146
ISSN: 2763-5724 / Vol. 05 - n 04 - ano 2025
USE OF BOTULINUM TOXIN TYPE A IN THE TREATMENT OF
MIGRAINE
Maykon Hayak Pereira Lopes1
Abstract: Patients with migraine often experience impacts on their personal, social, and professional
lives. The disease not only impacts the individual’s quality of life but also results in costs for the
healthcare system and society. Despite the impact on quality of life and the costs generated for
society, the disease remains underestimated, with old, nonspecic treatments of moderate efcacy
and frequent adverse effects, which limits patient adherence (NACAZUME, 2019). Recently, the
administration of botulinum toxin type A (BTA) has been studied as an alternative to reduce long-
term adverse effects observed with other prophylactic agents (PIOVESAN et al, 2017). Therefore,
the objective of this study is to analyze the efcacy of migraine treatment with BTA. To this end, a
systematic review of the literature on the use of BTA in migraine prophylaxis was conducted. Patients
treated with botulinum toxin type A were observed to have signicantly fewer migraine attacks per
month, reduced severity, fewer days using acute medications, and a reduced incidence of migraine-
associated vomiting.
Keywords: Botulinum toxin type A, migraine, pain.
1 Anesthesiologist certied by the Brazilian Society of Anesthesiology, he graduated in Medi-
cine from the University Center of Espírito Santo (UNESC) and completed a Medical Residency in
Anesthesiology. He also works as a Medical Residency Teacher in Anesthesiology at HMSJ.
INTRODUCTION
Migraine is a primary neurological disorder, in which episodes of debilitating headache are
accompanied by sensory changes, which can occur episodic or chronically. Migraine attacks are
disabling and limiting, causing a great impact on the lives of people who suffer from the disease.
147
ISSN: 2763-5724 / Vol. 05 - n 04 - ano 2025
Patients who have migraine often experience impacts on their personal, social, and professional
lives. The disease reects not only on the individual’s quality of life, but also results in costs for
the health system and society, both direct and indirect (NACAZUME, 2019). It is estimated that the
economic impact of migraine in Brazil can add up to 23.3 billion reais annually with indirect costs
alone (OLIVEIRA et al, 2019).
Despite the impact on quality of life and the costs generated for society, the disease remains
underestimated, with old, non-specic, medium-effective treatments, with frequent adverse effects,
which limits patient adherence (NACAZUME, 2019). Recently, the administration of botulinum toxin
type A (TBA) has been studied as an alternative to reduce long-term adverse effects, which are
observed with other prophylactic agents (PIOVESAN et al, 2017). It is believed that its mechanism
of action consists of blocking the release of neurotransmitters associated with the origin of pain
and consequent action of the central nervous system to inhibit and reverse the central sensitization
existing in chronic migraine.
Superior tolerability and efcacy have been demonstrated in various migraine outcomes in
many controlled trials and real-life studies. BTA has been shown to be a safe and effective treatment for
chronic migraine and possibly high-frequency episodic migraine (YUAN et al, 2020). Adverse effects
are rare, transient, and mild, the most frequent being: muscle weakness in the neck and shoulders,
post-application headache, facial asymmetries, and pain at the injection site. When compared to other
drugs used in the treatment of migraine, the toxin proved to be equivalent in efcacy and promoted
better tolerability and adherence. In addition, it demonstrates a prolonged action in the body, and its
results can be maintained for a few months (NACAZUME, 2019).
METHODOLOGY
This article is a systematic review of the literature on the use of botulinum toxin type A in
migraine prophylaxis. The review is based on articles available in databases such as PubMed, Bvsalud
148
ISSN: 2763-5724 / Vol. 05 - n 04 - ano 2025
and SciELO, using specic keywords. The included studies were published in Portuguese or English,
and followed specic inclusion and exclusion criteria. The review process included ve steps: dening
objectives, identifying relevant studies, selecting studies, mapping data, and interpreting results.
THEORETICAL FRAMEWORK
The initial idea for the use of Botulinum in migraine was after observations by Binder WJ,
who noticed a reduction in migraine pain symptoms in patients who received Botox® injections
in the head and neck muscles during cosmetic procedures. In 2000, the results of an open-label,
uncontrolled study conducted by Binder that demonstrated the efcacy and safety of Botox® as a
therapeutic agent for migraine prevention were published. In the same year, a randomized, double-
blind, placebo-controlled study was carried out, which conrmed the efcacy of botulinum in
preventing migraine. Since then, several clinical trials and meta-analyses have shown that botulinum
toxin injections effectively reduce the frequency, severity, and duration of headaches in patients with
chronic migraine (AISHA et al, 2023).
