The Journal of Bone & Joint Surgery

The Journal of Bone & Joint Surgery, Volume 89, Issue 2

Scientific Articles | February 01, 2007

Treatment of Chronic Radial Epicondylitis with Botulinum Toxin A: A Double-Blind, Placebo-Controlled, Randomized Multicenter Study

Richard Placzek, MD¹; Wolf Drescher, MD, PhD²; Georg Deuretzbacher, PhD³; Axel Hempfing, MD⁴; A. Ludwig Meiss, MD³

¹ Centrum für Muskuloskeletale Chirurgie, Kliniken für Orthopädie,Unfall- und Wiederherstellungschirurgie, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail address: richard.placzek@charite.de
² Orthopädische Universitätsklinik Frankfurt a.M. Marienburgstrasse 2, 60528 Frankfurt am Main, Germany
³ Orthopädische Universitätsklinik Hamburg-Eppendorf Martinistrasse 52, 20246 Hamburg, Germany
⁴ Orthopädische Universitätsklinik Heidelberg, Schlierbacher Landstrasse 200a, 69118 Heidelberg, Germany

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Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from Ipsen Pharma, Ettlingen, Germany. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

Investigation performed at Orthopädische Universitätsklinik Hamburg-Eppendorf, Hamburg, Germany

The Journal of Bone and Joint Surgery, Incorporated

J Bone Joint Surg Am, 2007 Feb 01;89(2):255-260. doi: 10.2106/JBJS.F.00401

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Abstract

Background: Radial epicondylitis (tennis elbow) is the most frequent type of myotendinosis. Patients can experience substantial loss of function, especially when this condition becomes chronic. A successful therapy has not yet been established. A preliminary study of injections of botulinum toxin A in patients with chronic epicondylitis has shown promising results.

Methods: In the present prospective, controlled, double-blinded clinical trial, 130 patients were examined at sixteen study centers. A single injection of botulinum toxin A into the painful origin of the forearm extensor muscles was performed. Follow-up examinations were performed at two, six, twelve, and eighteen weeks. Clinical findings were documented with use of a new clinical pain score and with a visual analogue scale. A global assessment of the result of treatment was also provided by the patient and the attending doctor. Strength of extension of the third finger and the wrist was evaluated with use of the Brunner method, and grip strength (fist closure strength) was measured with a vigorimeter.

Results: The group treated with botulinum toxin A was found to have a significant improvement in the clinical findings, compared with those in the placebo group, as early as the second week after injection (p = 0.003). Subjective general assessment also showed improvement in that group, compared with the placebo group, at six weeks (p = 0.001) and at the time of the final examination (at eighteen weeks) (p = 0.001). There was a consistent increase in fist closure strength in both the group treated with botulinum toxin A and the control group, but there was no significant difference between groups. As was expected as a side effect, extension of the third finger was observed to be significantly weakened at two weeks but this complication had completely resolved at eighteen weeks.

Conclusions: We concluded that local injection of botulinum toxin A is a beneficial treatment for radial epicondylitis (tennis elbow). The treatment can be performed in an outpatient setting and does not impair the patient's ability to work.

Level of Evidence: Therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence.

Figures in this Article

Radial epicondylitis (tennis elbow) was apparently first described in 1873 by Runge¹. With an incidence of four to five patients per thousand, it is the most frequently seen myotendinosis^1-3. A wide range of conservative treatment measures, such as physical therapy, special bandages, immobilization in a cast for several weeks, local steroid injections^1,4-9, and extracorporeal shock wave therapy, have been applied¹⁰. When conservative treatment is unsuccessful, surgical treatment options include a release of the forearm extensor muscles from the epicondyle^11,12 and division of the branches of the radial nerve¹³.

Injection of botulinum toxin A into the origin of the forearm extensor muscles was apparently first reported as a new treatment option in 1997, in a series of fourteen patients¹⁴. A more recent study demonstrated results that were similar to those of operative treatment¹⁵. The rationale for botulinum toxin treatment is that it reversibly paralyzes the extensor muscles by temporarily blocking the neuromuscular end plate, thus preventing repetitive microtrauma of the tendinous fibers at their origin from the osseous lateral epicondyle. Our preliminary study of sixteen patients showed a significant improvement in the clinical findings at the time of follow-up at fourteen weeks, compared with those at the time of injection (p < 0.002), and a decrease in subjective pain¹⁶. Recently, Hayton et al.¹⁷ reported that, compared with placebo treatment, botulinum toxin had no significant effect on the treatment of chronic radial epicondylitis. However, they studied only forty patients and followed them for only three months. Wong et al. reported on a larger study of sixty subjects¹⁸. At four weeks, their group treated with botulinum toxin A had a significant improvement in the visual analogue score for pain, compared with that in the placebo group (p < 0.001), and this improvement was maintained at twelve weeks (p = 0.006).

The aim of the present study was to explore the hypothesis that injection of botulinum toxin A into the proximal forearm extensor muscles is superior to use of a placebo in the treatment of chronic tennis elbow.

Materials and Methods

Materials and Methods | Results | Discussion | References

Approval for the study was obtained from the Ethical Committee of the Chamber of Physicians of Hamburg, and the study was registered as number 4018635 with the Federal Institute for Drugs and Medical Devices in Germany. All patients gave written informed consent.

