Non-insertional Achilles tendinopathy – Is there a role for non-operative treatment?

Brijesh Ayyaswamy and authors review exclusively non-operative treatments of mid-substance tendinopathy in the Achilles

 

Abstract

Non-insertional Achilles tendinopathy is a chronic, debilitating condition, mostly degenerative in pathology. For this condition, the normal collagen of the tendon is replaced by pathological tissue. Although highly prevalent in athletes, non-insertional Achilles tendinopathy may also affect the more sedentary population. This condition can present as pain and stiffness (or both), with a tender nodular swelling in the Achilles tendon, 2 to 6cm above the insertion. There are non-operative and operative treatment options, but the main stay of treatment is non-operative, as per current published evidence. This article focuses only on non-operative aspects of non-insertional Achilles tendinopathy treatment. The non-surgical options vary from eccentric loading exercise or combined eccentric concentric exercise, cryotherapy, hyperthermia, electric shock wave therapy, topical glycerol trinitrate patches and peritendinous injections. There are different peritendinous injection options available, such as corticosteroids, high volume image guided injections, prolotherapy, sclerotherapy, PRP injections, autologous blood and hyaluronic acid injection. Of all proven treatments, the most effective is reportedly eccentric loading exercises. Further treatments may be secondary options or adjuvant to eccentric loading. Among peritendinous injections, high volume guided injections and hyaluronic acid have shown promising early results. The success rate of non-operative treatment is approximately 70 per cent, reported in the majority of the studies. The indication for operative treatment remains to be the failure of non-operative treatment persisting for six to nine months.

 

Introduction

Achilles tendinopathy is a condition that results in loss of normal collagen architecture, replaced with an amorphous, mucinous material, with hyper cellularity and increased glycosaminoglycans and neovascularization [1,2]. The tendon can be affected within its mid-substance, typically 2cm to 6cm from the insertion point, or at the point of insertion itself [3]. This syndrome encompasses several overlapping pathologies and is clinically distinct from rupture or partial rupture. The spectrum varies from paratendinosis to tendinosis, both simultaneously, tendon rupture and insertional disorders [6,7]. The article reviews exclusively non-operative treatment of mid-substance tendinopathy, as insertional tendinopathy presents an elaborate topic to discuss in a separate article.

Achilles tendinopathy affects approximately 9 per cent of recreational runners and for up to 5 per cent of professional athletes this condition is career ending [4]. The incidence of mid-portion Achilles tendinopathy in general practice within the adult population is 2.35 per 1000 – and in 35 per cent of cases, a relationship with sports activity has been recorded [5]. It is often not possible to distinguish tendinosis from paratendinosis as these conditions frequently co-exist, thus the general term “tendinopathy” has been widely adopted.

 

Etiology, pathophysiology and histopathology

The high prevalence among runners points to mechanical overloading as an important etiological factor [8]. A minority of patients with Achilles tendinopathy lead sedentary lifestyles, with no identifiable history of mechanical overload, suggesting mechanical overload is not the only risk factor [8]. Other such risk factors include advanced age, male sex, high body mass index, hypercholesterolemia and presence of genetic variants of genes related to collagen mechanisms [9,10]. The postulated intrinsic etiological factors include tendon vascularity, weakness, as well as lack of flexibility of gastrocnemius – soleus complex, pes cavus and lateral ankle instability [11].

Mechanical overload results in inflammation, although the inflammation is not a typical full-blown inflammation [6]. The tenocytes produce inflammatory mediators such as Substance P and Prostaglandin E2. The peritendinous region becomes filled with fibrinous exudate (perceived as crepitus), forming adhesions, leading to chronic paratendinopathy. Imbalance between matrix degeneration and synthesis leads to intratendinous changes [2]. The activity of metalloproteinases (MMPs), particularly decreased expression of MMP3, is associated with Achilles tendinopathy [13].

The four cornerstones of histopathology are cellular activation/increase in cell numbers, increase in ground substance, collagen disarray and neovascularization [14]. There is also evidence of neurogenic inflammation in the presence of neuropeptides such as Substance P and calcitonin gene related peptide. Glutamate, which is a potent modulator of pain, is found in high levels in painful tendons [15]. The neural pathway may be associated with neovascularization. Biopsies have shown that nerves are in close relationship with neovascularization in areas of tendinosis [16,17].

