Extracorporeal Shockwave Therapy Treatment in Upper Limb Diseases: A Systematic Review

Background: Rotator cuff tendinopathy (RCT), subacromial impingement (SAIS), and medial (MEP) and lateral (LEP) epicondylitis are the most common causes of upper limb pain caused by microtrauma and degeneration. There are several therapeutic choices to manage these disorders: extracorporeal shockwave therapy (ESWT) has become a valuable option. Methods: A systematic review of two electronic medical databases was performed by two independent authors, using the following inclusion criteria: RCT, SAIS, MEP, and LEP, ESWT therapy without surgical treatment, with symptoms duration more than 2 months, and at least 6 months of follow-up. Studies of any level of evidence, reporting clinical results, and dealing with ESWT therapy and RCT, SAIS, MEP, and LEP were included. Results: A total of 822 articles were found. At the end of the first screening, following the previously described selection criteria, we selected 186 articles eligible for full-text reading. Ultimately, after full-text reading, and reference list check, we selected 26 articles following previously written criteria. Conclusions: ESWT is a safe and effective treatment of soft tissue diseases of the upper limbs. Even in the minority cases when unsatisfied results were recorded, high energy shockwaves were nevertheless suggested in prevision of surgical treatment.


Introduction
Rotator cuff tendinopathy (RCT), subacromial impingement (SAIS), and medial (MEP) and lateral (LEP) epicondylitis are the most common causes of upper limb pain [1]. Calcific tendinitis is a painful disorder characterized by either single or multiple presences of calcium deposits in the tendon or subacromial bursa [2], while the term noncalcific tendinitis refers to tendinitis without calcium deposits [1]. Both conditions are common in the shoulder and elbow and affect both sedentary people and athletes [3].
RCT is the most common source of shoulder pain, and its prevalence is estimated to be 2%-3.8% in the general population [4]. Subacromial impingement syndrome (SAIS) is a pathological state of the rotator cuff tendons [5], resulting from mechanical impingement causing 50%-70% of shoulder pain cases [6]. MEP, or "golfer's elbow", is the result of common flexor tendon (CFT) microtrauma and degeneration, and might affect <1% of the general population and as many as 3.8% to 8.2% of patients in occupational settings, and typically occurs from the fourth decade of life [7]. Lateral epicondylitis (LEP) is a common chronic inflammatory degeneration of the wrist extensor tendons at their insertion to the lateral epicondyle of the humerus, affecting 1%-3% of the general population,

Inclusion and Exclusion Criteria
Eligible studies for the present systematic review included extracorporeal shockwave therapy treatment in the upper limb. The initial titles and abstracts screening was made using the following inclusion criteria: Rotator cuff tendinopathy (RCT), subacromial impingement (SAIS), and medial (MEP) and lateral (LEP) epicondylitis, ESWT therapy without operative treatment, with more of 2 months symptoms and a minimum average of 6-months follow-up.
The exclusion criteria were groups of patients with primary or secondary surgical treatment, symptoms for less of 6 months, and animal trials. All remaining duplicates, articles focused on other topics or with poor scientific methodology and accessible abstract were excluded.

Risk of Bias Assessment
In this systematic review, risk of bias assessment was performed according to the ROBINS-I tool for non-randomized studies [23], consisting of three-stage assessment of the studies included. The first stage regards the planning of the systematic review, the second stage is the assessment of the common bias possibly found in these studies, and the latter is about the overall risk of bias.

ESWT 2000 (3) 0 and 1 month
Decrease of pain at the rest, compression and activities 1-month after the treatment compare to baseline (p < 0.05).
Patient's and physician's global post treatment self assessment scores were improved comparing the values preand post-operatively (p < 0.05

Included Studies
A total of 822 articles were found. After the exclusion of duplicates, 186 articles were selected. At the end of the first screening, following the previously described selection criteria, we selected 74 articles eligible for full-text reading. Metanalysis or systematic reviews were excluded from the study. Ultimately, after full-text reading, and checking of the reference list, we selected 26 articles, composed of randomized controlled human trials (hRCT) and prospective and retrospective cohort or series studies, following previously written criteria. A PRISMA [21] flowchart of the method of selection and screening is provided (Figure 1). The main findings of the included articles were summarized (Tables 1  and 2

).
A total of 822 articles were found. After the exclusion of duplicates, 186 articles were selected. At the end of the first screening, following the previously described selection criteria, we selected 74 articles eligible for full-text reading. Metanalysis or systematic reviews were excluded from the study. Ultimately, after full-text reading, and checking of the reference list, we selected 26 articles, composed of randomized controlled human trials (hRCT) and prospective and retrospective cohort or series studies, following previously written criteria. A PRISMA [21] flowchart of the method of selection and screening is provided (Figure 1). The main findings of the included articles were summarized (Tables 1 and 2).

