Headache 2011 American Headache Society

ISSN 0017-8748 doi: 10.1111/j.1526-4610.2011.01955.x Published by Wiley Periodicals, Inc.

Research Submission
Pathophysiology of Chronic Migraine and Mode of Action of Preventive Medications
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Ninan T. Mathew, MD, FRCPC

Evidence has accumulated in recent years indicating structural, physiologic, and biochemical alterations in the brain of patients with chronic migraine (CM). Altered pharmacologic responses to opioids and other analgesics have also been reported. Structural or morphologic changes include reduced cortical gray matter of the pain processing areas of the brain and iron accumulation in the periaqueductal gray matter (PAG), red nucleus, and basal ganglia structures.These changes correlate with the duration of migraine disorder and, therefore, are more marked in CM compared to episodic migraine (EM). A dysmodulation of trigeminovascular nociception resulting from changes in PAG may be an important factor in the pathophysiology of CM. Even though the pathophysiology and signicance of subcortical white matter lesions and infarct like cerebellar lesions are not fully understood, their occurrence in patients with frequent migraine is further evidence of structural alterations in the brain in CM. Physiologic changes in CM are altered brain metabolism, excitability, and central sensitization of nociceptive pathways. CM is associated with alterations in the brain metabolism conrmed by positron emission tomography (PET) studies. Of special interest is the reversible hypometabolism in the insula, thalamus, anterior cingulate, and parietal lobe and sustained hypometabolism in the orbitofrontal cortex in medication overuse headache. Cortical excitability is increased in CM compared to EM, as conrmed by magnetic suppression of visual accuracy. Cutaneous allodynia, which is more often seen in CM, is a marker of central sensitization. Central sensitization generates free radicals that damage PAG. Cutaneous allodynia is correlated with frequency of migraine attacks and duration of migraine illness. Chronically sensitized central nociceptive neurons may account for CM and its resistance to treatment. Alterations in central glutamate neurotransmission have been reported in the anterior cingulate and insula using magnetic resonance spectroscopy. Medications affecting central glutamatergic neurotransmission may have a potential therapeutic role in CM. Frequent use of opioids and analgesics in EM leads to CM. Opioid-induced hyperalgesia, recognized in recent years, can lead to intractability of migraine. Better understanding of the pathophysiology of CM should lead to better ways to treat these patients. The various effective preventive agents used in migraine prophylaxis, such as topiramate, valproate, b-blockers, and tricyclic antidepressants, appear to have a common effect of suppressing cortical excitability (cortical spreading depression).

From the Houston Headache Clinic, Houston, TX, USA. Funding Statement: This supplement is developed from the content presented during a symposium held at the 52nd Annual Scientic Meeting of the American Headache Society. Jointly sponsored by the Annenberg Center for Health Sciences and CogniMed Inc. This activity is supported by an independent educational grant provided by Allergan, Inc. Address all correspondence to N.T. Mathew, Houston Headache Clinic, Suite 305, 1213 Hermann Drive, Houston, TX 77004, USA, email: ntmathew@houstonheadacheclinic.com Accepted for publication March 14, 2011. Conict of Interest: Ninan T. Mathew, MD, FRCPC, has received research support from Allergan, Inc.; ENDO; GlaxoSmithKline; Merck & Co., Inc.; and Pzer Inc. He serves on the speakers bureaus of ENDO; GlaxoSmithKline; and Merck & Co., Inc.

