Switching CGRP(r) MoAbs in migraine: what evidence?

INTRODUCTION: Approximately 50% of patients that receive a CGRP(r) MoAb for the preventative treatment of migraine are expected to discontinue therapy. For patients that discontinue CGRP(r) MoAb therapy, few clinical options are available. One potential option is to switch CGRP(r) MoAbs, however, data concerning the efficacy of this intervention is scarce. AREAS COVERED: This manuscript aims to summarize all available data concerning the potential efficacy of switching CGRP(r) MoAbs following previous medication discontinuation. Data was sourced by completing a database search for the terms: 'CGRP monoclonal antibody switch OR CGRP monoclonal antibody switching.' EXPERT OPINION: While data considering the potential efficacy of CGRP(r) switching continues to grow, our expert opinion supports the most recent European Headache Federation statement regarding CGRP(r) MoAb prescribing practices, concluding that there remains insufficient data to determine the efficacy of this intervention. As this topic is of significant clinical importance, we recommend a call-to-action to expand on current data considering the therapeutic options for patients that discontinue CGRP(r) MoAb therapy.

The impact of primary headaches on disability outcomes: a literature review and meta-analysis to inform future iterations of the Global Burden of Disease study.

BACKGROUND: The burden and disability associated with headaches are conceptualized and measured differently at patients' and populations' levels. At the patients' level, through patient-reported outcome measures (PROMs); at population level, through disability weights (DW) and years lived with a disability (YLDs) developed by the Global Burden of Disease Study (GBD). DW are 0-1 coefficients that address health loss and have been defined through lay descriptions. With this literature review, we aimed to provide a comprehensive analysis of disability in headache disorders, and to present a coefficient referring to patients' disability which might inform future GBD definitions of DW for headache disorders. METHODS: We searched SCOPUS and PubMed for papers published between 2015 and 2023 addressing disability in headache disorders. The selected manuscript included a reference to headache frequency and at least one PROM. A meta-analytic approach was carried out to address relevant differences for the most commonly used PROMs (by headache type, tertiles of medication intake, tertiles of females' percentage in the sample, and age). We developed a 0-1 coefficient based on the MIDAS, on the HIT-6, and on MIDAS + HIT-6 which was intended to promote future DW iterations by the GBD consortium. RESULTS: A total of 366 studies, 596 sub-samples, and more than 133,000 single patients were available, mostly referred to cases with migraine. Almost all PROMs showed the ability to differentiate disability severity across conditions and tertiles of medication intake. The indexes we developed can be used to inform future iterations of DW, in particular considering their ability to differentiate across age and tertiles of medication intake. CONCLUSIONS: Our review provides reference values for the most commonly used PROMS and a data-driven coefficient whose main added value is its ability to differentiate across tertiles of age and medication intake which underlie on one side the increased burden due to aging (it is likely connected to the increased impact of common comorbidities), and by the other side the increased burden due to medication consumption, which can be considered as a proxy for headache severity. Both elements should be considered when describing disability of headache disorders at population levels.

Targeting the PACAP-38 pathway is an emerging therapeutic strategy for migraine prevention.

INTRODUCTION: The pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) has emerged as a key mediator of migraine pathogenesis. PACAP-38 and its receptors are predominantly distributed in arteries, sensory and parasympathetic neurons of the trigeminovascular system. Phase 2 trials have tested human monoclonal antibodies designed to bind and inhibit PACAP-38 and the pituitary adenylate cyclase-activating polypeptide type I (PAC1) receptor for migraine prevention. AREAS COVERED: This review focuses on the significance of the PACAP-38 pathway as a target in migraine prevention. English peer-reviewed articles were searched in PubMed, Scopus and ClinicalTrials.gov electronic databases. EXPERT OPINION: A PAC1 receptor monoclonal antibody was not effective for preventing migraine in a proof-of-concept trial, paving the way for alternative strategies to be considered. Lu AG09222 is a humanized monoclonal antibody targeting PACAP-38 that was effective in preventing physiological responses of PACAP38 and reducing monthly migraine days in individuals with migraine. Further studies are necessary to elucidate the clinical utility, long-term safety and cost-effectiveness of therapies targeting the PACAP pathway.

Real-world effectiveness of fremanezumab in patients with migraine switching from another mAb targeting the CGRP pathway.