Calcific Tendinopathy of the Rotator Cuff (CTRC)
Many articles [24,25] demonstrated a decrease of the pain and the amount of calcification [26][27][28] in patients treated with ESWT in calcific tendinopathy of the shoulder. Also, ESWT and ESWT associated with kinesio taping (KT) groups, Frassanito et al. [29] reported better outcome and a faster recovery in patients treated with functional taping. The combination of ESWT and dietary supplement (DS) containing methylsulfonylmethane, hydrolyzed swine collagen (Type I and Type II), l-arginine and l-lysine, vitamin C, condroitin sulfate, glucosamine, and curcuma longa has been shown to provide a greater and faster pain relief, with a significant reduction of NSAIDs consumption [11]. Chou et al. [30] emphasized that patients with Gartner and Heyer type I calcification, calcification >15 mm, and the duration of symptoms >11 months had poorer outcome after ESWT.

Non-Calcific Tendinopathy of the Rotator Cuff (NTRC)
Regarding the treatment of non-calcific tendinopathy of the rotator cuff, the evidence supporting the ESWT treatment in short-and long-term is controversial. Li et al. [31] found that, considering a total of 84 patients, pain symptomatology was improved in the high dose ESWT group. Galasso et al. [32] detected a remarkable short-term efficacy in functional recovery in ESWT patients relative to a placebo group. Wu et al. indicated that the high-dose ESWT posed superior clinical efficacy in type II/III calcification tendinosis compared to type I calcification and noncalcific shoulder tendinosis [33]. In non-calcific supraspinatus tendinopathy patients treated with ESWT, Efe et al. [34] did not record any effect on function or pain improvement after 10 years. Speed et al. [35] reported a significant and sustained placebo effect after moderate doses of ESWT, but no evidence of added benefit when compared with the sham treatment.

Subacromial Impingement Syndrome (SAIS)
As reported by Circi et al. [36], ESWT has been considered effective in the treatment of impingement syndrome in the early period, both for pain and functional outcome, regardless of acromion morphology. The study of Kvalvaag et al. [37], which included 143 subjects, reported no differences between the ESWT group and the control. In SAIS patients, superior functional recovery, muscle endurance, and decrease of pain in the short to medium term were recorded when ESWT was associated with isokinetic exercises [38].

Elbow
Thirteen studies assessed the outcome of patients treated with ESWT compared to a control group, tenotomy, acupuncture, local infiltration of corticosteroids, or cryoultrasound in medial and lateral epicondylitis.

Lateral Epicondylitis (LEP)
The results of the studies investing ESWT treatment of lateral epicondylitis affected patients are controversial. Similar to other authors [39][40][41], Pettrone et al. [42], in a study involving 114 patients, obtained satisfying results in the management of epicondylitis with ESWT (vs. a placebo group). When an ultrasonography-guided [43] approach was used, the authors reported a positive response in 75.7% of the patients after the first treatment. On the contrary, other authors [35,44] reported a similar outcome relative to the placebo group. Compared to surgical treatment, such as tenotomy, ESWT represented a valid alternative after long-term follow up [45], as well as compared to the local infiltration of corticosteroids [46]. Vulpiani et al. [47] highlighted an improvement of functional recovery in chronic epicondylitis in patients treated with ESWT relative to the cryoultrasound group after 12 months.

Medial Epicondylitis (MEP)
Lee et al. [46] compared the ESWT treatment of medial epicondylitis in the acute phase with local infiltration of corticosteroids. Although the corticosteroids injections had more satisfying results in the short term (after 1 year), the ESWT patients had a better functional outcome. Similar short-term values were achieved in ESWT patients compared to acupuncture treatment [48].

General Consideration
The findings addressing the treatment with ESWT in the chronic tendinopathies and diseases of the upper limbs are somewhat heterogeneous; many controversies remain unresolved. There is no consensus about the number of sessions of ESWT required. Generally, the protocols provide between one and six sessions per week, increasing the number of sessions does not seem to improve outcomes. There is no consensus regarding the energy setting that should be used [25]. The shock wave generator, the number of impulses, the focusing of the shockwave concerning the tendon insertion, the number and the interval between each treatment session, different stages of the disease, and types of calcification all are important factors that must be carefully considered [25,27,49].
ESWT requires expensive shockwave delivery apparatus and several clinical sessions [30]. Contraindications for ESWT included pregnancy, acute infection, malignant tumor and coagulopathy, fracture or calcific tendinitis coexisting with a rotator cuff tear [30].
Common complications and advised effects after ESWT include transient pain, skin erythema, pain, and local swelling [20].
At the best knowledge of the authors, this is the first article analyzing and summarizing the main literature evidences of the functional outcomes in patients affected by shoulder and elbow soft tissue diseases and treated with ESW.

