Conservative Treatment of Chronic Achilles Tendinopathy: A Systematic Review

Achilles tendinopathy is a common musculoskeletal disorder. Athletes, runners and jumpers, and the sedentary are frequently affected. Numerous are the therapeutic choices to manage these kinds of disorders. The aim of this review is to analyze the available literature to document the up-to-date evidence on conservative management of Achilles tendinopathy. A systematic review of two medical electronic databases was performed by three independent authors, using the following inclusion criteria: conservative treatment consisted of pharmacologic, physical therapy without operative treatment, with more of 6 months symptoms and a minimum average of 6-months follow-up. Studies of any level of evidence, reporting clinical results, and dealing with Achilles tendinopathy and conservative treatment were searched for. A total of n = 1228 articles were found. At the end of the first screening, following the previously described selection criteria, we selected n = 94 articles eligible for full-text reading. Ultimately, after full-text reading and a reference list check, we selected n = 29 articles. Achilles tendinopathy is a frequent musculoskeletal disorder and several conservative treatments have been proposed, but no therapy is universally accepted, except for eccentric exercise training, which is the gold standard and a commonly used protocol.


Introduction
Achilles tendinopathy is a common musculoskeletal disorder [1]. This pathology affects athletes, runners, and jumpers, and some patients between 30 and 55 years of age who do not participate in sports [2]. The annual incidence of tendinopathy is up to 9% among runners and up to 30% in people who are not physically active [3,4]. Some authors have considered the vascular anatomy theory, i.e., that in susceptible individuals, the insufficient blood support by an arterial branch from the peroneal artery could be insufficient to prevent degeneration and facilitate healing, and at the same time, have also considered choke zones, defined as the area between two vascular territories with narrow anastomotic vessels, which may reduce the tendon capacity for self-repair [5], representing a greater risk of rupture [5]. There are many risk factors and they can be either intrinsic or extrinsic risk factors. Intrinsic risk factors include sex, advanced age, and body mass index [2,6,7]. They could be correlated with hereditary factors or a genetic predisposition and endocrine, metabolic, and rheumatological diseases such as diabetes mellitus, hemochromatosis, amyloidosis, or rheumatoid arthritis [6][7][8][9]. Extrinsic risk factors include the factors that could alter the course and the prognosis of the disease, for example drugs such as glucocorticoids, statins, and some antibiotics such as fluoroquinolones and aromatase inhibitors [5][6][7]. Based on this assumption, functional overload could lead to a cumulative force on the tendon [10][11][12], while pronation and excessive supination can determine traction, because of incorrect neurological adaptations in the tendon and their further adjustments [10,11]. All of these factors should be considered at the appearance of pain or in the subclinical presentation to reach the correct diagnosis [7]. According to Mafulli et al. [6], tendinopathy is defined by the following triad: pain, swelling at the tendon, and functional impotence. In the initial phase, pain appears during and at the end of a sports activity and then it becomes permanent in the daily routine [12]. For tendinopathy, different conservative treatments are taken into account, but because they are heterogenous, it is difficult to identify a gold standard. Surgery is considered when the pathology persists for at least 6 months [13]. The aim of this systematic review is to analyze the last 10 years of available literature to document the up-to-date evidence on conservative treatment of chronic Achilles tendinopathy.

Study Selection
PubMed and Science Direct databases were systematically reviewed by three independent authors (VA, MG, and DS) from their date of inception to 14 April 2019, according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [14]. The following search was entered: "(Achilles Tendon disease OR chronic Achilles Tendinopathy OR Achilles Tendinosis) NOT (Achilles Tendon rupture OR Achilles Tendon lesion) AND (conservative treatment OR pharmacologic treatment OR pharmacology OR physical therapy) NOT (surgical treatment OR surgery OR suture)". The search was for a timeframe within the last 10 years (2008-2019). From each included original article, a standard data entry form was utilized to extract the number of patients, mean age at treatment, sex, type of treatment, minimum time of symptoms, duration of treatment, complication rate, and complication type, as well as the follow-up and year of the study. The quality assessment of the studies was performed in duplicate by two independent reviewers (VA and MG). Conflicts about the data were resolved by consultation with a senior surgeon (PV).

