Chronic Migraine: Epidemiology, Mechanisms, and Treatment

  • Teshamae S. MonteithEmail author


Chronic migraine is a debilitating primary headache disorder associated with high personal, familial, and social impact. The diagnosis is made when there are at least 15 headache days monthly including 8 migraine days per month for at least 3 months. The prevalence is 1.4–2.2% in the population. Among individuals diagnosed with chronic migraine, there may be significant variability in headache days with a potential to remit, remain unchanged, or progress to even greater disability. Most chronic migraine progresses from episodic migraine, with several identified risk factors for chronic migraine and migraine progression. The exact mechanism of chronic migraine is unknown but is associated with an increased cortical excitability, central sensitization, alternations in nociceptive signaling, as well as physiological, structural, and functional brain changes. There is evidence for both nonpharmacological and pharmacological treatment options to restore function. The best currently established pharmacologic evidence for the treatment of chronic migraine is onabotulinumtoxinA and topiramate. Behavioral treatments may improve headache symptoms and comorbidities. Emerging data shows potential benefit for neurostimulation, and large well-designed studies are needed. Multicenter randomized placebo-controlled studies of monoclonal antibodies to the calcitonin gene-related peptide, or its receptor, have demonstrated efficacy, tolerability, and safety. Biomarkers are needed to guide prognosis, treatment response, and clinical trials. The concept and management of refractory chronic migraine is discussed, and clinically meaningful endpoints are reviewed.


Chronic migraine Classification Epidemiology Risk factors Comorbidities Pathophysiology Management Neuromodulation Monoclonal antibodies to calcitonin gene-related peptide (CGRP) Disability 


  1. 1.
    Natoli JL, Manack A, Dean B, et al. Global prevalence of chronic migraine: a systematic review. Cephalalgia. 2010;30(5):599–609.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Aurora SK. Spectrum of illness: understanding biological patterns and relationships in chronic migraine. Neurology. 2009;72(5 Suppl):S8–13.CrossRefPubMedGoogle Scholar
  3. 3.
    Headache Classification Committee of the International Headache Society (IHS). The international classification of headache disorders, 3rd edition. Cephalalgia. 2018;38(1):1–211.CrossRefGoogle Scholar
  4. 4.
    Silberstein SD, Lipton RB, Dodick DW. Operational diagnostic criteria for chronic migraine: expert opinion. Headache. 2014;54(7):1258–66.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders: 2nd edition. Cephalalgia. 2004;24(Suppl 1):9–160.Google Scholar
  6. 6.
    Bigal ME, Sheftell FD, Tepper SJ, Rapoport AM, Lipton RB. Migraine days decline with duration of illness in adolescents with transformed migraine. Cephalalgia. 2005;25(7):482–7.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Silberstein SD, Lipton RB, Sliwinski M. Classification of daily and near-daily headaches: field trial of revised IHS criteria. Neurology. 1996;47(4):871–5.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ, Lipton RB. Chronic migraine is an earlier stage of transformed migraine in adults. Neurology. 2005;65(10):1556–61.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Lipton RB, Serrano D, Buse DC, et al. Improving the detection of chronic migraine: development and validation of identify chronic migraine (ID-CM). Cephalalgia. 2016;36(3):203–15.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Garcia-Chimeno Y, Garcia-Zapirain B, Gomez-Beldarrain M, Fernandez-Ruanova B, Garcia-Monco JC. Automatic migraine classification via feature selection committee and machine learning techniques over imaging and questionnaire data. BMC Med Inform Decis Mak. 2017;17(1):38.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    van Dongen RM, Zielman R, Noga M, et al. Migraine biomarkers in cerebrospinal fluid: a systematic review and meta-analysis. Cephalalgia. 2017;37(1):49–63.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Cernuda-Morollon E, et al. No change in interictal PACAP levels in peripheral blood in women with chronic migraine. Headache. 2016;56(9):1448–54.Google Scholar
  13. 13.
    Buse D, Manack A, Serrano D, et al. Headache impact of chronic and episodic migraine: results from the American Migraine Prevalence and Prevention study. Headache. 2012;52(1):3–17.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Buse DC, Manack A, Serrano D, Turkel C, Lipton RB. Sociodemographic and comorbidity profiles of chronic migraine and episodic migraine sufferers. J Neurol Neurosurg Psychiatry. 2010;81(4):428–32.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Messali A, Sanderson JC, Blumenfeld AM, et al. Direct and indirect costs of chronic and episodic migraine in the United States: a web-based survey. Headache. 2016;56(2):306–22.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Dodick DW, Loder EW, Manack Adams A, et al. Assessing barriers to chronic migraine consultation, diagnosis, and treatment: results from the Chronic Migraine Epidemiology and Outcomes (CaMEO) study. Headache. 2016;56:821.PubMedCentralCrossRefGoogle Scholar
  17. 17.