The study was performed and monitored at sixteen study centers. Data management and scientific analysis were centralized in an independent institution (Institut für Klinische Pharmakologie, Bobenheim, Germany).

A total of 132 patients with radial epicondylitis were included in the study. The inclusion and exclusion criteria are summarized in Table I. The patients were block randomized into two groups with use of computer-generated software (RanCode; IDV, Gauting, Germany). One group received an injection of botulinum toxin A (0.6 mL of NaCl 0.9% with 60 mouse units of Dysport; Ipsen Pharma, Ettlingen, Germany) and the other received a placebo (0.6 mL of NaCl 0.9% without botulinum toxin) with use of a double-blinded procedure. The solution was drawn up independently, and the injection was performed by a physician who was blinded to its content. Both injection solutions were colorless and of equal temperature.

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TABLE I Relevant Inclusion and Exclusion Criteria

Inclusion Criteria	Exclusion Criteria
Chronic radial epicondylitis (duration of the disorder of =4 mo after the initial diagnosis)	Cervicobrachial syndrome
Total score of 4 points, including 2 points for pressuresensitive pain, on standardized examination for radial epicondylitis (see Table II)	Radiographic evidence of osseous changes in the affected elbow region
	Prior surgical treatment of the affected elbow region
	Known allergy or antibodies to botulinum toxin A
=3 different conservative therapy measures tried without success	Known muscle diseases or diseases of neuromuscular transmission
No evidence of other specific diseases of the musculoskeletal system on physical examination	Injection of prohibited or undocumented concomitant medication such as glucocorticoids and/or local anesthetics
Availability of a routine radiograph or magnetic resonance tomogram made =12 mo previously	Depression
	Inability to work due to radial epicondylitis for >3 successive mo or current compensation claims due to radial epicondylitis
	Pregnancy or lactation
	Participation in other clinical studies

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TABLE I Relevant Inclusion and Exclusion Criteria

Inclusion Criteria	Exclusion Criteria
Chronic radial epicondylitis (duration of the disorder of =4 mo after the initial diagnosis)	Cervicobrachial syndrome
Total score of 4 points, including 2 points for pressuresensitive pain, on standardized examination for radial epicondylitis (see Table II)	Radiographic evidence of osseous changes in the affected elbow region
	Prior surgical treatment of the affected elbow region
	Known allergy or antibodies to botulinum toxin A
=3 different conservative therapy measures tried without success	Known muscle diseases or diseases of neuromuscular transmission
No evidence of other specific diseases of the musculoskeletal system on physical examination	Injection of prohibited or undocumented concomitant medication such as glucocorticoids and/or local anesthetics
Availability of a routine radiograph or magnetic resonance tomogram made =12 mo previously	Depression
	Inability to work due to radial epicondylitis for >3 successive mo or current compensation claims due to radial epicondylitis
	Pregnancy or lactation
	Participation in other clinical studies

The injection was administered with a standard 25-gauge 42-mm needle (Miraject; Hager and Werken, Duisburg, Germany) approximately 3 to 4 cm distal to the tender epicondyle, with infiltration of the muscle at two locations; the second location was injected after partial withdrawal of the needle and rotating it in the horizontal plane. Patients did not receive additional injections. Physical therapy was withheld for six weeks after injection, and only the use of diclofenac (50 to 150 mg/day) was permitted to treat resistant pain.

Follow-up examinations were performed at two, six, twelve, and eighteen weeks. Clinical findings were documented with use of a new clinical pain score (Table II) that we developed to assess patients' pain and that was shown to be reliable in a previous study¹⁶. The highest possible pain score—i.e., for the most severe disease—was 10 points, and a minimum of 4 points was necessary to be included in the study.

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TABLE II Clinical Pain Score

	Score^* (points)
Clinical Examination	Positive	Undefined	Negative
Pain on isometric extension of the wrist	2	1	0
Pain on isometric extension of the third finger	2	1	0
Pain on passive flexion of the wrist with the elbow extended	2	1	0
Pain on passive flexion of the third finger with the elbow extended	2	1	0
Localized tenderness at the lateral epicondyle	2	1	0

If all tests are positive, the score is 10 points.

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TABLE II Clinical Pain Score

	Score^* (points)
Clinical Examination	Positive	Undefined	Negative
Pain on isometric extension of the wrist	2	1	0
Pain on isometric extension of the third finger	2	1	0
Pain on passive flexion of the wrist with the elbow extended	2	1	0
Pain on passive flexion of the third finger with the elbow extended	2	1	0
Localized tenderness at the lateral epicondyle	2	1	0

If all tests are positive, the score is 10 points.

Additionally, the patients recorded their subjective assessment of pain on two visual analogue scales ranging from 0 to 10. One scale was for continuous pain during the previous forty-eight hours, and the other was for maximum pain during the previous forty-eight hours. Strength of extension of the third finger and the wrist was evaluated with use of the Brunner method (a strength scale of 0 to 5)¹⁹. Grip strength (fist closure strength) was measured with use of a vigorimeter (Gebrüder Martin, Tuttlingen, Germany) with the elbow fully extended²⁰. The result of treatment was globally assessed by the patient and by the attending doctor as substantially better than before the injection (4 points), slightly better (3 points), unchanged (2 points), slightly worse (1 point), or substantially worse (0 points). The amount of allowed ancillary pain medication (diclofenac) consumed was recorded.