 

Presentation and examination

The most common group presenting with non-insertional Achilles tendinopathy are athletes, especially middle to long-distance runners. A common symptom is morning stiffness or stiffness following a period of inactivity. As the condition progresses, pain may occur with even minor exertion and interfere with activities of daily living. In severe cases, pain persists at rest. In the acute phase the tendon is diffusely swollen and oedematous and tenderness is usually greatest 2-6cm proximal to the tendon insertion. A tender nodular swelling is present in chronic cases. (Figure 1)

Clinical examination is the best tool in diagnosing non-insertional Achilles tendinopathy [18]. The patient is examined standing and prone with legs exposed from the knee downwards. The foot and heel should be examined for malalignment, deformity, obvious asymmetry, tendon size, localised thickening and previous scars. The tendon excursion is examined to determine tightness of the tendon. A swelling in the tendon due to pure tendinopathy will move with the tendon on movement of the ankle, conversely a swelling of the paratenon will not move (the painful arc test). In the Royal London Hospital test, a swelling that is most painful when the ankle is in maximum dorsiflexion indicates tendinopathy. Maffulli et al studied sensitivity and specificity of palpation, painful arc test and Royal London Hospital test in 2003 and found that all three tests had good interobserver agreement [19]. A later study by Hutchinson et al in 2013, which studied ten clinical tests, found that only two tests, location of pain and pain on palpation, are most reliable and accurate [20].

 

Imaging

Imaging techniques include Ultrasound and Magnetic Resonance Imaging (MRI) scans. Ultrasound may be useful with power Doppler sonography, as Achilles tendinopathy seems to be related to areas of neovascularization. Early studies seem to indicate MRI scans are superior in characterisation of degeneration in the Achilles tendon [21,22]. Subsequent studies have shown equal or improved accuracy with ultrasound when compared with MRI scans in detecting tendinopathy [23]. Greyscale ultrasound has been found to be most sensitive, whereas colour Doppler ultrasound has higher correlation with patient symptoms [24]. The advantage of ultrasonography over other imaging modalities is interactive capability and cost effectiveness. Recently, ultrasound characterisation has been introduced as a reliable method to quantify tendon structure [25]. MRI gives extensive information about internal tendon morphology and surrounding bone and soft tissue; this helps to differentiate between paratendinopathy and tendinopathy and the extent of disease and, further, can detect incomplete ruptures [18]. (See figures 2-5)

 

 

 

Management

Currently, gold-standard management of Achilles tendinopathy lacks an evidence-based support consensus, and the appropriate moment to escalate from conservative to operative therapy is unknown. In a prospective observational follow-up study, the eight-year prognosis of patients with Achilles tendinopathy was generally good, though 29 per cent of patients required surgical intervention during follow-up period [26]. In general, non-operative care should be implemented for a minimum of three to six months prior to consideration for surgery, since Achilles tendinopathy may resolve in up to three quarters of patients.

 

NSAID

Although NSAIDs showed, at best, a modest short-term effect in various trials, the analgesic effect allows patients to ignore early symptoms, imposing further damage on the affected tendon, and delaying definitive healing – although NSAIDs may help patients moderate pain while performing eccentric stretching exercises. The potential harm of NSAIDS must be weighed up for each patient, balancing risks and benefits [27,18]. NSAIDs have not shown to alter the natural history of tendinopathy and, in absence of full-blown inflammation, have no major role apart from pain relief.

 

Rest

Rest is considered another first line therapy for Achilles tendinopathy, however data from recent studies shows patients may safely continue with their activity of choice [28,29].

 

Cryotherapy

Although cryotherapy may offer an analgesic effect, reducing metabolic rate within the tendon and decreasing extravasation of blood and protein from new capillaries found in tendon injuries, there is no evidence that cryotherapy is effective for the treatment of Achilles tendinopathy [30].

 

Exercises

Eccentric exercise has been shown to be the most effective treatment for non-insertional Achilles tendinopathy. The specific form of exercise varies from trial to trial, but the principal goal is to provide a strong, controlled, mechanical force to the Achilles tendon. This is usually achieved through eccentric muscle activity; for instance heel drop over a step [31]. As patient tolerance of the exercise improves, load can be progressively increased.

