Botulinum toxin in the treatment of myofascial pain syndrome
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
REVIEW DOI: 10.20986/resed.2021.3902/2021
Botulinum toxin in the treatment
of myofascial pain syndrome
Toxina botulínica en el tratamiento del síndrome
de dolor miofascial
D. C. Nájera Losada1, J. C. Pérez Moreno1 and A. Mendiola de la Osa2
1
Unidad del Dolor, Hospital Universitario Virgen de las Nieves. Granada, España. 2Unidad del Dolor,
Hospital Universitario Puerta de Hierro. Majadahonda, Madrid, España
ABSTRACT RESUMEN
Botulinum toxin injections have been used in pain Las infiltraciones con toxina botulínica han sido uti-
treatment associated with pathologies such as focal lizadas en el tratamiento del dolor asociado a múltiples
dystonia, spasticity, headaches and myofascial pain. patologías, como distonías focales, espasticidad, cefaleas
However, results from botulinum toxin trials in myofas- y dolor miofascial. Sin embargo, los resultados de los
cial pain syndrome (MPS) are contradictory. diferentes estudios realizados con toxina botulínica en el
The objective of this paper is to analyze the evidence síndrome de dolor miofascial (SDM) son contradictorios.
of botulinum toxin type A (BTA) efficacy compared to pla- El objetivo de la presente revisión es analizar la evidencia de
cebo in myofascial pain management. Literature search la eficacia de la toxina botulínica tipo A (TBA) frente a place-
was performed in PubMed, Web of Science (WoS), bo en la disminución del dolor crónico de origen miofascial.
Scielo and Scopus, using the following key words: myo- Se realizó una búsqueda bibliográfica en PubMed,
fascial pain, trigger point, botulinum toxin and botox. Web of Science (WoS), Scielo y Scopus, utilizando las
Eleven clinical trials comparing BTA versus normal saline siguientes palabras clave: dolor miofascial, punto gatillo,
toxina botulínica y bótox. Los estudios que cumplieron los
met the inclusion criteria. Although most of the clinical
criterios inclusión fueron once ensayos clínicos que com-
trials analyzed cannot demonstrate a BTA superiority,
paraban la TBA frente a solución salina normal (SSN).
it would not be correct to conclude that botulinum toxin
Aunque en la mayoría de los ensayos clínicos ana
is not indicated in miofascial pain treatment due to the
lizados no podemos evidenciar un beneficio de la TBA
great heterogeneous patient selection, variability in BTA
frente a SSN, no sería acertado concluir que la toxina
doses, different trigger points injections techniques, botulínica no está indicada en el tratamiento de dolor aso-
variability in trials duration, and absence of cost-effective ciado al SDM, dado que existe una selección de pacien
analysis. tes muy heterogénea, hay una gran variabilidad en la
More specific clinical trials are required using homo- dosis de toxina botulínica, se usan diferentes técnicas
geneous samples to provide conclusive evidence for BTA de infiltración de los puntos gatillo (PG), la duración de
in the MPS treatment. los estudios es variable y no hay estudios que realicen
un análisis costo-efectivo.
Se necesitan ensayos clínicos más específicos, con
muestras más homogéneas, que nos permitan sacar con-
clusiones acerca del papel de la TBA en el tratamiento
del SDM.
Key words: Myofascial pain, trigger point, botulinum Palabras clave: Dolor miofascial, punto gatillo, toxina
toxin, botox. botulínica, bótox.
Received: February 15, 2021
Accepted: April 17, 2021
Nájera Losada DC, Pérez Moreno JC, Mendiola de la Osa A. Botulinum
toxin for the treatment of myofascial pain syndrome. Rev Soc Esp Dolor. Correspondence: Diana Carolina Nájera Losada
2021;28(2):100-109 diananajeralosada@gmail.com
100BOTULINUM TOXIN FOR THE TREATMENT OF MYOFASCIAL PAIN SYNDROME 101
INTRODUCTION In the motor nerve ending, there is endocytosis of the
molecule mediated by its heavy chain. Subsequently,
Myofascial pain syndrome (MPS) is a very common the disulfide bridge between the heavy and light chains
musculoskeletal condition in the general population and is broken, causing the release of the light chain to the
underdiagnosed on several occasions. It is defined as cytosol. This will result in the rupture of the soluble
a regional muscle pain associated with the presence of NSF attachment protein receptors (SNAREs) that
TP. In turn, these TP are described as a tense muscular attach the synaptic vesicles to the cell membrane.
band, hypersensitive, that when palpated, generates a Therefore, the binding and subsequent fusion of these
referred pain and a muscular contraction (1,2). vesicles within the membrane is avoided, preventing
MPS can be classified as a primary syndrome where the release of neurotransmitters such as acetylcholine.
there is no association with other conditions or se This process takes two to three days to establish itself,
condary syndrome occurring in conjunction with other and after this time, muscle weakness begins to appear.
painful conditions such as whiplash syndrome, root pain, Clinical improvement is seen toward the third week, with
osteoarthritis, fibromyalgia, and fractures (3). a maximum effect observed two months after injection.
The exact etiology and pathophysiology of myofascial Muscle weakness may last six months; however, the
TP are still unknown. It has been suggested that its de- clinical effect lasts on average three months, which is
velopment is related to an excess release of acetylcho- the time it takes to regenerate nerve ending by creating
line, producing a sustained muscle contraction with the new connections with the motor endplate (5).
subsequent formation of a TP (1). This sustained muscle In patients with dystonia, pain improvement has been
contraction leads to an increase in the concentration of seen before five days after the administration of the to
nociceptive and inflammatory neurotransmitters within xin or even after three months of its injection, indicating
TP, making it a permanent nociceptive stimulus facili- that there is a different analgesic effect than the one
tating central sensitization, generating a chronic pain described above (5).