This is a summary of the research article entitled "Real-world effectiveness of fremanezumab in patients with migraine switching from another mAb targeting the CGRP pathway: A subgroup analysis of the Finesse Study".The discovery of calcitonin gene-related peptide (CGRP) as a therapeutic target in migraine has been one of the greatest achievements in neurology in recent years. Specific antibodies against CGRP bind to it either via a receptor (erenumab) or ligand (fremanezumab, galcanezumab, eptinezumab). Monoclonal antibodies (mAbs) are effective, safe and welltolerated drugs that have been approved for prophylactic treatment if there are at least 4 days with migraine per month. However, in clinical practice, the failure of treatment with mAbs has been observed, and thus the question arises whether it is worthwhile to include treatment using an antibody with a different mechanism of action.The Finesse Study was designed to evaluate the efficacy of fremanezumab in patients with a history of prior treatment failure with other mAbs against the CGRP pathway. Among the 153 patients with priorly failed mAbs, switching to fremanezumab led to a ≥50% reduction in the number of days with migraine per month in 42.8% of patients. The conclusion emphasizes that switching to another antibody should be considered in patients with prior therapy failure.

Mechanosensitive receptors in migraine: a systematic review.

BACKGROUND: Migraine is a debilitating neurological disorder with pain profile, suggesting exaggerated mechanosensation. Mechanosensitive receptors of different families, which specifically respond to various mechanical stimuli, have gathered increasing attention due to their potential role in migraine related nociception. Understanding these mechanisms is of principal importance for improved therapeutic strategies. This systematic review comprehensively examines the involvement of mechanosensitive mechanisms in migraine pain pathways. METHODS: A systematic search across the Cochrane Library, Scopus, Web of Science, and Medline was conducted on 8th August 2023 for the period from 2000 to 2023, according to PRISMA guidelines. The review was constructed following a meticulous evaluation by two authors who independently applied rigorous inclusion criteria and quality assessments to the selected studies, upon which all authors collectively wrote the review. RESULTS: We identified 36 relevant studies with our analysis. Additionally, 3 more studies were selected by literature search. The 39 papers included in this systematic review cover the role of the putative mechanosensitive Piezo and K2P, as well as ASICs, NMDA, and TRP family of channels in the migraine pain cascade. The outcome of the available knowledge, including mainly preclinical animal models of migraine and few clinical studies, underscores the intricate relationship between mechanosensitive receptors and migraine pain symptoms. The review presents the mechanisms of activation of mechanosensitive receptors that may be involved in the generation of nociceptive signals and migraine associated clinical symptoms. The gender differences of targeting these receptors as potential therapeutic interventions are also acknowledged as well as the challenges related to respective drug development. CONCLUSIONS: Overall, this analysis identified key molecular players and uncovered significant gaps in our understanding of mechanotransduction in migraine. This review offers a foundation for filling these gaps and suggests novel therapeutic options for migraine treatments based on achievements in the emerging field of mechano-neurobiology.

The World Health Organization Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders and the headache revolution: from headache burden to a global action plan for headache disorders.

The World Health Organization (WHO) Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders was developed by WHO to address the worldwide challenges and gaps in provision of care and services for people with epilepsy and other neurological disorders and to ensure a comprehensive, coordinated response across sectors to the burden of neurologic diseases and to promote brain health across life-course. Headache disorders constitute the second most burdensome of all neurological diseases after stroke, but the first if young and midlife adults are taken into account. Despite the availability of a range of treatments, disability associated with headache disorders, and with migraine, remains very high. In addition, there are inequalities between high-income and low and middle income countries in access to medical care. In line with several brain health initiatives following the WHOiGAP resolution, herein we tailor the main pillars of the action plan to headache disorders: (1) raising policy prioritization and strengthen governance; (2) providing effective, timely and responsive diagnosis, treatment and care; (3) implementing strategies for promotion and prevention; (4) fostering research and innovation and strengthen information systems. Specific targets for future policy actions are proposed. The Global Action Plan triggered a revolution in neurology, not only by increasing public awareness of brain disorders and brain health but also by boosting the number of neurologists in training, raising research funding and making neurology a public health priority for policy makers. Reducing the burden of headache disorders will not only improve the quality of life and wellbeing of people with headache but also reduce the burden of neurological disorders increasing global brain health and, thus, global population health.

