Mode and site of action of therapies targeting CGRP signaling

Calcitonin; Headache; MigraineCalcitonina; Dolor de cabeza; MigrañaCalcitonina; Mal de cap; MigranyaTargeting CGRP has proved to be efficacious, tolerable, and safe to treat migraine; however, many patients with migraine do not benefit from drugs that antagonize the CGRPergic system. Therefore, this review focuses on summarizing the general pharmacology of the different types of treatments currently available, which target directly or indirectly the CGRP receptor or its ligand. Moreover, the latest evidence regarding the selectivity and site of action of CGRP small molecule antagonists (gepants) and monoclonal antibodies is critically discussed. Finally, the reasons behind non-responders to anti-CGRP drugs and rationale for combining and/or switching between these therapies are addressed.The article-processing charges for the article has been sponsored by the European Headache Federation

Reply to the letter: Headaches during/after SARS-CoV-2 infection/vaccination can be primary and secondary as well as acute and chronic, by Finsterer J and Mehri S

Headaches; Infection; SARS-CoV-2Mals de cap; Infecció; SARS-CoV-2Dolores de cabeza; Infección; SARS-CoV-

Headaches and facial pain attributed to SARS-CoV-2 infection and vaccination: a systematic review

Chronic daily headache; Headache; Neurological disordersCefalea crònica diària; Mal de cap; Trastorns neurològicsCefalea crónica diaria; Dolor de cabeza; Trastornos neurológicosBackground and purpose The aim was to provide insights to the characteristics of headache in the context of COVID-19 on behalf of the Headache Scientific Panel and the Neuro-COVID-19 Task Force of the European Academy of Neurology (EAN) and the European Headache Federation (EHF). Methods Following the Delphi method the Task Force identified six relevant questions and then conducted a systematic literature review to provide evidence-based answers and suggest specific diagnostic criteria. Results No data for facial pain were identified in the literature search. (1) Headache incidence during acute COVID-19 varies considerably, with higher prevalence rates in prospective compared to retrospective studies (28.9%–74.6% vs. 6.5%–34.0%). (2) Acute COVID-19 headache is usually bilateral or holocranial and often moderate to severe with throbbing pain quality lasting 2–14 days after first signs of COVID-19; photo-phonophobia, nausea, anosmia and ageusia are common associated features; persistent headache shares similar clinical characteristics. (3) Acute COVID-19 headache is presumably caused by immune-mediated mechanisms that activate the trigeminovascular system. (4) Headache occurs in 13.3%–76.9% following SARS-CoV-2 vaccination and occurs more often amongst women with a pre-existing primary headache; the risk of developing headache is higher with the adenoviral-vector-type vaccines than with other preparations. (5) Headache related to SARS-CoV-2 vaccination is mostly bilateral, and throbbing, pressing, jolting or stabbing. (6) No studies have been conducted investigating the underlying mechanism of headache attributed to SARS-CoV-2 vaccines. Conclusion The results of this joint EAN/EHF initiative provide a framework for a better understanding of headache in the context of SARS-CoV-2 infection and vaccination

In search of a gold standard patient-reported outcome measure to use in the evaluation and treatment-decision making in migraine prevention: A real-world evidence study

Efficacy; Headache; Health-related quality of lifeEficàcia; Mal de cap; Qualitat de vida relacionada amb la salutEficacia; Dolor de cabeza; Calidad de vida relacionada con la saludBackground 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.The authors received no financial support for the research, authorship, and/or publication

Dynamic fluctuations of salivary CGRP levels during migraine attacks: association with clinical variables and phenotypic characterization

