REVIEW ARTICLE

A Critical Appraisal of the Evidence for

Botulinum Toxin Type A in the Treatment for

Cervico-Thoracic Myofascial Pain Syndrome

Mehul J. Desai, MD, MPH; Tatyana Shkolnikova, MD; Andrew Nava, MD;

Danielle Inwald, MD

The George Washington University Spine & Pain Center, Washington, District of Columbia,U.S.A.

& Abstract: Myofascial pain syndrome (MPS) is a musculo-

skeletal condition characterized by regional pain and muscle

tenderness associated with the presence of myofascial trigger

points (MTrPs). The last decade has seen an exponential

increase in the use of botulinum toxin (BTX) to treat MPS. To

understand the medical evidence substantiating the role of

therapeutic BTX injections and to provide useful information

for the medical practitioner, we applied the principles of

evidence-based medicine to the treatment for cervico-tho-

racic MPS. A search was conducted through MEDLINE (Pub-

Med, OVID, MDConsult), EMBASE, SCOPUS and the Cochrane

database for the period 1966 to 2012 using the following

keywords: myofascial pain, muscle pain, botulinum toxin,

trigger points, and injections. A total of 7 trials satisfied our

inclusion criteria andwere evaluated in this review. Although

the majority of studies found negative results, our analysis

identified Gobel et al.’s as the highest quality study among

these prospectively randomized investigations. This was due

to appropriate identification of diagnostic criteria, excellent

study design and objective endpoints. The 6 other identified

studies had significant failings due to deficiencies in 1 or

more major criteria. We conclude that higher quality, rigor-

ously standardized studies are needed to more appropriately

investigate this promising treatment modality. &

Key Words: botulinum toxin, myofascial pain syndrome,

neck pain, nociceptors, myofascial trigger points, review

INTRODUCTION

Myofascial pain syndrome (MPS) is a musculoskeletal

condition characterized by regional pain and muscle

tenderness associated with the presence of myofascial

trigger points (MTrPs). Clinically, these MTrPs are

focally hypersensitive taut bands (TBs), which produce a

local twitch response (LTR) and a typical referral

pattern on palpation.1,2 MTrPs are easily diagnosed

via physical examination by expert examiners; however,

inter-rater reliability of detection is poor and tender

points are often misdiagnosed as MTrPs.3

MPS affects up to 95% of patients with chronic pain

disorders and is a common finding in patients at

specialty pain medicine centers.4 It has also been

determined that neck and back pain affects up to 70%

of the general adult American population during their

lifetime and is considered the leading cause of job-

related disability in the United States.5 Traditional

treatment for MPS includes oral pharmacotherapy

(most commonly nonsteroidal anti-inflammatory drugs

[NSAIDs], steroids, muscle relaxants, antidepressants,

opioids, and vasodilators), injections (local anesthetic

Address correspondence and reprint requests to: Mehul J Desai, MD,MPH; GW Spine & Pain Center, 2131 K Street NW, Suite 600, WashingtonDC, 20037, U.S.A. E-mail: mdesai@mfa.gwu.edu

Submitted: December 21, 2012; Revision accepted: April 12, 2013DOI. 10.1111/papr.12074

© 2013 World Institute of Pain, 1530-7085/13/$15.00

Pain Practice, Volume ��, Issue �, 2013 ��–��

with or without steroid), physical therapy (PT), and dry

needling (TDN). These traditional methods have been

employed with varying degree of long-term benefit and

have demonstrated only transient pain relief. This has

driven the need for further research and understanding

of the underlying mechanism of MPS and the need for

the development of targeted treatments.

The pathophysiology of MTrPs is complex and

involves interactions between numerous mechanisms,

which results in the peripheral sensitization of local

muscle nociceptors.6 The inciting event in MTrP for-

mation is muscle overload whereby contractile forces

are irregularly distributed within a hypoperfused mus-

cle.7 Localized areas of muscle injury and ischemia

develop, causing low tissue pH and hypoxia. Low pH

inhibits acetylcholinesterase (AChE), increasing the

levels of acetylcholine (Ach) in the synapse, which

results in further local tenderness.7 Nociceptive termi-

nals in muscle tissue have a multitude of different

receptors in its membranes, including matched receptors

for biochemicals that are released from damaged or

hypoxic tissue such as CGRP (calcitonin gene–relatedpeptide), bradykinin, serotonin, protons (pH), and

prostaglandins.6 CGRP further increases ACh release

by the motor endplate (MEP). Continuous activation of

nociceptors by these and other endogenous substances

also leads to central sensitization of dorsal horn

neurons.6 Increased ACh concentration produces abnor-

mal MEP activity that leads to intense, self-sustaining

focal sarcomere compression under the MEP.7 Com-

pression further constricts local capillaries, increasing

hypoperfusion and ischemia. The continued presence of

these inflammatory mediators and other biochemicals

may be necessary for persistent pain conditions such as

MPS, resulting in an ongoing positive feedback loop.6

This supports Simon’s integrated hypothesis of local

ischemia and hypoxia, according to which the central

MTrP has multiple muscle fibers releasing excessive

ACh from dysfunctional MEPs.8 Therefore, if pain

arises in part due to excessive release of ACh from

dysfunctional MEPs, then blocking ACh with an agent

like botulinum toxin (BTX) may reduce the symptoms of

MPS.

