CNS Drugs

, Volume 27, Issue 9, pp 717–729 | Cite as

The Pipeline in Headache Therapy

Review Article


Migraine is a common, disabling, neurovascular disorder characterized by episodic attacks of head pain and associated disability plus systemic autonomic and neurologic symptoms. The advent of the triptan class of medication in the 1990s revolutionized the acute treatment of migraine, but many migraineurs do not respond optimally or at all to triptans, have intolerable adverse effects, or have contraindications to their use. Preventive pharmacotherapy has advanced mostly through serendipity, with new drugs being found effective while being used for other indications. There remains a significant need for new medications and devices that can provide effective, rapid, and sustained pain relief without adverse effects or recurrence. Several new acute and preventive therapies for the treatment of migraine and cluster headaches have shown promise and are currently under investigation. This article covers innovative delivery mechanisms, calcitonin gene-related peptide receptor antagonists, antibodies to calcitonin gene-related peptide and its receptor, 5-HT1F receptor agonists, transient receptor potential vanilloid receptor modulators, orexin receptor antagonists, glial cell modulators, and neurostimulation.


  1. 1.
    Robbins MS, Lipton RB. The epidemiology of primary headache disorders. Semin Neurol. 2010;30(2):107–19.PubMedCrossRefGoogle Scholar
  2. 2.
    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.PubMedCrossRefGoogle Scholar
  3. 3.
    Cambia (™) [prescribing information]. Nautilus Neurosciences, Inc.: Bedminster; 2010.Google Scholar
  4. 4.
    Diener H-C, Montagna P, Gàcs G, Lyczak P, Schumann G, Zoller B, et al. Efficacy and tolerability of diclofenac potassium sachets in migraine: a randomized, double-blind, cross-over study in comparison with diclofenac potassium tablets and placebo. Cephalalgia. 2006;26(5):537–47.PubMedCrossRefGoogle Scholar
  5. 5.
    Lipton RB, Grosberg B, Singer RP, Pearlman SH, Sorrentino JV, Quiring JN, et al. Efficacy and tolerability of a new powdered formulation of diclofenac potassium for oral solution for the acute treatment of migraine: results from the International Migraine Pain Assessment Clinical Trial (IMPACT). Cephalalgia. 2010;30(11):1336–45.PubMedCrossRefGoogle Scholar
  6. 6.
    Brandes JL, Cady RK, Freitag FG, Smith TR, Chandler P, Fox AW, et al. Needle-free subcutaneous sumatriptan (Sumavel(™) DosePro(™)): bioequivalence and ease of use. Headache. 2009;48:355–67.Google Scholar
  7. 7.
    SUMAVEL® DosePro® [prescribing information]. Zogenix: San Diego; 2011.Google Scholar
  8. 8.
    Rothrock JF, Cady RK, Aurora SK, Brandes JL, Meyers JA, Fox AW, et al. Needle-free subcutaneous sumatriptan for triptan users requiring a change in migraine therapy: efficacy and impact on patient-related functionality, satisfaction, and confidence. Curr Med Res Opin. 2011;27(11):2185–91.PubMedCrossRefGoogle Scholar
  9. 9.
    Cady RK, Aurora SK, Brandes JL, Rothrock JF, Myers JA, Fox AW, et al. Satisfaction with and confidence in needle-free subcutaneous sumatriptan in patients currently treated with triptans. Headache. 2011;51:1202–11.PubMedCrossRefGoogle Scholar
  10. 10.
    Patel SR, Zhong H, Sharma A, Kalia YN. In vitro and in vivo evaluation of the transdermal iontophoretic delivery of sumatriptan succinate. Eur J Pharmaceut Biopharmaceut. 2007;66:296–301.CrossRefGoogle Scholar
  11. 11.
    Vikelis M, Mitsikostas D, Rapoport AM. Sumatriptan transdermal iontophoretic patch (NP101-Zelrix(™)): review of pharmacology, clinical efficacy, and safety in the acute treatment of migraine. Neuropsychiatr Dis Treat. 2012;8:429–34.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Zecuity(™) [prescribing information]. Nupathe, Inc.: Conshohocken; 2013.Google Scholar
  13. 13.
    Siegel SJ, O’Neill CO, Dube LM, Kaldeway P, Morris R, Jackson D, et al. A unique iontophoretic patch for optimal transdermal delivery of sumatriptan. Pharm Res. 2007;24(10):1919–26.PubMedCrossRefGoogle Scholar
  14. 14.
