Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

New strategies for the treatment and prevention of primary headache disorders

Key Points

  • Calcitonin gene-related peptide (CGRP) is the best-validated therapeutic target for migraine

  • Monoclonal antibodies (mAbs) against CGRP or its receptor hold promise for migraine prevention, and small-molecule CGRP antagonists hold promise for acute and/or preventive treatment

  • Four mAbs targeting CGRP or its receptor have been effective in phase II studies and are being studied in phase III trials for migraine prevention

  • Non-oral systems to deliver triptans and dihydroergotamine mesylate for acute migraine treatment bypass hurdles posed by nausea, gastric stasis, and first-pass metabolism

  • Noninvasive electrical and electromagnetic neurostimulators for primary headache disorders are available for clinical use, but regulatory approval varies by country, and patients might be required to cover costs

  • For patients with intractable, medically refractory primary headache disorders, implantable neurostimulators targeting peripheral nerves, the sphenopalatine ganglion, and high cervical spinal cord are being studied

Abstract

The primary headache disorders, which include migraine, cluster headache and tension-type headache, are among the most common diseases and leading causes of disability worldwide. The available treatment options for primary headache disorders have unsatisfactory rates of efficacy, tolerability and patient adherence. In this Review, we discuss promising new approaches for the prevention of primary headache disorders, such as monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor, and small-molecule CGRP receptor antagonists. Neuromodulation approaches employing noninvasive or implantable devices also show promise for treating primary headache disorders. Noninvasive treatments, such as transcranial magnetic stimulation and transcutaneous peripheral nerve stimulation, are delivered by devices that patients can self-administer. Implantable devices targeting the occipital nerves, sphenopalatine ganglion or high cervical spinal cord are placed using percutaneous and/or surgical procedures, and are powered either wirelessly or by surgically implanted batteries. These new and emerging treatments have the potential to address unmet patient needs and reduce headache-associated disability.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: CGRP levels during migraine attacks.
Figure 2: Nasal administration of sumatriptan via Onzetra Xsail.
Figure 3: Non-invasive neuromodulation treatments.
Figure 4: Implantable neuromodulation treatments.
Figure 5: High cervical spinal cord stimulators.

References

  1. 1

    Steiner, T. J., Stovner, L. J. & Birbeck, G. L. Migraine: the seventh disabler. Cephalalgia 33, 289–290 (2013).

    Article  CAS  PubMed  Google Scholar 

  2. 2

    Steiner, T. J., Stovner, L. J. & Birbeck, G. L. Migraine: the seventh disabler. Headache 53, 227–229 (2013).

    Article  PubMed  Google Scholar 

  3. 3

    Steiner, T. J., Stovner, L. J. & Birbeck, G. L. Migraine: the seventh disabler. J. Headache Pain 14, 1 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4

    Steiner, T. J. et al. Headache disorders are third cause of disability worldwide. J. Headache Pain 16, 58 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Forouzanfar, M. H. et al. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 386, 2287–2323 (2015).

    Article  PubMed  Google Scholar 

  6. 6

    Ekbom, K., Svensson, D. A., Pedersen, N. L. & Waldenlind, E. Lifetime prevalence and concordance risk of cluster headache in the Swedish twin population. Neurology 67, 798–803 (2006).

    Article  PubMed  Google Scholar 

  7. 7

    Torelli, P., Beghi, E. & Manzoni, G. C. Cluster headache prevalence in the Italian general population. Neurology 64, 469–474 (2005).

    Article  PubMed  Google Scholar 

  8. 8

    Sjaastad, O. & Bakketeig, L. S. Cluster headache prevalence. Vaga study of headache epidemiology. Cephalalgia 23, 528–533 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. 9

    Tonon, C. et al. Prevalence and incidence of cluster headache in the Republic of San Marino. Neurology 58, 1407–1409 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. 10

    Evers, S., Fischera, M., May, A. & Berger, K. Prevalence of cluster headache in Germany: results of the epidemiological DMKG study. J. Neurol. Neurosurg. Psychiatry 78, 1289–1290 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    Rozen, T. D. & Fishman, R. S. Cluster headache in the United States of America: demographics, clinical characteristics, triggers, suicidality, and personal burden. Headache 52, 99–113 (2012).

    Article  PubMed  Google Scholar 

  12. 12

    Hepp, Z. et al. Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia 35, 478–488 (2015).

