1,133
Views
40
CrossRef citations to date
0
Altmetric
Review

Emerging drugs for migraine treatment: an update

, , & ORCID Icon
Pages 301-318 | Received 27 Sep 2018, Accepted 23 Nov 2018, Published online: 30 Nov 2018

References

  • Robbins MS, Lipton RB. The epidemiology of primary headache disorders. Semin Neurol. 2010;30(2):107–119.
  • Lipton RB, Bigal ME, Diamond M, et al. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68(5):343–349.
  • Younger DS. Epidemiology of migraine. Neurol Clinic. 2016 Nov;34(4):849–861.
  • Lipton RB, Bigal ME, Kolodner K, et al. The family impact of migraine: population-based studies in the USA and UK. Cephalalgia. 2003;23(6):429–440.
  • Steiner TJ, Stovner LJ, Vos T. GBD 2015: migraine is the third cause of disability in under 50s. J Headache Pain. 2016;17(1):104.
  • Dodick DW. Migraine. Lancet. 2018;31(391):1315–1330.
  • Dodick DW. A phase-by-phase review of migraine pathophysiology. Headache. 2018;58(Suppl 1):4–16.
  • Headache Classification Committee of the International Headache Society. The international classification of headache disorders, 3rd edition (beta version). Cephalalgia. 2013;33:629–808.
  • Manack AN, Buse DC, Lipton RB. Chronic migraine: epidemiology and disease burden. Curr Pain Headache Rep. 2011;15(1):70–78.
  • Evers S, Marziniak M. Clinical features, pathophysiology, and treatment of medication-overuse headache. Lancet Neurol. 2010;9(4):391–401.
  • Lionetto L, Negro A, Palmisani S, et al. Emerging treatment for chronic migraine and refractory chronic migraine. Expert Opin Emerg Drugs. 2012;17(3):393–406.
  • Zeeberg P, Olesen J, Jensen R. Discontinuation of medication overuse in headache patients: recovery of therapeutic responsiveness. Cephalalgia. 2006;26(10):1192–1198.
  • https://www.nice.org.uk/guidance/cg150/ifp/chapter/treatments-for-migraine
  • Diener HC, Limmroth V. Advances in pharmacological treatment of migraine. Expert Opin Investig Drugs. 2001;10(10):1831–1845.
  • Loder E. Triptan therapy in migraine. N Engl J Med. 2010;363(1):63–70.
  • Amin FM, Hougaard A, Cramer SP, et al. Increased brainstem perfusion, but no blood-brain barrier disruption, during attacks without aura. A 3T DCE. Eur J Neurol. 2017;24(9):1116–1124.
  • Hepp Z, Dodick DW, Varon SF, et al. Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015;35(6):478–488.
  • Aurora SK, Dodick DW, Turkel CC, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia. 2010;30(7):804–814.
  • Diener HC, Dodick DW, Aurora SK, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia. 2010;30(7):793–803.
  • Andreou AP, Trimboli M, Al-Kaisy A, et al. Prospective real-world analysis of OnabotulinumtoxinA in chronic migraine post-National Institute for Health and Care Excellence UK technology appraisal. Eur J Neurol. 2018;25(8):1069–e1083.
  • Martelletti P, Katsarava Z, Lampl C, et al. Refractory chronic migraine: a consensus statement on clinical definition from the European Headache Federation. J Headache Pain. 2014 Aug;28(15):47.
  • Palmisani S, Al-Kaisy A, Arcioni R, et al. A six year retrospective review of occipital nerve stimulation practice-controversies and challenges of an emerging technique for treating refractory headache syndromes. J Headache Pain. 2013;6:14–67.
  • Miller S, Watkins L, Matharu M. Long-term outcomes of occipital nerve stimulation for chronic migraine: a cohort of 53 patients. J Headache Pain. 2016;17(1):68.
  • Lipton R, Goadsby PJ, Cady R, et al. PRISM study: occipital nerve stimulation for treatment-refractory migraine. Cephalalgia. 2009;29(Suppl 1):30.
  • Saper JR, Dodick DW, Silberstein SD, et al. Occipital nerve stimulation for the treatment of intractable chronic migraine headache: ONSTIM feasibility study. Cephalalgia. 2011;31(3):271–285.
  • Silberstein SD, Dodick DW, Saper J, et al. Safety and efficacy of peripheral nerve stimulation of the occipital nerves for the management of chronic migraine: results from a randomized, multicenter, double-blinded, controlled study. Cephalalgia. 2012;32(11):1165–1179.