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Suppression of cortical spreading depression by these agents is correlated with the dosages and the duration of treatment. The benecial effect of botulinum toxin in CM may be due to its antinociceptive effect. Changes in the glutamate and calcitonin gene-related peptide at the peripheral nerve endings reduce peripheral sensitization, which eventually leads to reduced central sensitization. Key words: chronic migraine, pathophysiology, preventive medicine (Headache 2011;51;S2:84-92)

Although it is possible that cases of patients with chronic migraine (CM) had been described previously, when the concept of transformed migraine, or CM, was rst described 30 years ago, the changes that occur in the brain and the pathophysiology were unknown.1,2 Research in the last 15 years has greatly improved our understanding of the pathophysiology of CM and contributed to the advancement of prophylactic therapy.3 Accumulating evidence suggests that structural, functional, and pharmacologic changes occur in the brains of patients with chronic, progressive migraine headaches.3 Structural changes observed are periaqueductal gray (PAG) matter changes; iron deposition in certain areas of the brain, especially PAG matter; and the development of subcortical white matter lesions and cerebellar infarct-like lesions.4-6 Functional changes studied include focal changes in brain metabolism, hyperexcitability of the cortex, and central sensitization.3 Pharmacologic changes also were found to occur: changes in excitatory amino acid levels and ratios in certain areas of the brain particularly the anterior cingulate gyrus and insula and paradoxical responses to opioids.

CHANGES IN BRAIN STRUCTURE Valfr et al used magnetic resonance imaging (MRI) and voxel-based morphometry to compare the brains of 27 right-handed migraineurs and 27 healthy control subjects.7 Compared with control subjects, the migraineurs had signicantly decreased areas of gray matter in several brain regions involved in pain processing: the right superior temporal gyrus, right transverse temporal gyrus, right parietal operculum, right inferior frontal gyrus, and left precentral gyrus. In comparing the brains of patients who had CM (n = 11) with those of patients who had episodic

migraine (EM; n = 16), Valfr et al found that CM patients had signicant gray matter reductions in the left and right anterior cingulate; left amygdala; left parietal operculum; left middle, left inferior, and right inferior frontal gyrus; and left and right insular lobe. In addition, the investigators noted a signicant positive association between gray matter reductions in the anterior cingulate cortex and migraine attack frequency. Although not specically focusing on a CM population, but rather more generally on a migraine population, using a 3T magnetic resonance imaging (MRI) scanner and voxel-based morphometry, Rocca et al compared the gray matter of 16 migraine patients with T2-visible lesions and that of 15 healthy control subjects; patients with migraine had a mean number of T2-visible lesions of 26.9, and the control patients had normal brain scans with no lesions.8 Results showed signicantly reduced gray matter density in the brains of the migraineurs, particularly in the cortex of the frontal and temporal lobes bilaterally. The decreased gray matter density was strongly associated with age, disease duration, and T2-visible lesion load. Rocca et al also found increased PAG matter density in the brains of the migraineurs. Kim and colleagues sought to generalize Rocca et als ndings concerning gray matter changes in the brains of migraineurs who had T2-visible white matter lesions to migraine patients as a whole.4 Kim et al used voxel-based morphometry to contrast the gray matter volume of 20 patients with EM and 33 healthy controls. The patients with EM had signicant reductions in gray matter volume in several regions of the brain: bilateral insula, bilateral motor/premotor cortex, bilateral prefrontal cortex, left dorsal anterior cingulate cortex, right dorsal posterior cingulate cortex, right inferior and superior parietal cortex,

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Fig 1.Brain iron accumulation in migraine. Reproduced with permission.5 CA, cerebral aqueduct; CDH, chronic daily headache; EM, episodic migraine; PAG, periaqueductal gray; RN, red nucleus; SN, substantia nigra.

orbitofrontal cortex, and visual cortex. Progressive decreases in gray matter volume were noted with increasing migraine attack duration and increasing attack frequency, suggesting that repeated migraine attacks may produce atrophic changes in the painprocessing regions of the brain. Increased iron deposition is another structural change detected in the brains of migraineurs (Fig. 1).5 Using high-resolution MRI, Welch et al examined the PAG matter, red nucleus, and substantia nigra of patients with EM (n = 17), patients with chronic daily headache (CDH; n = 17), and control subjects (n = 17), comparing the amount of tissue iron present as determined by mapping transverse relaxation rates R2, R2*, and R2.5 The PAG matter exhibited increased tissue iron levels in the patients with CDH and EM compared with control subjects, and the accumulation of iron correlated positively with the duration of illness (Fig. 1). No differences in iron concentrations were detected between migraine with and without aura. These investigators also speculated that the increased R2 values in the EM and CDH groups indicated impaired iron homeostasis related to