In Alfredson’s protocol, which is the most commonly employed non-operative treatment method, exercises are performed in three sets of 15 repetitions, twice a day, for 12 weeks [32]. The regime was demonstrated in a 2009 systematic review and confirmed in a 2012 meta-analysis, which outlined the best pooled data supporting eccentric exercise, with the majority of studies using Alfredson’s protocol [34,35]. The evidence of histological changes following eccentric exercise are lacking and the mechanism by eccentric exercise helping to resolve the pain of tendinopathy is unclear [18]. Alfredson and other Scandinavian authors have reported excellent results in prospective RCT’s [36,37]. Outside Scandinavia, investigators have also found eccentric exercises effective, but not as high percentage success rate, with a 50-60 per cent good outcome [38]. Nevertheless, eccentric exercise has been the mainstay of treatment in Achilles tendinopathy, with the greatest amount of evidence.

Other exercise protocols, such as eccentric-concentric, progressing to eccentric and eccentric-concentric, has been described with similar success recently [37, 39]. Isokinetic, isotonic, and concentric loading has also been described, but is inferior to eccentric type exercise [35]. In general, the overall trend suggests a positive effect of eccentric exercise with no reported major adverse side effects [18].

 

ESWT (electric shock wave therapy)

This forms the second line management in non-insertional Achilles tendinopathy. The RCT study that compared ESWT with eccentric training showed favourable outcomes, with 60 per cent of patients showing improvement with a similar outcome to eccentric exercise and both groups were better than the “wait and see” subset [29]. Rompe et al showed eccentric strengthening plus repetitive low energy shock-wave therapy was better than eccentric strengthening alone. There was significant improvement in combined therapy than strengthening group alone [29]. EWST is normally performed three times, spaced at one week apart, 2000 pulses with a pressure of 2.5 bars and a frequency of eight pulses per second in an area of maximal tenderness in circumferential pattern [29, 35].

The clinical response to shockwave is linked to two aspects, one is tissue healing with an increased level of tissue healing factors and the other is pain transmission modulation by selective dysfunction of sensory unmyelinated nerve fibres, either directly or through neuropeptides [40-43].

 

Orthotics, splints, braces

Orthotics has been used extensively in non-operative management of Achilles tendinopathy, but with little evidence to support the use. An inflatable AirHeel brace that applies intermittent compression to minimise swelling and promote circulation has been proposed to patients who do not tolerate eccentric exercise. But a study comparing an AirHeel brace to eccentric training did not show any difference between eccentric training and Aircast brace [44]. In a subsequent larger study, Knobloch et al found that there is no difference in functional outcome between eccentric training and eccentric training plus AirHeel brace [33]. There is no evidence to show that the use of a night splint significantly improves the outcome in Achilles tendinopathy [45].

 

Topical application of Glyceryl trinitrate

In one RCT, topical Glycerl trinitrate was found to be effective, with benefits persisting for more than three years [46]. However, Kane et al, did not find any significant superiority in the outcomes to the patients who underwent application of the patch compared with control in terms of pain and disability at six months. No histological difference in neovascularisation, collagen synthesis or stimulated fibroblasts from the two groups who were operated was found [47].

 

Hyperthermia

This represents another option for management of Achilles tendinopathy patients, which may help in the repair process, allow an increase in their activity level and provide greater pain relief – these theoretical advantages have yet to be confirmed with RCT [18].

 

Ultrasound therapy

The systematic reviews and meta-analysis have not shown enough evidence to support the use at current clinical doses [18].

 

Injectable therapy for Achilles tendonitis

High volume image guided injection (HVIGI) consists of normal saline, local anaesthetics and corticosteroids. The procedure consists of injecting a mixture of 10ml of 0.5 per cent Bupivacaine hydrochloride, 25mg of hydrocortisone, and 40mls of injectable normal saline using 21-gauge needle. Some authors did not use corticosteroids [48,49]. In a systematic review of dry needling with HVIGI, HGIVI shows promising results and HVIGI with dry needling is more effective than dry needling alone [50]. The studies by Humphrey et al and Maffulli et al showed that it is effective in reducing pain and reducing neovascularisation [48, 51].