    Article  PubMed  Google Scholar 

  13. 13

    Mason, R. T. et al. Release of the predicted calcitonin gene-related peptide from cultured rat trigeminal ganglion cells. Nature 308, 653–655 (1984).

    Article  CAS  PubMed  Google Scholar 

  14. 14

    Brain, S. D., Williams, T. J., Tippins, J. R., Morris, H. R. & MacIntyre, I. Calcitonin gene-related peptide is a potent vasodilator. Nature 313, 54–56 (1985).

    Article  CAS  PubMed  Google Scholar 

  15. 15

    Walker, C. S. et al. A second trigeminal CGRP receptor: function and expression of the AMY1 receptor. Ann. Clin. Transl Neurol. 2, 595–608 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Lassen, L. H. et al. CGRP may play a causative role in migraine. Cephalalgia 22, 54–61 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. 17

    Hansen, J. M., Hauge, A. W., Olesen, J. & Ashina, M. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia 30, 1179–1186 (2010).

    Article  PubMed  Google Scholar 

  18. 18

    Underwood, E. Feature: Will antibodies finally put an end to migraines? Science http://www.sciencemag.org/news/2016/01/feature-will-antibodies-finally-put-end-migraines (2016).

  19. 19

    Bigal, M. E. 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. 14, 1081–1090 (2015).

    Article  CAS  PubMed  Google Scholar 

  20. 20

    Goadsby, P. J. & Edvinsson, L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann. Neurol. 33, 48–56 (1993).

    Article  CAS  PubMed  Google Scholar 

  21. 21

    Cady, R. K., Vause, C. V., Ho, T. W., Bigal, M. E. & Durham, P. L. Elevated saliva calcitonin gene-related peptide levels during acute migraine predict therapeutic response to rizatriptan. Headache 49, 1258–1266 (2009).

    Article  PubMed  Google Scholar 

  22. 22

    Cernuda-Morollón, E. et al. CGRP and VIP levels as predictors of efficacy of onabotulinumtoxin type A in chronic migraine. Headache 54, 987–995 (2014).

    Article  PubMed  Google Scholar 

  23. 23

    Cady, R. et al. An exploratory study of salivary calcitonin gene-related peptide levels relative to acute interventions and preventative treatment with onabotulinumtoxinA in chronic migraine. Headache 54, 269–277 (2014).

    Article  PubMed  Google Scholar 

  24. 24

    Connor, K. M. et al. Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology 73, 970–977 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Ho, T. W. et al. Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention. Neurology 83, 958–966 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Hewitt, D. J. et al. Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine. Cephalalgia 31, 712–722 (2011).

    Article  PubMed  Google Scholar 

  27. 27

    Marcus, R. et al. BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia 34, 114–125 (2014).

    Article  PubMed  Google Scholar 

  28. 28

    Olesen, J. et al. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N. Engl. J. Med. 350, 1104–1110 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. 29

    Shi, L. et al. Pharmacologic characterization of AMG 334, a potent and selective human monoclonal antibody against the calcitonin gene-related peptide receptor. J. Pharmacol. Exp. Ther. 356, 223–231 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Ramos, M. L. & Pascual, J. AMG 334 CGRP antibody for migraine: time to celebrate? Lancet Neurol. 15, 347–349 (2016).

    CAS  Google Scholar 

  31. 31

    Dodick, D. 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. 13, 885–892 (2014).

    Article  CAS  PubMed  Google Scholar 

  32. 32

    Dodick, D. 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. 13, 1100–1107 (2014).

    Article  CAS  PubMed  Google Scholar 

  33. 33

    Bigal, M. E. et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol. 14, 1091–1100 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. 34

    Sun, H. et al. Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. http://dx.doi.org/10.1016/s1474-4422(16)00019-3 (2016).

  35. 35

    Bigal, M. E. et al. TEV-48125 for the preventive treatment of chronic migraine: efficacy at early time points. Neurology http://dx.doi.org/10.1212/wnl.0000000000002801 (2016).

  36. 36

    US National Library of Medicine. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT02614183 (2016).

  37. 37

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02614196 (2016).

  38. 38

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02614261 (2016).

  39. 39

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02397473 (2016).

  40. 40

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02438826 (2016).

  41. 41

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02576951 (2016).

  42. 42

    Smith, J. et al. OR01 — proof of concept clinical trial of ALD403, ananti-calcitonin gene-related peptide (CGRP) antibody in the prevention of migraine — 6 month data. International Headache Society abstracts. Cephalalgia 35 (6 Suppl.), 4–5 (2015).

