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
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Current Treatment Options in Neurology
Published in: Current Treatment Options in Neurology 1/2012

01-02-2012 | Headache (JR Couch, Section Editor)

New Agents for Acute Treatment of Migraine: CGRP Receptor Antagonists, iNOS Inhibitors

Authors: Jan Hoffmann, MD, PhD, Peter J. Goadsby, MD, PhD

Published in: Current Treatment Options in Neurology | Issue 1/2012

Login to get access

Opinion statement

The treatment of migraine was advanced dramatically with the introduction of triptans in the early 1990s. Despite the substantial improvement in the quality of life that triptans have brought to many migraineurs, a substantial cohort of patients remain highly disabled by attacks and need new therapeutic approaches, which ideally should be quick-acting, have no vasoconstrictor activity, and have a longer duration of action and be better tolerated than current therapies. The calcitonin gene-related peptide (CGRP) receptor antagonists (gepants)—olcegepant (BIBN 4096 BS), telcagepant (MK-0974), MK3207, and BI 44370 TA—are effective in treating acute migraine. They have no vasoconstrictive properties, fewer adverse effects, and may act longer than triptans. Their development has been complicated by liver toxicity issues when used as preventives. Results from studies with BI 44370 TA do not support broad concern about a class effect, and further studies are ongoing in this respect. Many experimental studies and clinical trials suggest that nitric oxide may have a role in the pathophysiology of migraine. Therefore, the inhibition of nitric oxide synthase (NOS) for the acute or prophylactic treatment of migraine offered a feasible approach; as inducible NOS (iNOS) is involved in several pain states, such as inflammatory pain, it appeared to be an attractive target. However, despite high selectivity and potency, the iNOS inhibitor GW274150 was not effective for acute treatment or prophylaxis of migraine, suggesting that iNOS is very unlikely to be a promising target.
Literature
1.
Stovner L, Hagen K, Jensen R, et al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia. 2007;27(3):193–210.PubMedCrossRef
2.
Menken M, Munsat TL, Toole JF. The global burden of disease study: implications for neurology. Arch Neurol. 2000;57(3):418–20.PubMedCrossRef
3.
Rasmussen BK, Jensen R, Schroll M, Olesen J. Epidemiology of headache in a general population-a prevalence study. J Clin Epidemiol. 1991;44(11):1147–57.PubMedCrossRef
4.
Silberstein SD, Lipton RB. Headache epidemiology. Emphasis on migraine. Neurol Clin. 1996;14(2):421–34.PubMedCrossRef
5.
Scher AI, Stewart WF, Liberman J, Lipton RB. Prevalence of frequent headache in a population sample. Headache. 1998;38(7):497–506.PubMedCrossRef
6.
Lipton RB, Scher AI, Kolodner K, et al. Migraine in the United States: epidemiology and patterns of health care use. Neurology. 2002;58(6):885–94.PubMed
7.
Robbins MS, Lipton RB. The epidemiology of primary headache disorders. Semin Neurol. 2010;30(2):107–19.PubMedCrossRef
8.
Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet. 2001;358(9294):1668–75.PubMedCrossRef
9.
Ho TW, Edvinsson L, Goadsby PJ. CGRP and its receptors provide new insights into migraine pathophysiology. Nat Rev Neurol. 2010;6(10):573–82.PubMedCrossRef
10.
Goadsby PJ. The vascular theory of migraine - a great story wrecked by the facts. Brain. 2009;132(Pt 1):6–7.PubMed
11.
Diener HC. 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 Study Group. Cephalalgia. 1999;19(6):581–8.PubMedCrossRef
12.
Limmroth V, May A, Diener H. Lysine-acetylsalicylic acid in acute migraine attacks. Eur Neurol. 1999;41(2):88–93.PubMedCrossRef
13.•
Weatherall MW, Telzerow AJ, Cittadini E, et al. Intravenous aspirin (lysine acetylsalicylate) in the inpatient management of headache. Neurology 2010;75(12):1098–1103.PubMedCrossRef
14.•
Diener HC, Barbanti P, Dahlof C, et al. BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: results from a phase II study. Cephalalgia 2011;31(5):573–584.PubMedCrossRef
