Mechanism of Action of OnabotulinumtoxinA in Chronic Migraine: A Narrative Review

Abstract

Objective: To review the literature on the mechanism of action of onabotulinumtoxinA in chronic migraine.

Background: OnabotulinumtoxinA is a chronic migraine preventive treatment that significantly reduces headache frequency. The traditional mechanism described for onabotulinumtoxinA - reducing muscle contractions - is insufficient to explain its efficacy in migraine, which is primarily a sensory neurological disease.

Methods: A narrative literature review on the mechanism of action of onabotulinumtoxinA in chronic migraine.

Results: Following injection into tissues, onabotulinumtoxinA inhibits soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE)-mediated vesicle trafficking by cleaving one of its essential proteins, soluble N-ethylmaleimide-sensitive fusion attachment protein (SNAP-25), which occurs in both motor and sensory nerves. OnabotulinumtoxinA inhibits regulated exocytosis of motor and sensory neurochemicals and proteins, as well as membrane insertion of peripheral receptors that convey pain from the periphery to the brain, because both processes are SNARE dependent. OnabotulinumtoxinA can decrease exocytosis of pro-inflammatory and excitatory neurotransmitters and neuropeptides such as substance P, calcitonin gene-related peptide, and glutamate from primary afferent fibers that transmit nociceptive pain and participate in the development of peripheral and central sensitization. OnabotulinumtoxinA also decreases the insertion of pain-sensitive ion channels such as transient receptor potential cation channel subfamily V member 1 (TRPV1) into the membranes of nociceptive neurons; this is likely enhanced in the sensitized neuron. For chronic migraine prevention, onabotulinumtoxinA is injected into 31-39 sites in 7 muscles of the head and neck. Sensory nerve endings of neurons whose cell bodies are located in trigeminal and cervical ganglia are distributed throughout the injected muscles, and are overactive in people with migraine. Through inhibition of these sensory nerve endings, onabotulinumtoxinA reduces the number of pain signals that reach the brain and consequently prevents activation and sensitization of central neurons postulated to be involved in migraine chronification.

Conclusion: OnabotulinumtoxinA likely acts via sensory mechanisms to treat chronic migraine.

Keywords: botulinum; headache; migraine; trigeminal system.

Fig. 1

Mechanism of onabotulinumtoxinA at the synapse. The top panel shows fusion of large dense core synaptic vesicles with the nerve terminal membrane in the absence of onabotulinumtoxinA. By step 4, neurotransmitters contained in the synaptic vesicles are released into the synapse and receptors/ion channels are inserted into the nerve terminal membrane. The bottom panel shows the steps of onabotulinumtoxinA action at nerve terminals. The end result is that synaptic vesicles cannot fuse with the nerve terminal membrane, preventing release of neurotransmitters at the synapse, and inhibiting insertion of receptors/ion channels into the nerve terminal membrane.

Fig. 2

Neuroanatomy relevant to onabotulinumtoxinA injections sites. (A) Nerves originating from the trigeminal ganglion innervate intracranial structures and extend extracranially through cranial sutures. Spinal nerves originating from cervical dorsal root ganglia 2 and 3 innervate pericranial muscles and extend intracranially through cranial sutures, emissary canals, and fissures. (B) Extracranial injection sites correspond to anatomical region of extracranial nerves, many of which are adjacent to cranial sutures, emissary canals, and fissures.