BTX is a potent neurotoxin produced by the bacte-

rium Clostridium botulinum. It causes flaccid muscle

paralysis by blocking ACh release at the neuromuscular

junction (NMJ). BTX is thought to exert an analgesic

effect via muscle-relaxant properties and also directly

via inhibition of nociceptive neuropeptides.9 BTX is

commercially available in several subtypes, including

Type A and B (Botox [onabotulinumtoxinA] – Allergan,Inc., Irvine, CA, USA; Myobloc [rimabotulinumtoxinB]

– Solstice Neurosciences, Inc., South San Francisco, CA,

USA; Dysport [abobotulinumtoxinA] – Ipsen Biopharm

Ltd., Wrexham, UK; Xeomin [incobotulinumtoxinA] –Merz Pharma GmbH & Co KGaA, Frankfurt,

Germany), which are currently FDA-approved in the

United States to treat glabellar lines, cervical dystonia,

blepharospasm, strabismus, and severe primary axillary

hyperhidrosis that is inadequately managed by topical

agents. The off-label use of BTX in musculoskeletal

conditions currently extends to plantar fasciitis, pirifor-

mis syndrome, lateral epicondylitis, and MPS. Recently,

BTX has been shown in animal models to reduce the

levels of substance P and CGRP, key biochemicals

involved in pain mechanistic pathways.10 These results

have not been replicated in human models; however,

given the key role of these and other cytokines and

neuropeptides in MPS, the use of BTX is a natural

outlet.6

To understand the medical evidence substantiating

the role of therapeutic BTX injections, we applied the

principles of evidence-based medicine to the treatment

for cervico-thoracic MPS. Our purpose was to analyze

the science underlying the utility of BTX in treating

cervico-thoracic MPS in order to provide useful infor-

mation for the medical practitioner.

METHODS

We searched MEDLINE (PubMed, OVID, MDCon-

sult), EMBASE, SCOPUS, and the Cochrane database

for the period 1966 to 2012 using the following

keywords: myofascial pain, muscle pain, botulinum

toxin, trigger points, and injections. In addition, we

examined the references cited in these studies for those

key words. We did not review abstracts or unpublished

studies. Selected studies had to fulfill the following

criteria: (1) enrolled subjects had a chief complaint of

cervico-thoracic MPS, (2) each trial involved a prospec-

tive methodology, (3) 1 treatment arm received 1 or

more BTX injections, (4) the study must have been

published in English, and (5) the study had to be double-

blinded. We excluded studies that did not document

MTrPs, as well as nonspecific diagnoses such as low

back pain. We also excluded studies with small sample

sizes (n < 10), which could lead to erroneous treatment

outcomes.11,12

Articles meeting the study criteria were critically

evaluated. Data were compiled for each of the

2 � DESAI ET AL.

following categories: inclusion criteria, randomization

protocol (if appropriate), total number of subjects

enrolled initially and at final analysis, statistical

analysis used, documentation of technique, outcome

measures, follow-up intervals, results (positive or

negative), funding sources, and reported complica-

tions. The quality assessment systems developed by the

Agency for HealthCare Research and Quality (AHRQ)

(Table 1) and the Cochrane Database (Table 2) were

applied to the data.13 Two review authors indepen-

dently screened the trials and assessed the quality and

analysis of the results. If consensus was not reached,

data from the trial in question were reviewed as a

team again until the review authors resolved the

contentious issue.

A study was considered positive if the authors

concluded that BTX injection was more effective than

the reference/control treatment. Usually, this conclusion

was predicated on the conventional 5% level (P = 0.05)

for detecting a statistically significant difference in the

primary outcome measures. In a negative study, the

authors concluded either no difference between the

study treatments, or that better results were observed in

the reference/control treatment group.

RESULTS

A total of 7 trials satisfied the inclusion criteria,

were evaluated in this review, and are summarized in

Table 3.14–20 All 7 were published between 1998 and

2011 in peer-reviewed journals. Non-English studies

were excluded. All of the studies were prospective,

randomized, and double-blinded. One of the studies

used crossover design.14 All 7 studies incorporated a

placebo-controlled group using saline.

Methodology

In all 7 studies, the presenting complaint was cervico-

thoracic muscle pain. The duration in the studies varied

from 2 to 6 months. Gobel et al. specified that the

duration of symptoms criteria not exceed 24 months

with a minimum of 6 months of symptoms prior to

enrollment. Wheeler et al.16, however, recommended

average pain duration of 8.6 years prior to study

enrollment.