  • Oshinsky ML, Murphy AL, Hekierski H, et al. Noninvasive vagus nerve stimulation as treatment for trigeminal allodynia. Pain. 2014;155(5):1037–1042.
  • Andreou AP, Holland PR, Akerman S, et al. Transcranial magnetic stimulation and potential cortical and trigeminothalamic mechanisms in migraine. Brain. 2016;139(Pt 7):2002–2014.
  • Silberstein SD, Calhoun AH, Lipton RB, et al. Chronic migraine headache prevention with non-invasive vagus nerve stimulation: the EVENT study. Neurology. 2016;87(5):529–538.
  • Trimboli M, Al-Kaisy A, Andreou AP, et al. Non-invasive vagus nerve stimulation for the management of refractory primary chronic headaches: a real-world experience. Cephalalgia. 2018;38(7):1276–1285.
  • Starling AJ, Tepper SJ, Marmura MJ, et al. A multicenter, prospective, single arm, open label, observational study of sTMS for migraine prevention (ESPOUSE Study). Cephalalgia. 2018;38(6):1038–1048.
  • Denuelle M, Fabre N, Payoux P, et al. Hypothalamic activation in spontaneous migraine attacks. Headache. 2007;47(10):1418–1426.
  • Maniyar FH, Sprenger T, Monteith T, et al. Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks. Brain. 2014;137(Pt 1):232–241.
  • Schulte LH, Allers A, May A. Visual stimulation leads to activation of the nociceptive trigeminal nucleus in chronic migraine. Neurology. 2018;90(22):e1973–e1978.
  • Schulte LH, May A. The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks. Brain. 2016;139(Pt 7):1987–1993.
  • Schulte LH, May A. Of generators, networks and migraine attacks. Curr Opin Neurol. 2017;30(3):241–245.
  • Bartsch T, Goadsby PJ. Stimulation of the greater occipital nerve induces increased central excitability of dural afferent input. Brain. 2002;125(Pt 7):1496–1509.
  • Edvinsson L, Goadsby PJ. Neuropeptides in the cerebral circulation: relevance to headache. Cephalalgia. 1995;15(4):272–276.
  • Goadsby P, Charbit A, Andreou AP, et al. Neurobiology of migraine. Neuroscience. 2009;161(2):327–341.
  • Akerman S, Holland PR, Goadsby PJ. Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci. 2011;12(10):570–584.
  • Olesen J, Larsen B, Lauritzen M. Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Ann Neurol. 1981;9(4):344–352.
  • Leão AA. Pial circulation and spreading depression of activity in the cerebral cortex. J Neurophysiol. 1944;7:391–396.
  • Do Carmo RJ, Martins-Ferreira H. Glutamate-K+ interactions with relation to spreading cortical depression [proceedings]. An Acad Bras Cienc. 1979;51(3):579.
  • Lauritzen M, Hansen AJ. The effect of glutamate receptor blockade on anoxic depolarization and cortical spreading depression. J Cereb Blood Flow Metab. 1992;12(2):223–229.
  • Zhang X, Levy D, Kainz V, et al. Activation of central trigeminovascular neurons by cortical spreading depression. Ann Neurol. 2011;69(5):855–865.
  • Andreou AP, Sprenger T, Goadsby PJ. Cortical modulation of thalamic function during cortical spreading depression- Unraveling a new central mechanism involved in migraine aura. J Headache Pain. 2013;14:16.
  • Freitag FG. Divalproex in the treatment of migraine. Psychopharmacol Bull. 2003;37(Suppl 2):98–115.
  • Palermo A, Fierro B, Giglia G, et al. Modulation of visual cortex excitability in migraine with aura: effects of valproate therapy. Neurosci Lett. 2009;467(1):26–29.
  • Inaba M, Nishizawa Y, Morii H. Tissue distribution and physiologic role of calcitonin and CGRP. Nihon Rinsho. 1990;48(5):1011–1015.
  • Lawson SN, Crepps B, Perl ER. Calcitonin gene-related peptide immunoreactivity and afferent receptive properties of dorsal root ganglion neurones in guinea-pigs. J Physiol. 2002;540(Pt 3):989–1002.
  • Moreno MJ, Cohen Z, Stanimirovic DB, et al. Functional calcitonin gene-related peptide type 1 and adrenomedullin receptors in human trigeminal ganglia, brain vessels, and cerebromicrovascular or astroglial cells in culture. J Cereb Blood Flow Metab. 1990;19(11):1270–1278.
  • Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28:183±187.
  • Tvedskov JF, Lipka K, Ashina M, et al. No increase of calcitonin gene-related peptide in jugular blood during migraine. Ann Neurol. 2005;58(4):561–568.
  • Hansen JM, Hauge AW, Olesen J, et al. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia. 2010;30(10):1179–1186.
  • Hansen JM, Thomsen LL, Olesen J, et al. Calcitonin gene-related peptide does not cause the familial hemiplegic migraine phenotype. Neurology. 2008;71(11):841–847.
  • Mathew R, Andreou AP, Chami LA, et al. Immunohistochemical characterization of calcitonin gene-related peptide in the trigeminal system of the familial hemiplegic migraine 1 knock-in mouse. Cephalalgia. 2011;31(13):1368–1380.
  • Williamson DJ, Shepheard SL, Hill RG, et al. The novel anti-migraine agent rizatriptan inhibits neurogenic dural vasodilation and extravasation. Eur J Pharmacol. 1997;328(1):61–64.
  • Durham PL, Russo AF. Regulation of calcitonin gene-related peptide secretion by a serotonergic antimigraine drug. J Neurosci. 1999;19(9):3423–3429.
  • Biella G, Panara C, Pecile A, et al. Facilitatory role of calcitonin gene-related peptide (CGRP) on excitation induced by substance P (SP) and noxious stimuli in rat spinal dorsal horn neurons. An iontophoretic study in vivo. Brain Res. 1991;559(2):352–356.
  • 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;350:1104–1110.
  • 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;70:1304–1312.
  • 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;372:2115–2123.
  • Ho TW, Connor KM, Zhang Y, et al. Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention. Neurology. 2014;83:958–966.
  • 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;31:712–722.
  • Diener HC, Barbanti P, Dahlöf 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;31:573–584.
  • Voss T, Lipton RB, Dodick DW. A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine. Cephalalgia. 2016;36(9):887–898.
  • Marcus R, Goadsby PJ, Dodick D, et al. BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia. 2014;34:114–125.
  • Zeller J, Poulsen KT, Sutton JE, et al. CGRP function-blocking antibodies inhibit neurogenic vasodilatation without affecting heart rate or arterial blood pressure in the rat. Br J Pharmacol. 2008;155(7):1093–1103.
  • Sun H, Dodick DW, Silberstein S, et al. Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo controlled, phase 2 trial. Lancet Neurol. 2016;15(4):382–390.
  • Goadsby PJ, Reuter U, Hallstrom Y, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med. 2017;377(22):2123–2132.
  • Dodick DW, Ashina M, Brandes JL, et al. ARISE: a Phase III randomized trial of erenumab for episodic migraine. Cephalalgia. 2018;38(6):1026–1037.
  • Ashina M, Dodick D, Goadsby PJ, et al. Erenumab (AMG 334) in episodic migraine: interim analysis of an ongoing open-label study. Neurology. 2017;89(12):1237–1243.
  • Tepper S, Ashina M, Reuter U, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase II trial. Lancet Neurol. 2017;16(6):425–434.
  • Dodick DW, Goadsby PJ, Spierings EL, et al. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2014;13(9):885–892.
  • Skljarevski V, Oakes TM, Zhang Q. Effect of different doses of Galcanezumab vs Placebo for episodic migraine prevention: a randomized clinical trial. JAMA Neurol. 2018;75(2):187–193.
  • Stauffer VL, Dodick DW, Zhang Q, et al. Evaluation of Galcanezumab for the prevention of episodic migraine: the EVOLVE-1 randomized clinical trial. JAMA Neurol. 2018;75(9):1080–1088.
  • Skljarevski V, Matharu M, Millen BA, et al. Efficacy and safety of galcanezumab for the prevention of episodic migraine: results of the EVOLVE-2 phase 3 randomized controlled clinical trial. Cephalalgia. 2018;38(8):1442–1454.
  • Bigal ME, Dodick DW, Rapoport AM, et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a multicentre, randomised, double-blind, placebo- controlled, phase 2b study. Lancet Neurol. 2015;14:1081–1090.
  • Dodick DW, Silberstein SD, Bigal ME. Effect of fremanezumab compared with placebo for prevention of episodic migraine: a randomized clinical trial. JAMA. 2018 15;319(19):1999–2008.
  • Bigal ME, Dodick DW, Krymchantowski AV, et al. TEV-48125 for the preventive treatment of chronic migraine: efficacy at early time points. Neurology. 2016 5;87(1):41–48.
