By Marcello Cherchi, MD PhD
For patients
Botulinum toxins can be injected into muscles to make the muscles weaker. One type of botulinum toxin is also used to help people with chronic migraines. The risk of botulinum toxins is unplanned muscle weakness. If botulinum toxins are injected too often, they may no longer help.
For clinicians
Overview
Botulinum toxin blocks presynaptic release of acetylcholine, and thus can have effects such as muscle paralysis, and reduction of secretions (sialorrhea, axillary hyperhidrosis). Several synthetic botulinum toxins have been FDA approved in the United States (abobotulinumtoxinA, incobotulinumtoxinA, onabotulinumtoxinA and rimabotulinumtoxinB). Research has shown that onabotulinumtoxinA has other mechanisms of action (beyond blocking presynaptic acetylcholine release) which may explain its efficacy as a migraine prophylactic. The main risk of botulinum toxins is undesired muscle weakness. If injected too frequently, there is a risk of developing neutralizing antibodies.
Introduction
Botulinum toxin is a muscle paralytic expressed by the bacterium Clostridium botulinum. Synthetic versions of onabotulinum toxin are used in medicine for a variety of applications, such as to relieve muscle spasticity (in patients who have suffered a stroke), for cosmetic purposes, and for migraine prophylaxis.
Pharmacology
There are several subtypes of botulinum toxin that have received FDA approval for certain indications.
- AbobotulinumtoxinA (marketed in the USA as Dysport®) has received FDA approval for muscle spasticity, dystonia, and cosmetic applications.
- IncoboculinumtoxinA (marketed in the USA as Xeomin®) has received FDA approval for muscle spasticity.
- OnabotulinumtoxinA (marketed in the USA as Botox®) has received FDA approval for muscle spasticity, dystonia, blepharospasm, overactive bladder, neurogenic detrusor overactivity, primary axillary hyperhydrosis and migraine prophylaxis.
- RimabotulinumtoxinB (marketed in the USA as Myobloc®) has received FDA approval for dystonia and sialorrhea.
All botulinum toxins have a similar final common pathway of blocking presynaptic acetylcholine release, but the drugs are not identical (Car et al. 2021).
It was initially unclear how onabotulinumtoxinA could have any efficacy as a migraine prophylactic, but subsequent research showed that this drug has additional mechanisms of action. In particular, it cleaves soluble N‑ethylmaleimide-sensitive fusion attachment protein (SNAP‑25), thereby inhibiting soluble N‑ethylmaleimide-sensitive fusion attachment protein receptor (SNARE) vesicle trafficking. This has several consequences, as Burstein and colleagues explain:
“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” (Burstein et al. 2020).
Adverse effects
The main risk of botulinum toxin is that its muscle paralytic effect may “spread” beyond the injected muscles, causing undesired weakness.
Cautions and contraindications
When onabotulinumtoxinA is used for migraine prophylaxis (see below), the main risk is transient facial weakness, typically lasting weeks.
If onabotulinumtoxinA is administered too frequently, there is a risk of developing antibodies to it (Naumann et al. 2010), rendering subsequent injections ineffective.
A study of a drug safety database maintained by the drug manufacturer (Allergan) over 29 years reported the risk of adverse fetal effects of onabotulinumtoxinA to be “comparable with background rates in the general population” (Brin et al. 2023).
Relevance in otoneurology
The main application of botulinum toxin in otoneurology is in the prophylaxis of chronic migraine, and as of this writing, onabotulinumtoxinA is the only subtype of onabotulinum toxin that has received FDA approval for this purpose.
The use of onabotulinumtoxinA as prophylaxis for chronic migraine was based on the efficacy as demonstrated in the PREEMPT1 (Aurora et al. 2010) and PREEMPT2 (Diener et al. 2010) trials, which have been summarized elsewhere (Dodick et al. 2010). These trials used a standardized set of injection locations (Blumenfeld et al. 2017), though some practitioners may use a modified protocol in their clinical practice (Blumenfeld et al. 2010).
Based on the data regarding onabotulinumtoxinA for general migraine prophylaxis, some practitioners extrapolate its use to migraine associated vertigo, though there have been no systematic studies of this.
Other notes
While the use of other botulinum toxins (besides onabotulinumtoxinA) have been attempted in the treatment of migraine, the studies are much smaller and not systematic (and these drugs have not received an FDA indication for migraine). For example, there are small case series of incobotulinumtoxinA (Ion et al. 2018; Karschney and Greeley 2020; Kazerooni et al. 2015) and case reports of rimabotulinumtoxinB (Fadeyi and Adams 2002).
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
Blumenfeld AM, Silberstein SD, Dodick DW, Aurora SK, Brin MF, Binder WJ (2017) Insights into the Functional Anatomy Behind the PREEMPT Injection Paradigm: Guidance on Achieving Optimal Outcomes. Headache 57: 766-777. doi: 10.1111/head.13074
Brin MF, Kirby RS, Slavotinek A, Adams AM, Parker L, Ukah A, Radulian L, Elmore MRP, Yedigarova L, Yushmanova I (2023) Pregnancy Outcomes in Patients Exposed to OnabotulinumtoxinA Treatment: A Cumulative 29-Year Safety Update. Neurology 101: e103-e113. doi: 10.1212/WNL.0000000000207375
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
Car H, Bogucki A, Bonikowski M, Dec-Cwiek M, Druzdz A, Koziorowski D, Rudzinska-Bar M, Sarzynska-Dlugosz I, Slawek J (2021) Botulinum toxin type-A preparations are not the same medications – basic science (Part 1). Neurol Neurochir Pol 55: 133-140. doi: 10.5603/PJNNS.a2021.0027
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
Fadeyi MO, Adams QM (2002) Use of botulinum toxin type B for migraine and tension headaches. Am J Health Syst Pharm 59: 1860-2. doi: 10.1093/ajhp/59.19.1860
Ion I, Renard D, Le Floch A, De Verdal M, Bouly S, Wacongne A, Lozza A, Castelnovo G (2018) Monocentric Prospective Study into the Sustained Effect of Incobotulinumtoxin A (XEOMIN((R))) Botulinum Toxin in Chronic Refractory Migraine. Toxins (Basel) 10. doi: 10.3390/toxins10060221
Karschney VK, Greeley DR (2020) A Retrospective Cost Analysis of Patients Who Switched from OnabotulinumtoxinA to IncobotulinumtoxinA in a Private Neurology Practice. Am Health Drug Benefits 13: 205-210.
Kazerooni R, Lim J, Ashley Blake P, Lessig S (2015) IncobotulinumtoxinA for Migraine: A Retrospective Case Series. Clin Ther 37: 1860-4. doi: 10.1016/j.clinthera.2015.05.509
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
