Search

Migraine is considered one of the most disabling neurological disorder with a high socioeconomic burden. Pharmacological management includes many classes of drugs which in the most cases, are administrated in polytherapy. The therapeutic scheme of migraineurs is often affected by comorbidities which need concomitant medications, thus increasing the risk of side effects related to drug-drug interactions. Pharmacogenetics is a promising tool to achieve a personalized cure based on individual genetic profile while the availability of free online knowledge bases allows to check the potential DDIs of selected medications. Combining, these approaches may offer to clinicians a useful tool to improve the appropriateness of migraine polytherapy choice, aiming to increase the efficacy and reduce the toxicity of pharmacological treatments.

ABSTRACTIntroduction: Migraine is the most common of all neurological disorders. A breakthrough in migraine treatment emerged in the early nineties with the introduction of 5-HT1B/D receptor agonists called triptans. Triptans are used as the standard of care for acute migraine; however, they have significant limitations such as incomplete and inconsistent pain relief, high rates of headache recurrence, class- specific side effects and cardiovascular contraindications. First- and second-generation calcitonin gene-related peptide (CGRP) receptor antagonists, namely gepants, is a class of drugs primarily developed for the acute treatment of migraine. CGRP is the most evaluated target for migraine treatments that are in development.Areas covered: This article reviews the available data for first- and second-generation CGRP receptor antagonists, the role of CGRPs in human physiology and migraine pathophysiology and the possible mechanism of action and safety of CGRP-targeted drugs.Expert opinion: Available data suggest that second generation of gepants has clinical efficacy similar to triptans and lasmiditan (5-HT1F receptor agonist) and has improved tolerability. Future studies will assess their safety, especially in specific populations such as patients with cardiovascular disease and pregnant women.

ABSTRACTIntroduction: Migraine is a common and highly disabling neurological disorder whose acute treatment remains problematic and unsatisfactory in a high percentage of cases. Consequently, there remains a need for new symptomatic therapies that can be easily handled by patients (i.e. by oral administration).Area covered: This review reports on compounds currently under development for the oral treatment of acute migraine attacks, focusing on Calcitonin-Gene-Related-Peptide receptor antagonists, specifically ubrogepant and rimegepant. This article is based on literature obtained from PubMed and publicly available clinical trial data.Expert opinion: Both reviewed compounds meet the need for rapid and effective pain control, combined with the control of associated bothersome symptoms while also lacking significant adverse events and safety concerns. Though further studies should assess the profile of these compounds comparatively with existing and available treatments (namely triptans), the currently available data points to these new therapies as being very promising new symptomatic oral treatments of migraines.

ABSTRACTIntroduction: Migraine is a common neurological disorder with a complex pathophysiology. It has been estimated that incidence between adults of current headache disorder is about 50%. Different studies show that this condition has an important and complex genetic component in response to drug therapy.Areas covered: This review shows and summarizes the importance of the polymorphisms associated with the major antimigraine drug metabolizing enzymes. The research of bibliographic databases has involved only published peer-reviewed articles from indexed journals.Expert opinion: Pharmacogenetics is based on the identification of polymorphism and promises personalized therapy with efficacy and reduction of adverse events. The association between genotype and an altered metabolizer status could guide clinical decision to evade concomitant treatments and adverse events. The introduction of routine genetic testing could help to choose the efficacy drug on the individual and genetic profile.

ABSTRACTIntroduction: Migraine is a very frequent and disabling neurological disorder. The current treatment options are old, generally poorly tolerated and not migraine-specific, reflecting the low priority of migraine research and highlighting the vast unmet need in its management.Areas covered: Advancement in the understanding of migraine pathophysiological mechanisms and identification of novel potentially meaningful targets have resulted in a multitude of emerging acute and preventive treatments. Here we review the known putative migraine pathophysiological mechanisms in order to understand the rationale of the most promising novel treatments targeting the Calcitonin-Gene-Related Peptide receptor and ligand and the 5 hydroxytryptamine (5-HT)1F receptor. Key findings on the phase II and phase III clinical trials on these treatments will be summarized. Furthermore, a critical analysis on failed trials of potentially meaningful targets such the nitric oxide and the orexinergic pathways will be conducted. Future perspective will be outlined.Expert opinion: The recent approval of Erenumab and Fremanezumab is a major milestone in the therapy of migraine since the approval of triptans. Several more studies are needed to fully understand the clinical potential, long-term safety and cost-effectiveness of these therapies. This paramount achievement should stimulate the development of further research in the migraine field.

Non-syndromic sensorineural hearing loss (SNHL) is the most common sensory disorder, and it presents a high genetic heterogeneity. As part of our clinical genetic studies, we ascertained a previously unreported mutation in CCDC50 [c.828_858del, p.(Asp276Glufs*40)] segregating with hearing impairment in a Spanish family with SNHL associated with the autosomal dominant deafness locus DFNA44, which is predicted to disrupt protein function. To gain insight into the mechanism behind DFNA44 mutations, we analysed two Ccdc50 presumed loss-of-function mouse mutants, which showed normal hearing thresholds up to 6 months of age, indicating that haploinsufficiency is unlikely to be the pathogenic mechanism. We then carried out in vitro studies on a set of artificial mutants and on the p.(Asp276Glufs*40) and p.(Phe292Hisfs*37) human mutations, and determined that only the mutants containing the six-amino-acid sequence CLENGL as part of their aberrant protein tail showed an abnormal distribution consisting of perinuclear aggregates of the CCDC50 protein (also known as Ymer). Therefore, we conclude that the CLENGL sequence is necessary to form these aggregates. Taken together, the in vivo and in vitro results obtained in this study suggest that the two identified mutations in CCDC50 exert their effect through a dominant-negative or gain-of-function mechanism rather than by haploinsufficiency.