    Pierce M, Marbury T, O’Neill C, Siegel S, Du W, Sebree T. Zelrix(™): a novel transdermal formulation of sumatriptan. Headache. 2009;49:817–25.PubMedCrossRefGoogle Scholar
  15. 15.
    Goldstein J, Smith TR, Pugach N, Griesser M, Sebree T, Pierce M. A sumatriptan iontophoretic transdermal system for the acute treatment of migraine. Headache. 2012;52:1402–10.PubMedCrossRefGoogle Scholar
  16. 16.
    Smith TR, Goldstein J, Singer R, Pugach N, Silberstein S, Pierce MW. Twelve-month tolerability and efficacy study of np101, the sumatriptan iontophoretic transdermal system. Headache. 2012;52:612–24.PubMedCrossRefGoogle Scholar
  17. 17.
    Alsuma(™) [prescribing information]. Pfizer Inc.: New York; 2012.Google Scholar
  18. 18.
    Landy SH, Tepper SJ, Wein T, Schweizer E, Ramos E. An open-label trial of a sumatriptan auto-injector for migraine in patients currently treated with subcutaneous sumatriptan. Headache. 2013;53(1):118–25.PubMedCrossRefGoogle Scholar
  19. 19.
    Silberstein S. MAP0004: dihydroergotamine mesylate inhalation aerosol for acute treatment of migraine. Expert Opin Pharmacother. 2012;13(13):1961–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Shrewsbury SB, Cook RO, Taylor G, Edwards C, Ramadan NM. Safety and pharmacokinetics of dihydroergotamine mesylate administered via a novel (Tempo(™)) inhaler. Headache. 2008;48:355–67.PubMedCrossRefGoogle Scholar
  21. 21.
    Aurora SK, Rozen TD, Kori SH, Shrewsbury SB. A randomized, double blind, placebo-controlled study of MAP0004 in adult patients with migraine. Headache. 2009;49:826–37.PubMedCrossRefGoogle Scholar
  22. 22.
    Aurora SK, Silberstein SD, Kori SH, Tepper SJ, Borland SW, Wang M, et al. MAP0004, orally inhaled DHE: a randomized, controlled study in the acute treatment of migraine. Headache. 2011;51:507–17.PubMedCrossRefGoogle Scholar
  23. 23.
    Burstein R, Collins B, Jakubowski M. Defeating migraine pain with triptans: a race against the development of cutaneous allodynia. Ann Neurol. 2004;55(1):19–26.PubMedCrossRefGoogle Scholar
  24. 24.
    Burstein R, Jakubowski M. Analgesic triptan action in an animal model of intracranial pain: a race against the development of central sensitization. Ann Neurol. 2004;55(1):27–36.PubMedCrossRefGoogle Scholar
  25. 25.
    Tepper SJ, Kori SH, Borland SW, Wang MH, Hu B, Mathew NT, et al. Efficacy and safety of MAP0004, orally inhaled DHE in treating migraine with and without allodynia. Headache. 2012;52:37–47.PubMedCrossRefGoogle Scholar
  26. 26.
    Luthringer R, Djupesland PG, Sheldrake CD, Flint A, Boeijinga P, Danjou P, et al. Rapid absorption of sumatriptan powder and effects on glyceryl trinitrate model of headache following intranasal delivery using a novel bi-directional device. J Pharm Pharmacol. 2009;61(9):1219–28.PubMedCrossRefGoogle Scholar
  27. 27.
    Djupesland PG, Docekal P, Czech Migraine Investigators Group. Intranasal sumatriptan powder delivered by a novel breath-actuated bi-directional device for the acute treatment of migraine: a randomised, placebo-controlled study. Cephalalgia. 2010;30(8):933–42.PubMedGoogle Scholar
  28. 28.
    Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol. 1993;33:48–56.PubMedCrossRefGoogle Scholar
  29. 29.
    Tajti J, Uddman R, Moller S, Sundler F, Edvinsson L. Messenger molecules and receptor mRNA in the human trigeminal ganglion. J Auton Nerv Syst. 1999;76(2–3):176–83.PubMedCrossRefGoogle Scholar
  30. 30.