    Google Scholar 

  43. 43

    [No authors listed.] Alder reports phase 2b trial of ALD403 meets primary and secondary endpoints demonstrating migraine prevention in patients with chronic migraine. Alder http://investor.alderbio.com/releasedetail.cfm?releaseid=962238 (2016).

  44. 44

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02559895 (2016).

  45. 45

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02629861 (2016).

  46. 46

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02621931 (2016).

  47. 47

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02638103 (2016).

  48. 48

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01952574 (2016).

  49. 49

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02456740 (2016).

  50. 50

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02483585 (2016).

  51. 51

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02066415(2016).

  52. 52

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02174861 (2016).

  53. 53

    Lenz, R. et al. Prevention of episodic migraine with AMG 334, a human anti-calcitonin gene-related peptide receptor monoclonal antibody: phase 2 study results and 52-week analysis of open-label extension (S26.002). Neurology 86 (16 Suppl.), S26.002 (2016).

    Google Scholar 

  54. 54

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02630459 (2016).

  55. 55

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02575833 (2016).

  56. 56

    Voss,T. et al. A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine. Cephalalgia 38, 887–898 (2001).

  57. 57

    Goldstein, D. J. et al. Selective serotonin 1F (5-HT(1F)) receptor agonist LY334370 for acute migraine: a randomised controlled trial. Lancet 358, 1230–1234 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. 58

    Ferrari, M. D. et al. Acute treatment of migraine with the selective 5-HT1F receptor agonist lasmiditan — a randomised proof-of-concept trial. Cephalalgia 30, 1170–1178 (2010).

    Article  PubMed  Google Scholar 

  59. 59

    Farkkila, M. 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. 11, 405–413 (2012).

    Article  CAS  PubMed  Google Scholar 

  60. 60

    Reuter, U., Israel, H. & Neeb, L. The pharmacological profile and clinical prospects of the oral 5-HT1F receptor agonist lasmiditan in the acute treatment of migraine. Ther. Adv. Neurol. Disord. 8, 46–54 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00883051 (2016).

  62. 62

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02439320 (2016).

  63. 63

    Obaidi, M. et al. Improved pharmacokinetics of sumatriptan with Breath Powered nasal delivery of sumatriptan powder. Headache 53, 1323–1333 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  64. 64

    Cady, R. et al. A randomized, double-blind, placebo-controlled study of breath powered nasal delivery of sumatriptan powder (AVP-825) in the treatment of acute migraine (the TARGET study). Headache 55, 88–100 (2015).

    Article  PubMed  Google Scholar 

  65. 65

    Tepper, S. J. et al. AVP-825 breath-powered intranasal delivery system containing 22 mg sumatriptan powder versus 100 mg oral sumatriptan in the acute treatment of migraines (the COMPASS study): a comparative randomized clinical trial across multiple attacks. Headache 55, 621–635 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  66. 66

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02571049 (2016).

  67. 67

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02583425 (2016).

  68. 68

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02569853 (2016).

  69. 69

    Siegel, S. J. et al. A unique iontophoretic patch for optimal transdermal delivery of sumatriptan. Pharm. Res. 24, 1919–1926 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. 70

    Vikelis, M., Mitsikostas, D. D. & Rapoport, A. M. Sumatriptan transdermal iontophoretic patch (NP101-Zelrix): review of pharmacology, clinical efficacy, and safety in the acute treatment of migraine. Neuropsychiatr. Dis. Treat. 8, 429–434 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Hurtukova, D. Urgent – Zecuity (sumatriptan iontophoretic transdermal system) suspensionof marketing. Teva Pharmaceuticals http://www.fda.gov/downloads/Drugs/DrugSafety/UCM506332.pdf (2011).

  72. 72

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00623636 (2016).

  73. 73

    Aurora, S. et al. MAP0004, orally inhaled DHE: a randomized, controlled study in the acute treatment of migraine. Headache 51, 507–517 (2011).

    Article  PubMed  Google Scholar 

  74. 74

    Tepper, S. J. et al. MAP0004, orally inhaled dihydroergotamine for acute treatment of migraine: efficacy of early and late treatments. Mayo Clin. Proc. 86, 948–955 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Tepper, S. J. et al. Efficacy and safety of MAP0004, orally inhaled DHE in treating migraines with and without allodynia. Headache 52, 37–47 (2012).

