Calcitonin gene-related peptide (CGRP) receptor antagonists in the treatment of migraine

Paul L. Durham, Carrie V. Vause

Based on preclinical and clinical studies, the neuropeptide calcitonin gene-related peptide (CGRP) is proposed to play a central role in the underlying pathology of migraine. CGRP and its receptor are widely expressed in both the peripheral and central nervous systems by multiple cell types involved in the regulation of inflammatory and nociceptive responses. Peripheral release of CGRP from trigeminal nerve fibres within the dura and from the cell body of trigeminal ganglion neurons is likely to contribute to peripheral sensitization of trigeminal nociceptors. Similarly, the release of CGRP within the trigeminal nucleus caudalis can facilitate activation of nociceptive second-order neurons and glial cells. Thus, CGRP is involved in the development and maintenance of persistent pain, central sensitization and allodynia, events characteristic of migraine pathology. In contrast, CGRP release within the brain is likely to function in an anti-nociceptive capacity. Given the role of CGRP in migraine pathology, the potential of CGRP receptor antagonists in the treatment of migraine has been investigated. Towards this end, the non-peptide CGRP receptor antagonists olcegepant and telcagepant have been shown to be effective in the acute treatment of migraine. While telcagepant is being pursued as a frontline abortive migraine drug in a phase III clinical trial, an oral formulation of a novel CGRP receptor antagonist, BI 44370, is currently in phase II clinical trials. Encouragingly, data from clinical studies on these compounds have clearly demonstrated the potential therapeutic benefit of this class of drugs and support the future development of CGRP receptor antagonists to treat migraine and possibly other types of chronic pain.