Botulinum toxin A for the treatment of chronic neck pain

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1 Pain 94 (2001) 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 /01/$20.00 q 2001 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. PII: S (01)00358-X

2 256 A.H. Wheeler et al. / Pain 94 (2001) 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 therapeutic 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 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.

3 A.H. Wheeler et al. / Pain 94 (2001) Table 1 Group scores on the pre-injection measures Variable BTXA Saline t-test P value Chi square M SD M SD Age , Education (year) Duration (month) , Algometer (kg/cm 2 ) , NPAD Beck , SF-36 physical , SF-36 mental Employed (%) Gender-female (%) 80 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) 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 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)) (50.1) (39.1) Injection regions Mid-upper cervical (%) 2 0 Mid-lower cervical (%) Trapezius (%) Thoracic (%) 2 0 Total (%) 50 50

4 258 A.H. Wheeler et al. / Pain 94 (2001) 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 NPAD BTXA 54.2(14.8) 52.2(16) 45.6(21.7) 38.0(20.9) 40.1(16.7) NS 48.2(12.0) 39.0(16) 36.6(15.8) 34.6(15.8) 32.9(16.5) Patient-GAS BTXA 0.2(1.6) 0.8(1.9) 1.4(1.60) 1.0(1.7) NS 1.2(1.5) 1.3(1.6) 1.5(1.8) 1.3(1.9) Physician-GAS BTXA 0.2(1.6) 0.9(1.4) 1.4(1.2) 1.0(1.4) NS 1.1(1.1) 1.2(1.4) 1.3(1.4) 1.2(1.5) Algometer (control treatment) BTXA 3.4(1.1) 1.8(1.6) 1.9(1.4) 1.7(1.3) 1.9(1.6) NS 4.0(1.5) 1.6(2.2) 2.3(3.0) 1.9(2.3) 1.9(3.1) Beck BTXA 9.2(4.5) 6.8(5.1) 7.2(5.6) NS 8.0(4.5) 7.7(5.8) 6.8(5.8) SF-36 mental BTXA 44.4(9.6) 46.1(9.7) NS 50.2(9.0) 51.5(7.6) SF-36 physical BTXA 39.1(10.3) 42.5(8.4) NS 40.7(9.0) 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 ¼22:11; 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 ¼3:43; P, 0:02; for the physician GAS, Fð3; 126Þ ¼4:22; 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 ¼17:04; 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.

5 A.H. Wheeler et al. / Pain 94 (2001) 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 ¼7:07; P, 0:01; and a main effects of group Fð1; 43Þ ¼6:84; P, 0:01; and time, Fð3; 138Þ ¼29:90; 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 ¼6:84; 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 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.

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