    Article  PubMed  Google Scholar 

  76. 76

    Armer, T. A., Lynch, M., Moutvic, R. & Singer, A. Toxicological assessment of dihydroergotamine after chronic inhalation in dogs. Toxicol. Pathol. 39, 544–552 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. 77

    Cook, R. O., Shrewsbury, S. B. & Ramadan, N. M. Reduced adverse event profile of orally inhaled DHE (MAP0004) versus IV DHE: potential mechanism. Headache 49, 1423–1434 (2009).

    Article  PubMed  Google Scholar 

  78. 78

    Kellerman, D. et al. Lack of drug interaction between the migraine drug MAP0004 (orally inhaled dihydroergotamine) and a CYP3A4 inhibitor in humans. Cephalalgia 32, 150–158 (2012).

    Article  CAS  PubMed  Google Scholar 

  79. 79

    Kori, S., Kellerman, D. J., Voloshko, P. & Haugen, G. Effects of a supratherapeutic dose of investigational orally inhaled dihydroergotamine (MAP0004) on QT interval: a randomized, double-blind, active- and placebo-controlled crossover study in healthy volunteers. Clin. Ther. 34, 1920–1928 (2012).

    Article  CAS  PubMed  Google Scholar 

  80. 80

    Noveck, R. J. et al. Assessing acute systemic effects of an inhaled drug with serial echocardiography: a placebo-controlled comparison of inhaled and intravenous dihydroergotamine. Drug Des. Devel. Ther. 7, 619–625 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Shrewsbury, S. B., Cook, R. O., Taylor, G., Edwards, C. & Ramadan, N. M. Safety and pharmacokinetics of dihydroergotamine mesylate administered via a novel (Tempo) inhaler. Headache 48, 355–367 (2008).

    Article  PubMed  Google Scholar 

  82. 82

    Shrewsbury, S. B., Kori, S. H., Miller, S. D., Pedinoff, A. & Weinstein, S. Randomized, double-blind, placebo-controlled study of the safety, tolerability and pharmacokinetics of MAP0004 (orally-inhaled DHE) in adult asthmatics. Curr. Med. Res. Opin. 24, 1977–1985 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. 83

    Andreou, A. P., Sprenger, T. & Goadsby, P. J. Cortical modulation of thalamic function during cortical spreading depression — unraveling a new central mechanism involved in migraine aura. J. Headache Pain 14, I6 (2013).

    Article  PubMed Central  Google Scholar 

  84. 84

    Andreou, A. P. et al. Transcranial magnetic stimulation and potential cortical and trigeminothalamic mechanisms in migraine. Brain http://dx.doi.org/10.1093/brain/aww118 (2016).

  85. 85

    Teepker, M. et al. Low-frequency rTMS of the vertex in the prophylactic treatment of migraine. Cephalalgia 30, 137–144 (2010).

    Article  CAS  PubMed  Google Scholar 

  86. 86

    Misra, U. K., Kalita, J. & Bhoi, S. K. High-rate repetitive transcranial magnetic stimulation in migraine prophylaxis: a randomized, placebo-controlled study. J. Neurol. 260, 2793–2801 (2013).

    Article  PubMed  Google Scholar 

  87. 87

    Conforto, A. B. et al. Randomized, proof-of-principle clinical trial of active transcranial magnetic stimulation in chronic migraine. Cephalalgia 34, 464–472 (2014).

    Article  PubMed  Google Scholar 

  88. 88

    Lipton, R. B. et al. Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a randomised, double-blind, parallel-group, sham-controlled trial. Lancet Neurol. 9, 373–380 (2010).

    Article  PubMed  Google Scholar 

  89. 89

    Bhola, R. et al. Single-pulse transcranial magnetic stimulation (sTMS) for the acute treatment of migraine: evaluation of outcome data for the UK post market pilot program. J. Headache Pain 16, 535 (2015).

    Article  PubMed  Google Scholar 

  90. 90

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02357381 (2016).

  91. 91

    Schoenen, J., Roberta, B., Magis, D. & Coppola, G. Noninvasive neurostimulation methods for migraine therapy: the available evidence. Cephalalgia http://dx.doi.org/10.1177/0333102416636022 (2016).

    Google Scholar 

  92. 92

    Auvichayapat, P. et al. Migraine prophylaxis by anodal transcranial direct current stimulation, a randomized, placebo-controlled trial. J. Med. Assoc. Thai. 95, 1003–1012 (2012).

