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Two million people in the Netherlands regularly experience migraine. In addition to preventive medication, a large proportion of patients also use drugs for the acute treatment of a migraine attack. The cornerstone of this therapy are the triptans, as well as paracetamol and NSAIDs. However, these drugs do not work well for all patients, or have adverse effects, and sometimes they are contraindicated. A new drug with a different mode of action could then bring relief. Rimegepant is the first of the ‘gepant’-type drugs to be authorised in the Netherlands. It belongs to the category of ‘calcitonin gene-related peptide’ (CGRP) antagonists. The question is whether rimegepant represents a useful addition to the conventional drugs for the acute treatment of migraine which are recommended in the guidelines. [ABSTRACT FROM AUTHOR]

Introduction: We systematically reviewed the efficacy and safety of Calcitonin Gene‐Related Peptide (CGRP) antagonists for migraine treatment. Methods: Various databases including PubMed, Embase, The Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), WanFang Data were electronically searched for randomized controlled trials (RCTs) on CGRP antagonists for migraine treatment since inception to March 2021. The trials were screened for inclusion, after which the methodological quality of the included trials was assessed. Then meta‐analysis was performed using the Revman 5.3 software. Results: A total of 26 RCTs involving 21,736 patients were included. The CGRP antagonists group included 13,635 patients while the control group included 8101 patients. Meta‐analysis showed that compared to the control group, CGRP antagonists were associated with various significant effects, including the following outcome indicators: (1) number of patients with ≥50% reduction from baseline in mean monthly migraine days (RR = 1.50, 95% CI [1.39,1.62], p <.00001); (2) number of patients with pain free at 2 h postdose (RR = 1.98, 95% CI [1.77, 2.20], p <.00001), and (3) number of patients with 2–24 h sustained pain free postdose (RR = 2.18, 95% CI [1.93, 2.46], p <.00001). However, the number of patients with any adverse events was significantly high in the antagonists group, relative to the control group (RR = 1.08, 95% CI [1.04, 1.12], p <.0001). Conclusions: CGRP antagonists are significantly effective for migraine treatment; however, they are associated with various adverse events. Due to limitations with regards to quantity and quality of the included studies, the above conclusions should be verified by more high quality studies. [ABSTRACT FROM AUTHOR]

Abstract Introduction We systematically reviewed the efficacy and safety of Calcitonin Gene‐Related Peptide (CGRP) antagonists for migraine treatment. Methods Various databases including PubMed, Embase, The Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), WanFang Data were electronically searched for randomized controlled trials (RCTs) on CGRP antagonists for migraine treatment since inception to March 2021. The trials were screened for inclusion, after which the methodological quality of the included trials was assessed. Then meta‐analysis was performed using the Revman 5.3 software. Results A total of 26 RCTs involving 21,736 patients were included. The CGRP antagonists group included 13,635 patients while the control group included 8101 patients. Meta‐analysis showed that compared to the control group, CGRP antagonists were associated with various significant effects, including the following outcome indicators: (1) number of patients with ≥50% reduction from baseline in mean monthly migraine days (RR = 1.50, 95% CI [1.39,1.62], p < .00001); (2) number of patients with pain free at 2 h postdose (RR = 1.98, 95% CI [1.77, 2.20], p < .00001), and (3) number of patients with 2–24 h sustained pain free postdose (RR = 2.18, 95% CI [1.93, 2.46], p < .00001). However, the number of patients with any adverse events was significantly high in the antagonists group, relative to the control group (RR = 1.08, 95% CI [1.04, 1.12], p < .0001). Conclusions CGRP antagonists are significantly effective for migraine treatment; however, they are associated with various adverse events. Due to limitations with regards to quantity and quality of the included studies, the above conclusions should be verified by more high quality studies.