Botulinum toxin (TB) is produced by the gram-positive and anaerobic bacterium Clostridium
botulinum, belonging to the Clostridiaceae family, developed in an amine medium and yeast extract.
Currently, eight immunologically distinct serotypes of botulinum toxin have been identied, of these,
seven serotypes (A, B, C1, D, E, F and G) are classied as neurotoxins that differ serologically due to
their phenotypic and genetic characteristics. Type A and B neurotoxins have been widely used both in
aesthetics and in therapeutic procedures. However, only type A neurotoxin, commercially presented
as BOTOX® or OnabotulinumtoxinA, is used in migraine prophylaxis (ARAUJO et al, 2017).
Toxin type A (TBA) is divided into ve subtypes (A1, A2, A3, A4, A5) that differentiate
according to amino acid sequences, and these differences may determine the immunological and
biological properties of the toxin. Among the ve subtypes, only A1, A2 and A5 are puried forms
that have been analyzed at an amino acid sequencing level (METELO et al, 2014). The purication
149
ISSN: 2763-5724 / Vol. 05 - n 04 - ano 2025
of the toxin is extremely important to avoid any type of adverse reactions and prevent the increase in
antigenicity, and for this it is essential to leave the toxin free of ribonucleic acids and contaminating
materials by removing these residues. This process occurs through precipitation of the culture solution
in an acid medium, until the acquisition of a crystalline compound formed by a high molecular
weight protein associated with hemagglutin. The acquired compound is redissolved in saline solution
integrating albumin and then sterile ltered before vacuum freezing (ARAUJO et al, 2017).
The neurotoxins produced by C. botulinum are synthesized in the form of a 150 kDa
polypeptide chain, composed of a 50 kDa light chain and a 100 kDa heavy chain joined by a non-
covalent disulde bond, associated with a zinc atom. The heavy chain can be functionally divided into
two domains, an amine terminal domain, with cellular and homologous function in the various types
of toxin, and a carboxyl terminal domain, associated with membrane fusion activity and ion channel
formation. The toxicity of TB is due to the activity of a zinc-dependent metalloprotease, located in
the light chain. This chain has a proteolytic activity that cleaves the target neuronal proteins, that is, it
cleaves the SNARE (soluble N-ethylmaleimide-sensitive fusion attachment protein receptor) complex,
made up of complex proteins that are critical for the release of the neurotransmitter acetylcholine
(ACh). After its synthesis, this molecular part is associated with non-toxic proteins, which have, among
other properties, hemagglutinin. These proteins associate in order to stabilize and protect molecules
from temperature changes, pH decreases, and enzymatic degradation (METELO et al, 2014).
One mechanism of the analgesic effect of TBA is believed to be the inhibition of the release
of certain pain neurotransmitters, such as Substance P, calcitonin gene-related peptide (CGRP), and
glutamate, which are involved in the transmission of pain signals during a migraine attack. A second
mechanism proposed for the analgesic effect of TB is to control the expression of pain receptors on
the surface of neurons. For example, some studies have discussed the role of toxin A in the treatment
of migraine through a mechanism of modulating ion channel expression in nociceptors. Although
the effects of botulinum toxin A on ion channel expression in nociceptors have not been directly
investigated in people with migraine, studies in patients with overactive bladder suggest that it may
150
ISSN: 2763-5724 / Vol. 05 - n 04 - ano 2025
reduce and normalize levels of vanilloid 1 (TRPV1) and purinergic (P2X3) receptors. Botulinum
toxin may also have a third antinociceptive mechanism related to its effect on the central nervous
system. This was demonstrated in rat studies, where the toxin affected pain on the opposite side of the
body to the injection site. The toxin is believed to be transported from the injection site to the central
nervous system, but the mechanism of this action has yet to be claried (AISHA et al, 2023).
Some clinical studies show that BTA is effective soon after the rst application. The
duration of its effects can be observed from four to six months after treatment, depending on the dose,
metabolism of each patient, severity of the clinical condition, capacity for neurological regeneration
and whether or not other therapies are used. The applications are usually made in the frontal area,
nape and temporalis muscle, are administered intramuscularly, with xed doses between 155U and
195U, performed bilaterally, divided from the head and neck on the right and left side. There must be
dened care, the diagnosis must be made by a specialist and the BTA must always be administered
with maximum supervision. In case of overdose due to application in the wrong muscle or by injection,
there is the possibility of administering botulinum antitoxin within 21 hours after application, in order
to block or reduce the effect of TBA (ARAUJO et al, 2017).
