There were no significant differences between BoNT-A and placebo groups using the SF-36 scale for quality of life measures (Table 5) comparing week 26 to baseline. However, as noted in Table 5, improvement in the interference scores for general activity (P = 0.046 [0.038, 3.700]) and sleep (P = 0.02 [0.37, 4.33]) were found in subjects who received BoNT-A compared to placebo. Other BPI interference scores that appeared to trend with an improvement of a larger degree in the BoNT-A group compared to placebo over the 26-week time period were mood, work, and enjoyment.
There were no significant associations found between treatment groups and physical examination findings, such as internal rounding of shoulders, forward head syndrome,25 coracoid-to-tragus measurements plumb line, and number of painful trigger points.
Subjects who received BoNT-A had a reduction in the number of headaches experienced per week (P = 0.04 [0.07, 4.55]) (Table 5), when comparing week 26 to baseline. A decrease in the worst headache VNS pain scores from week 0 to week 26 (P = 0.07) was found to trend toward a greater reduction in the BoNT-A group compared to placebo. Best and average headache VNS pain scores and duration of headache were not found to have any significant change between treatment groups from week 26 compared to baseline.
To compare mean average BPI VNS scores over time between the BoNT-A and placebo groups, a GEE model was used. The terms of the GEE model were time, group, and a group/time interaction. The group effect tests whether there was an overall mean difference between BPI pain scores between the BoNT-A and placebo groups over time. The hypothesis was not that there was an overall difference in the BPI pain scores between groups, but that the decrease in BPI pain scores was “steeper” in the BoNT-A group than the placebo group over time (interaction term). From the GEE model, we found a significant time × treatment interaction (−0.27 [0.51, −0.03]); P value = 0.028. This means that for each timepoint, the difference in mean average BPI VNS score between BoNT-A and placebo decreases by about 0.27 units. Thus, in the presence of a significant interaction term, the group main effect is no longer relevant because the interaction term is telling us that the group effect does matter and that it depends on another variable, time. The interpretation of this finding is that both groups decrease over time, but that the BoNT-A group decreases significantly more than the placebo group over time.
Outcomes Analysis: Phase 2
The second phase of the study was analyzed separately from the first phase of the study to determine whether there was further significant improvement that could be appreciated after a second dose of BoNT-A. The week 26 visit was compared to the week 12 visit (this visit can be considered the “new baseline” because all patients entering the second phase of the trial had received BoNT-A).
Analysis of the outcome measures to distinguish an effect of the BoNT-A injections revealed that there was a significant decrease in the average (P = 0.02 [0.30, 2.91]) and worst (P = 0.03 [0.21, 3.86]) VNS pain scores from week 26 to week 12, as measured by the BPI in the BoNT-A–injected group compared to placebo (Table 6). No other significant changes were found in best VNS pain scores, postural analysis, and NDI.
Physical functioning as measured by the SF-36 scale was found to be significantly different in those who received placebo compared to BoNT-A, indicating that physical functioning worsened after they received a placebo injection (P = 0.02 [−1.30, −0.16]) (Table 7) for week 26 compared to week 12. The General Health SF-36 quality of life outcome appeared to trend toward improvement compared to placebo (P = 0.10). No other significant associations were found with regard to quality of life outcomes using the SF-36 or BPI interference scores.
Subjects who received placebo were found to have an increased number of headaches per week compared to subjects who received BoNT-A injection (P = 0.049 [0.007, 3.61]) (Table 7). There was a decrease in the worst headache VNS pain scores from week 26 to week 12 (P = 0.08) in those who received a second dose of BoNT-A; however, an increase in this pain measure was found in those who received placebo injection. Best and average headache VNS pain scores and duration of headache were not found to have any significant change between treatment groups.
False discovery rates were computed on the 4 exploratory secondary outcome measures as found in Tables 5 and 7, to assess the possibility of false positives from running multiple tests. The calculated FDRs for these Tables were 16.1% and 19.6%, respectively. With the FDRs in this range, this allows for a reasonable level of confidence that there is an overall treatment effect signal within the secondary outcome measure analyses. Thus, among the results found to be significant by the traditional standard alpha level of 0.05, it can be expected that a clear majority (80%–85%) of these are true effects rather than false positives.
The results of this study suggest that injection of BoNT-A into painful muscle groups of the neck and shoulder area improves pain relief in subjects with cervical and shoulder girdle myofascial pain syndrome. In a study by Ferrante et al.,9 no significant improvement in cervicothoracic myofascial pain was found when patients underwent injection of BoNT-A directly into painful trigger points. The conclusions of that study were 2-fold in the mechanism of inefficacy: either BoNT-A lacked efficacy in treating cervicothoracic myofascial pain or the lack of efficacy could be methodological, meaning the optimal way to treat myofascial pain with BoNT-A is to not inject directly into trigger points. The latter conclusion is most likely, given the findings of our present study. Our results advocate using a combined follow-the-pain and pattern injection technique in lieu of direct trigger point injections.