Biomarker; Endophenotyping; MigraineBiomarcador; Endofenotipat; MigranyaBiomarcador; Endofenotipado; MigrañaBackground Migraine is a complex neurological disorder with significant heterogeneity in its clinical presentation and molecular mechanisms. Calcitonin gene-related peptide (CGRP) has emerged as a key player in migraine pathophysiology, but challenges remain in its utilization as a biomarker. This study aimed to investigate salivary CGRP levels during migraine attacks across the frequency spectrum and explore associations with clinical variables. Methods A prospective longitudinal pilot study was conducted, recruiting migraine patients from an outpatient headache clinic. Salivary CGRP levels were measured at interictal, onset, post-2 h of onset and end-of-attack. Using generalized linear mixed models, we explored the effect of CGRP changes over the attack in presence of depressive symptoms (DS), acute attack treatment, and after three-months of erenumab treatment. Finally, patients were classified and compared according to their CGRP phenotype. Results A total of 44 migraine patients were included (90.9% women), with 80 migraine attacks analyzed. Salivary CGRP levels increased at the onset of migraine attacks. We observed statistically significant interactions between DS and both the linear (Est. [SE]: 19.4 [5.8], p = 0.001) and quadratic terms of time (-19.1 [6.0], p = 0.002). Additionally, a significant three-way interaction within the use of acute treated attack (linear-term: -18.5 [6.2], p = 0.005; quadratic-term: 19.2 [6.8], p = 0.005) was also found. Molecular phenotyping revealed that 72.7% (32/44) of patients presented only CGRP-dependent attacks, while 27.3% (12/44) presented non-CGRP-dependent migraine attacks. Patients with only CGRP-dependent attacks were associated with younger age, shorter disease evolution time, a higher proportion of aura, and fewer monthly headache days (p < 0.05). Exploratory analysis of erenumab treatment effects did not result in changes in CGRP levels during migraine attacks. Conclusions Our study underscores the dynamic nature of migraine at a molecular level and emphasizes the importance of integrating clinical variables, such as depressive symptoms, in understanding its pathophysiology. The identification of distinct migraine subtypes based on CGRP dependence suggests potential opportunities for personalized treatment approaches.This study was funded by a grant from Instituto de Salud Carlos III (ISCIII - PI16/01525)

Anti-CGRP monoclonal antibodies in chronic migraine with medication overuse: real-life effectiveness and predictors of response at 6 months

Erenumab; Migranya; Anticossos monoclonalsErenumab; Migraña; Anticuerpos monoclonicosErenumab; Migraine; Monoclonal antibodiesBackground In daily practice, anti-CGRP monoclonal antibodies (MAbs) may be useful in chronic migraine (CM) with medication overuse (MO), but data is limited. We evaluated their effectiveness in a real-life clinical cohort. Methods This is a prospective study conducted in CM patients with and without medication overuse treated with monthly MAbs during 6 months (erenumab/galcanezumab). We collected headache characteristics, including acute medication intake, through an electronic diary. We compared patients (1) with and without MO at baseline, (2) with and without ongoing MO after treatment, defining MO resolution as < 10 or 15 days/month of acute medication intake, according to analgesic type, during the 6-month treatment. Results Of 139 CM patients completing 6-month treatment with anti-CGRP MAbs, 71.2% (99/139) had MO at baseline. After 6 months, patients with and without MO at baseline had significant and similar proportions of ≥50% reduction in migraine days/month (MO: 63.6% vs. non-MO: 57.5%, p = 0.500). 60.6% (60/99) no longer satisfied MO definition. Reduction in headache frequency compared to baseline occurred in both MO-ongoing and MO-resolution group, although those who stopped overusing had a greater improvement (headache days/month: − 13.4 ± 7.6 vs. -7.8 ± 7.2, p < 0.0001). No differences in MO resolution were observed according to the MAbs used. Baseline lower pain severity was associated with MO resolution (OR [95%]:0.236[0.054–0.975]; p = 0.049). Conclusions In real-life anti-CGRP MAbs are as effective in CM patients with MO as in patients without it and facilitate MO cessation. Reduction in headache frequency and acute medication days/month occurs regardless of whether patients stop overusing or not.No funding was received for this study

Improvement of migraine depressive symptoms is not related to headache frequency: exploring the impact of anti-CGRP therapies

Calcitonin gene-related peptide; Depression; Migraine preventionPèptid relacionat amb el gen de la calcitonina; Depressió; Prevenció de la migranyaPéptido relacionado con el gen de la calcitonina; Depresión; Prevención de la migrañaBackground The present study aimed to describe the prevalence and evolution of depressive symptoms in a cohort of migraine patients treated with anti-CGRP monoclonal antibodies. Methods This is an exploratory, prospective, unicentric, one-year longitudinal study. We included migraine patients who started treatment with anti-CGRP monoclonal antibodies. Baseline demographic data, medical history, concomitant medication and migraine characteristics were collected. The presence of depressive symptoms was evaluated using the Beck Depression Inventory-II quarterly and treatment response was categorized according to the reduction in monthly headache days. A generalized mixed-effect regression model was used to model depression score over a one-year treatment taking into account frequency response rates. Results We included 577 patients: 84.2% females; median (range) age 47.0 (39.0–53.0) years, 46.1% (266/577) of them presented depressive symptoms at baseline (16.1% mild, 13.3% moderate and 16.6% severe). After six-month treatment, 47.4% (126/266) reduced headache frequency ≥50% after one year and 63.5% (169/266) achieved a clinically significant improvement in depression symptoms. We observed a 30.8% (−50.0%, −3.2%) main reduction in depression score during the first quarter. The improvement in depression symptoms was independently associated with headache frequency response: non-responders, −25.0% (−43.9%, −1.1%); partial responders, −30.2% (−51.3%, −7.6%); and good responders, −33.3% (−54.6%, −7.5%). Conclusions Anti-CGRP monoclonal antibodies targeting CGRP are effective in reducing depressive symptoms in patients with migraine. The main change of depression score happens during the first three months of treatment. The reduction in depressive symptoms is independent of migraine frequency improvement

