Preventive CGRP-targeted therapies for chronic migraine with and without medication-overuse headache

Chronic migraine; Medication-overuse; Monoclonal antibodiesMigranya crònica; Abús de medicaments; Anticossos monoclonalsMigraña crónica; Abuso de medicamentos; Anticuerpos monoclonalesBackground: Calcitonin gene-related peptide (CGRP) targeted therapies are an important breakthrough in migraine prevention. Randomized clinical trials, post-hoc analyses, and phase IV studies have demonstrated their efficacy and safety in chronic migraine patients, including those with concomitant medication-overuse and medication-overuse headache. Real world evidence studies support these findings and provide realistic endpoints for estimation of effect. Methods and results We have performed a narrative review including results from double-blind placebo-controlled randomized clinical trials and real-world evidence studies regarding efficacy of the CGRP(-receptor) monoclonal antibodies and CGRP-receptor antagonists (gepants) in patients with chronic migraine with concomitant medication overuse (headache). We have included patient profiles and main efficacy endpoints (monthly migraine days, monthly headache days, monthly acute medication days and percentage responder rates). Conclusion The results of this review show that CGRP monoclonal antibodies are effective in chronic migraine patients, also in those with medication overuse (headache). At the time of this review, atogepant clinical trials in chronic migraine have not been communicated. Direct comparative studies are needed for comparison with other treatment options

OnabotulinumtoxinA: An Effective Tool in the Therapeutic Arsenal for Chronic Migraine With Medication Overuse

Objective: To evaluate the early response of onabotulinumtoxinA as a treatment tool in patients with chronic migraine (CM) and medication overuse (MO).Patients and Methods: This is a retrospective study in patients with CM and MO who received two cycles of onabotulinumtoxinA infiltrations following PREEMPT protocol. We evaluated the efficacy of onabotulinumtoxinA in MO resolution, defined as less than 10 days/month of acute medication intake (triptans, opioids, and combinations) or 15 days/month (non-steroidal anti-inflammatory drugs - and simple analgesics). In addition, we analyzed changes in headache frequency, pain intensity, and headache-related disability (MIDAS scale). A multivariate analysis was carried out to identify factors independently related to MO resolution.Results: We included 139 consecutive patients with CM and MO. After 2 cycles of onabotulinumtoxinA, 73.4% had ≥50% reduction in acute medication intake and 57.6% achieved MO resolution. 7.9% of patients did not use any acute medication after treatment. Even though both MO-ongoing group and MO-resolution group improve in headache frequency, the reduction was significantly higher for the group which discontinued the use of acute medication after onabotulinumtoxinA treatment (p < 0.001). In this group, 73.0% reduced headache frequency ≥50%. Daily headache changed from 71.2 to 23.2% (p < 0.001). Both groups showed an improvement in pain intensity and in MIDAS score (p < 0.05). In the multivariate analysis we observed that MO resolution had an inverse association with medication intake at baseline (OR:0.294, p < 0.05) and a direct association with frequency (OR:20.455, p < 0.001) and MIDAS score (OR: 6.465, p < 0.05) improvements.Conclusion: OnabotulinumtoxinA has an early beneficial effect on the discontinuation of acute medication in a substantial proportion of patients with CM and MO. Therefore, onabotulinumtoxinA might be considered a therapeutic tool in CM with MO

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)

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

Early and annual projected savings from anti-CGRP monoclonal antibodies in migraine prevention: a cost-benefit analysis in the working-age population

