➢ Eccentric exercises protect the tendon, exert a beneficial mechanical effect, and reduce the number of pain mediators within affected tendons. Eccentric exercises have a positive effect on the tendon, with no reported adverse effects, and have been associated with increased success rates when combined with extracorporeal shock-wave therapy (ESWT).
➢ High-volume injections of normal saline solution, corticosteroids, and local anesthetics exert a mechanical effect that causes stretching, breaking, or occluding of new blood vessels as well as damage to the accompanying nerve supply through either trauma or ischemia. The effects of such injections are therefore to decrease pain and to improve function in the short and long term.
➢ The best available evidence suggests that the use of platelet-rich plasma or other autologous blood products is of no benefit for the treatment of Achilles tendinopathy.
➢ Surgery consists of excising fibrotic adhesions, removing areas of failed healing, and performing multiple longitudinal incisions in the tendon to detect intratendinous lesions and to restore vascularity and possibly to stimulate the remaining viable cells to initiate cell matrix response and healing. Minimally invasive procedures reduce postoperative complications and accelerate recovery times.
➢ Randomized controlled trials are needed to better clarify the best treatment for Achilles tendinopathy.
Achilles tendinopathy is an overuse condition accounting for as many as 18% of injuries in runners and 4% of injuries in patients presenting to sports medicine clinics1,2. A major cause of chronic pain and functional disability, Achilles tendinopathy represents a failed healing response after overuse stimulation of the tendon with no direct evidence of intratendinous inflammation. After overuse, the healing process is incomplete and disorganized, with histological evidence of haphazard proliferation of tenocytes, intracellular abnormalities, disruption of collagen fibers, and increase in noncollagenous matrix3. These changes may decrease the mechanical properties of the tendon, making it more susceptible to damage4. The cause of Achilles tendinopathy is multifactorial. Overuse, adverse lower limb biomechanics, and inappropriate footwear are well-known risk factors. The recent evidence on the associations between Achilles tendinopathy and diabetes, dyslipidemia, and inflammatory and autoimmune conditions should induce physicians to more thoroughly investigate patients with Achilles tendinopathy as this condition could be the first manifestation of such metabolic and immune disorders5. The purpose of the present review is to provide the most updated evidence on the diagnosis and treatment of Achilles tendinopathy.
Etiology and Pathophysiology
Overuse stresses, poor vascularity, lack of flexibility, genetic makeup, female sex, and endocrine or metabolic factors all may be predisposing factors6-8. The response of the Achilles tendon to repetitive overloads may trigger an inflammatory reaction of its sheath, a failed healing response process within the body, or a combination of the two9. In athletes, the traumatic insult is frequent and cumulative. Each trauma triggers a physiological reparative reaction within the tendon, but the high frequency of the insults and their cumulative effect do not allow the tendon to organize a reparative response. Also, non-uniform stresses or different forces from the gastrocnemius and soleus muscles produce abnormal frictional forces and loads between the fibrils of the tendon, with localized tendon damage10. Active repair of fatigue damage must occur or the tendon will weaken and eventually rupture. The repair is likely mediated by resident tenocytes that respond to different properties of the extracellular matrix11. Failure to adapt to recurrent excessive loads results in the release of cytokines, leading to further modulation of cell activity12,13.
Tendon disorders may be acute or chronic, and their occurrence may be related to the presence and interaction of intrinsic and extrinsic factors. Acute injuries are usually posttraumatic and typically are associated with extrinsic factors, whereas chronic disorders are associated with both intrinsic and extrinsic factors6,14. Age, sex, body weight and height, gastrocnemius-soleus dysfunction, tendon vascularity, lateral ankle instability, pes cavus, excessive motion of the hindfoot in the frontal plane, and marked forefoot varus are all intrinsic factors15,16, but no cause-and-effect relationships have been demonstrated. Conversely, changes in training patterns, poor technique, previous injuries, footwear, and training on hard, slippery, or slanting surfaces are extrinsic factors17.
