Botulinum toxin A for the treatment of chronic neck pain

Pain 94 (2001) 255–260
www.elsevier.com/locate/pain
Botulinum toxin A for the treatment of chronic neck pain
Anthony H. Wheeler a,*, Paula Goolkasian b, Stephanie S. Gretz c
a
Charlotte Spine Center, Suite 210, 2001 Randolph Road, Charlotte, NC 28207, USA
b
University of North Carolina, Charlotte, NC, USA
c
Georgia School of Professional Psychology, USA
Received 2 February 2001; received in revised form 16 April 2001; accepted 7 June 2001
Abstract
A clinical study tested the therapeutic efficacy of Botulinum toxin A (BTXA) when injected into symptomatic neck muscles after one
injection session. Patients with chronic neck pain were randomly assigned to receive either a high dose of an active treatment or an injection
of the same volume of normal saline. Patients were compared for 4 months using a comprehensive set of outcome measures that included the
Neck Pain and Disability Scale (Spine 24 (1999) 1290) and pressure algometry (Arch Phys Med Rehabil 67 (1986) 406; Pain 30 (1987) 115;
Clin J Pain 2 (1987) 207). Analyses were consistent in showing significant benefits from the injection session; however, the effects were not
specific to the group treated with BTXA. Both treatment and control groups showed a significant decline in pain and disability across time
and an increased ability to withstand pressure on trigger points. The heavy incidence of adverse events in the treatment group may partly
explain the absence of a treatment effect specific to BTXA. The results show that a single dose treatment without physical therapy is not
effective for chronic neck pain. q 2001 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights
reserved.
Keywords: Neck pain; Chronic pain; Botulinum toxin; Neck Pain and Disability Scale; Cervical pain
1. Introduction
The prevalence of neck pain and disability and its societal
impact is well documented. A Norwegian study revealed
that over 34% of adults experienced neck pain within the
prior year (Bovim et al., 1994). A similar Danish study
(Drewes and Jennum, 1995) found that musculoskeletal
pain in 37% of the men and 54% of the women could be
attributed to a localized muscular disorder. Involuntary
overactive muscle contraction or spasm is theorized by
many (Argoff and Wheeler, 1998; Wheeler et al., 1998) as
playing a key role in producing neck pain and dysfunction.
Muscular involvement is typically described as muscle
spasm or as a myofasical pain syndrome (MPS), which
has defined diagnostic criteria (Simons et al., 1999).
Although a variety of medical treatments have been
proposed to alleviate pain in these muscular conditions,
non-operative therapies are often ineffective and costly
(Kurz, 1998).
Both MPS and muscle spasm contribute to an overall
shortened length of the involved muscle with increased
tension. Clinical terminology is often determined by the
size of the affected area of muscle(s) and the presence of
* Corresponding author.
other characteristics. For example, muscle spasm is a state
of abnormal contraction demonstrating electromyographic
activity that is not under voluntary control or dependent
upon posture (Simons et al., 1999). It may be painful and
characteristically involves the entire muscle, as well as other
associated muscles.
Similarly, MPS is characterized by an overall shortened
length of the involved muscle with increased tone or tension
and stiffness containing trigger points (TrPs) (Simons et al.,
1999). TrP palpation produces aching pain in localized
reference zones and will often elicit flinching of the patient
disproportionate to the pressure applied (Simons et al.,
1999). Although the pathogenesis of myofasical TrPs is
unknown, recent theories (Simons et al., 1999) suggest the
presence of abnormally increased motor end plate activity
with increased production and excessive release of acetylcholine at the neuromuscular junction. Therefore, if pain
from muscle spasm and TrPs is caused by mechanisms
that result from refractory muscle contraction, then blocking
neuromuscular transmission may reduce or eliminate these
symptoms.
Botulinum toxin (BTX) is a potent neurotoxin produced
by the bacterium Clostridium botulinum, which acts by
blocking acetylcholine release at the neuromuscular junction. Botulinum toxin A (BTXA) has been under investiga-
0304-3959/01/$20.00 q 2001 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.