picture (1). Although BTA inhibits the release of neurotransmi
In the early stages of MPS, central sensitization can be tters in peripheral nociceptors, not all nerve cells exhibit
reversed with pharmacological treatment (using NSAIDs, receptors for the toxin, therefore, the effect at the level
corticosteroids, tricyclic antidepressants, vasodilators, of sensory nerve endings is not as predictable as that
muscle relaxants) or by puncturing TP with local anes- observed in motor nerve endings (5).
thetic (with or without corticosteroid), dry puncture, and In migraine, where there is sensitization of the tri-
physiotherapy. The results may be incomplete with per- geminal system, subcutaneously administered BTA
sistent pain in TP because the long-term benefit of these decreases pain perception and intensity, secondary hy-
treatments is transient. Botulinum toxin was chosen (out peralgesia, and blood flow in the affected area. In this
of the data sheet) looking for long-term treatment due to case, the effect of BTA would be mediated by its action
its long duration of action and its localized effect on TP on C fibers and the TRPV1 receptor (5).
itself, which theoretically could be effective by avoiding re- An additional effect of BTA has been described in hemi-
currences because it would cause the decrease of elec- facial spasm because the toxin is taken with high avidity by
trical activity at this level, inhibiting muscle contraction the nerve endings of the muscles that show higher activity,
and preventing recurrence of the painful point. Botulinum such as those involved in involuntary movements (6).
toxin type A (BTA) has also been used in several cases In models of inflammatory pain induced by the ad-
of chronic pain associated with focal dystonia, spasticity, ministration of formalin in the rat’s leg, BTA has been
and headaches (1,4,5). found to reduce substance P and glutamate release.
BTA has a fascinating history; it was described in At the peripheral level, BTA decreases inflammation and
Germany by Justinus Kerner in the 18th century (as local glutamate accumulation, improving pain rates in
a picture of what we now know as botulism) after an assessment scales in the rat. At the central level, BTA
epidemic produced by the consumption of poisoned sau- travels through the spinal cord, inhibiting the release
sages (botulus in Latin means sausage). Kerner thought of substance P from spinal neurons. In the model of
that there was a toxin affecting autonomic and motor ischemic pain secondary to sciatic nerve ligation in the
nerve conduction that could be effective in hyperexci rat, BTA injection into the affected leg has shown a
tability situations if used in low doses. Hypotheses about reduction in the release of nociceptive interleukins and
potential therapeutic uses of the toxin subsequently be- a compensatory increase in antinociceptive interleukins
gan, but it was not until 1977 that the Food and Drug with the subsequent improvement in the pain behaviors
Administration of the United States (FDA) authorized of the animal. In in vitro studies, the application of BTA
Alan B. Scott to study BTA in humans. Scott founded the in cultured cells inhibits the release of the calcitonin
company Oculinum that would produce the BTA, and this gene-related peptide (CGRP), glutamate, and other pain
allowed the other researchers to conduct studies with mediators, very interesting data because they can be
this compound. Before the end of 1980, BTA was al- extended to humans. Another interesting effect of BTA
ready widely used to treat strabismus, blepharospasm, has been described, causing inhibition of sodium chan-
dystonia, hemifacial spasm, and spasticity. At present, nel function in sensory neurons and in the periphery,
the indications of BTA have expanded exponentially, due which can play a very important role in pain transmission.
in part to its mechanism of action because it is now Recently, studies in animals and healthy volunteers su
known that BTA acts on multiple levels, as we will ex- ggest a central analgesic effect of BTA because they have
plain later (6). shown improvement of pain in the two affected limbs with
BTA alters muscle contraction by preventing acetylcho- the unilateral application of the toxin, but further studies
line from being released at the neuromuscular junction. are needed to confirm these findings (7).102 D. C. NÁJERA LOSADA ET AL Rev. Soc. Esp. del Dolor, Vol. 28, N.º 2, Marzo-Abril 2021
As a summary of the above, BTA could act on mul- Initially, the search for these words was conducted in
tiple levels, affecting pain transmission in the central the title, abstract, and keywords, finding 452 articles
and peripheral nervous system, decreasing behavioral (Figure 1). By excluding book chapters, conference co
manifestations secondary to pain through a wide va mmunications, and limiting the search to human stu
riety of mechanisms; among these, its effect mediating dies, presented in English or Spanish, published from
nociception is almost as important as its effect at the January 2000 to May 2020, we found 346 articles.
level of the neuromuscular junction. We obtained 65 articles by focusing the search of key-
Furthermore, physical therapy has been shown to be words on the titles of the articles found. After reading
beneficial in MPS. However, some patients have difficulty the titles of the articles, we found that there were seve
completing physiotherapy due to severe pain from a ral meta-analyses related to craniofacial myofascial pain
spasm refractory to conventional treatment. Therefore, (mainly associated with temporomandibular disorders
a relaxation maintained with BTA could relieve pain in a or dysfunction), so studies related to this anatomical
prolonged manner, allowing patients to complete physi- region were excluded from the present review; there-
cal rehabilitation programs that eventually produce long- fore, we obtained 49 articles; of these were excluded:
term pain relief (1). review articles, letters to the editor, editorials, clinical
However, the efficacy of BTA remains unknown due cases and case series, finally leaving 27 articles to
to the limited number of studies, size of samples used, read in full text.