Unmet Needs in the Acute Treatment of Migraine.

Migraine represents the most common neurologic disorder, ranking second among the world's causes of disability [expressed as years lived with disability (YLDs)]. Patients often do not receive the best therapy because of safety issues, tolerance, and prescription accessibility. General practitioners are not always educated about the disease, and specialists are few and often difficult to reach. Therapies are limited and have many side effects that can impede the prescription. Prophylactic therapy is recommended in case of four or more headaches a month, eight or more headache days a month, debilitating headaches, and medication-overuse headaches. The available therapeutic options are in constant development. The classic one consists of non-specific drugs: ß-blockers, tricyclics, antiepileptics, and botulinum toxin. Monoclonal antibodies targeting the calcitonin gene receptor (CGRP) peptide or its receptor are the only ones specifically designed to treat migraine. Their efficiency and convenient safety profile have been demonstrated in a number of trials versus both placebo and classic therapies. The treatment of acute migraine attack consists of medications designed to affect the painful symptoms. For over 30 years, the cornerstones of treatment in clinical practice have continued to be represented by triptans and non-steroidal anti-inflammatory drugs (NSAIDs), with the well-know related adverse effects. Opioids are used inappropriately and overprescribed. Polytherapy is strongly not recommended but is still a common practice because treatment is not optimized and thus not efficient. Great promise comes from gepants, also targeting CGRP, and ditans, 5-HT1F receptor agonists. They seem to outweigh the risk of medication overuse headache because of their efficacy and rapid onset and have no cardiovascular contraindications. Nonetheless, these points remain to be confirmed. Although therapies have been implemented in the last years, significant unmet treatment needs remain a reality in patients' lives. This commentary aims to identify the most important unmet needs in the acute treatment of migraine, analyzing the current status of available therapies and their limits. We also analyzed some of the prophylactic therapies available, especially focusing on anti-CGRP monoclonal antibodies, to better understand the importance of setting a therapeutic strategy that includes the two modes, both acute and prophylactic, to reach the best result. We hope that having an overview of the shortcomings will help to provide constructive ideas for improvement.

What to do with non-responders to CGRP(r) monoclonal antibodies: switch to another or move to gepants?

In this editorial we aim to provide potential therapeutic options in patients who do not benefit from treatment with CGRP(r) monoclonal antibodies. Based on current real-life studies and analysis of practical and economic aspects, we will analyze the potential benefits of changing CGRP-targeted treatment.

The Effect of OnabotulinumtoxinA on Headache Intensity and Number of Monthly Headache Days in Individuals with Chronic Migraine with Different Levels of Neck Disability.

One of the treatment methods used in chronic migraine is OnabotulinumtoxinA. The effects of OnabotulinumtoxinA on headache intensity (HI) and number of monthly headache days (NMHD) in chronic migraine (CM) patients classified according to neck disability levels are unknown. Our aim was to investigate the effect of OnabotulinumtoxinA on the HI and the NMHD in individuals with CM with different levels of neck disability. One hundred sixteen patients were enrolled in the study. The OnabotulinumtoxinA protocol was administered as per Follow-the-Pain PREEMPT. The Neck Disability Index was used to evaluate neck disability. Primary outcome measures were headache intensity, assessed with the Visual Analogue Scale, and the number of monthly headache days recorded from patients' diaries. Secondary outcome measures were migraine disability, assessed with the Migraine Disability Assessment Test, and quality-of-life, assessed with the Headache Impact Test-6. All assessments were made at baseline and end of the treatment. The OnabotulinumtoxinA treatment showed a greater improvement effect in the number of monthly headache days (p = 0.000) and migraine disability (p = 0.000) parameters in the severe and complete disability groups. CM patients with complete and severe neck disability received the most benefit in reducing the NMHD at 3 months after OnabotulinumtoxinA treatment, but the HI decreased at a similar level in all neck disability groups.

Metabolic and toxicological considerations regarding CGRP mAbs and CGRP antagonists to treat migraine in COVID-19 patients: a narrative review.