PII: S 0304-395 9(01)00358-X
256
A.H. Wheeler et al. / Pain 94 (2001) 255–260
tion since 1968 and widely used for the treatment of focal
muscle overactivity for greater than 15 years. BTXA has
been Federal Drug Administration (FDA) approved for
treatment of strabismus, blepharospasm, and seventh
nerve disorders in patients 12 years or older (Jankovic and
Brin, 1991; Wheeler, 1997). Clinical investigation supports
the treatment of many painful dystonic and non-dystonic
disorders of muscle spasm with BTXA, which have not
yet received FDA approval (Jankovic and Schwartz,
1990a; Jankovic et al. 1990b, 1991; O’Brien, 1998; Tsui
et al., 1986; Wheeler and Goolkasian, 2001). The therapeutic effect from neuromuscular blockade from BTXA
injected into humans usually lasts 3–4 months (Jankovic
and Brin, 1991; Wheeler, 1997), however, the degree and
duration of pain relief may be greater than the motor benefit
observed (Guyer, 1999; Wheeler and Goolkasian, 2001).
Recently, BTXA has been used as a treatment for chronic
neck pain. Wheeler and Goolkasian (2001) examined the
medical records in a private patient setting, and BTXA
was shown to be an effective treatment for chronic neck
pain patients when it was used together with physical therapy (Porta, 2000; Wheeler and Goolkasian, 2001). In clinical studies, however, when BTXA is compared to an
appropriate control treatment, limited or no BTXA benefits
are demonstrated with patients suffering from chronic neck
pain. However, the studies are only preliminary efforts at
evaluating the therapeutic efficacy of BTXA. For example,
Cheshire et al. (1994) reported that BTXA treatments of
myofasical neck pain demonstrated some improvement
when compared to saline injections. However, improvement
criteria were weak, requiring only a 30% decline in visual
analog scores for pain intensity during any 2-week period
and only six patients were tested. Wheeler et al. (1998)
report pilot data which showed no significant benefit in
the BTXA-tested group when compared to a control
group, but analysis of the individual patient data suggested
that BTXA therapy aimed at pain reduction in MPS may be
more effective when treatments are applied, initially using a
low dosage, followed, if necessary, by repeated injections.
Freund and Schwartz (2000a,b) reported that BTXA
treatment of whiplash associated neck pain and headache
resulted in improvement in range of motion and subjective
pain, however, patient data were compared across time
rather than to the control group, and the treated patients
indicated as much pain after the injections as the pre-injection data from the control group. Porta (2000) compared
BTXA to methylprednisolone. Both were administered by
intramuscular injection with 0.5% bupivicaine into symptomatic, chronic myofasical pain in the piriformis, iliopsoas,
or anterior scalene muscles. Improvement in the BTXA
group was superior to the methylprednisolone group at 2
months, when initial improvement in the comparison
group waned. However, because two treatments of unproven efficacy for muscular pain were compared, the findings
are difficult to interpret.
The purpose of our research was to evaluate the therapeu-
tic efficacy of BTXA when injected into symptomatic,
cervicothoracic, paravertebral areas of muscle spasm or
myofasical dysfunction at a dosage judged as adequate to
manage the patient’s pain with just one injection session.
Active treatment (BTXA) was compared with an injection
of the same volume of normal saline (NS). This study
differed from previous research by using a comprehensive
set of outcome measures. Clinically significant improvement was measured using a spring-loaded pressure
algometer (Pain Diagnostics and Thermography, Great
Neck, NY, USA; Fischer, 1986, 1987a,b, 1988), the Neck
Pain and Disability Scale (NPAD; Wheeler et al., 1999) and
the patient’s subjective assessment of improvement.
2. Method
2.1. Participants
Fifty volunteers with chronic neck pain were recruited
from a group of 251, who responded to a newspaper advertisement. Patients were included in the study if they had
significant neck pain for at least 3 months and did not
have any other serious medical or psychological conditions.
Reasons for exclusion were as follows: 24% were not interested in completing the study; 21% suffered from another
serious medical condition; 20% did not have a muscular
pain disorder; 16% did not have a pain duration of more
than 3 months or a NPAD score indicating significant pain
(NPAD , 23); 6% had psychological problems such as
depression; 5% were outside the age range of 21–70; 3%
were excluded because of pending litigation; and 2% had
previous neck surgery.
The sample consisted of 38 women and 12 men with an
average age of 43.6 years (SD ¼ 10.7). Pain duration ranged
from 5 months to 39.5 years (M ¼ 8.6 years, SD ¼ 9.6).
Incidence and designation of injury within this sample
was 36% no injury, 4% work-related, 40% auto-related,
14% personal injury, and 6% other. Using a double-blind
procedure, participants were randomly assigned to one of
the two treatment groups so that there were 25 participants
who received BTXA and 25 who received NS injections.