and variability of the doses used for each TP (2,8). A total of 16 out of the 27 articles (Table I) were dis-
Adverse effects of BTA are well documented and carded because they did not meet the inclusion criteria
include: Excessive muscle weakness, weakness of the of this review. Five clinical trials were not included: The
muscles adjacent to the infiltrated muscles, weakness first clinical trial evaluated the effect of motor versus
of muscles in other body areas due to hematogenous sensory stimulation associated with BTA in TP (9), the
spread, dry mouth (xerostomia), decreased sweating second clinical trial compared NSS versus local anes-
and ocular lubrication, rash, flu-like symptoms, brachial thetic with corticosteroid (10), the third clinical trial
neuritis-like syndrome, ecchymosis, bleeding, and pain compared BTA alone or associated with lidocaine (11)
at the injection site (1). Most of the side effects obtained developed without apparent cause, being refractory to
in studies with BTA in the MPS are related to flu-like pharmacological and physical treatments, and is accom-
symptoms and localized muscle weakness, which are panied by the presence of trigger points and palpable
transient and usually resolved within 7 to 10 days (1). taut bands in the muscle. Its prevalence is estimated to
OBJECTIVE
Initial Search:
452 articles
The main objective of this review is to assess the
Only publications in English
efficacy of BTA versus normal saline solution (NSS)
and Spanish were
(placebo) in reducing chronic pain of myofascial origin. considered. We exclude
conference articles
STUDIES CONSIDERED IN THIS REVIEW 346 articles: keywords
included in title, abstract
Only randomized, double-blind, controlled clinical tri- and keywords
The search for keywords
als were considered to use studies with low biases or was limited exclusively
confounding variables. to the title and
craniofacial pathology
was excluded
STUDIES THAT WERE NOT CONSIDERED 49 articles
IN THIS REVIEW to read abstracts
Not included: Review
Clinical trials with a sample of less than 10 patients articles, letters to the
in any of the groups to compare, observational studies, editor, editorials, clinical
clinical case studies, and in general any type of study cases, and case series
that was not randomized. Studies comparing BTA with
27 articles
another type of injection that had a medication (e.g., to read the full text
local anesthetic or corticosteroid) were also not taken 16 studies were discarded
into account. Studies related to myofascial pain of cra- (see Table I):
niofacial or pelvic origin were excluded from this review. 5 clinical trials,
3 observational studies,
3 retrospective studies,
4 open trials
LITERATURE SEARCH and 1 single-blind trials
11 Clinical trials
for the review
A literature search was performed in PubMed, Web of
(see Table II)
Science (WoS), SciELO, and Scopus, using the Boolean
operators AND/OR and the following keywords: Myo
fascial pain, trigger point, botulinum toxin, and Botox. Fig. 1. Flowchart for the search of review studies.BOTULINUM TOXIN FOR THE TREATMENT OF MYOFASCIAL PAIN SYNDROME 103
vary between 30 and 85 %. The psoas, quadratus lum- of their pain on a visual analog scale (VAS and 1 sin-
borum and pyramidal muscles are the most frequently gle-blind clinical trials (23).
involved in the pelvic girdle MPS. One of the main alter- Finally, 11 clinical trials (Table II) comparing BTA ver-
natives to treat MPS is botulinum toxin type A (BT, the sus NSS were considered for this review.
fourth clinical trial compared BTA versus bupivacaine
(12), and the fifth clinical trial compared BTA versus
methylprednisolone (13); 3 prospective observational ANALYSIS OF CLINICAL TRIALS INCLUDED
studies (14-16) open-label, single-center chart review.
Charts of all patients who received either BTX-A or Although the quality of the clinical trials used for this
BTX-B for MPS between January and November 2001 review is very good (they score equal to or above four
were included in the review. Patients rated the intensity on the Jadad scale), their analysis is complex because
TABLE I
STUDIES DISCARDED FROM THIS REVIEW
Author Year Reason to discard the study Study results Conclusion
A clinical trial comparing BTA
BTA is superior to
Porta 2000 versus methylprednisolone. Positive
methylprednisolone
There is no placebo group.
Wheeler BTA decreases multifocal myofascial
2001 Retrospective cohort study Positive
y cols. pain for long-term
A retrospective study comparing
Carrasco
2003 BTA vs. mixing (local anesthetic BTA has a longer effect than mixing Positive
y cols.
with corticosteroid)
BTA achieves a larger decrease
An open clinical trial comparing BTA
Lang 2003 in VAS than TBB, without systemic Positive
and TBB
adverse events
Positive correlation of BTA and VAS/
De Andrés An open clinical trial analyzing
2003 physical disability/depression-anxiety Positive
y cols. the efficacy of BTA
scale
Kamanli A single-blind clinical trial comparing Lidocaine is more cost-effective
2004 Negative
y cols. BTA vs. lidocaine vs. dry puncture than BTA and dry puncture
Clinical trial with sample of less
Graboski Bupivacaine is more cost-
2005 than 10 patients and without Negative
y cols. effective than BTA in MPS
placebo group
Castro
2006 Prospective observational study BTA is effective and safe Positive
y cols.
Torres BTA is effective in MPS by decreasing
2010 Prospective observational study Positive
y cols. the VAS and improve the quality of life
Jerosch An open clinical trial comparing Both doses of BTA are effective in
2012 Positive
y cols. different doses of BTA relieving pain
A clinical trial comparing sensory Sensory stimulation was superior
Seo Not
2013 versus motor electrical stimulation to motor stimulation in the
y cols. applicable
associated with BTA improvement of VAS
Avendaño- BTA with physiotherapy should be
2014 Retrospective study Positive
Coy y cols. considered in refractory MPS
Velazquez- Clinical trial comparing Significant difference between
2014 Positive
Rivera y cols. BTA vs. BTA + lidocaine the two groups on the third day
Cartagena- Two-phase study: BTA decreases the VAS for an
2016 Positive
Sevilla y cols. Retrospective and open clinical trial extended period
Improvement of the VAS and quality
An observational study evaluating the
Kim y cols. 2018 of life in the MPS. Safe and effective Positive
safety and efficacy of BTA (Nabota®)
BTA
Clinical trial comparing NSS
Roldan It is preferable to use NSS
2020 vs. mixture (local anesthetic Negative
y cols. for TP infiltration
with corticosteroid)
TP: Trigger point. MPS: Myofascial pain syndrome. VAS: Visual analog scale. BTA: Botulinum toxin type A. NSS: Normal saline.104 D. C. NÁJERA LOSADA ET AL Rev. Soc. Esp. del Dolor, Vol. 28, N.º 2, Marzo-Abril 2021
many aspects vary in each study: Design, inclusion crite- In contrast with the Göbel et al. study, which infiltrated
ria, location of TPs, number and location of infiltrations, ten TP, this study did not include patients with more
duration of the study, toxin dose, and method for mea- than five active TP at the neck and shoulder levels (maxi-
surement of results. In addition, not all report whether mum five TP could be infiltrated). These inclusion criteria
they maintained routine analgesia, initiation of physical could lead us to think that the severity of the MPS in
therapy, rescue medication, and other complementary these patients was lower, and considering that three
therapies throughout the studies, which poses a major analgesic drugs associated with physical therapy were
challenge in drawing conclusions about the usefulness administered concomitantly, we could see that a pa-
of BTA in MPS. tient with a mild MPS (as presented in this case) would
Ojala et al. (24) compared small doses of BTA improve with conventional medical treatment without
(15 - 35 U) versus NSS; they infiltrated three to seven the need for interventional techniques; therefore, the
TP at trapezius, levator scapulae, and infraspinatus le results of this study should be carefully evaluated.
