644951

research-article2016
CRE0010.1177/0269215516644951Clinical RehabilitationWu et al.

CLINICAL
Article REHABILITATION

Clinical Rehabilitation

Intra-articular injections of 2017, Vol. 31(4) 435­–443

© The Author(s) 2016
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DOI: 10.1177/0269215516644951
https://doi.org/10.1177/0269215516644951

joint pain: a systematic review journals.sagepub.com/home/cre

and meta-analysis

Tao Wu1*, Hai-xin Song1*, Yan Dong2,

Ye Ye1 and Jian-hua Li1

Abstract
Objective: To assess the benefit of intra-articular injection of Botulinum toxin A (BoNT-A) for chronic
refractory joint pain regardless of joint or pathology.
Data sources: The search was performed on Ovid MEDLINE(R) In-Process and Other Non-Indexed
Citations, Ovid MEDLINE(R), Ovid EMBASE, Web of Science, and Scopus inception through Week 12, 2016.
Trial selection: Clinical randomized controlled trials that evaluated BoNT-A intra-articular injection in
patients with refractory joint pain were included.
Data extraction: Two independent reviewers conducted data extraction.
Results: A total of 6 out of 284 records were included. The analysis indicated that a statistically significant
decreased pain score was found in BoNT-A therapy group than control group with WMD=1.10 (95% CI:
0.35 to 1.85; P<0.001; I2=95%); WMD=0.7 (95% CI: 0.09 to 1.32; P=0.02; I2=0%) at week 4, and 8 after
injection, respectively. WOMAC score was also significant decreased in BoNT-A therapy group than
control group with WMD=4.71 (95% CI: 2.76 to 6.67; P<0.001; I2=0%); WMD=3.67 (95% CI: 1.08 to 6.26;
P=0.006; I2=27%) at week 4 and12 after injection, respectively. There was no difference in adverse event
between BoNT-A therapy group and control group with OR=1.25 (95% CI: 0.88 to 1.78; P=0.47; I2=0%).
Conclusion: As compared with conventional therapy, BoNT-A intra-articular injection have beneficial
effects with improved pain score and WOMAC score in adult patients with refractory joint pain.

Keywords
Osteoarthritis, botulinum toxin, Intra-articular injection, systematic review, pain

Received: 10 September 2015; accepted: 27 March 2016

1Department of Rehabilitation Medicine, Sir Run Run Shaw Corresponding author:

Hospital, College of Medicine, Zhejiang University, Hang
Zhou, PR China.
2Department of Rehabilitation Medicine, Hangzhou Hospital of
Zhejiang CAPF, Hang Zhou, PR China
*Tao Wu and Hai-xin Song contributed equally to this work.
Jian-hua Li, Department of Rehabilitation Medicine, Sir Run
Run Shaw Hospital, College of Medicine, Zhejiang University,
3, East Qin Chun Road, Hangzhou, Zhe Jiang, 310016, PR
China.
Email: zjdxsyfkfk@126.com
436 Clinical Rehabilitation 31(4)
Introduction
Chronic joint pain is the most common joint dis-
ease and is among the most frequent and sympto-
matic health problems for middle aged and older
people.1,2 In a European survey of pain preva-
lence in the general population, moderate to
severe pain lasting 6-months or longer was
reported by 19% respondents, of whom 40% had
joint pain3. Intra-articular injections are now con-
sidered part of an established option for sympto-
matic chronic arthritis or osteoarthritis if a patient
has been unable to tolerate conservative treat-
ments, including oral medications and/or physi-
cal therapy.4,5 Meanwhile, patients who failed
corticosteroid or hyaluronic acid injection were
not always willing to consider joint replacement
surgery. In addition, small joints such as the wrist
and ankle are not currently amenable to joint-
replacement surgery. So the availability of a new
therapeutic option would be desirable.
Botulinum toxin A (BoNT-A) is recently dis-
covered its effect on pain control. Animal experi-
ments demonstrate that BoNT-A inhibits not only
the acetylcholine at the neuromuscular junctions
but also other neurotransmitters such as glutamate,
substance P and calcitonin gene related peptide,6,7
all of which have been indicated in pain transmis-
sion.8 Small open label trials have also been con-
ducted with intra- articular injection at shoulder
joints, knee joints and ankle joints. 9,10
However, with many nonrandomized studies
have had small sample sizes that were reviewed
retrospectively without comparisons to control
group, the clinical efficacy of BoNT-A injection
therapy in the treatment of arthritis pain is still
unclear. Thus, we conducted this systematic review
to synthesize all evidence on BoNT-A as a thera-
peutic intervention in the management of refrac-
tory joint pain. The objective of this review was to
assess the benefit of BoNT-A for refractory arthri-
tis or osteoarthritis pain, as compared to placebo,
hyaluronate or steroid injection.
Materials and methods
The study protocol was finalized in advance of any
data collection, which defined objectives, search
strategy, inclusion/exclusion criteria, data extrac-
tion, outcomes of interest, and analytical approaches.
This systematic review is in according with the
Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) statement.11
The search was performed on Ovid
MEDLINE(R) In-Process and Other Non-Indexed
Citations, Ovid MEDLINE(R), Ovid EMBASE,
Web of Science, and Scopus from database incep-
tion through Week 12, 2016. Searching terms were
broad and without country restrictions but pub-
lished in English. Controlled vocabulary supple-
mented with key words was used to search for
studies of arthritis pain with Botulinum toxin.
Relevant studies were identified using the follow-
ing search terms as (BTX or BoNT or Botulinum)
and (arthritis or osteoarthritis or joint pain) as key-
words or text words or the MeSH (Medical Subject
Headings). Two reviewers, working independently
and in duplicate (TW and HS), reviewed titles and
abstracts and then, full texts in order to exclude
irrelevant studies. All conflicts were discussed and
resolved with a third author (JL). The reference
sections of the included articles were used to iden-
tify additional relevant articles.
We included clinical randomized controlled tri-
als (RCTs) that evaluated BoNT-A injection on
refractory joint pain patients who were failed by
physical therapy, non-steroidal anti-inflammatory
drugs (NSAIDs), or exercise therapy. We did not
restrict the type of intervention in control groups.
We did not restrict study country. Studies focusing
on the therapeutic effect of BoNT-A injection for
myofascial pain syndrome were excluded. Case
reports, case series, reviews, notes, letters, com-
mentaries, and studies published only as abstracts
were also excluded.
Study details were extracted from the full texts.
The following data was extracted: author, year