The enriched protocol design used for this study is unique and may have advantages over the standard randomized clinical trial design for studies evaluating the effect of an intervention for chronic pain.22 One advantage is that it provides information of a response rate after phase one of the study. In our study, 50% of subjects were characterized as responders. This is useful information in its own right, as it serves to be an important predictor of what will happen with the drug in clinical practice.28 In addition, in standard randomized clinical trials, there is always the possibility that the true effect size may be underestimated due to the inclusion of patients who are unlikely to respond to therapy. This could possibly lead to the appearance of a negative trial, when in fact a subgroup may have experienced a genuine benefit. With the enriched protocol design, only the responders are included in the randomized controlled trial, which may lead to a more accurate representation of the true effect and response of the treatment.
In the present study, subjects who received a second dose of BoNT-A in the second phase of the study had continued dramatic improvement in their pain scores, which was statistically significant compared to those who received placebo. Subjects who received placebo injections in the second phase of the study had worsening of their pain scores in the 12 weeks after the second injection. Given that the subgroup of patients included in the second phase of the study were responders to BoNT-A, this fact serves to support the statement that there is a true treatment effect and that the difference is not purely a placebo effect. This also may indicate that repetitive dosing of BoNT-A may be indicated to provide sustained pain relief in clinical practice.
Quality of life remains a very important secondary outcome to measure in chronic pain populations, and the results of this study suggest that BoNT-A reduces the interference of chronic pain in certain facets of everyday living. There was a reduction over the 26-week time period in the interference of chronic pain for general activity and sleep, as measured by BPI interference scores. Many other BPI interference scores (mood, work, and enjoyment) appear to trend with an improvement of a larger degree in the BoNT-A group compared to placebo over the 26-week time period. When the second phase of the study (week 12 to week 26) was analyzed for quality of life measures, there was a worsening in physical functioning in those subjects who received placebos compared to BoNT-A. All other quality of life measures, as measured by BPI interference scores and SF-36 scores, failed to show any significant improvement in the second phase of the study for those subjects who received BoNT-A. However, the trend toward improvement continued after a second injection.
Given that quality of life measures were secondary, hypothesis-generating outcomes, it is possible that the current study was not adequately powered to reveal associations across all quality of life measures. Substantial improvement was found in 2 BPI interference scores, and many interference scores were improved to a larger degree when compared to the placebo group. This trend suggests that BoNT-A may improve multiple facets of quality of life. Thus, further large-scale studies that are adequately powered to reveal associations for quality of life outcome measures are warranted to confirm this. It is also notable that most quality of life scores worsened for those who received placebo injection. This likely represents a decrease in the efficacy of the BoNT-A toxin over time and likely supports the notion that repetitive injections are necessary for continued and sustained improvement. Analysis of headaches as a secondary end point demonstrated that subjects who received a second dose of BoNT-A had a significantly decreased number of headaches per week compared to those who received placebo. However, it deserves mention that subjects who received placebo actually had an increase in the number of headaches per week compared to baseline, which may indicate that repetitive dosing of BoNT-A may be indicated to treat this condition.
Given the correlation of depression with chronic pain, there was concern for confounding of results due to underlying depression.29 However, baseline Beck Depression scores were <13 in both placebo and BoNT-A groups, which correlates to minimal depression.30 Because there was no significant depression in the study cohort, the likelihood of depression being a confounder of the results of this study is unlikely.
Adverse effects related to BoNT-A injections have been well reported in the literature and include excessive weakness of injected muscles, weakness of uninjected muscles through regional spread, weakness of remote muscles due to hematogenous spread, dry mouth, reduced sweating, reduced lacrimation, skin rash, flu-like illness, brachial neuritis–like syndrome, bruising, bleeding, and pain at injection site.31–33 Most adverse effects are related to muscle weakness, either those injected or those nearby, which become weak due to local spread of the toxin.34 The specific symptoms that arise tend to correlate to the region the toxin is injected. Injections in the neck can produce weakness of neck movement, difficulty holding up the head against gravity, difficulty swallowing, and weakness of the voice. In the present study, there was a low incidence of these well-described adverse effects, including flu-like illness (n = 9), arthralgias (n = 1), and fatigue (n = 4). Twenty-nine patients reported a mild and vague sensation of weakness in the neck; however, of these, 4 patients reported significant weakness. These 4 patients described the weakness sensation as being such that when they would bend forward to brush their teeth, they would have a sensation that their head was “flopping forward.” All the patients who reported significant sensation of weakness in the neck were urgently seen and examined. None of these 4 patients, nor any of the patients in the present study, developed paralysis of any injected or uninjected muscles, and all had full range of motion and control. In patients who reported a sensation of weakness in the neck, the effects were transient and resolved within 7 to 10 days.