ABSTRACTIntroduction: Migraine is one of the most common diseases in the world, with high economical and subjective burden. Migraine acute therapy is nowadays based on specific and non-specific drugs but up to 40% of episodic migraineurs still have unmet treatment needs and over 35% do not benefit from triptans administration. Serotonin-1F receptors have been identified in trigeminal system and became an ideal target for anti-migraine drug development as potential trigeminal neural inhibitors. Lasmiditan, a novel serotonin1F receptor agonist, showed specific affinity in vitrofor the receptor without any vasoconstrictive action and inhibited markers associated with electrical stimulation of trigeminal ganglion in migraine animal models.Areas covered: This article reviews both preclinical and clinical studies on lasmiditan as a potential acute therapy for migraine, as well as pharmacokinetic and pharmacodynamic features. It also summarizes safety and tolerability data gathered in the various human studies.Expert opinion: The absence of vasoconstrictive effects makes lasmiditan a promising novel migraine acute therapy. Although preclinical and Phase I and II studies established a significant efficacy, the limited knowledge about pharmacokinetics and metabolism, the high rate of non-serious central nervous system side effects and the lack of larger studies remain still a matter of concern that should be addressed in future studies.

ABSTRACTIntroduction: The cornerstones of cluster headache therapy are based on the tripod of acute, transitional and preventative treatments that respectively aim to the control of the bouts, the transitional suppression of the relapse and the prevention of the entire cluster period. Particularly in chronic cluster headache, where a long-term preventative therapy is necessary, multiple drug regimens increase the risk of drug-drug interactions leading to variability in the clinical efficacy and to potentially harmful adverse effects.Areas covered: We focused on how clinically significant pharmacokinetic drug-drug and food-drug interactions can be carefully managed both in cluster headache patients with a progressive frequency of bouts and in chronic cluster headache sufferers. In fact, in these cases a long-term preventive therapy is indicated, increasing the possibility of interactions both with other transitional and acute cluster headache medications and with other foods or xenobiotics.Expert opinion: Pharmacokinetic interactions for both preventive, transitional and acute drugs are significant with a number of xenobiotics and other medications. Therefore, the pharmacokinetic issues knowledge is advisable for a safe and effective cluster headache management.

ABSTRACTIntroduction: Drugs used in the treatment of migraine have been reported to be highly associated with the occurrence of clinically significant drug-drug interactions (DDIs). Multiple drug therapy regimens are used for migraine treatment, particularly for chronic migraine. In fact, additional pharmacological agents are usually administered during an acute migraine attack in patients chronically treated with the prophylactic therapy. The variety of drugs available for migraine prophylactic and acute treatment, and consequently their pharmacological interactions, might complicate the choice of a safe combination therapy.Areas covered: This study discusses the prophylactic-acute DDIs from a pharmacokinetic and pharmacodynamic perspective, particularly interactions between antiepileptic drugs, tricyclic antidepressants, β-blockers, calcium channel blockers, triptans, nonsteroidal anti-inflammatory drugs and ergot derivatives. The available online tools have been used to evaluate the clinically significant DDIs.Expert opinion: The interactions between different drugs might be accurately predicted by the huge and detailed knowledge about the molecular pathways involved in pharmacodynamics and pharmacokinetics. Pharmacogenomic research has shed further light onto the mechanisms involved in the inter-individual variation in drug response and DDIs. Based on this knowledge, this paper will provide suggestions to improve the appropriateness of the drug choice in the prescription of preventative and acute migraine medications.

The therapeutic management of cluster headache is based on a very stable triad of drugs. Acute treatment has, in subcutaneous sumatriptan, its gold standard if compared to pure oxygen or indomethacin. Preventative treatment is based on verapamil at high doses (≥ 360 mg) and is a gold standard if compared to lithium carbonate or topiramate. Transitional treatments, based on the short-term use of corticosteroids with either systemic or local administration (GON), can be useful for the suppression of most resistant cluster periods, but with a well-known carry-over phenomenon related to the length of the cluster period itself. The role of invasive or noninvasive neuromodulation approaches must still be determined on a large scale; therefore, its use is not recommended as of yet. Lifestyle changes, including alcohol avoidance during the active phase of the disease, sleep hygiene and use of vasodilation drugs, should be carefully considered and the patients should be fully informed.

Introduction:Migraine is a highly prevalent and disabling neurological condition whose personal, social and economic impact is substantial. Abortive and preventative treatments of this condition are still unsatisfactory, with poor control of the acute symptoms of the single attacks in many cases and a frequent progression towards chronicity.Areas covered:The major drug classes recently developed and/or in current development for migraine treatment are discussed. These include: Calcitonin-Gene-Related Peptide (CGRP) receptor antagonists, mAbs against CGRP or its receptor, selective 5 hydroxytryptamine (5-HT)1F receptor agonists, drugs targeting Acid-Sensing Ion Channels, Transient Receptor Potential channels and Nitric Oxide.Expert opinion:The most convincing results appear those obtained with mAbs against CGRP, particularly in migraine preventative treatment, given the absence of serious adverse events, and the good response in terms of pain relief. If these results are confirmed in larger studies, these compounds have the potential to significantly improve the pharmacological control of migraine and also its evolution towards chronicity.