    PubMed  Google Scholar 

  93. 93

    Dasilva, A. F. et al. tDCS-induced analgesia and electrical fields in pain-related neural networks in chronic migraine. Headache 52, 1283–1295 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  94. 94

    Vigano, A. et al. Transcranial direct current stimulation (tDCS) of the visual cortex: a proof-of-concept study based on interictal electrophysiological abnormalities in migraine. J. Headache Pain 14, 23 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  95. 95

    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 31, 820–828 (2011).

    Article  PubMed  Google Scholar 

  96. 96

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02562222 (2016).

  97. 97

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02562196 (2016).

  98. 98

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02122757 (2016).

  99. 99

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02120326 (2016).

  100. 100

    Schoenen, J. et al. Migraine prevention with a supraorbital transcutaneous stimulator: a randomized controlled trial. Neurology 80, 697–704 (2013).

    Article  PubMed  Google Scholar 

  101. 101

    [No authors listed.] Migraine prevention with a supraorbital transcutaneous stimulator: a randomized controlled trial. Neurology 85, 1997 (2015).

  102. 102

    Magis, D., Sava, S., d'Elia, T. S., Baschi, R. & Schoenen, J. Safety and patients' satisfaction of transcutaneous supraorbital neurostimulation (tSNS) with the Cefaly® device in headache treatment: a survey of 2,313 headache sufferers in the general population. J. Headache Pain 14, 95 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  103. 103

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02590939 (2016).

  104. 104

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02411513 (2016).

  105. 105

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02438553 (2016).

  106. 106

    National Institute of Health and Care Excellence. Interventional procedure overview of transcutaneous stimulation of the cervical branch of the vagus nerve for cluster headache and migraine. NICE https://www.nice.org.uk/guidance/ipg552 (2015).

  107. 107

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01701245 (2016).

  108. 108

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01958125 (2016).

  109. 109

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01792817 (2016).

  110. 110

    Gaul, C. et al. Non-invasive vagus nerve stimulation for PREVention and Acute treatment of chronic cluster headache (PREVA): a randomised controlled study. Cephalalgia 36, 534–546 (2016).

    Article  PubMed  Google Scholar 

  111. 111

    Silberstein, S. D. et al. Non-Invasive Vagus Nerve Stimulation for the ACute Treatment of Cluster Headache: Findings From the Randomized, Double-Blind, Sham-Controlled ACT1 Study. Headache 56, 1317–1332 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  112. 112

    Barbanti, P. et al. Non-invasive vagus nerve stimulation for acute treatment of high-frequency and chronic migraine: an open-label study. J. Headache Pain 16, 61 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  113. 113

    Goadsby, P. J., Grosberg, B. M., Mauskop, A., Cady, R. & Simmons, K. A. Effect of noninvasive vagus nerve stimulation on acute migraine: an open-label pilot study. Cephalalgia 34, 986–993 (2014).

    Article  CAS  PubMed  Google Scholar 

  114. 114

    Silberstein, S. D. et al. Chronic migraine headache prevention with noninvasive vagus nerve stimulation: the EVENT study. Neurology 87, 1–10 (2016).

    Article  Google Scholar 

  115. 115

    Magis, D., Gérard, P. & Schoenen, J. Transcutaneous vagus nerve stimulation (tVNS) for headache prophylaxis: initial experience. J. Headache Pain 14, P198 (2013).

    Article  PubMed Central  Google Scholar 

  116. 116

    Straube, A., Ellrich, J., Eren, O., Blum, B. & Ruscheweyh, R. Treatment of chronic migraine with transcutaneous stimulation of the auricular branch of the vagal nerve (auricular t-VNS): a randomized, monocentric clinical trial. J. Headache Pain 16, 543 (2015).

    Article  PubMed  Google Scholar 

  117. 117

    Fontaine, D., Vandersteen, C., Magis, D. & Lanteri-Minet, M. Neuromodulation in cluster headache. Adv. Techn. Stand. Neurosurg. 42, 3–21 (2015).

    Article  Google Scholar 

  118. 118

    Wilbrink, L. A. et al. Occipital nerve stimulation in medically intractable, chronic cluster headache. The ICON study: rationale and protocol of a randomised trial. Cephalalgia 33, 1238–1247 (2013).

    Article  PubMed  Google Scholar 

  119. 119

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01151631 (2016).

  120. 120

    Burns, B., Watkins, L. & Goadsby, P. J. Treatment of hemicrania continua by occipital nerve stimulation with a bion device: long-term follow-up of a crossover study. Lancet Neurol. 7, 1001–1012 (2008).

