Insights into the mechanism of onabotulinumtoxinA in chronic migraine

Abstract

OnabotulinumtoxinA has recently been approved by regulatory agencies in the UK and United States for treatment of chronic migraine based on data generated from the PREEMPT studies. As such, onabotulinumtoxinA is the only prophylactic therapy specifically approved for chronic migraine. Most headache clinicians would agree that acute episodic migraine and chronic migraine differ in their pathophysiology, etiology, diagnosis, and response to pharmacological as well as nonpharmacological therapies. Of the 7 botulinum neurotoxin serotypes, botulinum neurotoxin type A (onabotulinumtoxinA) has been the most thoroughly investigated in preclinical and clinical studies. Based on preclinical studies, onabotulinumtoxinA is known to inhibit the release of excitatory neurotransmitters from both motor and sensory neurons by preventing vesicle fusion to the cell membrane. In addition to the well-documented myorelaxant effects of this neurotoxin, onabotulinumtoxinA can exert a direct analgesic effect that likely involves inhibition of primary and secondary nociceptive neurons. The inhibitory effects of onabotulinumtoxinA are also likely to involve suppressing the activity of myogenic trigger points and decreasing the persistent nociceptive barrage that promotes and maintains central sensitization. This article describes possible mechanisms to explain how onabotulinumtoxinA functions as a therapy for chronic migraine and considers why treatment with the neurotoxin is not effective in some chronic migraineurs.

Fig 1

Proposed cellular targets of onabotulinumtoxinA. Injection of neurotoxin in specific sites in the head, neck, and shoulders would result in endocytosis in motor neurons and sensory neurons. Internalization of onabotulinumtoxinA in motor neurons would inhibit release of acetylcholine at the neuromuscular synapse and suppress tonic contractions. OnabotulinumtoxinA would also indirectly repress the release of the proinflammatory mediators including protons (H+), calcitonin gene-related peptide (CGRP), and glutamate. This relase occurs with muscle contraction and is known to promote sensitization and activation of nociceptive neurons. Similarly, onabotulinumtoxinA internalization in sensory neurons would block the release of neuropeptides and other inflammatory mediators that promote peripheral sensitization at the level of the muscles and within trigeminal ganglia. In addition, internalization of the neurotoxin would inhibit the release of proinflammatory mediators at the level of the spinal cord, and thus, suppress activation of second-order nociceptive neurons and glial cells implicated in central sensitization.