UNIVERSITY OF CALGARY

TREATMENT OF ACHILLES TENDINOPATHY

by

RITHESH RAM

A THESIS

SUBMITTED TO THE FACULTY OF GRADUATE STUDIES

IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE

DEGREE OF DOCTOR OF PHILOSPHY

DEPARTMENT OF COMMUNITY HEALTH SCIENCES

CALGARY, ALBERTA

November 2011

© Rithesh Ram 2011

The author of this thesis has granted the University of Calgary a non-exclusive license to reproduce and distribute copies of this thesis to users of the University of Calgary Archives. Copyright remains with the author. Theses and dissertations available in the University of Calgary Institutional Repository are solely for the purpose of private study and research. They may not be copied or reproduced, except as permitted by copyright laws, without written authority of the copyright owner. Any commercial use or re-publication is strictly prohibited. The original Partial Copyright License attesting to these terms and signed by the author of this thesis may be found in the original print version of the thesis, held by the University of Calgary Archives. Please contact the University of Calgary Archives for further information: E-mail: [email protected] Telephone: (403) 220-7271 Website: http://archives.ucalgary.ca

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Abstract This research sought to influence clinical management and treatment of Achilles tendinopathy by: 1) evaluating the efficacy of sclerotherapy (with a 25% dextrose and 0.5% lidocaine sclerosant) over the course of one year; 2) evaluating the effectiveness of a 12 week standardized home based heavy load eccentric training program; and 3) describing the prevalence of neovascularisation in adults with disease and without, and prevalence after treatment. Specifically, it provides the first short term data from a prospective triple blinded randomized controlled trial on the efficacy of ultrasound guided sclerosing 25% dextrose and 0.5% lidocaine injections following failure of eccentric exercises. Sclerotherapy was an efficacious treatment in the short term (3 months) with all patients showing statistically significant improvement in pain and function (as measured by the Victorian Institute of Sport Assessment-Achilles outcome measure), but its positive effects decreased for some patients after one year. With regards to neovascularisation, it was present in all affected tendons (and in one individual without the disease), but change in the number of neovessels does not appear to affect symptoms. With regard to eccentric training, it was found to not be effective in the majority of patients with only two patients considering themselves satisfied with treatment. Based on these results, a treatment paradigm and future research directions are provided. Most notably, eccentric training is not recommended as an effective treatment option for Achilles tendinopathy. Sclerotherapy is recommended as a treatment option for both mid-portion and enthesopathy.

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Acknowledgements Thank you to the Department of Community Health Sciences, the Leaders’ in Medicine program, the Faculty of Graduate Studies, and CIHR for their funding support. Thank you to Dr. Marilynne Hebert and Crystal Elliot for your guidance and direction during my tenure with CHS. I want to thank Drs. Scott Patten, Margaret Russell, and Brent Hagel for allowing me the opportunity to help educate graduate students in the field of epidemiology – it provided a unique opportunity to concentrate and enhance my knowledge in the area. Thank you to Dr. Paul Beck, Dr. Morley Hollenberg, and Michelle Sellman for support during my time with LIM – without it I would not have been able to make my goal of the combined MD/PhD a reality. Thank you to Dr. Tom Noseworthy for igniting my passion in healthcare policy and leadership, and for your constant mentorship and support. Thank you to all current and past senior leadership at the University of Calgary including Dr. Tom Feasby, Dr. Fred Hall, Dr. Alan Harrison, Dr. Bruce Wright, Mr. Jack Perraton, Mr. Charlie Fischer, Ms. Joanne Cuthbertson, Mr. Ken McKinnon, Mr. David Johnston and Ms Ann Tierney. Leadership is best learned through role models, and I could not imagine having a better pool of experience than what was available at the U of C. Thank you to all of the participants in this study. It is obvious that without your involvement this study could not have succeeded. Thank you to Drs David Wiseman and Chirag Patel, along with the staff of the Diagnostic Imaging Department at the Foothills Medical Centre, for their assistance with the ultrasound imaging and injections. Thank you to Drs Liam Martin and Lauren Beaupre for your involvement with the dissertation defence. Thank you to my committee members: Drs Nick Mohtadi and Brent v