published, sample size, patients’ age, population,
study design, main evaluation index, and follow
up time. The outcomes of interest were pain score
(numeric rating scale (NRS) or visual analog scale
(VAS), 0-10), McGill score, and Western Ontario
McMaster Universities Arthritis Index (WOMAC)
score. McGill Pain Questionnaire is with 4 items
for affective dimension, 11 items for sensory
Wu et al. 437
dimensions, and total pain score of 15 items
(score, 0–45; higher values represented worse
pain). The WOMAC (Western Ontario McMaster
Universities Arthritis Index) score is a disease and
lower extremity-specific questionnaire evaluating
joint pain (5 items), stiffness (2 items), and func-
tion (17 items), which has been widely used in
clinical trials with 0 being the best and 100 the
worst score.
We used the Cochrane Risk of bias tool to
assess the methodological quality of the included
study in terms of sequence generation, allocation
concealment, blinding, incomplete outcome
data, selective outcome reporting, and other
sources of bias.12
Statistical analysis
For continuous outcomes using the same measure-
ment, we pooled weighted mean difference (WMD)
using the D-L random effect models. For summa-
rizing dichotomous outcomes like adverse event
rate, the risk ratio (RR) was used. We used the I2
statistic to measure the heterogeneity across the
included studies, in which I2>50% suggests high
heterogeneity. All analyses were performed using
the generic inverse variance method (Rev Man 5.3,
The Cochrane Library). The significance level was
defined as P < 0.05.
Results
We identified 284 records, of which 6
RCTs13,14,15, 16,17, 18 (326 patients) were eligible for
this review (Figure 1). Characteristics of the
enrolled studies are described in Table 1. Three
studies included patients with refractory
shoulder13,14,17 pain, three studies with refractory
knee14,15,16 pain (One study14 focused on both
shoulder and knee) and one study with refractory
ankle pain.18 All the patients in control groups were
received non BoNT-A therapy such as steroid16,17
or placebo injection13,14,15 or hyaluronate.18 The
mean follow up time is 18.7 weeks (1-6 months).
For subgroup analysis we collected and compared
decreased pain score, WOMAC score and McGill
score at the same time point of each study.
All of the studies assessed pain using numeric
rating scale (NRS, 0-10) or visual analog scale
(VAS, 0-10) after treatment. We collected the
decreased pain scores at the end of follow up
period of each study. The analysis indicated a sta-
tistically significant decreased pain score in
BoNT-A therapy group than control group during
the previous 8 week since injection with
WMD=1.10 (95% CI: 0.35 to 1.85; P<0.001;
I2=95%); WMD=0.7 (95% CI: 0.09 to 1.32;
P=0.02; I2=0%) at week 4, and 8 after injection,
respectively (See Figure 2).
Three studies14,15,16 assessed knee WOMAC
score after BONT-A treatment. The analysis indi-
cated a statistically significant decreased WOMAC
score in BoNT-A therapy group than control group
during the previous 12 week since injection with
WMD=4.71 (95% CI: 2.76 to 6.67; P<0.001;
I2=0%); WMD=3.67 (95% CI: 1.08 to 6.26;
P=0.006; I2=27%) at week 4 and 12 after injection,
respectively (see Figure 3).
Only two studies14,15 assessed joint McGill
score after BoNT-A treatment. The analysis indi-
cated there was no statistically significant in joint
McGill score between BoNT-A therapy group and
control group during the 16 weeks follow up period
(with total WMD=0.13 (95% CI:-0.83 to 1.10;
p=0.79; I2=19%), see Figure 4).
No severe adverse events were reported in all
included studies. Two studies13,17 systematically
reported the adverse events rate after injection.
Local adverse events included increased pain in
the study joint or muscle weakness around study
joint.13 The most common systemic adverse
events included dry mouth, cough, dizziness,
accidental injury, and flu-like symptoms.13,17
The analysis indicated there was no statistically
significant in adverse events between BoNT-A
injection group and control group with OR=1.25
(95% CI: 0.88 to 1.78; P=0.47; I2=0%) (see
Figure 5).
The studies reported low risk of bias in terms of
incomplete outcome data and selective outcome
reporting. However one study was not blinding of
outcome assessment,17 three studies were high risk
of other bias, including limited by the follow-up
time only 4 weeks or small number of patients.15,16,17
438 Clinical Rehabilitation 31(4)