    Couch JR, Lipton RB, Stewart WF, Scher AI. Head or neck injury increases the risk of chronic daily headache: a population-based study. Neurology. 2007;69(11):1169–77.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Scher AI, Stewart WF, Lipton RB. Caffeine as a risk factor for chronic daily headache: a population-based study. Neurology. 2004;63(11):2022–7.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Scher AI, Lipton RB, Stewart WF. Habitual snoring as a risk factor for chronic daily headache. Neurology. 2003;60(8):1366–8.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Odegård SS, Sand T, Engstrøm M, Stovner LJ, Zwart JA, Hagen K. The long-term effect of insomnia on primary headaches: a prospective population-based cohort study (HUNT-2 and HUNT-3). Headache. 2011;51(4):570–80.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Scher AI, Stewart WF, Buse D, Krantz DS, Lipton RB. Major life changes before and after the onset of chronic daily headache: a population-based study. Cephalalgia. 2008;28(8):868–76.CrossRefPubMedGoogle Scholar
  22. 22.
    Scher AI, Stewart WF, Ricci JA, Lipton RB. Factors associated with the onset and remission of chronic daily headache in a population-based study. Pain. 2003;106(1–2):81–9.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study. Headache. 2008;48(8):1157–68.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Serrano D, Lipton RB, Scher AI, et al. Fluctuations in episodic and chronic migraine status over the course of 1 year: implications for diagnosis, treatment and clinical trial design. J Headache Pain. 2017;18(1):101.PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Lipton RB, Fanning KM, Serrano D, Reed ML, Cady R, Buse DC. Ineffective acute treatment of episodic migraine is associated with new-onset chronic migraine. Neurology. 2015;84(7):688–95.PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Reed ML, Fanning KM, Serrano D, Buse DC, Lipton RB. Persistent frequent nausea is associated with progression to chronic migraine: AMPP study results. Headache. 2015;55(1):76–87.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Manack A, Buse DC, Serrano D, Turkel CC, Lipton RB. Rates, predictors, and consequences of remission from chronic migraine to episodic migraine. Neurology. 2011;76(8):711–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Gormley P, Anttila V, Winsvold BS, et al. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nat Genet. 2016;48:856–66.Google Scholar
  29. 29.
    Perry CJ, Blake P, Buettner C, Papavassiliou E, Schain AJ, Bhasin MK, Burstein R. Upregulation of inflammatory gene transcripts in periosteum of chronic migraineurs: implications for extracranial origin of headache. Ann Neurol. 2016;79(6):1000–13.PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Leao AAP. Spreading depression of activity in thecerebral cortex. J Neurophysiol. 1944;7:359–90.Google Scholar
  31. 31.
    Zhang X, Levy D, Noseda R, Kainz V, Jakubowski M, Burstein R. Activation of meningeal nociceptors by cortical spreading depression:Implications for migraine with aura. J Neurosci. 2010;30(26):8807–14.Google Scholar
  32. 32.
    Zhang X, Levy D, Kainz V, Noseda R, Jakubowski M, Burstein R. Activation of central trigeminovascular neurons by cortical spreading depression. Ann Neurol. 2011;69:855-865.Google Scholar
  33. 33.
    Hansen JM, Lipton RB, Dodick DW, et al.Migraine headache is present in the aura phase:A prospective study. Neurology.2012;79:2044-2049.Google Scholar
  34. 34.
    Dodick DW. A Phase-by-Phase Review of Migraine Pathophysiology.Headache. 2018;58Suppl 1:4-16.Google Scholar
  35. 35.