    Article  PubMed  Google Scholar 

  121. 121

    Lambru, G., Shanahan, P., Watkins, L. & Matharu, M. S. Occipital nerve stimulation in the treatment of medically intractable SUNCT and SUNA. Pain Physician 17, 29–41 (2014).

    PubMed  Google Scholar 

  122. 122

    Saper, J. R. et al. Occipital nerve stimulation for the treatment of intractable chronic migraine headache: ONSTIM feasibility study. Cephalalgia 31, 271–285 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  123. 123

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00200109 (2016).

  124. 124

    Silberstein, S. D. 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 32, 1165–1179 (2012).

    Article  PubMed  Google Scholar 

  125. 125

    Dodick, D. W. et al. Safety and efficacy of peripheral nerve stimulation of the occipital nerves for the management of chronic migraine: long-term results from a randomized, multicenter, double-blinded, controlled study. Cephalalgia 35, 344–358 (2015).

    Article  PubMed  Google Scholar 

  126. 126

    Janiski, H. Important product usage information. St. Jude Medical https://www.swissmedic.ch/recalllists_dl/10612/Vk_20141022_21-e1.pdf (2014).

    Google Scholar 

  127. 127

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01775735 (2016).

  128. 128

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02725554 (2016).

  129. 129

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02729480 (2016).

  130. 130

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01255813 (2016).

  131. 131

    Schoenen, J. et al. Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: a randomized, sham-controlled study. Cephalalgia 33, 816–830 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  132. 132

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02168764 (2016).

  133. 133

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01540799 (2016).

  134. 134

    Wolter, T., Kiemen, A. & Kaube, H. High cervical spinal cord stimulation for chronic cluster headache. Cephalalgia 31, 1170–1180 (2011).

    Article  PubMed  Google Scholar 

  135. 135

    Gaul, C., Jurgens, T. & May, A. Concerning high cervical spinal cord stimulation for chronic cluster headache. Cephalalgia 31, 1588–1589 (2011).

    Article  PubMed  Google Scholar 

  136. 136

    De Agostino, R., Federspiel, B., Cesnulis, E. & Sandor, P. S. High-cervical spinal cord stimulation for medically intractable chronic migraine. Neuromodulation 18, 289–296 (2015).

    Article  PubMed  Google Scholar 

  137. 137

    Kapural, L. et al. Novel 10-kHz high-frequency therapy (HF10 therapy) is superior to traditional low-frequency spinal cord stimulation for the treatment of chronic back and leg pain: the SENZA-RCT randomized controlled trial. Anesthesiology 123, 851–860 (2015).

    Article  PubMed  Google Scholar 

  138. 138

    Arcioni, R. et al. Cervical 10 kHz spinal cord stimulation in the management of chronic, medically refractory migraine: a prospective, open-label, exploratory study. Eur. J. Pain 20, 70–78 (2016).

    Article  CAS  PubMed  Google Scholar 

  139. 139

    BioMed Central. HF10 spinal cord stimulation in the treatment of refractory chronic migraine. ISRCTN registry http://www.isrctn.com/ISRCTN94247798 (2016).

  140. 140

    Mitsikostas, D. D. et al. Refractory chronic cluster headache: a consensus statement on clinical definition from the European Headache Federation. J. Headache Pain 15, 79 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  141. 141

    Bartsch, T., Levy, M. J., Knight, Y. E. & Goadsby, P. J. Differential modulation of nociceptive dural input to [hypocretin] orexin A and B receptor activation in the posterior hypothalamic area. Pain 109, 367–378 (2004).

    Article  CAS  PubMed  Google Scholar 

  142. 142

    Holland, P. R., Akerman, S. & Goadsby, P. J. Modulation of nociceptive dural input to the trigeminal nucleus caudalis via activation of the orexin 1 receptor in the rat. Eur. J. Neurosci. 24, 2825–2833 (2006).

    Article  CAS  PubMed  Google Scholar 

  143. 143

    Holland, P. R., Akerman, S. & Goadsby, P. J. Orexin 1 receptor activation attenuates neurogenic dural vasodilation in an animal model of trigeminovascular nociception. J. Pharmacol. Exp. Ther. 315, 1380–1385 (2005).

    Article  CAS  PubMed  Google Scholar 

  144. 144

    Hoffmann, J. et al. Evidence for orexinergic mechanisms in migraine. Neurobiol. Dis. 74, 137–143 (2015).