  • Silberstein SD, Dodick DW, Bigal ME, et al. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med. 2017 30;377(22):2113–2212.
  • Dodick DW, Goadsby PJ, Silberstein SD, et al. Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo- controlled, exploratory phase 2 trial. Lancet Neurol. 2014;13:1100–1107.
  • Bruinvels AT, Landwehrmeyer B, Gustafson EL, et al. Localization of 5-HT1B, 5-HT1D alpha, 5-HT1E and 5-HT1F receptor messenger RNA in rodent and primate brain. Neuropharmacology. 1994;33(3–4):367–386.
  • Johnson KW, Schaus JM, Durkin MM. 5-HT1F receptor agonists inhibit neurogenic dural inflammation in guinea pigs. Neuroreport. 1997;8:2237–2240.
  • Goldstein DJ, Roon KI, Offen WW, et al. Selective serotonin 1F (5-HT (1F)) receptor agonist LY334370 for acute migraine: a randomised controlled trial. Lancet. 2001;358:1230–1234.
  • Ferrari MD, Färkkilä 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;30:1170–1178.
  • Färkkilä M, Diener HC, Géraud G, et al. 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. 2012;11:405–413.
  • Tuka B, Helyes Z, Markovics A, et al. Alterations in PACAP-38-like immunoreactivity in the plasma during ictal and interictal periods of migraine patients. Cephalalgia. 2013;33(13):1085–1095.
  • Edvinsson L. PACAP and its receptors in migraine pathophysiology: commentary on Walker et al., Br J Pharmacol 171: 1521-1533. Br J Pharmacol. 2015;172(19):4782–4784.
  • Edvinsson L, Tajti J, Szalardy L, et al. PACAP and its role in primary headaches. J Headache Pain. 2018;19(1):21.
  • Eftekhari S, Salvatore CA, Johansson S, et al. Localization of CGRP, CGRP receptor, PACAP and glutamate in trigeminal ganglion. Relation to the blood-brain barrier. Brain Res. 2015;1600:93–109.
  • Eftekhari S, Warfvinge K, Blixt FW, et al. Differentiation of nerve fibers storing CGRP and CGRP receptors in the peripheral trigeminovascular system. J Pain. 2013;14(11):1289–1303.
  • Palkovits M, Somogyvari-Vigh A, Arimura A. Concentrations of pituitary adenylate cyclase activating polypeptide (PACAP) in human brain nuclei. Brain Res. 1995;699(1):116–120.
  • Uddman R, Tajti J, Moller S, et al. Neuronal messengers and peptide receptors in the human sphenopalatine and otic ganglia. Brain Res. 1999;826(2):193–199.
  • Markovics A, Kormos V, Gaszner B, et al. Pituitary adenylate cyclase-activating polypeptide plays a key role in nitroglycerol-induced trigeminovascular activation in mice. Neurobiol Dis. 2012;45(1):633–644.
  • Akerman S, Goadsby PJ. Neuronal PAC1 receptors mediate delayed activation and sensitization of trigeminocervical neurons: relevance to migraine. Sci Transl Med. 2015;7(308):308ra157.
  • Gazerani P, Cairns BE. New insight in migraine pathogenesis: vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) in the circulation after sumatriptan. Scand J Pain. 2013;4(4):208–210.
  • Cernuda-Morollon E, Riesco N, Martinez-Camblor P, et al. No change in interictal PACAP levels in peripheral blood in women with chronic migraine. Headache. 2016;56(9):1448–1454.
  • Körtési T, Tuka B, Tajti J, et al. Kynurenic acid inhibits the electrical stimulation induced elevated pituitary adenylate cyclase-activating polypeptide expression in the TNC. Front Neurol. 2018;16(8):745.
  • Guo S, Vollesen AL, Hansen RD, et al. Part I: pituitary adenylate cyclase-activating polypeptide-38 induced migraine-like attacks in patients with and without familial aggregation of migraine. Cephalalgia. 2017;37(2):125–135.
  • Hansen JM, Sitarz J, Birk S, et al. Vasoactive intestinal polypeptide evokes only a minimal headache in healthy volunteers. Cephalalgia. 2006;26(8):992–1003.
  • Iversen HK, Olesen J, Tfelt-Hansen P. Intravenous nitroglycerin as an experimental model of vascular headache. Basic characteristics. Pain. 1989;38(1):17–24.
  • Andreou AP, Summ O, Charbit AR, et al. Animal models of headache: from bedside to bench and back to bedside. Expert Rev Neurother. 2010;10(3):389–411.
