Current Pain and Headache Reports

, Volume 15, Issue 1, pp 57–63 | Cite as

Mechanism of Chronic Migraine

  • Sheena K. Aurora
  • Arun Kulthia
  • Patricia M. Barrodale


Chronic migraine typically evolves from episodic migraine over months to years in susceptible individuals. Headaches increase in frequency over time, becoming less intense but more disabling and less responsive to treatment. Results of electrophysiologic and functional imaging studies indicate that chronic migraine is associated with abnormalities in the brainstem that may be progressive. Additionally, chronic migraine is associated with a greater degree of impairment in cortical processing of sensory stimuli than is episodic migraine, perhaps due to a more pervasive or persistent cortical hyperexcitability. These findings fit with the model of migraine as a spectrum disorder, in which the clinical and pathophysiological features of migraine may progress over time. This progression is postulated to result from changes in nociceptive thresholds and ensuing central sensitization caused by recurrent migraine in susceptible individuals, for whom a variety of risk factors have been described. This may lead to changes in baseline neurologic function between episodes of headache, evident not only in electrophysiologic and functional imaging studies, but also as an increase in depression, anxiety, nonhead pain, fatigue, gastrointestinal disorders, and other somatic complaints that may occur after years of episodic migraine. From the current research and migraine models, a conceptualization of chronic migraine, in which relatively permanent and pervasive central changes that warrant novel and tolerable treatments have occurred, is emerging. This model also implies that prevention of chronic migraine is an important goal in the management of episodic migraine, particularly in individuals who exhibit risk factors for chronic transformation.