    Article  CAS  PubMed  Google Scholar 

  145. 145

    Herring, W. J. et al. Orexin receptor antagonism for treatment of insomnia: a randomized clinical trial of suvorexant. Neurology 79, 2265–2274 (2012).

    Article  CAS  PubMed  Google Scholar 

  146. 146

    Chabi, A. et al. Randomized controlled trial of the orexin receptor antagonist filorexant for migraine prophylaxis. Cephalalgia 35, 379–388 (2015).

    Article  PubMed  Google Scholar 

  147. 147

    Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 33, 629–808 (2013).

  148. 148

    Martelletti, P. et al. Refractory chronic migraine: a consensus statement on clinical definition from the European Headache Federation. J. Headache Pain 15, 47 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  149. 149

    Cady, R. A novel intranasal breath-powered delivery system for sumatriptan: a review of technology and clinical application of the investigational product AVP-825 in the treatment of migraine. Expert Opin. Drug Deliv. 12, 1565–1577 (2015).

    Article  CAS  PubMed  Google Scholar 

  150. 150

    Cady, R. The pharmacokinetics and clinical efficacy of AVP-825: a potential advancement for acute treatment of migraine. Expert Opin. Pharmacother. 16, 2039–2051 (2015).

    Article  CAS  PubMed  Google Scholar 

  151. 151

    Goldstein, J. et al. A sumatriptan iontophoretic transdermal system for the acute treatment of migraine. Headache 52, 1402–1410 (2012).

    Article  PubMed  Google Scholar 

  152. 152

    Bigal, M. E., Lipton, R. B., Newman, L. C., Pierce, M. W. & Silberstein, S. D. Sumatriptan iontophoretic transdermal system reduces treatment-emergent nausea and is effective in patients with and without nausea at baseline — results from a randomized controlled trial. Headache 55, 1124–1132 (2015).

    Article  PubMed  Google Scholar 

  153. 153

    Smith, T. R. et al. Twelve-month tolerability and efficacy study of NP101, the sumatriptan iontophoretic transdermal system. Headache 52, 612–624 (2012).

    Article  PubMed  Google Scholar 

  154. 154

    [No authors listed.] Zosano Pharma announces positive phase 1 results for Its ZP-Triptan Patch program for treatment of migraine. Zozano Pharma https://globenewswire.com/news-release/2015/11/02/782591/0/en/Zosano-Pharma-Announces-Positive-Phase-1-Results-for-Its-ZP-Triptan-Patch-Program-for-Treatment-of-Migraine.html (2015).

  155. 155

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02745392 (2016).

  156. 156

    Acorda Therapeutics, Inc. Acorda presents phase 1 data on CVT-427 for acute treatment of migraine at 58th Annual Scientific Meeting of the American Headache Society. Business Wire http://www.businesswire.com/news/home/20160609005119/en/ (2016).

  157. 157

    House, D. W. Acorda on go with CVT-427 phase 2. Acorda Therapeutics, Inc. http://seekingalpha.com/news/3165610-acorda-go-cvtminus-427-phase-2 (2016).

    Google Scholar 

  158. 158

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02609945 (2016).

  159. 159

    Biocentury Online Intellegence. Atogepant (AGN-241689, MK-8031). Biocentury.com http://www.biocentury.com/products/mk-8031 (2016).

  160. 160

    Grace, P. M. et al. Activation of adult rat CNS endothelial cells by opioid-induced toll-like receptor 4 (TLR4) signaling induces proinflammatory, biochemical, morphological, and behavioral sequelae. Neuroscience 280, 299–317 (2014).

    Article  CAS  PubMed  Google Scholar 

  161. 161

    Grace, P. M., Maier, S. F. & Watkins, L. R. Opioid-induced central immune signaling: implications for opioid analgesia. Headache 55, 475–489 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  162. 162

    Poulsen, J. N., Larsen, F., Duroux, M. & Gazerani, P. Primary culture of trigeminal satellite glial cells: a cell-based platform to study morphology and function of peripheral glia. Int. J. Physiol. Pathophysiol. Pharmacol. 6, 1–12 (2014).

    PubMed  PubMed Central  Google Scholar 

  163. 163

    Cooper, Z. D. et al. The effects of ibudilast, a glial activation inhibitor, on opioid withdrawal symptoms in opioid-dependent volunteers. Addict. Biol. http://dx.doi.org/10.1111/adb.12261 (2015).

