The pharmacotherapeutic management of episodic and chronic migraine with gepants

The small molecule non-peptide calcitonin gene-related peptide (CGRP) receptor antagonists named gepants offer a breakthrough novel approach in migraine acute and prophylactic drug treatment. This review aimed to determine the place of gepants in the treatment of episodic and chronic migraine.The new-generation gepants are ubrogepant, atogepant, rimegepant and zavegepant. Ubrogepant is ratified for acute migraine treatment, atogepant is validated for preventive therapy, whereas rimegepant is retified for both indications, all via oral administration, while zavegepant is administered intranasally for migraine attacks. Gepants are effective, safe, and well-tolerated in the acute or prophylactic therapy. The PubMed literature search included randomized controlled trials, meta-analyses, real-world data, and review articles published in English until January 2023.Whether gepants will be real game changers in the acute treatment of migraine compared to triptans and ditans, or in the prophylactic therapy compared to standard-of-care preventive drugs or CGRP-targeting monoclonal antibodies can not be answered yet based on the available literature data

Chronic Migraine as a Primary Chronic Pain Syndrome and Recommended Prophylactic Therapeutic Options : A Literature Review

Chronic pain conditions have a high socio-economic impact and represent a burden for patients, and their management is a challenge for healthcare professionals. Chronic migraine is one of the chronic primary headache disorders, which belong to chronic primary pain syndromes as per the new concept of multiple parenting. The aims of this review were to provide an overview of the latest classification systems involving both entities, the epidemiological data, and the currently recommended prophylactic treatment options for chronic migraine. Randomized controlled clinical trials, meta-analyses, real-world data, and review articles were analyzed. Chronic migraine is a prevalent and highly burdensome disease and is associated with high headache-related disability and worsening health-related quality of life. Treatment of chronic migraine includes pharmacological or, in drug-refractory cases, non-pharmacological (e.g., neuromodulatory) approaches. Among pharmacological treatment options, injectable botulinum toxin type A and calcitonin gene-related peptide-targeting human and fully humanized monoclonal antibodies (i.e., eptinezumab, erenumab, fremanezumab, and galcanezumab) are highly recommended in the preventive treatment of chronic migraine. Novel migraine-specific therapies offer a solution for this devastating and difficult-to-treat chronic pain condition

From CGRP to PACAP, VIP, and Beyond: Unraveling the Next Chapters in Migraine Treatment

Migraine is a neurovascular disorder that can be debilitating for individuals and society. Current research focuses on finding effective analgesics and management strategies for migraines by targeting specific receptors and neuropeptides. Nonetheless, newly approved calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) have a 50% responder rate ranging from 27 to 71.0%, whereas CGRP receptor inhibitors have a 50% responder rate ranging from 56 to 71%. To address the need for novel therapeutic targets, researchers are exploring the potential of another secretin family peptide, pituitary adenylate cyclase-activating polypeptide (PACAP), as a ground-breaking treatment avenue for migraine. Preclinical models have revealed how PACAP affects the trigeminal system, which is implicated in headache disorders. Clinical studies have demonstrated the significance of PACAP in migraine pathophysiology; however, a few clinical trials remain inconclusive: the pituitary adenylate cyclase-activating peptide 1 receptor mAb, AMG 301 showed no benefit for migraine prevention, while the PACAP ligand mAb, Lu AG09222 significantly reduced the number of monthly migraine days over placebo in a phase 2 clinical trial. Meanwhile, another secretin family peptide vasoactive intestinal peptide (VIP) is gaining interest as a potential new target. In light of recent advances in PACAP research, we emphasize the potential of PACAP as a promising target for migraine treatment, highlighting the significance of exploring PACAP as a member of the antimigraine armamentarium, especially for patients who do not respond to or contraindicated to anti-CGRP therapies. By updating our knowledge of PACAP and its unique contribution to migraine pathophysiology, we can pave the way for reinforcing PACAP and other secretin peptides, including VIP, as a novel treatment option for migraines

Cluster headache and kynurenines

The glutamatergic neurotransmission has important role in the pathomechanism of primary headache disorders. The kynurenine metabolites derived from catabolism of tryptophan (Trp) have significant involvement not only in glutamatergic processes, but also in the neuroinflammation, the oxidative stress and the mitochondrial dysfunctions. Previously we identified a depressed peripheral Trp metabolism in interictal period of episodic migraineurs, which prompted us to examine this pathway in patients with episodic cluster headache (CH) as well. Our aims were to compare the concentrations of compounds both in headache-free and attack periods, and to find correlations between Trp metabolism and the clinical features of CH. Levels of 11 molecules were determined in peripheral blood plasma of healthy controls (n = 22) and interbout/ictal periods of CH patients (n = 24) by neurochemical measurements.Significantly decreased L-kynurenine (KYN, p < 0.01), while increased quinolinic acid (QUINA, p < 0.005) plasma concentrations were detected in the interbout period of CH patients compared to healthy subjects. The levels of KYN are further reduced during the ictal period compared to the controls (p < 0.006). There was a moderate, negative correlation between disease duration and interbout QUINA levels (p < 0.048, R = - 0.459); and between the total number of CH attacks experienced during the lifetime of patients and the interbout KYN concentrations (p < 0.024, R = - 0.516). Linear regression models revealed negative associations between age and levels of Trp, kynurenic acid, 3-hdyroxyanthranilic acid and QUINA in healthy control subjects, as well as between age and ictal level of anthranilic acid.Our results refer to a specifically altered Trp metabolism in CH patients. The onset of metabolic imbalance can be attributed to the interbout period, where the decreased KYN level is unable to perform its protective functions, while the concentration of QUINA, as a toxic compound, increases. These processes can trigger CH attacks, which may be associated with glutamate excess induced neurotoxicity, neuroinflammation and oxidative stress. Further studies are needed to elucidate the exact functions of these molecular alterations that can contribute to identify new, potential biomarkers in the therapy of CH