neuronal damage or dysfunction caused by repeated headache attacks. A 2008 population study further corroborated and extended Welch et als ndings.9 Kruit and colleagues demonstrated that iron deposition was signicantly increased in the red nucleus, putamen, and globus pallidus of migraine patients younger than age 50 years compared with control subjects. Among the migraineurs in this age group, iron concentrations (as reected by reduced T2 values) were signicantly higher in those with a longer history of migraine. Functional MRI shows persistent activation and hyperoxia in the substantia nigra and red nucleus, implicated in nociception and autonomic dysfunction.10 The increased accumulation of iron in the antinociceptive network of migraineurs may have a role in chronication to CM or may be a physiologic response to repeated activation of nuclei involved in central pain processing.9 In recent years, community-based epidemiologic MRI studies of patients with migraine have helped to elucidate these issues, particularly those conducted in the Netherlands. In a population-based study in

Headache Reykjavik, Iceland, migraineurs (n = 4689; 57% women) were followed from 1967, examined, and interviewed about migraine symptoms 25 to 30 years later (mean age, 51 years; range, 33 to 65 years).11 At about 10 years, participants reporting one or more headaches per month were asked about nausea, unilateral location, photophobia, visual disturbance, and numbness. Then, between 2002 and 2006, highresolution, thin-slice (1.5-mm) MRI scans showed infarct-like lesions in 39.3% of men and 24.6% of women. After adjusting for age, sex, and follow-up time, subjects with migraine with aura (n = 361) had an increased risk of late-life infarct-like lesions compared with those not reporting one or more headaches per month (n = 3243; adjusted odds ratio [OR], 1.4; 95% condence interval [CI], 1.1-1.8). Cerebellar lesions were associated with female sex (prevalence of infarcts: 23.0% for women with migraine with aura vs 14.5% for women not reporting headaches [adjusted OR, 1.9; 95% CI, 1.4-2.6] and 19.3% for men with migraine with aura vs 21.3% for men not reporting headaches [adjusted OR, 1.0; 95% CI, 0.61.8]; P < .04 for interaction by sex). Migraine without aura and non-migraine headache were not associated with an increased risk of cerebellar infarct-like lesions, whereas migraine with aura in midlife was associated with late-life prevalence. The release of metallic proteinases during cortical spreading depression (CSD) has been proposed as a cause of bloodbrain barrier alterations in subcortical structures, in turn increasing white matter lesions.3,12,13 White matter lesions may be thought to be manifestations of infarcts. Radiologists may interpret white matter lesions to indicate multiple strokes or multiple sclerosis, but physicians should reassure migraine patients that white matter lesions are a common pathophysiologic feature in CM.3 However, white matter lesions in a migraine patient may rarely indicate underlying CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes), or central nervous system vasculitis.14 Therefore, it is important for headache physicians to be able to distinguish between nonspecic and disease-specic white matter lesions in migraine

87 sufferers, particularly because the long-term consequences and pathophysiology of these nonspecic white matter lesions are unknown and may cause uncertainty for physicians and anxiety for patients.14,15 While differential diagnosis may be extensive, white matter lesions should be understood within the context of family history, history of viral infection, metabolic factors, cardiovascular risk factors, and physical examination.15,16 (For more details about differential diagnosis of multifocal white matter abnormalities, please see table 1 of Gladstone et al.15)