    Schwedt TJ, Chong CD, Wu T, Gaw N, Fu Y, Li J. Accurate classification of chronic migraine via brain magnetic resonance imaging. Headache. 2015;55(6):762–77.PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Valfre W, Rainero I, Bergui M, Pinessi L. Voxel-based morphometry reveals gray matter abnormalities in migraine. Headache. 2008;48(1):109–17.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Welch KMA, Nagesh V, Aurora SK, Gelman N. Periaqueductal gray matter dysfunction in migraine: cause or the burden of illness? Headache. 2001;41(7):629–37.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Aurora SK. Is chronic migraine one end of a spectrum of migraine or a separate entity? Cephalalgia. 2009;29(6):597–605.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Aurora SK, Barrodale PM, Tipton RL, Khodavirdi A. Brainstem dysfunction in chronic migraine as evidenced by neurophysiological and positron emission tomography studies. Headache. 2007;47(7):996–1003; discussion 1004–1007.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Matharu MS, Bartsch T, Ward N, Frackowiak RS, Weiner R, Goadsby PJ. Central neuromodulation in chronic migraine patients with suboccipital stimulators: a PET study. Brain. 2004;127(Pt 1):220–30.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Mathew NT. Pathophysiology of chronic migraine and mode of action of preventive medications. Headache. 2011;51(Suppl 2):84–92.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Schulte et al. Visual stimulation leads to activation of the nociceptive trigeminal nucleus in chronic migraine. Neurology.2018;90(22).Google Scholar
  43. 43.
    Coppola G, Iacovelli E, Bracaglia M, Serrao M, Di Lorenzo C, Pierelli F. Electrophysiological correlates of episodic migraine chronification: evidence for thalamic involvement. J Headache Pain. 2013;14:76.PubMedCentralCrossRefPubMedGoogle Scholar
  44. 44.
    Niddam DM, Lai KL, Tsai SY, et al. Neurochemical changes in the medial wall of the brain in chronic migraine. Brain. 2017;141(2):377–90.CrossRefGoogle Scholar
  45. 45.
    Maniyar FH, Sprenger T, Monteith T, Schankin C, Goadsby PJ. Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks. Brain. 2014;137(Pt 1):232–41.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Schulte LH, Allers A, May A. Hypothalamus as a mediator of chronic migraine: evidence from high-resolution fMRI. Neurology. 2017;88(21):2011–6.CrossRefPubMedGoogle Scholar
  47. 47.
    Schwedt TJ, Schlaggar BL, Mar S, et al. Atypical resting-state functional connectivity of affective pain regions in chronic migraine. Headache. 2013;53(5):737–51.PubMedCentralCrossRefPubMedGoogle Scholar
  48. 48.
    Bernstein C, Burstein R. Sensitization of the trigeminovascular pathway: perspective and implications to migraine pathophysiology. J Clin Neurol. 2012;8(2):89–99.PubMedCentralCrossRefPubMedGoogle Scholar
  49. 49.
    Androulakis XM, Krebs K, Peterlin BL, et al. Modulation of intrinsic resting-state fMRI networks in women with chronic migraine. Neurology. 2017;89(2):163–9.PubMedCentralCrossRefPubMedGoogle Scholar
  50. 50.
    Young WB. Allodynia as a complication of migraine: background and management. Curr Treat Options Neurol. 2009;11(1):3–9.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Dodick DW. Adv Stud Med. 2003;3(6C):S550-S555.Google Scholar
  52. 52.
    Ashina S, Serrano D, Lipton RB, et al. Depression and risk of transformation of episodic to chronic migraine. J Headache Pain. 2012;13(8):615–24.PubMedCentralCrossRefPubMedGoogle Scholar
  53. 53.
    Scher AI, Buse DC, Fanning KM, Kelly AM, Franznick DA, Adams AM, Lipton RB. Comorbid pain and migraine chronicity: The Chronic Migraine Epidemiology and Outcomes Study. Neurology. 2017;89(5):461–8.PubMedCentralCrossRefPubMedGoogle Scholar
  54. 54.
    Farris SG, Thomas JG, Abrantes AM, et al. Pain worsening with physical activity during migraine attacks in women with overweight/obesity: a prospective evaluation of frequency, consistency, and correlates. Cephalalgia. 2017:333102417747231.Google Scholar
  55. 55.
    Bigal ME, Lipton RB. Obesity is a risk factor for transformed migraine but not chronic tension-type headache. Neurology. 2006;67(2):252–7.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Bond DS, Thomas JG, Lipton RB, et al. Behavioral weight loss intervention for migraine: a randomized controlled trial. Obesity (Silver Spring). 2018;26(1):81–7.CrossRefGoogle Scholar
  57. 57.