Many other local features also may predispose patients to Achilles tendinopathy. The release of free radicals following reperfusion after a state of ischemia and a condition of local environmental hypoxia and hyperthermia may impair the process of tenocyte apoptosis and predispose to Achilles tendinopathy18,19. The administration of cytokines and prostaglandins may also predispose to the development of Achilles tendinopathy20. Interestingly, ciprofloxacin enhances the release of matrix metalloproteinase-3 (MMP3), inhibits tenocyte proliferation, and reduces the synthesis of collagen and other matrix proteins21. From a molecular viewpoint, tendinopathy is associated with an altered expression of the genes that regulate cell-cell and cell-matrix interactions. Specifically, the main alterations involve the downregulation of MMP3 messenger RNA (mRNA) and the upregulation of MMP2 and vascular endothelial growth factor22. The specific effect of these altered factors on tendinopathy is unknown. Nevertheless, as metalloprotease 3 regulates degradation and remodeling of the extracellular matrix of the tendon, it may be hypothesized that repeated mechanical insults may impair its proper regulation and its activity and possibly predispose to tendinopathy. Tendinopathic tendons contain a different connective structure and increased levels of type-I and type-III collagen mRNA compared with normal tendons22. Although overt inflammation is not a clear histological feature of overuse tendinopathy, it is possible that neural inflammation and subclinical inflammation may play a role13. The absence of clear histological evidence of inflammation in painful tendons and the presence of similar changes on magnetic resonance imaging (MRI) or ultrasound evaluation of asymptomatic patients suggest that tendinopathy is due to a failed healing response as opposed to the classical notion that it is secondary to inflammation. The etiology of pain is therefore multifactorial, related to mechanical and biochemical factors. Microdialysis has shown that tendinopathic tendons contain twofold higher levels of lactate and glutamate than normal tendons, without any increase in proinflammatory prostaglandins (e.g., prostaglandin E2)23. The role of sensory neuropeptides is still debated as increased levels of substance P have been found in both animals and humans with tendon disorders24,25.
The Achilles tendon can be divided into two parts: non-insertional (proximal) and insertional (distal). Del Buono et al. described a novel anatomical classification system based on clinical, ultrasound, and MRI findings26. In this system, the non-insertional region is considered to be the midportion of the tendon and the insertional region includes a pre-insertion site, located about 2 cm above the calcaneus, and a calcaneal insertion, where the tendon is attached to the bone.
The diagnosis of Achilles tendinopathy is mainly based on history and clinical examination. Pain is the first symptom and usually occurs at the beginning and end of a training session, with a period of diminished discomfort in between. Over time, patients become symptomatic during exercise and complain of discomfort and disability during daily activities. In the acute phase, edema and tenderness may be appreciated on palpation, mostly 2 to 6 cm proximal to the insertion. Sometimes, the fibrinogen-rich fluid around the tendon may produce fibrin precipitate and palpable crepitation. In patients with chronic Achilles tendinopathy, exercise-induced pain is the cardinal symptom, but crepitation and effusion are less frequent. Some nodular swelling may be palpable7,15.
Diagnostic imaging may be required to verify a clinical suspicion or, occasionally, to exclude other musculoskeletal disorders. MRI and ultrasound have similar accuracy for the evaluation of Achilles tendon disorders27.
Magnetic Resonance Imaging
Under normal conditions, the Achilles tendon has no internal signal intensity on any sequence, except at its insertion. Nevertheless, changes in signal intensity may be evident in the distal portion of the tendon on axial FLASH (fast low-angle shot) MRI sequences, probably because of vascularization of the septa of the tendon in this area28,29. Nevertheless, small ground-glass areas, often visible within asymptomatic tendons, could be the earliest signs of tendinopathy30. On MRI scans, paratenon and paratendinous adhesions must be differentiated from alterations of surrounding soft tissues and disorders of the tendon itself. MRI allows one to distinguish non-insertional (proximal) tendinopathy from insertional tendinopathy. In cases of non-insertional tendinopathy (Fig. 1), the affected tendon presents nodular hyperintense lesions and is often edematous and fibrillated31. In cases of insertional Achilles tendinopathy (Fig. 2), the distal portion of the tendon is thicker, with a vaguely defined high signal intensity, which may be appreciated especially on longitudinal fat-suppressed images. On sagittal MRI scans, the typical internal signal observed in cases of insertional tendinopathy may mimic a tear, even though the tear usually is more proximal (Fig. 3).