    Eftekhari S, Salvatore CA, Calamari A, Kane SA, Tajti J, Edvinsson L. Differential distribution of calcitonin gene related peptide and its receptor components in the human trigeminal ganglion. Neuroscience. 2010;169(2):683–96.PubMedCrossRefGoogle Scholar
  31. 31.
    Edvinsson L, Gulbenkian S, Barrosco CP, Cunha e Sá M, Polack JM, Mortensen A, et al. Innervation of the human middle meningeal artery: immunohistochemistry, ultrastructure, and role of endothelium for vasomotility. Peptides. 1998;19(7):1213–25.PubMedCrossRefGoogle Scholar
  32. 32.
    Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28:183–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Gallai V, Sarchielli P, Floridi A, Franceschini M, Cadini M, Glioti G, et al. Vasoactive peptide levels in the plasma of young migraine patients with and without aura assessed both interictally and ictally. Cephalalgia. 1995;15:384–90.PubMedCrossRefGoogle Scholar
  34. 34.
    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.PubMedCrossRefGoogle Scholar
  35. 35.
    Fanciullacci M, Alessandri M, Figini M, Geppetti P, Michelacci S. Increase in plasma calcitonin-gene-related peptide from the extracerebral circulation during nitroglycerin-induced cluster headache attack. Pain. 1995;60(2):119–23.PubMedCrossRefGoogle Scholar
  36. 36.
    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.PubMedCrossRefGoogle Scholar
  37. 37.
    Goadsby PJ. Recent advances in understanding migraine mechanisms, molecules, and therapeutics. Trends Mol Med. 2007;13(1):39–44.PubMedCrossRefGoogle Scholar
  38. 38.
    Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, Meier U, 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.PubMedCrossRefGoogle Scholar
  39. 39.
    Ho TW, Mannix LK, Fan X, Assaid C, Furtek C, Jones CJ, et al. Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology. 2008;70(16):1304–12.PubMedCrossRefGoogle Scholar
  40. 40.
    Hewitt DJ, Martin V, Lipton RB, Brandes J, Ceesay P, Gottwald R, et al. Randomized controlled study of telcagepant plus ibuprofen or acetominophen in migraine. Headache. 2011;51:533–43.PubMedCrossRefGoogle Scholar
  41. 41.
    Ho TW, Ferrari MD, Dodick DW, Galet V, Kost J, Fan X, 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 randomized, placebo-controlled, parallel-treatment trial. Lancet. 2008;372(9656):2115–23.PubMedCrossRefGoogle Scholar
  42. 42.
    Connor KM, Shapiro RE, Diener HC, Lucus S, Kost J, Fan X, et al. Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology. 2009;73(12):970–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Hewitt DJ, Aurora SK, Dodick DW, Goadsby PJ, Ge YJ, Bachman R, et al. Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine. Cephalalgia. 2011;31(6):712–22.PubMedCrossRefGoogle Scholar
  44. 44.
    Ho TW, Ho AP, Chaitman BR, Johnson C, Mathew NT, Kost J, et al. Randomized, controlled study of telcagepant in patients with migraine and coronary artery disease. Headache. 2012;52(2):224–35.PubMedCrossRefGoogle Scholar
  45. 45.
    van der Schueren BJ, Blanchard R, Murphy MG, Palcza J, De Lepeleire I, Van Hecken A, et al. The potent calcitonin gene-related peptide receptor antagonist, telcagepant, does not affect nitroglycerin-induced vasodilation in healthy men. Br J Clin Pharmacol. 2010;71(5):708–17.CrossRefGoogle Scholar
  46. 46.
    Ho AP, Dahlof CG, Silberstein SD, Saper JR, Ashina M, Kost JT, et al. Randomized, controlled trial of telcagepant over four migraine attacks. Cephalalgia. 2010;30(12):1443–57.PubMedCrossRefGoogle Scholar
  47. 47.
    Connor KM, Aurora SK, Loeys T, Ashina M, Jones C, Giezek H, et al. Long-term tolerability of telcagepant for acute treatment of migraine in a randomized trial. Headache. 2011;51(1):73–84.PubMedCrossRefGoogle Scholar
  48. 48.
    Ho TW, Olesen J, Dodick DW, Kost J, Lines C, Ferrari MD. Antimigraine efficacy of telcagepant based on patient’s historical triptan response. Headache. 2011;51(1):64–72.PubMedCrossRefGoogle Scholar
  49. 49.