    Midgette LA, Scher AI. The epidemiology of chronic daily headache. Curr Pain Headache Rep. 2009;13(1):59–63.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Loder E, Burch R, Rizzoli P. The 2012 AHS/AAN guidelines for prevention of episodic migraine: a summary and comparison with other recent clinical practice guidelines. Headache. 2012;52(6):930–45.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Couch JR. Amitriptyline in the prophylactic treatment of migraine and chronic daily headache. Headache. 2011;51(1):33–51.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Yurekli VA, Akhan G, Kutluhan S, Uzar E, Koyuncuoglu HR, Gultekin F. The effect of sodium valproate on chronic daily headache and its subgroups. J Headache Pain. 2008;9(1):37–41.PubMedCentralCrossRefPubMedGoogle Scholar
  61. 61.
    Spira PJ, Beran RG. Gabapentin in the prophylaxis of chronic daily headache: a randomized, placebo-controlled study. Neurology. 2003;61(12):1753–9.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Saper JR, Lake AE III, Cantrell DT, Winner PK, White JR. Chronic daily headache prophylaxis with tizanidine: a double-blind, placebo-controlled, multicenter outcome study. Headache. 2002;42(6):470–82.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    May A, Schulte LH. Chronic migraine: risk factors, mechanisms and treatment. Nat Rev Neurol. 2016;12(8):455–64.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Charles A, Flippen C, Romero Reyes M, Brennan KC. Memantine for prevention of migraine: a retrospective study of 60 cases. J Headache Pain. 2007;8(4):248–50.PubMedCentralCrossRefPubMedGoogle Scholar
  65. 65.
    Calandre EP, Garcia-Leiva JM, Rico-Villademoros F, Vilchez JS, Rodriguez-Lopez CM. Pregabalin in the treatment of chronic migraine: an open-label study. Clin Neuropharmacol. 2010;33(1):35–9.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Engel ER, Kudrow D, Rapoport AM. A prospective, open-label study of milnacipran in the prevention of headache in patients with episodic or chronic migraine. Neurol Sci. 2014;35(3):429–35.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Pascual-Gomez J, Alana-Garcia M, Oterino A, Leira R, Lainez-Andres JM. Preventive treatment of chronic migraine with zonisamide: a study in patients who are refractory or intolerant to topiramate. Rev Neurol. 2008;47(9):449–51.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Cernuda-Morollon E, Ramon C, Martinez-Camblor P, Serrano-Pertierra E, Larrosa D, Pascual J. OnabotulinumtoxinA decreases interictal CGRP plasma levels in patients with chronic migraine. Pain. 2015;156(5):820–4.Google Scholar
  69. 69.
    Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: the American Headache Society evidence assessment of migraine pharmacotherapies. Headache. 2015;55(1):3–20.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Serrano D, Buse DC, Manack Adams A, Reed ML, Lipton RB. Acute treatment optimization in episodic and chronic migraine: results of the American Migraine Prevalence and Prevention (AMPP) Study. Headache. 2015;55(4):502–18.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Holland PR, Goadsby PJ. Targeted CGRP small molecule antagonists for acute migraine therapy. Neurotherapeutics. 2018;15(2):304–12. Review. PMID: 29556965
  72. 72.
    Färkkilä 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. 2012;11(5):405–13.–4422(12)70047–9.
  73. 73.
    Aurora SK, Brin MF. Chronic migraine: an update on physiology, imaging, and the mechanism of action of two available pharmacologic therapies. Headache. 2017;57(1):109–25.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Hoffmann J, Akerman S, Goadsby PJ. Efficacy and mechanism of anticonvulsant drugs in migraine. Expert Rev Clin Pharmacol. 2014;7(2):191–201.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Andreou AP, Goadsby PJ. Topiramate in the treatment of migraine: a kainate (glutamate) receptor antagonist within the trigeminothalamic pathway. Cephalalgia. 2011;31(13):1343–58.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Hebestreit JM, May A. Topiramate modulates trigeminal pain processing in thalamo-cortical networks in humans after single dose administration. PLoS One. 2017;12(10):e0184406.PubMedCentralCrossRefPubMedGoogle Scholar
  77. 77.