However, whether the addition of corticosteroids, or Aprotinin in some studies, has attributed to a favourable result must to be taken into consideration.

A corticosteroid injection may offer short-term pain-relieving effects, however there may be no effect and further potential detrimental effects, in longer term [52]. There is a well-defined relationship between repeated corticosteroid injection and tendon rupture [53]. Reversible atrophy of tendon was seen in less than 50 per cent of patients. This confirms that corticosteroid should be carefully considered as a treatment to use preferably if a diagnosis of tendonitis has been established [54].

PRP injections were not able to show any superiority over placebo injections when combined with an eccentric loading exercise programme in terms of clinical outcome and healing of tendon [55]. Zhang et al in his meta-analysis has shown that PRP is not effective in Achilles tendinopathy and did not recommend it for general use in Achilles tendinopathy [56]. The peritendinous autologous blood has not shown to improve outcome in patients with Achilles tendinopathy. Bell et al failed to show any benefit of peritendinous autologous blood injection over six months, in addition to standard training [57].

The RCT by Alfredson and Ohberg focused on the potential benefit of sclerosing substance on Achilles tendinopathy. The VAS and patient satisfaction significantly improved in polidocanol compared with an injection of local anaesthetic only. When crossed over, the treatment in the second group also received the benefits [58]. A positive effect of a polidocanol injection has been demonstrated in two RCTs. It acts by causing thrombosis of local vessels, which results in inflammation. They are effective after two injections and are not dose dependent. These results have not yet been reproduced by other independent centers [59].

Brown et al trialed Aprotinin, a protease inhibitor, and found the overall difference between those treated with Aprotinin and a placebo were not significant [60]. The study of deproteinised hemodialysate extracted from calf blood showed promising results in the very short term, however long term results are not available [3].

Yelland et al evaluated 43 patients with painful mid-portion Achilles tendinopathy into three groups: eccentric loading, prolotherapy, which consists of injecting with a solution of 20 per cent glucose, 0.1 per cent Lignocaine and 0.1 per cent Ropivacaine, and combined treatment.

All patients showed improvement, however the eccentric loading alone group showed least improvement [61]. Prolotherapy mode of action initiates an inflammatory response at the site of application, promoting collagen deposition. However, Prolotherapy was found not to provide any improvements in the long-term over results achievable by the typical physical therapy program adopted for Achilles tendinopathy [54].

Hyaluronic acid (HA) is one of the main components of synovial fluid, produced within the tendon sheath, and is a main component of the extracellular matrix. HA may increase tenocyte viability and increase collagen one deposition and production. A RCT evaluating HA injection versus ESWT found significant improvement in the HA injection group at three months and six months [62]. Initial results for HA treatment appear to be promising, however further multi-centre RCTs and longer-term follow-up is required.

Our experience

In our experience, patients are typically referred following a course of physiotherapy for a minimum of three months, as prescribed by the general practitioner. We establish whether there are any risk factors or intrinsic causes for Achilles tendinopathy and aim to rectify this first. If the patient has not yet undergone physiotherapy, we will refer the patient for eccentric loading exercises and, for appropriate patients, ESWT. If the patient’s symptoms do not improve satisfactorily, following this we move on to injection therapy. In our centre we offer high volume image-guided injections performed by our musculoskeletal radiologist, or we offer patients hyaluronic acid peri-tendinous injections.

In our pilot study, 16 patients who had a previously failed the initial eccentric stretching programme were treated with hyaluronic acid injection. The mean VAS score showed statistically significant improvement at three months.

There was also significant improvement in functional scoring with MOxFQ patient outcome scores at three months. No adverse effects were observed. We found 87 per cent success rate at three months. We are currently evaluating our mid-term results and are due to submit a paper including full results soon.

 

Conclusion

Non-insertional Achilles tendinopathy is a painful, chronic and debilitating condition affecting athletes and some non-athletes. It is a degenerative condition due to failed healing of the tendon. Most patients with non-insertional Achilles tendinopathy can be treated non-operatively. Eccentric stretching appears to be the most successful evidence-based treatment, with adjuvants such as ESWT and peritendinous injection therapy, although limited on evidence for long-term benefits. Recent advances in injection techniques including PRP, hyaluronic acid, prolotherapy and high-volume image-guided injection appears promising in short-term studies, but requires further long-term review.

