By Marcello Cherchi, MD PhD
For patients
Injected botulinum toxin can make muscles weak, but it can also help with some kinds of headaches. It is sometimes used in people who get lots of migraines.
For clinicians
Overview
Botulinum toxins interfere with the release of presynaptic neurotransmitters and neuropeptides. Limiting the release of presynaptic acetylcholine can cause flaccid paralysis. Limiting the release of cGRP and PACAP 38 can reduce vasodilation, which may be the mechanism underlying the prophylactic efficacy of onabotulinumtoxinA for chronic migraine.
Introduction
Botulinum toxin is a neurotoxin expressed by Clostridium botulinum and related species of bacteria. At toxic levels its main effect is flaccid paralysis. In very small quantities various subtypes of botulinum toxin can have medical applications, including for treatment of muscle spasticity (incobotulinumtoxinA) and for cosmetic purposes (daxibotulinumtoxinA, prabobotulinumtoxinA), or both (abobotulinumtoxinA). One type of botulinum toxin (onabotulinumtoxinA) has also been FDA approved for the treatment of chronic migraine.
Pharmacology
The paralytic effect of botulinum toxins is the result of their effect at peripheral nerve terminals, which impairs presynaptic acetylcholine release at the neuromuscular junction, thereby preventing muscle contraction. This property was leveraged in the treatment of various movement disorders (such as dystonias) and spasticity (such as following a stroke).
When onabotulinumtoxinA is used in the treatment of chronic migraine, its efficacy only marginally correlates with the degree of induced muscle weakness, suggesting that some other pharmacologic mechanism of action must be at play. It appears that onabotulinumtoxinA impairs exocytosis by interfering with the formation of the SNARE (soluble N‑ethylmaleimide sensitive fusion-attachment protein receptor) protein, a protein which is required for the docking, priming and fusion of vesicles (containing neurotransmitters and neuropeptides) with the neuronal synaptic membrane. The involved synaptic vesicles can contain small molecules (such as acetylcholine and glutamate) or neuropeptides (such as calcitonin gene-related peptide, substance P and pituitary adenylate cyclase activating peptide 38) (Burstein et al. 2020). Inhibiting the release of calcitonin gene-related peptide (cGRP) and pituitary adenylate cyclase activating peptide 38 (PACAP 38) at peripheral nerve terminals of meningeal and trigeminal nociceptors is thought to be the main mechanism by which onabotulinumtoxinA influences migraine; these molecules have vasodilatory effects. The efficacy of onabotulinumtoxinA in the treatment of chronic migraine was established in several large studies from the PREEMPT clinical trials (Aurora et al. 2010; Blumenfeld et al. 2010; Diener et al. 2010; Dodick et al. 2010).
Relevance in otoneurology
Insofar as onabotulinumtoxinA has efficacy for treatment of chronic migraine, it may have some role in otoneurology. We have administered onabotulinum toxin injections to several hundred patients for the treatment of chronic migraine, and appreciate its efficacy against actual migraine headache, but are less impressed with its effects on the non-pain components of migraine, particularly migraine associated vertigo.
Cautions and contraindications
Even when used in the minute quantities relevant for migraine prophylaxis, onabotulinumtoxinA can still have muscle paralytic effects, usually affecting the frontalis muscles. Our practice has been to take photographs of patients’ faces prior to administering injection in order to track this potential complication.
If administered too frequently there is some risk of a patient developing neutralizing antibodies against botulinum toxin, though this risk is low, estimated in one study to affect 1.28% of patients (Naumann et al. 2010).
References
Aurora SK, Dodick DW, Turkel CC, DeGryse RE, Silberstein SD, Lipton RB, Diener HC, Brin MF, Group PCMS (2010) OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia 30: 793-803. doi: 10.1177/0333102410364676
Blumenfeld A, Silberstein SD, Dodick DW, Aurora SK, Turkel CC, Binder WJ (2010) Method of injection of onabotulinumtoxinA for chronic migraine: a safe, well-tolerated, and effective treatment paradigm based on the PREEMPT clinical program. Headache 50: 1406-18. doi: 10.1111/j.1526-4610.2010.01766.x
Burstein R, Blumenfeld AM, Silberstein SD, Manack Adams A, Brin MF (2020) Mechanism of Action of OnabotulinumtoxinA in Chronic Migraine: A Narrative Review. Headache 60: 1259-1272. doi: 10.1111/head.13849
Diener HC, Dodick DW, Aurora SK, Turkel CC, DeGryse RE, Lipton RB, Silberstein SD, Brin MF, Group PCMS (2010) OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia 30: 804-14. doi: 10.1177/0333102410364677
Dodick DW, Turkel CC, DeGryse RE, Aurora SK, Silberstein SD, Lipton RB, Diener HC, Brin MF, Group PCMS (2010) OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache 50: 921-36. doi: 10.1111/j.1526-4610.2010.01678.x
Naumann M, Carruthers A, Carruthers J, Aurora SK, Zafonte R, Abu-Shakra S, Boodhoo T, Miller-Messana MA, Demos G, James L, Beddingfield F, VanDenburgh A, Chapman MA, Brin MF (2010) Meta-analysis of neutralizing antibody conversion with onabotulinumtoxinA (BOTOX(R)) across multiple indications. Mov Disord 25: 2211-8. doi: 10.1002/mds.23254