Impact of anti-CGRP monoclonal antibodies on migraine attack accompanying symptoms: A real-world evidence study

Migraine; Anti-CGRP monoclonal antibodies; PhonophobiaMigraña; Anticuerpos monoclonales anti-CGRP; FonofobiaMigranya; Anticossos monoclonals anti-CGRP; FonofòbiaBackground 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

Headache attributed to SARS-CoV-2 infection, vaccination and the impact on primary headache disorders of the COVID-19 pandemic: A comprehensive review

COVID-19; Telemedicine; VaccineCOVID-19; Telemedicina; VacunaCOVID-19; Telemedicina; VacunaObjective The objective is to summarize the knowledge on the epidemiology, pathophysiology and management of secondary headache attributed to SARS-CoV-2 infection and vaccination; as well as to delineate their impact on primary headache disorders. Methods This is a narrative review of the literature regarding primary and secondary headache disorders in the setting of COVID-19 pandemic. We conducted a literature search in 2022 on PubMed, with the keywords “COVID 19” or “vaccine” and “headache” to assess the appropriateness of all published articles for their inclusion in the review. Results Headache is a common and sometimes difficult-to-treat symptom of both the acute and post-acute phase of SARS-CoV-2 infection. Different pathophysiological mechanisms may be involved, with the trigeminovascular system as a plausible target. Specific evidence-based effective therapeutic options are lacking at present. Headache attributed to SARS-CoV-2 vaccinations is also common, its pathophysiology being unclear. People with primary headache disorders experience headache in the acute phase of COVID-19 and after vaccination more commonly than the general population. Pandemic measures, forcing lifestyle changes, seemed to have had a positive impact on migraine, and changes in headache care (telemedicine) have been effectively introduced. Conclusions The ongoing COVID-19 pandemic is a global challenge, having an impact on the development of secondary headaches, both in people with or without primary headaches. This has created opportunities to better understand and treat headache and to potentiate strategies to manage patients and ensure care

A study of differential microRNA expression profile in migraine: the microMIG exploratory study

Epigenetics; Migraine; MicroRNAEpigenética; Migraña; MicroARNEpigenètica; Migranya; MicroARNBackground Several studies have described potential microRNA (miRNA) biomarkers associated with migraine, but studies are scarcely reproducible primarily due to the heterogeneous variability of participants. Increasing evidence shows that disease-related intrinsic factors together with lifestyle (environmental factors), influence epigenetic mechanisms and in turn, diseases. Hence, the main objective of this exploratory study was to find differentially expressed miRNAs (DE miRNA) in peripheral blood mononuclear cells (PBMC) of patients with migraine compared to healthy controls in a well-controlled homogeneous cohort of non-menopausal women. Methods Patients diagnosed with migraine according to the International Classification of Headache Disorders (ICHD-3) and healthy controls without familial history of headache disorders were recruited. All participants completed a very thorough questionnaire and structured-interview in order to control for environmental factors. RNA was extracted from PBMC and a microarray system (GeneChip miRNA 4.1 Array chip, Affymetrix) was used to determine the miRNA profiles between study groups. Principal components analysis and hierarchical clustering analysis were performed to study samples distribution and random forest (RF) algorithms were computed for the classification task. To evaluate the stability of the results and the prediction error rate, a bootstrap (.632 + rule) was run through all the procedure. Finally, a functional enrichment analysis of selected targets was computed through protein–protein interaction networks. Results After RF classification, three DE miRNA distinguished study groups in a very homogeneous female cohort, controlled by factors such as demographics (age and BMI), life-habits (physical activity, caffeine and alcohol consumptions), comorbidities and clinical features associated to the disease: miR-342-3p, miR-532-3p and miR-758-5p. Sixty-eight target genes were predicted which were linked mainly to enriched ion channels and signaling pathways, neurotransmitter and hormone homeostasis, infectious diseases and circadian entrainment. Conclusions A 3-miRNA (miR-342-3p, miR-532-3p and miR-758-5p) novel signature has been found differentially expressed between controls and patients with migraine. Enrichment analysis showed that these pathways are closely associated with known migraine pathophysiology, which could lead to the first reliable epigenetic biomarker set. Further studies should be performed to validate these findings in a larger and more heterogeneous sample.This study was solely funded by the Migraine Research Foundation