Most tears and tendinopathy lesions occur approximately 2 to 6 cm proximal to the insertion of the Achilles tendon on the calcaneus32. Some asymptomatic patients, especially if very active, have positive findings on ultrasound, and ultrasound may be unable to provide prognostic indications as the association between imaging changes over time and the development of clinical symptoms is weak at best27,33. Gray-scale ultrasonography is cost-effective for the evaluation of Achilles tendinopathy as it is operator-dependent and relies on the detection of hypoechoic lesions and the assessment of tendon thickening and widening (Fig. 4 and Fig. 5)34,35. Color Doppler ultrasonography is an established technique that is useful for the investigation of tendinopathy, with a sensitivity of 92% and a specificity of 100%36,37. Positive correlation has been shown between positive findings on color-flow and power Doppler ultrasonography and those on gray-scale ultrasonography as well as between neovascularization and pain2. Ohberg et al. found vessels through the entire thickness of the widened part of the tendon in patients with advanced tendinopathy, demonstrating the correlation between the occurrence of neovascularization and ventral-side widening of the tendon38. The mechanism of this increased flow remains speculative39. To standardize the pattern of vascularization in Achilles tendinopathy, we proposed a system to classify findings on Doppler ultrasound, consisting of five grades. Grades I and II are characterized by the presence of one and two vessels within the tendon, respectively, whereas Grades III, IV, and V are characterized by neovascularization involving <50%, 50% to 90%, and >90% of the tendon tissue, respectively26. However, this system must be assessed in studies involving patients. In addition, it should be kept in mind that the presence of neovascularity is not necessarily a sign of Achilles tendinopathy: in light of the most recent well-performed research, the detection of neovessels has no additional value for diagnosis, no firmly confirmed prognostic value, and no proven relation with symptoms40.
The first-line treatment for non-insertional Achilles tendinopathy involves nonoperative measures41, including rest, modification of training activities with eccentric exercises, and the use of orthoses for the correction of underlying lower limb malalignment42,43. Nonoperative treatment is effective for approximately 70% of patients, allowing for the return to previous activities. Paavola et al., in a study of eighty-three patients who were followed for an average of eight years, reported that only twenty-four patients (29%) were unresponsive to nonoperative measures44. The scientific evidence in support of the use of nonsteroidal anti-inflammatory drugs (NSAIDs) for the treatment of chronic tendinopathy is somewhat inconsistent as inflammation is largely absent on histological analysis of tendinopathic tendons45. The short-term benefit after the administration of NSAIDs is likely due to an analgesic effect, and these drugs may be detrimental46. Specifically, celecoxib inhibits tendon cell migration and proliferation47. NSAIDs increase leukotriene B448, inducing pathological changes within the tendon and potentially predisposing to Achilles tendinopathy. Corticosteroid injections reduce pain and swelling and improve the appearance of the tendon on ultrasound45, probably as a result of their vasoconstrictive action mediated by prostacyclin, adrenoceptors, and inhibition of nitric oxide synthetase49. Nevertheless, any possible benefit of corticosteroid injection seems to be outweighed by potential risks50 as many adverse effects have been observed, including tendon rupture and decreased tendon strength51-53.
Eccentric exercises promote collagen fiber cross-link formation within the tendon and facilitate tendon remodeling54. The concept is that the musculotendinous unit undergoes structural adaptation to protect itself from increased stresses and to prevent reinjury. Eccentric exercises may improve this adaptation process, exerting a beneficial mechanical effect and also reducing the number of pain mediators within affected tendons. Although higher levels of glutamate55, substance P, and neurokinin-1 receptor56 have been found in tendinopathic painful Achilles tendons than in normal pain-free tendons, in vivo eccentric protocols reduce symptoms without having any influence on glutamate levels55. The rationale for these exercises could be to produce pain in order to habituate patients to painful stimulations46,57,58. Eccentric training reduces neovascularization as seen on color Doppler ultrasound59,60, decreasing infiltrating vessels, possibly through a mechanism of repeated constriction61. Excellent clinical results have been reported for both athletic and sedentary patients62,63, although these results were not reproduced by other study groups. In general, the effect of eccentric exercises is positive, with no reported adverse effects; in the study by Rompe et al., the combination of eccentric protocols with extracorporeal shock-wave therapy (ESWT) increased the success rate compared with those observed after eccentric loading alone or shock-wave therapy alone64. In the randomized study by Silbernagel et al., sixteen (84%) of nineteen patients returned to normal activities after twelve weeks of eccentric training, with persistent improvement after one year65. The twelve-week regimen is considered as the reference standard for the treatment of tendinopathy, but six-week protocols have also provided reasonable outcomes63,66,67.