The results in the botulinum group were compared with those in the placebo group at the point of injection and at the four follow-up intervals. The Mann-Whitney U test was performed with a standard software program (STATISTICA 6.0; StatSoft, Bedford, United Kingdom) for statistical analysis, and differences were considered significant when the p value was <0.05. A rough estimate was based on the pilot study, which revealed significant results at six weeks after injection (p = 0.0007 for the clinical evaluation score, p = 0.0229 for the visual analogue score for continuous pain, and p = 0.0061 for the visual analogue score for maximum pain).

Results

Materials and Methods | Results | Discussion | References

Overall, 132 patients were included in the treatment phase of the study and were randomly assigned to receive either botulinum toxin A (seventy patients) or a placebo (sixty-two patients). Sixty-eight patients (thirty-seven women and thirty-one men with an average age [and standard deviation] of 47.4 ± 8.7 years) treated with botulinum toxin A and sixty-two patients (thirty-two women and thirty men with an average age of 46.9 ± 9.4 years) in the placebo group completed the study (n = 130). The median duration of the disease prior to inclusion in the study was 9.0 months in the total patient population, 8.0 months in the group treated with botulinum toxin A, and 10.0 months in the placebo group. The overall period of recruitment lasted from March 2002 to December 2003. The follow-up was completed in May 2004. The total patient population had been treated with an average of 3.6 preceding conservative treatment measures without adequate improvement.

In the group treated with botulinum toxin A, the clinical pain score showed significant improvement (p < 0.025), compared with the score in the placebo group, and progressive improvement during the entire follow-up period (Table III). The visual analogue scores for continuous pain during the previous forty-eight hours were also significantly improved, compared with those in the placebo group, from the sixth week onward (p = 0.01). There was considerable variation in the scores for maximum pain during the previous forty-eight hours, and no significant difference in those scores was found between the botulinum and placebo groups (Table IV). From the sixth week onward, the patients' global assessment of their satisfaction compared with that before the injection was significantly better (p < 0.05) in the botulinum group, as was the (blinded) doctors' global assessment (p < 0.05) (Table V). Analysis of side effects showed no significant differences between the botulinum and placebo groups with respect to the strength of wrist extension against resistance and fist closure strength during the period of action of the medication of about fourteen weeks. Only the strength of extension of the third finger was decreased significantly in the botulinum group at two weeks (p = 0.0007). This weakness persisted until the fourteenth week and had ceased completely by eighteen weeks. Table VI shows the values for extension strength of the third finger against resistance and for wrist extension against resistance as measured with the Brunner method (on a scale of 0 to 5 points) at each of the follow-up intervals.

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TABLE III Comparison of Clinical Pain Scores Between Groups

	Score^*
Visit	Botulinum	Placebo	P Value†
Injection	8.43 ± 0.24 (68)	8.55 ± 0.21 (62)	0.920
Week 2	5.24 ± 0.38 (68)	6.85 ± 0.35 (61)	0.003
Week 6	4.53 ± 0.37 (68)	5.69 ± 0.37 (61)	0.020
Week 12	3.76 ± 0.36 (68)	5.02 ± 0.41 (61)	0.023
Week 18	2.88 ± 0.35 (68)	4.29 ± 0.41 (57)	0.009

^*The values are given as the mean clinical pain score (see Table II) and the standard error of the mean with the number of patients in parentheses. †The level of significance of the difference between the botulinum and placebo groups as assessed with the Mann-Whitney U test.

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TABLE III Comparison of Clinical Pain Scores Between Groups

	Score^*
Visit	Botulinum	Placebo	P Value†
Injection	8.43 ± 0.24 (68)	8.55 ± 0.21 (62)	0.920
Week 2	5.24 ± 0.38 (68)	6.85 ± 0.35 (61)	0.003
Week 6	4.53 ± 0.37 (68)	5.69 ± 0.37 (61)	0.020
Week 12	3.76 ± 0.36 (68)	5.02 ± 0.41 (61)	0.023
Week 18	2.88 ± 0.35 (68)	4.29 ± 0.41 (57)	0.009

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TABLE IV Comparison, Between Groups, of Visual Analogue Scores for Continuous Pain and Maximum Pain During the Last Forty-eight Hours Between Groups

	Score^*
	Botulinum			Placebo			P Value†
Visit	Continuous Pain	Maximum Pain	Continuous Pain	Maximum Pain	Continuous Pain	Maximum Pain
Injection	4.79 ± 0.27 (68)	7.56 ± 0.20 (68)	4.79 ± 0.30 (62)	7.15 ± 0.22 (62)	0.938	0.158
Week 2	3.60 ± 0.31 (68)	6.22 ± 0.31 (68)	4.25 ± 0.29 (61)	6.36 ± 0.26 (61)	0.147	0.874
Week 6	2.93 ± 0.26 (68)	4.94 ± 0.31 (68)	4.07 ± 0.32 (61)	5.72 ± 0.31 (61)	0.010	0.103
Week 12	2.47 ± 0.28 (68)	4.16 ± 0.35 (68)	3.16 ± 0.31 (61)	4.70 ± 0.30 (61)	0.098	0.224
Week 18	1.82 ± 0.26 (68)	3.56 ± 0.33 (68)	2.68 ± 0.31 (57)	4.13 ± 0.35 (57)	0.035	0.259

^*The values are given as the visual analogue score (on a scale of 0 to 10) and the standard error of the mean with the number of patients in parentheses. †The level of significance of the difference between the botulinum and placebo groups as assessed with the Mann-Whitney U test.

