Abstract
The understanding of migraine pathophysiology has evolved from the belief that migraine is a vascular disorder, to evidence that better defines migraine as a neurogenic disorder associated with secondary changes in brain perfusion. There is evidence to suggest that the early phase of migraine pain results from neurogenic infiammation affecting cranial blood vessels and dura. Allodynia, hyperalgesia, and expansion of nociceptive fields occur during most well-established migraine attacks. These clinical features of migraine are evocative of those traditionally associated with neuropathic pain. A hypothesis that defines migraine pain as a unique neuropathic pain disorder can imply the potential for neural plasticity and may provide insight into the mechanisms that underlie the transformation of episodic to chronic forms of migraine. The neuropathic pain model of migraine pathophysiology not only paves the way for mechanism-based treatment strategies that can improve the acute and preventive management of migraine attacks, but also opens the door for the discovery of novel therapeutic targets. It also lends momentum to an understanding of clinically intriguing topics such as opiate-induced hyperalgesia and medication-overuse headache (rebound headache), opioid resistance in the treatment of chronic headache, and disease modification in defending against the potential for migraine transformation.
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References and Recommended Reading
Lipton RB, Stewart WF: Prevalence and impact of migraine. Neurol Clin 1997, 15:1–13.
Peroutka SJ: Genetic basis of migraine. Clin Neurosci 1998, 5:34–37.
Lipton RB, Stewart WF, Diamond ML, Reed M: Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 2001, 41:656–647.
Hu XH, Markson LE, Lipton RB, et al.: Burden of migraine in the United States. Arch Intern Med 1999, 159:813–818.
Lipton RB, Stewart WF, Simon D: Work-related disability: results from the American Migraine Study. Cephalalgia 1996, 16:231–238.
Scher AI, Stewart WF, Liberman J, Lipton RB: Prevalence of frequent headache in a population sample. Headache 1998, 38:497–506.
Welch KM, Negesh V, Aurora SK, Gelman N: Periaqueductal gray matter dysfunction in migraine: Cause or the burden of illness? Headache 2001, 41:629–637. Using a specialized MRI protocol, this paper reports the finding of nonheme iron deposition in periaqeductal gray neurons of migraineurs, but not control subjects. This finding may suggest injury to or degeneration of this rostral brainstem region that is an integral part of the intrinsic pain modulation systems.
Kruit MC, van Buchem MA, Hofman PAM, et al.: Migraine as a risk factor for subclinical brain lesions. JAMA 2004, 291:427–434.
Khalil NM, Legg NJ, Anderson DJ: Long-term decline of P100 amplitude in migraine with aura. J Neurol Neurosurg Psychiatry 2000, 69:507–511.
Lee H, Lopez I, Ishiyama A, Baloh RW: Can migraine damage the inner ear? Arch Neurol 2000, 57:1631–1634.
Welsh KM, Goadsby PJ Chronic daily headache. Curr Opin Neurol 2002, 15:287–295. This paper is a thorough review of the pathogenesis and cellular mechanisms that underlie CHD and the transformation of episodic migraine to chronic forms of migraine.
Kitaj MB, Klink M: Pain thresholds in daily transformed migraine versus episodic migraine headache patients. Headache 2005, 45:992–998. This paper reports the results of a clinical study that demonstrated the development of persistent hyperalgesia and allodynia in cases of chronic migraine.
Headache Classification of the International Headache Society: The International Classification of Headache Disorders, edn 2. Cephalalgia 2004, 24(suppl 1):1–160.
Vingen JV, Sand T, Stover LJ: Sensitivity to various stimuli in primary headaches: a questionnaire study. Headache 1999, 39:552–558.
Selby G, Lance JW: Observation on 500 cases of migraine and allied vascular headaches. J Neurol Neurosurg Psychiatry 1960, 23:23–32.
Stewart WF, Schechter A, Lipton RB: Migraine heterogeneity: disability, pain intensity, attack frequency, and duration. Neurology 1994, 44:S24-S39.
Rasmussen BK, Olesen J: Migraine with aura and migraine without aura: an epidemiological study. Cephalalgia 1992, 12:221–228.
Cady R, Dodick DW, Levine HL, et al.: Sinus headache: a neurology, otolaryngology, allergy, and primary care consensus on diagnosis and treatment. Mayo Clin Proc 2005, 80:908–916.