    Diener HC, Bussone G, Van Oene JC, Lahaye M, Schwalen S, Goadsby PJ. Topiramate reduces headache days in chronic migraine: a randomized, double-blind, placebo-controlled study. Cephalalgia. 2007;27(7):814–23.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Silberstein SD, Lipton RB, Dodick DW, et al. Efficacy and safety of topiramate for the treatment of chronic migraine: a randomized, double-blind, placebo-controlled trial. Headache. 2007;47(2):170–80.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Diener HC, Dodick DW, Goadsby PJ, et al. Utility of topiramate for the treatment of patients with chronic migraine in the presence or absence of acute medication overuse. Cephalalgia. 2009;29(10):1021–7.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Silberstein SD. Topiramate in migraine prevention: a 2016 perspective. Headache. 2017;57(1):165–78.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Lipton RB, Silberstein S, Dodick D, et al. Topiramate intervention to prevent transformation of episodic migraine: the topiramate INTREPID study. Cephalalgia. 2011;31(1):18–30.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Silberstein SD, Dodick DW, Lindblad AS, et al. Randomized, placebo-controlled trial of propranolol added to topiramate in chronic migraine. Neurology. 2012;78(13):976–84.PubMedCentralCrossRefPubMedGoogle Scholar
  83. 83.
    Johnson J, Brittain S, Schwabe S. Cognitive effects of extended-release once-daily SPN-538 (Trokendi XR™) vs bid immediate-release topiramate (TPM-IR, Topamax®) in healthy volunteers. Neurology. 2014;82(10 Suppl):S43.002.Google Scholar
  84. 84.
    Brittain ST, Wheless JW. Pharmacokinetic simulations of topiramate plasma concentrations following dosing irregularities with extended-release vs. immediate-release formulations. Epilepsy Behav. 2015;52(Pt A):31–6.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Shen C, Chen F, Zhang Y, Guo Y, Ding M. Association between use of antiepileptic drugs and fracture risk: a systematic review and meta-analysis. Bone. 2014;64:246–53.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Lovati C, Giani L. Action mechanisms of Onabotulinum toxin-A: hints for selection of eligible patients. Neurol Sci. 2017;38(Suppl 1):131–40.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Schaefer SM, Gottschalk CH, Jabbari B. Treatment of chronic migraine with focus on botulinum neurotoxins. Toxins. 2015;7(7):2615–28.PubMedCentralCrossRefPubMedGoogle Scholar
  88. 88.
    Burstein R, Zhang X, Levy D, Aoki KR, Brin MF. Selective inhibition of meningeal nociceptors by botulinum neurotoxin type A: therapeutic implications for migraine and other pains. Cephalalgia. 2014;34(11):853–69.PubMedCentralCrossRefPubMedGoogle Scholar
  89. 89.
    Drinovac Vlah V, Filipovic B, Bach-Rojecky L, Lackovic Z. Role of central versus peripheral opioid system in antinociceptive and anti-inflammatory effect of botulinum toxin type A in trigeminal region. Eur J pain 2,2,3 (583–591), 2017.Google Scholar
  90. 90.
    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):793–803.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    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):804–14.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Dodick DW, Turkel CC, DeGryse RE, et al. 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):921–36.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Boudreau GP, Grosberg BM, McAllister PJ, Lipton RB, Buse DC. Prophylactic onabotulinumtoxinA in patients with chronic migraine and comorbid depression: an open-label, multicenter, pilot study of efficacy, safety and effect on headache-related disability, depression, and anxiety. Int J Gen Med. 2015;8:79–86.PubMedCentralCrossRefPubMedGoogle Scholar
  94. 94.
    Negro A, Curto M, Lionetto L, Martelletti P. 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):1.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Guerzoni S, Pellesi L, Baraldi C, et al. Long-term treatment benefits and prolonged efficacy of onabotulinumtoxinA in patients affected by chronic migraine and medication overuse headache over 3 years of therapy. Front Neurol. 2017;8:586.PubMedCentralCrossRefPubMedGoogle Scholar
  96. 96.
    Moore KL, Dalley AF, Agur AMR. Clinically oriented anatomy. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2013.Google Scholar
  97. 97.
    Cady R, Turner I, Dexter K, Beach ME, Durham P. An exploratory study of salivary calcitonin gene-related peptide levels relative to acute interventions and preventative treatment with onabotulinumtoxinA in chronic migraine. Headache. 2014;54(2):269–77.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Hubbard CS, Becerra L, Smith JH, et al. Brain changes in responders vs. non-responders in chronic migraine: markers of disease reversal. Front Hum Neurosci. 2016;10:497.PubMedCentralCrossRefPubMedGoogle Scholar
  99. 99.