  • Lassen LH, Ashina M, Christiansen I, et al. Nitric oxide synthase inhibition in migraine. Lancet. 1997;349(9049):401–402.
  • 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):1458–1467.
  • Hougaard A, Hauge AW, Guo S, et al. The nitric oxide synthase inhibitor and serotonin-receptor agonist NXN-188 during the aura phase of migraine with aura: a randomized, double-blind, placebo-controlled cross-over study. Scand J Pain. 2013;4(1):48–52.
  • Jones ML, Ganopolsky JG, Labbe A, et al. Antimicrobial properties of nitric oxide and its application in antimicrobial formulations and medical devices. Appl Microbiol Biotechnol. 2010;88(2):401–407.
  • Bartsch T, Levy MJ, Knight YE, et al. Differential modulation of nociceptive dural input to [hypocretin] orexin A and B receptor activation in the posterior hypothalamic area. Pain. 2004;109(3):367–378.
  • Connor KM, Mahoney E, Jackson S, et al. A phase II dose-ranging study evaluating the efficacy and safety of the orexin receptor antagonist filorexant (MK-6096) in patients with primary insomnia. Int J Neuropsychopharmacol. 2016;19:8.
  • Hoffmann J, Supronsinchai W, Akerman S, et al. Evidence for orexinergic mechanisms in migraine. Neurobiol Dis. 2015;74:137–143.
  • Chabi A, Zhang Y, Jackson S, et al. Randomized controlled trial of the orexin receptor antagonist filorexant for migraine prophylaxis. Cephalalgia. 2015;35(5):379–388.
  • Andreou AP, Goadsby PJ. Therapeutic potential of novel glutamate receptor antagonists in migraine. Expert Opin Investig Drugs. 2009;18(6):789–803.
  • Sang CN, Ramadan NM, Wallihan RG, et al. LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine. Cephalalgia. 2004;24(7):596–602.
  • Andreou AP, Holland PR, Goadsby PJ. Activation of iGluR5 kainate receptors inhibits neurogenic dural vasodilatation in an animal model of trigeminovascular activation. Br J Pharmacol. 2009;157(3):464–473.
  • Waung MW, Akerman S, Wakefield M, et al. Metabotropic glutamate receptor 5: a target for migraine therapy. Ann Clin Transl Neurol. 2016;3(8):560–571.
  • Chan K, MaassenVanDenBrink A. Glutamate receptor antagonists in the management of migraine. Drugs. 2014;74(11):1165–1176.
  • Blanco MJ, Benesh DR, Knobelsdorf JA, et al. Discovery of dual positive allosteric modulators (PAMs) of the metabotropic glutamate 2 receptor and CysLT1 antagonists for treating migraine headache. Bioorg Med Chem Lett. 2017;27(2):323–328.
  • Curto M, Lionetto L, Fazio F, et al. Fathoming the kynurenine pathway in migraine: why understanding the enzymatic cascades is still critically important. Intern Emerg Med. 2015;10(4):413–421.
  • Stone TW, Darlington LG. Endogenous kynurenines as targets for drug discovery and development. Nat Rev Drug Discov. 2002;1(8):609–620.
  • Stone TW, Perkins MN. Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS. Eur J Pharmacol. 1981;72(4):411–412.
  • Nagy-Grócz G, Laborc KF, Veres G, et al. The effect of systemic nitroglycerin administration on the kynurenine pathway in the rat. Front Neurol. 2017;14(8):278.
  • Fejes-Szabó A, Bohár Z, Vámos E, et al. Pre-treatment with new kynurenic acid amide dose-dependently prevents the nitroglycerine-induced neuronal activation and sensitization in cervical part of trigemino-cervical complex. J Neural Transm (Vienna). 2014;121(7):725–738.
  • Greco R, Demartini C, Zanaboni AM, et al. Effects of kynurenic acid analogue 1 (KYNA-A1) in nitroglycerin-induced hyperalgesia: targets and anti-migraine mechanisms. Cephalalgia. 2017;37(13):1272–1284.
  • Vámos E, Fejes A, Koch J, et al. Kynurenate derivative attenuates the nitroglycerin-induced CamKIIα and CGRP expression changes. Headache. 2010;50(5):834–843.
  • Lukács M, Warfvinge K, Tajti J, et al. Topical dura mater application of CFA induces enhanced expression of c-fos and glutamate in rat trigeminal nucleus caudalis: attenuated by KYNA derivate (SZR72). J Headache Pain. 2017;18(1):39.