Kaniecki RG: Migraine and tension-type headache: an assessment of challenges in diagnosis. Neurology 2002, 58(supp16):S15-S20.
Tepper SJ, Dahlof CG, Dowson A, et al.: Prevalence and diagnosis of migraine in patients consulting their physician with a complaint of headache: data from the Landmark Study. Headache 2004, 44:856–864.
Rapoport AM, Stang P, Gutterman DL, et al.: Analgesic rebound headache in clinical practice: data from a physician survey. Headache 1996, 36:14–19.
Vingen JV, Sand T, Stover LJ: Sensitivity to various stimuli in primary headaches: a questionnaire study. Headache 1999, 39:552–558.
Mathew NT, Stubits E, Nigam M: Transformation of migraine into daily headache: analysis of factors. Headache 1982, 22:66–68.
Linton-Dahlof P, Linde M, Dahlof C: Withdrawal therapy improves chronic daily headache associated with longterm misuse of headache medication: a retrospective study. Cephalalgia 2000, 20:658–662.
Fritsche G, Eberl A, Katsarava Z, et al.: Drug-induced headache: long-term follow-up of withdrawal therapy and persistence of drug misuse. Eur Neurol 2001, 45:229–235.
Katsarava Z, Fritsche G, Muessig M, et al.: Clinical features of withdrawal headache following overuse of triptans and other headache drugs. Neurology 2001, 57:1694–1698.
Silberstein SD, Silberstein JR: Chronic daily headache: prognosis following inpatient treatment with repetitive IV DHE. Headache 1992, 32:439–445.
Diener HC, Dahlof CG: Headache associated with chronic use of substances. In The Headaches, edn 2. Edited by Olesen J, Tfelt-Hansen P, Welch KM. Philadelphia: Lippincott Williams & Wilkins; 2000:871–878.
Scher AI, Lipton RB, Stewart WF: Natural history and prognostic factors for chronic daily headache: results from the Frequent Headache Epidemiology Study. Neurology 2002, 58(suppl 3):A171.
Lu SR, Fuh JL, Chen WT, et al.: Chronic daily headache in Taipei, Taiwan: prevalence, follow-up, and outcome predictors. Cephalalgia 2001, 20:900–906.
VonKorff M, Stewart WF, Simon DJ, Lipton RB: Migraine and reduced work performance: a population-based diary study. Neurology 1998, 50:1741–1745.
Diener HC, Dichgans J, Scholz E, et al.: Analgesic-induced chronic headache: long-term results of withdrawal therapy. J Neurol 1989, 236:9–14.
Verri AP, Cecchini P, Galli C, et al.: Psychiatric comorbidity in chronic daily headache. Cephalalgia 1998, 18:45–49.
Graham JR, Wolff HG: Mechanisms of migraine headache and action of ergotamine tartrate. Arch Neurol Psychiatry 1938, 39:737–763.
Moskowitz MA: The neurobiology of vascular head pain. Ann Neurol 1984, 15:157–168.
Goadsby PJ, Zagami AS, Lambert GA: Neural processing of craniovascular pain: a synthesis of the central structures involved in migraine. Headache 1991, 31:365–371.
Pietrobon D, Streissnig J: Neurobiology of migraine. Nat Rev Neurosci 2003, 4:386–398. This paper provides a thorough review of migraine pathophysiology based on available preclinical and clinical evidence. Neurogenic and cellular mechanisms of the migraine attack including neurogenic infiammation, peripheral sensitization, and central sensitization are succinctly summarized.
Ferrari MD: Migraine. Lancet 1998, 351:1043–1051.
Aurora SK, Welch KM, Al-Sayed F: The threshold for phosphenes is lower in migraine. Cephalalgia 2003, 23:258–263.
Peroutka SJ: Neurogenic infiammation and migraine: implications for the therapeutics. Mol Interv 2005, 5:304–311.
Burstein R, Yarnitsky D, Goor-Aryeh I, et al.: An association between migraine and cutaneous allodynia. Ann Neurol 2000, 47:614–624. This paper provided the original evidence that allodynia is associated with acute migraine attacks.
Kelman L: The premonitory symptoms (prodrome): a tertiary care study of 893 migraineurs. Headache 2004, 44:865–872.
Peroutka SJ: Dopamine and migraine. Neurology 1997, 49:650–656.
Hadjikhani N, Sanchez del Rio M, Schwartz D, et al.: Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A 2001, 98:4687–4692.