Usually, botulinum toxin is well tolerated, and adverse outcomes are rare and short-lived,
directed at muscle weakness and pain at the injection site. The effect decreases with increasing
distance from the injection site, however, when injected in large volume, it can be dispersed to nearby
muscles. Eventually, momentary bruising may occur at the injection site or the injection is followed by
rapid pain or headache [6]. Other, less common, side effects include transient increase in intraocular
pressure and secondary biliary colic. Most events are associated with the region in which the injection
is administered, being one of the crucial points for the occurrence of the reduction of adverse effects
(METELO et al, 2014).
151
ISSN: 2763-5724 / Vol. 05 - n 04 - ano 2025
RESULTS AND DISCUSSIONS
Current migraine preventive therapies are often unsatisfactory due to their limited efcacy,
adverse effects, and drug interactions. To evaluate the efcacy of botulinum toxin A in the prophylactic
treatment of migraine, Silberstein et al. (2001) conducted a double-blind, randomized study with
123 patients who had a history of two to eight moderate to severe migraine attacks per month, with
or without aura. During the study, participants were randomized to receive single administrations
of placebo or botulinum toxin type A, at a dosage of 25 U and 75 U, injected at various sites of
the pericranial muscles. Over the course of 3 months after the injections, participants recorded the
frequency, severity, and occurrence of symptoms associated with migraine. Compared to the placebo
group, subjects in the 25-U TBA treatment group showed signicantly fewer migraine attacks per
month, a reduced severity, a reduced number of days using acute medications, and a reduced incidence
of migraine-associated vomiting. Regardless of the dose, both groups that received the toxin treatment
achieved signicant improvement when compared to the placebo group. In addition, treatment with
TBA was well tolerated, only the group that received the 75 U dosage exhibited a higher rate of
treatment-related adverse events compared to the placebo group (SILBERSTEIN et al, 2001)
Similarly, a study conducted by Anand et al. (2006) suggested some benets in the use of
BTA in migraine patients. The randomized, double-blind, vehicle-controlled study was conducted
in 32 patients with a history of 2 to 8 episodes of migraine attacks per month, with or without aura.
Participants were randomized to receive single administrations of 50-U or placebo injected at multiple
sites of the pericranial muscles. Patients kept diaries in which they recorded outcome measures such
as frequency, severity, and occurrence of symptoms associated with migraine. About 75% of patients
reported complete headache relief after administration of TBA and no improvement was observed
by the placebo group. Quality of life parameters were also evaluated, and showed a considerable
improvement. No adverse effects were reported in either group during the study. It is evident from the
study that pericranial injection of 50-U of TBA showed good efcacy and tolerability as a prophylactic
152
ISSN: 2763-5724 / Vol. 05 - n 04 - ano 2025
agent in migraine (ANAND et al, 2006)
In this same perspective, a study conducted by Robertson and Garza (2012) also reported the
effectiveness of the use of BTA. For four months, 41 migraine patients participated in the research
in order to understand the effectiveness of TB for the treatment of chronic migraine. These patients
were randomly assigned to either 100U of onabotulinumtoxinA or placebo. The doses were xed and
applied to the glabella, temporalis, frontal, suboccipital and trapezius muscles. Patients who used
caffeine and analgesics were excluded. According to the research, headaches decreased signicantly
after the injection of TB-A, with the frequency of reduction of episodes from 13.8 to 10.1 episodes
per month. Comparatively, patients who had been treated with placebo had an increase in migraine
frequency from 14.6 episodes to 15.4 per month (ROBERTSON et al, 2012)
Similar results were demonstrated in a prospective study by Burstein, Dodick, and Silberstein.
In order not to inuence the results intended in this study, patients who only had tension headache,
peripheral nervous system lesions or who had taken opioids were not included. The total number
of patients in this study was then 82 individuals with migraine, mostly women, whose ages ranged
from 21 to 75 years. Participants had a history of migraine attacks, starting at 19 and 21 years of age,
33% had an episodic migraine (about 8 episodes per month) and 67% had chronic migraine (about 26
episodes per month). After administration of TBA, the average number of days of migraine episodes
per month decreased by about 43%. Greater results were observed in patients who classied their
pain as explosive. These results suggest that the efcacy of TB-A in migraine therapy may also be
associated with the type of pain presented by the patient (BURSTEIN et al, 2010).
