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Treatment of Chronic Radial Epicondylitis with Botulinum Toxin AA 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
View Disclosures and Other Information
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.

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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    Richard Placzek, M.D.
    Posted on March 27, 2008
    Dr. Placzek et al. respond to Dr. Namazi
    Centrum für Muskuloskeletale Chirurgie, Charité-Universitätsmedizin Berlin, Germany

    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 don’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 Orthopädie 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 gene¨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 cell¨Cmatrix and cell¨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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