Operative treatment should be reserved for patients who have failed the conservative modalities for a minimum for six to nine months and forms only a small percentage of patients.

 

Authors

Main author: Brijesh Ayyaswamy, BOA Clinical Fellow in Foot and Ankle Surgery, North Tees and Hartlepool NHS Trust

Co-authors: Hemant Sharma, Registrar, Orthopaedics, North Tees and Hartlepool NHS Trust; Nimesh Jain, Registrar, Orthopaedics, North Tees and Hartlepool NHS Trust; Manesh Vaghela, Associate Specialist, Orthopaedics, North Tees Hospital NHS Trust; and Rajiv Limaye, Consultant Foot and Ankle Surgeon, North Tees and Hartlepool NHS Trust

 

References

1. Cook JL, Purdam CR;Is tendon pathology a continuum? A pathology model to explain the clinical presentation of load-induced tendinopathy; British Journal of Sports Medicine 2009; 43:409-416.
2. Ames P R J, Longo U G, Denaro V, Maffulli N(2008) Achilles tendon problems: Not just an orthopaedic issue, Disability and Rehabilitation, 30:20-22, 1646-1650,DOI: 10.1080/09638280701785882.
3. Gross, C. E., Hsu, A. R., Chahal, J., & Holmes, G. B. (2013). Injectable Treatments for Noninsertional Achilles Tendinosis: A Systematic Foot & Ankle International, 34(5), 619–628. https://doi.org/10.1177/1071100713475353.
4. Lysholm, J., & Wiklander, (1987). Injuries in runners. The American Journal of Sports Medicine, 15(2), 168–171. https://doi.org/10.1177/036354658701500213.
5. De Jonge S, vVan den Berg C, De Vos   RJ, et al, Incidence of midportion Achilles t e n d i n o p a t h y i n t h e g e n e r a l p o p u l a t i o n ; B r i t i s h J o u r n a l o f S p o r t s Medicine 2011;45:1026-1028.
6. Anderson Influences of paratendinous innervation and nonneuronal substance P in tendinopathy: studies on human tendon tissue and an experimental model of Achilles tendinopathy, Umea (S):Umea University;2010.
7. Backman, C., Boquist, L., Fridén, J., Lorentzon, R. and Toolanen, (1990), Chronic Achilles paratendonitis with tendinosis: An experimental model in the rabbit. J. Orthop. Res., 8: 541-547. doi:10.1002/jor.1100080410.
8. Maffulli, Nicola et al,ason Wong, Types and epidemiology of tendinopathy;Clinics in Sports Medicine,Volume 22, Issue 4, 675 –
9. Gaida, James & Alfredson, Lotta & Kiss, Zoltan & Wilson, Andrew & Alfredson, Håkan & Cook, Jill. (2009). Dyslipidemia in Achilles Tendinopathy Is Characteristic of Insulin Resistance. Medicine and science in sports and exercise. 41. 1194-7. 10.1249/ MSS.0b013e31819794c3.
10. Michael Posthumus, Malcolm Collins, Jill Cook, Christopher J. Handley, William J. Ribbans, Roger K. Smith, Martin P. Schwellnus, Stuart M. Raleigh, Components of the transforming growth factor-β family and the pathogenesis of human Achilles tendon pathology—a genetic association study, Rheumatology, Volume 49, Issue 11, November 2010, Pages 2090–2097, https://doi.org/10.1093/rheumatology/keq072.
11. Leadbetter WB, Cell-matrix response in tendon Clin Sports Med 1992;11:533-78.
12. aavola M,Kannus P,Jarvinen TA et al, Achilles tendinopathy Bone Joint Surg(Am)2002;84:2062-2076.
13. Alfredson, H., Lorentzon, M., Bäckman, S., Bäckman, A. and Lerner, U.H. (2003), cDNA‐arrays and real‐time quantitative PCR techniques in the investigation of chronic Achilles tendinosis. J. Orthop. Res., 21: 970-975. doi:10.1016/S0736-0266(03)00107-4.
14. Alfredson, Håkan, and J Cook. “A treatment algorithm for managing Achilles tendinopathy: new treatment options.” British journal of sports medicine 41,4 (2007): 211-6. doi:10.1136/bjsm.2007.035543
