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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.

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.

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., Plain Language Summary Migraine is a significant contributor to the global burden of disease. Migraine symptoms can lead to substantial disability and can significantly impact an individual’s ability to perform everyday tasks and their overall quality of life. While individuals with infrequent migraine attacks might have success with acute treatments alone, those with more frequent attacks or who have severe migraine-related impairment may require preventive treatment. Although recommendations on the use of preventive treatment exist, only about one-third of individuals who qualify for preventive therapy actually receive it, resulting in a substantial unmet need. Calcitonin gene-related peptide (CGRP) has a demonstrated role in migraine. Galcanezumab is a humanized monoclonal antibody that binds to the CGRP ligand and prevents receptor binding. In clinical trials of patients with ≥ 4 migraine headache days per month, treatment with galcanezumab was associated with a reduction in the average number of migraine headache days per month. The majority of galcanezumab groups had greater responder rates compared with the placebo groups, and levels of disability and daily functioning were generally improved. Galcanezumab was well tolerated, with the most common adverse events being injection site reactions. The results from the clinical trials of galcanezumab suggest that this drug may fulfill an unmet need in the treatment of individuals with migraine who require preventive therapy.

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.

Migren, mide bulantısı ile ilişkili ciddi bir primer baş ağrısı hastalığıdır. Çalışmalar, en yaygın üçüncü hastalık olduğunu ve 50 yaşın altındaki en yüksek üçüncü sakatlık nedeni olduğunu bildirmiştir. Hastalığın kompleks patofizyolojisi, mevcut farmakoterapi için sayısız hedefleri ortaya koymaktadır. Migrenin farmakoterapisi, akut atak ve önleme yönetiminde kullanılan ilaçları içerir. Akut atak farmakoterapisi, NSAID’leri, ergot alkaloitlerini, triptanları ve antiemetik / dopamin reseptörü antagonistlerini içerir. Seçici bir serotonin 1F reseptörü agonisti ve CGRP antagonistleri olan Lasmiditan, akut atak tedavisi için ilaç geliştirme hattında bulunmaktadır. Profilaktik migren tedavisi sıklığa, süreye ve sakatlık derecesine göre başlar. Profilaktik farmakoterapide antihipertansifler, antidepresanlar, antikonvülsanlar reçete edilir. CGRP antagonistleri son zamanlarda önlenmesi için ilaçları onayladılar. Tedavi kararı, eşlik eden hastalıklara bağlı olabilir. Farmakolojik olmayan müdahaleler için öneri, ‘migren döneminde erken dönemde akut atak tedavisi başlatılması, migren hasta yönetiminde aşırı ilaç kullanımından kaçınılması önemlidir., Migraine is a severe primary headache disorder frequently associated with nausea. Studies have documented it is the third most prevalent disorder and it is reported as the third-highest cause of disability under the age of 50 years. The complex pathophysiology of the disease makes numerous targets for pharmacotherapy available. The pharmacotherapy of migraine involves medications used in acute attack and prevention management. Acute attack pharmacotherapy involves NSAIDs, ergot alkaloids, triptans, and antiemetic/dopamine receptor antagonists. Lasmiditan, a selective serotonin 1F receptor agonist and CGRP antagonists are in the drug development pipeline for acute attack treatment. Prophylactic migraine treatment is started according to frequency duration, and degree of disability. In prophylactic pharmacotherapy antihypertensives, antidepressants, anticonvulsants are prescribed. CGRP antagonists have recently approved drugs for prevention. Therapy decision may depend on concomitant diseases. Recommendation for nonpharmacologic interventions, ‘initiation of acute attack therapy early in the course of migraine, Avoidance of medication overuse is important in migraine patient management.

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.

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.

Opiate analgesics and tricyclic antidepressants (TCAs) are two major classes of therapeutic agents which are used to alleviate symptoms due to chronic nociception. But these chemotherapeutic agents pose side effects like constipation, physical dependence along with insufficient pain relief. Hence these complications aggravate the necessity of designing a molecule which acts on new target in order to overcome the side effects caused by the above said class of drugs. Meanwhile, the distribution of Calcitonin Gene Related Peptide (CGRP), a 37 amino acid neuropeptide both in central and peripheral nervous system and its role in visceral pain has opened up a new gateway for treating visceral nociceptive pain. Thus, the main aim of the project was to merge CGRP antagonist property as well as Antidepressant property in a single molecule, to provide a synergistic effect and to treat Chronic, inflammatory and neglected diseases like Irritable bowel syndrome (IBS) and Crohn’s disease., Analgésiques opiacés et les antidépresseurs tricycliques (ATC) sont deux grandes classes d'agents thérapeutiques qui sont utilisés pour soulager les symptômes dus au nociception chronique. Mais ces agents chimio thérapeutiques présentent des effets secondaires comme la constipation, dépendance physique plus soulagement de la douleur insuffisante. D'où des complications aggravent la nécessité de concevoir une molécule qui agit sur nouvelle cible en vue de surmonter les effets secondaires causés par la classe dit ci-dessus de médicaments. Pendant ce temps, la distribution du peptide lié au gène de la calcitonine (CGRP), un neuropeptide de 37 acides aminés deux dans le système nerveux central et périphérique et son rôle dans la douleur viscérale a ouvert une nouvelle porte d'entrée pour le traitement de la douleur nociceptive viscérale. Ainsi, l'objectif principal du projet de fusionner propriété antagoniste de CGRP ainsi que la propriété antidépresseur dans une seule molécule, pour fournir un effet de synergie et de traiter les maladies chroniques, inflammatoires et négligées comme le syndrome du côlon irritable (IBS) et la maladie de Crohn.