INTRODUCTION: Migraine pharmacological therapies targeting calcitonin gene-related peptide (CGRP), including monoclonal antibodies and gepants, have shown clinical effect and optimal tolerability. Interactions between treatments of COVID-19 and CGRP-related drugs have not been reviewed. AREAS COVERED: An overview of CGRP, a description of the characteristics of each CGRP-related drug and its response predictors, COVID-19 and its treatment, the interactions between CGRP-related drugs and COVID-19 treatment, COVID-19 and vaccination-induced headache, and the neurological consequences of Covid-19. EXPERT OPINION: Clinicians should be careful about using gepants for COVID-19 patients, due to the potential drug interactions with drugs metabolized via CYP3A4 cytochrome. In particular, COVID-19 treatment (especially nirmatrelvir packaged with ritonavir, as Paxlovid) should be considered cautiously. It is advisable to stop or adjust the dose (10 mg atogepant when used for episodic migraine) of gepants when using Paxlovid (except for zavegepant). CGRP moncolconal antibodies (CGRP-mAbs) do not have drug - drug interactions, but a few days' interval between a COVID-19 vaccination and the use of CGRP mAbs is recommended to allow the accurate identification of the possible adverse effects, such as injection site reaction. Covid-19- and vaccination-related headache are known to occur. Whether CGRP-related drugs would be of benefit in these circumstances is not yet known.

New drugs targeting calcitonin gene-related peptide for the management of migraines.

INTRODUCTION: Significant advances in migraine research have contributed to the development of new drugs for the treatment of migraine. Monoclonal antibodies (mAbs) against Calcitonin Gene-Related Peptide (CGRP) or its receptor and CGRP receptor antagonists (gepants) have been associated with a good safety profile and resulted in an overall efficacy in reducing the number of monthly migraine days both in episodic and chronic forms of migraine. AREAS COVERED: The results from main investigation studies (phase 2 or 3) of CGRP-targeting drugs (both anti-CGRP mAbs and gepants) are reported in this expert-opinion review. EXPERT OPINION: The introduction of new drugs targeting CGRP is a significant breakthrough in the migraine field, and represents a new generation of therapeutic agents that are available to manage migraine. The evaluation of efficacy and safety in the long-term follow-up and the development of trials comparing the available drugs could improve the current knowledge. The economic sustainability of these drugs remains to be clarified, and a cost-cutting campaign should be promoted based on the high burden of migraine.

Rethinking headache as a global public health case model for reaching the SDG 3 HEALTH by 2030.

The 2030 Agenda for Sustainable Development sets out, through 17 Sustainable Development Goals (SDGs), a path for the prosperity of people and the planet. SDG 3 in particular aims to ensure healthy lives and promote well-being for all at all ages and includes several targets to enhance health. This review presents a "headache-tailored" perspective on how to achieve SDG 3 by focusing on six specific actions: targeting chronic headaches; reducing the overuse of acute pain-relieving medications; promoting the education of healthcare professionals; granting access to medication in low- and middle-income countries (LMIC); implementing training and educational opportunities for healthcare professionals in low and middle income countries; building a global alliance against headache disorders. Addressing the burden of headache disorders directly impacts on populations' health, as well as on the possibility to improve the productivity of people aged below 50, women in particular. Our analysis pointed out several elements, and included: moving forward from frequency-based parameters to define headache severity; recognizing and managing comorbid diseases and risk factors; implementing a disease management multi-modal management model that incorporates pharmacological and non-pharmacological treatments; early recognizing and managing the overuse of acute pain-relieving medications; promoting undergraduate, postgraduate, and continuing medical education of healthcare professionals with specific training on headache; and promoting a culture that favors the recognition of headaches as diseases with a neurobiological basis, where this is not yet recognized. Making headache care more sustainable is an achievable objective, which will require multi-stakeholder collaborations across all sectors of society, both health-related and not health-related. Robust investments will be needed; however, considering the high prevalence of headache disorders and the associated disability, these investments will surely improve multiple health outcomes and lift development and well-being globally.

Emerging experimental drugs in clinical trials for migraine: observations and key talking points.

