Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
The Journal of Headache and Pain
Published in: The Journal of Headache and Pain 1/2019

Open Access 01-12-2019 | Migraine | Review article

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

Authors: Willem Sebastiaan van Hoogstraten, Antoinette MaassenVanDenBrink

Published in: The Journal of Headache and Pain | Issue 1/2019

Login to get access

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-HT1F 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-HT1B/D and higher 5-HT2A 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-HT1F 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-HT1F receptor agonists (lasmiditan) and the small molecule CGRP receptor antagonists (gepants). Data on the effects of 5-HT1F receptor agonism in relation to MOH, as well as the effects of chronic CGRP receptor blockade, are awaited with interest.
Literature
1.
Bigal ME, Lipton RB (2009) The epidemiology, burden, and comorbidities of migraine. Neurol Clin 27:321–334CrossRefPubMed
2.
3.
Disease GBD, Injury I, Prevalence, C. Global (2018) Regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the global burden of Disease study 2017. Lancet 392:1789–1858CrossRef
4.
Monteith TS, Goadsby PJ (2011) Acute migraine therapy: new drugs and new approaches. Curr Treat Options Neurol 13:1–14CrossRefPubMed
5.
Wrobel Goldberg S, Silberstein SD (2015) Targeting CGRP: a new era for migraine treatment. CNS Drugs 29:443–452CrossRefPubMed
6.
Cady RJ, Shade CL, Cady RK (2012) Advances in drug development for acute migraine. Drugs 72:2187–2205CrossRefPubMed
7.
Headache Classification Committee of the International Headache Society (2018) (IHS) the international classification of headache disorders. 3rd edition Cephalalgia 38:1–211
8.
Srikiatkhachorn A, Maneesri S, Govitrapong P, Kasantikul V (1998) Derangement of serotonin system in migrainous patients with analgesic abuse headache: clues from platelets. Headache 38:43–49CrossRefPubMed
9.
De Felice M et al (2010) Triptan-induced latent sensitization: a possible basis for medication overuse headache. Ann Neurol 67:325–337PubMedPubMedCentral
10.
11.
Edvinsson L, Villalon CM, MaassenVanDenBrink A (2012) Basic mechanisms of migraine and its acute treatment. Pharmacol Ther 136:319–333CrossRefPubMed
12.
Rubio-Beltran E, Labastida-Ramirez A, Villalon CM, MaassenVanDenBrink A (2018) Is selective 5-HT1F receptor agonism an entity apart from that of the triptans in antimigraine therapy? Pharmacol Ther 186:88–97CrossRefPubMed
13.
Chan KY, Vermeersch S, de Hoon J, Villalon CM, Maassenvandenbrink A (2011) Potential mechanisms of prospective antimigraine drugs: a focus on vascular (side) effects. Pharmacol Ther 129:332–351CrossRefPubMed
14.
15.
16.
MaassenVanDenBrink A, Meijer J, Villalon CM, Ferrari MD (2016) Wiping out CGRP: potential cardiovascular risks. Trends Pharmacol Sci 37:779–788CrossRefPubMed
17.
Arulmani U, Maassenvandenbrink A, Villalon CM, Saxena PR (2004) Calcitonin gene-related peptide and its role in migraine pathophysiology. Eur J Pharmacol 500:315–330CrossRefPubMed
18.
Tepper SJ, Cleves C (2009) Telcagepant, a calcitonin gene-related peptide antagonist for the treatment of migraine. Curr Opin Investig Drugs 10:711–720PubMed
19.
Ho TW et al (2011) Antimigraine efficacy of telcagepant based on patient’s historical triptan response. Headache 51:64–72CrossRefPubMed
20.
21.
Farkkila M et al (2012) Efficacy and tolerability of lasmiditan, an oral 5-HT (1F) receptor agonist, for the acute treatment of migraine: a phase 2 randomised, placebo-controlled, parallel-group, dose-ranging study. Lancet Neurol 11:405–413CrossRefPubMed
22.
Limmroth V, Katsarava Z, Fritsche G, Przywara S, Diener HC (2002) Features of medication overuse headache following overuse of different acute headache drugs. Neurology 59:1011–1014CrossRefPubMed
23.
Katsarava Z, Fritsche G, Muessig M, Diener HC, Limmroth V (2001) Clinical features of withdrawal headache following overuse of triptans and other headache drugs. Neurology 57:1694–1698CrossRefPubMed
24.
Lance F, Parkes C, Wilkinson M (1988) Does analgesic abuse cause headaches de novo? Headache 28:61–62CrossRefPubMed