vels. The infiltrations were guided by electromyography Qerama et al. (29) included patients with very spe-
(EMG). In this study, the authors report that using the cific pain in their study: Shoulder pain irradiating to the
algometer (to quantify the pressure pain threshold) is arm for more than six months, associated with a TP of
a reliable and objective measure, complemented with the infraspinatus muscle. As negative points, patients
VAS. They found no difference in pain score or the having concomitant TP in other ipsilateral muscles (tra-
pressure pain threshold in TP when using low doses of pezius, supraspinatus) were excluded, and 12 patients
toxin in the neck muscles. (7 in the BTA group and 6 in the control group) had
Wheeler et al. (25) They compared the efficacy of an associated diagnosis of complex regional pain syn-
BTA versus NSS in TP of the neck muscles (mainly tra- drome. The authors concluded that BTA given in the
pezius and lower neck part). They found no statistically TP of the infraspinatus muscle causes a significant de-
significant differences in the improvement in the neck crease in motor plaque activity but has no effect on the
pain and disability scale (NPAD), quality of life (with the intensity or threshold of pain.
SF-36 survey), or overall patient assessment score. Benecke et al. (30) used a protocol of ten TP to
On the contrary, they found a high incidence of side infiltrate in a standardized way in patients with neck
effects, mainly weakness of the operated muscles. One and shoulder pain of myofascial origin, administering
unfavorable point this study could present is that most 40 U of BTA per TP. This study has the same metho
of the patients studied had a long-standing MPS (on dology used as the study by Göbel et al., except for the
average eight years), which can be difficult to control standardization of the zones to be infiltrated. When
given the complexity of the already structured pain. The comparing these two studies, the authors reported that
authors also emphasize the importance of combining administering BTA in individualized TP has an earlier and
BTA with physical therapy to optimize treatment and longer effect than the standardized TP regimen.
suggest that repeated sessions with low doses of BTA De Andrés et al. (31) evaluated myofascial pain at
may be effective. the lumbar level, selected quadratus lumborum mus-
Lew et al. (26) compared the efficacy of BTA versus cle and iliopsoas muscle for ease of exploration, and
NSS at the level of the neck and upper-back muscles: for the referred pain pattern triggered by pressing TP.
trapezius, levator scapulae, head splenic, and other A positive point in this study is that they guided the
muscles in the posterior region of the neck. They infiltra puncture by fluoroscopy. They did not find that BTA
ted 50 U per TP, not exceeding the total dose of 200 U decreases VAS, nor does it improve the daily activities
or 100 U on each side (no more than two muscles on or psychological status of the patients studied. They
each side were infiltrated). Their results found that BTA only found a decrease in post-infiltration VAS, and given
improved neck pain and disability, but when compared the high cost of BTA; the authors considered that BTA
with the results of the control group (NSS), no statis- should be used only in cases of pain refractory to other
tically significant difference was found. They concluded invasive techniques.
that this result could be due to a placebo effect. Nicol et al. (1) presented a study with a different
Göbel et al. (27) compared two groups (BTA vs. NSS). methodology because they performed a test with BTA
Their main objective was to assess the percentage of before conducting the clinical trial to determine which
patients who had mild pain or no pain after five weeks patients were going to have a positive response at six
of administering BTA in the upper-back muscles. Unlike weeks. The authors assessed not only VAS but also the
other authors, they used higher maximum doses of BTA quality of life (SF-36 survey), disability (using the neck
(40 U per TP, maximum ten TP). The results of his study disability index: NDI), and headache (frequency and du-
were favorable: Given 400 U of BTA in ten TP, there ration). The authors infiltrated the neck muscles, but
was a significant improvement in VAS from the fifth to not the stabilizing muscles of the scapula (infraspinatus,
the eighth week, associated with the presence of more supraspinatus, and rhomboid) because of the possi-
pain-free days per week until the twelfth week. bility of worsening the symptoms by weakening these
Ferrante et al. (28) compared the efficacy of three muscles. The dilution was 25 U/ml, and a maximum
different doses of BTA (10, 25, and 50 U) versus NSS of 300 U was injected. The BTA was administered at
in TP infiltration. This is the only clinical trial that stan- half the thickness of the painful muscle, regardless of
dardized a regimen of concomitant medical treatment the location of the TP.
(amitriptyline, ibuprofen, and paracetamol) associated Their results showed a decrease in VAS, improve-
with physical therapy. The authors found no differences ment in overall activity, and improvement in sleep after
between the BTA and NSS groups in pain reduction 26 weeks of BTA administration; they also found a de-
in VAS, pressure algometry, and rescue medication. crease in the number of headache episodes per week.BOTULINUM TOXIN FOR THE TREATMENT OF MYOFASCIAL PAIN SYNDROME
TABLE II
CLINICAL TRIALS INCLUDED IN THIS REVIEW
Number Duration
Pain Duration Mean Sex Additional Evaluated
Author Year Study design Toxin dose of of the Results Conclusion
location of pain age (M/F) treatment indicators
patients study
NPAD There is no
(Neck Pain benefit when
and Disability using BTA
2 groups:
2001
Wheeler Randomized, >3 I.25 I. 43 Scale). compared
Neck I. 231.20 12/38 Not mentioned 16 weeks Negative
y cols. double-blind months II. 25 II 45 SF-36. Global to NSS. High
II. NSS
progression incidence of
adverse events
with BTA
VAS at 24 h No differences
and 1, 2, in VAS, pressure
4, 6, 8, pain threshold,
4 groups:
I. 32 I. 43,3 Amitriptyline, 12 weeks. rescue
I. 10 U
2005
Ferrante Randomized, Neck and >6 II. 34 II. 46,6 ibuprofen, and Rescue medication
II. 25 U 52/80 12 weeks Negative
y cols. double-blind shoulders months III. 31 III. 46,5 acetaminophen. medication. (p > 0.05).
