, Science Direct and ClinicalTrials.gov database, from inception to December 2021. Articles were selected according to prespecified criteria of inclusion and exclusion. Efficacy and safety outcomes included were: change from baseline in monthly migraine days (MMD); ≥50% reduction of MMD values from baseline; change from baseline in monthly acute migraine-specific medication days (MAMD); Migraine-specific Quality of Life Questionnaire (MSQ); and registered adverse events. Additionally, we used the Cochrane risk of bias tool (RoB 2) to assess the risk of bias of the included studies. Results: Four studies were included in this systematic review, involving 2811 resistant chronic migraine patients, 667 in a study using erenumab, 838 in a study using fremanezumab and 1306 in two studies using galcanezumab. When compared to placebo, all investigated anti-CGRP mAb and respective doses demonstrate effectiveness in decreasing MMD, reducing acute medication use and improving the MSQ scores, including, sometimes, reversion of chronic to episodic migraine (efficacy outcomes). Regarding the safety outcomes, the number and type of adverse events did not differ between anti-CGRP mAb-treated and placebo groups. Conclusions: Anti-CGRP or anti-CGRP receptor monoclonal antibodies are a promising preventive migraine therapy which can be particularly useful for resistant chronic migraine patients. [ABSTRACT FROM AUTHOR]

Migraine is a common chronic neurological disease. Many neurogenic, vascular, autonomic, and other mechanisms at different levels of the central and peripheral nervous systems are assumed to be implicated in the pathophysiology of headache and other manifestations of migraine. Advances in understanding the neurobiology of migraine have made it possible to clarify the main patterns of neurogenic-vascular relationships that explain the leading clinical manifestations of migraine, as well as to identify some biological markers that have triggered the creation of new targeted therapies for the disease. This review is dedicated to the latest advances in studying the pathophysiology of migraine and to new pharmacological approaches to its treatment.

Background: Patient-Reported Outcomes (PROs) have been developed to numerically quantify disability, impact and quality of life. They have been widely used in migraine clinical trials. However, we still do not know which PRO more accurately reflects preventive treatment response from a patient's perspective or which one may help us with treatment decisions in clinical practice. They have been used to enforce the efficacy results in clinical trials and real-world evidence so far. The aim of this study was to analyze which PROM is (1) better correlated with all primary efficacy endpoints and (2) which one is better associated with treatment continuation with CGRP-mAbs at week-12, which is usually the moment when this decision is made. Methods: Patients with migraine who had received 3 administrations of CGRP-mAbs were evaluated in this prospective cohort study. Primary efficacy outcomes considered: a change in migraine days (MMD), headache days (MHD), pain intensity (INT), acute medication days (AMD) and 50% responder rate. The Spearman coefficient (rs) was the measure used for quantify the strength of the correlation between PROMs and treatment efficacy outcomes changes. A stepwise logistic regression identified which PROM was independently associated with treatment continuation at week-12. Results: 263 patients completed 12 weeks of treatment. The efficacy outcomes and PROMs scores were statistically significantly reduced at week-12 for all patients. The role function-restrictive (RFR) domain of the Migraine-Specific Quality of Life (MSQ) questionnaire was statistically significantly correlated with all primary efficacy outcomes. Relative changes in MSQ total score (OR[95%]: 0.840[0.619-0.973]; p=0.037) and Patient Global Impression of Change (PGIC) scale (OR[95%]: 15.569[6.254-31.533]; p<0.001) were the PROMs associated with treatment continuation as independent factors at week-12. Conclusions: Changes in MSQ questionnaire and PGIC scale at week-12 were the PROMs with higher association with CGRP-mAbs response from a patient's perspective and medical decision-taking. [ABSTRACT FROM AUTHOR]

Abstract Background Chronic migraine is a disabling condition that is currently underdiagnosed and undertreated. In this narrative review, we discuss the future of chronic migraine management in relation to recent progress in evidence-based pharmacological treatment. Findings Patients with chronic migraine require prophylactic therapy to reduce the frequency of migraine attacks, but the only currently available evidence-based prophylactic treatment options for chronic migraine are topiramate and onabotulinumtoxinA. Improved prophylactic therapy is needed to reduce the high burden of chronic migraine in Italy. Monoclonal antibodies that target the calcitonin gene-related peptide (CGRP) pathway of migraine pathogenesis have been specifically developed for the prophylactic treatment of chronic migraine. These anti-CGRP/R monoclonal antibodies have demonstrated good efficacy and excellent tolerability in phase II and III clinical trials, and offer new hope to patients who are currently not taking any prophylactic therapy or not benefitting from their current treatment. Conclusions Treatment of chronic migraine is a dynamic and rapidly advancing area of research. New developments in this field have the potential to improve the diagnosis and provide more individualised treatments for this condition. Establishing a culture of prevention is essential for reducing the personal, social and economic burden of chronic migraine.