The group assignment was based on a coded number that the
patient was assigned when they arrived at the clinic for their
injection. Table 1 outlines demographic characteristics and
compares the groups on a number of pre-injection variables.
Contingency Chi squares and t-tests (at the P , 0.05 level of
significance) show that the groups were equivalent on all of
the measured variables except for the SF-36 mental score.
The BTXA group scored slightly below the saline group –
means are, respectively, 43 and 49.
2.2. Measures
The NPAD (Wheeler et al., 1999) was the primary
outcome measure. It consists of 20 items that use a visual
analog scale to measure neck pain and associated problems.
A.H. Wheeler et al. / Pain 94 (2001) 255–260
257
Table 1
Group scores on the pre-injection measures
Variable
Age
Education (year)
Duration (month)
Algometer (kg/cm 2)
NPAD
Beck
SF-36 physical
SF-36 mental
Employed (%)
Gender-female (%)
BTXA
Saline
M
SD
M
SD
43
14
111
1.60
54
8.92
39
43
11.4
2.7
121
0.60
13.8
4.6
11.2
10
45
15
96.8
1.62
49
8.36
41
49.8
10.2
2.2
113.1
1.04
12.7
4.7
7.5
9.8
92
80
t-Test
P value
,1
2 1.50
,1
,1
1.28
,1
,1
2.37
0.54
0.14
0.66
0.50
0.20
0.67
0.66
0.02
76
72
Scoring on each item ranges from 0 to 5, and a NPAD score
is produced by summing the item scores. Scores above 23
indicate clinically significant neck pain and the higher the
score, the greater the degree of pain and disability. Interpretive guidelines are presented in Wheeler et al. (1999).
The NPAD has been shown to be an internally consistent
instrument that measures four underlying factors – problems
with the neck, intensity of pain, interference with functional
aspects of living, and the presence of associated emotional
factors. It was used because it incorporates the visual analog
scale used in previous research (Cheshire et al., 1994;
Freund and Schwartz, 2000a,b), and it provides a comprehensive measure of neck pain and disability.
Other measures that were used for patient screening were
the SF-36 health survey (Ware et al., 1994a) and the Beck
depression inventory (BDI; Turner and Romano, 1984). The
SF-36 is a general measure of physical and mental health.
We calculated physical and mental component scaled scores
by using the recommended norm-based scoring procedure
(Ware et al., 1994b). The BDI is a 21-item questionnaire
frequently used to measure depression in pain patients
(Turner and Romano, 1984).
2.3. Procedure
Participants were required to come to the Charlotte Spine
Center for an initial screening followed by a clinic evaluation for 4 successive months. During the screening visit, the
participants completed the NPAD, BDI, informed consent,
and an intake form that included questions about medical
history and demographic characteristics such as age, education level, gender, pain duration, and type of injury.
At the first clinic visit following the screening (week 0),
participants were randomly assigned to receive injections of
either NS or BTXA. A double-blind procedure was used
throughout the 4-month study so that neither the physician,
the clinic assistant, nor the participants were aware of the
nature of the injections. Prior to the injections, each participant was examined to correlate abnormal muscle tone
with the patient’s complaint and to identify the tenderest
Chi square
2.38
,1
0.12
0.50
areas of muscle spasm, especially TrPs. TrPs were determined by palpatory identification of a tender taut band,
which reproduced the patient’s pain locally, and by regional
referral. A score was calculated by taking the difference
between the pressure threshold measurement (kg/cm 2)
obtained from a non-tender control muscle (usually the
opposite deltoid), and the tenderest TrP (Fischer, 1986,
1987a,b, 1988). Precise measurements plotting the site of
the target TrPs were recorded by Polaroid photographs.
Injections were placed in multiple sites in symptomatic
muscles at the discretion of the physician. Table 2
summarizes the amount and the sites of the injections for
each group. Most of the participants received injections in
either the mid-lower cervical or the trapezius muscles.
During each of the follow-up monthly visits (4, 8, 12, and
16 weeks), participants completed the NPAD and a diary,
which recorded the frequency and intensity of adverse
events (AEs) from the injections. An AE’s score was calculated by summing the number of events reported during
each time period weighted by a number to indicate severity.