    Blumenfeld AM, Silberstein SD, Dodick DW, Aurora SK, Brin MF, Binder WJ. Insights into the functional anatomy behind the PREEMPT injection paradigm: guidance on achieving optimal outcomes. Headache. 2017;57:766–77.PubMedCentralCrossRefPubMedGoogle Scholar
  100. 100.
    Edvinsson L. The journey to establish CGRP as a migraine target: a retrospective view. Headache. 2015;55(9):1249–55.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28:183–7.CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Edvinsson L, Warfvinge K. Recognizing the role of CGRP and CGRP receptors in migraine and its treatment. Cephalalgia. 2017;333102417736900.Google Scholar
  103. 103.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  104. 104.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Vanmolkot F, Van der Schueren B, de Hoon J. Sumatriptan causes parallel decrease in plasma CGRP concentration and migraine headache during nitroglycerin-induced migraine attack. Cephalalgia. 2006;26(8):1037–8; author reply 1038–9.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Olesen J, Diener HC, Husstedt IW, Goadsby PJ, BIBN 4096 BS Clinical Proof of Concept Study Group, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Ong JJY, Wei DY, Goadsby PJ. Recent advances in pharmacotherapy for migraine prevention: from pathophysiology to new drugs. Drugs. 2018;78:411. Scholar
  108. 108.
    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 2 trial. Lancet Neurol. 2017;16(6):425–34.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Silberstein SD, Dodick DW, Bigal ME, Yeung PP, et al. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med. 2017;377(22):2113–22.CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Detke H, Wang S, Skljarevski V, Ahl J, Millen B, Aurora S, Yang JY. A phase 3 placebo-controlled study of galcanezumab in patients with chronic migraine: results from the 3-month double-blind treatment phase of the REGAIN study. American Headache Society, 2017. Poster sponsored by Eli Lilly and Company and/or one of its subsidiaries.Google Scholar
  111. 111.
    Lipton, R. et al. A Phase 3, Randomized, Double-blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Eptinezumab for the Preventive Treatment of Chronic Migraine: Results of the PROMISE-2 (PReventionOf Migraine via Intravenous eptinezumab Safety and Efficacy‒2) Trial. Plenary Presentation. American Academy of Neurology Conference, 2018Google Scholar
  112. 112.
    Melo-Carrillo A, Strassman AM, Nir RR, et al. Fremanezumab-A humanized monoclonal anti-CGRP antibody-inhibits thinly myelinated (Adelta) but not unmyelinated (C) meningeal nociceptors. J Neurosci. 2017;37(44):10587–96.PubMedCentralPubMedGoogle Scholar
  113. 113.
    Melo-Carrillo A, Noseda R, Nir RR, et al. Selective inhibition of trigeminovascular neurons by fremanezumab: a humanized monoclonal anti-CGRP antibody. J Neurosci. 2017;37(30):7149–63.PubMedCentralCrossRefPubMedGoogle Scholar
  114. 114.
    Eftekhari S, Salvatore CA, Johansson S, Chen TB, Zeng Z, Edvinsson L. Localization of CGRP, CGRP receptor, PACAP and glutamate in trigeminal ganglion. Relation to the blood-brain barrier. Brain Res. 2015;1600:93–109.CrossRefPubMedGoogle Scholar
  115. 115.
    Linde K, Allais G, Brinkhaus B, et al. Acupuncture for the prevention of episodic migraine. Cochrane Database Syst Rev. 2016(6):CD001218.Google Scholar
  116. 116.
    Yang CP, Chang MH, Li TC, Hsieh CL, Hwang KL, Chang HH. Predicting prognostic factors in a randomized controlled trial of acupuncture versus topiramate treatment in patients with chronic migraine. Clin J Pain. 2013;29(11):982–7.CrossRefPubMedGoogle Scholar
  117. 117.
    Devineni T, Blanchard EB. A randomized controlled trial of an internet-based treatment for chronic headache. Behav Res Ther. 2005;43(3):277–92.CrossRefPubMedGoogle Scholar
  118. 118.
    Powers SW, Kashikar-Zuck SM, Allen JR, et al. Cognitive behavioral therapy plus amitriptyline for chronic migraine in children and adolescents: a randomized clinical trial. JAMA. 2013;310(24):2622–30.PubMedCentralCrossRefPubMedGoogle Scholar
  119. 119.
    Cha MJ, Kim BK, Moon HS, Ahn JY, et al. Stress is associated with poor outcome of acute treatment for chronic migraine: a multicenter study. Pain Med. 2017.
  120. 120.