CHANGES IN BRAIN METABOLISM, HYPEREXCITABILITY, AND CENTRAL SENSITIZATION The brains of patients who have CM exhibit metabolic changes, evidence of hyperexcitability of the central nervous system, and central sensitization. Fumal et al used positron emission tomography (PET) scans to compare glucose metabolism in the brains of 16 chronic migraineurs who overused medications and 68 control subjects.17 The patients with CM who overused combination analgesics had more pronounced hypometabolism in the orbitofrontal cortex than did patients who overused singlecompound non-narcotic analgesics. There is evidence to suggest the orbitofrontal cortex plays an important role in aspects of addictive behavior. Using transcranial magnetic stimulation indexes of cortical excitability, Aurora et al demonstrated that magnetic suppression of perceptual accuracy was signicantly diminished in 25 patients with CM compared with patients with EM and control subjects, indicating increased cortical excitability.18 The investigators also performed PET scan studies in a subset of 10 of the patients with CM and found increased metabolism in the pons and right temporal cortex compared to global cerebral metabolism. Areas of decreased metabolism were found in the medial frontal, parietal, and somatosensory cortices and in the bilateral caudate nuclei. The activation and inhibition of certain brainstem areas suggest that cortical excitability is raised in patients with CM. The investigators concluded that high cortical excitability may cause CM patients to be unusually susceptible to

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Fig 2.Sensitization of central trigeminovascular neurons in nucleus caudalis mediates cutaneous allodynia. Adapted with permission.19

migraine triggers and explain the high frequency of migraine attacks. Central sensitization is a clinical phenomenon familiar to headache specialists3 (Fig. 2). During a migraine attack, peripheral sensitization occurs; the trigeminal nerve and the blood vessels supplied by them are sensitized, resulting in throbbing pain that is aggravated by walking, bending over, headshaking, coughing, or other routine movements or activities.3,19 This stage of a migraine is termed rst-order neuron sensitization.3 Second-order neuron sensitization occurs when sensitization spreads to the second-order trigeminovascular neurons in the spinal trigeminal nucleus, causing scalp hypersensitivity, or cutaneous allodynia.19 When sensitization spreads to the thalamus, the result is generalized third-order neuron sensitization, which causes extracephalic hypersensitivity (ie, allodynia of the trunk and/or limbs).3,19 Allodynia is therefore the clinical expression of second- and third-order neuron sensitization and a sign of migraine progression.20 Research has shown that allodynia symptoms occur with greater frequency in patients who have a long history of CM.20 Allodynia is correlated with not only the duration of migraine illness but also the frequency of migraine attacks. In a study by Mathew et al, the percentage of migraine patients who had

allodynia was 33% among those who had 1 to 4 migraine attacks per month but 58% among those who had more than 8 attacks. Ashkenazi and colleagues found that 43% of 89 patients with CM had mechanical (brush) allodynia, even between headache exacerbations.21 Therefore, allodynia, which occurs more commonly than vomiting in migraine patients, is a useful diagnostic symptom.20 That allodynia may lead to triptan failure is not a view shared by all: Schoenen et al have suggested there is a complex relationship between headache intensity, allodynia, and treatment outcome.22 Migraine headache may be treated effectively with triptans administered soon after the onset of a migraine attack, before allodynia becomes established.19 Migraine patients who do not have allodynia, however, can obtain effective pain relief by taking triptans at any point during an attack.

CHANGES IN BRAIN PHARMACOLOGY Alterations in Glutamate Transmission in Migraine.Brains of patients with migraine differ pharmacologically from those of non-migraine sufferers. Evidence suggests that some of those differences pertain to the glutamate ratios in various areas of the brain.3 The use of magnetic resonance spectroscopy to compare the interictal brain chemistry of 10