Patient and physician’s global assessments of improvement
(GAS) following treatment were also taken. The patient’s
and physician’s GAS were measured independently on a
scale that ranged from 24 (100% worse) to 14 (100%
improvement), with each interval representing a 25%
change of condition. Control and target measurement
changes in TrP tenderness were also measured at each
Table 2
Dosages and injection sites for participants in each group (data reported are
percent of the total research participants who were injected in that region)
BTXA
Saline
Dosage units (M (SD))
231.20 (50.1)
206.80 (39.1)
Injection regions
Mid-upper cervical (%)
Mid-lower cervical (%)
Trapezius (%)
Thoracic (%)
2
12
34
2
0
14
36
0
Total (%)
50
50
258
A.H. Wheeler et al. / Pain 94 (2001) 255–260
visit. The SF-36 health survey and the BDI were administered prior to the injections and then a second time at the
16th week visit.
Patients who received NS injections and did not show
significant improvement by the 16th week were invited to
receive BTXA injections in a follow-up open label study.
Nine patients participated. Follow-up study visits involved
the same procedures and data collection; however, the
physician and patients knew the identity and dosage of the
injection.
3. Results
Of the 50 participants who were injected, five (four from
the BTXA group and one from the NS) were not included in
data analysis because they did not complete the study. The
data from the remaining participants on each of the outcome
measures were analyzed separately with a 2 £ 5 unweighted
means analysis, which tested for the between-group effect of
treatment (BTXA vs. NS), the within-subject effect of time
(0, 4th, 8th, 12th, and 16th week), and for the interaction of
these variables. Effects were significant when associated
with a probability value of 0.05 or less.
Group averages for each of the outcome measures are
presented in Table 3 and Fig. 1. Analyses were consistent
in showing significant benefits from the injections across
Table 3
Outcome measures for each group (tabled data are means and standard
deviations)
Measure
Time (weeks)
Group
0
4
8
12
16
NPAD
BTXA
NS
54.2(14.8)
48.2(12.0)
52.2(16)
39.0(16)
45.6(21.7)
36.6(15.8)
38.0(20.9)
34.6(15.8)
40.1(16.7)
32.9(16.5)
Patient-GAS
BTXA
NS
0.2(1.6)
1.2(1.5)
0.8(1.9)
1.3(1.6)
1.4(1.60)
1.5(1.8)
1.0(1.7)
1.3(1.9)
Physician-GAS
BTXA
NS
0.2(1.6)
1.1(1.1)
0.9(1.4)
1.2(1.4)
1.4(1.2)
1.3(1.4)
1.0(1.4)
1.2(1.5)
Algometer (control–treatment)
BTXA
3.4(1.1)
1.8(1.6)
NS
4.0(1.5)
1.6(2.2)
1.9(1.4)
2.3(3.0)
1.7(1.3)
1.9(2.3)
1.9(1.6)
1.9(3.1)
Beck
BTXA
NS
6.8(5.1)
7.7(5.8)
9.2(4.5)
8.0(4.5)
7.2(5.6)
6.8(5.8)
SF-36 mental
BTXA
44.4(9.6)
NS
50.2(9.0)
46.1(9.7)
51.5(7.6)
SF-36 physical
BTXA
39.1(10.3)
NS
40.7(9.0)
42.5(8.4)
41.1(8.2)
Fig. 1. Group means for each of the outcome measures across time. Error
bars are standard errors. Neck pain and disability score (NPAD), algometer
score (control–treatment), global assessment score (GAS).
time on all of the outcome measures. NPAD scores point
to a significant decline in pain and disability across time
Fð4; 172Þ ¼ 22:11; P , 0:01: A measure of effect size
calculated on these data indicates a large effect size,
(Cohen’s d 0 ¼ 1.62).
However, the treatment effects were not specific to the
BTXA group. The groups did not differ from each other on
any of the outcome measures and there were no significant
time by group interactions. The benefits shown in the
outcome measures across time were similar for both
BTXA and NS groups.
Patient and physician GAS scores indicated a significant
improvement in the pain condition following treatment (for
the patient GAS Fð3; 126Þ ¼ 3:43; P , 0:02; for the physician GAS, Fð3; 126Þ ¼ 4:22; P , 0:01Þ: Patients reported a
25% improvement in their pain 8 weeks after the injections.
Pressure algometry scores were also consistent with the
other measures in showing a significant improvement
following treatment Fð4; 168Þ ¼ 17:04; P , 0:01: Participants were able to withstand significantly more pressure
on the TrPs 4 weeks after the initial injection sessions
than they could before the injections.
A.H. Wheeler et al. / Pain 94 (2001) 255–260
Fig. 2. Group differences in AEs across time. Error bars are standard errors.