15.
Ho TW, Ferrari MD, Dodick DW, et al. 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. 2008;372(9656):2115–23.PubMedCrossRef
16.
Ho TW, Mannix LK, Fan X, et al. Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology. 2008;70(16):1304–12.PubMedCrossRef
17.
Olesen J, Diener HC, Husstedt IW, et al. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med. 2004;350(11):1104–10.PubMedCrossRef
18.
Nelson DL, Phebus LA, Johnson KW, et al. Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan. Cephalalgia. 2010;30(10):1159–69.PubMedCrossRef
19.
Pilgrim AJ, Dussault B, Rupniak NMJ, et al. COL-144, an orally bioavailable selective 5-HT1F receptor agonist for acute migraine therapy. Cephalalgia. 2009;29:24–5.
20.
Olesen J. 5-Hydroxyptryptamine 1F (5-HT1F) receptor agonism. A possible new treatment principle for acute migraine attacks. Cephalalgia. 2010;30(10):1157–8.PubMedCrossRef
21.••
Ferrari MD, Farkkila M, Reuter U, et al. Acute treatment of migraine with the selective 5-HT1F receptor agonist lasmiditan--a randomised proof-of-concept trial. Cephalalgia 2010;30(10):1170–1178.PubMedCrossRef
22.
Limmroth V, May A, Auerbach P, et al. Changes in cerebral blood flow velocity after treatment with sumatriptan or placebo and implications for the pathophysiology of migraine. J Neurol Sci. 1996;138(1–2):60–5.PubMedCrossRef
23.
Amara SG, Jonas V, Rosenfeld MG, et al. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature. 1982;298(5871):240–4.PubMedCrossRef
24.
Wimalawansa SJ. Calcitonin gene-related peptide and its receptors: molecular genetics, physiology, pathophysiology, and therapeutic potentials. Endocr Rev. 1996;17(5):533–85.PubMed
25.
Tajti J, Uddman R, Moller S, et al. Messenger molecules and receptor mRNA in the human trigeminal ganglion. J Auton Nerv Syst. 1999;76(2–3):176–83.PubMedCrossRef
26.
Eftekhari S, Salvatore CA, Calamari A, et al. Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion. Neuroscience. 2010;169(2):683–96.PubMedCrossRef
27.
Edvinsson L, Gulbenkian S, Barroso CP, et al. Innervation of the human middle meningeal artery: immunohistochemistry, ultrastructure, and role of endothelium for vasomotility. Peptides. 1998;19(7):1213–25.PubMedCrossRef
28.
Hokfelt T, Arvidsson U, Ceccatelli S, et al. Calcitonin gene-related peptide in the brain, spinal cord, and some peripheral systems. Ann N Y Acad Sci. 1992;657:119–34.PubMedCrossRef
29.
van Rossum D, Hanisch UK, Quirion R. Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci Biobehav Rev. 1997;21(5):649–78.PubMedCrossRef
30.
Limmroth V, Katsarava Z, Liedert B, et al. An in vivo rat model to study calcitonin gene related peptide release following activation of the trigeminal vascular system. Pain. 2001;92(1–2):101–6.PubMedCrossRef
31.
Offenhauser N, Zinck T, Hoffmann J, et al. CGRP release and c-fos expression within trigeminal nucleus caudalis of the rat following glyceryltrinitrate infusion. Cephalalgia. 2005;25(3):225–36.PubMedCrossRef
32.
Storer RJ, Akerman S, Goadsby PJ. Calcitonin gene-related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat. Br J Pharmacol. 2004;142(7):1171–81.PubMedCrossRef
33.
Goadsby PJ. Recent advances in understanding migraine mechanisms, molecules and therapeutics. Trends Mol Med. 2007;13(1):39–44.PubMedCrossRef
34.
Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol. 1993;33(1):48–56.PubMedCrossRef
35.
Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28(2):183–7.PubMedCrossRef
36.
Goadsby PJ, Edvinsson L, Ekman R. Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann Neurol. 1988;23(2):193–6.PubMedCrossRef
37.
Lassen LH, Haderslev PA, Jacobsen VB, et al. CGRP may play a causative role in migraine. Cephalalgia. 2002;22(1):54–61.PubMedCrossRef
38.
Olesen J, Thomsen LL, Iversen H. Nitric oxide is a key molecule in migraine and other vascular headaches. Trends Pharmacol Sci. 1994;15(5):149–53.PubMedCrossRef
39.