Bolay H, Reuter U, Dunn AK, et al.: Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med 2002, 8:136–142.
Goadsby PJ: Migraine pathophysiology. Headache 2005, 45(suppl 1):S14-S24.
Burstein R, Cutrer FM, Yarnitsky D: The development of cutaneous allodynia during a migraine attack: clinical evidence for sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain 2000, 123:1703–1709.
Williamson DJ, Hargreaves RJ: Neurogenic infiammation in the context of migraine. Microsc Res Tech 2001, 53:167–178.
Strassman AM, Raymond SA, Burstein R: Sensitization of meningeal sensory neurons and the origin of headaches. Nature 1996, 384:560–564.
Burstein R, Collins B, Jakubowski M: Defeating migraine pain with triptans: a race against the development of cutaneous allodynia. Ann Neurol 2004, 55:19–26. This paper demonstrated differences in treatment efficacy during migraine attacks based on the presence or absence of allodynia. These findings lent momentum to migraine treatment strategies that encouraged early treatment intervention, which consistently has resulted in better abortive treatment efficacy.
Montagna P, Cevoli S, Marzocchi N, et al.: The genetics of chronic headaches. Neurol Sci 2003, 24(suppl 2):S51-S56.
Katsarava Z, Schneeweiss S, Kurth T, et al.: Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology 2004, 62:788–790.
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, 106:81–89.
Chronicle E, Mulleners W: Might migraines damage the brain? Cephalalgia 1994, 14:415–418.
Khalil NM, Legg NJ, Anderson DJ: Long-term decline of P100 amplitude in migraine with aura. J Neurol Neurosurg Psychiatry 2000, 69:507–511.
Mulder EJ, Linssen WH, Passchier J, et al.: Interictal and postictal cognitive changes in migraine. Cephalalgia 1999, 19:557–565.
Sandor PS, Mascia A, Seidel L, et al.: Subclinical cerebellar impairment in the common types of migraine: a threedimensional analysis of reaching movements. Ann Neurol 2001, 49:668–672.
Jacome DE: Neuromuscular transmission in migraine: a single-fiber EMG study in clinical subgroups. Neurology 2002, 58:1316–1367.
Bennett GJ: Neuropathic pain: A crisis in definition? Anesth Analg 2003, 97:619–620.
Bridges D, Thompson SW, Rice AS: Mechanisms of neuropathic pain. Br J Anaesth 2001, 87:12–26.
Rasmussen PV, Sindrup SH, Jensen TS, Bach FW: Symptoms and signs in patients with suspected neuropathic pain. Pain 2004, 110:461–469.
Hargreaves K, Dubner R, Brown F, et al.: A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 1988, 32:77–88.
Woolf CJ, Salter MW: Neuronal plasticity: increasing the gain in pain. Science 2000, 288:1765–1769.
Ossipov MH, Lai J, Malan TP Jr, Porreca F: Spinal and supraspinal mechanisms of neuropathic pain. Ann N Y Acad Sci 2000, 909:12–24.
Watkins LR, Maier S: Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov 2003, 2:973–985.
Kidd BL, Urban LA: Mechanisms of infiammatory pain. Br J Anesth 2001, 87:3–11.
Rome HP, Rome JD: Limbicly augmented pain syndrome (LAPS): kindling, corticolimbic, sensitization, and the conversions of affective and sensory symptoms in chronic pain disorders. Pain Med 2000, 1:7–23.
Backonja MM: Defining neuropathic pain. Anesth Analg 2003, 97:785–790. This paper is a thoughtful review of the controversy surrounding current definitions for pain classification and proposes a revised classification of pain disorders based on pain mechanisms and clinical presentation.
Larkin GL, Prescott JE: A randomized, double-blind, comparative study of the efficacy of ketorolac tromethanine versus meperidine in the treatment of severe migraine. Ann Emerg Med 1992, 21:919–924.
Lainez MJ: Clinical benefits of early triptan therapy for migraine. Cephalalgia 2004, 24(suppl 2):24–30.
Scholpp J, Schellenberg R, Moeckesch B, Banik N: Early treatment of a migraine attack while pain is still mild increases the efficacy of sumatriptan. Cephalalgia 2004, 24:925–933.
Klapper J, Lucas C, Rosjo O: Benefits of treating highly disabled migraine patients with zolmitriptan while pain is mild. Cephalalgia 2004, 24:918–924.