Migraine is the leading cause of years lived with disability in people under 50. Electrophysiological phenomena at the basis of prodromal and headache attack phases and of chronification processes involve calcitonin-gene related peptide (CGRP) as a fundamental player become a game changer of migraine pharmacotherapy. The purpose of the present review is to retrace fundamental stages of CGRP from its discovery to the role in migraine pathogenesis and therapy to underscore the change of paradigm offered by the newly approved small molecules to antagonize CGRP receptor, the gepants. In particular, the development of this new class is gone over from the initial synthesis of C-terminus truncated CGRP antagonists to the development of the first generation of gepants ending with Zavegepant that can be considered the third generation. The history of CGRP in migraine draws the successful road to follow for key signaling pathways of modulation of nociceptive facilitation by diencephalic and brainstem nuclei, including dopaminergic neurotransmission, orexin A and the large-conductance calcium-activated potassium (BKCa) and ATP-sensitive potassium (KATP) channels also investigating the potential of essential oils and the role of polymorphisms. Real-world post marketing long-term data are needed for gepants. [ABSTRACT FROM AUTHOR]

Background: The majority of CGRP monoclonal antibodies for migraine prevention are administered subcutaneously. Therefore, we attempted to calculate the pooled placebo response with subcutaneous placebo injections in this systematic review and meta-analysis. Methods: We identified 16 randomized controlled trials that met our inclusion and exclusion criteria through a comprehensive search in five electronic databases (PubMed Central, EMBASE, MEDLINE, Cochrane library and clinicaltrials.gov). The risk of bias was assessed for all included studies. Random effects model was used to calculate pooled mean monthly migraine days and 50% response rates. Results: A total of 4240 subjects were included from 16 studies in this meta-analysis. The pooled mean monthly migraine day reduction with subcutaneous placebo injections was 2.15 (95% CI: 1.60–2.69). The pooled proportion of patients achieving a 50% reduction in mean monthly headache days was 26% (95% CI: 20%–31%). Placebo response accounted for more than 50% of therapeutic gain in our study. Conclusion: A substantial placebo response was noted with subcutaneous injections in migraine CGRP monoclonal antibody clinical trials. This meta-analysis may serve as a reference point to calculate sample size in clinical trials using subcutaneous interventions for migraine prevention. We registered our study at PROSPERO (CRD42020185300). [ABSTRACT FROM AUTHOR]

This systematic review evaluates the efficacy and safety of contemporary migraine treatments, synthesizing evidence from recent randomized controlled trials (RCTs). The focus is on both pharmacological interventions, such as calcitonin gene-related peptide (CGRP) monoclonal antibodies and non-specific oral migraine preventives, and non-pharmacological approaches like myofascial release. Through a detailed examination of the studies, this review identifies superior strategies for acute and preventive migraine management, assessing their impact on patient-reported outcomes and determining the prevalence of associated adverse events. Findings suggest that while CGRP monoclonal antibodies show promise as first-line treatments due to their efficacy and safety, myofascial release offers considerable benefits for pain and disability in tension-type and cervicogenic headaches. Challenges such as the variability in individual response and potential side effects emphasize the need for personalized treatment plans. This review underscores the importance of integrating new therapeutic discoveries into clinical practice to enhance the quality of care for migraine sufferers., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Achiatar et al.)

The worldwide treatment gap for migraine before COVID-19 inevitably widens as attention focuses on an international emergency. Migraine hits people particularly in their early and middle years, potentially reduces quality of life and productivity, and remains a common emergency presentation. This article examines the impact of COVID-19 on migraine, and changing aspects of migraine care during and after the pandemic. Many risk factors for severe COVID-19—older age, male gender, cardiac and respiratory diseases, diabetes, obesity, and immunosuppression—are less frequent in migraineurs. Telemedicine is effective for migraine follow-up, and needs ongoing evaluation. Most migraine treatments can start or continue in acute COVID-19, with care to avoid drug interactions. Close contact procedures (botulinum toxin, acupuncture and steroid injections) are avoided in lockdown or in the vulnerable. Secondary effects of COVID-19, including long COVID and its economic impact, are probably equal or greater in people with migraine. Migraine and other long-term conditions need adequate resourcing to prevent personal, social and economic suffering. Treating migraine, a sequel of COVID, potentially reduces the impact of long COVID. [ABSTRACT FROM AUTHOR]

Chronic pain is typically defined as pain that persists after acute tissue damage and inflammation or as pain that follows a chronic disease process and lasts more than three months. Because of its debilitating impact on the quality of life of patients, recent research aims to investigate the mechanisms behind nociception to discover novel therapeutic agents to alleviate pain. One such target is the neuropeptide calcitonin gene-related peptide (CGRP), which has shown to play an integral role in migraine pathophysiology. Effective treatments of migraines with CGRP antagonists have stimulated our efforts toward checking a possible involvement of CGRP in nonheadache pain conditions such as hypertension, congestive heart failure, Alzheimer's disease, and vascular ischemia. Here, we provide a brief overview of chronic pain, with a particular emphasis on the role of CGRP as a fundamental mediator of nociceptive pain as well as a target for novel therapeutic agents. [ABSTRACT FROM AUTHOR]