Aiyar N, Rand K, Elshourbagy NA, et al. A cDNA encoding the calcitonin gene-related peptide type 1 receptor. J Biol Chem. 1996;271(19):11325–9.PubMedCrossRef
40.
McLatchie LM, Fraser NJ, Main MJ, et al. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature. 1998;393(6683):333–9.PubMedCrossRef
41.
Ma W, Chabot JG, Powell KJ, et al. Localization and modulation of calcitonin gene-related peptide-receptor component protein-immunoreactive cells in the rat central and peripheral nervous systems. Neuroscience. 2003;120(3):677–94.PubMedCrossRef
42.
Eftekhari S, Edvinsson L. Possible sites of action of the new calcitonin gene-related peptide receptor antagonists. Ther Adv Neurol Disord. 2010;3(6):369–78.PubMedCrossRef
43.
Oliver KR, Wainwright A, Edvinsson L, et al. Immunohistochemical localization of calcitonin receptor-like receptor and receptor activity-modifying proteins in the human cerebral vasculature. J Cereb Blood Flow Metab. 2002;22(5):620–9.PubMedCrossRef
44.
Lennerz JK, Ruhle V, Ceppa EP, et al. Calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and calcitonin gene-related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: differences between peripheral and central CGRP receptor distribution. J Comp Neurol. 2008;507(3):1277–99.PubMedCrossRef
45.
Ferrari MD, Goadsby PJ, Roon KI, Lipton RB. Triptans (serotonin, 5-HT1B/1D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials. Cephalalgia. 2002;22(8):633–58.PubMedCrossRef
46.••
Connor KM, Shapiro RE, Diener HC, et al. Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology 2009;73(12):970–977.PubMedCrossRef
47.
48.
Sur C, Hargreaves R, Bell I, et al. CSF levels and binding pattern of novel CGRP receptor antagonists in rhesus monkey and human central nervous system: toward the development of a PET tracer. Cephalalgia. 2009;29 Suppl 1:136–7. Abstract PO326.
49.•
Ho AP, Dahlof CG, Silberstein SD, et al. Randomized, controlled trial of telcagepant over four migraine attacks. Cephalalgia 2010;30(12):1443–1457.PubMedCrossRef
50.•
Ho TW, Olesen J, Dodick DW, et al. Antimigraine efficacy of telcagepant based on patient's historical triptan response. Headache 2011;51(1):64–72.PubMedCrossRef
51.
Ho T, Connor K, Dahlof C, et al. Assessment of the long term safety and tolerability of telcagepant for the intermittent treatment of acute migraine: a double-blind, active-controlled study. Cephalalgia. 2009;29 Suppl 1:12. Abstract PO03.
52.
Connor KM, Aurora SK, Loeys T, et al. Long-term tolerability of telcagepant for acute treatment of migraine in a randomized trial. Headache. 2011;51(1):73–84.PubMedCrossRef
53.
Han TH, Blanchard RL, Palcza J, et al. Single- and multiple-dose pharmacokinetics and tolerability of telcagepant, an oral calcitonin gene-related peptide receptor antagonist, in adults. J Clin Pharmacol. 2010;50(12):1367–76.PubMedCrossRef
54.
55.
Salvatore CA, Moore EL, Hershey JC, et al. Pharmacological characterization of MK-3207, a potent and orally bioavailable CGRP receptor anagonist. Cephalalgia. 2009;29 Suppl 1:139. Abstract PO333.
56.
Hewitt DJ, Aurora SK, Dodick DW, et al. Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine. Cephalalgia. 2011;31(6):712–22.PubMedCrossRef
57.
Chan KY, Edvinsson L, Eftekhari S, et al. Characterization of the calcitonin gene-related peptide receptor antagonist telcagepant (MK-0974) in human isolated coronary arteries. J Pharmacol Exp Ther. 2010;334(3):746–52.PubMedCrossRef
58.
De Col R, Koulchitsky SV, Messlinger KB. Nitric oxide synthase inhibition lowers activity of neurons with meningeal input in the rat spinal trigeminal nucleus. Neuroreport. 2003;14(2):229–32.PubMedCrossRef
59.
Tassorelli C, Joseph SA. Systemic nitroglycerin induces Fos immunoreactivity in brainstem and forebrain structures of the rat. Brain Res. 1995;682(1–2):167–81.PubMedCrossRef
60.
Lambert GA, Hoskin KL, Zagami AS. Nitrergic and glutamatergic neuronal mechanisms at the trigeminovascular first-order synapse. Neuropharmacology. 2004;47(1):92–105.PubMedCrossRef
61.