Chronic migraine Imaging Physiology Mechanism 



Dr. Sheena K. Aurora has received grants and/or research support received from Advanced Bionics, Alexza Pharmaceuticals, Allergan, CAPNIA, Inc., GlaxoSmithKline, MAP Pharmaceuticals, Merck and Co., Ortho-McNeil Pharmaceutical, Inc., Neuralieve, NuPathe, and Takeda Pharmaceuticals; has served as a consultant for Ortho-McNeil Pharmaceutical, Inc., Medtronic, Merck and Co., GlaxoSmithKline, Allergan, Neuralieve, NuPathe, and MAP Pharmaceuticals; and has received honoraria from Merck and Co., GlaxoSmithKline, Kowa Pharmaceuticals, NuPathe, Ortho-McNeil Pharmaceutical, Inc., and Zogenix.A. Kulthia: none; P. Barrodale: none.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    World Health Organization (WHO). Headache disorders. Available at: Accessed December 3, 2007.
  2. 2.
    International Headache Society. IHS Classification ICDH II. Migraine. Available at: Accessed December 3, 2007.
  3. 3.
    Bigal M, Rapoport A, Sheftell F, Tepper S, Lipton R. The International Classification of Headache Disorders revised criteria for chronic migraine-field testing in a headache specialty clinic. Cephalalgia. Jan 29 2007.Google Scholar
  4. 4.
    The International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;24 Suppl 1:9–160.Google Scholar
  5. 5.
    Mathew NT, Stubits E, Nigam MP. Transformation of episodic migraine into daily headache: analysis of factors. Headache. Mar 1982;22(2):66–68.PubMedCrossRefGoogle Scholar
  6. 6.
    •• Bigal ME, Lipton RB. Concepts and mechanisms of migraine chronification. Headache. Jan 2008;48(1):7–15. This article unravels the link of medication overuse and other risk factors for chronification.Google Scholar
  7. 7.
    Cady RK, Schreiber CP, Farmer KU. Understanding the patient with migraine: the evolution from episodic headache to chronic neurologic disease. A proposed classification of patients with headache. Headache. May 2004;44(5):426–435.PubMedCrossRefGoogle Scholar
  8. 8.
    Scher AI, Midgette LA, Lipton RB. Risk factors for headache chronification. Headache. Jan 2008;48(1):16–25PubMedCrossRefGoogle Scholar
  9. 9.
    Bigal ME, Rapoport AM, Lipton RB, Tepper SJ, Sheftell FD. Assessment of migraine disability using the migraine disability assessment (MIDAS) questionnaire: a comparison of chronic migraine with episodic migraine. Headache. Apr 2003;43(4):336–342.PubMedCrossRefGoogle Scholar
  10. 10.
    Freitag FG, Kozma CM, Slaton T, Osterhaus JT, Barron R. Characterization and prediction of emergency department use in chronic daily headache patients. Headache. Jul–Aug 2005;45(7):891–898.PubMedCrossRefGoogle Scholar
  11. 11.
    Goadsby PJ. Advances in the understanding of headache. British medical bulletin. 2005;73–74:83–92PubMedCrossRefGoogle Scholar
  12. 12.
    Penzien DB, Rains JC, Lipton RB. Introduction to the special series on the chronification of headache: mechanisms, risk factors, and behavioral strategies aimed at primary and secondary prevention of chronic headache. Headache. Jan 2008;48(1):5–6CrossRefGoogle Scholar
  13. 13.
    •• Ferrari A, Leone S, Vergoni AV, et al. Similarities and differences between chronic migraine and episodic migraine. Headache. Jan 2007;47(1):65–72. This article shows that imaging demonstrates differences between episodic and chronic migraine.Google Scholar
  14. 14.
    De Tommaso M, Losito L, Difruscolo O, Libro G, Guido M, Livrea P. Changes in cortical processing of pain in chronic migraine. Headache. Oct 2005;45(9):1208–1218.PubMedCrossRefGoogle Scholar
  15. 15.
    Mongini F, Keller R, Deregibus A, Barbalonga E, Mongini T. Frontal lobe dysfunction in patients with chronic migraine: a clinical-neuropsychological study. Psychiatry research. Jan 30 2005;133(1):101–106PubMedCrossRefGoogle Scholar
  16. 16.
    Obermann M, Gizewski ER, Limmroth V, Diener HC, Katsarava Z. Symptomatic migraine and pontine vascular malformation: evidence for a key role of the brainstem in the pathophysiology of chronic migraine. Cephalalgia. Jun 2006;26(6):763–766.PubMedCrossRefGoogle Scholar
  17. 17.
    Goadsby PJ. Recent advances in understanding migraine mechanisms, molecules and therapeutics. Trends in molecular medicine. Jan 2007;13(1):39–44.PubMedCrossRefGoogle Scholar
  18. 18.
    Lauritzen M. Pathophysiology of the migraine aura. The spreading depression theory. Brain. Feb 1994;117 ( Pt 1):199–210.PubMedCrossRefGoogle Scholar
  19. 19.
    Wang HZ, Simonson TM, Greco WR, Yuh WT. Brain MR imaging in the evaluation of chronic headache in patients without other neurologic symptoms. Academic radiology. May 2001;8(5):405–408.PubMedCrossRefGoogle Scholar
  20. 20.
    Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell. Nov 1 1996;87(3):543–552PubMedCrossRefGoogle Scholar
  21. 21.
    De Fusco M, Marconi R, Silvestri L, et al. Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nature genetics. Feb 2003;33(2):192–196.PubMedCrossRefGoogle Scholar
  22. 22.
    Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ, Lipton RB. Chronic migraine is an earlier stage of transformed migraine in adults. Neurology. Nov 22 2005;65(10):1556–1561PubMedCrossRefGoogle Scholar
  23. 23.
    Bigal ME, Sheftell FD, Tepper SJ, Rapoport AM, Lipton RB. Migraine days decline with duration of illness in adolescents with transformed migraine. Cephalalgia. Jul 2005;25(7):482–487.PubMedCrossRefGoogle Scholar
  24. 24.
    MC Kruit et al Cephalalgia 30[2] 129–136; IHS 2010Google Scholar
  25. 25.