Inclusion criteria included (1) a regional pain com-

plaint, (2) pain or paresthesia in the typical distribution

Table 1. Agency for Healthcare Research and Quality(AHRQ) Domains and Elements for Randomized Con-trolled Trials*

Domain Elements†

Study Question Clearly focused and appropriate questionStudy Population Description of study population

Specific inclusion and exclusion criteriaSample size justification

Randomization Adequate approach to sequence generationAdequate concealment method usedSimilarity of groups at baseline

Blinding Double-blinding to treatment allocationInterventions Intervention(s) clearly detailed for all study groups

Compliance with interventionEqual treatment of groups except for interventions

Outcomes Primary and secondary outcome measures specifiedAssessment method standard, valid and reliable

Statistical Analysis Appropriate analytic techniques that address studywithdrawals, loss to follow-up, missing data, andintention to treat

Power CalculationAssessment of confoundingAssessment of heterogeneity, if applicable

Results Measure of effect for outcomes and appropriate

measure of precisionProportion of eligible subjects recruited into studyand followed up at each assessment

Discussion Conclusion supported by results with possiblebiases and limitations taken into consideration

Funding orSponsorship

Type and sources of support for study

*Adapted fromCenter for Regulatory Effectiveness prepared for Agency for HealthcareResearch and Quality, US. Department of Health and Human Services.†Elements appearing in italics are those with an empirical basis. Elements appearing inbold are those considered essential to give a system a full Yes rating for the domain.

Table 2. Methodological Quality Criteria List of CochraneMusculoskeletal Review Group*

Patient Selection1. Treatment AllocationWas the method of randomization describedand adequate?Was the treatment allocation concealed?

Yes No Don’tKnow

2. Were the groups similar at baseline regardingthe most important prognostic indicators?

Yes No Don’tKnow

Intervention3. Was the care provider blinded? Yes No Don’t

Know4. Was controlled for co-interventions whichcould explain the results?

Yes No Don’tKnow

5. Was the compliance rate (in each group)unlikely to cause bias?

Yes No Don’tKnow

6. Was the patient blinded? Yes No Don’tKnow

Outcome measurement

7. Was the outcome assessor blinded? Yes No Don’tKnow

8. Was at least one of the primary outcomemeasures applied?

Yes No Don’tKnow

9. Was the withdrawal/drop-out rate unlikely tocause bias?

Yes No Don’tKnow

Statistics10 Did the analysis include an intention-to-treatanalysis?

Yes No Don’tKnow

*Adapted from Manchikanti et al.

Botulinum Toxin in the Treatment for Myofascial Pain � 3

Table

3.Resu

ltsofPublish

edInvestigationsofBotulinum

Toxin

TypeA

intheTreatm

entofCervico-ThoracicMyofascialPain

Syndrome

Author

StudyDesign

DurationofPain

Dose

Regim

en

NConcu

rrent

Therapy

Study

Duration

Outcome

Measures

Results

AHRQ

C

Ojala

etal.

(2006)

DBRCT,

crossove

r>2month

ave

rage:

10.0

�8.6

months

Total

15–3

5U,

Mean

28�

6U

31(T

=15,

C=16)

Paracetamol,

n=13used

NSA

IDS

8weeks

(4week

treatm

ent)

SNP,PPT

Nosignificant

difference

betw

een

treatm

entand

controlgroups

7/10

4/11

Ferrante

etal.

(2005)

DBRCT

>6month

0/TP,10/TP,25/TP,

50/TP

Max5TPs

132(T1=32,

T2=34,

T3=31,

C=35)

Standardized

regim

enof

amitriptyline

10mg2hours

before

bedtime,

25mgafter

1week,ibuprofen

800mgQID,and

propoxyphene-

acetaminophen1

tabletQ4prn

12weeks

VASat

24hours,

1,2,4,6,8

and12weeks;

rescue

medication

use;PPT;SF-36

Nosignificant

difference

betw

een

treatm

entand

controlgroups

8/10

7/11

Wheeleretal.

(2001)

DBRCT

Atleast

5month

ave

ragewas

8.6

�9.6

years

231.20�

50.1

of

BTAX

206.80�

39.1

ofsaline

50(T

=25,

C=25)

Notstated

16weeks

NPAD;GAS;

SF-36;BDI

Nodifference

betw

een

treatm

entandco

ntrol

groups,howeve

rmore

AEswere

reportedby

theBTXA

thantheNS

groupduringthe4th

and8th

week.

7/10

3/11

Wheeleretal.

(1998)

DBRCT

>3month

Placebo,50Units

BTXA,100Units

BTXA

allin

2cc

ofnorm

alsaline

33(T1=11,

T2=11,

C=11)

NR

4monthsand

thenoffered

aseco

nd

injection

of100units

ofBTXA

NPAD;PPT

Nostatistical

significance

inBTX-A

ove

rplacebobutsome

subjectsasymptomatic

afterseco

ndinjection

of100uBTXA.

7/10

4/11

Gobeletal.

(2006)

DBRCT

6–2

4month

(ave

rage

18.5

month)

40U

persite

with

10most

tender

triggerpoints

145(T

=75,

C=70)

Noopioids,inva

sive

therapymethods,

NM

blocks,

corticosteroidsor

muscle

relaxa

nts.