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TABLE IV Comparison, Between Groups, of Visual Analogue Scores for Continuous Pain and Maximum Pain During the Last Forty-eight Hours Between Groups

	Score^*
	Botulinum			Placebo			P Value†
Visit	Continuous Pain	Maximum Pain	Continuous Pain	Maximum Pain	Continuous Pain	Maximum Pain
Injection	4.79 ± 0.27 (68)	7.56 ± 0.20 (68)	4.79 ± 0.30 (62)	7.15 ± 0.22 (62)	0.938	0.158
Week 2	3.60 ± 0.31 (68)	6.22 ± 0.31 (68)	4.25 ± 0.29 (61)	6.36 ± 0.26 (61)	0.147	0.874
Week 6	2.93 ± 0.26 (68)	4.94 ± 0.31 (68)	4.07 ± 0.32 (61)	5.72 ± 0.31 (61)	0.010	0.103
Week 12	2.47 ± 0.28 (68)	4.16 ± 0.35 (68)	3.16 ± 0.31 (61)	4.70 ± 0.30 (61)	0.098	0.224
Week 18	1.82 ± 0.26 (68)	3.56 ± 0.33 (68)	2.68 ± 0.31 (57)	4.13 ± 0.35 (57)	0.035	0.259

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TABLE V Comparison, Between Groups, of Patient's and Doctor's Global Assessments

	Score^*
	Botulinum			Placebo			P Value†
Visit	Patient's	Doctor's	Patient's	Doctor's	Patient's	Doctor's
Week 2	2.47 ± 0.11 (68)	2.63 ± 0.10 (68)	2.26 ± 0.10 (61)	2.37 ± 0.09 (61)	0.107	0.034
Week 6	2.90 ± 0.11 (68)	3.06 ± 0.10 (68)	2.34 ± 0.12 (61)	2.45 ± 0.11 (61)	0.001	0.000
Week 12	3.00 ± 0.12 (68)	3.09 ± 0.11 (68)	2.69 ± 0.11 (61)	2.68 ± 0.11 (61)	0.047	0.006
Week 18	3.31 ± 0.10 (68)	3.29 ± 0.10 (68)	2.76 ± 0.12 (57)	2.81 ± 0.11 (57)	0.001	0.002

^*The values are given as the global assessment score and the standard error of the mean with the number of patients in parentheses. The score was prompted by the question "Is your (the patient's) condition substantially better (4 points), slightly better (3 points), unchanged (2 points), slightly worse (1 point), or substantially worse (0 points) compared with your (the patient's) condition at the time before injection?" †The level of significance of the difference between the botulinum and placebo groups as assessed with the Mann-Whitney U test.

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TABLE V Comparison, Between Groups, of Patient's and Doctor's Global Assessments

	Score^*
	Botulinum			Placebo			P Value†
Visit	Patient's	Doctor's	Patient's	Doctor's	Patient's	Doctor's
Week 2	2.47 ± 0.11 (68)	2.63 ± 0.10 (68)	2.26 ± 0.10 (61)	2.37 ± 0.09 (61)	0.107	0.034
Week 6	2.90 ± 0.11 (68)	3.06 ± 0.10 (68)	2.34 ± 0.12 (61)	2.45 ± 0.11 (61)	0.001	0.000
Week 12	3.00 ± 0.12 (68)	3.09 ± 0.11 (68)	2.69 ± 0.11 (61)	2.68 ± 0.11 (61)	0.047	0.006
Week 18	3.31 ± 0.10 (68)	3.29 ± 0.10 (68)	2.76 ± 0.12 (57)	2.81 ± 0.11 (57)	0.001	0.002

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TABLE VI Comparison, Between Groups, of Extension Strengths of the Third Finger and the Wrist

	Extension Strength^*
	Botulinum			Placebo			P Value†
Visit	Third Finger	Wrist	Third Finger	Wrist	Third Finger	Wrist
Injection	3.56 ± 0.13 (68)	3.66 ± 0.13 (68)	3.44 ± 0.17 (62)	3.56 ± 0.17 (62)	0.702	0.805
Week 2	2.92 ± 0.18 (68)	3.95 ± 0.11 (68)	3.82 ± 0.15 (61)	3.92 ± 0.14 (61)	0.001	0.990
Week 6	3.32 ± 0.14 (68)	4.12 ± 0.09 (68)	3.95 ± 0.12 (61)	4.02 ± 0.12 (61)	0.004	0.631
Week 12	3.56 ± 0.15 (68)	4.35 ± 0.10 (68)	4.12 ± 0.12 (61)	4.22 ± 0.11 (61)	0.007	0.379
Week 18	4.09 ± 0.13 (68)	4.53 ± 0.08 (68)	4.11 ± 0.14 (57)	4.21 ± 0.13 (57)	0.834	0.095

^*The values are given as the extension strength (as graded according to the Brunner scale of 0 to 5) and the standard error of the mean with the number of patients in parentheses. †The level of significance of the difference between the botulinum and placebo groups as assessed with the Mann-Whitney U test.