    Hoffmann J, Goadsby PJ. New agents for acute treatment of migraine: CGRP receptor antagonists, iNOS inhibitors. Curr Treat Options Neurol. 2012;14(1):50–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Han TH, Blanchard RL, Palcza J, McCrea JB, Laethem T, Willson K, 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.PubMedCrossRefGoogle Scholar
  51. 51.
    Diener HC, Barbanti P, Dahlof C, Reuter U, Habeck J, Podhorna J. BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine: results from a phase II study. Cephalalgia. 2011;31(5):573–84.PubMedCrossRefGoogle Scholar
  52. 52.
    Bigal ME, Walter S, Rapoport AM. Calcitonin gene-related peptide (CGRP) and migraine: current understanding and state of development. Headache. 2013 (in press).Google Scholar
  53. 53.
    Neeb L, Meents J, Reuter U. 5-HT-1F receptor agonists: a new treatment option for migraine attacks? Neurotherapeutics. 2010;7:176–82.PubMedCrossRefGoogle Scholar
  54. 54.
    Ferrari MD, Farkkila M, Reuter U, Pilgrim A, Davis C, Krauass M. Acute treatment of migraine with the selective 5-HT-1F receptor agonist lasmitidan—a randomised proof-of-concept trial. Cephalalgia. 2010;30:1170–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Fakkila M, Diener HC, Geraud G, Laniz JM, Schoenen J, Pilgrim AJ. Lasmitidan (COL-144), a selective 5HT1F agonist, is a rapid and effective oral treatment for acute migraine. J Headache Pain. 2010;11(Suppl 1):S43.Google Scholar
  56. 56.
    Jansen-Olesen I, Mortensen A, Edvinsson L. Calcitonin gene-related peptide is released from capsaicin-sensitive nerve fibres and induces vasodilation of human cerebral arteries concomitant with activation of adenylyl cyclase. Cephalalgia. 1996;16:310–6.PubMedCrossRefGoogle Scholar
  57. 57.
    Rapoport AM. The therapeutic future in headache. Neurol Sci. 2012;22(Suppl 1):S119–25.CrossRefGoogle Scholar
  58. 58.
    Saper JR, Klapper J, Mathew NT, Rapoport A, Phillips SB, Bernstein JE. Intranasal civamide for the treatment of episodic cluster headache. Arch Neurol. 2002;59:990–4.PubMedCrossRefGoogle Scholar
  59. 59.
    Civamide nasal solution for cluster headache (ECH). NCT01341548. Accessed 26 Feb 2013.
  60. 60.
    Diamond S, Freitag F, Phillips SB, Bernstein JE, Saper JR. Intranasal civamide for the acute treatment of migraine headache. Cephalalgia. 2000;20:597–602.PubMedCrossRefGoogle Scholar
  61. 61.
    Bartsch T, Levy MJ, Knight YE, Goadsby PJ. Differential modulation of nociceptive dural input to [hypcretin] orexin A and B receptor activation in the posterior hypothalamic area. Pain. 2004;109:367–78.PubMedCrossRefGoogle Scholar
  62. 62.
    Holland PR, Akerman S, Goadsby PJ. Modulation of nociceptive dural input to the trigeminal nucleus caudalis via activation of the orexin 1 receptor in the rat. Eur J Neurosci. 2006;24:2825–33.PubMedCrossRefGoogle Scholar
  63. 63.
    Winrow CJ, Gotter AL, Cox CD, Tannenbaum PL, Garson SL, Doran SM, et al. Pharmacololgical characterization of MK-6096—a dual orexin receptor antagonist for insomnia. Neuropharmacology. 2012;62:978–87.PubMedCrossRefGoogle Scholar
  64. 64.
    A study of the safety and efficacy of MK-6096 for migraine prophylaxis in participants with episodic migraine (MK-6096-020). NCT01513291. Accessed 26 Feb 2013.
  65. 65.
    Eftekhari S, Salvatore CA, Calamari A, Kane SA, Tajti J, Edvinsson L. Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion. Neuroscience. 2010;169:683–96.PubMedCrossRefGoogle Scholar
  66. 66.
    Hanani M. Satellite glial cells in sensory ganglia: from form to function. Brain Res Brain Res Rev. 2005;48(3):457–76.PubMedCrossRefGoogle Scholar
  67. 67.