NoTylenol,ice,

heat,massageor

rheumatism

bath

therapyonday

priorto

treatm

ent

12weeks

Proportionof

subjectswith

mildorno

pain

atweek

5;ch

angesin

pain

intensity;

numberof

pain-freedays

perweek;

pain

on

palpationof

muscles;GAS

Positive

primary

outcomeof

significantlymore

patients

onBTX-A

at

week5showedmildor

nopain

compared

withplacebo.In

additiontheBTX-A

groupalsoalloweda

significantlygreater

changefrom

baseline

inpain

intensity

duringweek5–8

and

significantlyfewer

days

perweekwith

outpain

betw

een

weeks5and12.

9/10

11/11

4 � DESAI ET AL.

Table

3.(Continued)

Author

StudyDesign

DurationofPain

Dose

Regim

en

NConcu

rrent

Therapy

Study

Duration

Outcome

Measures

Results

AHRQ

C

Qeramaetal.

(2006)

DBRCT

>6month

50U

/.25mLor

0.25mLof

isotonic

salineper

triggerpoint

30(T

=15,

C=15)

Physicalandmanual

treatm

ents

were

stoppedduring

studyperiod

4weeks

NRS,

spontaneous

andevo

ked

pain;shoulder

move

ments;

interference

pattern

and

spontaneous

electrical

activityon

EMG

BTX-A

reducedMEP

activityandthe

interference

pattern

ofEMG

significantly

buthadnoeffect

on

eitherpain

(spontaneousor

referred)orpain

thresholdsco

mpared

withisotonic

saline.

7/10

7/11

Lew

Etal.

(2008)

DBRCT

Atleast

2months

50U

perinjection

site

notto

exceed

totaldose

of200U

29(T

=14,

C=15)

NR

6months

VAS;

NDI;SF-36

Nosignificant

difference

betw

een

treatm

entandco

ntrol

groupexceptin

regard

totheSF

36there

was

astatistically

significantdifference

seenin

bodilypain

at2

and4month

and

mentalhealthscale

atonemonth.

8/10

7/11

BDI,Beck

DepressionInve

ntory;BTIG,BTX-A

injection;DNG,Dry

needling;GAS,

Patientandphysician’sglobalassessmentofim

prove

ment;LIG,Lidocaineinjection;NDI,Neck

DisabilityIndex;

NHP,Nottingham

HealthProfile;NPAD,

Neck

pain

anddisabilityScale

(consistsof20itemswhichuse

avisuala

nalogscale

tomeasure

neck

pain

andassociatedproblems;PPT,P

ain

pressure

threshold

withalgometry;

PS,

Pain

score

uponpalpation0-3;S

F-36,3

6item

short

form

healthsurveyasaquality

oflife

measurement;NRS,Numericratingscale

forpain;SNP,Seve

rity

ofneck-shoulderpain;T

P,T

riggerpoint;MEP,M

otorendplate;V

AS,Visuala

nalogpain

scale

ove

rthelast24hours;C

,Coch

raneassessment

scale;AHRQ,Agency

forHealthCare

ResearchandQuality;DBRCT,Double-blindrandomizedco

ntrolledtrial:NM,Neuromuscular;NR,Notreco

rded.

Botulinum Toxin in the Treatment for Myofascial Pain � 5

of the MTrP, (3) a TB in the muscle, (4) exquisite

tenderness found in that TB, and (5) a restricted range of

motion (ROM) in the affected muscle. Exclusion criteria

included history of diffuse pain, a history of cervical disk

or bone disease, neurologic deficits, trauma to the

shoulder or neck region, previous cervical surgery, and

radiculopathy of the upper extremities. Additionally,

patients were excluded if they suffered from another

serious medical condition or had psychologic problems,

including depression.

In 3 of the 7 studies, patients were randomized via

computer-generated randomization schedules18–20 One

study utilized block randomization,14 another study

used a randomization table,15 and 1 used numerical

coding17 to randomize subjects. Wheeler16 did not

report their randomization process.

Ojala randomized 31 subjects to total doses of 15-

35 units (U) of botulinum toxin A (BTX-A, Botox)

with 5 U per MTrP for a total of 3 to 7 sites (n = 15)

or just saline (0.05 mL) per MTrP in 3 to 7 sites

(n = 16). At 4 weeks, the subjects were crossed over.

Following randomization, Ferrante performed MTrP

injections in 4 total groups. The experimental groups

received 10, 25, or 50 U (n = 32, n = 34, and n = 31,

respectively) of BTX-A (Botox) in up to 5 sites for a

maximum total of 50, 125, or 250 U. The control

group received saline placebo (amount not reported) in

up to 5 sites (n = 35).

Twenty-five subjects were randomized by Wheeler16

to receive BTX-A injections (231.2 � 50.1 U) in the

cervico-thoracic musculature. Total sites injected were

not reported. An additional 25 subjects received saline

placebo (206.8 � 39.1 U). The conversion of milliliters

to units of saline was not explained. Wheeler17 ran-

domized 11 subjects into 1 of 3 groups. The first group

underwent BTX-A injection with 50 U in 2 mL of

normal saline, the second group received 100 U in 2 mL

of normal saline, and the third group was injected with

2 mL of normal saline. These injections were conducted

in the subject’s most sensitive MTrP as identified via

examination.