Hagel for your guidance and support throughout my degree. You challenged me through out my degree, which provided the needed growth for me to progress from BSc to PhD. Thank you to Dr. Willem Meeuwisse for agreeing to become my co-supervisor when I transitioned from the MSc to PhD. Without your involvement, I would not have been able to pursue this goal. A special thanks to Dr. Preston Wiley. My transition from engineer to graduate student to MD/PhD would never have occurred if it had not been for his mentorship and dedication to my academic pursuits. Dr. Wiley provided me with the opportunity to prove that with sufficient guidance I would be able to succeed in a number of different areas of leadership and academics. Under his watchful eye, I have excelled in a number of different arenas at the U of C, and with a clear direction and pursuit. His unwavering support during unexpected personal and family hardships goes above and beyond the definition of an excellent supervisor. Thank you so much for everything that you have done.

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Dedication This dissertation is dedicated to my family. My Mother, Rajammal Ram, and my Father, the late Dr. Sewbarath Ram, for their never-ending belief in what I could and can accomplish. Samson, my loyal companion, who has been with me through some of the hardest personal journeys one ever has to make. My daughter Lalina, you are the apple of my eye whose smile brightens even my worst days. Veronique, you are my soul mate and my strength, everything that I accomplish is a testament to your love and belief in me.

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Table of Contents Approval Page…………………………………………………………………………….ii Abstract .............................................................................................................................. iv   Acknowledgements ..............................................................................................................v   Dedication ......................................................................................................................... vii   Table of Contents ............................................................................................................. viii   List of Tables ..................................................................................................................... xi   List of Figures and Illustrations ........................................................................................ xii   List of Symbols, Abbreviations and Nomenclature ......................................................... xiii   Chapter  One:  INTRODUCTION  .............................................................................................................  1   The state of evidence in Achilles tendinopathy research .................................................1   Objective and Research questions ...................................................................................2   Dissertation format ..........................................................................................................4   Chapter  Two:  REVIEW  OF  THE  LITERATURE  ...............................................................................  5   Literature Review ............................................................................................................5   (a)   Methods ..............................................................................................................5   (b)   Anatomy.............................................................................................................7   (c)   Nomenclature .....................................................................................................9   (d)   Aetiology and Pathophysiology .......................................................................12   (e)   Pain and Histology ...........................................................................................16   (f)   Epidemiology ...................................................................................................18   (g)   Evaluation: Diagnosis, Imaging and Outcome Assessment ............................20   (h)   Management Strategies ....................................................................................33   Chapter  Three:  THE  EFFECTIVENESS  OF  A  HOME-­‐BASED  HEAVY  LOAD   ECCENTRIC  TRAINING  PROGRAM  FOR  TREATMENT  OF  ACHILLES   TENDINOPATHY  ...........................................................................................................................  52   Introduction ....................................................................................................................55   Material & Methods .......................................................................................................57   Procedure & Patients ................................................................................................57   Outcome Measures & Analysis ................................................................................58   Ethical Considerations ...................................................................................................60   Results ............................................................................................................................60   Discussion ......................................................................................................................62   Perspective .....................................................................................................................65   Acknowledgements ........................................................................................................65   Chapter  Four:  THE  EFFICACY  OF  SCLEROTHERAPY  WITH  A  SOLUTION  OF   DEXTROSE  AND  LIDOCAINE  TO  TREAT  CHRONIC  ACHILLES   TENDINOPATHY:  A  RANDOMIZED  CONTROLLED  TRIAL  ..........................................  71   Introduction ....................................................................................................................75   Methodology ..................................................................................................................76   Participants ...............................................................................................................76   viii