25.
Yisarakun W et al (2015) Up-regulation of calcitonin gene-related peptide in trigeminal ganglion following chronic exposure to paracetamol in a CSD migraine animal model. Neuropeptides 51:9–16CrossRefPubMed
26.
Srikiatkhachorn A, Anthony M (1996) Platelet serotonin in patients with analgesic-induced headache. Cephalalgia 16:423–426CrossRefPubMed
27.
Kopruszinski CM et al (2017) Prevention of stress- or nitric oxide donor-induced medication overuse headache by a calcitonin gene-related peptide antibody in rodents. Cephalalgia 37:560–570CrossRefPubMed
28.
Belanger S, Ma W, Chabot JG, Quirion R (2002) Expression of calcitonin gene-related peptide, substance P and protein kinase C in cultured dorsal root ganglion neurons following chronic exposure to mu, delta and kappa opiates. Neuroscience 115:441–453CrossRefPubMed
29.
Tumati S, Roeske WR, Vanderah TW, Varga EV (2010) Sustained morphine treatment augments prostaglandin E2-evoked calcitonin gene-related peptide release from primary sensory neurons in a PKA-dependent manner. Eur J Pharmacol 648:95–101CrossRefPubMedPubMedCentral
30.
Yan H, Yu LC (2013) Expression of calcitonin gene-related peptide receptor subunits in cultured neurons following morphine treatment. Neurosci Lett 544:52–55CrossRefPubMed
31.
Ho TW, Edvinsson L, Goadsby PJ (2010) CGRP and its receptors provide new insights into migraine pathophysiology. Nat Rev Neurol 6:573–582CrossRefPubMed
32.
Villalon CM, Olesen J (2009) The role of CGRP in the pathophysiology of migraine and efficacy of CGRP receptor antagonists as acute antimigraine drugs. Pharmacol Ther 124:309–323CrossRefPubMed
33.
Ferrari MD, Roon KI, Lipton RB, Goadsby PJ (2001) Oral triptans (serotonin 5-HT (1B/1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet 358:1668–1675CrossRefPubMed
34.
35.
36.
Lipton RB, Baggish JS, Stewart WF, Codispoti JR, Fu M (2000) Efficacy and safety of acetaminophen in the treatment of migraine: results of a randomized, double-blind, placebo-controlled, population-based study. Arch Intern Med 160:3486–3492CrossRefPubMed
37.
Silberstein, S. D. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the quality standards Subcommittee of the American Academy of neurology. Neurology 55, 754–762 (2000)
38.
Diener HC (1999) Efficacy and safety of intravenous acetylsalicylic acid lysinate compared to subcutaneous sumatriptan and parenteral placebo in the acute treatment of migraine. A double-blind, double-dummy, randomized, multicenter, parallel group study. The ASASUMAMIG St Cephalalgia 19:581–588; discussion 542
39.
Silberstein SD, McCrory DC (2003) Ergotamine and dihydroergotamine: history, pharmacology, and efficacy. Headache 43:144–166CrossRefPubMed
40.
Dahlof C, Maassen Van Den Brink AD (2012) Ergotamine, methysergide and sumatriptan - basic science in relation to migraine treatment. Headache 52:707–714CrossRefPubMed
41.
Saxena PR, Ferrari MD (1989) 5-HT (1)-like receptor agonists and the pathophysiology of migraine. Trends Pharmacol Sci 10:200–204CrossRefPubMed
42.
Maassen Van Den Brink A, Saxena PR (2004) Coronary vasoconstrictor potential of triptans: a review of in vitro pharmacologic data. Headache 44(Suppl 1):S13–S19CrossRefPubMed
43.
MaassenVanDenBrink A, Reekers M, Bax WA, Ferrari MD, Saxena PR (1998) Coronary side-effect potential of current and prospective antimigraine drugs. Circulation 98:25–30CrossRefPubMed
44.
Rubio-Beltrán Haanes K, Labastida A, de Vries R, Danser J, Michael G et al (2016) E. Lasmiditan and sumatriptan: comparison of in vivo vascular constriction in the dog and in vitro contraction of human arteries. Cephalalgia 36:104–105
45.
Diener HC, Holle D, Solbach K, Gaul C (2016) Medication-overuse headache: risk factors, pathophysiology and management. Nat Rev Neurol 12:575–583CrossRefPubMed
46.
Calabresi P, Cupini LM (2005) Medication-overuse headache: similarities with drug addiction. Trends Pharmacol Sci 26:62–68CrossRefPubMed
47.
48.
Chiang CC, Schwedt TJ, Wang SJ, Dodick DW (2016) Treatment of medication-overuse headache: a systematic review. Cephalalgia 36:371–386CrossRefPubMed
49.