    Buse DC, Silberstein SD, Manack AN, Papapetropoulos S, Lipton RB. Psychiatric comorbidities of episodic and chronic migraine. J Neurol. 2013;260(8):1960–9.CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Seng EK, Buse DC, Klepper JE, J Mayson S, et al. Psychological factors associated with chronic migraine and severe migraine-related disability: an observational study in a tertiary headache center. Headache. 2017;57(4):593–604.PubMedCentralCrossRefPubMedGoogle Scholar
  122. 122.
    Smitherman TA, Walters AB, Davis RE, et al. Randomized controlled pilot trial of behavioral insomnia treatment for chronic migraine with comorbid insomnia. Headache. 2016;56(2):276–91.CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Raggi A, Giovannetti AM, Leonardi M, et al. Predictors of 12-months relapse after withdrawal treatment in hospitalized patients with chronic migraine associated with medication overuse: a longitudinal observational study. Headache. 2017;57(1):60–70.CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Grazzi L, Sansone E, Raggi A, D’Amico D, et al. Mindfulness and pharmacological prophylaxis after withdrawal from medication overuse in patients with chronic migraine: an effectiveness trial with a one-year follow-up. J Headache Pain. 2017;18(1):15.PubMedCentralCrossRefPubMedGoogle Scholar
  125. 125.
    Rausa M, Palomba D, Cevoli S, et al. Biofeedback in the prophylactic treatment of medication overuse headache: a pilot randomized controlled trial. J Headache Pain. 2016;17(1):87.PubMedCentralCrossRefPubMedGoogle Scholar
  126. 126.
    Lan L, Zhang X, Li X, Rong X, Peng Y. The efficacy of transcranial magnetic stimulation on migraine: a meta-analysis of randomized controlled trails. J Headache Pain. 2017;18(1):86.PubMedCentralCrossRefPubMedGoogle Scholar
  127. 127.
    Rapinesi C, Del Casale A, Scatena P, et al. Add-on deep transcranial magnetic stimulation (dTMS) for the treatment of chronic migraine: a preliminary study. Neurosci Lett. 2016;623:7–12.CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Di Fiore P, Bussone G, Galli A, et al. Transcutaneous supraorbital neurostimulation for the prevention of chronic migraine: a prospective, open-label preliminary trial. Neurol Sci. 2017;38(Suppl 1):201–6.CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Goadsby P, Grosberg BM, Mauskop A, Cady R, Simmons KA. Effect of noninvasive vagus nerve stimulation on acute migraine: an open-label pilot study. Cephalalgia. 2014;34(12):986–93.CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Akerman S, Simon B, Romero-Reyes M. Vagus nerve stimulation suppresses acute noxious activation of trigeminocervical neurons in animal models of primary headache. Neurobiol Dis. 2017;102:96–104.CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Chen SP, Ay I, de Morais AL, Qin T, et al. Vagus nerve stimulation inhibits cortical spreading depression. Pain. 2016;157(4):797–805.PubMedCentralCrossRefPubMedGoogle Scholar
  132. 132.
    Oshinsky ML, Murphy AL, Hekierski H Jr, Cooper M, Simon BJ. Noninvasive vagus nerve stimulation as treatment for trigeminal allodynia. Pain. 2014;155(5):1037–42.PubMedCentralCrossRefPubMedGoogle Scholar
  133. 133.
    Tassorelli C. Noninvasive vagus nerve stimulation as acute therapy for migraine: The randomized PRESTO study. Neurology.2018 Jun 15.pii: 10.1212 WNL.0000000000005857. doi: 10.1212/WNL.0000000000005857. [Epub ahead of print]
  134. 134.
    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. 2015;16:543.CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Silberstein SD, Calhoun AH, Lipton RB, et al. Chronic migraine headache prevention with noninvasive vagus nerve stimulation: the EVENT study. Neurology. 2016;87(5):529–38.PubMedCentralCrossRefPubMedGoogle Scholar
  136. 136.