Gobel randomized a total of 145 subjects into 2

groups. The experimental group received 40 units of

BTX-A (Dysport) at 10 sites (n = 75), while the control

group underwent saline placebo injection at 10 sites

(n = 70).

Qerama randomized a total of 30 subjects to 50 U of

BTX-A (Botox) (n = 15) or 0.25 mL of normal saline

(n = 15) in the infraspinatus muscle. Fourteen subjects

underwent BTX-A (Botox) injection with 50 U per site

for a total dose of up to 200 U and 100 U per side with

up to 2 muscles per side in the experimental group in a

study by Lew. The control group received saline placebo

(n = 15).

Four of the 7 studies disclosed funding support in

entirety or in part from Allergan, Inc.15,16,19,20; 1 study

was funded institutionally14; 2 studies did not disclose

any external funding sources.18

Statistical Analysis

The only study to calculate the population base to power

analysis was the study by Gobel et al., who also used

Wilcoxon–Mann–Whitney test to assess baseline equiv-

alence between treatment groups. To calculate the

differences in efficacy between the 2 treatment groups,

Gobel used Wilcoxon rank sum test or Fisher’s exact

test. When multiple tests were conducted, the P value

was corrected using the Bonferroni’s method. Ojala

et al. used an analysis of variance (ANOVA) and

samples t-test to compare the difference of change in

severity of neck and shoulder pain (SNP) and the

minimum pressure that produced pain (pain pressure

threshold, or PPT) between the different treatments. To

compare the verbal assessments, Ojala used chi-square

analysis and a 2-tailed nonparametric Mann–Whitney

U-test to evaluate the difference between the groups at

separate time points. The crossover effects were esti-

mated using repeated measures of ANOVA. Ferrante

et al. used chi-square analysis with Fisher’s exact test for

nonparametric data and Student’s t-test and ANOVA

for parametric data.

For the 36-item short-form Health Survey (SF-36),

Ferrante et al. used generalized estimation regression

models that adjusted for multiple values per patient, and

for each subscale of the SF-36, 3 separate intergroup

analyses were performed. Wheeler et al.16 analyzed

their data with a 2 9 5 unweighted means analysis,

which tested for the between-group effect of treatment.

Wheeler et al.17 used ANOVA for each outcome mea-

sure to identify effects of treatment group’s pre- and

post-treatment and the Kruskall–Wallis test because of

the small sample size at each of the testing periods to

assess the differences between groups. Qerama et al.

also compared medians using the nonparametric Mann–Whitney and Wilcoxon rank test. Kamali et al. used the

chi-square for measurements of original variables and

the Wilcoxon’s signed-rank test for comparisons

between groups. Lew et al. used the Wilcoxon rank

sum test (1-sided t-test) and the Wilcoxon signed-rank

6 � DESAI ET AL.

test (2-sided paired t-test) for the between- and within-

group comparisons, respectively.

Outcomes

The Ojala’s study reported no difference between small

doses of BTX-A and saline for MPS. 100% of enrolled

subjects completed the study and were available for

follow-up at 4 and 8 weeks. Outcome measures

included SNP and PPT via pain pressure dolorimetry.

No statistically significant differences in these measures

were observed following the interventions.

Ferrante analyzed visual analog scores (VAS), PPT,

SF-36 quality-of-life measure, and use of propoxyphene-

acetaminophen napsylate as a rescue medication at

weeks 1, 2, 4, 6, 8, and 12. Ferrante reported that

injection of BTX-A directly into MTrPs did not improve

cervico-thoracic MPS when compared with placebo.

The study reported no statically significant improvement

in VAS sum of changes from baseline, analysis of mean

weekly VAS scores, comparison of rescue dosing among

groups, or analysis of mean MTrP PPT. Interestingly, all

groups including placebo showed significant improve-

ments in VAS scores, while the use of rescue medication

and PPT demonstrated no observed differences among

treatment groups.

Neck Pain and Disability Visual Analogue Scale

(NPAD; 20 items including the VAS to measure neck

pain and associated problems), SF-36, and the Beck

Depression Inventory (BDI) were assessed by Wheeler16

at 4, 8, 12, and 16 weeks. Of the 50 subjects enrolled,

45 completed the study. The authors reported benefits in

both groups on Neck Pain and Disability Visual Ana-

logue Scale (NPAD). Improvements in subject and

physician global assessments of improvement (GAS),

PPT, BDI, and SF-36 were also noted but were not

specific to either treatment. Wheeler16 concluded that

single-dose treatment of BTX-A was not effective for

chronic neck pain.

All 33 subjects enrolled by Wheeler17 were available

for final evaluation at 1, 3, 6, 9, 12, and 16 weeks.

NPAD and PPT measurements were collected. All 3

groups showed decline in neck pain and disability by

VAS. All 3 groups showed an increase in PPT. The

placebo group did not reach pain-free status as much as

the BTX-A groups when given a second injection.