Green AL et al (2014) Increased susceptibility to cortical spreading depression in an animal model of medication-overuse headache. Cephalalgia 34:594–604CrossRefPubMed
50.
De Felice M, Ossipov MH, Porreca F (2011) Persistent medication-induced neural adaptations, descending facilitation, and medication overuse headache. Curr Opin Neurol 24:193–196CrossRefPubMedPubMedCentral
51.
Supornsilpchai W, le Grand SM, Srikiatkhachorn A (2010) Involvement of pro-nociceptive 5-HT2A receptor in the pathogenesis of medication-overuse headache. Headache 50:185–197CrossRefPubMed
52.
53.
Tipton AF, Tarash I, McGuire B, Charles A, Pradhan AA (2016) The effects of acute and preventive migraine therapies in a mouse model of chronic migraine. Cephalalgia 36:1048–1056CrossRefPubMedPubMedCentral
54.
Sufka KJ et al (2016) Clinically relevant behavioral endpoints in a recurrent nitroglycerin migraine model in rats. J Headache Pain 17(40)
55.
56.
Melo-Carrillo A, Lopez-Avila A (2013) A chronic animal model of migraine, induced by repeated meningeal nociception, characterized by a behavioral and pharmacological approach. Cephalalgia 33:1096–1105CrossRefPubMed
57.
Chou TM, Chen SP (2018) Animal models of chronic migraine. Curr Pain Headache Rep 22(44)
58.
Ma W, Zheng WH, Kar S, Quirion R (2000) Morphine treatment induced calcitonin gene-related peptide and substance P increases in cultured dorsal root ganglion neurons. Neuroscience 99:529–539CrossRefPubMed
59.
Tumati S, Yamamura HI, Vanderah TW, Roeske WR, Varga EV (2009) Sustained morphine treatment augments capsaicin-evoked calcitonin gene-related peptide release from primary sensory neurons in a protein kinase A- and Raf-1-dependent manner. J Pharmacol Exp Ther 330:810–817CrossRefPubMedPubMedCentral
60.
Dobson CF, Tohyama Y, Diksic M, Hamel E (2004) Effects of acute or chronic administration of anti-migraine drugs sumatriptan and zolmitriptan on serotonin synthesis in the rat brain. Cephalalgia 24:2–11CrossRefPubMed
61.
Reuter U, Salomone S, Ickenstein GW, Waeber C (2004) Effects of chronic sumatriptan and zolmitriptan treatment on 5-HT receptor expression and function in rats. Cephalalgia 24:398–407CrossRefPubMed
62.
Srikiatkhachorn A, Anthony M (1996) Serotonin receptor adaptation in patients with analgesic-induced headache. Cephalalgia 16:419–422CrossRefPubMed
63.
Srikiatkhachorn A, le Grand SM, Supornsilpchai W, Storer RJ (2014) Pathophysiology of medication overuse headache--an update. Headache 54:204–210CrossRefPubMed
64.
Supornsilpchai W, Sanguanrangsirikul S, Maneesri S, Srikiatkhachorn A (2006) Serotonin depletion, cortical spreading depression, and trigeminal nociception. Headache 46:34–39CrossRefPubMed
65.
Saengjaroentham C, Supornsilpchai W, Ji-Au W, Srikiatkhachorn A, Maneesri-le Grand S (2015) Serotonin depletion can enhance the cerebrovascular responses induced by cortical spreading depression via the nitric oxide pathway. Int J Neurosci 125:130–139CrossRefPubMed
66.
le Grand SM, Supornsilpchai W, Saengjaroentham C, Srikiatkhachorn A (2011) Serotonin depletion leads to cortical hyperexcitability and trigeminal nociceptive facilitation via the nitric oxide pathway. Headache 51:1152–1160CrossRefPubMed
67.
68.
69.
70.
71.
Quartu M et al (2016) TRPV1 receptor in the human trigeminal ganglion and spinal nucleus: immunohistochemical localization and comparison with the neuropeptides CGRP and SP. J Anat 229:755–767CrossRefPubMedPubMedCentral
72.
73.
Meents JE et al (2015) Two TRPV1 receptor antagonists are effective in two different experimental models of migraine. J Headache Pain 16(57)
74.
Maubach KA et al (2009) BGC20-1531, a novel, potent and selective prostanoid EP receptor antagonist: a putative new treatment for migraine headache. Br J Pharmacol 156:316–327CrossRefPubMedPubMedCentral
75.
76.
Ferrari MD et al (2010) Acute treatment of migraine with the selective 5-HT1F receptor agonist lasmiditan--a randomised proof-of-concept trial. Cephalalgia 30:1170–1178CrossRefPubMed
77.
78.
79.
80.
MaassenVanDenBrink A et al (2000) Craniovascular selectivity of eletriptan and sumatriptan in human isolated blood vessels. Neurology 55:1524–1530CrossRefPubMed
81.