  • Veres G, Fejes-Szabó A, Zádori D, et al. A comparative assessment of two kynurenic acid analogs in the formalin model of trigeminalactivation: a behavioral, immunohistochemical and pharmacokinetic study. J Neural Transm (Vienna). 2017;124(1):99–112.
  • Csáti A, Edvinsson L, Vécsei L, et al. Kynurenic acid modulates experimentally induced inflammation in the trigeminal ganglion. J Headache Pain. 2015;16:99.
  • Lukács M, Warfvinge K, Kruse LS, et al. KYNA analogue SZR72 modifies CFA-induced dural inflammation- regarding expression of pERK1/2 and IL-1β in the rat trigeminal ganglion. J Headache Pain. 2016;17(1):64.
  • Curto M, Lionetto L, Negro A, et al. Altered kynurenine pathway metabolites in serum of chronic migraine patients. J Headache Pain. 2015;17:47.
  • Curto M, Lionetto L, Negro A, et al. Altered serum levels of kynurenine metabolites in patients affected by cluster headache. J Headache Pain. 2015;17:27.
  • Matsuda LA, Lolait SJ, Brownstein MJ, et al. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 1990;346(6284):561–564.
  • Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365(6441):61–65.
  • Tsou K, Brown S, Sanudo-Pena MC, et al. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience. 1998;83(2):393–411.
  • Akerman S, Holland PR, Goadsby PJ. Cannabinoid (CB1) receptor activation inhibits trigeminovascular neurons. J Pharmacol Exp Ther. 2007;320(1):64–71.
  • Van der Schueren B. J., K. Van Laere, Gérard N., et al. Interictal type 1 cannabinoid receptor binding is increased in female migraine patients. Headache. 2012;52(3):433–440.
  • Juhasz G, Lazary J, Chase D, et al. Variations in the cannabinoid receptor 1 gene predispose to migraine. Neurosci Lett. 2009;461(2):116–120.
  • Lochte BC, Beletsky A, Samuel NK, et al. The use of cannabis for headache disorders. Cannabis Cannabinoid Res. 2017;2(1):61–71.
  • Dodick DW, Turkel CC, DeGryse RE, et al. PREEMPT chronic migraine study group. OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache. 2010;50(6):921–936.
  • Negro A, Curto M, Lionetto L, et al. A two years open-label prospective study of OnabotulinumtoxinA 195 U in medication overuse headache: a real-world experience. J Headache Pain. 2015;17:1.
  • Andreou AP, Trimboli M, Al-Kaisy A, et al. Prospective real-world analysis of OnabotulinumtoxinA in chronic migraine post-National Institute for Health and Care Excellence UK technology appraisal. Eur J Neurol. 2018;25(8):1069–e83.
  • Zhang X, Strassman AM, Novack V, et al. Extracranial injections of botulinum neurotoxin type A inhibit intracranial meningeal nociceptors’ responses to stimulation of TRPV1 and TRPA1 channels: are we getting closer to solving this puzzle? Cephalalgia. 2016;36(9):875–886.
  • Dolly JO, Wang J, Zurawski TH, et al. Novel therapeutics based on recombinant botulinum neurotoxins to normalize the release of transmitters and pain mediators. FEBS J. 2011;278(23):4454–4466.
  • Wang J, Zurawski TH, Meng J, et al. A dileucine in the protease of botulinum toxin A underlies its long-lived neuroparalysis: transfer of longevity to a novel potential therapeutic. J Biol Chem. 2011;286(8):6375–6385.
  • Torres-Perez JV, Chamberlain J, Miedzik AA. Non-paralytic botulinum chimeras increase the activation threshold of the trigeminovascular system in migraine models. Cephalalgia. 2015;35:4.
  • Paraskevopoulou M, Perez JT, Miedzik A, et al. Non-paralytic botulinum molecules for the control of migraine. Cephalalgia. 2016;36:135.
  • Mangione AS, Obara I, Maiaru M, et al. Nonparalytic botulinum molecules for the control of pain. Pain. 2016;157(5):1045–1055.
  • Maiaru M, Leese C, Certo M, et al. Selective neuronal silencing using synthetic botulinum molecules alleviates chronic pain in mice. Sci Transl Med. 2018;10(450):eaar7384.
  • Edvinsson L. The trigeminovascular pathway: role of CGRP and CGRP receptors in migraine. Headache. 2017;57(Suppl 2):47–55.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.