15. Alfredson, H,Forseen S,Thorsen,et al. In vivo microdialysis and immunohistochemical analyses of tendon tissue demonstrated high amounts of free glutamate and glutamate NMDAR1 receptors, but no signs of inflammation, in Jumper’s knee-J Orthop Res 2001; 19;881-6.
16. Bjur, , Alfredson, H. & Forsgren, S. The innervation pattern of the human Achilles tendon: studies of the normal and tendinosis tendon with markers for general and sensory innervation. Cell Tissue Res 320, 201–206 (2005) doi: 10.1007/s00441-004-1014-3
17. Ljung B,Alferdson H,Forsgren H;Neurokinin 1-receptors and sensory neuropeptides in tendon insertions at the medial and lateral epicondyles of the humerus. Studies on tennis elbow and medial epicondylalgia;j Orthop Res 2004;22;321-7
18. Maffulli N,Longo UG,Kadakia A,Spiezia F;Achilles tendinopathy;Foot and Ankle surgery;2019,doi.org/10.1016.j.fas.2019.03.009.
19. N,Kenward MG,Testa V,et al;Clinical diagnosis of Achilles tendinopathy with tendonitis;CLIN J Sport Med 2003,13.11-15.
20. Hutchinson AM,Evans R,Bodger O,et al;What is the best clinical test for Achilles tendinopathy; Foot and Ankle Surg 2013;19;112-117.
21. Neuhold A; Stiskal M; Kainberger F; Schwaighofer B; Degenerative Achilles tendon disease: assessment by magnetic resonance and ultrasonography;Eur J Radiol 1992;14;213-220.
22. Movin, , Kristoffersen-Wiberg, M., Shalabi, A., Gad, A., Aspelin, P., & Rolf, C. (1998). Intratendinous Alterations as Imaged by Ultrasound and Contrast Medium-Enhanced Magnetic Resonance in Chronic Achillodynia. Foot & Ankle International, 19(5), 311–https://doi.org/10.1177/107110079801900508
23. Khan KM, Forster BB, Robinson J, et al; Are ultrasound and magnetic resonance imaging of value in assessment of Achilles tendon disorders? A two year prospective study; British Journal of Sports Medicine 2003;37:149-153.
24. Warden, J., Kiss, Z. S., Malara, F. A., Ooi, A. B. T., Cook, J. L., & Crossley, K. M. (2007). Comparative Accuracy of Magnetic Resonance Imaging and Ultrasonography in Confirming Clinically Diagnosed Patellar Tendinopathy. The American Journal of Sports Medicine, 35(3), 427–436. https://doi.org/10.1177/0363546506294858.
25. Van Schie HT, de Vos RJ, de Jonge S, Bakker EM, Heijboer MP, Verhaar JA, Tol JL, Weinans (2010) Ultrasonographic tissue characterization of human Achilles tendons: quantification of tendon structure through a novel non-invasive approach. Br J Sports Med. 2010 Dec; 44(16): 1153-1159.
26. Paavola M, Kannus P, Paakkala T, Pasanen M, Järvinen M. Long-term prognosis of patients with Achilles tendinopathy. An observational 8-year follow-up An observational 8-year follow-up study. Am J Sports Med. 2000 Sep-Oct; 28 (5):634–642.
27. Troy Glaser, Sourav Poddar, Beth Tweed, Charles Webb; What’s the best way to treat Achilles tendinopathy?;J Fam Prct 2008;57;261-3.
28. Silbernagel, K. G., Thomeé, R., Eriksson, B. I., & Karlsson, J. (2007). Continued Sports Activity, Using a Pain-Monitoring Model, during Rehabilitation in Patients with Achilles Tendinopathy: A Randomized Controlled The American Journal of Sports Medicine, 35(6), 897–906. https://doi.org/10.1177/0363546506298279.
29. Rompe, J. D., Nafe, B., Furia, J. , & Maffulli, N. (2007). Eccentric Loading, Shock- Wave Treatment, or a Wait- and-See Policy for Tendinopathy of the Main Body of Tendo Achillis: A Randomized Controlled Trial. The American Journal of Sports Medicine, 35(3), 374–383. https://doi.org/10.1177/0363546506295940.