III. 50 U
IV. 35 IV. 45,3 Physical therapy Pressure pain Low score on
IV. NSS
threshold. the SF-36 scale
SF-36 to the BTA group
(p < 0.05)
VAS. No difference
They are Pressure pain in VAS at
2 groups:
Randomized, allowed to use threshold at cervical level,
2006
Ojala y Neck and >2 I. 15-35 I: 15 I. 44,9
double-blind, 3/28 paracetamol. 4 weeks 4 weeks nor increase in Negative
cols. shoulders months U (28.6) II. 16 II. 43,8
crossover Only 7 used pressure pain
II. NSS
NSAIDs threshold n
(p > 0.05)
Presence Improvement
of mild or of VAS during
Analgesic non-pain at week 5 to week
2 groups:
treatment was week 5, VAS, 8 (p < 0.05),
I. 40 U/TP
2006
Göbel Randomized, 6 to 24 I. 75 I. 44 discontinued duration higher number
Upper back (maximum 29/116 12 weeks Positive
y cols. double-blind months II. 70 II. 45 progressively of sleep, of days per
400 U)
prior to the improvement week without
II. NSS
study of TP, number pain from week
of pain-free 5 to week 12
days per week (p < 0.05)
Spontaneous No differences
pain and in the decrease
evoked of spontaneous
pain. Motor (p = 0.53)
2 groups:
endplate and evoked
2006
Qerama Randomized, >6 I. 50 U/ I. 15 I. 54.5
Shoulder 12/18 Not mentioned 4 weeks activity. (p = 0.90) Negative
y cols. double-blind months muscle II. 15 II. 46,7
Pressure pain pain. There is
II. NSS
threshold. a decrease in
Pain relief motor endplate
activity with BTA
105
(p < 0.05)
(Continuation in the next page)106 D. C. NÁJERA LOSADA ET AL
TABLE II (CONT.)
CLINICAL TRIALS INCLUDED IN THIS REVIEW
Number Duration
Pain Duration Mean Sex Additional Evaluated
Author Year Study design Toxin dose of of the Results Conclusion
location of pain age (M/F) treatment indicators
patients study
VAS, SF-36, BTA does not
NDI. Baseline improve VAS or
registration, 2 NDI (p > 0.05).
2 groups:
They continued weeks, months Improvement in
Neck and I. 50 U/
2008
Lew y Randomized, 2 to 6 I. 14 I. 48,7 with medication 24 1, SF-36 in body pain
upper muscle (max 20/9 Negative
cols. double-blind months II. 15 II. 48,5 and usual weeks 2, 3, 4, at 2 y 4 months
back 200 U total)
physical therapy and 6 months (p < 0.25) and
II. NSS
mental health
after 1 month
(p < 0.25)
VAS baseline No improvement
and at 15, 30, in the VAS, or in
3 groups:
and 90 days. the daily activities
De I. 50 U (25U/ I. 27 I. 51 They continued
2010
Randomized, >6 12 Improvement of patients or
Andrés y Lumbar muscle)II. NSS II. 14 II. 51 8/20 with regular Negative
double-blind months weeks of their daily their psychological
cols. III. Bupivacaine III. 13 III. 51 medication
activities and condition
0.25%
psychological
stage
They continued VAS and No improvement
2 groups:
with regular Pressure pain in VAS (p = 0.83).
I. 100-300U/
2011
Fenollosa Randomized, Neck >2 I. 12 I. 41 medication 12 threshold No improvement
muscle (max 2/22 Negative
y cols. double-blind and back years II. 12 II. 44,8 and started weeks in the pressure
Rev. Soc. Esp. del Dolor, Vol. 28, N.º 2, Marzo-Abril 2021
500 U)
physiotherapy pain threshold at
II. NSS.
prior to the study TP (p =0.74)
Presence of Improvement in
Analgesic
mild or non- VAS from week
2 groups: treatment was
pain at week 5, 8 (p = 0,008).
2011
Benecke Randomized, Neck and 6 to 24 I. 40 U/PG I. 81 I. 48 discontinued 12
52/96 VAS, number of Decreased daily Positive
y cols. double-blind shoulders months (max. 400 U) II. 72 II.45 progressively weeks
pain-free days pain at week 9
II. NSS prior to the
per week and week 10
study
(p = 0.04)
VAS. BPI (brief Improvement of
2 groups: pain inventory), VAS and quality of
They were
I. 25-50U/ NDI, SF-36. life (mainly general
2014
Nicol y Randomized, Neck and >8 I. 29 I. 48,8 allowed to use 26
muscle (max 12/42 Headache activity and Positive
cols. double-blind shoulders months II. 25 II. 47,4 ibuprofen and weeks
300 U) sleep). Decreased
tramadol
II. NSS number of
headaches
VAS. Pressure No improvement
pain threshold in VAS (p = 0.11).