Headache patients with migraine and 8 control subjects revealed distinct groups, distinguished by N-acetyl-aspartylglutamate (NAAG) to glutamine ratio in the anterior cingulate cortex and insula of the migraineurs.23 Medication Overuse and Migraine Chronication.Bigal and Lipton analyzed the results of various clinic- and population-based studies of medication use by patients with CDH to assess the association with migraine chronication.24 Among the investigators ndings were that patients who took barbiturates on more than 5 days per month were at greater risk for chronication from EM to CM and that risk was higher for women. Patients who took opioids on more than 8 days per month were at greater risk for headache chronication, and that risk was higher for men. Further, triptans caused migraine progression in patients who had frequent migraines (ie, headache 10 to 14 days per month). Nonsteroidal anti-inammatory drugs were protective against chronication to CM, but only in patients who had fewer than 10 headaches per month. Opioid-induced hyperalgesia, a paradoxical increase in pain sensitivity in response to opioids, is clinically relevant in CM.25 Opioid-induced hyperalgesia may account for declining levels of analgesia or worsening of pain in patients taking opioids.Headache specialists commonly encounter patients who report increasingly severe headaches despite taking as many as 15 tablets of hydrocodone/acetaminophen per day.3 Such patients may have opioid-induced hyperalgesia, which can occur even after brief exposure to opioids.26 Furthermore, based on the premise that supporting glia, their receptors, and their secreted mediators may play an important role in neuronal function regulation and so may contribute to migraine,27 Watkins and others have posited a mechanism whereby chronic morphine exposure may modulate glial function, suggesting that the clinical efcacy of opiates for pain control is limited by analgesic tolerance and hyperalgesia.28 A recent study pointed to common cellular mechanisms of opioid-induced desensitization and sensitization mediated through activation of the central glutamatergic system.29 Opioid tolerance and opioid-induced hyperalgesia are distinct pharmaco-

89 logic phenomena, but over time, each results in decreased effectiveness of a given opioid dose, leading to dose escalation.25 In opioid-induced hyperalgesia, patients experience pain or increased sensitivity to pain even when serum opioid levels are low. Even at baseline (before the start of the opioid infusion), their pain tolerance is decreased compared to that of opioid-naive patients. In opioid tolerance, the administered dose is no longer effective and the dose must be increased to get the same effect. This reects desensitization of patients antinociceptive pathways from chronic use of opioid medications; no change in pain sensitivity occurs at baseline. How Migraine Medications Work.Five medications commonly used in migraine prophylaxis topiramate, valproate, propranolol, amitriptyline, and methysergide have a common mechanism of action.30 Chronic administration of these 5 migraine preventive medications, but not the control L-propranolol, has been shown to reduce CSD in rats, suggesting that suppression of CSD is a common mechanism of action for migraine preventive medications. Ayata et al tested the hypothesis that all of these medications suppress CSD, implicated in migraine attacks. The investigators administered various doses of each of the 5 medications to male SpragueDawley rats. Prophylactic efcacy of the 5 medications positively correlated with duration of treatment. Chronic treatment with each of the 5 medications almost completely suppressed CSD after a 17-week course of treatment,30 whereas in human beings, a trial of at least 3 months may be necessary to determine the efcacy of those medications in migraine prevention.3 The study also showed that the efcacy of the medications is dose-dependent.30 Therefore, physicians should begin with a low dose and titrate the dose up when prescribing any of those medications for their patients with migraine.3 Several preclinical studies support the hypothesis that botulinum toxin is effective in the treatment of migraine because of its direct effect on peripheral sensitization and indirect effect on central sensitization. Botulinum toxin mediated substance P release in embryonic rat dorsal root ganglia neurons,31 glutamate inhibition in the rat formalin model,32 and calcitonin gene-related peptide (cGRP) inhibition in

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Fig 3.Effect of botulinum toxin type A on stimulated and evoked calcitonin gene-related peptide (cGRP) release from trigeminal nerve cells: implications for migraine therapy. Reproduced with permission.33 BTX, onabotulinumtoxinA; CON, control; KCl, potassium chloride; VEH, vehicle. aP < .01 when compared with untreated control levels. bP < .01 when compared with KCl-treated levels.