Jones MG, Lever I, Bingham S, et al. Nitric oxide potentiates response of trigeminal neurones to dural or facial stimulation in the rat. Cephalalgia. 2001;21(6):643–55.PubMedCrossRef
62.
Hoskin KL, Bulmer DC, Goadsby PJ. Fos expression in the trigeminocervical complex of the cat after stimulation of the superior sagittal sinus is reduced by L-NAME. Neurosci Lett. 1999;266(3):173–6.PubMedCrossRef
63.
Akerman S, Williamson DJ, Kaube H, Goadsby PJ. Nitric oxide synthase inhibitors can antagonize neurogenic and calcitonin gene-related peptide induced dilation of dural meningeal vessels. Br J Pharmacol. 2002;137(1):62–8.PubMedCrossRef
64.
Lin Q, Palecek J, Paleckova V, et al. Nitric oxide mediates the central sensitization of primate spinothalamic tract neurons. J Neurophysiol. 1999;81(3):1075–85.PubMed
65.
Olesen J, Iversen HK, Thomsen LL. Nitric oxide supersensitivity: a possible molecular mechanism of migraine pain. Neuroreport. 1993;4(8):1027–30.PubMedCrossRef
66.
Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;24 Suppl 1:9–160.
67.
Christiansen I, Thomsen LL, Daugaard D, et al. Glyceryl trinitrate induces attacks of migraine without aura in sufferers of migraine with aura. Cephalalgia. 1999;19(7):660–7.PubMedCrossRef
68.
Koulchitsky S, Fischer MJ, De Col R, et al. Biphasic response to nitric oxide of spinal trigeminal neurons with meningeal input in rat–possible implications for the pathophysiology of headaches. J Neurophysiol. 2004;92(3):1320–8.PubMedCrossRef
69.
Afridi SK, Kaube H, Goadsby PJ. Glyceryl trinitrate triggers premonitory symptoms in migraineurs. Pain. 2004;110(3):675–80.PubMedCrossRef
70.
Lassen LH, Ashina M, Christiansen I, et al. Nitric oxide synthase inhibition in migraine. Lancet. 1997;349(9049):401–2.PubMedCrossRef
71.
72.
Alderton WK, Angell ADR, Craig C, et al. GW274150 and GW273629 are potent and highly selective inhibitors of inducible nitric oxide synthase in vitro and in vivo. Brit J Pharmacol. 2005;145(3):301–12.CrossRef
73.
De Alba J, Clayton NM, Collins SD, et al. GW274150, a novel and highly selective inhibitor of the inducible isoform of nitric oxide synthase (NOS), shows analgesic effects in rat models of inflammatory and neuropathic pain. Pain. 2006;120(1–2):170–81.PubMedCrossRef
74.•
Palmer JE, Guillard FL, Laurijssens BE, et al. A randomised, single-blind, placebo-controlled, adaptive clinical trial of GW274150, a selective iNOS inhibitor, in the treatment of acute migraine. Cephalalgia 2009;29:124.
75.•
Hoivik HO, Laurijssens BE, Harnisch LO, et al. Lack of efficacy of the selective iNOS inhibitor GW274150 in prophylaxis of migraine headache. Cephalalgia 2010;30(12):1458–67.PubMedCrossRef
76.
Høye K. LB, Harnisch LO, Twomey CK, Dixon RM, Kirkham, Williams PM, Wentz AL. Efficacy and tolerability of the iNOS inhibitor GW274150 administered up to 120 mg daily for 12 weeks in the prophylactic treatment of migraine. Cephalalgia. 2009;29:132.
Metadata
Title
New Agents for Acute Treatment of Migraine: CGRP Receptor Antagonists, iNOS Inhibitors
Authors
Jan Hoffmann, MD, PhD
Peter J. Goadsby, MD, PhD
Publication date
01-02-2012
Publisher
Current Science Inc.
Published in
Current Treatment Options in Neurology / Issue 1/2012
Print ISSN: 1092-8480
Electronic ISSN: 1534-3138
DOI
https://doi.org/10.1007/s11940-011-0155-4

Other articles of this Issue 1/2012

Current Treatment Options in Neurology 1/2012 Go to the issue

Neurologic Ophthalmology and Otology (RK Shin, Section Editor)

Treatment of Vision Loss in Giant Cell Arteritis

Neurologic Ophthalmology and Otology (RK Shin, Section Editor)

Treatment of Nystagmus

Headache (JR Couch, Section Editor)

Menstrual Migraine: Update on Pathophysiology and Approach to Therapy and Management

Headache (JR Couch, Section Editor)

Hypnic Headache: Clinical Course and Treatment

Headache (JR Couch, Section Editor)

Posttraumatic Headache in Military Personnel and Veterans of the Iraq and Afghanistan Conflicts

Neurologic Ophthalmology and Otology (RK Shin, Section Editor)

Treatment of Ocular Myasthenia Gravis