INTRODUCTION: There have been significant advances in the treatment of migraine. In response to the clinical success of monoclonal antibodies targeting calcitonin gene-related peptide, there is interest in the clinical trial outcomes of alternative emerging drugs that act on novel targets associated with migraine pathophysiology. As approximately 50% of patients do not respond to CGRP therapies, there is significant value in future drug innovation. Emerging drugs in clinical trials for the treatment of migraine aim to fill this need. AREAS COVERED: The emerging drugs that will be discussed in this review include zavegepant, lasmiditan, delta opioid receptor agonists, neuronal nitric oxide synthase inhibitors, monoclonal antibodies targeting pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor, dual orexin receptor antagonists, metabotropic glutamate receptor 5 antagonists, and inducers of ketosis. EXPERT OPINION: When considering the preclinical and clinical research related to the emerging drug classes discussed in this review, most therapies are derived from highly supported targets of migraine pathogenesis. Although the individual drugs discussed in this review may be of dubious clinical value, the importance of the therapeutic targets on which they act cannot be understated. Future research is necessary to appropriately target the pathways elucidated by preclinical studies.

The measurement of the left ventricle ejection fraction by a bedside FoCUS examination.

The use of point-of-care ultrasound is rapidly increasing in medical practice. This study aims to evaluate the left ventricle systolic function by the bedside focus cardiac ultrasound (FoCUS). We consecutively enrolled n.59 patients of the Emergency Medicine Unit of S. Andrea Hospital. Every patient received a bedside FoCUS examination to estimate the left ventricle (LV) ejection fraction (EF); the LV EF measurements were compared with those obtained by standard echocardiography (as gold standard). The LV EF obtained by the bedside FoCUS examination and the standard echocardiography, resulted, respectively: 50.2 ± 15.1% (by the Quinones equation), 39.5 + 12.0% (by the Lvivo app) and 53.7 + 11.1% (by the standard echocardiography). The correlations between the bedside FoCUS EF measurements versus standard echocardiography were statistically significant: r = + 0.694 p < 1.9 × 10-6 (Quinones equation, Bland-Altman analysis mean = - 2.3%) and r = + 0.571 p < 0.01 (Lvivo app, Bland-Altman analysis mean = - 13.3%). In conclusion, the present study showed a high accuracy of the bedside FoCUS EF evaluations, which may support the diagnosis of the heart failure in an emergency setting without delaying. The EF measurements by the operational method are more precise than those obtained by the unselected images of the software application.

The Efficacy of Physical Therapy and Rehabilitation Approaches in Chronic Migraine: A Systematic Review and Meta-Analysis.

BACKGROUND: Pharmacological treatment is the primary approach in chronic migraine (CM), although non-drug interventions such as physical therapy are used as adjunct treatments. We aimed to review the efficacy of physical therapy and rehabilitation approaches for CM and their impact on quality of life (QoL) and disability. METHODS: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and included randomized controlled trials (RCTs) in adults with CM. The primary outcomes were changes in intensity, frequency, duration of headache, disability, and QoL. Methodological quality was assessed using the Physiotherapy Evidence Database (PEDro) scale. Data synthesis and quantitative analysis were conducted on relevant studies. RESULTS: Seven RCTs were included in the narrative review, and five of them were eligible for quantitative analysis. Aerobic exercise (AE), osteopathic manipulative treatment (OMT), occipital transcutaneous electrical stimulation (OTES), acupressure, hydrotherapy, instrument-assisted soft tissue mobilization (IASTM), facial proprioceptive neuromuscular facilitation (FPNF), and connective tissue massage (CTM) were used in CM. AE combined with pharmacological therapy reduced the frequency, duration, and intensity of headache. OMT combined with medication improved QoL and reduced disability, intensity of pain, and migraine days per month. Hydrotherapy combined with medication also resulted in improvements in the intensity of headache, frequency, and overall QoL. IASTM and OTES reduced the intensity of headache, alleviated neck pain, and improved QoL, although there were conflicting findings following OTES alone on disability and intensity of headache. Both FPNF and CTM reduced the intensity of headache. Acupressure as an adjunct to medication did not show additional benefits on the intensity of headache and QoL. Quantitative analysis of the data showed that manual physical therapy combined with medication reduced the intensity of headache (p = 0.0796), and manual or AE combined with medication reduced the headache days per month (p = 0.047). CONCLUSIONS: A limited number of RCTs investigating the efficacy of physical therapy and rehabilitation approaches show promise in improving headache symptoms, reducing disability, and enhancing QoL in CM. Meta-analysis of the data also supported favorable outcomes for both intensity and headache days per month. Further research is needed to better understand the efficacy, optimal duration, and safety of physical therapy and rehabilitation approaches for CM, and to explore alternative interventions.