Mathew NT, Kailasam J, Meadors L: Early treatment of migraine with rizatriptan: a placebo-controlled study. Headache 2004, 44:669–673.
Mathew NT: Early intervention with almotriptan improves sustained pain-free response in acute migraine. Headache 2003, 43:1075–1079.
Brandes JL, Kudrow D, Cady R, et al.: Eletriptan in the early treatment of acute migraine: infiuence of pain intensity and time of dosing. Cephalalgia 2005, 25:735–742.
Panconesi A, Anselmi B, Franchi G: Increased adverse effects of opiates in migraine patients. Cephalalgia 1995, 15:159–160.
Arner S, Meyerson BA: Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain. Pain 1988, 33:11–23.
Benedetti F, Vighetti S, Amanzio M, et al.: Dose-response relationship of opioids in nociceptive and neuropathic postoperative pain. Pain 1998, 74:205–211.
Attal N, Guirimand F, Brasseur L, et al.: Effects of IV morphine in central pain. Neurology 2002, 58:554–563.
Dellemijn P: Are opioids effective in relieving neuropathic pain? Pain 1999, 80:453–462.
Rowbotham MC, Reisner-Keller LA, Fields HL: Both intravenous lidocaine and morphine reduce the pain of postherpetic neuralgia. Neurology 1991, 41:1024–1028.
Eisenberg E, McNicol ED, Carr DB: Efficacy and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin: systematic review and metaanalysis of randomized controlled trials. JAMA 2005, 293:3043–3052.
Devulder J: Hyperalgesia induced by high-dose intrathecal sufentanil in neuropathic pain. J Neurosurg Anesthesiol 1997, 9:146–148.
Sjogren P, Josson T, Jesen NH, et al.: Hyperalgesia and myoclonus in terminal cancer patients treated with continuous intravenous morphine. Pain 1993, 55:93–97.
Silberstein SD: Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000, 55:754–762.
Carleton SC, Shesser RF, Pietrzak MP, et al.: Doubleblind, multicenter trial to compare the efficacy of intramuscular dihydroergotamine plus hydroxyzine versus intramuscular meperidine plus hydroxyzine for the emergency department treatment of acute migraine headache. Ann Emerg Med 1998, 32:129–138.
Saper JR, Lake AE III, Hamel RL, et al.: Daily scheduled opioids for intractable head pain: long-term observations of a treatment program. Neurology 2004, 62:1687–1694.
Rothrock J: The role of chronic opioid therapy in managing chronic daily headache: a roundtable discussion. Presented at the Annual Scientific Meeting of the American Headache Society. Seattle, WA: June 21–23, 2002.
Biondi DM: Opioid resistance in chronic daily headache: a synthesis of ideas from the bench and bedside. Curr Pain Headache Rep 2003, 7:67–75.
Backonja MM, Irving G, Argoff C: Rational multidrug therapy in the treatment of neuropathic pain. Curr Pain Headache Rep 2006, 10:34–38.
Edvinsson L: Clinical data on the CGRP antagonist BIBN4096BS for treatment of migraine attacks. CNS Drug Rev 2005, 11:69–76.
Lassen LH, Christiansen I, Iversen HK, et al.: The effect of nitric oxide synthase inhibition on histamine-induced headache and arterial dilatation in migraineurs. Cephalalgia 2003, 23:877–886.
Sang CN, Ramadan NM, Willihan RG, et al.: LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine. Cephalalgia 2004, 24:596–602.
Classey JD, Knight YE, Goadsby PJ: The NMDA receptor antagonist MK-801 reduces Fos-like immunoreactivity within the trigeminocervical complex following superior sagittal sinus stimulation in the cat. Brain Res 2001, 907:117–124.
Goadsby PJ, Hoskin KL, Storer RJ, et al.: Adenosine A1 receptor agonists inhibit trigeminovascular nociceptive transmission. Brain 2002, 125:1392–1401.
Akerman S, Kaube H, Goadsby PJ: Anandamine is able to inhibit trigeminal neurons using an in vivo model of trigeminovascular-mediated nociception. J Pharmacol Exp Ther 2004, 309:56–63.
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Biondi, D.M. Is migraine a neuropathic pain syndrome?. Current Science Inc 10, 167–178 (2006). https://doi.org/10.1007/s11916-006-0042-y
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DOI: https://doi.org/10.1007/s11916-006-0042-y