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TABLE VI Comparison, Between Groups, of Extension Strengths of the Third Finger and the Wrist

	Extension Strength^*
	Botulinum			Placebo			P Value†
Visit	Third Finger	Wrist	Third Finger	Wrist	Third Finger	Wrist
Injection	3.56 ± 0.13 (68)	3.66 ± 0.13 (68)	3.44 ± 0.17 (62)	3.56 ± 0.17 (62)	0.702	0.805
Week 2	2.92 ± 0.18 (68)	3.95 ± 0.11 (68)	3.82 ± 0.15 (61)	3.92 ± 0.14 (61)	0.001	0.990
Week 6	3.32 ± 0.14 (68)	4.12 ± 0.09 (68)	3.95 ± 0.12 (61)	4.02 ± 0.12 (61)	0.004	0.631
Week 12	3.56 ± 0.15 (68)	4.35 ± 0.10 (68)	4.12 ± 0.12 (61)	4.22 ± 0.11 (61)	0.007	0.379
Week 18	4.09 ± 0.13 (68)	4.53 ± 0.08 (68)	4.11 ± 0.14 (57)	4.21 ± 0.13 (57)	0.834	0.095

Table VII shows the values for fist closure strength, standardized to 1.00 relative units to demonstrate the change from the first examination (100%) at each of the follow-up intervals. There was a constant increase over time in both groups, with no significant difference between the groups.

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TABLE VII Comparison of Fist Closure Strength Between Groups

	Fist Closure Strength^*
Visit	Botulinum	Placebo	P Value†
Week 2	1.01 ± 0.08 (68)	1.14 ± 0.05 (61)	0.006
Week 6	1.34 ± 0.14 (68)	1.20 ± 0.07 (61)	0.876
Week 12	1.45 ± 0.15 (68)	1.27 ± 0.07 (61)	0.963
Week 18	1.56 ± 0.14 (68)	1.42 ± 0.11 (57)	0.532

^*The values are given as the fist closure strength (as assessed with a vigorimeter) and the standard error of the mean with the number of patients in parentheses. To enable comparisons, the values were normalized to 1.00 (100%) at the time of injection. †The level of significance of the difference between the botulinum and placebo groups as assessed with the Mann-Whitney U test.

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TABLE VII Comparison of Fist Closure Strength Between Groups

	Fist Closure Strength^*
Visit	Botulinum	Placebo	P Value†
Week 2	1.01 ± 0.08 (68)	1.14 ± 0.05 (61)	0.006
Week 6	1.34 ± 0.14 (68)	1.20 ± 0.07 (61)	0.876
Week 12	1.45 ± 0.15 (68)	1.27 ± 0.07 (61)	0.963
Week 18	1.56 ± 0.14 (68)	1.42 ± 0.11 (57)	0.532

Discussion

Materials and Methods | Results | Discussion | References

Although radial epicondylitis is a self-limiting disease, patients often request treatment and about one-quarter have recurrent symptoms. More than 40% of patients have been reported to have limitations of particular activities due to persistent pain²¹. When the disease becomes chronic, surgery can be considered. The result is often gratifying, but sometimes surgery is the beginning of an unfavorable clinical course^22,23. Therefore, we investigated the effects of injection of botulinum toxin A on chronic epicondylitis in a double-blind placebo-controlled multicenter study.

We concluded that botulinum toxin is clinically effective and beneficial for these patients. Our results are in agreement with those of our preliminary study¹⁶ and the conclusions of Morré et al.¹⁴ and Keizer et al.¹⁵.

However, Hayton et al.¹⁷ reached a different conclusion, finding no difference between the results of treatment with botulinum toxin and a placebo in their clinical trial. Their study was based on the injection of 50 U of Botox. Both Botox (Allergan, Irvine, California) and Dysport (Ipsen Pharma) are botulinum toxin A with a molecular weight of 900 kDa. Botulinum toxin A blocks the presynaptic release of acetylcholine at the motor end plate by intracellular division of SNAP-25 (synaptosomal-associated protein of 25 kDa). Additionally, it blocks the cholinergic sympathetic nerve endings of salivary glands and all acetylcholine-mediated parasympathetic processes of the internal organs. This results in palsy of skeletal muscles and atony of smooth muscles as well as dysfunction of parasympathetically innervated internal organs (so-called autonomic dysfunction) and attenuation of sympathetically innervated salivation²⁴. Botulinum toxin A does not pass the blood-brain barrier and has no cytotoxic effects^25,26. One hundred units of Dysport are equal to 20 to 40 U of Botox in their effect. Dysport is widely used in Europe, Asia, and Australia.

The study by Hayton et al.¹⁷ included only forty patients, who were examined prior to injection and at three months, without longer continuous follow-up. The authors found similar improvements in the scores for pain and quality of life in their botulinum and placebo groups. It is possible that the number of patients recruited into their study was too small to show a difference.