Figure 1.  Flow of participants through trial.

The risk of bias for assessment in terms of blinding studies was medium due to potential publication
outcome assessment was judged to be of unclear in bias and unknown quality (see Figure 6 supple-
one study.14 In summary, the risk of bias within the mentary material).
Wu et al. 439

Table 1.  The characteristics of the enrolled studies.

Study Population Intervention / Sample Age Timing Study Main evaluation
comparison size follow up design index

Singh 200913 Chronic refractory Botulinum toxin A 36 Mean 71.2, 1 month RCTs VAS, Range of
moderate/severe (Botox, 100 units) vs SD 2.5 motion (ROM),
shoulder arthritis placebo (saline) (years) McGill score
pain failed prior
corticosteroid injection,
Maren Lawson Refractory shoulder Botulinum toxin A 78 Median 3 months RCTs NRS, McGill score,
200914 or knee pain (arthritis) (Botox, 100 units) + 73, range, WOMAC score
and not responded lidocaine vs saline + 48–81
adequately to lidocaine (years)
corticosteroids injection.
Singh 201015 Patients with refractory, Botulinum toxin A 49 Mean 67, 4 months RCTs VAS, McGill score,
chronic total knee (Botox,100 units) vs SD 10.8 WOMAC score
arthroplasty pain. placebo (saline) (years)
Andrea 201016 Patients with moderate Botulinum toxin A 60 Mean 61.9, 6 months RCTs VAS, WOMAC
knee osteoarthritis. (Botox 100 or 200 SD 11 score, 40-m walk
units) vs corticosteroid (years) time, SF score
injection
Young-Jin Joo Patients with severe Botulinum toxin A 28 Mean 54.5, 8 weeks RCTs NRS, ROM
201317 adhesive capsulitis (Dysport,200u) vs SD 11.5
shoulder pain corticosteroid injection (years)
Shu-Fen Sun Patients with refractory Botulinum toxin A 75 Mean 50, 6 months RCTs VAS, Ankle
201418 ankle OA. (Botox 100) vs 2 ml SD 10.6 Osteoarthritis
Sodium hyaluronate (years) Scale (AOS)

Discussion peptide,23,24,25 all of which have been indicated in

The primary finding of this meta-analysis is that
BoNT-A treatments resulted in small to moderate
pain relief and decreased Western Ontario
McMaster Universities Arthritis Index (WOMAC)
score. There was no statistically significant in
adverse events between BoNT-A therapy and con-
trol group.
All joint structures except articular cartilage are
innervated with articular nerves.19,20 Joint injury or
inflammation is associated with decrease in the
excitation threshold of these nociceptors. This
leads to enhanced responses to both innocuous and
noxious mechanical, chemical and thermal
stimuli.21 A variety of mediators can sensitize joint
nerves and nociceptors to mechanical stimuli
including prostaglandin E2 and I2, bradykinin, sub-
stance P, serotonin and neuro peptide.22 Animal
experiments demonstrate that BoNT-A inhibits not
only the acetylcholine at the neuromuscular junc-
tions but also other neurotransmitters such as gluta-
mate, substance P, and calcitonin gene related
pain transmission.26 Meanwhile, interleukin-1 is
the prototypical pro-inflammatory cytokine that
contributes to cartilage degradation in chronic
arthritis or osteoarthritis.27 There is evidence that
botulinum toxin specifically inhibits Rho GTP,
which is necessary for activation of interleukin-1
inflammation pathway.28 So intra-articular injec-
tion of the BoNT-A may be a useful therapy for
chronic arthritis or osteoarthritis.
In our meta analysis, most studies included
patients (mean age 65.5 years) with refractory
joint pain due to arthritis or other underlying
arthritic conditions. These patients were resistant
to conventional treatments of physical therapy,
nonsteroidal anti-inflammatory drugs (NSAIDs),17
inadequate (efficacy <2 months) or no response to
intra-articular corticosteroid injections,13,14 pain
score ⩾4.513,14,18 or ⩾517 or ⩾615,16 on 0–10
numeric rating scale. Mahowald et al.14 found that
in patients with severe pain, the intra-articular
BoNT-A injection produced a 38% decrease in the
VAS daytime pain and a 25% decrease in
440 Clinical Rehabilitation 31(4)
Figure 2.  Decreased pain score (NRS & VAS) change after BONT-A treatment.
nighttime pain. Meanwhile, in the moderate pain
group, both intra-articular BoNT-A and placebo
injections produced little change. Important
changes in function were also seen primarily in the
severe pain group. Interestingly, 100 units of intra-
articular BoNT-A injection produced no signifi-
cant changes in those with mild pain at baseline.14
Generally speaking, the results form included
studies demonstrated that there was a greater
change in those with severe pain at baseline and
little change in those with moderate pain.
There are two types of BoNT utilized in clinical
practice: Type A (Botox and Dysport) and Type B
(Myobloc). Type A is more widely used in pain
control and spasticity treatment than Type B. In
this meta-analysis, only BoNT-A (Botox and
Dysport) was utilized for joint injection. The mean
dosage was 100-200 u with Botox and 200u with
Dysport. Only one study observed the different
effects between low (Botox, 100u) and high
(Botox, 200u) dosage.16 However due to the small
sample size and patients with moderate knee OA,
when change from baseline was compared across
groups, there was no significant difference between
the low and high dosage groups.16 So the current
study does not support the use of 200 units of
BoNT-A for intra-articular injection. Nonetheless,
it was reassuring that the high-dose BoNT-A group
did not show any increase in adverse effects com-
pared with low-dose BoNT-A during 6 months fol-
low up after injection. So further clinical researches
are needed to compare the therapy effect in refrac-
tory arthritis pain relief when use in various doses
of BoNT-A in severe joint pain patients.
It is well known that BONT-A can decrease
muscular tone and associated symptoms of pain by
inhibiting the release of acetylcholine at neuromus-
cular junctions.29 However, there is little known
about the temporality of its anti-nociceptive effect
in humans. Our analysis shown that significant
Wu et al. 441