Kwan- 2 groups: They were only
2015
Randomized, Neck and >3 I.24 I. 39,8 at 3 and Decrease the
chuay y I. 20 U 6/42 allowed to use 6 weeks Negative
double-blind shoulders months II. 24 II. 38,8 6 weeks pressure pain
cols. II. NSS. paracetamol
threshold at 6
weeks (p = 0.03)BOTULINUM TOXIN FOR THE TREATMENT OF MYOFASCIAL PAIN SYNDROME 107
In contrast, patients receiving placebo had a worsening before the start of the study; they included patients with
of pain and quality of life, which shows us the residual pain between six months and two years, while other
effect in patients who had received BTA in the first studies (where there was no benefit from BTA) such as
phase of this study, and that the differences observed in those by Wheeler et al. and Ojala et al. had on average
this second phase are not only due to a placebo effect. pain progression times of 8.6 years and 10.5 years,
Kwanchuay et al. (32) used small doses of BTA respectively. Some authors considered that this time
(20 U) and limited their study to the most painful TP at of progression is crucial because patients with pain
the trapezius level. They did not find that BTA reduced of more than 1.5 years of progression have a worse
pain at six weeks compared to NSS. They considered response to BTA, possibly due to fibrotic changes in the
VAS to be a subjective, uncertain, and inappropriate affected muscle fibers (34,35). We believe that these
measure to assess musculoskeletal disease because three points could be important in assessing the positive
it may be biased due to pain originating in adjacent results of BTA in the MPS.
muscles, without accurately assessing TP pain. On the The third positive study for BTA is that of Nicol et al.,
contrary, they consider the algometer to be an instru- in which the methodology was totally different from that
ment that gives objective and accurate measurements. of the other published studies. Their protocol had two
They conclude that their study findings are positive be- phases: In the first one, they used the BTA to know the
cause they demonstrated the effectiveness of BTA in responders (of 114 patients including only 57 were re-
MPS due to an increase in the pain threshold after toxin sponders), and in the second phase, a clinical trial was
administration. The authors also emphasized trapezius conducted with the group of responders. We believe
stretches during study time. that it is a good thing to confirm that patients had a
Fenollosa et al. (33) found no statistically significant positive test before the clinical trial; although we thought
differences in the decrease in VAS or increase in the pre it would have been more cost-effective if this diagnostic
ssure pain threshold in TPs when comparing BTA versus test had been performed with a local anesthetic to know
placebo. These authors used an average dose of 300 U the patients who were responders, thus lowering the
BTA, and all patients received physical therapy before costs of using BTA (this is what we usually do in daily
and during the study. Although BTA was not statistically practice). Another important point in this study is the in-
higher than placebo, for the authors, an improvement clusion criteria: They included patients with moderate to
in the two-point VAS was clinically relevant in finding a severe pain and a minimum pain duration of 8 months.
44.6% decrease in VAS in the BTA group versus 26% in Regarding negative studies, we could say that it is
the placebo group in the twelfth week. They conclude that very difficult to integrate clinical trial data from studies
BMT associated with rehabilitation therapy may be helpful that were not favorable to BTA, because they all have
in the treatment of patients with neck or dorsal MPS. a different design, starting with inclusion and exclusion
criteria up to infiltration technique. In most of the clin-
ical trials analyzed, we could find a decrease in VAS in
DISCUSSION both the BTA and the control groups without finding
a statistically significant difference. It is likely that for
Following the main objective of the present review, this reason, authors such as Lew et al. suggest that
we could state that there was no statistically significant the results obtained could be due to a placebo effect.
improvement in VAS in patients receiving BTA versus Other authors do not agree with this conclusion and
NSS in the decrease of chronic pain of myofascial ori- believe that the results obtained are due to the effect
gin in eight of the eleven studies analyzed. This finding of needles, similar to that obtained in acupuncture (36).
should be analyzed in depth because if viewed lightly, it There are other parameters that may be crucial in
could lead to the conclusion that BTA is not indicated obtaining positive or negative results in clinical trials,
in MPS. Before we continue with the negative studies such as patient follow-up time. Although most stud-
for BTA, we would like to discuss the positive studies ies have a duration of 12 weeks, some studies have
for BTA in MPS. a short duration: Ojala et al. (4 weeks) and Qerama
The same group of researchers performed two of the et al. (4 weeks), and Kwanchuay et al. (6 weeks). In
three studies showing an improvement in VAS with BTA. all of them, the BTA was not superior to the NSS in
The studies had the same design and differed mainly by controlling the MPS. A more evident example of the im-
the technique followed to infiltrate the TP. In the study portance of follow-up time is found in the Benecke et al.
conducted by Göbel et al., the 10 most painful TP were study. They found no statistically significant differences
infiltrated; and in the study conducted by Benecke et al., at 4 weeks of follow-up in terms of neck pain improve-
the 10 TP were standardized for all patients. This leads ment but found differences at 8 weeks.
us to wonder what is the difference between the design We have found much variability in the site and the
of these studies and the other clinical trials. There are number of injections performed regarding the infiltration
several points in the design that the other studies do not technique. Ferrante et al. infiltrated a maximum of 5 TP,
have: The first point is pain intensity because patients Ojala et al. infiltrated up to 7 TP, while other authors such
had moderate to severe pain, while other studies where as Benecke et al. infiltrated 10 TP. On the contrary, Nicol
BTA did not show a positive result (such as Qerama et et al. did not consider that TPs should guide infiltration
al and Ferrante et al) had mild pain. The second point but that infiltration should be performed in half the painful
is that the number of TP patients should have to be muscle thickness, not on TP. This variability of criteria
included in the study (10 or more TP), which is directly again creates difficulty in interpreting the results.
related to the intensity of pain they suffered. The third The puncture of TPs was performed based on ana-
point is the time of pain progression that patients had tomical landmarks in most studies; few studies guided108 D. C. NÁJERA LOSADA ET AL Rev. Soc. Esp. del Dolor, Vol. 28, N.º 2, Marzo-Abril 2021
it by electromyography or fluoroscopy. In the present re- of infiltration of TP, the duration of the studies, and the
view, we found no clinical trial using ultrasound to guide lack of cost-effective analysis; We consider that more
TP infiltration. For future clinical trials, we consider that specific clinical trials with more homogeneous samples
the use of ultrasound to optimize the effectiveness of are needed to allow us to draw conclusions regarding
infiltration may be interesting because it is a device we treatment with BTA in the MPS.
have in our usual clinical practice.