Shoulder
Several [25][26][27][28][29][30][31][32][33][34] studies reported satisfying results for functional outcome and decrease of pain after ESWT treatment in CTRC, NTRC, and SAIS affected patients. Some authors even reported the use of ESWT to be more effective than the use of transcutaneous electric nerve stimulation (TENS) [26] in patients with chronic calcific tendinitis of the shoulder, especially of the rotator cuff with arc-type calcific plaque [28]. Galasso [32] and Li et al. [31], despite Speed et al. [35] showed the contrary, reporting encouraging effect for treated patients with CTRC and NTRC in the short-term follow-up, unconfirming improvement in long-term compared to the placebo group [34]. Several causes could influence the outcome at 10 years: (1) other treatment interventions, in particular, physical therapy with or without a focus on scapular kinematics; (2) change in occupation and workload; (3) changes in lifestyle; and (4) changes in sports activity.
Chou et al. [30] aimed to predict the outcome in these subjects, identifying Gartner and Heyer type I classification (calcification >15 mm, and duration of symptoms >11 months) as negative prognostic parameters [33]. The timing could be considered as an additional predictor factor; in fact, Malliaropoulos et al. [24] found a correlation between pre-treatment and post-treatment pain duration, suggesting to start the management as soon as possible.
The application of taping as adjuvant therapy is interesting; in fact, KT seems to reinforce the analgesic and regenerative action of ESWT in the short term and promoted a faster therapeutic response at the mid-long term. Some authors [29] have speculated that KT performs its therapeutic functions mainly by proprioceptive feedback, through an immediate and constant stimulation of the mechanoreceptors in the skin, protecting the joint and reducing wrong movements. KT is advantageous because it is non-invasive, non-pharmacological, localized, and relatively cheap. On the other hand, further research is necessary to define the therapeutic indications, identify the best application methods, and clarify which factors determine the clinical result. Similarly, nutraceutical supplementation seems to improve the function and pain symptomatology in CTRC and NTRC patients [11].
Regarding ESWT treatment of SAIS, Circi et al. [36] reported successful results in a manner that is independent of acromion morphology in recovering the pain and functional outcome. Santamato et al. [38] encouraged the association between the ESWT and isokinetic exercise, explaining how the pathogenesis of this syndrome is multifactorial, resulting by the combination of several factors, including degenerative process, the alerted kinematics, postural aberrations, muscle deficit of performance [38]. Nonetheless, in a randomized, double-blind trial based on a large sample, Kvalvaag et al. [37], contradicted the efficiency of ESWT in subacromial impingement relative to patients treated with physical therapy.

Elbow
More than 40 different modalities of treatment of medial and lateral epicondylitis, used either alone or in combination, have been reported [50]. Numerous studies have reported good results of ESWT in decreasing of pain, improving the functional outcome and grip strength, in calcific and non-calcific tendinopathies [39] with a chronic presentation. Moreover, Köksa et al. [41] described an improvement of symptomatology and functionality, suggesting not only the absence of exacerbation or increase of the inflammation, but recommending ESWT for acute symptoms, thereby avoiding progression to the chronic phase or suffering from long-term pain.
Nevertheless, the efficacy of ESWT was not superior to other treatments. In fact, Lee et al. [46] reported that local steroid injection was more effective at the beginning, and similar results were reported after the first 2 weeks of therapy when the shockwaves were compared to acupuncture [47].
Some authors, who have described unsatisfied results in the use of low energy ESWT, have nevertheless suggested applying a method involving alternative doses and/or different dosage intervals [30] or before surgical treatment in refractory or relapsing cases [43,44].
Several adjuvants therapies or methods have been described to improve the effectiveness of ESWT. The use of focal ultrasonography improved the functionality of shockwaves [43], as well as the use of DS, because of their advantage to be not pharmacologic and to contain compounds with modulatory effects on inflammation [3]. The combination of ESWT and DS produce an increased bioavailability of the supplement to the tendon tissue, due to the neo-angiogenic properties [51,52], which results in a decrease in the use of NSAIDs [11].

Limits of the Study
The heterogenous of the scores considered to assess the patient functional outcome and the absence of ESWT standard protocol are the main limits in the comparison of studies results. We extensively searched and identified all relevant ESWT in upper limb soft tissue diseases articles. Therefore, risk of bias assessment showed moderate overall risk which could influence our analysis.

Conclusions
Extracorporeal shock wave therapy is a safe and effective treatment of upper limbs soft tissue diseases. Despite similar result to other therapies in short and middle terms, numerous studies have suggested the use of high energy shockwaves in chronic tendinopathies. In the minority of cases when unsatisfied results were recorded, high energy shockwaves were nevertheless suggested in prevision of surgical treatment. Adjuvant therapies, as the kinesio taping and dietary supplementation, seems to be useful in the treatment of upper limb soft tissues diseases but further findings are mandatory, we encourage high-profile clinical studies to investigate adjuvant therapy or other methods able to improve the effectiveness of ESWT. The literature available on the ESWT treatment in upper limb soft tissue diseases presents major limitations in terms of great heterogeneity and lack of high-profile studies. Further randomized control trials are strongly encouraged.