Anti-CGRP monoclonal antibodies; Migraine prevention; Cost-benefitAnticuerpos monoclonales anti-CGRP; Prevención de la migraña; Costo-beneficioAnticossos monoclonals anti-CGRP; Prevenció de la migranya; Cost-beneficiBackground Migraine is one of the main causes of disability worldwide. Anti-CGRP monoclonal antibodies (MAbs) have proven to be safe and efficacious as preventive migraine treatments. However, their use is restricted in many countries due to their apparently high cost. Cost-benefit studies are needed. Objective To study the cost-benefit of anti-CGRP MAbs in working-age patients with migraine. Methods This is a prospective cohort study of consecutive migraine patients treated with anti-CGRP MAbs (erenumab, fremanezumab and galcanezumab) following National reimbursement policy in a specialized headache clinic. Migraine characteristics and the work impact scale (WPAI) were compared between baseline (M0) and after 3 (M3) and 6 months (M6) of treatment. Using WPAI and the municipal average hourly wage, we calculated indirect costs (absenteeism and presenteeism) at each time point. Direct costs (emergency visits, acute medication use) were also analysed. A cost-benefit study was performed considering the different costs and savings of treating with MAbs. Based on these data an annual projection was conducted. Results From 256 treated working-age patients, 148 were employed (89.2% women; mean age 48.0 ± 8.5 years), of which 41.2% (61/148) were responders (> 50% reduction in monthly headache days (MHD)). Statistically significant reductions between M0 and M3/M6 were found in absenteeism (p < 0.001) and presenteeism (p < 0.001). Average savings in indirect costs per patient at M3 were absenteeism 105.4 euros/month and presenteeism 394.3 euros/month, similar for M6. Considering the monthly cost of anti-CGRP MAbs, the cost-benefit analysis showed savings of 159.8 euros per patient at M3, with an annual projected savings of 639.2 euros/patient. Both responders and partial responders (30–50% reduction in MHD) presented a positive cost-benefit balance. The overall savings of the cohort at M3/M6 compensated the negative cost-benefit balance for non-responders (< 30% reduction in MHD). Conclusion Anti-CGRP MAbs have a positive impact in the workforce significantly reducing absenteeism and presenteeism. In Spain, this benefit overcomes the expenses derived from their use already at 3 months and is potentially sustainable at longer term; also in patients who are only partial responders, prompting reconsideration of current reimbursement criteria and motivating the extension of similar cost-benefit studies in other countries

Effectiveness and Safety of OnabotulinumtoxinA in Adolescent Patients with Chronic Migraine

Migraine; OnabotulinumtoxinA; AdolescentsMigranya; Onabotulinumtoxin A; AdolescentsMigraña; Onabotulinumtoxina A; AdolescentesChronic migraine (CM) significantly affects underage individuals. The study objectives are (1) to analyze the effectiveness and safety of onabotulinumtoxinA (BTX-A) in adolescents with CM; (2) to review the literature on BTX-A use in the pediatric population. This prospective observational study included patients under 18 years old with CM treated with BTX-A (PREEMPT protocol) as compassionate use. Demographic, efficacy (monthly headache days—MHD; monthly migraine days—MMD; acute medication days/month—AMDM) and side effect data were collected. A ≥ 50% reduction in MHD was considered as a response. Effectiveness and safety were analyzed at 6 and 12 months. A systematic review of the use of BTX-A in children/adolescents was conducted in July 2023. In total, 20 patients were included (median age 15 years [14.75–17], 70% (14/20) females). The median basal frequencies were 28.8 [20–28] MHD, 18 [10–28] MMD and 10 [7.5–21.2] AMDM. Compared with baseline, at 6 months (n = 20), 11 patients (55%) were responders, with a median reduction in MHD of −20 days/month (p = 0.001). At 12 months (n = 14), eight patients (57.1%) were responders, with a median reduction in MHD of −17.5 days/month (p = 0.002). No adverse effects were reported. The literature search showed similar results. Our data supports the concept that BTX-A is effective, well tolerated, and safe in adolescents with CM resistant to oral preventatives

Exploring sensory sensitivity, cortical excitability, and habituation in episodic migraine, as a function of age and disease severity, using the pattern-reversal task