Opiate analgesics and tricyclic antidepressants (TCAs) are two major classes of therapeutic agents which are used to alleviate symptoms due to chronic nociception. But these chemotherapeutic agents pose side effects like constipation, physical dependence along with insufficient pain relief. Hence these complications aggravate the necessity of designing a molecule which acts on new target in order to overcome the side effects caused by the above said class of drugs. Meanwhile, the distribution of Calcitonin Gene Related Peptide (CGRP), a 37 amino acid neuropeptide both in central and peripheral nervous system and its role in visceral pain has opened up a new gateway for treating visceral nociceptive pain. Thus, the main aim of the project was to merge CGRP antagonist property as well as Antidepressant property in a single molecule, to provide a synergistic effect and to treat Chronic, inflammatory and neglected diseases like Irritable bowel syndrome (IBS) and Crohn’s disease.; Analgésiques opiacés et les antidépresseurs tricycliques (ATC) sont deux grandes classes d'agents thérapeutiques qui sont utilisés pour soulager les symptômes dus au nociception chronique. Mais ces agents chimio thérapeutiques présentent des effets secondaires comme la constipation, dépendance physique plus soulagement de la douleur insuffisante. D'où des complications aggravent la nécessité de concevoir une molécule qui agit sur nouvelle cible en vue de surmonter les effets secondaires causés par la classe dit ci-dessus de médicaments. Pendant ce temps, la distribution du peptide lié au gène de la calcitonine (CGRP), un neuropeptide de 37 acides aminés deux dans le système nerveux central et périphérique et son rôle dans la douleur viscérale a ouvert une nouvelle porte d'entrée pour le traitement de la douleur nociceptive viscérale. Ainsi, l'objectif principal du projet de fusionner propriété antagoniste de CGRP ainsi que la propriété antidépresseur dans une seule molécule, pour fournir un effet de synergie et de traiter les maladies chroniques, inflammatoires et négligées comme le syndrome du côlon irritable (IBS) et la maladie de Crohn.

Opiate analgesics and tricyclic antidepressants (TCAs) are two major classes of therapeutic agents which are used to alleviate symptoms due to chronic nociception. But these chemotherapeutic agents pose side effects like constipation, physical dependence along with insufficient pain relief. Hence these complications aggravate the necessity of designing a molecule which acts on new target in order to overcome the side effects caused by the above said class of drugs. Meanwhile, the distribution of Calcitonin Gene Related Peptide (CGRP), a 37 amino acid neuropeptide both in central and peripheral nervous system and its role in visceral pain has opened up a new gateway for treating visceral nociceptive pain. Thus, the main aim of the project was to merge CGRP antagonist property as well as Antidepressant property in a single molecule, to provide a synergistic effect and to treat Chronic, inflammatory and neglected diseases like Irritable bowel syndrome (IBS) and Crohn’s disease.; Analgésiques opiacés et les antidépresseurs tricycliques (ATC) sont deux grandes classes d'agents thérapeutiques qui sont utilisés pour soulager les symptômes dus au nociception chronique. Mais ces agents chimio thérapeutiques présentent des effets secondaires comme la constipation, dépendance physique plus soulagement de la douleur insuffisante. D'où des complications aggravent la nécessité de concevoir une molécule qui agit sur nouvelle cible en vue de surmonter les effets secondaires causés par la classe dit ci-dessus de médicaments. Pendant ce temps, la distribution du peptide lié au gène de la calcitonine (CGRP), un neuropeptide de 37 acides aminés deux dans le système nerveux central et périphérique et son rôle dans la douleur viscérale a ouvert une nouvelle porte d'entrée pour le traitement de la douleur nociceptive viscérale. Ainsi, l'objectif principal du projet de fusionner propriété antagoniste de CGRP ainsi que la propriété antidépresseur dans une seule molécule, pour fournir un effet de synergie et de traiter les maladies chroniques, inflammatoires et négligées comme le syndrome du côlon irritable (IBS) et la maladie de Crohn.

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.