In patients with chronic pain, there are many outcomes by which treatment success can be measured. In the present study, pain scores and quality of life measures were used to determine proof-of-concept for the injection method used. In future studies, an outcome that would be of utmost importance to measure is the evaluation of medication usage (analgesics, topicals, and muscle relaxants) and its change with treatment. It would be expected for medication usage to decrease or cease upon successful treatment of myofascial pain. In addition, recovery of function (physical and mental) would be essential to measure in this population. Successful treatment of myofascial pain should yield improved physical functioning such as activity level and ability to work as well as improved mental functioning by way of enriched mood, interpersonal relationships, and sleep.
Prospective, placebo-controlled studies evaluating the efficacy of BoNT-A for the treatment of myofascial pain are limited, with contradicting results. Freund and Schwartz35 performed a double-blind, randomized, placebo-controlled trial of direct trigger point injection in patients with chronic whiplash injuries, showing a significant reduction in pain and improved cervical range of motion 4 weeks after BoNT-A injection. Göbel et al.36 performed a double-blind, randomized, placebo-controlled trial that showed significant improvement in pain levels 4 to 6 weeks after treatment using a single trigger point injection technique. A recent study by Benecke et al.37 showed significant improvement in pain levels for patients receiving BoNT-A using a fixed-location injection technique; however, the authors note that the length of time to significant pain relief was longer in those who received the fixed-location injections compared to injection directly into trigger points. Miller et al.38 performed a prospective, double-blind, placebo-controlled study using a “follow the pain” and fixed-location injection technique. They found a significant reduction in pain intensity that lasted for at least 2 months.
Wheeler et al.39 performed a double-blind, randomized, placebo-controlled trial of direct trigger point injection without significant positive results after a single injection session. However, in that study, most patients only had BoNT-A injected into their trapezius muscle, with the remainder having injections into 7 different neck sites. Injection sites did not include the upper or middle cervical regions. Ojala et al.40 performed a randomized, double-blind, placebo-controlled, crossover trial that showed no significant improvement in cervical and shoulder girdle myofascial pain syndrome. This study used small doses of BoNT-A (5 units per trigger point), which may have been too small to provide a clinical benefit.
A minority of the published data evaluating the efficacy of BoNT-A for myofascial pain have used trigger point injections with local anesthetic as the control treatment because these injections are the more common form of treatment. In a prospective crossover study by Graboski et al.,41 subjects received 25 units of BoNT-A or 0.5 mL of 0.5% bupivacaine in a maximum of 8 trigger points and after pain returned for at least 2 consecutive weeks with an additional 2 week “washout” period, received injections of the other substance. They found no statistically significant difference between the 2 treatments and deemed bupivacaine to be more cost-effective. Despite no clinical significance, there was a definite trend toward a greater decrease in pain and longer duration of action of BoNT-A. Possible limitations of this study leading to a negative result were a small sample size and the limited number of trigger points injected. Kamanli et al.42 compared BoNT-A trigger point injections with dry needling and lidocaine injections. Pain scores were lower in subjects treated with BoNT-A and dry needling, and at a 4-week follow-up, the lidocaine and BoNT-A groups had significantly decreased visual analog scale scores. BoNT-A was not found to be inferior to lidocaine or dry needling in this study. Possible issues in the interpretation of the results of this study were that only a single trigger point was treated and the sample size per group was relatively low.
In conclusion, we examined the efficacy of BoNT-A, not only with respect to pain relief but also examined the constructs of postural analysis, health-related quality of life, disability, and headache. The results of the present study suggest that injection of BoNT-A into painful cervical and shoulder girdle muscle groups, as opposed to direct injection of painful trigger points, provides improvement in average pain scores, a reduction in the number of headaches per week, and improvement in certain facets of quality of life for at least 12 weeks. Furthermore, large-scale studies using the technique of injecting painful muscle groups instead of painful trigger points are warranted, given our positive findings. Further studies evaluating whether repetition of BoNT-A injections has a synergistic or additive effect may be of more than passing interest.37
Name: Andrea L. Nicol, MD, MS.
Contribution: Dr. Nicol helped in data collection, data analysis, and manuscript preparation.
Attestation: Dr. Nicol approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Irene I. Wu, MD.
Contribution: Dr. Wu helped in data collection and manuscript preparation.
Attestation: Dr. Wu approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: F. Michael Ferrante, MD.
Contribution: Dr. Ferrante helped in design and conduct of the study, data collection, data analysis, and manuscript preparation.
Attestation: Dr. Ferrante approved the final manuscript, attests to the integrity of the original data and the analysis reported in this manuscript, and is the archival author.
This manuscript was handled by: Spencer S. Liu, MD.
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© 2014 International Anesthesia Research Society
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