Figure 3.  Decreased WOMAC score change after BONT-A treatment.

pain relief effect during the previous 12 weeks
after injection was statistically significantly greater
in the BoNT-A injection group compared to pla-
cebo or steroid. Mahowald et al.14 reported that
time to maximal pain relief varied from 4 to 12
weeks, and the effects lasted 3 to13 months. The
mean duration of pain relief for the first BoNT-A
treatments was 2.0 months.
Our meta-analysis has a several limitations.
First, although we conducted a comprehensive
search of five databases, only five studies were
included in this systematic review. This small num-
ber of studies limited the statistical power of detect-
ing significant finding. Second, we did not explore
other factors, such as variation response
to different dosage between moderate and sever
osteoarthritis patients or gender differences
because of the existing clinical heterogeneity of the
population. We were also unable to test potential
publication bias due to the small number of studies.
Third, in our meta analysis, we included the differ-
ence of comparative regimens, hyaluronate, corti-
costeroid and placebo as control group. It was
inappropriate to consider corticosteroid or hyaluro-
nate as placebo during comparison. In fact, tree
included studies found that there are no significant
short-term differences between the intra-articular
injections of BoNT-A and corticosteroid15,16 or
hyaluronate.18 Fourth, we only included the study
published in English-language papers. Therefore,
442 Clinical Rehabilitation 31(4)

Figure 4.  Decreased McGill score change after BONT-A treatment.

Figure 5.  Adverse event.

larger studies are needed to assess the most effec-

tive dose, the long-term safety of intra-articular
injections and to define as to which patients might
be the best candidates for this treatment option.
This review’s findings suggest that BoNT-A
showed more persistent clinical benefits in pain
reduction and Western Ontario McMaster
Universities Arthritis Index (WOMAC) score
improvement than steroid or placebo in patients
with refractory joint pain. Intra-articular BoNT-A
injection could be a considerable option and safety
strategy for refractory joint pain treatment and
meanwhile more research is required in this area.
Clinical messages
•• Botulinum toxin A injection was associ-
ated with improvements in pain and
function in patients with refractory joint
pain due to arthritis or other underlying
arthritic conditions.
•• More studies are needed to assess the
long-term safety of Botulinum Toxin A
intra-articular injection and to define
which patients might be the best candi-
dates for this treatment option.
Wu et al. 443
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest
with respect to the research, authorship, and/or publication
of this article.
Funding
The author(s) received no financial support for the
research, authorship, and/or publication of this article.
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