    Garrison CJ, Dougherty PM, Carlton SM. GFAP expression in lumbar spinal cord of naive and neuropathic rats treated with MK-801. Exp Neurol. 1994;129:237–43.PubMedCrossRefGoogle Scholar
  68. 68.
    Watkins LR, Milligan ED, Maier SF. Glial activation: a driving force for pathological pain. Trends Neurosci. 2001;24(8):450–5.PubMedCrossRefGoogle Scholar
  69. 69.
    Wieseler-Frank J, Maier SF, Watkins LR. Glial activation and pathological pain. Neurochem Int. 2004;45(2–3):389–95.PubMedCrossRefGoogle Scholar
  70. 70.
    Takeda M, Takahashi M, Matsumoto S. Contribution of the activation of satellite glia in sensory ganglia to pathological pain. Neurosci Biobehav Rev. 2009;33(6):784–92.PubMedCrossRefGoogle Scholar
  71. 71.
    Thalakoti S, Patil VV, Damodaram S, Vause CV, Langford LE, Freeman SE, et al. Neuron-glia signaling in trigeminal ganglion: implications for migraine pathology. Headache. 2007;47:1008–23.PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Capuano A, DeCorato A, Lisi L, Tringali G, Navarra P, Dello Russo C. Proinflammatory-activated trigeminal satellite cells promote neuronal sensitization: relevance for migraine pathology. Mol Pain. 2009;5:43–55.PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Kruuse C, Thomsen LL, Jacobsen TB, Olesen J. The phosphodiesterase 5 inhibitor sildenafil has no effect on cerebral blood flow or blood velocity, but nevertheless induces headache in healthy subjects. J Cereb Blood Flow Metab. 2002;22(9):1124–31.PubMedCrossRefGoogle Scholar
  74. 74.
    Ledeboer A, Tongyao L, Ahumilla JA, Mahoney JH, Vijay S, Gross MI, et al. The glial modulatory drug AV411 attenuates mechanical allodynia in rat models of neuropathic pain. Neuron Glio Biol. 2006;2:279–291.Google Scholar
  75. 75.
    Ledeboer A, Hutchinson MR, Watkins LR, Johnson KW. Ibudilast (AV-411): a new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes. Expert Opin Investig Drugs. 2007;16(7):935–50.PubMedCrossRefGoogle Scholar
  76. 76.
    Schwedt TJ, Dodick DW, Hentz J, Trentman TL, Zimmerman RS. Occipital nerve stimulation for chronic headache—long-term safety and efficacy. Cephalalgia. 2007;27(2):153–7.PubMedCrossRefGoogle Scholar
  77. 77.
    Matharu MS, Bartsch T, Ward N, Frackowiak RSJ, Weiner R, Goadsby PJ. Central neuromodulation in chronic migraine patients with suboccipital stimulators: a PET study. Brain. 2004;127(Pt 1):220–30.PubMedCrossRefGoogle Scholar
  78. 78.
    Saper JR, Dodick DW, Silberstein SD, McCarville S, Sun M, Goadsby PJ. Occipital nerve stimulation for the treatment of intractable chronic migraine headache: ONSTIM feasibility study. Cephalalgia. 2011;31(3):271–85.PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Reed KL, Black SB, Banta CJ II, Will KR. Combined occipital and supraorbital neurostimulation for the treatment of chronic migraine headaches: initial experience. Cephalalgia. 2010;30(3):260–71.PubMedGoogle Scholar
  80. 80.
    Schytz HW, Barlose M, Guo S, Selb J, Caparso A, Jensen R, et al. Experimental activation of the sphenopalatine ganglion provokes cluster-like attacks in humans. Cephalalgia. 2013, 1–11 (Epub ahead of print).Google Scholar
  81. 81.
    Tepper SJ, Rezai A, Narouze S, Steiner C, Mohajer P, Ansarinia M. Acute treatment of intractable migraine with sphenopalatine ganglion electrical stimulation. Headache. 2009;49(7):983–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Schoenen J, Jensen RH, Lanteri-Minet M, Lainez MJ, Gaul C, Goodman AM, et al. Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: a randomized, sham-controlled study. Cephalalgia. 2013;6:1–15 (Epub ahead of print).Google Scholar
  83. 83.