The energy of ESWT causes selective dysfunction of sensory unmyelinated nerve fibers and induces changes in the dorsal root ganglia68. Cavitation is suspected to be involved in both interstitial and extracellular disruptions, triggering a healing response68. In cultured tenocytes, ESWT modifies the expression of transforming growth factor-beta1 (TGF-β1) and insulin-like growth factor-1 (IGF-1) and decreases some interleukins and MMPs69,70. Therefore, the rationale for the clinical use of ESWT is the stimulation of soft-tissue healing and the inhibition of pain receptors. There is no consensus on the use of repetitive low-energy ESWT, which does not require local anesthesia, or the use of high-energy ESWT, which requires local or regional anesthesia71. Conflicting results have been reported after ESWT. As discussed in the previous section, a randomized controlled trial demonstrated improved outcomes when ESWT was combined with eccentric exercises; these outcomes are particularly promising for women64. Saxena et al. recently reported that fifty-eight (78%) of seventy-four tendons that underwent one session of low-energy ESWT weekly for three weeks were improved at one year, but no control group was used for comparison72. When used, high-energy ESWT is administered only once. Although ESWT provides encouraging outcomes, only short-term effects have been reported and the literature is not strong enough to recommend the use of ESWT for the treatment of tendinopathy.
High-volume injections of normal saline solution, corticosteroids, and anesthetics have been used to treat Achilles tendinopathy. Achilles tendinopathy is generally associated with nerve ingrowth and neovascularization73,74. The ingrowth of new blood vessels and nerves from the peritendinous tissues is the cause of pain38. Neurokinin-1 receptor and alpha-1-adrenoreceptor have been identified in biopsy specimens from the ventral area of tendinopathic Achilles tendons, as have elevated levels of the neurotransmitter glutamate and its receptor, the N-methyl-d-aspartate receptor type 175-78. The rationale is that high-volume injections of normal saline solution, corticosteroids, or anesthetics exert a mechanical effect that results in stretching, breaking, or occluding of new blood vessels. The mechanical effects on these vessels damage the accompanying nerve supply through either trauma or ischemia, decreasing pain and improving function in the short and long term79. High-volume injections are safe, are relatively inexpensive, and allow quicker return to sports80. The reason to inject hydrocortisone acetate is primarily to prevent an acute mechanical inflammatory reaction produced by the amount of fluid injected in the proximity of the tendon. The injection is performed under ultrasound guidance to prevent a direct injection in the tendon with the associated risk of rupture81. High-volume injections are infrequently used in the United States but are used extensively elsewhere.
Platelet-rich plasma is a bioactive component of whole blood that is now widely tested in different fields of medicine82. Platelet-rich plasma originally was used to facilitate wound-healing83 and only recently has been advocated to improve tendon-healing84-86. Platelet-rich plasma products contain a higher concentration of platelets than blood does. Platelets contain dense granules and alpha granules: dense granules contribute to tissue modulation and regeneration by releasing adenosine, serotonin, histamine, and calcium, whereas alpha granules release TGF-β, platelet-derived growth factor, and vascular endothelial growth factor, with concentrations increasing linearly with increasing platelet concentration87,88. These factors bind to transmembrane receptors on the surface of local or circulating cells and induce intracellular signaling, cellular chemotaxis, matrix synthesis, and proliferation. It has been suggested that this cascade leads to the tendon-healing process, which occurs through three phases: inflammation, proliferation, and remodeling85. Platelet-rich plasma products promote the tendon-healing, but the exact mechanism through which the tendon-healing occurs is still unclear. Some studies have demonstrated improved tendon-healing in patients managed with platelet-rich plasma as compared with controls89-92, but symptoms have not been significantly reduced when platelet-rich plasma has been used for the treatment of Achilles tendinopathy89,93. A randomized, double-blind, placebo-controlled study evaluating eccentric exercises and injections of either platelet-rich plasma or saline solution showed no difference between the groups in terms of pain and activity at six months93, and a recent randomized, controlled study showed no significant difference in terms of Victorian Institute of Sports Assessment-Achilles (VISA-A) scores at the primary end point of six months after treatment with either eccentric exercises or injection of platelet-rich plasma94. The meta-analysis by Sadoghi et al. indicated that platelet-rich plasma may increase healing strength after Achilles tendon repair following an acute rupture but that there is no benefit when platelet-rich plasma is used for the treatment of Achilles tendinopathy95.