It can be suspected that the 50 U of Botox used by Hayton et al.¹⁷ had a greater paralyzing effect than the 60 U of Dysport employed in our study. We chose the 60-U dose to avoid a complete paresis and maintain the working capability of our patients. Accordingly, no patient lost time from work as a result of weakness of the forearm extensor muscles. In a larger, recent study with a design similar to ours, Wong et al. found that injection of 60 U of Dysport resulted in significant relief of pain at twelve weeks after treatment (p = 0.006)¹⁸.

Even though the main mechanism of botulinum toxin treatment may be weakening of the strength of the forearm extensor muscles, a direct analgesic and/or anti-inflammatory effect must also be considered^27-29. As expected, even the patients in our placebo group showed continuous improvement in the pain score, but the improvement was less pronounced. The clinical pain score was similar to the visual analogue score for continuous pain during the previous forty-eight hours. We believe that the congruence between our newly developed clinical pain score and the patients' pain assessment indicates the utility of this score. The fact that we noted no significant improvement in the visual analogue score for maximum pain within the previous forty-eight hours can probably be explained by the occurrence of one or more temporary pain peaks, due to physical activity, despite a generally decreased pain level.

During the injection, no attempt was made to distinguish between the origin of the extensor carpi radialis brevis and the extensor digitorum communis, since this is difficult anatomically and hence unrealistic under clinical conditions³⁰. Our method of selecting the injection site by palpation seems to be more practical in an outpatient setting than an electromyography-controlled injection as suggested by Keizer et al.¹⁵ and Morré et al.¹⁴.

The use of a new score for clinical evaluation can be debated. We chose to develop the new score because, on the basis of our detailed literature research, we could not find a validated instrument specifically designed to assess tennis elbow.

In conclusion, we have shown that the injection of botulinum A toxin into the origin of the forearm extensor muscles is an effective treatment for chronic radial epicondylitis. It is minimally invasive, can be performed in an outpatient setting, and does not impair the patient's ability to work. ?

References

Materials and Methods | Results | Discussion | References

Runge F. Zur Genese und Behandlung des Schreibekrampfes. Berliner klin. Wochenschr.1873;10: 245-8.10245 1873

Hamilton PG. The prevalence of humeral epicondylitis: a survey in general practice. J R Coll Gen Pract.1986;36: 464-5.36464 1986 [PubMed]

Verhaar J, Walenkamp G, Kester A, van Mameren H, van der Linden T. Lateral extensor release for tennis elbow. A prospective long-term follow-up study. J Bone Joint Surg Am.1993;75: 1034-43.751034 1993 [PubMed]

Cyriax JH. The pathology and treatment of tennis elbow. J Bone Joint Surg Am.1936;18: 921-40.18921 1936

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Placzek R, Lindner MS, Deuretzbacher G, Meiss AL. [Therapy for chronic radial epicondylitis with botulinum toxin A]. Z Orthop Ihre Grenzgeb.2004; 142: 701-5. German.142701 2004 [CrossRef]

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Topics

botulinum toxins, type a ; double-blind method ; multicenter studies ; pain ; epicondylitis

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Richard Placzek, M.D.

Posted on March 27, 2008

Dr. Placzek et al. respond to Dr. Namazi

To The Editor:

We would like to reply to Dr.Namazi(1) who in his letter suggested a novel molecular mechanism of botulinum toxin A (BoNT/A) in the treatment of chronic radial epicondylitis.

The pathogenesis of the chronic radial epicondylitis remains unknown. Dr. Namazi outlined the recent literature and discussed various models of the molecular mechanism of the disease. However, the first description of the treatment of chronic tennis elbow with botulinum toxin type A came from Morre et al. 1997(2). Regarding the current level I/II trials we refer to the publication of Placzek et al. 2007(3).

We disagree with the proposed molecular mechanism of action of botulinum toxin type A in the treatment of chronic radial epicondylitis. There might be a misunderstanding between the effects of clostridial substrates and the mainly clinically used botulinum neurotoxin type A. Botulinum neurotoxins are a group of proteins produced by different strains of Clostridium botulinum. There are seven immunologically distinct serotypes(A through G). The neurotoxins share a common structure, being di-chain proteins consisting of a heavy chain bond to a light chain. The light chain is a zinc-dependent endopeptidase that cleaves a protein essential to synaptic vesicle docking and fusion machinery (SNARE complex) and thereby inhibits neurotransmitter release. Each neurotoxin with the exception of BoNT/CI cleaves just one of the SNARE proteins at a single peptide bond that is specific to the particular neurotoxin. The clinically widely used BoNT/A acts at the protein SNAP-25 of the SNARE complex(4-6). When injected, BoNT/A prevents the release of acetylcholine from presynaptic vesicles, thus inducing the chemical denervation of extra- and intrafusal motor fibers(7). BoNT/A also blocks cholinergic parasympathetic and postganglionic sympathetic nerve synapses in the autonomic nervous system(8). Additionally, a possible central mechanism of action is discussed(9). Other enzymes mentioned in the letter of Namazi donâ€™t play any role in the action of BoNT/A.

