Mechanism of Action of OnabotulinumtoxinA in Chronic Migraine

A Narrative Review

Rami Burstein, PhD; Andrew M. Blumenfeld, MD; Stephen D. Silberstein, MD; Aubrey Manack Adams, PhD; Mitchell F. Brin, MD


Headache. 2020;60(7):1259-1272. 

In This Article

Abstract and Introduction


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.


Botulinum neurotoxin type A (BoNTA) is a potent inhibitor of muscle contraction that acts by preventing the release of acetylcholine at the neuromuscular junction. This property led to the development of an injectable formulation, commonly referred to as BOTOX (onabotulinumtoxinA), for the treatment of ocular conditions characterized by focal muscle overactivity, particularly blepharospasm and strabismus.[1,2] Subsequently, the clinical use expanded and onabotulinumtoxinA became a first-line treatment for cervical dystonia and a treatment for upper and lower limb spasticity in adults[3] and pediatrics. In clinical trials, treatment of cervical dystonia[4–6] and spasticity[7–9] with onabotulinumtoxinA reduced both muscle contractions and pain. The clinical use of onabotulinumtoxinA expanded to other conditions that involve abnormal muscle contractions.[10] In the early 1990s, some patients described improvement in their migraine following treatment of facial lines with onabotulinumtoxinA.[11] Since migraine is primarily a sensory disease, these reports raised the possibility that onabotulinumtoxinA had an ability to block activation of nociceptive pathways. The literature on onabotulinumtoxinA has largely focused on its mechanism of action at the neuromuscular junction, and there is a gap in understanding how it may affect the sensory system as well.[12] Thus, this narrative literature review aims to summarize our current understanding of the mechanism of action for onabotulinumtoxinA for the treatment of chronic migraine.

In 2010, 2 double-blind placebo-controlled trials confirmed onabotulinumtoxinA's effectiveness for the prevention of headaches in chronic migraine patients. In these trials, a migraine-specific injection paradigm (155–195 U, 31–39 injection sites in head and neck muscles, which correspond to areas innervated by sensory nerves) resulted in significant reduction of headache and migraine days per month compared to placebo (Table 1).[13] These results led to the regulatory approval for chronic migraine in 2010, and lent credence to the idea that onabotulinumtoxinA treatment could modulate sensory neurons,[14] which is the focus of this review.