rat trigeminal ganglion cell cultures.33 Two of the studies are described here. Cui et al assessed the physiologic effects of onabotulinumtoxinA on pain using the rat formalin model.32 Results of the study demonstrated that subcutaneously injected onabotulinumtoxinA produced dose-dependent inhibition of formalin-induced glutamate release at the site of peripheral inammation and centrally reduced c-Fos expression in the spinal cord.3,32 Those ndings indicated that some of the antinociceptive effect of onabotulinumtoxinA is due to its inhibition of neurotransmitter release from primary sensory neurons.32 Local injection of onabotulinumtoxinA inhibits peripheral sensitization from local neurotransmitter release, resulting in an indirect decrease in central sensitization. Sensitization and activation of the trigeminal nerves stimulate the release of neuropeptides, such as cGRP, that cause the vascular and inammatory changes associated with migraine pain in human beings.3 Durham and colleagues conducted a study to determine whether onabotulinumtoxinA can directly

reduce cGRP secretion from the sensory trigeminal neurons of rats.33 The investigators found that onabotulinumtoxinA did not inhibit unstimulated (basal) cGRP release in rat trigeminal ganglions (Fig. 3, left) but did inhibit release of cGRP from those neurons when they were stimulated with potassium chloride or capsaicin (Fig. 3, right). Thus, onabotulinumtoxinA inhibits evoked release, but not basal release, of cGRP. To summarize, preclinical studies show that botulinum toxin, injected subcutaneously, can inhibit substance P, inhibit glutamate peripherally, and inhibit cGRP released peripherally. Once peripheral sensitization is reduced, central sensitization is also decreased, leading to the alleviation of migraine pain. In conclusion, our understanding of the complex changes that occur within the brain and central nervous system of the patient with CM has progressed signicantly. Timely, early intervention with appropriate prophylactic therapy may succeed in reversing the pathophysiologic, and perhaps even the structural, changes that occur in the brains of migraine sufferers.

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15. Gladstone JP, Dodick DW. Migraine and cerebral white matter lesions: When to suspect cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Neurologist. 2005;11:19-29. 16. Longstreth WT Jr, Manolio TA, Arnold A, et al. Clinical correlates of white matter ndings on cranial magnetic resonance imaging of 3301 elderly people: The Cardiovascular Heath Study. Stroke. 1996;27:1274-1282. 17. Fumal A, Laureys S, Di Clemente L, et al. Orbitofrontal cortex involvement in chronic analgesicoveruse headache evolving from episodic migraine. Brain. 2006;129:543-550. 18. Aurora SK, Borrodale PM, Tipton RL, Khodavirdi A. Brainstem dysfunction in chronic migraine as evidenced by neurophysiological and positron emission tomography studies. Headache. 2007;47:996-1003. 19. Burstein R, Jakubowski M. Implications of multimechanism therapy: When to treat? Neurology. 2005;64(Suppl. 2):S16-S20. 20. Mathew NT, Kailasam J, Seifert T. Clinical recognition of allodynia in migraine. Neurology. 2004; 63:848-852. 21. Ashkenazi A, Sholtzow M, Shaw JW, Burstein R, Young WB. Identifying cutaneous allodynia in chronic migraine using a practical clinical method. Cephalalgia. 2007;27:111-117. 22. Schoenen J, De Klippel N, Giurgea S, et al; Belgian Headache Society. Almotriptan and its combination with aceclofenac for migraine attacks: A study of efcacy and the inuence of auto-evaluated brush allodynia. Cephalalgia. 2008;28:1095-1105. 23. Prescot A, Becerra L, Pendse G, et al. Excitatory neurotransmitters in brain regions in interictal migraine patients. Mol Pain. 2009;5:34. 24. Bigal ME, Lipton RB. Excessive acute migraine medication use and migraine progression. Neurology. 2008;71:1821-1828. 25. Chu LF, Angst MS, Clark D. Opioid-induced hyperalgesia in humans: Molecular mechanisms and clinical considerations. Clin J Pain. 2008;24:479496. 26. Saper JR, Lake AE III. Continuous opioid therapy (COT) is rarely advisable for refractory chronic daily headache: Limited efcacy, risks, and proposed guidelines. Headache. 2008;48:838-849. 27. Bartley J. Could glial activation be a factor in migraine? Med Hypotheses. 2009;72:255-257.

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