Matrix Metalloproteinase Inhibitors
Although enzyme inhibitors have not been extensively evaluated for the treatment of tendinopathy, there is evidence that patients with Achilles tendinopathy may benefit from peritendinous injections of aprotinin, a broad protease inhibitor96. A small randomized trial of patients with Achilles tendinopathy showed that combined treatment with aprotinin and eccentric exercises did not significantly improve outcomes compared with placebo, although the results were satisfactory in both groups97. However, that trial was relatively underpowered, and the authors continued to use aprotinin in their clinical practice. Despite the theoretical benefits, aprotinin is no longer available in most countries for use as an injectable MMP inhibitor (in small doses). This indication was always “off label,” and the number of specialists using it worldwide was fairly limited, although it had been used in Europe for the treatment of tendinopathy since the 1970s96. The major indication for aprotinin was to reduce bleeding during major surgery (especially cardiac surgery) with use of large intravenous doses. Data from large-scale trials recently have shown that the risk profile outweighs the benefit for this indication—hence the worldwide withdrawal of aprotinin. Aprotinin may induce allergic reactions in some patients98, without any superiority to other injectable products such as platelet-rich plasma or glucose prolotherapy. Alternate MMP inhibitors, such as tranexamic acid, theoretically could be used for the treatment of tendinopathy, but laboratory and clinical trials are needed to test their use99.
Other Nonoperative Therapies
Paoloni et al., in a randomized, double-blind, placebo-controlled study, reported a reduction of symptoms in patients with Achilles tendinopathy who were managed with glyceryl trinitrate patches100, with significantly greater benefit after three years101. A more recent study showed that glyceryl trinitrate patches did not provide greater benefit compared with standard nonoperative management after six months, with no histological changes in terms of the formation of new blood vessels, collagen synthesis, or stimulated fibroblasts102. On the contrary, it has been hypothesized that glyceryl trinitrate may be detrimental to the underlying pathological process103.
Prolotherapy essentially irritates the tendon to stimulate a healing response through the release of proinflammatory mediators104. Yelland et al. reported that, in the short term (at six weeks), prolotherapy and eccentric loading exercise combined with prolotherapy provided greater improvements in terms of pain, stiffness, and limitation of activity than eccentric loading exercise alone105.
Kinesiotape (elastic therapeutic skin tape) also has been used for the treatment of Achilles tendinopathy, but the evidence on its effectiveness is scarce106. Therapeutic ultrasound supposedly reduces the swelling that is observed during the acute inflammatory phase of the healing process and favors tendon-healing107, but a systematic review and a meta-analysis did not demonstrate any benefit of therapeutic ultrasound compared with placebo for the treatment of tendinopathy108.
Operative treatment is our preferred method when symptoms persist after at least six months of proper conservative treatment.
Operative treatment of Achilles tendinopathy involves long incisions, wide exposures, and dissections to excise surrounding fibrosis, to remove adhesions within and outside the tendon, and to promote the healing process26. Increased blood flow improves the nutrition of the tendon and favors the healing process itself109. Open procedures provide encouraging results, but the associated risks of damage to soft tissues and nerves, wound-healing complications, and infections are relatively high110,111. Over the decades, minimally invasive procedures have been proposed to reduce postoperative complications and to accelerate recovery times112.