    Kim JH et al. Cephalalgia. 2008;28[6]:598–604PubMedCrossRefGoogle Scholar
  26. 26.
    Borsook D et al Mol Pain. 2007 Sep 11;3:25PubMedCrossRefGoogle Scholar
  27. 27.
    •• Aurora SK, Barrodale PM, Tipton RL, Khodavirdi A. Brainstem dysfunction in chronic migraine as evidenced by neurophysiological and positron emission tomography studies. Headache. Jul–Aug 2007;47(7):996–1003; discussion 1004–1007. This article demonstrates persistent brainstem dysfunction in chronic migraine.Google Scholar
  28. 28.
    Aurora, S.K.; Spectrum of illness: understanding biological patterns and relationships in chronic migraine.; Neurology. 2009 Feb 3;72(5 Suppl):S8–13. Review.PMID: 19188565 [PubMed–indexed for MEDLINE]Google Scholar
  29. 29.
    Aurora SK, Barrodale P, Chronicle EP, Mulleners WM. Cortical inhibition is reduced in chronic and episodic migraine and demonstrates a spectrum of illness. Headache. May 2005;45(5):546–552.PubMedCrossRefGoogle Scholar
  30. 30.
    Moliadze V, Zhao Y, Eysel U, Funke K. Effect of transcranial magnetic stimulation on single-unit activity in the cat primary visual cortex. The Journal of physiology. Dec 1 2003;553(Pt 2):665–679PubMedCrossRefGoogle Scholar
  31. 31.
    Mulleners WM, Chronicle EP, Palmer JE, Koehler PJ, Vredeveld JW. Suppression of perception in migraine: evidence for reduced inhibition in the visual cortex. Neurology. Jan 23 2001;56(2):178–183PubMedGoogle Scholar
  32. 32.
    Chiapparini L, Ferraro S, Grazzi L, Bussone G.; Neuroimaging in chronic migraine.; Neurol Sci. 2010 Jun;31 Suppl 1:S19–22. Review.PMID: 20464577 [PubMed–indexed for MEDLINE]PubMedCrossRefGoogle Scholar
  33. 33.
    Kruit MC, Launer LJ, Overbosch J, van Buchem MA, Ferrari MD.; Iron accumulation in deep brain nuclei in migraine: a population-based magnetic resonance imaging study.; Cephalalgia. 2009 Mar;29(3):351–9. Epub 2008 Nov 19.PMID: 19025553 [PubMed–indexed for MEDLINE]PubMedCrossRefGoogle Scholar
  34. 34.
    Srikiatkhachorn A.; Towards the better understanding about pathogenesis of chronic daily headache : J Med Assoc Thai. 2006 Sep;89 Suppl 3:S234–43. Review.PMID: 17718291 [PubMed–indexed for MEDLINE]PubMedGoogle Scholar
  35. 35.
    Weiller C, May A, Limmroth V, et al. Brain stem activation in spontaneous human migraine attacks. Nature medicine. Jul 1995;1(7):658–660.PubMedCrossRefGoogle Scholar
  36. 36.
    Welch KM, Cao Y, Aurora S, Wiggins G, Vikingstad EM. MRI of the occipital cortex, red nucleus, and substantia nigra during visual aura of migraine. Neurology. Nov 1998;51(5):1465–1469.PubMedGoogle Scholar
  37. 37.
    Cao Y, Aurora SK, Nagesh V, Patel SC, Welch KM. Functional MRI-BOLD of brainstem structures during visually triggered migraine. Neurology. Jul 9 2002;59(1):72–78PubMedGoogle Scholar
  38. 38.
    Chudler EH, Dong WK. The role of the basal ganglia in nociception and pain. Pain. Jan 1995;60(1):3–38.PubMedCrossRefGoogle Scholar
  39. 39.
    Brown LL, Schneider JS, Lidsky TI. Sensory and cognitive functions of the basal ganglia. Current opinion in neurobiology. Apr 1997;7(2):157–163.PubMedCrossRefGoogle Scholar
  40. 40.
    Iadarola MJ, Berman KF, Zeffiro TA, et al. Neural activation during acute capsaicin-evoked pain and allodynia assessed with PET. Brain. May 1998;121 ( Pt 5):931–947.PubMedCrossRefGoogle Scholar
  41. 41.
    Afridi SK, Matharu MS, Lee L, et al. A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain. Apr 2005;128(Pt 4):932–939.PubMedCrossRefGoogle Scholar
  42. 42.
    Welch KM, Nagesh V, Aurora SK, Gelman N. Periaqueductal gray matter dysfunction in migraine: cause or the burden of illness? Headache. Jul–Aug 2001;41(7):629–637.PubMedCrossRefGoogle Scholar
  43. 43.
    Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Annals of neurology. May 2000;47(5):614–624.PubMedCrossRefGoogle Scholar
  44. 44.
    Lovati C, D’Amico D, Rosa S, et al. Allodynia in different forms of migraine. Neurol Sci. May 2007;28 Suppl 2:S220–221.PubMedCrossRefGoogle Scholar
  45. 45.
    Cooke L, Eliasziw M, Becker WJ. Cutaneous allodynia in transformed migraine patients. Headache. Apr 2007;47(4):531–539.PubMedGoogle Scholar
  46. 46.
    Burstein R, Jakubowski M. Analgesic triptan action in an animal model of intracranial pain: a race against the development of central sensitization. Annals of neurology. Jan 2004;55(1):27–36.PubMedCrossRefGoogle Scholar
  47. 47.
    Kitaj MB, Klink M. Pain thresholds in daily transformed migraine versus episodic migraine headache patients. Headache. Sep 2005;45(8):992–998.PubMedCrossRefGoogle Scholar
  48. 48.
    de Tommaso M, Valeriani M, Guido M, et al. Abnormal brain processing of cutaneous pain in patients with chronic migraine. Pain. Jan 2003;101(1–2):25–32.PubMedCrossRefGoogle Scholar
  49. 49.
    Cortelli P, Pierangeli G.; Chronic pain-autonomic interactions; Neurol Sci. 2003 May;24 Suppl 2:S68–70. Review.PMID: 12811596 [PubMed–indexed for MEDLINE]PubMedGoogle Scholar
  50. 50.
    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 Jan;127(Pt 1):220–30. Epub 2003 Nov 7.PMID: 14607792 [PubMed–indexed for MEDLINE]PubMedCrossRefGoogle Scholar
  51. 51.
    Lipton RB, Bigal ME. Looking to the future: research designs for study of headache disease progression. Headache. Jan 2008;48(1):58–66.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Sheena K. Aurora
    • 1
  • Arun Kulthia
    • 1
  • Patricia M. Barrodale
    • 1
  1. 1.Swedish Headache Center, Swedish Neurosciences InstituteSeattleUSA

Personalised recommendations