Group differences across time were apparent, however, in
Fig. 2 with the AE scores. An analysis shows a group by
time interaction, Fð3; 138Þ ¼ 7:07; P , 0:01; and a main
effects of group Fð1; 43Þ ¼ 6:84; P , 0:01; and time,
Fð3; 138Þ ¼ 29:90; P , 0:01: Follow-up comparisons
(Ps , 0.05) within the interaction show that more AEs
were reported by the BTXA than the NS group during the
4th and 8th week of testing. The most frequent events
reported were excessive weakness of the injected muscle,
pain or soreness of the injection site and flu-like symptoms.
A pre- and post-injection analysis of the Beck depression
and the SF-36 mental and physical scores did not show any
significant changes as a result of time or the interaction of
time by group. There was, nevertheless, a significant group
effect for the SF-36 mental score, ðFð1; 43Þ ¼ 6:84; P ,
0:01Þ: The lower scores shown by the participants in the
BTXA group in comparison to the NS group at the start of
the study were again evident at the 16th week.
4. Discussion
When treated with one session of injections into symptomatic neck muscles, participants showed a significant
decline in pain and disability and an increased ability to
withstand pressure on TrPs, however, no specific benefit
from the active substance (BTXA) could be identified.
Instead, participants treated with NS showed comparable
outcomes to those treated with BTXA across the 4-month
study. Group differences were apparent only in the AEs. For
the first 2 months following the injections, the BTXA-treated group reported more AEs than the control group.
Our findings are largely consistent with other studies of
BTXA treatment for chronic muscular pain. Although other
investigators have reported a modest benefit associated with
BTXA, benefits were found in only a few patients (Cheshire
et al., 1994) or when data were compared across time rather
than to a control group (Freund and Schwartz, 2000a,b).
Furthermore, the strength of the effect of the injections
observed in our study was greater than those reported in the
other studies we mentioned, but it was not specific to BTXA.
The benefit observed by fluid injections into symptomatic
259
neck muscles in both groups is difficult to explain because
dry needling was not included as an additional comparison
group (Garvey et al., 1989). Also, the heavy incidence of
AEs in the BTXA group suggests that perhaps the injection
dosages were too high. There is evidence from patients in
clinical practice that low dosages may provide more beneficial effects. Previous work (Wheeler et al., 1998) showed a
similar improvement in both magnitude and duration of
neck pain and related symptoms using lower BTXA
dosages, but the incidence of AEs was significantly reduced.
Furthermore, the 1998 study and our more recent examination of injection techniques with clinic patients (Wheeler
and Goolkasian, 2001) suggests that BTXA therapy aimed
at pain reduction in MPS may be more effective when treatments are applied sequentially by using lower BTXA dosing
for the initial injection session, and then if necessary,
providing additional BTXA at a second treatment session
in 1–4 months with caution to avoid immunogenecity.
Other therapies combined with BTXA may be essential to
achieve reduction of muscular neck pain (Taimela et al.,
2000). Porta (2000) stressed the importance of combining
BTXA injections with physiotherapy; indeed, in our recent
retrospective evaluation of privately treated patients, we
found physiotherapy to be a necessary programmatic
element before and after injection sessions and suggest
that it may be requisite for long-term resolution of pain,
beyond any influence by the toxin. Chronic pain implies
the presence of a refractory condition that has persisted
beyond the usual period of tissue healing despite access to
standard medical care, advice, and treatment. Operant
barriers to recovery coexist with a multiplicity of ineffective
treatments. In fact, chronic pain treatment is a contemporary
oxymoron (Wheeler, 1995).
A single BTXA injection session without physical therapy is not an effective treatment for chronic neck pain. As
research methodology is refined to better evaluate the efficacy of BTX for pain treatment, then perhaps a consensus
statement delineating its clinical utility and agreed-upon
practice parameters can be established. Multiple questions
and other variables impede research, including study design,
i.e. exclusion/inclusion criteria, procedural methodology,
and injection techniques. BTXA has been demonstrated as
an effective treatment for some painful disorders. However,
the procedure that appears most effective in clinical practice
for neck pain is one that includes low-dose applications with
one or two repeat injection sessions. Future research is
aimed at studying the effectiveness of repeated dosing of
BTXA in comparison to NS.
Acknowledgements
This study was supported by a grant from Allergan Pharmaceutical Corporation. The authors wish to acknowledge
the valuable assistance and contribution of Cynthia L.
Tucker, R.N. during the various phases of this project.
260
A.H. Wheeler et al. / Pain 94 (2001) 255–260
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