Although randomized placebo studies have shown its clinical efcacy, the mechanisms by
which it exerts its therapeutic effect are still poorly understood and debated. In this regard, a study
conducted by Sebastianelli et al. (2023) evaluated the cephalic and extracephalic nociceptive and
lemniscal sensory systems in 15 patients with chronic migraine, using electrophysiological techniques
before and after 3 months after a session of pericranial injections of OnabotulinumtoxinA (BoNT-A).
The nociceptive blink reex (nBR), the trigeminal-cervical reex (nTCR), the pain-related cortical
153
ISSN: 2763-5724 / Vol. 05 - n 04 - ano 2025
evoked potential (PREP), and the somatosensory evoked potential of the upper limb (SSEP) were
recorded. Three months after a single session of prophylactic therapy with BoNT-A in migraine
patients, an increase in homolateral and contralateral nBR AUC, an increase in contralateral nBR
AUC habituation slope and nTCR habituation slope, a decrease in 1st and 2nd block of PREP NP
amplitude, and no effect on SSEP were found. These results provide electrophysiological evidence
for the ability of a single session of BoNT-A injections to exert a neuromodulatory effect at the level
of the trigeminal system through a reduction in the entry of meningeal and other trigeminovascular
nociceptors. In addition, by reducing activity in the cortical areas of pain processing, BoNT-A restores
normal functioning of descending pain modulation systems (SEBASTIANELLI et al, 2023).
FINAL CONSIDERATIONS
Current migraine preventive therapies are often unsatisfactory due to their limited efcacy,
adverse effects, and drug interactions. It was observed that patients treated with botulinum toxin
type A had signicantly fewer migraine attacks per month, a reduced severity, a reduced number of
days using acute medications, and a reduced incidence of migraine-associated vomiting. In addition,
the results demonstrated good efcacy and tolerability in the use of BTA as a prophylactic agent in
migraine. Although the use of onabotulinum toxin has shown benets in migraine patients, it has a
higher cost and, therefore, its access is restricted to a few patients, since it is not available in the SUS
or in the list of minimum coverage of health plans (NACAZUME, 2019).
REFERENCES
NACAZUME, J. Treatment and prophylaxis of migraine in Brazil: current scenario and new
perspectives. Final Paper of the Pharmacy-Biochemistry Course of the Faculty of Pharmaceutical
Sciences of the University of São Paulo. São Paulo, 2019.
154
ISSN: 2763-5724 / Vol. 05 - n 04 - ano 2025
OLIVEIRA, A. B.; QUEIROZ, L. P.; PERES, M. F. P. Annual Indirect Costs Secondary to Headache
Disability in Brazil. In IHC 2019 Abstracts. Cephalalgia, v. 39, n. 1_suppl, p. 1–337, 1 set. 2019.
PIOVESAN, E.; CADECARO, P.; PEPE, C. Cost-effectiveness analysis of onabotulinum toxin A
in the preventive treatment of chronic migraine from the perspective of the private health system in
Brazil. Brazilian Journal of Health Economics, v. 9, n. Suppl1, p. 71–80, 2017.
YUAN, H.; SILBERSTEIN, S. The Use of Botulinum Toxin in the Management of Headache
Disorders. Springer, 2020.
AISHA, Z.; ALTYNAY, K.; BAZBEK, D. Beyond aesthetics: expanding the applications of botulinum
neurotoxins in chronic migraine medicine. European Journal of Neuroscience, 2023.
ARAÚJO, L. The use of botulinum toxin in the treatment of migraine. Bachelor’s Degree in
Biomedicine. Brasilia, 2017.
METELO, C. Therapeutic Applications of Botulinum Toxin, 2014. Integrated Master’s Dissertation in
Pharmaceutical Sciences at the Instituto Superior de Ciências da Saúde Egas Moniz, Portugal, 2014.
SILBERSTEIN, S. et al. Botulinum Toxin Type A as a Migraine Preventive Treatment. The Journal
of Head and Face Pain, 2001.
ANAND, K. et al. Botulinum Toxin Type A in Prophylactic Treatment of Migraine. American Journal
of Therapeutics, 2006.
ROBERTSON, E.; GARZA, I. Critical analysis of the use of onabotulinumtoxinA (botulinum toxin
type A) in migraine. Neuropsychiatric Disease and Treatment, 2012.
BURSTEIN, R.; DODICK, D.; SILBERSTEIN, S. Migrain prophylaxis with Botulinum Toxin A is
associated witch perception of headache. NIH, 2010.
SEBASTIANELLI, G. et al. Effects of Botulinum Toxin Type A on the Nociceptive and Lemniscal
Somatosensory Systems in Chronic Migraine: An Electrophysiological Study. Toxins, 2023.