Migraine is a debilitating neurologic disease. People who experience migraine can have substantial disability, impaired functioning and a decreased quality of life (QoL). Expert recommendations suggest that people with frequent migraine attacks or severe impairment related to attacks may benefit from preventive treatment. Despite these recommendations and the existence of evidence-based guidelines for the use of preventive medication, many people who are candidates for preventive therapies do not receive them. Thus, there is still a substantial unmet need for preventive migraine treatment. Calcitonin gene-related peptide (CGRP) has a demonstrated role in the pathophysiology of migraine. Galcanezumab-gnlm (galcanezumab) is a humanized monoclonal antibody that binds to the CGRP ligand and prevents binding to its receptor. It is administered as a once-monthly subcutaneous injection. The aim of this review is to present a comprehensive overview of the existing short- and long-term efficacy and safety data for galcanezumab in patients with migraine. Data from the phase 3, randomized, double-blind, placebo-controlled EVOLVE-1, EVOLVE-2 and REGAIN studies show that galcanezumab treatment for 3 or 6 months results in overall reduction in mean monthly migraine headache days in patients with episodic (EVOLVE-1 and EVOLVE-2) and chronic (REGAIN) migraine. Greater proportions of patients with episodic migraine receiving galcanezumab versus placebo demonstrated a ≥ 50%, ≥ 75% and 100% response to therapy and reported a lower level of disability and an improvement in functioning and QoL. Similarly, when compared with placebo, greater proportions of patients with chronic migraine treated with galcanezumab demonstrated a ≥ 50% and ≥ 75% response and reported improved functioning. A 12-month open-label study demonstrated the continued efficacy of galcanezumab for up to 12 months. In all studies galcanezumab was well tolerated. In conclusion, data from pivotal studies show that galcanezumab may fulfill an unmet need in the treatment of patients with migraine who require preventive therapy. [ABSTRACT FROM AUTHOR]

There are many acute care and preventive medications for the treatment of migraine. However, patients may often find that their headaches are not under optimal control. There are several targets that have been looked at and studied for the production of new, more effective medications. There are also effective devices for therapy of migraine. A list of targets will be put forth and a small number of them will be described in greater detail in this paper.

The article focuses on two small molecule Calcitonin gene-related peptide (CGRP) receptor antagonists, ubrogepant, and rimegepant. The main results of large Phase 3 trials of the drugs were reportedly presented as abstracts at several medical conferences in the first half of 2018. It adds that pain-free at 2 hours has been used as the primary efficacy outcome measure in most randomized controlled trials of newer treatments for migraine.

Triptans, serotonin 5-HT1B/1D receptor agonists, more than revolutionizing the treatment of migraine, stimulated also ground breaking research that provided insights into the anatomy, physiology, and molecular pharmacology of migraine. This knowledge, in turn, is stimulating research on new mechanisms of action for the treatment of migraine. Accordingly, it is opportune to critically review the main advances in migraine science that happened in the triptan era. Herein we first review and conceptualize some of the progresses achieved in migraine science during the triptan era. We then review the class of the triptans - mechanism of action and clinical evidence. We close by briefly discussing the class of CGRP receptor antagonists, which is currently being developed for the acute treatment of migraine.Os triptanos, agonistas serotoninérgicos 5-HT1B/1D, revolucionaram o tratamento da migrânea promovendo pesquisas que evidenciaram aspectos da anatomia, fisiologia e farmacologia molecular deste tipo prevalente de cefaléia primária. Esse conhecimento, por sua vez vem estimulando ainda mais a descoberta de novos mecanismos de ação para drogas anti-migranosas. Assim, é oportuno rever de forma crítica, os maiores avanços na ciência das cefaléias ocorridos durante a era dos triptanos. Inicialmente reveremos e conceituaremos alguns dos progressos obtidos nesta fase seguido de uma revisão profunda dos mecanismos de ação e evidências clínicas para o uso desta classe de fármacos. Finalmente, discutiremos a nova classe dos antagonistas dos receptores do peptideo geneticamente relacionado à calcitonina (CGRP) atualmente em desenvolvimento.