    Andrade SM, de Brito Aranha REL, de Oliveira EA, et al. Transcranial direct current stimulation over the primary motor vs prefrontal cortex in refractory chronic migraine: a pilot randomized controlled trial. J Neurol Sci. 2017;378:225–32.CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Chen YF, Bramley G, Unwin G, Hanu-Cernat D, Dretzke J, Moore D, Bayliss S, Cummins C, Lilford R. Occipital nerve stimulation for chronic migraine--a systematic review and meta-analysis. PLoS One. 2015;10(3):e0116786.PubMedCentralCrossRefPubMedGoogle Scholar
  138. 138.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Dilli E, Halker R, Vargas B, et al. Occipital nerve block for the short-term preventive treatment of migraine: a randomized, double-blinded, placebo-controlled study. Cephalalgia. 2015;35(11):959–68.CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Inan LE, Inan N, Karadas O, et al. Greater occipital nerve blockade for the treatment of chronic migraine: a randomized, multicenter, double-blind, and placebo-controlled study. Acta Neurol Scand. 2015;132(4):270–7.CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Cuadrado ML, Aledo-Serrano A, Navarro P, et al. Short-term effects of greater occipital nerve blocks in chronic migraine: a double-blind, randomised, placebo-controlled clinical trial. Cephalalgia. 2017;37(9):864–72.CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Yarnitsky D, Goor-Aryeh I, Bajwa ZH, Ransil BI, Cutrer FM, Sottile A, Burstein R. 2003 Wolff Award: Possible parasympathetic contributions to peripheral and central sensitization during migraine. Headache. 2003;43(7):704–14.CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Csati A, Tajti J, Tuka B, Edvinsson L, Warfvinge K. Calcitonin gene-related peptide and its receptor components in the human sphenopalatine ganglion -- interaction with the sensory system. Brain Res. 2012;1435:29–39.CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Cady R, Saper J, Dexter K, Manley HR. A double-blind, placebo-controlled study of repetitive transnasal sphenopalatine ganglion blockade with tx360((R)) as acute treatment for chronic migraine. Headache. 2015;55(1):101–16.CrossRefPubMedPubMedCentralGoogle Scholar
  145. 145.
    Cady RK, Saper J, Dexter K, Cady RJ, Manley HR. Long-term efficacy of a double-blind, placebo-controlled, randomized study for repetitive sphenopalatine blockade with bupivacaine vs. saline with the Tx360 device for treatment of chronic migraine. Headache. 2015;55(4):529–42.CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Schulman EA, Peterlin BL, Lake AE III, et al. Defining refractory migraine: results of the RHSIS Survey of American Headache Society members. Headache. 2009;49(4):509–18.CrossRefPubMedPubMedCentralGoogle Scholar
  147. 147.
    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;15:47.PubMedCentralCrossRefPubMedGoogle Scholar
  148. 148.
    Lee HJ, Choi KS, Won SY, et al. Topographic relationship between the supratrochlear nerve and corrugator supercilii muscle--can this anatomical knowledge improve the response to botulinum toxin injections in chronic migraine? Toxins. 2015;7(7):2629–38.PubMedCentralCrossRefPubMedGoogle Scholar
  149. 149.
    Nagy AJ, Gandhi S, Bhola R, Goadsby PJ. Intravenous dihydroergotamine for inpatient management of refractory primary headaches. Neurology. 2011;77(20):1827–32.CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Rosen N, Marmura M, Abbas M, Silberstein S. Intravenous lidocaine in the treatment of refractory headache: a retrospective case series. Headache. 2009;49(2):286–91.CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Pomeroy JL, Marmura MJ, Nahas SJ, Viscusi ER. Ketamine infusions for treatment refractory headache. Headache. 2017;57(2):276–82.CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    Lake AE III, Saper JR, Hamel RL. Comprehensive inpatient treatment of refractory chronic daily headache. Headache. 2009;49(4):555–62.CrossRefPubMedPubMedCentralGoogle Scholar
  153. 153.
    Silberstein S, Tfelt-Hansen P, Dodick DW, Limmroth V, Lipton RB, Pascual J, Wang SJ, for the Task Force of the International Headache Society Clinical Trials Subcommittee. Guidelines for controlled trials of prophylactic treatment of chronic migraine in adults. Cephalalgia. 2008;28:484–95.CrossRefPubMedPubMedCentralGoogle Scholar
  154. 154.
    Dodick DW, Turkel CC, DeGryse RE, et al. Assessing clinically meaningful treatment effects in controlled trials: chronic migraine as an example. J pain. 2015;16(2):164–75.CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Trimboli M, Al-Kaisy A, Andreou A, Murphy M, Lamru G. Non-invasive vagus nerve stimulation for the management of refractory primary chronic headaches: a real-world experience. Cephalalgia. 2017;2017:1–10.Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Neurology, Miller School of MedicineUniversity of MiamiMiamiUSA

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