Inclusion and Exclusion Criteria
Eligible studies for the present systematic review included conservative Achilles tendinopathy treatment in last 10 years. The initial titles and abstract screening was performed using the following inclusion criteria: conservative treatment consisting of pharmacologic and physical therapy without operative treatment, symptoms with more than 6 months duration, and a minimum average follow-up of 6 months. The exclusion criteria included patients with primary or secondary surgical treatment, symptom duration of less than 6 months, and animal trials. We also excluded all the remaining duplicates, as well as articles dealing with other topics, articles not in the English language, and those without an accessible abstract. Reference lists were also hand-searched for further relevant studies. Abstracts, case reports, conference presentations, editorials, and expert opinions were also excluded.

Included Studies
There were 1228 articles that were identified. After excluding duplicates, 384 articles were selected. After the first screening and following the previously described selection criteria, 94 articles were eligible for full-text reading. Meta-analyses or systematic reviews were excluded. Ultimately, after full-text reading and checking the reference list, 29 articles were selected based on previously written criteria. These 29 studies comprised randomized controlled human trials (RCTs) and prospective and retrospective cohorts or series studies. A PRISMA [14] flowchart of the selection method was provided at the screening ( Figure 1). The included articles  mainly focused on physical exercise, platelet rich plasma (PRP), and leukocyte-and platelet-rich plasma (L-PRP), extracorporeal shockwave therapy (ESWT), topical and systemic pharmacology therapy, or combination therapies. The main findings of the included articles are summarized in Table 1. Both groups had improvement in the short-and long-term ranges over the baseline (p < 0.05), but no differences between the treatments were recorded.
[ After 12-, 26-and 52-week follow-ups, Astym + ECC patients showed better outcomes than ECC groups for insertional tendinopathy. Both groups recorded significant improvements in pain over the baseline, but there was no difference between cohorts, except at the 12-week intervention period in the combined group.  There was superior patient satisfaction for the ECC group compared to the control. No statistically significant assessments at 12 weeks in groups of the satisfied and not satisfied patients were made, nor were improvements recorded at the subsequent follow-up. There was better color Doppler activity during their second ultrasound.

Platelet Rich Plasma and Leukocyte-and Platelet-Rich Plasma
Deans et al. [30] showed an increased in the quality of life and functional outcomes in patients treated with PRP, but de Vos [31] in 2010 and de Jong et al. [32] in 2011 reported no significant difference in improvement using the functional scores at 6, 12, and 24 weeks and at 1 year when PRP was compared to the ECC and placebo groups. Among patients who were treated with L-PRP, 91.6-93.0% [33,34] were satisfied after treatment and 89% returned to sport [33] with no Achilles tendon rupture [34] (Table 1).

Platelet Rich Plasma and Leukocyte-and Platelet-Rich Plasma
Deans et al. [30] showed an increased in the quality of life and functional outcomes in patients treated with PRP, but de Vos [31] in 2010 and de Jong et al. [32] in 2011 reported no significant difference in improvement using the functional scores at 6, 12, and 24 weeks and at 1 year when PRP was compared to the ECC and placebo groups. Among patients who were treated with L-PRP, 91.6-93.0% [33,34] were satisfied after treatment and 89% returned to sport [33] with no Achilles tendon rupture [34] (Table 1).

Extracorporeal Shockwave Therapy
Six articles [35][36][37][38][39][40] explored the use of extracorporeal shockwave therapy (ESWT) to treat Achilles insertional and non-insertional tendinopathy, and all reported successful outcomes. There was no major advantage with the addition of an ultrasound for guiding shock waves [35]. At the 12-month follow-up, Pavone et al. [36] reported that 65.0% of patients did not complain about pain, 27.5% of patients returned to normal daily activities and sports despite residual pain, and three patients still had pain (pain score (Visual Analog Scale) > 4). Rompe et al. [37] recorded that 64% of subjects treated with ESWT achieved a level of 1 (completely recovered) or 2 (much improved) on the Likert scale after treatment (Table 1).

