Implications of multimechanism therapy

Migraine headache is a neurovascular disorder of intracranial origin that involves meningeal blood vessels and the pain fibers that innervate them. This theory has originated from reports that electrical and mechanical stimulation of dural vasculature (but not the surface of the brain) produced referred head pain in awake patients undergoing craniotomy:1,2 (a) periorbital pain, by stimulating the superior sagittal sinus or blood vessels of the floor of the anterior fossa; (b) parietal/temporal pain, by stimulating the middle meningeal artery; and (c) occipital pain, by stimulating the dura at the floor of the posterior fossa and the sigmoid, transverse, and occipital sinuses. No sensation other than pain was evoked by stimulation of these structures, and stimulation of nonvascular areas of the dura was largely not painful. These findings reflect dural innervation patterns whereby sensory nerves that originate in trigeminal and upper cervical ganglia closely follow meningeal blood vessels but not nonvascular areas of the dura.2 In the 1980s the nature of dural innervation was proved to be nociceptive when it was shown that the dura is richly innervated by unmyelinated (C-fibers) and thinly myelinated (Aδ-fibers) axons that originate in the trigeminal ganglion and in C1–C3 dorsal root ganglia,3–6 and that these pain fibers contain vasoactive neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP).7,8 These lines of evidence promoted the theory that the headache phase of migraine is mediated by activation of nociceptors that innervate meningeal blood vessels (i.e., meningeal nociceptors), and provided the basis for developing animal models of neurovascular head pain with intracranial origin. In recent years it has become apparent that many types of prolonged or chronic pain are associated with long-lasting activation and sensitization of peripheral nociceptors and/or central nociceptive neurons in the dorsal horn. By incorporating these concepts into basic …