Wheeler17 concluded that although there was no statis-

tical significance in BTX-A over placebo, some subjects

were asymptomatic after second injection suggesting

possible benefit with sequential injections and accumu-

lating dosages.

Of the 145 subjects initially enrolled by Gobel, 24

were excluded from final analysis due to major protocol

deviations. Outcome measures included proportion of

subjects with mild or no pain at week 5, changes in pain

intensity, number of pain-free days per week, pain on

muscle palpation at each follow-up visit, and GAS. At

the end of the study, subject and physician preference for

repeated treatment was also determined. These mea-

surements were recorded at 4, 8, and 12 weeks. Gobel

noted that at week 5, significantly more patients with

Dysport injections had mild or no pain (51%). BTX-A

injection resulted in significantly greater change from

baseline in pain intensity from weeks 5 to 8. Fewer days

with pain per week were noted from week 5 to 12 in the

BTX-A group. No significant differences in duration of

daily pain or duration of sleep were noted. Mean pain

intensity score for all MTrPs was significantly lower in

the BTX-A group at week 4 until the conclusion of the

study. GAS rating favored BTX-A at weeks 4, 8, and 12.

Patients and physicians were significantly in favor of

repeated treatments with BTX-A. Gobel concluded that

subjects with upper back MPS treated with BTX-A had

significantly improved pain levels 4 to 6 weeks after

treatment.

All 30 subjects recruited by Qerama were available

for final evaluation at 3 days and 28 days after treat-

ment. Spontaneous and evoked pain by NRS, shoulder

movements, and interference pattern of electromyogra-

phy (EMG) during maximal voluntary contraction of

the infraspinatous muscle were measured. MEP activity

and interference pattern on EMG were reduced in the

BTX-A group. No change in PPT or pain was noted in

comparison with saline placebo. Qerama concluded that

the results did not support an anti-nociceptive or

analgesic role for BTX-A.

All 29 subjects enrolled in the Lew’s study were

available at 2, 4, 8, 12, 16, and 24 months. VAS, Neck

Disability Index (NDI), and SF-36 were collected. VAS

and NDI demonstrated a trend toward improvement but

were not significant. Statistically significant improve-

ments in bodily pain at 2 and 4 months and SF-36 at

1 month were noted, and statistically significant

improvements in VAS and NDI were seen in all groups

compared with baseline. These results led to the

conclusion by Lew that although this study had limited

power and population base, the trend toward improve-

ment justified further studies.

Botulinum Toxin in the Treatment for Myofascial Pain � 7

Complications

Ojala reported no significant difference in prevalence of

side effects between saline and BTX-A groups. Almost

half (48%, n = 15) after the first injections, compared

with 1 quarter (26%, n = 8) after the second injections

reported some side effects, most of which were minor

and short-lived. Pain at the injection site was commonly

reported. Other side effects included vertigo (1 after

placebo and 2 after BTX-A), sweating (1 after BTX-A),

fatigue of the hands (1 after placebo and 1 after BTX-A),

headache (2 after BTX-A), and swelling of the eyelids (1

after placebo).

Three subjects in the Ferrante’s trial who received

BTX-A injections experienced flu-like symptoms, which

were transient and resolved during the course of the

study. No other adverse events (AEs) occurred.

Wheeler16 reported differences across groups with

regards to AE scores. Follow-up comparisons demon-

strated that more AEs were reported in the BTX-A

group compared with saline placebo during the 4th and

8th weeks. The most frequent AEs were weakness of the

injected muscles, pain or soreness of the injection sites,

and flu-like symptoms.

Wheeler17 reported mild AEs in the BTX-A group.

Two subjects reported transient ipsilateral arm heavi-

ness and numbness, which resolved with 1 week.

Additionally, 2 subjects noted transient discomfort

opposite the injection site. Two other subjects reported

a shift of their pain, and 1 to a mirror-image muscular

area. Moreover, 1 subject reported a shift of neck pain to

the midline.

Gobel reported at total of 65 AEs during the study (46

in 31 subjects in the Dysport group and 19 in 11 subjects

in the placebo group). Most AEs were mild or moderate

(48/64, data unavailable for 1 AE). The most common

AE was muscle soreness in both groups. No serious

adverse events (SAEs) were reported. Qerema reported

no severe or persistent AEs. Nine subjects in the BTX-A

group and 8 in the placebo group denied any AEs.

Headaches and neck pain were reported in 4 subjects in

the BTX-A group and 3 in the control group. Lew did

not report any SAEs although further description was

not provided.

DISCUSSION

The last decade has seen an exponential increase in the

use of BTX to treat MPS. The number of clinical

applications of BTX-A has also expanded, albeit with

varying results. Much of this variability in clinical

outcomes might be partly explained by the different

chemical makeup of various BTX preparations. The 3

aforementioned preparations have similar mechanisms

of action although their chemical formulation, clinical

potency, migration, diffusion, and safety profile are

different. This may result in problems of clinical and

economic bioequivalence.21 Dysport (Ispen Biopharm

Ltd.) is less expensive and therefore more economically

competitive. Compared with Botox (Allergan, Inc.),

Xeomin (Merz Pharma) and MyoBloc (Solstice Neuro-

sciences, Inc. [botulinum toxin type B]) have been shown

to have slightly lower efficacy.22

Due to the heterogeneous nature of each study, our

review of BTX in the treatment for MPS produced

mixed results. The vast heterogeneity of exclusion

criteria, concomitant interventions, diagnostic criteria,

patient population size, volume injected, injection tech-

niques, short-duration studies, and outcome measures

render any conclusions exceedingly difficult. The major-

ity of studies found negative results. The negative studies

were relatively similar with regard to their quality.

