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      The need for new acutely acting antimigraine drugs: moving safely outside acute medication overuse

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          Abstract

          Background

          The treatment of migraine is impeded by several difficulties, among which insufficient headache relief, side effects, and risk for developing medication overuse headache (MOH). Thus, new acutely acting antimigraine drugs are currently being developed, among which the small molecule CGRP receptor antagonists, gepants, and the 5-HT 1F receptor agonist lasmiditan. Whether treatment with these drugs carries the same risk for developing MOH is currently unknown.

          Main body

          Pathophysiological studies on MOH in animal models have suggested that decreased 5-hydroxytryptamine (5-HT, serotonin) levels, increased calcitonin-gene related peptide (CGRP) expression and changes in 5-HT receptor expression (lower 5-HT 1B/D and higher 5-HT 2A expression) may be involved in MOH. The decreased 5-HT may increase cortical spreading depression frequency and induce central sensitization in the cerebral cortex and caudal nucleus of the trigeminal tract. Additionally, low concentrations of 5-HT, a feature often observed in MOH patients, could increase CGRP expression. This provides a possible link between the pathways of 5-HT and CGRP, targets of lasmiditan and gepants, respectively. Since lasmiditan is a 5-HT 1F receptor agonist and gepants are CGRP receptor antagonists, they could have different risks for developing MOH because of the different (over) compensation mechanisms following prolonged agonist versus antagonist treatment.

          Conclusion

          The acute treatment of migraine will certainly improve with the advent of two novel classes of drugs, i.e., the 5-HT 1F receptor agonists (lasmiditan) and the small molecule CGRP receptor antagonists (gepants). Data on the effects of 5-HT 1F receptor agonism in relation to MOH, as well as the effects of chronic CGRP receptor blockade, are awaited with interest.

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          Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial.

          Stewart Tepper, Messoud Ashina, Uwe Reuter … (2017)
          The calcitonin gene-related peptide (CGRP) pathway is important in migraine pathophysiology. We assessed the efficacy and safety of erenumab, a fully human monoclonal antibody against the CGRP receptor, in patients with chronic migraine.
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            Galcanezumab in chronic migraine

            Holland Detke, Peter J Goadsby, Shufang Wang … (2018)
            Objective To evaluate the efficacy and safety of galcanezumab, a humanized monoclonal antibody that selectively binds to calcitonin gene-related peptide, in the preventive treatment of chronic migraine. Methods A phase 3, randomized, double-blind, placebo-controlled study of LY2951742 in patients with chronic migraine (Evaluation of Galcanezumab in the Prevention of Chronic Migraine [REGAIN]) was a phase 3 study with a 3-month double-blind, placebo-controlled treatment phase and a 9-month open-label extension. Eligible patients 18 to 65 years of age with chronic migraine were randomized 2:1:1 to monthly subcutaneous injections of placebo (n = 558), galcanezumab 120 mg (with a 240-mg loading dose, n = 278), or galcanezumab 240 mg (n = 277). The primary endpoint was the overall mean change from baseline in the number of monthly migraine headache days (MHDs) during the 3-month double-blind treatment phase. Results Mean number of monthly MHDs at baseline was 19.4 for the total sample. Both galcanezumab dose groups demonstrated greater overall mean reduction in the number of monthly MHDs compared to placebo (placebo −2.7, galcanezumab 120 mg −4.8, galcanezumab 240 mg −4.6) (p < 0.001 for each dose compared to placebo). There were no clinically meaningful differences between galcanezumab doses and placebo on any safety or tolerability outcome except for a higher incidence of treatment-emergent injection-site reaction (p < 0.01), injection-site erythema (p < 0.001), injection-site pruritus (p < 0.01), and sinusitis (p < 0.05) in the galcanezumab 240-mg group relative to placebo. Conclusions Both doses of galcanezumab were superior to placebo in reducing the number of monthly MHDs. Galcanezumab appears efficacious, safe, and well tolerated for the preventive treatment of chronic migraine. ClinicalTrials.gov identifier NCT02614261. Classification of evidence This interventional study provides Class I evidence that galcanezumab is superior to placebo in the reduction of the number of monthly MHDs.
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              CGRP and its receptors provide new insights into migraine pathophysiology.

              Tony Ho, Lars Edvinsson, Peter J Goadsby (2010)
              Over the past 300 years, the migraine field has been dominated by two main theories-the vascular theory and the central neuronal theory. The success of vasoconstrictors such as ergotamine and the triptans in treating acute migraine bolstered the vascular theory, but evidence is now emerging that vasodilatation is neither necessary nor sufficient to induce a migraine attack. Attention is now turning to the core migraine circuits in the brain, which include the trigeminal ganglia, trigeminal nucleus, medullary modulatory regions, pons, periaqueductal gray matter, hypothalamus and thalamus. Migraine triggers are likely to reflect a disturbance in overall balance of the circuits involved in the modulation of sensory activity, particularly those with relevance to the head. In this Review, we consider the evidence pointing towards a neuronal mechanism in migraine development, highlighting the role of calcitonin gene-related peptide (CGRP), which is found in small to medium-sized neurons in the trigeminal ganglion. CGRP is released during migraine attacks and can trigger migraine in patients, and CGRP receptor antagonists can abort migraine. We also examine whether other drugs, such as triptans, might exert their antimigraine effects via their actions on the neuronal circuit as opposed to the intracranial vasculature.
              Article 0 comments Cited 165 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Willem Sebastiaan van Hoogstraten: w.vanhoogstraten@erasmusmc.nl
                Antoinette MaassenVanDenBrink: (+31) 10 70 43 537/47 , a.vanharen-maassenvandenbrink@erasmusmc.nl
                Journal
                Journal ID (nlm-ta): J Headache Pain
                Journal ID (iso-abbrev): J Headache Pain
                Title: The Journal of Headache and Pain
                Publisher: Springer Milan (Milan )
                ISSN (Print): 1129-2369
                ISSN (Electronic): 1129-2377
                Publication date (Electronic): 16 May 2019
                Publication date PMC-release: 16 May 2019
                Publication date Collection: 2019
                Volume: 20
                Issue: 1
                Electronic Location Identifier: 54
                Affiliations
                [1 ]ISNI 000000040459992X, GRID grid.5645.2, Dept. of Neuroscience Erasmus University Medical Centre, ; PO Box 2040, 3000 CA Rotterdam, The Netherlands
                [2 ]ISNI 000000040459992X, GRID grid.5645.2, Div. of Pharmacology, Dept. of Internal Medicine, , Erasmus University Medical Centre, ; PO Box 2040, 3000 CA Rotterdam, The Netherlands
                Article
                Publisher ID: 1007
                DOI: 10.1186/s10194-019-1007-y
                PMC ID: 6734450
                PubMed ID: 31096904
                SO-VID: fc762d09-3195-4c4b-bb83-6b34f6217fc7
                Copyright © © The Author(s). 2019
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Date received : 26 February 2019
                Date accepted : 26 April 2019
                Categories
                Subject: Review Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2019

                ScienceOpen disciplines: Anesthesiology & Pain management
                Keywords: migraine,medication overuse headache,chronic migraine,acute antimigraine drugs,triptans,gepants,ditans,lasmiditan
                Data availability:
                ScienceOpen disciplines: Anesthesiology & Pain management
                Keywords: migraine, medication overuse headache, chronic migraine, acute antimigraine drugs, triptans, gepants, ditans, lasmiditan

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