Intervention...............................................................................................................76   Outcomes ..................................................................................................................77   Statistical Analysis ...................................................................................................79   Sample Size ..............................................................................................................80   Ethical Approval and Adverse Effects .....................................................................82   Results ............................................................................................................................82   Patient flow and baseline characteristics ..................................................................82   Efficacy of sclerotherapy ..........................................................................................83   Interpretation ..................................................................................................................84   Limitations ................................................................................................................86   Conclusion ................................................................................................................87   Competing Interests .......................................................................................................87   Affiliations .....................................................................................................................87   Contributors ...................................................................................................................87   Funding ..........................................................................................................................88   Acknowledgements ........................................................................................................88   Chapter  Five:  THE  EFFICACY  OF  SCLEROTHERAPY  WITH  A  SOLUTION  OF   DEXTROSE  AND  LIDOCAINE  TO  TREAT  CHRONIC  ACHILLES   TENDINOPATHY:  ONE-­‐YEAR  FOLLOW-­‐UP  FOLLOWING  THE  CONCLUSION   OF  A  TRIPLE  BLINDED  RANDOMIZED  CONTROLLED  TRIAL  ...................................  95   Introduction ....................................................................................................................98   Methodology ..................................................................................................................99   Design of the study and Study Population ...............................................................99   Follow-up visits description and schedule ...............................................................99   Treatment with sclerosing dextrose injections .......................................................100   Outcome Measures .................................................................................................100   Data Analysis..........................................................................................................101   Ethics ......................................................................................................................101   Results ..........................................................................................................................102   Discussion ....................................................................................................................103   Chapter  Six:  SUMMARY  ......................................................................................................................  110   Treatment of Achilles tendinopathy ............................................................................110   Scheme for Achilles tendinopathy ...............................................................................112   Future research directions ............................................................................................116   APPENDICES  ...........................................................................................................................................  117   A: Literature Search and Abstract Selection Criteria ..................................................118   B: Physican Approach Letter .......................................................................................121   C: Recruitment E-poster ..............................................................................................123   D: Recruitment Poster ..................................................................................................124   E: Recruitment E-poster – Adults Without Condition .................................................125   F: Recruitment Poster – Adults Without Condition.....................................................126   G: Recruitment Poster – Athletes/Graduate Students Without Condition ...................127   H: Inclusion / Exclusion Criteria .................................................................................128   I: Sample Size Calculations .........................................................................................130   ix

J: Baseline Data Questionnaire ....................................................................................132   K: VISA-A Questionnaire ...........................................................................................133   L: Visual Analog Scale ................................................................................................136   M: Tegner Activity Scale .............................................................................................137   N: History and Physical Exam Form ...........................................................................138   O: 12-week Eccentric Exercise Program .....................................................................139   P: Follow-up Data Questionnaire ................................................................................140   Q: Participant Log Form ..............................................................................................142   R: Ultrasound Imaging Form .......................................................................................143   S: Eccentric Log Book .................................................................................................144   T: Adverse Event Report .............................................................................................145   U: Treatment Allocation Assessment Form.................................................................146   V: Consent Form – Study Sample (Unilateral & Bilateral) .........................................147   W: Consent Form – Adults Without Condition ...........................................................158   X: Consent Form – Athletes/Graduate Students Without Condition ...........................161   REFERENCES  ..........................................................................................................................................  163  

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List of Tables Chapter 2 Table 1: Summary of studies included in the critical review of non-surgical treatments of Achilles tendinopathy ......................................................................... 33   Chapter 3 Table 1: Baseline characteristics of adults diagnosed with Achilles tendinopathy, normative graduate students, and normative adults ........................... 66   Chapter 3 Table 2: Ultrasound and outcome results for adults diagnosed with Achilles tendinopathy, normative graduate students, and normative adults ........................... 67   Chapter 3 Table 3: Characteristics of 25 tendons in 20 patients with chronic painful Achilles tendinopathy: comparison between subjects who were satisfied and not satisfied with treatment ............................................................................................. 68   Chapter 3 Table 4: Means, 95% confidence intervals and p-values of the change in outcome measure score from baseline to 12 weeks in the satisfied and not satisfied patients with chronic painful Achilles tendinopathy .................................. 69   Chapter 4 Table 1: Baseline characteristics of Active and Placebo Group ...................... 92   Chapter 4 Table 2: Comparison of Change in Study Outcomes in Active Injection Group and Placebo Injection Group Patients from Baseline to 12 Weeks ............... 93   Chapter 5 Table 1: Baseline data on the 17 patients with chronic painful Achilles tendinopathy that were treated with sclerotherapy ................................................. 107   Chapter 5 Table 2: Means, 95% confidence intervals and p-values of the change in outcome measure score from end of treatment to 6 months and to 12 months in the satisfied and not satisfied participants with chronic painful Achilles tendinopathy that were treated with sclerotherapy ................................................. 108  

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List of Figures and Illustrations Chapter 3 Figure 1: Scores during the 12-week treatment schedule for all patients with chronic painful Achilles tendinopathy. The graph illustrates the score for each patient who was either satisfied (dot) or not satisfied (circle) after 12 weeks. (a) VISA-A, (b) VAS scores (overall pain in Achilles tendon during tendon loading activity), (c) VAS scores (overall pain in Achilles tendon during regular activities of daily living), and (d) Tegner. .................................................... 70   Chapter 4 Figure 1: Sclerotherapy procedure: close up of the sclerotherapy needle during insertion (right picture). Informed consent was obtained for publication of these figures. ......................................................................................................... 89   Chapter 4 Figure 2: Consolidated Standards of Reporting Trials (CONSORT) diagram of patient flow through the trial. ................................................................. 90   Chapter 4 Figure 3: Adapted Consolidated Standards of Reporting Trials (CONSORT) diagram of patient flow through the follow-up and crossover scheme....................................................................................................................... 91   Chapter 4 Figure 4: VISA-A scores during the 12-week treatment schedule for all participants with chronic painful Achilles tendinopathy. The graph illustrates the score for each participant who was either receiving Placebo (dot) or Active injection (circle). ....................................................................................................... 94   Chapter 4 Figure 5: Sagittal Achilles Color Doppler ultrasound findings in a patient with chronic painful Achilles tendinopathy (mid-portion) with arrows pointing to the areas of neovascularisation (blue solid arrows) and Achilles tendon (yellow, dashed arrow). ........................................................................................................... 94   Chapter 5 Figure 1: Adapted Consolidated Standards of Reporting Trials (CONSORT) diagram of patient flow through the crossover and one-year follow-up. ................................................................................................................ 106   Chapter 5 Figure 2: VISA-A scores during the one-year follow-up for all participants with chronic painful Achilles tendinopathy. The graph illustrates the score for each participant who was either satisfied with treatment (dot) or not satisfied with treatment (circle). ............................................................................................ 109   Chapter 6 Figure 1: Scheme for treating Achilles tendinopathy..................................... 113   Chapter 6 Figure 2: Applying the scheme (fictional case) ............................................. 114  

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List of Symbols, Abbreviations and Nomenclature Symbol or Phrase Tendinopathy Achilles Enthesopathy Mid-portion Achilles Tendinopathy Tendinosis Eccentric Training Neovascularisation Sclerotherapy VISA-A Tegner Activity Scale Doppler Ultrasound (Color and Power)

Definition Any painful condition of the Achilles tendon, further subdivided into Achilles enthesopathy and mid-portion Achilles tendinopathy. Pain occurring at or around the most distal portion of the Achilles at its attachment on the calcaneal tuberosity Pain that involves the area of the tendon 2 to 6 cm proximal to the calcaneal insertion Describes a degenerative tendon change within the tendon without accompanying inflammation (1). Consists of exercises where the muscle lengthens while producing a force (2). Growth of new blood vessels and nerves into a damaged area of the tendon Injecting a solution that results in the ablation of vessels Victorian Institute of Sports Assessment – Achilles is an Achilles tendinopathy specific scale that measures pain and activity level to serve as an index of severity for Achilles tendinopathy A simple 10-point scoring system measuring activity level in a compact, single-page format. Medical sonography (ultrasonography) is a useful ultrasoundbased diagnostic medical imaging technique used to visualize muscles, tendons, and many internal organs, their size, structure and any pathological lesions. It can be enhanced with Doppler measurements which employ the Doppler effect to assess whether structures (usually blood) are moving towards or away from the probe, and its relative velocity (3). Color Doppler uses a computer to convert the Doppler sounds into colours that are overlaid on the image of the blood vessel and that represent the speed and direction of blood flow through the vessel. Power Doppler is a technique that is up to five times more sensitive in detecting blood flow than color Doppler. Power Doppler can obtain some images that are difficult or impossible to obtain using standard color Doppler. However, power Doppler is most commonly used to evaluate blood flow through vessels within solid organs. Blood flow in individual blood vessels is most commonly evaluated by combining techniques as together they are able to provide better information on the direction and speed of blood flow than when these techniques are used individually.

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Chapter One: INTRODUCTION Of all the mighty man, the small remains A little urn, and scarcely fill'd, contains. Yet great in Homer, still Achilles lives; And equal to himself, himself survives. Book 12, Ovid's Metamorphoses Achilles was the greatest and most central character of Homer’s Illiad. Although Achilles’s dominance on the battlefield is described as god-like, his death came from an arrow to the heel – his only unprotected area. From that time, the Achilles tendon has been considered a weak point of the human body. The state of evidence in Achilles tendinopathy research Tendon pain is common and, although there are no accurate figures it is estimated that overuse injuries (including tendinopathies) account for almost 7 percent of all injuryrelated physician office visits in the United States (1, 4, 5). Although it is classically related to the workplace, Statistics Canada reported over two million Canadians had a repetitive strain injury (injuries that affect the muscles, nerves and tendons) serious enough to limit their normal activities between 2000 to 2001 (6). Aside from the physical symptoms and emotional strain of individuals and families, in Canada the economic cost of these injuries is estimated at $26 billion each year; much of this paid for by taxpayers in the form of health care and income assistance (7). Specifically with Achilles tendinopathy, it is not simply a disease managed in the office of health care professionals. Patients will seek out cures and explanations in the domains which are common and accessible to them. For example, patrons of Running Room will find articles like Dr. Beauchamp’s titled “Achilles Tendonosis” with an overview of the disease with treatment suggestions (8). Researchers in the field describe

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the disease as “no longer [being] an uncomplicated diagnosis” with “tendon injury… recognised as a major clinical problem” (9). New treatment protocols and directions for research are introduced and suggested yearly in response to the changing patient population, shifting clinical expectations and technological advances (10). The evidence base for treatments remains tenuous. It is largely unknown how the shifting patient population may respond to new and long standing treatment options. For example, assuming that young patients would expect better response to exercise than older patients becomes complicated by the obesity epidemic and lack of physical activity in the younger generations. There is currently no magic formula for treatment prescription, and better data from randomized controlled trials would greatly assist clinicians in fine tuning their practice and advancing our knowledge base (11). For patients in which treatment progress and compliance are monitored frequently, or with highly motivated patients, eccentric exercises has proven its efficacy (10, 12). However, there is limited evidence on its effectiveness. Ultrasound guided sclerosing injections have emerged as a new and exciting option in the Achilles tendinopathy treatment paradigm. But evidence on its efficacy is limited by the lack of randomized controlled trials, lack of long term clinical effect, and lack of available sclerosants. This thesis addresses these gaps in knowledge and will provide suggestions for its use in clinical practice. Objective and Research questions The results of this study will be used to influence clinical management and treatment of Achilles tendinopathy. Additionally, the results may be utilized in the

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consideration and development of future research in Achilles tendinopathy and other tendinopathies. The primary research question of the study was: In adults with chronic painful Achilles tendinopathy with existing neovascularisation (shown by Doppler ultrasound) who have failed a standardized heavy load eccentric training program, is there a difference in VISA-A score (Victorian Institute for Sport Assessment – Achilles) between injections of a 25% dextrose and 0.5% lidocaine sclerosant compared with injection of 1% lidocaine alone outside the tendon with neovascularisation as measured over 12 weeks? The secondary research questions of the study are: 1) For adults with clinically diagnosed chronic painful Achilles tendinopathy will a standardized home based heavy load eccentric training program result in a mean subjective patient satisfaction within the range of 60 to 90%? 2) For healthy adults with no clinical diagnosis of a lower extremity disease or injury, what is the effect of a standardized heavy load eccentric training program on their Achilles tendon using Doppler ultrasound? 3) For what proportion of adults clinically diagnosed with chronic painful Achilles tendinopathy that fail a standardized heavy load eccentric training program is neovascularisation present as measured with Doppler ultrasound? 4) What is the prevalence of neovascularisation (as measured with Doppler ultrasound) in adults clinically diagnosed with chronic painful Achilles tendinopathy compared to adults with no history of Achilles tendinopathy or general heal pain?

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5) What are the clinical effects and subjective patient satisfaction over the course of 1-year following treatment with sclerosing 25% dextrose and 0.5% lidocaine injections to adults clinically diagnosed with chronic painful Achilles tendinopathy? Dissertation format This thesis consists of a collection of three manuscripts of which the candidate is the primary author. These papers have a cohesive, unitary character making them a report of a single program of research. Chapter 3 explores the effectiveness of a home based heavy load eccentric training program. Chapter 4 is a triple blinded randomized controlled trial (RCT) exploring the efficacy of ultrasound guided sclerosing 25% dextrose and 0.5% lidocaine injections over 3 months for those participants from Chapter 3 with neovascularisation and for whom the eccentric program failed to alleviate their symptoms. Chapter 5 describes the 1-year follow-up data of the RCT. These manuscripts are supported by a comprehensive review of the literature (Chapter 2) and a summary with future research directions (Chapter 6). Additional information, including consent forms, are included in the appendix for completeness and to allow clear and precise judgment to be made of the importance and originality of the research reported in this dissertation.

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Chapter Two: REVIEW OF THE LITERATURE Literature Review The purpose of this literature review was to determine the current state of treatment of chronic Achilles tendinopathy. This review was used to inform and provide background materials for the study protocol, and to situate the new treatment protocol in the world literature. A critical review of the literature was provided for the conservative management strategy sections only, and this was limited to randomized controlled trials. However, the scope of articles was expanded where necessary to provided information directly relevant to the primary research question. A summary table is provided, which includes a qualitative assessment of efficacy/effectivness, a quantitative assessment using the Oxford score (13), and Level of Evidence (14). (a) Methods Step 1 A literature search was performed in the Medline, EMBASE, Cochrane Database of Systematic Reviews, EBM Reviews, and Cochrane Controlled Trials Register databases. The search used both controlled vocabulary (example: Medical Subject Headings [MeSH]) and keywords. Other names for the disease include “Achilles tendinitis”, “Achilles tendinosis”, “Achilles paratenonitis”, and “Achilles tendon.” For those databases that offer MeSH headings, these same keywords were also used to yield MeSH headings of which the relevant headings were combined (using the Boolean operator AND) and exploded. The original search was limited to years 1998-2008, English language and adult population, and yielded 559 titles (Appendix A). Criteria for the selection of relevant abstracts were developed (Appendix A). Fifty abstracts were

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reviewed by one reviewer against the criteria which were subsequently revised and tested on another 50 abstracts. All remaining abstracts were reviewed by one reviewer. One hundred eighty abstracts from the first group of 559 were identified as of potential interest for the objective. A second search identified 252 additional abstracts between 2008-2011, of which 5 were identified as of potential interest for the objectives. Step 2 A second search in Medline, EMBASE and Cochrane databases, using briefer search criteria (general ‘sclerotherapy’, ‘neovascularisation’, ‘prolotherapy’, ‘Polidocanol’, ‘sclerosant’ terms instead of detailed list) was performed. This search was limited only to English language and years 1998-2008 and yielded 77 titles (Appendix A). From these, 28 articles were selected for further reviewing. Note that articles not specifically related to Achilles but related to neovascularisation or sclerotherapy were kept. A second search identified 42 additional abstracts between 2008-2011, of which 16 were identified as of potential interest for the objectives. Step 3 A citation search was conducted using the titles selected in the previous 2 steps. From resulting abstracts, 4 were selected for further reviewing. Step 4 The full-text of the articles selected in the previous 3 steps was obtained. The reference lists of these articles were hand-searched by the reviewer and 2 more papers were selected for further reviewing.