Migraine is the second leading cause of years lived with disability. Patients with chronic migraine (CM) face enormous barriers in accessing care and in receiving an accurate diagnosis and appropriate treatment. This article reviews the following: epidemiology, definition, pathophysiology, medication overuse, and acute and preventive treatment., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Migraine is a neurovascular condition characterized by episodes of severe headache with inter-individual variability. Inflammation of neurogenic origin contributes to the mechanism of occurrence of migraine and other primary headaches. Neurovascular headache is a condition in which neural events have as a result dilation of blood vessels and the appearance of painful sensation. CGRP (calcitonin-gene-related peptide) is a neuropeptide widespread both in the central and peripheral nervous system, being one of the most potent vasodilator substances with important role in controlling blood pressure in both normal and abnormal conditions. The releasing of perivascular peptides relaxes cerebral arteries while stimulating cAMP accumulation or release of EDRF (endothelium derived relaxing factor). An alternative to acute treatment of migraine used so far is the CGRP receptor blockade with selective antagonists. They represent potential therapeutic molecules with superior advantages to triptans and a longer duration of action. [ABSTRACT FROM AUTHOR]

Migraine is a complex disorder of the brain that is common and highly disabling. As understanding of the neural pathways has advanced, and it has become clear that the vascular hypothesis does not explain the disorder, new therapeutic avenues have arisen. One such target is calcitonin gene-related peptide (CGRP)-based mechanisms. CGRP is found within the trigeminovascular nociceptive system widely from the trigeminal ganglion to second-order and third-order neurons and in regulatory areas in the brainstem. Studies have shown CGRP is released during severe migraine attacks and the reversal of the attack with effective triptan treatment normalizes those levels. CGRP administration triggers migraine in patients, and CGRP receptor antagonists have been shown to abort migraine. Here, we review the current state of CGRP mechanism antagonist therapy as its research and development is increasing in migraine therapeutics. We discuss several recent trials, highlighting the evidence base behind these novel drugs, and their potential future contribution to migraine management. [ABSTRACT FROM AUTHOR]

Abstract: Calcitonin gene-related peptide (CGRP) has been implicated in acute migraine pathogenesis. In an effort to identify novel CGRP receptor antagonists for the treatment of migraine, we have discovered thiazolidinone 49, a potent (K i =30pM, IC50 =1nM), orally bioavailable, CNS-penetrant CGRP antagonist with good pharmacokinetic properties. [Copyright &y& Elsevier]

In this review, the authors provide an overview of erenumab, a monoclonal antibody used for the preventative treatment of episodic migraine by targeting the CGRP pathway. Randomized controlled trials have shown that erenumab is associated with a statistically significant decrease in monthly migraine days in patients with episodic migraine at monthly doses of 70 or 140 mg when given for a period of 9-12 weeks. Post hoc analyses have also shown long-term maintenance of efficacy. Clinical trials have found erenumab at doses of both 70 and 140 mg to have a favorable safety profile. Erenumab faces significant limitations because of its high financial cost. Additional long-term real-world data are needed to understand the role of erenumab in the treatment of migraine.

There are numerous headache therapies available for our patients, more for migraine than for any of the other primary headache disorders. Only four medications have been approved for migraine prevention in the last few decades in the US and onabotulinumtoxinA was recently approved in the UK and the US for chronic migraine. We have been more fortunate in the acute care arena where in the US we have had seven triptans and one nonsteroidal anti-inflammatory medication approved by the FDA and currently available. There are several other acute care medications in various stages of development and there are two new methods of administering a triptan and others under investigation. We are always looking for faster, easier and more efficient administration of medications with fewer adverse events, as optimal migraine therapy requires these characteristics. What follows is a brief review of the progress in development for four of the many new acute care medications being investigated: the CGRP antagonist tablet telcagepant, the sumatriptan iontophoretic patch, sumatriptan powder for use in the OptiNose apparatus and the dihydroergotamine oral inhaler. I will not include transcranial magnetic stimulation, a 5-HT agonist, large conductance calcium-activated potassium channel openers, glial modulators or other medications and devices in early stages of development []. [ABSTRACT FROM AUTHOR]

Migraine is a complex, neurovascular disorder in which genetic and environmental factors interact. At present, frontline therapies in the acute treatment of migraine include the use of non-steroidal anti-inflammatory drugs and triptans. Evidence indicates that calcitonin gene-related peptide (CGRP) plays a fundamental role in the mechanism of migraine. CGRP is a strong vasodilatatory neuropeptide that is released from activated trigeminal sensory nerves. The development of CGRP antagonists has also been driven by the fact that triptans are vasoconstrictive and cannot be safely used in patients with cardiovascular risk factors. Olcegepant (BIBN4096) is the first CGRP antagonist for the treatment of migraine that has been tested in clinical trials, but because of its poor oral bioavailability, only the intravenous formulation has been tested. The first oral non-peptide CGRP antagonist, telcagepant, has been shown recently to be highly effective in the treatment of migraine attacks. This development can be considered as the most important pharmacological breakthrough for migraine treatment since the introduction of sumatriptan in the early 1990s. These results are also of importance, since they support an interesting pathophysiological hypothesis of migraine. The pipeline of future compounds for the treatment of acute migraine headaches include TPRV1 antagonists, prostaglandin E receptor 4 (EP4) receptor antagonists, serotonin 5HT1F receptor agonists and nitric oxide synthase inhibitors. The immediate future of a preventative treatment for migraine headaches is well represented by botulinum toxin type-A, glutamate NMDA receptor antagonists, gap-junction blocker tonabersat and an angiotensin type 1 blocker candesartan. [ABSTRACT FROM AUTHOR]

ABSTRACT Basal studies have shown that calcitonin gene-related peptide (CGRP) is a major sensory neuronal messenger in the trigeminovascular system, the pathway conveying intracranial pain. In migraine and cluster headache attacks, CGRP is released in parallel with the pain and successful treatment of the attacks abort both the associated pain and the CGRP release. The search for a potent small molecule CGRP antagonist has been successful and such an agent has been tested in preclinical and clinical studies. The aim of the present study was to examine current knowledge on the clinical pharmacology of systemic BIBN4096BS, which has been shown in man to abort acute migraine attacks as well or better than oral sumatriptan. BIBN4096BS is a specific and potent CGRP receptor antagonist in humans. In safety and tolerability studies the substance is well tolerated with no or only mild side effects. In acute migraine attacks the overall response was 66% with the drug and 27% with placebo. A difference as compared to placebo was seen at 30 min; the response was still rising at 4 h suggesting a long duration of action. At 24 h the pain-free rate was better than that with triptans, suggesting a lower grade of rebound and perhaps even a prophylactic possibility. [ABSTRACT FROM AUTHOR]

• CGRP promotes prostate tumor growth in bone microenvironment. • CGRP antagonists inhibits prostate tumor growth in bone microenvironment. • 3. CGRP treatment activates ERKs/STAT3 signaling in prostate cancer cells. • 4. CGRP may be a therapeutic target for advanced prostate cancer patients. Advanced stage of prostate cancer cells preferentially metastasizes to varying bones of prostate cancer patients, resulting in incurable disease with poor prognosis and limited therapeutical treatment options. Calcitonin gene-related peptide (CGRP), a neuropeptide produced by prostate gland, is known to play a pivotal role in facilitating tumor growth and metastasis of numerous human cancers. In this study, we aim to investigate the clinical relevance of CGRP in prostate cancer patients and the effects of CGRP and CGRP antagonists on prostate tumor growth in the mouse model. The prostate tumor-bearing mice were received either CGRP or CGRP antagonist treatment, and the tumor growth was monitored by quantification of luminescence intensities. We found that the CGRP+ nerve fiber density and serum CGRP levels were substantially upregulated in the bone or serum specimens from advanced prostate cancer patients as well as in prostate tumor-bearing mice. Administration of CGRP promoted, whereas treatment of CGRP antagonists inhibited prostate tumor growth in the femurs of mice. In addition, CGRP treatment activated extracellular signal-regulated kinases (ERKs)/ Signal transducer and activator of transcription 3 (STAT3) signaling in prostate cancer cells. Targeting CGRP may serve as a potential therapeutic strategy for advanced prostate cancer patients. [ABSTRACT FROM AUTHOR]