MacIntyre PD, Bhargava B, Hogg KJ, Gemmill JD, Hillis WS (1993) Effect of subcutaneous sumatriptan, a selective 5HT1 agonist, on the systemic, pulmonary, and coronary circulation. Circulation 87:401–405CrossRefPubMed
82.
de Hoon JN, Willigers JM, Troost J, Struijker-Boudier HA, Van Bortel LM (2000) Vascular effects of 5-HT1B/1D-receptor agonists in patients with migraine headaches. Clin Pharmacol Ther 68:418–426CrossRefPubMed
83.
Rubio-Beltrán Labastida-Ramírez A., van den Bogaerdt A., Bogers A. J. J. C., Zanelli E. E. & Meeus L, et al.. In vitro characterization of agonist binding and functional activity at a panel of serotonin receptor subtypes for lasmiditan, triptans and other 5-HT receptor ligands and activity relationships for contraction of human isolated coronary artery. Cephalalgia 37, 363 (2017)
84.
Schuster NM, Rapoport AM (2017) Calcitonin gene-related peptide-targeted therapies for migraine and cluster headache: a review. Clin Neuropharmacol 40:169–174CrossRefPubMed
85.
86.
Kee Z, Kodji X, Brain SD (2018) The role of calcitonin gene related peptide (CGRP) in neurogenic vasodilation and its Cardioprotective effects. Front Physiol 9(1249)
87.
Gangula PR et al (2000) Increased blood pressure in alpha-calcitonin gene-related peptide/calcitonin gene knockout mice. Hypertension 35:470–475CrossRefPubMed
88.
Smillie SJ et al (2014) An ongoing role of alpha-calcitonin gene-related peptide as part of a protective network against hypertension, vascular hypertrophy, and oxidative stress. Hypertension 63:1056–1062CrossRefPubMed
89.
Bohm, S. K., Grady, E. F. & Bunnett, N. W. Regulatory mechanisms that modulate signalling by G-protein-coupled receptors. Biochem J 322 ( Pt 1, 1–18 (1997)
90.
91.
92.
Masson J, Emerit MB, Hamon M, Darmon M (2012) Serotonergic signaling: multiple effectors and pleiotropic effects. Wiley Interdiscip Rev Membr Transp Signal 1:685–713CrossRef
93.
Raymond JR et al (2001) Multiplicity of mechanisms of serotonin receptor signal transduction. Pharmacol Ther 92:179–212CrossRefPubMed
94.
Nilsson T et al (1999) Characterisation of 5-HT receptors in human coronary arteries by molecular and pharmacological techniques. Eur J Pharmacol 372:49–56CrossRefPubMed
95.
Grazzi L, Grignani E, D’Amico D, Sansone E, Raggi A (2018) Is medication overuse drug specific or not? Data from a review of published literature and from an original study on Italian MOH patients. Curr Pain Headache Rep 22(71)
96.
Ho TW et al (2008) Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial. Lancet 372:2115–2123CrossRefPubMed
97.
Ho TW et al (2014) Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention. Neurology 83:958–966CrossRefPubMed
98.
Gingell JJ, Hendrikse ER, Hay DL (2019) New insights into the regulation of CGRP-family receptors. Trends Pharmacol Sci 40:71–83CrossRefPubMed
99.
100.
101.
Tepper S et al (2017) Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol 16:425–434CrossRefPubMed
102.
Negro A, Koverech A, Martelletti P (2018) Serotonin receptor agonists in the acute treatment of migraine: a review on their therapeutic potential. J Pain Res 11:515–526CrossRefPubMedPubMedCentral
Metadata
Title
The need for new acutely acting antimigraine drugs: moving safely outside acute medication overuse
Authors
Willem Sebastiaan van Hoogstraten
Antoinette MaassenVanDenBrink
Publication date
01-12-2019
Publisher
Springer Milan
Published in
The Journal of Headache and Pain / Issue 1/2019
Print ISSN: 1129-2369
Electronic ISSN: 1129-2377
DOI
https://doi.org/10.1186/s10194-019-1007-y

Other articles of this Issue 1/2019

The Journal of Headache and Pain 1/2019 Go to the issue

Consensus article

Consensus of the Hellenic Headache Society on the diagnosis and treatment of migraine

Research article

Migraine: a major debilitating chronic non-communicable disease in Brazil, evidence from two national surveys

Research article

Development and validation of the ID-EC - the ITALIAN version of the identify chronic migraine

Review article

Novel hypotheses emerging from GWAS in migraine?

Review article

Spreading depression as a preclinical model of migraine

Review article

Aura and Stroke: relationship and what we have learnt from preclinical models