Background and purpose: Monoclonal antibodies targeting CGRP or its receptor, anti‐CGRP mAbs, are proven to be effective treatments in migraine prevention. Real‐world evidence studies assessing their efficacy are scarce. Methods: Our objective was to assess the efficacy of anti‐CGRP mAbs in our clinical cohort resistant to onabotulinumtoxinA. We prospectively analyzed ≥50% response rate in patients who initiated treatment with anti‐CGRP mAbs and who were partial or nonresponders to onabotulinumtoxinA. Results: One hundred fifty‐five patients completed treatment with anti‐CGRP mAbs at 3 months of follow‐up. No statistically significant differences were found in ≥50% response in headache frequency in patients with prior onabotulinumtoxinA treatment partial or complete failure. Regarding dual therapy with onabotulinumtoxinA and anti‐CGRP mAbs, no statistically significant differences were found in ≥50% response in headache frequency between monotherapy or dual therapy. Conclusions: Patients with prior treatment failure or partial efficacy to onabotulinumtoxinA respond to anti‐CGRP mAbs. After 3 months, in our cohort, dual therapy does not seem to add more benefit than anti‐CGRP mAbs in monotherapy. [ABSTRACT FROM AUTHOR]

Introduction and objective: Monoclonal antibodies targeting the calcitonin gene-related peptide pathway (anti-CGRP mAbs) have shown promising efficacy in randomised clinical trials for the prevention of episodic and chronic migraine, but no head-to-head comparisons with established treatments are available. We aimed to examine absolute differences in benefit-risk ratios between anti-CGRP mAbs, topiramate and propranolol for the prevention of episodic migraine and between anti-CGRP mAbs, topiramate and onabotulinumtoxinA for the prevention of chronic migraine using a likelihood to help versus harm analysis. Methods: The number of patients needed to be treated for a patient to achieve ≥ 50% reduction in migraine days (NNTB50%) was used as an effect size metric of efficacy. The number of patients needed to be treated for a patient to experience an adverse event that led to treatment discontinuation (NNTHD-AE) was used as a measure of risk. Likelihood to help versus harm values – which are the ratios of NNTH:NNTB – were calculated using data from phase 3 randomised clinical trials. Results: All agents tested were more likely to be beneficial than harmful (likelihood to help versus harm > 1) with the exception of topiramate at 200 mg per day for the prevention of episodic migraine. Anti-CGRP mAbs in all tested doses had higher LHH values than propranolol or topiramate for episodic migraine and onabotulinumtoxinA or topiramate for chronic migraine prevention. Fremanezumab had the highest LHH ratio in episodic migraine and galcanezumab in chronic migraine. Conclusion: This analysis showed that anti-CGRP mAbs exhibit a more favourable benefit-risk ratio than established treatments for episodic and chronic migraine. Head-to-head studies are needed to confirm these results. [ABSTRACT FROM AUTHOR]

Introduction: Anti-calcitonin gene-related peptide antibodies proved effective in the preventive treatment of chronic migraine. In this open label study, we aim to assess the effects of erenumab administration on neurophysiological and biomolecular profiles in a representative cohort of chronic migraine patients.Methods: Forty patients with a history of chronic migraine for at least 12 months prior to enrollment, and previous failure of at least two different preventive therapies, were enrolled. After a 1-month observation period (T0), patients were treated with erenumab 70 mg s.c. (every 28 days) for a total of three administrations. At week 12, they returned for the end-of-protocol visit (T3). At T0 and T3, patients underwent recording of clinical features, recording of single stimulus (RTh), temporal summation (TST) thresholds of the nociceptive withdrawal reflex, venous blood sampling for miR-382-5p, and miR-34a-5p quantification.Results: At T3, 31 patients (77.5%) qualified as 30% Responders (reduction in monthly migraine days by at least 30% in the last 4-week observation period). RTh (T0: 15.4 ± 8.1 mA, T3: 19.7 ± 8.2 mA) as well as TST (T0: 11.2 ± 5.8 mA, T3: 13.4 ± 5.0 mA) significantly increased at T3 in 30% Responders (p = 0.001 for both), while we did not observe significant changes in NON-responder patients. MiR-382-5p and miR-34a-5p levels were significantly lower after erenumab administration in the overall study population (p = 0.015, and p = 0.001, respectively), without significant differences between 30% Responder and NON-responder groups.Conclusions: Different migraine phenotypes, characterized by different treatment susceptibility, may exist as suggested by the divergent behavior between neurophysiological and biomolecular findings in 30% Responder vs. NON-responder patients.The study protocol was registered at clinicaltrials.gov (NCT04361721). [ABSTRACT FROM AUTHOR]