30. Umile Longo;Mario Ronga;Nicola Maffulli; Achilles Tendinopathy; Sports Medicine and Arthroscopy 17(2):112-126, JUNE 2009;DOI: 10.1097/JSA.0b013e3181a3d625.
31. Scott A,Huisman E,Khan Conservative treatment of chronic Achilles tendinopathy;CMAJ 2011;doi;10.1503/cmaj.101680.
32. Alfredson H,Pietila T,Jonsson P,Lorentzon R;Heavy –load eccentric calf muscle training for the treatment of chronic Achilles tendinosis; Am Sports Med 1998;26;360-366.
33. Robert Magnussen;Warren Dunn;A Thomson; Nonoperative Treatment of Midportion Achilles Tendinopathy: A Systematic Review; Clinical Journal of Sport Medicine. 19(1):54-64, JANUARY 2009;DOI: 10.1097/JSM.0b013e31818ef090 .
34. Sussmilch-Leitch et al. Physical therapies for Achilles tendinopathy: systematic review and meta-analysis. Journal of Foot and Ankle Research 2012, 5:15 doi:10.1186/1757-1146-5-15.
35. Pearce CJ, Tan Non-insertional Achilles tendinopathy. EFORT Open Rev 2016;1:383-390. DOI: 10.1302/2058-5241.1.160024.
36. Silbernagel KG, Thomeé R, Thomeé P, Karlsson J. Eccentric overload training for patients with chronic Achilles tendon pain – a randomized controlled study with reliability testing of the evaluation methods. Scand J Med Sci Sports 2001; 11:197-206.
37. Roos EM, Engström M, Lagerquist A, Söderberg B. Clinical improvement after 6 weeks of eccentric exercise in patients with mid-portion Achilles tendinopathy – a randomized trial with 1-year follow-up. Scand J Med Sci Sports 2004; 14:286-295.
38. Maffulli N, Walley G, Sayana MK, Longo UG, Denaro Eccentric calf muscle training in athletic patients with Achilles tendinopathy. Disabil Rehabil 2008; 30:1677-1684.
39. Stanish WD, Rubinovich RM, Curwin S. Eccentric exercise in chronic tendinitis. Clin Orthop Relat Res 1986; 208:65-68.
40. Rompe JD, Furia JP, Maffulli N. Mid-portion Achilles tendinopathy–current options for treatment. Disabil Rehabil 2008; 30;22:1666-1676.
41. Chen YJ, Wang CJ, Yang KD, et al. Extracorporeal shock waves promote healing of collagenase-induced Achilles tendinitis and increase TGF-beta1 and IGF-I expression. J Orthop Res 2004; 22:854-861.
42. Rees JD, Wilson AM, Wolman Current concepts in the management of tendon disorders. Rheumatology (Oxford) 2006;45:508-521.
43. Han SH, Lee JW, Guyton GP, Parks BG, Courneya JP, Schon LC. J. Leonard Goldner Award Effect of extracorporeal shock wave therapy on cultured tenocytes. Foot Ankle Int 2009; 30:93-98.
44. Petersen W, Welp R, Rosenbaum D. Chronic Achilles tendinopathy: a prospective randomized study comparing the therapeutic effect of eccentric training, the AirHeel brace, and a combination of both. Am J Sports Med 2007; 35:1659–67.
45. e Vos RJ, Weir A, Visser RJ, et al. The additional value of a night splint to eccentric exercises in chronic midportion Achilles tendinopathy: a randomised controlled trial. Br J Sports Med 2007; 41:e5.
46. Paoloni JA, Appleyard RC, Nelson J, et al. Topical glyceryl trinitrate treatment of chronic noninsertional achilles tendinopathya randomized, double-blind, placebo-controlled trial, J Bone Joint Surg, 2004, vol. 86(pg. 916-22).
47. Kane TP, Ismail M, Calder JD. Topical glyceryl trinitrate and noninsertional Achilles tendinopathy a clinical and cellular investigation, Am J Sports Med, 2008, vol. 36(pg. 1160-3).
48. Maffulli N, Spiezia F, Longo UG, Denaro V, Maffulli GD. High volume image guided injections for the management of chronic tendinopathy of the main body of the Achilles tendon. Phys Ther Sport. 2013;14(3):163–167. doi: 1016/j.ptsp.2012.07.002.