Although a standard dose to infiltrate the muscu-
lature is not yet agreed, we could affirm that doses REFERENCES
less than 50 U as used in the study by Ojala et al. are
ineffective. In contrast, doses higher than 200 U may 1. Nicol AL, Wu II, Ferrante FM. Botulinum toxin type a injections
have side effects, although clinical trials using maximum for cervical and shoulder girdle myofascial pain using an enri-
doses of 300 U and 400 U did not find any significant ched protocol design. Anesth Analg. 2014;118(6):1326–
side effects and, if present, were related to muscle 35.
weakness in the infiltrated area or to flu-like symptoms, 2. Ho KY, Tan KH. Botulinum toxin A for myofascial trigger point
which were transient. In our opinion, it may be more injection: A qualitative systematic review. Vol. 11, European
important to assess the type of muscle to be infiltrat- Journal of Pain. 2007. p. 519–27.
ed than to establish a standard dose of BTA per TP 3. Avendaño-Coy J, Gómez-Soriano J, Valencia M, Estrada J,
because bulky muscles such as iliopsoas or quadratus Leal F, Ruiz-Campa R. Botulinum toxin type a and myofascial
lumborum should have doses of 100 U and muscles pain syndrome: A retrospective study of 301 patients. J Back
such as trapezius 50 U. In the case of the study De Musculoskelet Rehabil. 2014;27(4):485–92.
Andrés et al., we consider that the use of higher doses 4. Raj PP. Botulinum toxin therapy in pain management. Vol. 21,
of BTA would have been interesting because they used Anesthesiology Clinics of North America. W.B. Saunders;
50 U to infiltrate robust muscles such as the quadratus 2003. p. 715–31.
lumborum and the iliopsoas. 5. Gerwin R. Botulinum toxin treatment of myofascial pain: A
Dilution is another source of controversy; the first critical review of the literature. Vol. 16, Current Pain and
clinical trials used dilutions of 100 U/ml, while the last Headache Reports. 2012. p. 413–22.
clinical trials used dilutions of 100 U/5 ml. We think it 6. Hallett M. Mechanism of action of botulinum neurotoxin:
might be interesting to study whether the results are Unexpected consequences. Toxicon. 2018;147:73–6.
affected by using a concentrated higher or lower dilu- 7. Safarpour Y, Jabbari B. Botulinum toxin treatment of
tion, and according to the results, we could standardize pain syndromes –an evidence based review. Toxicon.
dilutions to have more homogeneous clinical trials. 2018;147:120–8.
Based on the results of the Nicol et al. study where 8. Reilich P, Fheodoroff K, Kern U, Mense S, Seddigh S, Wissel
the placebo group had some residual effect of BTA given J, et al. Consensus statement: Botulinum toxin in myofacial
within 14 weeks prior to the beginning of the clinical pain. In: Journal of Neurology, Supplement. 2004. p. 36–8.
trial; it may be interesting to perform studies deter- 9. Seo HG, Bang MS, Chung SG, Jung SH, Lee SU. Effect of
mining when the second dose of BTA would be optimal electrical stimulation on botulinum toxin a therapy in patients
to assess the possible increase in therapeutic effects. with chronic myofascial pain syndrome: A 16-week rando-
We know that pain is difficult to assess because it mized double-blinded study. Arch Phys Med Rehabil. 2013
has a biopsychosocial component; to try to be a little Mar;94(3):412–8.
more objective in its assessment, some researchers 10. Roldan CJ, Osuagwu U, Cardenas-Turanzas M, Huh BK. Nor-
use the algometer with which they have obtained very mal Saline Trigger Point Injections vs. Conventional Active
good results; we should bear in mind the use of scales Drug Mix for Myofascial Pain Syndromes. Am J Emerg Med.
and surveys that value the quality of life of patients that 2020 Feb 1;38(2):311–6.
are no less important than VAS. Most studies inject BTA 11. Velázquez Rivera I, Muñoz Vico M, Velázquez Clavarana L,
if the patient has a minimum VAS of 4, but some studies García Velasco P, Zénner del Castillo A, Ruiz Olivares J, et
could be biased, such as the study of Ferrante et al., al. Comparación de resultados obtenidos en el tratamiento
because they considered a very low VAS as inclusion del dolor miofascial de la cintura pélvica con toxina botulínica
criteria. In our opinion, it could be patients with mild pain sola y asociada con lidocaína.
who had a clinical improvement with the prescribed drug 12. Graboski CL, Shaun Gray D, Burnham RS. Botulinum toxin A
regimen together with physiotherapy, thus improving versus bupivacaine trigger point injections for the treatment
with conservative management even without having to of myofascial pain syndrome: A randomised double blind cros-
administer BTA. Thus, the findings of this study may not sover study. Pain. 2005 Nov;118(1–2):170–5.
have been favorable for BTA. 13. Porta M. A comparative trial of botulinum toxin type A and
Finally, we would like to end with the statements common methylprednisolone for the treatment of myofascial pain syn-
for all the studies analyzed. The first statement concerns drome and pain from chronic muscle spasm. Pain. 2000
the high cost of botulinum toxin; most authors believe Mar 1;85(1–2):101–5.
that BTA should be reserved for cases in which conven- 14. Castro M, Cánovas L, García-Rojo B, Morillas P, Martínez-
tional medical and interventional treatment fails (23,31). Salgado J, Gómez-Pombo A, et al. Tratamiento del síndrome
de dolor Miofascial con toxina botulínica tipo A. Rev la Soc
Esp del Dolor. 2006;13(2):96–102.