Migraine is one of the most frequent disabling neurological disorder with a major impact on these patients' quality of life. Current profylactic drugs for migraine treatment contain betablockers, calcium channel blockers, antiepileptic drugs, antidepressants. All these drugs are non-specific for the migraine therapy. Monoclonal antibodies acting on the calcitonin gene-related peptide (CGRP) or on its receptor are newK drugs targeted for migraine. EHF (European Headache Federation) and AHS (American Headache Society) guidelines contain the usage of monoclonal antibodies for migraine prevention [ABSTRACT FROM AUTHOR]

Medication overuse headache (MOH) is a secondary headache characterized by frequent use of acute or symptomatic migraine medications at a sufficient frequency to transform patients from episodic to chronic migraine. MOH represents a significant medical problem, with a serious burden on patients' lives and on society as a whole. MOH patients often have additional comorbidities, and the clinical challenge of helping patients reduce acute medication use and revert to episodic headache can be marked. Treatment includes education and prevention; withdrawal programs; pharmacological prophylaxis; multidisciplinary therapies with behavioral and noninvasive neuromodulation options; and scheduled, frequent follow-up to prevent relapses. The advent of anti-CGRP therapy monoclonal antibodies may provide an alternative to more extensive programs for less complex patients. This review also provides guidance for which patients may benefit most from coordinated integrated programs., (Copyright © 2024 Elsevier B.V. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Growth in knowledge about calcitonin gene‐related peptide (CGRP) in the pathophysiology of migraine brought CGRP antagonism to headache medicine. Failures in development of small molecule CGRP receptor antagonists and increasing knowledge and use of monoclonal antibodies (mAbs) in medicine led to the breakthrough development of large molecule anti‐CGRP mAbs: eptinezumab, erenumab, fremanezumab, and galcanezumab. This specifics about CGRP immunology aims to outline: (1) knowledge needed for CGRP antagonism and (2) developmental issues of specific CGRP antagonists for provider use. This clinically oriented review documents IgG structure and function; state of the art of monoclonal IgG production and ligand‐antigen‐antibodies in migraine therapeutics contributing to immunogenic risks and off‐target toxicities. Specifics to CGRP ligand, receptor, antagonism, and molecules, small and large, complete this review. Completion will facilitate assessment of the similarities, differences, and application of the forthcoming anti‐CGRP receptor and ligand antagonists for patients. [ABSTRACT FROM AUTHOR]

Introduction: Relative to migraine generally, chronic migraine (CM) imposes greater disability, healthcare utilization and socioeconomic burden. Six therapies currently possess a credible evidence base for prevention/suppression of CM. This review is intended to provide an assessment of their relative utility, defined as a blend of safety, tolerability and efficacy, focusing in particular on their safety and tolerability.Areas Covered: We discuss all six medications currently FDA-approved for migraine prevention which also specifically possess credible evidence of efficacy in treating CM. While we do address the efficacy of each, our primary emphasis involves assessment of safety and tolerability data derived from clinical trials and post-marketing experience.Expert Opinion: Recent research involving CM has led to the identification of highly targeted and typically well-tolerated therapies. For patients who experience obstacles to accessing these newer therapies, topiramate is available as an evidence-based alternative, but contraindications, drug-drug interactions and poor tolerability may limit or prevent its use. Although data to support such intervention presently is limited, clinically challenging CM cases may benefit from combination therapy. 'Real world' studies are needed to evaluate such polytherapy, along with studies intended to assess the long-term safety of the individual therapies and their use during pregnancy and breast-feeding.

Background: Chronic migraine is a disabling condition that is currently underdiagnosed and undertreated. In this narrative review, we discuss the future of chronic migraine management in relation to recent progress in evidence-based pharmacological treatment. Findings: Patients with chronic migraine require prophylactic therapy to reduce the frequency of migraine attacks, but the only currently available evidence-based prophylactic treatment options for chronic migraine are topiramate and onabotulinumtoxinA. Improved prophylactic therapy is needed to reduce the high burden of chronic migraine in Italy. Monoclonal antibodies that target the calcitonin gene-related peptide (CGRP) pathway of migraine pathogenesis have been specifically developed for the prophylactic treatment of chronic migraine. These anti-CGRP/R monoclonal antibodies have demonstrated good efficacy and excellent tolerability in phase II and III clinical trials, and offer new hope to patients who are currently not taking any prophylactic therapy or not benefitting from their current treatment. Conclusions: Treatment of chronic migraine is a dynamic and rapidly advancing area of research. New developments in this field have the potential to improve the diagnosis and provide more individualised treatments for this condition. Establishing a culture of prevention is essential for reducing the personal, social and economic burden of chronic migraine. [ABSTRACT FROM AUTHOR]