49. Wheeler PC, Mahadevan D, Bhatt R, Bhatia M. A comparison of two different high- volume image-guided injection procedures for patients with chronic non insertional Achilles tendinopathy: a pragmatic retrospective cohort J Foot Ankle Surg. 2016;55(5):976–979. doi: 10.1053/j.jfas.2016.04.017.
50. Chaudhry Effectiveness of dry needling and high-volume image-guided injection in the management of chronic mid-portion Achilles tendinopathy in adult population: a literature review. Eur J Orthop Surg Traumatol. 2017;27(4):441–448. doi: 10.1007/s00590-017-1957-1.
51. Humphrey J, Chan O, Crisp T, Padhiar N, Morrissey D, Twycross-Lewis R, King J, Maffulli N. The short-term effects of high volume image guided injections in resistant non- insertional Achilles tendinopathy. J Sci Med Sport. 2010;13(3):295–298. doi: 10.1016/ j.jsams.2009.09.007.
52. DaCruz D, Geeson M, Allen M, et al. Achilles paratendonitis: an evaluation of steroid injection, Br J Sports Med, 1988, vol. 22(pg. 64-5).
53. Ford LT, DeBender J. Tendon rupture after local steroid injection, South Med J, 1979, vol. 72(pg. 827-30).
54. Nicola Maffulli, Rocco Papalia, Stefano D’Adamio, Lorenzo Diaz Balzani, Vincenzo Denaro, Pharmacological interventions for the treatment of Achilles tendinopathy: a systematic review of randomized controlled trials, British Medical Bulletin, Volume 113, Issue 1, March 2015, Pages 101–115, https://doi.org/10.1093/bmb/ldu040.
55. de Jonge, S., de Vos, J., Weir, A., van Schie, H. T. M., Bierma-Zeinstra, S. M. A., Verhaar, J. A. N., … Tol, J. L. (2011). One-Year Follow-up of Platelet-Rich Plasma Treatment in Chronic Achilles Tendinopathy: A Double-Blind Randomized Placebo-Controlled Trial. The American Journal of Sports Medicine, 39(8), 1623–1630. https://doi.org/ 10.1177/0363546511404877.
56. Zhang YJ, Xu SZ, Gu PC, et al. Is Platelet-rich Plasma Injection Effective for Chronic Achilles Tendinopathy? A Meta-analysis. Clin Orthop Relat Res. 2018;476(8):1633–1641. doi:10.1007/s11999.0000000000000258.
57. Bell KJ, Fulcher ML, Rowlands DS, Kerse N. Impact of autologous blood injections in treatment of mid-portion Achilles tendinopathy: double blind randomised controlled trial. BMJ. 2013;346:f2310. Published 2013 Apr 18. doi:10.1136/bmj.f2310.
58. Alfredson, & Öhberg, L. Knee Surg Sports Traumatol Arthrosc (2005) 13: 338. https://doi.org/10.1007/s00167-004-0585-6.
59. van Sterkenburg, M. N., de Jonge, M. C., Sierevelt, I. N., & van Dijk, C. N. (2010). Less Promising Results with Sclerosing Ethoxysclerol Injections for Midportion Achilles Tendinopathy: A Retrospective The American Journal of Sports Medicine, 38(11), 2226–2232. https://doi.org/10.1177/0363546510373467.
60. Brown R, Orchard J, Kinchington M, et al; Aprotinin in the management of Achilles tendinopathy: a randomised controlled trial; British Journal of Sports Medicine 2006;40:275-279.
61. Yelland MJ, Sweeting KR, Lyftogt JA, et al; Prolotherapy injections and eccentric loading exercises for painful Achilles tendinosis: a randomised trial; British Journal of Sports Medicine 2011;45:421-428.
62. Lynen, De Vroey et al;Comparison of Peritendinous Hyaluronan Injections Versus Extracorporeal Shock Wave Therapy in the Treatment of Painful Achilles’ Tendinopathy: A Randomized Clinical Efficacy and Safety Study;Arch Phy Med Rehabil; 2017 Jan;98(1):64-71. doi: 10.1016/j.apmr.2016.08.470. Epub 2016 Sep