Topical and Systemic Pharmacologic Therapy
Pharmacological therapy was investigated in three of the included articles. Wetke et al. [41] described the results of topical glucocorticoids (GCS) in a cohort of 113 subjects and reported good short-term effects and a similar outcome in a long-term training group. Lynen et al. [42] compared two peritendinous hyaluronic acid (HA) injection protocols to ESWT and highlighted greater treatment success in Achilles midportion tendinopathy in pain at 4 weeks (p = 0.0304), 3 months (p = 0.0030), and 6 months (p = 0.0018) with the HA protocol. Maquirriain et al. [43] recommended etoricoxib as opposed to diclofenac because significantly fewer side effects were reported (0% and 14.2%, respectively, p = 0.037; Table 1).

Discussion
Conservative treatments for Achilles tendinopathy to date are exercise with eccentric loading, pharmacological therapies, pressure manipulation (Astym therapy), injections therapies with GCS, HA, and PRP, and ESWT.
Training with eccentric loading exercises is a treatment for the middle part of Achilles tendinopathy and it is considered to be the gold standard [6]. ECCs have been proposed to promote collagen fiber cross-link formation within the tendon by facilitating tendon remodelling [43]. Henriksen et al. [44] observed the changes in force oscillations and electromyographic amplitudes, which have distinctive biomechanical features in eccentric loading exercises, and they play a role in stimulating fibroblasts. However, the eccentric exercises could affect nervous system sensitization and enhance healthy tissue tolerance, rather than cause degeneration or dysfunctional tissue [45]. Yu et al. [46] confirmed that eccentric is more effective than concentric strengthening for reducing pain and improving function in patients with Achilles tendinopathy. In a study by Stasinopoulos [16], an exercise program based on the Alfredson protocol was superior to the Stanish model, and Vanderplus et al. [29] showed good results in a long-term follow-up study. While the success of these treatments is well-known, these studies are heterogeneous because, even if the Alfredson protocol could be standardized, it is commonly undermined by the increasingly selective exercises. For example, Verrell et al. [25] modified the traditional Alfredson protocol to incorporate body weight loading for at least 15 to 20 s and a 6-week dosage period, and they achieved a substantial decrease in pain and a high degree of effectiveness. Some authors found better outcomes by following different protocols. Rikke Beyer et al. [15], for example, used heavy slow resistance training (HSR) and showed good results and a greater degree of patient satisfaction, but they did not include a long-term follow-up. Thus, further trials that include long-term follow-ups are needed. Research suggests that if eccentric loading exercise is combined with other non-invasive treatment modalities, there are significant improvements in outcome measures. The injection of a solution of hypertonic glucose, called "prolotherapy", promotes pro-inflammation reactions followed by collagen deposition, and stimulates neovascularisation in tendinosis [20]. In association with ECC, this could be one of most prospective adjuvant therapies, however, a small increase in cost and temporary patient discomfort was described [20]. Conversely, many studies such as Jong et al. [24] showed that after a 1-year follow-up, there was no difference in functional outcomes between treatment with eccentric loading exercises or a combination of eccentric loading exercises and the use of a night splint. Recently, some authors have tried to improve the effectiveness of eccentric loading exercises by combining them with some orthotic devices [27], but the effects are not better than for patients who followed only the physiotherapy treatment.
De Vos [31] investigated the clinical use of a PRP injection and found that there was no benefit in pain and function. De Jorge [32] also showed no clinical or sonographic benefit when compared with secondary outcomes, and this treatment has limits related to its composition. However, Guelfi et al. [34] showed beneficial effects and a low complication rate after a single L-PRP injection to heal mid-portion chronic recalcitrant Achilles tendinopathy (CRAT) in a large cohort of patients with mid-to long-term follow-ups, without eccentric loading exercises training.
GCS injections are another adjunct that are used in clinics. These injections around the Achilles tendon are controversial because the exact location of the inflammation is rarely found [47]. Moreover, in some cases it is not recommended because of the risk of tendon rupture [48]. To date, GCS infiltration is also not recommended, but studies such as that by Wetke [41] suggest using it in association with eccentric loading exercises in patients who are unable to begin or continue training because of intolerable pain. HA injection is another controversial treatment [42]. Pain was observed to change significantly at 3 months post-treatment. Because this study was the first to analyze the results after an HA injection, the reliability of these results are unknown. Another treatment is prolotherapy, a