Wheeler16,17 scored the lowest in quality on both the

AHRQ and Cochrane assessment scales. These trials,

however, did adequately describe the randomization

and blinding process. The 2001 study did not control for

co-interventions, while the 1998 study lacked similar

groups in the study arms with regard to the most

important prognostic indicators. Wheeler17 included

subjects who were involved in automobile accidents

with a higher number of these subjects represented in the

BTX-A group. Furthermore, the 1998 study included

statistician supervision of the medical assistant in the

preparation of the study injections. Only 1 study, Gobel

et al., demonstrated a significant improvement in pain

levels 4 to 6 weeks after treatment. This particular study

also scored the highest in study quality on both the

AHRQ and Cochrane assessment scales.

Overall, the exclusion criteria were not uniform

between the studies. Ferrante et al. based their exclusion

criteria mainly on the number of totalMTrPs (restricting

to fewer than 5) and their location. This restricted the

study population to a milder form of MPS. Gobel et al.

required that patients have at least 10 MTrPs to be

included in the study, thereby creating a study popula-

tion with a more severe form of MPS compared with the

study population used by Ferrante.

In addition, the majority of the studies did not

standardize subjects’ concurrent analgesic medications

during the study period. Wheeler et al.17 excluded

8 � DESAI ET AL.

anesthetic or corticosteroid injections, while others

allowed patients to receive these injections during the

study period. Gobel et al. was the only trial that

controlled for co-interventions by excluding common

analgesic medications such as NSAIDS, opioids, and

parenteral or oral corticosteroids. Ferrante controlled

for co-interventions by ensuring that all enrolled

patients were maintained on a common analgesic

regimen. The analgesic regimen included ibuprofen

800 mg 4 times daily, amitriptyline, acetaminophen

prn (as needed), and PT. In addition, Ferrante’s was the

only study to utilize PT during the study period.

There were also considerable dissimilarities in the

diagnostic criteria of MPS and MTrP identification.

A majority of the studies used duration of pain for

enrollment rather than actual MPS diagnostic criteria.

Furthermore, the duration of pain varied greatly among

the studies; some studies required pain duration of

greater than 2 months, while others required pain of

greater than 6 months prior to enrollment. Ojala et al.’s

was the only trial that used a definition of MPS as a part

of their inclusion criteria. The definition that was

utilized by Ojala was the proposed diagnostic criteria

of MPS from the study by Tunks et al. which included

(1) a regional pain complaint, (2) pain or paresthesia in

the typical distribution of the MTrP, (3) a TB in the

muscle, (4) exquisite tenderness in the TB, and (5)

restricted range of movement in the affected muscle.

Criteria 1 to 4 had to be met by all patients. The subjects

also needed one of the following minor criteria: (1)

reproduction of pain complaint by pressure on the

MTrP, (2) LTR in the TB and (3) alleviation of theMTrP

by stretch.

There are several factors which lead to reasonable

deduction that some percentage of treated MTrPs in

these studies were in fact tender points, including the

lack of uniformity in applying MPS diagnostic criteria,

the lack of comments on how MPS was diagnosed, and

the known existence of inter-rater unreliability in

diagnosing MPS. The significant difference in treatment

of these discrete clinical entities (i.e., MTrPs) makes it

vital to pursue their accurate diagnosis. An MTrP is a

hyperirritable point in skeletal muscle that is associated

with a hypersensitive palpable nodule.23 Compression

of an MTrP causes referred pain to a distant region. In

contrast, a tender point only causes pain locally.24

Tender points are areas of tenderness occurring in

muscle, muscle–tendon junction, bursa, or fat pads.

When tender points occur in a widespread manner, they

are usually considered characteristic of fibromyalgia.25

Although there is no known cure for fibromyalgia,

symptoms and function may improve with patient

education, aerobic exercise, cognitive behavioral

therapy, and pharmacologic therapies, such as serotonin

norepinephrine reuptake inhibitors and alpha 2-delta

receptor ligands.26 Other treatments used for tender

points include acupuncture and counterstrain, which is

an osteopathic manipulation technique.

In addition to dissimilarities in diagnostic criteria, the

number of subjects included and volume injected also

varied greatly among the 7 studies. Only 2 studies had

greater than 100 patients in their trial.15,18 This begs the

question of whether the studies were adequately pow-

ered. In fact, the majority of studies enrolled < 50

subjects. Compounded by the profound variations in

other selection criteria, this issue significantly calls into

question the ability to generalize conclusions drawn

from these works. The volume injected also varied

greatly. BTX-A concentrations ranged from 15 U to

400 U. The smallest volumes were used by Ojala et al.

while the largest units were used by Gobel. Ojala’s was a

crossover study of 4 weeks only.