Local treatment with BoNT/A reduces pain as in several controlled trials was reported(10). The mechanism of this action, especially at noncholinergic synapses and the pain soothing potential of BoNT/A beyond muscle relaxation, are not well understood. With the exception of migraine, all pain syndromes studied were associated with an increased muscle tone. The role of local inflammation in the pathophysiology of these disorders is not evident. Moreover, the negative findings of some authors(11-12) in human application contradicts results found in a rat model, in which formalin was used to produce allodynia and local inflammation(13). Pretreatment with BoNT/A caused a dose dependent reduction of behavioural phenomena usually associated with pain perception. The interpretation of these results is difficult, as systemic effects of BoNT/A were also observed in animals. Thus, it could not be ruled out that the altered behaviour of the animals was due to weakness caused by BoNT/A.

In contrast to the proposal of Dr. Namazi, we suggest that an antinociceptive effect of BoNT/A might be attributed to a reduction of the muscle tone.

References:

1. Placzek R, Drescher W, Deuretzbacher G, Hempfing A, Meiss AL. Treatment of chronic readial epicondylitis with botulinum toxin A. A double-blind, placebo-controlled, randomized multicenter study. J Bone Joint Surg Am. 2007;89:255-260. [Letter to The Editor] J Bone Joint Surg Am. epub 11 Mar 2008. http://www.ejbjs.org/cgi/eletters/89/2/255.

2. Morre HH, Keizer SB, van Os JJ. Treatment of chronic tennis elbow with botulinum toxin. Lancet 1997;349-9067:1746.

3. Placzek R, Drescher W, Deuretzbacher G, Hempfing A, Meiss AL. Treatment of chronic radial epicondylitis with botulinum toxin A. A double -blind, placebo-controlled, randomized multicenter study. J Bone Joint Surg Am 2007;89-2:255-60.

4. Aguado F, Gombau L, Majo G, Marsal J, Blanco J, Blasi J. Regulated secretion is impaired in AtT-20 endocrine cells stably transfected with botulinum neurotoxin type A light chain. J Biol Chem 1997;272-41:26005-8.

5. Marsal J, Ruiz-Montasell B, Blasi J, Moreira JE, Contreras D, Sugimori M, Llinas R. Block of transmitter release by botulinum C1 action on syntaxin at the squid giant synapse. Proc Natl Acad Sci U S A 1997;94- 26:14871-6.

6. Mahrhold S, Rummel A, Bigalke H, Davletov B, Binz T. The synaptic vesicle protein 2C mediates the uptake of botulinum neurotoxin A into phrenic nerves. FEBS Lett 2006;580-8:2011-4.

7. Simpson LL. The origin, structure, and pharmacological activity of botulinum toxin. Pharmacol Rev 1981;33-3:155-88.

8. Naumann M, Jost W. Botulinum toxin treatment of secretory disorders. Mov Disord 2004;19 Suppl 8:S137-41.

9. Wohlfarth K, Schubert M, Rothe B, Elek J, Dengler R. Remote F-wave changes after local botulinum toxin application. Clin Neurophysiol 2001;112-4:636-40.

10. Placzek R. In: Placzek R, editor. Botulinumtoxin in OrthopÃ¤die und Sportmedizin. Bremen: UNI-MED Verlag AG, 2006.

11. Blersch W, Schulte-Mattler WJ, Przywara S, May A, Bigalke H, Wohlfarth K. Botulinum toxin A and the cutaneous nociception in humans: a prospective, double-blind, placebo-controlled, randomized study. J Neurol Sci 2002;205-1:59-63.

12. Schulte-Mattler WJ, Opatz O, Blersch W, May A, Bigalke H, Wohlfahrt K. Botulinum toxin A does not alter capsaicin-induced pain perception in human skin. J Neurol Sci 2007;260-1-2:38-42.

13. Cui M, Khanijou S, Rubino J, Aoki KR. Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Pain 2004;107-1-2:125- 33.

Hamid Namazi, M.D.

Posted on January 23, 2008

Treatment of chronic radial epicondylitis with botulinum toxin A: A novel molecular mechanism.

Shiraz University, IRAN

To The Editor:

I read with great interest the article by Placzek and colleagues(1). This work shows that botulinum toxin relieves the pain of radial epicondylitis and improves grip strength. I would like to add to the discussion of Placzek and coworkers(1) by suggesting a mechanism by which botulinum toxin suppresses epicondylitis.

The pathogenesis of lateral epicondylitis, or tennis elbow, has been obscure. Several causes have been suggested by many studies; microruptures of the proximal extensor tendons, granulation tissue, and degenerative changes without signs of inflammation have been proposed(2,3,4). Recently, Ljung et al. have suggested that sympathetic and sensory innervation may contribute to the pathogenesis of this condition. They showed that nerve fibers associated with small vessels expressed positive immunoreactivities of substance P, calcitonin geneÂ¨Crelated peptide (CGRP), and neuropeptide Y. The authors argued that neuropeptides such as substance P and CGRP may not only transmit nociceptive information induced by unfavorable load to the spinal cord but they may also contribute to vasodilatation and the proliferation of connective tissue, so-called neurogenic inflammation(5).

Recent studies have revealed that cytokines not only play an important role as inflammatory mediators but also interact with neuropeptides in all organs. Some experimental studies have demonstrated that an injection of interleukin 1 into the enthesis of the extensor carpi radialis brevis of the rat induced an increase of neuropeptides such as substance P, CGRP, and neuropeptide Y in the enthesis and the cerebrospinal fluid, suggesting a connection of the neuropeptide and cytokine system to tennis elbow(6,7). Uchio et al. demonstrated that IL-1 was expressed in endothelial cells and fibroblasts at the origin of the extensor carpi radialis brevis muscle in association with the expression of substance P and CGRP in the nerves of the cases. These findings suggest that the neuropeptides might stimulate the expression of IL-1, enhancing the proliferation and collagen synthesis of fibroblasts without inflammatory cell infiltration(8). How do these findings relate to the possible mechanism of action of Botulinum toxin?

Botulinum toxin has been used to treat lateral epicondylitis since its introduction for clinical use in the 1990(9,10). Clostridium botulinum, produces two classes of enzymes that have very specific protein targets, the neurotoxin A-G and the ADP- ribosyltransferases C2, C3 bot 1, and C3 bot 2. C2 and C3 bot are part of a larger family of ADP-ribosylating toxins, including diphtheria toxin and cholera toxin, which cleave NAD and transfer ADP-ribose to target proteins. Although the members of this family have homologous enzymatic domains and similar active sites, these toxins disable a range of cellular targets. Rho family GTPases control the assembly of both cellÂ¨Cmatrix and cellÂ¨Ccell adhesion complexes. IL-1 receptor signaling complex contains these G proteins, and Rho GTPase is an essential unit for activation of IL-1 inflammatory pathway. C3 transferase exoenzyme specifically inhibits Rho GTPase by ADP- ribosylation of amino acid asparagine-41(11,12,13). Botulinum toxin has also been shown to suppress the release of substance P, CGRP, and neuropeptide Y, neurotransmitters involved in nociception(14).

Therefore, I suggest that botulinum toxin acts to inhibit the cytokine and neuropeptide in the enthesis of the tendon.

The author did not receive any outside funding or grants in support of his research for or preparation of this work. Neither he nor a member of his immediate family received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the author, or a member of his immediate family, is affiliated or associated .

References:

1. Placzek R, Drescher W, Dueretzbacher G, et al. Treatment of chronic radial epicondylitis with botulinum toxin A. A double-blind, placebo- controlled, randomized multicenter study. J Bone Joint Surg Am 2007; 89(2):255-60.

2. Coonrad RW and Hooper WR. Tennis elbow: its course, natural history, conservative and surgical management. J Bone Joint Surg Am 1973; 55: 1177-1182.

3. Nirschl RP. Elbow tendinitis/tennis elbow. Clin Sports Med 1992; 11: 851-870.

4. Regan W, Wold LE, Coonrad R, et al. Microscopic histopathology of chronic refractory lateral epicondylitis. Am J Sports Med 1992; 20: 746-759.

5. Ljung BO, Forsgren S and J. Friden. Substance P and calcitonin gene- related peptide expression at the extensor carpi radialis brevis muscle origin: implications for the etiology of tennis elbow. J Orthop Res 1999; 17: 554-559.

6. Harker E, Theodorsson E and Lundeberg T. An experimental model of tennis elbow in rats: a study of contribution of the nervous system. Inflammation 1998; 22: 435-444.

7. Harker E, Theodorsson E and Lundeberg T. An experimental study of the neurogenic and the immunological contribution to tennis elbow in rats. Inflammation 1997; 21: 35-44.

8. Uchio Y, Ochi M, Ryoke K, et al. Expression of neuropeptides and cytokines at the extensor carpi radialis brevis muscle origin. J Shoulder Elbow Surg 2002; 11(6): 570-5.

9. Wong SM, Hui AC, Tong PY, et al. Treatment of lateral epicondylitis with Botulinum toxin. A randomized, double blind, placebo controlled trial. Ann Intern Med 2005; 143: 793-7.

10. Monnier G, Tatu L, Michel F. New indications for botulinum toxin in rheumatology. Joint Bone Spine. 2006; 73(6):667-71.

11. Holbourn KP, Sutton JM and Shore C, et al. Molecular recognition of an ADP-ribosyl transferase; clostridium botulinum C3 exoenzyme. Proc Natl Acad Sci 2005; 102: 535-5364.

12. Harmey D, Stenbeck G, Nobes CD, et al. Regulation of osteoblast differentiation by Pasteurella multocida toxin (PMT): a role for Rho GTPase in bone formation. J Bone Miner Res 2004; 19 (4): 661-667.

13. Singh R, Wang B, Shirraikar A, et al. The IL-1 receptor and Rho directly associate to drive cell activation in inflammation. J Clin Invest 1999; 103 (11): 1561-1570.

14. Dolly JO, Aoki KR. The structure and mode of action of different botulinum toxins. Eur J Neurol 2006;13( 4): 1-9

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Richard Placzek, Wolf Drescher, Georg Deuretzbacher, Axel Hempfing, A. Ludwig Meiss; Treatment of Chronic Radial Epicondylitis with Botulinum Toxin AA Double-Blind, Placebo-Controlled, Randomized Multicenter Study. The Journal of Bone & Joint Surgery. 2007 Feb;89(2):255-260.

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