The Pathophysiological and Pharmacological Basis of Current Drug Treatment of Migraine Headache

Doodipala Samba Reddy


Expert Rev Clin Pharmacol. 2013;6(3):271-288. 

In This Article

Five-year View

Development of new drugs for migraine is hampered due to lack of validated animal models and biomarkers for rapid clinical assessment. There is wide genetic and clinical heterogeneity of migraine headaches; the primary mechanisms of migraine onset remain incompletely understood. There is also emerging information on the pathophysiology of migraine and animal paradigms that simulate some aspects of migraine features. Neural and vascular theories are providing basic understanding of headache mechanisms in migraine. Despite advances in understanding the migraine headache, the upstream factors that trigger migraine attacks are not very well understood. There is little mechanistic approach for designing prophylactic drug therapy. Many patients benefit from triptans, but triptans have certain limitations. Some patients exhibit refractory migraine to triptans. Current migraine prophylaxis has been largely based on serendipitous observations with specific β-blockers and additional features of antiepileptic drugs. There is more optimism about CSD as the final common pathophysiological target for currently approved drugs or some experimental migraine prophylactic agents. Consequently, CSD is being intensely utilized as a validated parameter for preclinical migraine drug-screening paradigms. Four clinically effective migraine prophylactic drugs (valproate, topiramate, propranolol and amitriptyline) have been demonstrated to suppress CSD susceptibility.[7,86,117–123] Despite being chemically and pharmacologically quite different, these drugs promote effective suppression of CSD. There are several outstanding questions including the types of genes involved in migraines, the primary brain dysfunctions and mechanisms of activation and sensitization of the trigeminovascular pain pathway. So far, only three migraine genes have been identified. They account for only half of patients with the rare disorder FHM. Within the next few years, migraine genetics will be significantly advanced and hopefully a new class of drug for acute migraine will be identified from such findings.

Several new drugs are being developed for migraine with an overall goal of higher efficacy and improved side effect profile (Table 5).[118,120] Calcitonin gene-related peptide (CGRP) has long been hypothesized to play a key role in migraine pathophysiology.[92] This field is expected to make substantial progress in the next 5 years. As described earlier, triptans currently represent the antimigraine therapy of choice. However, some patients do not respond optimally to triptans and some only partially respond. In the past few years, evidence began to mount linking CGRP to the pathophysiology of migraine.[121–123] These observations suggested antagonism of the CGRP receptor might represent a novel approach to migraine treatment. In the next 5 years, there will be more data and evidence for CGRP's role in migraine. Several CGRP-receptor antagonists are being tested for clinical efficacy for the treatment of migraine.[121] There will be more information to ascertain the role of CGRP agents for a highly effective new therapy for migraine sufferers. Onabotulinum toxin A (Botox®, Allergan, CA, USA) has been approved by the FDA for migraine prophylaxis. It has been tested extensively for migraine and the efficacy is marginal and controversial.[124–127] At 24 weeks, 47.1% of onabotulinum toxin A-treated patients had a ≥50% decrease from baseline in frequency of headache days (primary end point), compared with 35.1% of placebo-treated patients.[125] In addition, there are two studies comparing onabotulinum toxin A and topirimate for prevention of chronic migraine finding similar efficacy.[126,127] There is some consensus that it may be beneficial to a subgroup of migraine patients such as refractory chronic migraine. In the next 5 years, several new targets will be identified and validated for migraine therapy.