Pathophysiology of Chronic Migraine and Mode of Action of Preventive Medications

Authors


  • Funding Statement: This supplement is developed from the content presented during a symposium held at the 52nd Annual Scientific 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.

  • Conflict of Interest: Ninan T. Mathew, MD, FRCPC, has received research support from Allergan, Inc.; ENDO; GlaxoSmithKline; Merck & Co., Inc.; and Pfizer Inc. He serves on the speakers bureaus of ENDO; GlaxoSmithKline; and Merck & Co., Inc.

N.T. Mathew, Houston Headache Clinic, Suite 305, 1213 Hermann Drive, Houston, TX 77004, USA, email: ntmathew@houstonheadacheclinic.com

Abstract

(Headache 2011;51;S2:84-92)

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 significance 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 confirmed 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 confirmed 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, β-blockers, and tricyclic antidepressants, appear to have a common effect of suppressing cortical excitability (cortical spreading depression). Suppression of cortical spreading depression by these agents is correlated with the dosages and the duration of treatment. The beneficial 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.

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