simpler injection that does not require an ultrasound. A solution of hypertonic glucose and local anesthetic is injected alongside the painful areas of the tendon [12] to stimulate inflammation, which is followed by collagen deposition [49]. A study of glucose-lignocaine injections versus saline injections into injured rat knee ligaments has shown additional thickening of the healing ligaments, but no differences in biomechanical properties [50]. Yellan [20] compared the effectiveness of eccentric loading exercises with prolotherapy injections and found that the mean functional outcome score improvements are greater with the combined treatment compared to only eccentric exercise. However, the proportion of patients who achieve important improvements in the functional outcome scores was similar for all groups. In this case, a more in-depth clinical trial is needed to evaluate these findings.
The mechanical stimulus provided by ESWT can aid in initiating tendon regeneration in tendinopathy by promoting pro-inflammation. This was confirmed by a microdialysis study that quantified the concentration of interleukins and metalloproteases after treatment with ESWT [51,52]. In this study, Waugh et al. [52] analyzed the in vivo the biological response to extracorporeal shockwaves, and they showed that in the dialysated tendon, there were some predominant cytokines, some of which had an elevated concentration immediately after ESWT, and then remained significantly elevated for several hours post-ESWT. The efficacy of ESWT is strictly related to energy level, the number of impulses, and the range of action used during treatment, and these indications must be taken into consideration. ESWT outcomes were better in patients without Haglund's deformity compared to patients with Haglund's deformity [53]. However, different studies showed that there were no major advantages to be had by adding an ultrasound to guide shock waves [35]. Pavone [36] and Saxena [39] suggested that using a low-energy radial shockwave is more convenient. It has been demonstrated that ESWT treatment produces better results than the wait-and-see policy, and when it is combined with eccentric training [54], ESWT treatment does not preclude surgery and may even improve the tendon's condition for surgery [38].
Another approach to use in Achilles tendinopathy is IPL. The first experimental studies showed that in vitro, there were potential physiological effects in the treatment of patients with Achilles tendinosis. However, Hutchinson [17] conducted a double-blind randomized controlled trial (RCT) and showed that there was no significantly different outcomes in the control group, and that IPL was not effective for acute treatment. In addition, laser-induced photobiomodulation (PBM) was shown to induce changes in membrane permeability, stimulate cytokine reactions, release growth factors, and upregulate ATP, nitric oxide (NO), and oxidation-reduction (REDOX) signaling, and thereby increase metabolism and cell proliferation [55,56]. According to Tumilty et al. [21], this technique showed statistically significant improvements. Moreover, this study suggests that PBM (using the right parameters as an adjunct to minor sessions of eccentric exercise) can provide an added benefit at 12 weeks. In addition to ECC treatment, orally administered drugs provided different results, depending on the drugs that were used. Praet et al. [22] proposed an RCT to treat tendinopathy with magnesium and vitamin E, because the author self-administered the drug and the symptoms resolved. Specific collagen peptides with high glycine content may accelerate the clinical benefits of a well-structured calf-strengthening and return-to-running program in patients with unilateral or bilateral chronic Achilles tendinopathy symptoms [22].
Another approach is Astym therapy, which is a noninvasive therapeutic approach that is used for soft-tissue dysfunction. It works via handheld instrumentation and it is applied topically to locate the underlying dysfunctional soft tissue and then transfer a certain amount of pressure to the dysfunctional tissue using specific protocols and patterns that were developed based on scientific and clinical study [56,57]. Mccormack [23] showed significant improvements in pain over the short-and long-term, but to evaluate the real benefits of this therapy on a variety of musculoskeletal disorders, more studies are needed.
According to the data available in the literature, the evidence does not support any approach strongly. The eccentric loading exercises are commonly investigated and considered the benchmark of Achilles tendinopathy conservative treatments and the use of adjuvant therapies such as prolotherapy, photobiomodulation, oral supplementation, and soft tissue treatment seems to improve the fuctional outcome of the patients, but additional studies are needed. We encourage high-profile clinical studies to examine more recent techniques.

Conclusions
Achilles tendinopathy is a common musculoskeletal disorder and several conservative treatments have been proposed, but no therapy is universally accepted, except for eccentric exercise training, which is the gold standard and a commonly used protocol.