    Sadler RM, Purdy RA, Rahey S. Vagal nerve stimulation aborts migraine in patient with intractable epilepsy. Cephalalgia. 2002;22(6):482–4.PubMedCrossRefGoogle Scholar
  84. 84.
    Mauskop A. Vagus nerve stimulation relieves chronic refractory migraine and cluster headaches. Cephalalgia. 2005;25(2):82–6.PubMedCrossRefGoogle Scholar
  85. 85.
    Hord ED, Evans MS, Mueed S, Adamolekun B, Naritoku DK. The effect of vagus nerve stimulation on migraines. J Pain. 2003;4(9):530–4.PubMedCrossRefGoogle Scholar
  86. 86.
    Lenaerts ME, Oommen KJ, Couch JR, Skaggs V. Can vagus nerve stimulation help migraine? Cephalalgia. 2008;28(4):392–5.PubMedCrossRefGoogle Scholar
  87. 87.
    Cecchini AP, Mea E, Tullo V, Curone M, Franzoni A, Broggi G, et al. Vagus nerve stimulation in drug-resistant daily chronic migraine with depression preliminary data. Neurol Sci. 2009;30(Suppl 1):S101–4.PubMedCrossRefGoogle Scholar
  88. 88.
    Oshinsky ML, Murphy AL, Cooper ME, Simon BJ. Trigeminal pain is suppressed by non-invasive vagal nerve stimulation in a rat headache model. J Headache Pain. 2013;1(Suppl 1):P80.CrossRefGoogle Scholar
  89. 89.
    Goadsby P. Non-invasive vagus nerve stimulation (nVNS) for acute treatment of migraine: an open-label pilot study. American Academy of Neurology’s 65th AAN annual meeting, San Diego.Google Scholar
  90. 90.
    Nesbitt AD, Marin JCA, Tomkins E, Ruttledge MH, Goadsby PJ. Non-invasive vagus nerve stimulation for the treatment of cluster headache: a case series. J Headache Pain. 2013;1(Suppl 1):P231.CrossRefGoogle Scholar
  91. 91.
    Gerardy PY, Fabry D, Fumal A, Schoenen J. A pilot study on supra-orbital surface electrotherapy in migraine. Cephalalgia. 2009;29:134.Google Scholar
  92. 92.
    Schoenen J, Vandermissen B, Jeangette S, Herroelen L, Vandenheede M, Gerard P, et al. Migraine prevention with a supraorbital transcutaneous stimulator: a randomized controlled trial. Neurology. 2013;80(8):697–704.PubMedCrossRefGoogle Scholar
  93. 93.
    Lipton RB, Dodick DW, Silberstein SD, Saper JR, Aurora SK, Pearlman SH, et al. Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a randomized, double-blind, parallel-group, sham-controlled trial. Lancet Neurol. 2010;9(4):373–80.PubMedCrossRefGoogle Scholar
  94. 94.
    Clarke BM, Upton ARM, Kamath MV, Al-Harbi T, Castellasnos CM. Transcranial magnetic stimulation for migraine: clinical effects. J Headache Pain. 2006;7(5):341–6.PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Teepker M, Hotzel J, Timmesfeld N, Reis J, Mylius V, Haag A, et al. Low-frequency rTMS of the vertex in the prophylactic treatment of migraine. Cephalalgia. 2010;30(2):137–44.PubMedGoogle Scholar
  96. 96.
    Bringhina F, Piazza A, Vitello G, Aloisio A, Palermo A, Daniele O, et al. rTMS of the prefrontal cortex in the treatment of chronic migraine: a pilot study. J Neurol Sci. 2004;227(1):67–71.CrossRefGoogle Scholar
  97. 97.
    Misra UK, Kalita J, Bhoi SK. High frequency repetitive transcranial magnetic stimulation (rTMS) is effective in migraine prophylaxis: an open labeled study. Neurol Res. 2012;34(6):547–51.PubMedCrossRefGoogle Scholar
  98. 98.
    Antal A, Kriener N, Lang N, Boros K, Paulus W. Cathodal transcranial direct current stimulation of the visual cortex in the prophylactic treatment of migraine. Cephalalgia. 2011;31(7):820–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Department of Neurology, Montefiore Headache CenterAlbert Einstein College of MedicineNYUSA
  2. 2.Director-Emeritus, New England Center for HeadacheStamfordUSA
  3. 3.The David Geffen School of Medicine at UCLALos AngelesUSA

Personalised recommendations