CONCLUSIONS 15. Kim DY, Kim JM. Safety and efficacy of prabotulinumtoxina
(Nabota®) injection for cervical and shoulder girdle myofas-
Given the heterogeneous selection of patients, the cial pain syndrome: A pilot study. Toxins (Basel). 2018 Sep
large variability of BTA doses, the different techniques 1;10(9).BOTULINUM TOXIN FOR THE TREATMENT OF MYOFASCIAL PAIN SYNDROME 109
16. Torres Huerta JC, Hernández Santos JR, Ortiz Ramírez EM, treatment (Dysport®) for the relief of upper back myofas-
Tenopala Villegas S. Toxina botulínica tipo A para el mane- cial pain syndrome: Results from a randomized double-blind
jo del dolor en pacientes con síndrome de dolor miofascial placebo-controlled multicentre study. Pain. 2006 Nov;125
crónico. Rev la Soc Esp del Dolor. 2010 Jan;17(1):22–7. (1–2):82–8.
17. Carrasco AT, Wescoat L, Roman A. A retrospective review 28. Ferrante FM, Bearn L, Rothrock R, King L. Evidence aga-
of Botulinum toxin type A compared with standard therapy in inst trigger point injection technique for the treatment of
the treatment of lumbar myofascial back pain patients. Vol. cervicothoracic myofascial pain with botulinum toxin type A.
15, Pain Clinic. 2003. p. 205–11. Anesthesiology. 2005;103(2):377–83.
18. Wheeler AH, Goolkasian P. Open label assessment of botuli- 29. Qerama E, Fuglsang-Frederiksen A, Kasch H, Bach FW, Jen-
num toxin A for pain treatment in a private outpatient setting. sen TS. A double-blind, controlled study of botulinum toxin A in
J Musculoskelet Pain. 2001;9(1):67–82. chronic myofascial pain. Neurology. 2006 Jul;67(2):241–5.
19. Lang AM. A preliminary comparison of the efficacy and tole- 30. Benecke R, Heinze A, Reichel G, Hefter H, Göbel H. Botu-
rability of botulinum toxin serotypes A and B in the treatment linum type A toxin complex for the relief of upper back
of myofascial pain syndrome: A retrospective, open-label myofascial pain syndrome: How do fixed-location injections
chart review. Clin Ther. 2003 Aug 1;25(8):2268–78. compare with trigger point-focused injections? Pain Med.
20. Cartagena-Sevilla J, García-Fernández MR, Vicente-Villena 2011;12(11):1607–14.
JP. Analgesic Effect of Botulinum Toxin A in Myofascial Pain
31. De Andrés J, Adsuara VM, Palmisani S, Villanueva V, López-
Syndrome Patients Previously Treated with Local Infiltration of
Alarcón MD. A double-blind, controlled, randomized trial to
Anesthetic and Steroids. J Pain Palliat Care Pharmacother.
evaluate the efficacy of botulinum toxin for the treatment of
2016 Oct 1;30(4):269–75.
lumbar myofascial pain in humans. Reg Anesth Pain Med.
21. Jerosch J, Söhling M. Open-label, multicenter, randomized
2010 May;35(3):255–60.
study investigating the efficacy and safety of botulinum toxin
32. Kwanchuay P, Petchnumsin T, Yiemsiri P, Ma NP, Hathaia-
type A in the treatment of myofascial pain syndrome in
reerug C. Efficacy and Safety of Single Botulinum Toxin Type
the neck and shoulder girdle. J Musculoskelet Pain. 2012
A (Botox ® ) Injection for Relief of Upper Trapezius Myofascial
Jun;20(2):95–9.
Trigger Point: A Randomized, Double-Blind, Placebo-Contro-
22. De Andrés J, Cerda-Olmedo G, Valía JC, Monsalve V, Lopez-
lled Study. Vol. 98, J Med Assoc Thai. 2015.
Alarcón, Minguez A. Use of botulinum toxin in the treatment of
33. Fenollosa P, De Barutell C, Figueroa J, Míguez A, Nieto C.
chronic myofascial pain. Clin J Pain. 2003 Jul;19(4):269–75.
23. Kamanli A, Kaya A, Ardicoglu O, Ozgocmen S, Zengin FO, Toxina botulínica A (Dysport®) asociada a rehabilitación, en
Bayık Y. Comparison of lidocaine injection, botulinum toxin pacientes con dolor miofascial cervical o dorsal primario:
injection, and dry needling to trigger points in myofascial pain Un estudio piloto multicéntrico aleatorizado. Rehabilitacion.
syndrome. Rheumatol Int. 2005;25(8):604–11. 2011 Apr;45(2):139–47.
24. Ojala T, Arokoski JPA, Partanen J. The effect of small doses 34. Reilich P, Schoser BGH. Accuracy of botulinum toxin injec-
of botulinum toxin A on neck-shoulder myofascial pain syn- tions in myofascial pain. Response to Gobel et al. Pain
drome: A double-blind, randomized, and controlled crossover 2006;125:82-8. Vol. 130, Pain. 2007. p. 299.
trial. Clin J Pain. 2006 Jan;22(1):90–6. 35. Göbel H. Authors’ reply to the letter to the editor by Peter
25. Wheeler AH, Goolkasian P, Gretz SS. Botulinum toxin A for the Reilich and Benedikt G.H. Schoser regarding the published
treatment of chronic neck pain. Pain. 2001;94(3):255–60. article entitled “Efficacy and safety of a single botulinum type
26. Lew HL, Lee EH, Castaneda A, Klima R, Date E. Therapeutic A toxin complex treatment (Dysport®) for the relief of upper
Use of Botulinum Toxin Type A in Treating Neck and Upper- back myofascial pain syndrome: Results from a randomi-
Back Pain of Myofascial Origin: A Pilot Study. Arch Phys Med sed double-blind placebo-controlled multicentre study”, Pain
Rehabil. 2008 Jan;89(1):75–80. 2006;125:82-8. Vol. 130, Pain. 2007. p. 299–300.
27. Göbel H, Heinze A, Reichel G, Hefter H, Benecke R. Effi- 36. Hsieh RL, Lee WC. Are the Effects of Botulinum Toxin Injec-
cacy and safety of a single botulinum type A toxin complex tion on Myofascial Trigger Points Placebo Effects or NeedlingYou can also read