Multiple Percutaneous Longitudinal Tenotomies
We recently reported the results of percutaneous longitudinal tenotomies for thirty-nine (75%) of fifty-two patients after an average duration of follow-up of seventeen years (range, fifteen to twenty-two years)113. At the time of the latest assessment, all patients were able to walk on the tiptoes, without using a heel lift or walking with a visible limp. The mean VISA-A score was 78.5, without any significant differences between patients with and without paratendinopathy on ultrasound. Thirty (77%) of the thirty-nine patients also reported good or excellent outcomes according to the system of Boyden et al.114, and all patients had returned to their preinjury working occupation. Twenty patients were still active in middle and long-distance running, eight were still active in low-weight-bearing activities, six had completely given up any sport practice, and five had changed sports. At the time of the latest follow-up, the tendon was generally thicker (p = 0.003) than the contralateral asymptomatic tendon, without any significant difference between patients with good or excellent outcomes and those with fair or poor results113.
Minimally Invasive Stripping
Minimally invasive stripping involves four skin incisions. The first two are 0.5-cm longitudinal incisions that are performed over the proximal portion of the Achilles tendon, medial and lateral to its origin, and the other two are 0.5-cm longitudinal incisions that are performed 1 cm distal to the distal end of the tendon insertion over the calcaneus. The Achilles tendon is freed from peritendinous adhesions and fibrosis by passing a mosquito clamp through the proximal two incisions; suture thread is inserted proximally, through the two proximal incisions, and then is retrieved from the distal incisions, at the posterior aspect of the Achilles tendon. With use of a gentle seesaw motion, the suture thread is made to slide posterior to the tendon to strip and free it from the Kager triangle. The procedure is also performed to free the superficial layer of the tendon from paratendinous adherences115. Postoperatively, the patient is allowed to bear full weight; proprioception, plantar flexion of the ankle, and inversion and eversion exercises are started after two weeks.
Thermann et al. used an endoscopic approach to debride the ventral neovascularized area, the peritenon, and the Achilles tendon in eight patients with chronic painful mid-portion Achilles tendinopathy116. At the time of the six-month follow-up, all patients reported improvement in terms of pain, tendon function, and global satisfaction. No postoperative complications were recorded.
Recent interest has focused on the role of the plantaris tendon in Achilles tendinopathy. Tethering the plantaris tendon to the medial aspect of the Achilles tendon may trigger an inflammatory response, and, over time, may produce tendinopathy117,118. Conversely, stripping the plantaris tendon with use of endoscopic techniques has been reported to provide good outcomes in terms of pain and function119,120.
The gastrocnemius release is also beneficial. Duthon et al., in a study of fourteen patients who underwent this procedure, reported that eleven patients (79%) had returned to their previous sport activities at the time of the two-year follow-up and that the quality of the tendon was improved on MRI at the time of the one-year follow-up121.
Perspectives for the Future
Many clinical and biological aspects of Achilles tendinopathy are still unclear. This condition is considered to be an overuse injury, but some patients seem to be more prone to it than others despite similar training and competition loads. In certain individuals, the tendons carry specific variations of genetic sequence that may make them more susceptible to injury122. Alterations in the structure or relative amounts of the components of tendon and fine control of activity within the extracellular matrix affect the response of the tendon to loading, with failure in certain cases. Advances in molecular biology and genetics may allow for the identification of factors that influence tenocyte metabolism and favor the healing process.
Although Achilles tendinopathy has been widely studied, there is still much to learn about its etiology, pathology, and optimal treatment123,124. Most patients with mid-portion Achilles tendinopathy fare well after conservative management. Rest, eccentric exercises, paratenon injections, and ESWT may be useful in many cases; operative treatment, which has been associated with an approximately 85% rate of satisfactory outcomes, should be considered for patients who do not respond to conservative management.
Although much has been written about prevention, we are not aware of any published guidelines, and efforts should be aimed at identifying correctable risk factors and undertaking secondary prevention for subjects who have recovered from Achilles tendinopathy.
Source of Funding: No external funds were received in support of this study.
Investigation performed at the Department of Musculoskeletal Disorders, University of Salerno, Salerno, Italy
Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. None of the authors, or their institution(s), have had any financial relationship, in the thirty-six months prior to submission of this work, with any entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. Also, no author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.
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