Cortical excitability; Migraine; Visual sensitivityExcitabilitat cortical; Migranya; Sensibilitat visualExcitabilidad cortical; Migraña; Sensibilidad visualBackground Migraine is a cyclic, neurosensory disorder characterized by recurrent headaches and altered sensory processing. The latter is manifested in hypersensitivity to visual stimuli, measured with questionnaires and sensory thresholds, as well as in abnormal cortical excitability and a lack of habituation, assessed with visual evoked potentials elicited by pattern-reversal stimulation. Here, the goal was to determine whether factors such as age and/or disease severity may exert a modulatory influence on sensory sensitivity, cortical excitability, and habituation. Methods Two similar experiments were carried out, the first comparing 24 young, episodic migraine patients and 28 healthy age- and gender-matched controls and the second 36 middle-aged, episodic migraine patients and 30 healthy age- and gender-matched controls. A neurologist confirmed the diagnoses. Migraine phases were obtained using eDiaries. Sensory sensitivity was assessed with the Sensory Perception Quotient and group comparisons were carried out. We obtained pattern-reversal visual evoked potentials and calculated the N1-P1 Peak-to-Peak amplitude. Two linear mixed-effects models were fitted to these data. The first model had Block (first block, last block) and Group (patients, controls) as fixed factors, whereas the second model had Trial (all trials) and Group as fixed factors. Participant was included as a random factor in both. N1-P1 first block amplitude was used to assess cortical excitability and habituation was defined as a decrease of N1-P1 amplitude across Blocks/Trials. Both experiments were performed interictally. Results The final samples consisted of 18 patients with episodic migraine and 27 headache-free controls (first experiment) and 19 patients and 29 controls (second experiment). In both experiments, patients reported increased visual hypersensitivity on the Sensory Perception Quotient as compared to controls. Regarding N1-P1 peak-to-peak data, there was no main effect of Group, indicating no differences in cortical excitability between groups. Finally, significant main effects of both Block and Trial were found indicating habituation in both groups, regardless of age and headache frequency. Conclusions The results of this study yielded evidence for significant hypersensitivity in patients but no significant differences in either habituation or cortical excitability, as compared to headache-free controls. Although the alterations in patients may be less pronounced than originally anticipated they demonstrate the need for the definition and standardization of optimal methodological parameters.The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: AMM salary has been partially financed by a predoctoral grant from the “Fundacio Institut de Recerca Hospital Universitari Vall d’Hebron” (VHIR/BEQUESPREDOC/2020/MARTI). AVB salary has been partially financed by a Juan de la Cierva-Formacion grant (FJC2018-036804-I) and a Juan de la Cierva-Incorporación grant (IJC2020-043139-I) from the Spanish Ministry of Science and Innovation. XCC salary has been co-funded by the European Regional Development Fund (001-P-001682) under the framework of the FEDER Operative Programme for Catalunya 2014–2020, with 1,527,637.88 euros. EC salary has been funded by Rıo Hortega grant Accion Estrategica en Salud 2017–2020, Instituto de Salud Carlos III (CM20/00217). SSF has been supported by grants from the Ministerio de Ciencia e Innovación (PID2019-108531 GB-I00 AEI/FEDER) and AGAUR Generalitat de Catalunya (2021 SGR 00911). The project leading to these results has received funding from “la Caixa” Foundation under the project code “LCF/PR/PR16/51110005”

Cortical metabolic and structural differences in patients with chronic migraine. An exploratory 18FDG-PET and MRI study

Migranya crònica; Gruix cortical; NeuroimatgeMigraña crónica; Espesor cortical; NeuroimagenChronic migraine; Cortical thickness; NeuroimagingBackground To describe interictal brain structural and metabolic differences between patients with episodic migraine (EM), chronic migraine (CM) and healthy controls (HC). Methods This is an exploratory study including right-handed age-matched women with EM, CM and HC. On the same day, a sequential interictal scan was performed with 18FDG-PET and MRI. 3D T1-weighted images were segmented with FreeSurfer, normalized to a reference atlas and the mean values of metabolism, cortical thickness (CTh) and local gyrification index (IGI) were determined. Groups were compared using age-adjusted linear models, corrected for multiple comparisons. 18FDG-PET measurements between groups were also analysed adjusting by patient’s age, CTh and lGI. The variables independently associated with diagnosis were obtained using a logistic regression analysis. Results Fifteen patients (8 EM, 7 CM) and 11 HC were included. Morphometric data showed an increased CTh in 6 frontal areas (L/R-Caudal Middle Frontal, L/R-Rostral Middle Frontal, L-Medial Orbitofrontal and L-Superior Frontal) in CM patients compared to HC without differences for IGI. The structural adjusted analysis in CM showed a statistically significantly hypometabolism in 9 frontal areas (L-Lateral Orbitofrontal, L/R-Medial Orbitofrontal, L-Frontal Superior, R-Frontal pole, R-Parts Triangularis, L/R-Paracentral and R-Precentral) and 7 temporal areas (L/R-Insula, L/R-Inferior temporal, L/R-Temporal pole and R-Banks superior temporal sulcus) compared to HC. EM patients presented intermediate metabolic values ​​between EM and HC (non-significant). Conclusions CM patients showed frontotemporal hypometabolism and increased frontal cortical thickness when compared to HC that may explain some cognitive and behavioural pain-processing and sensory integration alterations in CM patients. Combined information from sequential or simultaneous PET and MRI could optimize the study of complex functional neurological disorders such as migraine.The project leading to these results has received funding The Headache Study Group Grant 2016 of Spanish Neurological Society and Mutual Medica Grant 2016 and “La Caixa” Foundation under the project code LCF/PR/PR16/151110005