  164. 164

    Johnson, J. L. et al. Glial attenuation with ibudilast in the treatment of medication overuse headache: a double-blind, randomized, placebo-controlled pilot trial of efficacy and safety. Headache 55, 1192–1208 (2015).

    Article  PubMed  Google Scholar 

  165. 165

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01389193 (2016).

  166. 166

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02686034 (2016).

  167. 167

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02378844 (2016).

  168. 168

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01630044 (2016).

  169. 169

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01899040 (2016).

  170. 170

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02307071 (2016).

Download references

Author information

Affiliations

Authors

Contributions

N.M.S. and A.M.R. contributed equally to researching data for the article, discussion of the article's content, and writing and editing the manuscript before submission.

Corresponding author

Correspondence to Nathaniel M. Schuster.

Ethics declarations

Competing interests

N.M.S. received an American Headache Society travel grant with funding from Avanir. A.M.R. serves on the speaker's bureaus of Avanir, Depomed and Teva, consults for Eli Lilly and serves on the advisory boards of Autonomic Technologies, Doctor Reddy's, Pernix, Teva and Zosano.

PowerPoint slides

Glossary

CGRP receptor

The calcitonin gene-related peptide (CGRP) receptor is a complex between the calcitonin receptor-like receptor and the receptor activity-modifying protein 1 (RAMP1). Expression of the CGRP receptor has been confirmed in the vasculature, the trigeminal ganglion, and the spinal trigeminal complex of the brainstem.

LY2951742

A fully humanized anti-calcitonin gene-related peptide IgG4 monoclonal antibody with a 28-day half-life (also known as galcanezumab).

Fast-track status

Fast-track status is granted by the FDA to investigational drugs anticipated to fill an unmet need in treating a serious condition.

ALD403

A genetically engineered, desialylated, humanized anti-calcitonin gene-related peptide IgG1 antibody with a 31-day half-life.

TEV-48125

A fully humanized anti-calcitonin gene-related peptide IgG2a monoclonal antibody with a half-life of 40–48 days (previously known as LBR-101).

AMG 334

A human IgG2 monoclonal antibody that is targeted against the calcitonin gene-related peptide receptor. AMG 334 has a half-life of 21 days.

Ubrogepant

An orally administered small-molecule calcitonin gene-related peptide antagonist for the acute treatment of migraine (also known as MK-1602).

MK-8031

An orally administered small-molecule calcitonin gene-related peptide antagonist for the prevention of migraine.

Acute treatments

Treatments that are used as needed while experiencing a headache, with the purpose of aborting the headache. These treatments include simple analgesics, triptans, and ergot derivatives such as dihydroergotamine mesylate.

Paraesthesia

An abnormal sensation, often described as a 'pins and needles' feeling, that can be caused by medications or by damage, compression, or stimulation of peripheral nerves.

Double-dummy

A double-dummy study is a form of double-blind study that is used when the two treatments being studied cannot be made to appear identical. For example, it can be used to compare an inhaled medication with an oral medication. All participants are administered two treatments — one inhaled and one oral. Participants are randomly assigned to receive either the active inhaled treatment and placebo oral treatment or the placebo inhaled treatment and active oral treatment.

Atypical triptan sensations

Atypical triptan sensations are often reported following the use of triptans. Atypical triptan sensations include tightness and tingling in the chest, limbs and face. They are benign, but can be mistaken for much more serious conditions.

Cutaneous allodynia

In cutaneous allodynia, central sensitization to pain causes normally non-noxious tactile stimuli to skin (such as showering, shaving, brushing the hair or wearing tight clothing) to be experienced as painful.

Status migrainosus

A migraine attack lasting more than 72h.

Hemicrania continua

A primary headache disorder that results in continuous pain in one side of the face and head, with associated ipsilateral autonomic symptoms.

Lead migration

The displacement of an electrical neurostimulation lead following implantation. Lead migration is the most common complication following the surgical implantation of a peripheral nerve stimulator or spinal cord stimulator.

Sphenopalatine ganglion

The sphenopalatine ganglion, also known as the pterygopalatine ganglion, sits in the pterygopalatine fossa and contains parasympathetic nerve bodies and postsynaptic sympathetic fibres.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Schuster, N., Rapoport, A. New strategies for the treatment and prevention of primary headache disorders. Nat Rev Neurol 12, 635–650 (2016). https://doi.org/10.1038/nrneurol.2016.143

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing