Accepted Manuscript Effectiveness of Botulinum Toxin for Shoulder Pain Treatment: A Systematic Review and Meta-Analysis Tao Wu, Yu Fu, Haixin Song, Ye Ye, Dong Yan, Jian hua Li PII:
S0003-9993(15)00560-2
DOI:
10.1016/j.apmr.2015.06.018
Reference:
YAPMR 56246
To appear in:
ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION
Received Date: 22 May 2015 Revised Date:
29 June 2015
Accepted Date: 30 June 2015
Please cite this article as: Wu T, Fu Y, Song H, Ye Y, Yan D, Li Jh, Effectiveness of Botulinum Toxin for Shoulder Pain Treatment: A Systematic Review and Meta-Analysis, ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION (2015), doi: 10.1016/j.apmr.2015.06.018. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Running title: Botulinum Toxin for Shoulder Pain
Effectiveness of Botulinum Toxin for Shoulder Pain Treatment: A Systematic Review and
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Meta-Analysis
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Tao Wu1*, Yu Fu2, Haixin Song1, Ye Ye1, Yan Dong3, Jian hua Li1;
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1 Department of Rehabilitation Medicine, Sir Run Run Shaw Hospital, College of Medicine,
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Zhejiang University, East Qin Chun Road, NO. 3,Hang Zhou, 310016, PR China.
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2 Department of Rehabilitation Medicine, Alxa League Central Hospital. Yabulai E Rd, Alxa
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Zuoqi, Alxa, Inner Mongolia Autonomous Region, 750306，PR China.
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3 Department of Rehabilitation Medicine, Hangzhou Hospital of Zhejiang CAPF, Jiang Nan
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Road, NO. 86, Hang Zhou, 310016, PR China
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Corresponding Author (*):
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Tao Wu, MD.
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Department of Rehabilitation Medicine
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Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University.
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3, East Qin Chun Road, Hangzhou, Zhe Jiang, PR China
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Zip code: 310016
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Phone: 86-571-8600 6054
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Email: [email protected]
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We declare that the manuscript have not been and will not be submitted elsewhere
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for publication. All authors declare no conflicts of interest. All authors have
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participated sufficiently to take public responsibility for this work, and agreed to its
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submission to Archives of Physical Medicine and Rehabilitation.
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Effectiveness of Botulinum Toxin for Shoulder Pain Treatment: A Systematic Review and
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Meta-Analysis
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Abstract Objective: To evaluate current evidence of the effectiveness of Botulinum toxin (BTX) treatment
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for shoulder pain.
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Data Sources: Ovid MEDLINE(R) In-Process and Other Non-Indexed Citations，Ovid MEDLINE(R),
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Ovid EMBASE, Web of Science, and Scopus from database were searched inception through Week 18,
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2015.
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Study Selection: Randomized controlled trials (RCTs) comparing the clinical efficacy (pain intensity and
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shoulder range of motion) of BTX injection to conventional therapy (steroid or placebo injection) were
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included.
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Data Extraction: Two reviewers independently screened abstracts and full texts. The results of the pain
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intensity and shoulder range of motion were extracted in the form of mean and SD. We constructed random
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effects models and calculated mean difference (MD) for continuous outcomes. Two hundred and nineteen
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articles were identified and among them nine articles were eligible for the final analysis.
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Data Synthesis: Meta-analyses were performed using RevMan version 5.3. The analysis indicated a
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statistically significant decreased pain score in BTX therapy group than control group with MD=1.35 (95%
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CI: 0.80 to 1.91; p50% suggests high heterogeneity. All analyses were performed using the
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generic inverse variance method (Rev Man 5.3, The Cochrane Library). The significance level was defined
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as P < 0.05.
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RESULTS
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Study characteristics
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We identified 219 articles, of which 9 RCTs (268 patients) were eligible for this review (Fig-1).
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， ， ， ， ， Characteristics of the enrolled studies are described in Table-1. Six studies8 9 12 13 14 15 used BTX muscle
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injection. Two studies16
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，17
utilized intra-articular BTX injection and another one study18 utilized
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ultrasound-guided sub-acromial bursitis (SB) or shoulder impingement syndrome (SIS) BTX injection. All
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the patients in control groups were received non BTX therapy such as steroid or Placebo injection. The
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mean fellow up time is 11.1 weeks (4-24 weeks). All of the studies assessed pain score (VAS or NRS) and
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shoulder ROM as the main outcome evaluation index after treatment.
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Clinical outcomes
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1. The decreased pain score (VAS & NRS) after BTX treatment
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All of the studies assessed pain score (VAS or NRS) after treatment. We collected the pain scores at the
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end of fellow up period of each study. The analysis indicated a statistically significant decreased pain score
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in BTX therapy group than control group with MD=1.35 (95% CI: 0.80 to 1.91; p 50%) in all analyses. So the risk of bias within the studies was
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medium due to potential publication bias and unknown quality (Fig 4).
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DISCUSSION
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As we know, there is already a cochrane report focus on the BTX-A for shoulder pain19. In that systematic
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review, the author included 6 studies (five focused on stroke survivors with shoulder pain and one with
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chronic refractory moderate/severe shoulder arthritis pain) They concluded that BTX-A injections decreased
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pain and improved shoulder function in patients with chronic shoulder pain due to spastic hemiplegia or
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arthritis In our study we reviewed nine small RCTs of BTX injection in patients with shoulder pain. The
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shoulder pain was due to hemiplegia in six studies 8,9,12,13,14,15. The other causes of shoulder pain were
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adhesive capsulitis17, sub-acromial bursitis (SB) or shoulder impingement syndrome (SIS) 18, and shoulder
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arthritis pain16. The primary finding of this meta-analysis is that BTX treatments resulted in small to
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moderate pain relief and shoulder abduction ROM increase in patients with chronic shoulder pain due to
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spastic hemiplegia or arthritis or sub-acromial bursitis or adhesive capsulitis.
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In evaluating shoulder pain, it is critical to identify the pathophysiological and anatomical substrates
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involved so that appropriate and effective therapies can be implemented rapidly. Currently, conventional
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therapy plays an important role in alleviating shoulder pain. Non-steroidal anti-inflammatory drugs
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(NSAIDs), muscle relaxants, opioid analgesics, physiotherapy and acupuncture are some of the most
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common conventional treatments. However, these treatments may not be effective in many patients5, and
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therefore we need new treatment options for intolerant or refractory shoulder pain.
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In the past two decades, BTX was popularly used to treat disorders associated with muscle over activity or
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spasticity. It has been proven that BTX could inhibit the acetylcholine release at the neuromuscular
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junction. It was also found that it could alleviate pain that occurred either with or without concomitant
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excess muscle contractions20. In addition to their effects on muscle tightness, BTX may modulate pain by
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inhibiting other non-cholinergic transmitters involved in pain pathways21.
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The route of BTX administration for shoulder pain
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The route of administration differed in the three conditions, intramuscular for hemiplegia8,9,12,13,14,15,
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intra-articular for arthritis16 or adhesive capsulitis17, and intra sub-acromial bursitis for shoulder
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impingement syndrome18.
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In hemiplegia shoulder pain (HSP) patients, a single intramuscular injection of BTX was compared to with
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intra-muscular placebo8,9,12,,14,15 or with intra-articular triamcinolone13. Stroke related shoulder pain is very
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common and may be associated with hypertonicity. In the setting of hemiplegic shoulder pain with
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spasticity, the target muscle include pectoralis major9,13,14,15, teres major15, subscapular muscle8,12, 13, biceps
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brachii9, and infraspinatus13. Many studies evaluating the effect of BTX in the treatment of hemiplegic
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shoulder pain have found different results. Because saline injections such as in trigger point injections in
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the setting of myofascial pain syndrome may release muscular pain, this may have impacted pain
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evaluation in short fellow up period22. So in the short fellow up period the difference is not significant, but
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pain reduction at long fellow up (12-24 weeks) was statistically significantly greater in the botulinum toxin
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injection group compared to placebo9,14.
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Adhesive capsulitis and arthritis are also the most common causes of shoulder pain
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intra-articular steroid injections are relatively well tolerated in the short-term, its long-term use can weaken
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the shoulder tendons and cause histological changes such as inflammation, focal necrosis and
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fragmentation of the collagen bundles24. Many studies have shown that intra-articular injection with BTX
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may be useful relieve pain and improve the ROM in patients with chronic osteoarthritic in the knee, chronic
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joint pain disorders, and chronic arthritis joint pain25,26,27,28. Animal experiments demonstrate that BTX
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inhibits not only the acetylcholine at the neuromuscular junctions but also other neurotransmitters such as
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glutamate, substance P, and calcitonin gene related peptide, all of which have been indicated in pain
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transmission29. Under the fluoroscopic guidance, Young-Jin Joo et al17 inserted needle vertically into the
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anterior aspect of the shoulder joint. Because the fellow up period was not long enough (8 weeks), there
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were no significant pain relief differences between the intra-articular injections of BTX and steroid in
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Young-Jin Joo ‘s study. But BTX has a safe alternative of steroid to avoid the steroid-induced side effects
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or as a second-line agent, for patients who have failed to respond to the current treatments.
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. Although the
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Subacromial and subdeltoid bursitis or shoulder impingement syndrome (SIS) are another common causes
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of pain or disability of the shoulder joint30. Jung Hwan Lee et al18 found that BTX showed more persistent
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clinical benefits in pain reduction and functional improvement than steroid in patients with SASD bursitis
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or SIS. It is very important that BTX showed longer periods of clinical effectiveness when compared with
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steroid treatment31,
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Dosage of BTX for shoulder pain
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There are two types of BTX: Type A (Dysport and Botox) and Type B (Myobloc). Botulinum Toxin type A
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is more widely used in pain control and spasticity treatment than Type B. But recently Dressler D et al33
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found that type B was thought to have a greater affinity for the sympathetic nerve system and therefore was
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more likely to relieve pain than the type A toxin. In this meta-analysis, there were no studies that
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specifically examined the dose response relationship. The mean dosage in the muscle injection route was
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100-200 u with Botox and 500 u with Dysport. In the intra articular injection route, the mean dosage was
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100-200 u with Botox. There was only one study used Type B (Myobloc) to treat the SASD bursitis and the
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dosage was 25000u (See table 1). So further clinical researches are needed to compare the therapy effect in
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shoulder pain relief when use in various type and doses of BTX.
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Duration of effectiveness
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It is well known that BTX can decrease muscular tone and associated symptoms of pain by inhibiting the
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release of acetylcholine at neuromuscular junctions34. However, there is little known about the temporality
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of its anti-nociceptive effect in humans. Our analysis shown that the period of significant pain relief effect
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at long fellow up (4-24 weeks, mean 11.1 weeks) was statistically significantly greater in the BTX injection
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group compared to placebo or steroid.
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Study limitations
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Our meta-analysis has a several limitations. First, although we conducted a comprehensive search of six
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databases, only nine studies (268 patients) were included in this systematic review. This small number of
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studies limited the statistical power of detecting significant finding. Second, we did not explore other
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factors, such as variation in injection techniques or gender differences because of the existing clinical
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heterogeneity of the population. We were also unable to test potential publication bias due to the small
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number of studies. We were unable to evaluate potential publication bias due to high heterogeneity and the
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limited number of studies included. The overall quality of the evidence was moderate due to the likelihood
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of publication bias.
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Conclusions
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In conclusion, BTX showed more persistent clinical benefits in pain reduction and ROM improvement than
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steroid or placebo in patients with shoulder pain due to spastic hemiplegia or arthritis or sub-acromial
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bursitis or adhesive capsulitis. These results suggest that BTX could be a useful and safety strategy for
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treatment for shoulder pain.
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Suppliers
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RevMan version 5.3.
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Keywords: Shoulder pain, Botulinum toxin, Systematic review
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Table 1: The characteristics of the enrolled studies
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Figure 1 Flow of participants through trial
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Figure 2 The pain score (VAS & NRS) after BTX treatment
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Figure 3 The shoulder abduction ROM after BTX treatment
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Figure 4 Risk of bias graph
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REFERENCES
1 Bjelle A. Epidemiology of shoulder problems. Baillieres Clin Rheumatol 1989;3:437-51.
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2 Tuzun EH. Quality of life in chronic musculoskeletal pain. Best Pract Res Clin Rheumatol 2007;21:567–579.
3 Eccleston C, Crombez G, Aldrich S, Stannard C. Attention and somatic awareness in chronic pain. Pain 1997; 72:209–215
4 Ferrante FM, Bearn L, Rothrock R, King L. Evidence against trigger point injection technique for the treatment of cervicothoracic myofascial pain with botulinum toxin type A. Anesthesiology 2005;103:377–83.
SC
5 Charles PD. Botulinum neurotoxin serotype A: a clinical update on non-cosmetic uses. Am J Health Syst Pharm 2004;61: S11–S23. 6 Hoving JL, Gross AR, Gasner D, Kay T, Kennedy C, Hondras MA, et al. A critical appraisal of review articles on the effectiveness
M AN U
of conservative treatment for neck pain. Spine (Phila Pa 1976) 2001;26:196–205.
7 Cui M, Khanijou S, Rubino J, Aoki KR. Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Pain 2004;107:125–33.
8 De Boer KS, Arwert HJ, de Groot JH, Meskers CG, Mishre AD, Arendzen JH, et al. Shoulder pain and external rotation in spastic hemiplegia do not improve by injection of botulinum toxin A into the subscapular muscle. J Neurol Neurosurg Psychiatry 2008;79:581-583.
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9 Kong KH, Neo JJ, Chua KS. A randomized controlled study of botulinum toxin A in the treatment of hemiplegic shoulder pain associated with spasticity. Clin Rehabil 2007;21:28-35.
10 Higgins J, Green S, "Cochrane Handbook for Systematic Reviews of Interventions Version 510," The Cochrane Collaboration, 2011.
EP
11 Higgins J, Green S, "Cochrane Handbook for Systematic Reviews of Interventions," Cochrane Book Series, pp.187-241, 2008. 12 Yelnik AP, Colle FM, Bonan IV, Vicaut E. Treatment of shoulder pain in spastic hemiplegia by reducing spasticity of the subscapular muscle: a randomised, double blind, placebo controlled study of botulinum toxin A. J Neurol Neurosurg Psychiatry. 2007;
AC C
211
78:845-848.
13 Lim JY, Koh JH, Paik NJ. Intramuscular botulinum toxin-A reduces hemiplegic shoulder pain: a randomized, double-blind, comparative study versus intraarticular triamcinolone acetonide. Stroke. 2008; 39:126-131. 14 Marco E, Duarte E, Vila J, Tejero M, Guillen A, Boza R, et al. Is botulinum toxin type A effective in the treatment of spastic shoulder pain in patients after stroke? A double-blind randomized clinical trial. J Rehabil Med 2007; 39:440-447. 15 Marciniak CM, Harvey RL, Gagnon CM, Duraski SA, Denby FA, McCarty S, et al. Does botulinum toxin type A decrease pain and lessen disability in hemiplegic survivors of stroke with shoulder pain and spasticity? A randomized, double-blind, placebo-controlled trial. Am J Phys Med Rehabil 2012;91:1007-19.
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16 Singh JA, Mahowald ML, Noorbaloochi S. Intra-articular botulinum toxin A for refractory shoulder pain: a randomized, double-blinded, placebo-controlled trial. Transl Res 2009; 153:205-16. 17 Joo YJ, Yoon SJ, Kim CW, Lee JH, Kim YJ, Koo JH, et al. A comparison of the short-term effects of a botulinum toxin type a and
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triamcinolone acetate injection on adhesive capsulitis of the shoulder. Ann Rehabil Med 2013; 37:208-14.
18 Lee JH, Lee SH, Song SH. Clinical effectiveness of botulinum toxin type B in the treatment of subacromial bursitis or shoulder impingement syndrome. Clin J Pain 2011; 27:523-8. 19
Singh JA, Fitzgerald PM. Botulinum toxin for shoulder pain: a cochrane systematic review. J Rheumatol. 2011; 38:409-18.
SC
20 Aoki KR. Pharmacology and immunology of botulinum toxin serotypes. J Neurol 2001;248:3–10.
21 Ishikawa H, Mitsui Y, Yoshitomi T. Presynaptic effects of botulinum toxin type A on the neuronally evoked response of albino
M AN U
and pigmented rabbit iris sphincter and dilator muscles. Jpn J Ophthalmol 2000;44:106-9
22 Ojala T, Arokoski JP, Partanen J. The effect of small doses of botulinum toxin a on neck-shoulder myofascial pain syndrome: A double-blind, randomized, and controlled crossover trial. Clin J Pain 2006;22: 90-6.
23 Grey RG. The natural history of “idiopathic” frozen shoulder. J Bone Joint Surg Am 1978;60:564. 24 Tillander B, Franzen LE, Karlsson MH, Norlin R. Effect of steroid injections on the rotator cuff: an experimental study in rats. J Shoulder Elbow Surg 1999;8:271-4.
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25 Goyal N. Intra-articular knee joint Botox injection for chronic osteoarthritic pain. Anaesth Intensive Care 2008;36:123. 26 Singh JA, Mahowald ML. Intra-articular botulinum toxin A as an adjunctive therapy for refractory joint pain in patients with rheumatoid arthritis receiving biologics: a report of two cases. Joint Bone Spine 2009;76:190-4. 27 Singh JA, Mahowald ML, Kushnaryov A, Goelz E, Dykstra D. Repeat injections of intra-articular botulinum toxin a for the
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treatment of chronic arthritis joint pain. J Clin Rheumatol 2009;15:35-8. 28 Mahowald ML, Singh JA, Dykstra D. Long term effects of intra-articular botulinum toxin A for refractory joint pain. Neurotox
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Res 2006;9:179–188.
29 Bach-Rojecky L, Salkovic-Petrisic M, Lackovic Z. Botulinum toxin type A reduces pain supersensitivity in
experimental diabetic neuropathy: Bilateral effect after unilateral injection. Eur J Pharmacol. 2010; 633:10–4. 30 MacDonald PB, Clark P, Sutherland K. An analysis of the diagnostic accuracy of the Hawkins and Neer subacromial impingement signs. J Shoulder Elbow Surg 2000;9:299–301. 31 Keizer SB, Rutten HP, Pilot P. Botulinum toxin injection versus surgical treatment for tennis elbow: a randomized pilot study. Clin Orthop Relat Res 2002;401:125–131. 32 Jabbari B, Ney J, Sichani A. Treatment of refractory, chronic low back pain with botulinum neurotoxin A: an openlabel, pilot study. Pain Med 2006;7:260–264.
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33 Dressler D, Eleopra R. Clinical use of non-A botulinum toxins: botulinum toxin type B. Neurotox Res 2006;9:121–125. 34 Borodic GE, Acquadro M, Johnson EA. Botulinum toxin therapy for pain and inflammatory disorders: mechanisms and
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therapeutic effects. Expert Opin Investig Drugs 2001;10:1531-4.
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Table 1: The characteristics of the enrolled studies Population
Sample size
Mean age, male/female
2012 Young-Jin Joo17
BTX-A (Dysport, 200u)/ steroid triamcinolone acetate(40mg)
Patients with adhesive capsulitis
28
54, 17/11
2012 Marciniak CM15
BTX-A(Botox,140-200 units)/Placebo (saline)
Stroke survivors with shoulder pain and spasticity
21
60, 13/8
BTX-B (Myobloc,2500U)/ Trimacinolone (40mg)
Patients with subacromial bursitis (SB) or shoulder impingement syndrome
61
BTX-A （Botox, 100 u
Chronic refractory moderate/severe shoulder arthritis pain
43
A.
）/Placebo（ saline）
Intra-articular injection (IA)
Study design
8 weeks
Main evaluation index
RCTs
Numeric Rating Scale (NRS), Range of motion (ROM)
RCTs
VAS, Disability
12 weeks
56, 25/36
Ultrasoundguided Injection (SB/SIS)
3 months
RCTs
Numeric Rating Scale (NRS), Range of motion (ROM)
71, 42/1
Intra-articular injection
1 month
RCTs
VAS, ROM
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2009 JASVINDER SINGH16
Timing fellow up
Muscle injection: pectoralis major with or without teres major
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2011 Jung Hwan Lee18
Route
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Intervention / Comparison
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Study
Assessment Scale, Fugl-Meyer Scale
BTX-A (Botox, 2*50 u)/Placebo
Stroke survivors with shoulder pain and spasticity
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57, 12/9
Muscle injection: subscapular muscle
12 weeks
RCTs
VAS, ROM
2007 Keng-He Kong9
BTX-A (Dysport ,500 u)/Placebo
Stroke survivors with shoulder pain and spasticity
16
50, 11/5
Muscle injection: pectoralis major and biceps brachii
12 weeks
RCTs
VAS, ROM, Ashworth Scale
2007 Jae-Young Lim13
BTX-A (Botox, 100u) /Triamcinolone acetonide(TA,40mg)
Stroke survivors with shoulder pain and spasticity
29
61, 15/14
Muscle injection (infraspinatus, pectoralis & subscapularis)/ TA:IA
12 weeks
RCTs
VAS, ROM, FuglMeyer score, Ashworth Scale
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2007 K S de Boer8
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BTX-A (Dysport, 500u)/Placebo
Stroke survivors with shoulder pain and spasticity
29
64, 21/8
Muscle injection: pectoralis major
6 months
RCTs
VAS, ROM, Ashworth Scale
2006 Alain P Yelnik12
BTX-A (Dysport, 500u)/Placebo
Stroke survivors with shoulder pain and spasticity
20
52, 15/5
Muscle injection: subscapularis
4 weeks
RCTs
VAS, ROM
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2007 Ester Marco14
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S0003-9993(15)00560-2
DOI:
10.1016/j.apmr.2015.06.018
Reference:
YAPMR 56246
To appear in:
ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION
Received Date: 22 May 2015 Revised Date:
29 June 2015
Accepted Date: 30 June 2015
Please cite this article as: Wu T, Fu Y, Song H, Ye Y, Yan D, Li Jh, Effectiveness of Botulinum Toxin for Shoulder Pain Treatment: A Systematic Review and Meta-Analysis, ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION (2015), doi: 10.1016/j.apmr.2015.06.018. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
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Running title: Botulinum Toxin for Shoulder Pain
Effectiveness of Botulinum Toxin for Shoulder Pain Treatment: A Systematic Review and
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Meta-Analysis
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Tao Wu1*, Yu Fu2, Haixin Song1, Ye Ye1, Yan Dong3, Jian hua Li1;
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1 Department of Rehabilitation Medicine, Sir Run Run Shaw Hospital, College of Medicine,
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Zhejiang University, East Qin Chun Road, NO. 3,Hang Zhou, 310016, PR China.
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2 Department of Rehabilitation Medicine, Alxa League Central Hospital. Yabulai E Rd, Alxa
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Zuoqi, Alxa, Inner Mongolia Autonomous Region, 750306，PR China.
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3 Department of Rehabilitation Medicine, Hangzhou Hospital of Zhejiang CAPF, Jiang Nan
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Road, NO. 86, Hang Zhou, 310016, PR China
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Corresponding Author (*):
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Tao Wu, MD.
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Department of Rehabilitation Medicine
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Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University.
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3, East Qin Chun Road, Hangzhou, Zhe Jiang, PR China
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Zip code: 310016
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Phone: 86-571-8600 6054
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Email: [email protected]
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We declare that the manuscript have not been and will not be submitted elsewhere
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for publication. All authors declare no conflicts of interest. All authors have
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participated sufficiently to take public responsibility for this work, and agreed to its
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submission to Archives of Physical Medicine and Rehabilitation.
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Effectiveness of Botulinum Toxin for Shoulder Pain Treatment: A Systematic Review and
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Meta-Analysis
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Abstract Objective: To evaluate current evidence of the effectiveness of Botulinum toxin (BTX) treatment
4
for shoulder pain.
5
Data Sources: Ovid MEDLINE(R) In-Process and Other Non-Indexed Citations，Ovid MEDLINE(R),
6
Ovid EMBASE, Web of Science, and Scopus from database were searched inception through Week 18,
7
2015.
8
Study Selection: Randomized controlled trials (RCTs) comparing the clinical efficacy (pain intensity and
9
shoulder range of motion) of BTX injection to conventional therapy (steroid or placebo injection) were
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included.
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Data Extraction: Two reviewers independently screened abstracts and full texts. The results of the pain
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intensity and shoulder range of motion were extracted in the form of mean and SD. We constructed random
13
effects models and calculated mean difference (MD) for continuous outcomes. Two hundred and nineteen
14
articles were identified and among them nine articles were eligible for the final analysis.
15
Data Synthesis: Meta-analyses were performed using RevMan version 5.3. The analysis indicated a
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statistically significant decreased pain score in BTX therapy group than control group with MD=1.35 (95%
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CI: 0.80 to 1.91; p50% suggests high heterogeneity. All analyses were performed using the
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generic inverse variance method (Rev Man 5.3, The Cochrane Library). The significance level was defined
80
as P < 0.05.
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RESULTS
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Study characteristics
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We identified 219 articles, of which 9 RCTs (268 patients) were eligible for this review (Fig-1).
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， ， ， ， ， Characteristics of the enrolled studies are described in Table-1. Six studies8 9 12 13 14 15 used BTX muscle
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injection. Two studies16
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utilized intra-articular BTX injection and another one study18 utilized
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ultrasound-guided sub-acromial bursitis (SB) or shoulder impingement syndrome (SIS) BTX injection. All
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the patients in control groups were received non BTX therapy such as steroid or Placebo injection. The
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mean fellow up time is 11.1 weeks (4-24 weeks). All of the studies assessed pain score (VAS or NRS) and
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shoulder ROM as the main outcome evaluation index after treatment.
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Clinical outcomes
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1. The decreased pain score (VAS & NRS) after BTX treatment
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All of the studies assessed pain score (VAS or NRS) after treatment. We collected the pain scores at the
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end of fellow up period of each study. The analysis indicated a statistically significant decreased pain score
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in BTX therapy group than control group with MD=1.35 (95% CI: 0.80 to 1.91; p 50%) in all analyses. So the risk of bias within the studies was
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medium due to potential publication bias and unknown quality (Fig 4).
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DISCUSSION
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As we know, there is already a cochrane report focus on the BTX-A for shoulder pain19. In that systematic
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review, the author included 6 studies (five focused on stroke survivors with shoulder pain and one with
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chronic refractory moderate/severe shoulder arthritis pain) They concluded that BTX-A injections decreased
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pain and improved shoulder function in patients with chronic shoulder pain due to spastic hemiplegia or
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arthritis In our study we reviewed nine small RCTs of BTX injection in patients with shoulder pain. The
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shoulder pain was due to hemiplegia in six studies 8,9,12,13,14,15. The other causes of shoulder pain were
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adhesive capsulitis17, sub-acromial bursitis (SB) or shoulder impingement syndrome (SIS) 18, and shoulder
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arthritis pain16. The primary finding of this meta-analysis is that BTX treatments resulted in small to
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moderate pain relief and shoulder abduction ROM increase in patients with chronic shoulder pain due to
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spastic hemiplegia or arthritis or sub-acromial bursitis or adhesive capsulitis.
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In evaluating shoulder pain, it is critical to identify the pathophysiological and anatomical substrates
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involved so that appropriate and effective therapies can be implemented rapidly. Currently, conventional
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therapy plays an important role in alleviating shoulder pain. Non-steroidal anti-inflammatory drugs
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(NSAIDs), muscle relaxants, opioid analgesics, physiotherapy and acupuncture are some of the most
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common conventional treatments. However, these treatments may not be effective in many patients5, and
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therefore we need new treatment options for intolerant or refractory shoulder pain.
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In the past two decades, BTX was popularly used to treat disorders associated with muscle over activity or
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spasticity. It has been proven that BTX could inhibit the acetylcholine release at the neuromuscular
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junction. It was also found that it could alleviate pain that occurred either with or without concomitant
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excess muscle contractions20. In addition to their effects on muscle tightness, BTX may modulate pain by
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inhibiting other non-cholinergic transmitters involved in pain pathways21.
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The route of BTX administration for shoulder pain
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The route of administration differed in the three conditions, intramuscular for hemiplegia8,9,12,13,14,15,
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intra-articular for arthritis16 or adhesive capsulitis17, and intra sub-acromial bursitis for shoulder
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impingement syndrome18.
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In hemiplegia shoulder pain (HSP) patients, a single intramuscular injection of BTX was compared to with
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intra-muscular placebo8,9,12,,14,15 or with intra-articular triamcinolone13. Stroke related shoulder pain is very
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common and may be associated with hypertonicity. In the setting of hemiplegic shoulder pain with
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spasticity, the target muscle include pectoralis major9,13,14,15, teres major15, subscapular muscle8,12, 13, biceps
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brachii9, and infraspinatus13. Many studies evaluating the effect of BTX in the treatment of hemiplegic
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shoulder pain have found different results. Because saline injections such as in trigger point injections in
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the setting of myofascial pain syndrome may release muscular pain, this may have impacted pain
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evaluation in short fellow up period22. So in the short fellow up period the difference is not significant, but
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pain reduction at long fellow up (12-24 weeks) was statistically significantly greater in the botulinum toxin
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injection group compared to placebo9,14.
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Adhesive capsulitis and arthritis are also the most common causes of shoulder pain
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intra-articular steroid injections are relatively well tolerated in the short-term, its long-term use can weaken
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the shoulder tendons and cause histological changes such as inflammation, focal necrosis and
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fragmentation of the collagen bundles24. Many studies have shown that intra-articular injection with BTX
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may be useful relieve pain and improve the ROM in patients with chronic osteoarthritic in the knee, chronic
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joint pain disorders, and chronic arthritis joint pain25,26,27,28. Animal experiments demonstrate that BTX
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inhibits not only the acetylcholine at the neuromuscular junctions but also other neurotransmitters such as
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glutamate, substance P, and calcitonin gene related peptide, all of which have been indicated in pain
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transmission29. Under the fluoroscopic guidance, Young-Jin Joo et al17 inserted needle vertically into the
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anterior aspect of the shoulder joint. Because the fellow up period was not long enough (8 weeks), there
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were no significant pain relief differences between the intra-articular injections of BTX and steroid in
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Young-Jin Joo ‘s study. But BTX has a safe alternative of steroid to avoid the steroid-induced side effects
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or as a second-line agent, for patients who have failed to respond to the current treatments.
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. Although the
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Subacromial and subdeltoid bursitis or shoulder impingement syndrome (SIS) are another common causes
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of pain or disability of the shoulder joint30. Jung Hwan Lee et al18 found that BTX showed more persistent
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clinical benefits in pain reduction and functional improvement than steroid in patients with SASD bursitis
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or SIS. It is very important that BTX showed longer periods of clinical effectiveness when compared with
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steroid treatment31,
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Dosage of BTX for shoulder pain
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There are two types of BTX: Type A (Dysport and Botox) and Type B (Myobloc). Botulinum Toxin type A
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is more widely used in pain control and spasticity treatment than Type B. But recently Dressler D et al33
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found that type B was thought to have a greater affinity for the sympathetic nerve system and therefore was
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more likely to relieve pain than the type A toxin. In this meta-analysis, there were no studies that
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specifically examined the dose response relationship. The mean dosage in the muscle injection route was
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100-200 u with Botox and 500 u with Dysport. In the intra articular injection route, the mean dosage was
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100-200 u with Botox. There was only one study used Type B (Myobloc) to treat the SASD bursitis and the
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dosage was 25000u (See table 1). So further clinical researches are needed to compare the therapy effect in
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shoulder pain relief when use in various type and doses of BTX.
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Duration of effectiveness
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It is well known that BTX can decrease muscular tone and associated symptoms of pain by inhibiting the
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release of acetylcholine at neuromuscular junctions34. However, there is little known about the temporality
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of its anti-nociceptive effect in humans. Our analysis shown that the period of significant pain relief effect
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at long fellow up (4-24 weeks, mean 11.1 weeks) was statistically significantly greater in the BTX injection
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group compared to placebo or steroid.
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Study limitations
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Our meta-analysis has a several limitations. First, although we conducted a comprehensive search of six
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databases, only nine studies (268 patients) were included in this systematic review. This small number of
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studies limited the statistical power of detecting significant finding. Second, we did not explore other
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factors, such as variation in injection techniques or gender differences because of the existing clinical
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heterogeneity of the population. We were also unable to test potential publication bias due to the small
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number of studies. We were unable to evaluate potential publication bias due to high heterogeneity and the
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limited number of studies included. The overall quality of the evidence was moderate due to the likelihood
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of publication bias.
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Conclusions
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In conclusion, BTX showed more persistent clinical benefits in pain reduction and ROM improvement than
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steroid or placebo in patients with shoulder pain due to spastic hemiplegia or arthritis or sub-acromial
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bursitis or adhesive capsulitis. These results suggest that BTX could be a useful and safety strategy for
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treatment for shoulder pain.
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Suppliers
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RevMan version 5.3.
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Keywords: Shoulder pain, Botulinum toxin, Systematic review
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Table 1: The characteristics of the enrolled studies
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Figure 1 Flow of participants through trial
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Figure 2 The pain score (VAS & NRS) after BTX treatment
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Figure 3 The shoulder abduction ROM after BTX treatment
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Figure 4 Risk of bias graph
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REFERENCES
1 Bjelle A. Epidemiology of shoulder problems. Baillieres Clin Rheumatol 1989;3:437-51.
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2 Tuzun EH. Quality of life in chronic musculoskeletal pain. Best Pract Res Clin Rheumatol 2007;21:567–579.
3 Eccleston C, Crombez G, Aldrich S, Stannard C. Attention and somatic awareness in chronic pain. Pain 1997; 72:209–215
4 Ferrante FM, Bearn L, Rothrock R, King L. Evidence against trigger point injection technique for the treatment of cervicothoracic myofascial pain with botulinum toxin type A. Anesthesiology 2005;103:377–83.
SC
5 Charles PD. Botulinum neurotoxin serotype A: a clinical update on non-cosmetic uses. Am J Health Syst Pharm 2004;61: S11–S23. 6 Hoving JL, Gross AR, Gasner D, Kay T, Kennedy C, Hondras MA, et al. A critical appraisal of review articles on the effectiveness
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of conservative treatment for neck pain. Spine (Phila Pa 1976) 2001;26:196–205.
7 Cui M, Khanijou S, Rubino J, Aoki KR. Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Pain 2004;107:125–33.
8 De Boer KS, Arwert HJ, de Groot JH, Meskers CG, Mishre AD, Arendzen JH, et al. Shoulder pain and external rotation in spastic hemiplegia do not improve by injection of botulinum toxin A into the subscapular muscle. J Neurol Neurosurg Psychiatry 2008;79:581-583.
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9 Kong KH, Neo JJ, Chua KS. A randomized controlled study of botulinum toxin A in the treatment of hemiplegic shoulder pain associated with spasticity. Clin Rehabil 2007;21:28-35.
10 Higgins J, Green S, "Cochrane Handbook for Systematic Reviews of Interventions Version 510," The Cochrane Collaboration, 2011.
EP
11 Higgins J, Green S, "Cochrane Handbook for Systematic Reviews of Interventions," Cochrane Book Series, pp.187-241, 2008. 12 Yelnik AP, Colle FM, Bonan IV, Vicaut E. Treatment of shoulder pain in spastic hemiplegia by reducing spasticity of the subscapular muscle: a randomised, double blind, placebo controlled study of botulinum toxin A. J Neurol Neurosurg Psychiatry. 2007;
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211
78:845-848.
13 Lim JY, Koh JH, Paik NJ. Intramuscular botulinum toxin-A reduces hemiplegic shoulder pain: a randomized, double-blind, comparative study versus intraarticular triamcinolone acetonide. Stroke. 2008; 39:126-131. 14 Marco E, Duarte E, Vila J, Tejero M, Guillen A, Boza R, et al. Is botulinum toxin type A effective in the treatment of spastic shoulder pain in patients after stroke? A double-blind randomized clinical trial. J Rehabil Med 2007; 39:440-447. 15 Marciniak CM, Harvey RL, Gagnon CM, Duraski SA, Denby FA, McCarty S, et al. Does botulinum toxin type A decrease pain and lessen disability in hemiplegic survivors of stroke with shoulder pain and spasticity? A randomized, double-blind, placebo-controlled trial. Am J Phys Med Rehabil 2012;91:1007-19.
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16 Singh JA, Mahowald ML, Noorbaloochi S. Intra-articular botulinum toxin A for refractory shoulder pain: a randomized, double-blinded, placebo-controlled trial. Transl Res 2009; 153:205-16. 17 Joo YJ, Yoon SJ, Kim CW, Lee JH, Kim YJ, Koo JH, et al. A comparison of the short-term effects of a botulinum toxin type a and
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triamcinolone acetate injection on adhesive capsulitis of the shoulder. Ann Rehabil Med 2013; 37:208-14.
18 Lee JH, Lee SH, Song SH. Clinical effectiveness of botulinum toxin type B in the treatment of subacromial bursitis or shoulder impingement syndrome. Clin J Pain 2011; 27:523-8. 19
Singh JA, Fitzgerald PM. Botulinum toxin for shoulder pain: a cochrane systematic review. J Rheumatol. 2011; 38:409-18.
SC
20 Aoki KR. Pharmacology and immunology of botulinum toxin serotypes. J Neurol 2001;248:3–10.
21 Ishikawa H, Mitsui Y, Yoshitomi T. Presynaptic effects of botulinum toxin type A on the neuronally evoked response of albino
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and pigmented rabbit iris sphincter and dilator muscles. Jpn J Ophthalmol 2000;44:106-9
22 Ojala T, Arokoski JP, Partanen J. The effect of small doses of botulinum toxin a on neck-shoulder myofascial pain syndrome: A double-blind, randomized, and controlled crossover trial. Clin J Pain 2006;22: 90-6.
23 Grey RG. The natural history of “idiopathic” frozen shoulder. J Bone Joint Surg Am 1978;60:564. 24 Tillander B, Franzen LE, Karlsson MH, Norlin R. Effect of steroid injections on the rotator cuff: an experimental study in rats. J Shoulder Elbow Surg 1999;8:271-4.
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25 Goyal N. Intra-articular knee joint Botox injection for chronic osteoarthritic pain. Anaesth Intensive Care 2008;36:123. 26 Singh JA, Mahowald ML. Intra-articular botulinum toxin A as an adjunctive therapy for refractory joint pain in patients with rheumatoid arthritis receiving biologics: a report of two cases. Joint Bone Spine 2009;76:190-4. 27 Singh JA, Mahowald ML, Kushnaryov A, Goelz E, Dykstra D. Repeat injections of intra-articular botulinum toxin a for the
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treatment of chronic arthritis joint pain. J Clin Rheumatol 2009;15:35-8. 28 Mahowald ML, Singh JA, Dykstra D. Long term effects of intra-articular botulinum toxin A for refractory joint pain. Neurotox
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Res 2006;9:179–188.
29 Bach-Rojecky L, Salkovic-Petrisic M, Lackovic Z. Botulinum toxin type A reduces pain supersensitivity in
experimental diabetic neuropathy: Bilateral effect after unilateral injection. Eur J Pharmacol. 2010; 633:10–4. 30 MacDonald PB, Clark P, Sutherland K. An analysis of the diagnostic accuracy of the Hawkins and Neer subacromial impingement signs. J Shoulder Elbow Surg 2000;9:299–301. 31 Keizer SB, Rutten HP, Pilot P. Botulinum toxin injection versus surgical treatment for tennis elbow: a randomized pilot study. Clin Orthop Relat Res 2002;401:125–131. 32 Jabbari B, Ney J, Sichani A. Treatment of refractory, chronic low back pain with botulinum neurotoxin A: an openlabel, pilot study. Pain Med 2006;7:260–264.
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33 Dressler D, Eleopra R. Clinical use of non-A botulinum toxins: botulinum toxin type B. Neurotox Res 2006;9:121–125. 34 Borodic GE, Acquadro M, Johnson EA. Botulinum toxin therapy for pain and inflammatory disorders: mechanisms and
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therapeutic effects. Expert Opin Investig Drugs 2001;10:1531-4.
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Table 1: The characteristics of the enrolled studies Population
Sample size
Mean age, male/female
2012 Young-Jin Joo17
BTX-A (Dysport, 200u)/ steroid triamcinolone acetate(40mg)
Patients with adhesive capsulitis
28
54, 17/11
2012 Marciniak CM15
BTX-A(Botox,140-200 units)/Placebo (saline)
Stroke survivors with shoulder pain and spasticity
21
60, 13/8
BTX-B (Myobloc,2500U)/ Trimacinolone (40mg)
Patients with subacromial bursitis (SB) or shoulder impingement syndrome
61
BTX-A （Botox, 100 u
Chronic refractory moderate/severe shoulder arthritis pain
43
A.
）/Placebo（ saline）
Intra-articular injection (IA)
Study design
8 weeks
Main evaluation index
RCTs
Numeric Rating Scale (NRS), Range of motion (ROM)
RCTs
VAS, Disability
12 weeks
56, 25/36
Ultrasoundguided Injection (SB/SIS)
3 months
RCTs
Numeric Rating Scale (NRS), Range of motion (ROM)
71, 42/1
Intra-articular injection
1 month
RCTs
VAS, ROM
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Timing fellow up
Muscle injection: pectoralis major with or without teres major
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Route
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Intervention / Comparison
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Study
Assessment Scale, Fugl-Meyer Scale
BTX-A (Botox, 2*50 u)/Placebo
Stroke survivors with shoulder pain and spasticity
21
57, 12/9
Muscle injection: subscapular muscle
12 weeks
RCTs
VAS, ROM
2007 Keng-He Kong9
BTX-A (Dysport ,500 u)/Placebo
Stroke survivors with shoulder pain and spasticity
16
50, 11/5
Muscle injection: pectoralis major and biceps brachii
12 weeks
RCTs
VAS, ROM, Ashworth Scale
2007 Jae-Young Lim13
BTX-A (Botox, 100u) /Triamcinolone acetonide(TA,40mg)
Stroke survivors with shoulder pain and spasticity
29
61, 15/14
Muscle injection (infraspinatus, pectoralis & subscapularis)/ TA:IA
12 weeks
RCTs
VAS, ROM, FuglMeyer score, Ashworth Scale
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BTX-A (Dysport, 500u)/Placebo
Stroke survivors with shoulder pain and spasticity
29
64, 21/8
Muscle injection: pectoralis major
6 months
RCTs
VAS, ROM, Ashworth Scale
2006 Alain P Yelnik12
BTX-A (Dysport, 500u)/Placebo
Stroke survivors with shoulder pain and spasticity
20
52, 15/5
Muscle injection: subscapularis
4 weeks
RCTs
VAS, ROM
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2007 Ester Marco14
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