Injection techniques varied among the studies

reviewed. A myriad of injection techniques exists, and

there is considerable debate regarding optimal methods.

Less debatable is the fact that correct placement of the

injection is key to therapeutic efficacy. One method that

is fairly well accepted is needle insertion approximately 1

to 1.5 cm away from the MTrP. This technique facili-

tates the advancement of the needle into the MTrP at a

30-degree angle. The grasping fingers isolate the TB and

prevent it from rolling out of the trajectory of the needle.

A “fast-in, fast-out” technique should be used to elicit an

LTR, which can be described as a characteristic response

ofMTrPs.23 TBs are groups ofmuscle fibers that are hard

and painful on palpation.24 LTR is a brisk contraction of

the muscle fibers in and around the TB elicited by

snapping palpation or rapid insertion of a needle into the

MTrP.23 This LTR has been shown to predict the

effectiveness of the MTrP injection, which can help a

clinician identify a true MTrP.27 The efficacy of injec-

tions, however, is highly dependent of the clinician’s skill

to localize the active MTrP with a small needle.23

Outcome measures were also quite variable among

the studies reviewed. For example, outcome measures in

the Ojala’s study included SNP and PPT, whereas

Ferrante used VAS, PPT, and the SF-36. Wheeler et al.16

used the NPAD, SF-36, and BDI. This heterogeneity

among outcome measures makes it difficult to draw

conclusions based on the results.

Botulinum Toxin in the Treatment for Myofascial Pain � 9

Most significantly, none of the 7 studies used a true

placebo-control group. A true placebo group involves a

sham injection. In the studies reviewed, normal saline

was injected into the members of the control group. It is

important to understand the difference between inject-

ing normal saline, sham injections, and TDN. It has been

suggested that injection of normal saline can have

therapeutic value. The saline injections may have

resulted in some clinical improvement in the control

group. Although a sham injection is an ideal placebo, its

use may not be practical in this setting. There was no

sedation of subjects in these studies, so subjects in the

control group might have realized that they received a

sham injection instead of BTX-A. This awareness by the

subjects would make the use of a sham injection

technically challenging.

Kamanli et al.28 investigated the differences between

efficacies of local injection of lidocaine, TDN, and low-

dose injections of BTX-A. In this study, injection of local

anesthetics, treatment with TDN, and the injection of

BTX-A had therapeutic efficacies of different degrees in

the MTrPs of all patients. When looking at the thera-

peutic effect on MTrPs, all of the variables measured by

VAS and disability scores showed no significant differ-

ence between lidocaine and BTX-A injection. However,

when compared with TDN, lidocaine injection was

more effective than BTX-A. PPT and pain scores

significantly improved in all 3 groups. Kamanli con-

cluded that injection of lidocaine is more practical and

rapid than TDN because it causes fewer disturbances

during the injection. A lidocaine injection is more cost

effective than BTX-A injection andmay be the treatment

of choice in MPS. However, BTX-A could be of use in

patients with MPS resistant to conventional treat-

ments.28

In addition, Kamanli found that to increase efficacy,

injections should be complemented with a strict PT

program as opposed to repeating injections.28 There is a

potential for lasting therapeutic efficacy when BTX is

combined with PT. In the 7 studies cited in this article,

Ferrante’s was the only study to utilize PT. Wheeler

et al.16 concluded that a single BTX-A injection session

without PT is not an effective treatment for chronic neck

pain. It is possible that repeated injections of BTX-A

have an additive effect and would be a more plausible

treatment for MPS. Future research should be aimed at

studying the effectiveness of repeat dosing of BTX-A

combined with PT.

Hong investigated the effects of injection with a local

anesthetic agent or TDN into an MTrP of the upper

trapezius muscle.27 Patients treated with TDN had a

greater intensity and longer duration of postinjection

soreness compared with those treated with a 0.5%

lidocaine injection. Hong concluded that it is essential to

elicit LTRs during injection to obtain an immediate and

desirable effect.

Overall, none of the studies used a true placebo-

control group. Therefore, the negative outcomes of the

studies may not demonstrate true failure of the BTX-A

interventions. Given this analysis, we believe that these

studies do not answer the question of whether or not

BTX-A is an effective treatment modality for MPS. The

heterogeneity of the various study parameters prevents

pooling the data from all 7 studies to perform a

meaningful meta-analysis. More research needs to be

performed to investigate BTX-A as a treatment for MPS.

CONCLUSIONS

Although of short duration, our analysis identified

Gobel et al.’s study as the highest quality study among

these prospectively randomized investigations. This was

due to appropriate identification of diagnostic criteria,

excellent study design, and objective endpoints. The

other studies had significant failings due to deficiencies

in 1 or more major criteria. It is readily apparent that

higher quality, rigorously standardized studies are

needed to more appropriately investigate this promising

treatment modality.

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Botulinum Toxin in the Treatment for Myofascial Pain � 11