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(b) Anatomy The Achilles tendon is fibrous tissue that connects the heel (calcaneus) to two major calf muscles: the gastrocnemius and the soleus. The soleus originates below the knee, from the posterior surfaces of the proximal end of the tibia and fibula and the interposed tendinous arch, and has no action on the knee joint (15). The soleus as a postural muscle acts only on the ankle joint, and assists plantar flexion for toe off during propulsion. The soleus contracts to counteract the tendency for the body to tilt forward at the ankle when the center of gravity passes in front of the axis of movement of the knee joint (15). The soleus also acts as a peripheral vascular pump, and is composed of mainly slow twitch type I fibers (15). The gastrocnemius muscle, with two bellies, originates from the posterior surface of the femoral condyles (16). The gastrocnemius consists mainly of fast twitch fibers and when it plantar flexes the foot on the ankle and flexes the knee, the body is propelled forward (15). The small plantaris muscle also connects with the Achilles; however, it is absent in 6% to 8% of individuals (15). The Achilles tendon begins at the musculotendinous junction of the gastrocnemius and soleus, and inserts onto the middle part of the posterior surface of the calcaneus. There is a rotational twist before inserting on calcaneus with the gastrocnemius fibers inserting laterally and the soleus fibers inserting medially. Two bursae (fluid filled sacs that act as a cushion and lubricant between tendon and muscles sliding over bone) are located just superior to the insertion. Anterior or deep to the tendon is the lined retrocalcaneal (subtendinous) bursa, which is located between the Achilles tendon and the tuberosity on the posterior surface of the calcaneus (15). Posterior or superficial to the Achilles tendon is the subcutaneous calcaneal bursa, also

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called the Achilles bursa, and is located between the skin and posterior aspect of the distal Achilles tendon (15). The Achilles tendon does not have a true synovial sheath but is surrounded by a paratenon, a thin gliding membrance of loose areolar connective tissue. The paratenon allows the tendon to glide freely against the surrounding tissue. The connective tissue consists mainly of type I collagen, minor component of type III collagen, type IV collagen in the basement membrane as well as traces of type V collagen (15). Fluid is located between the paratenon and the epitonen and reduces friction (15). The neural, vascular, and lymphatic supply to the tendon comes by the collagen fibers and fiber bundles which are bound by the endotenon (the inner surface of the epitenon is continuous with the endotenon). The tension generated by the intracellular contractile proteins of muscle fibers are transmitted to the collagen fibrils at the myotendinous junction as a result of tendinous collagen fibrils being inserted into deep recesses formed by myocyte processes (17). Although this complex architecture reduces the tensile stress exerted on the tendon during muscle contractive, the junction still remains the weakest point of the muscle-tendon unit (17). The osteotendinous junction (enthesitis) prevents collagen or fiber bending, fraying, shearing and failure (17). It is comprised of four areas: fibrocartilage, bone, dense tendon zone, and mineralized fibrocartilage. Blood is supplied to the Achilles tendon in two main ways: the intrinsic vascular system proximally from the myotendinous and distally from the osteotendinous junctions, and the extrinsic system through the paratenon (especially the ventral mesotendon) (17-

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19). A zone of relative hypovascularity has been noted at a point approximately 2-7 cm proximal to the tendon insertion (17, 20). The sensory nerves of the Achilles tendon is supplied mainly from the muscles (via the tibial nerve) along with some innervations from surrounding cutaneous nerves (including the sural nerve) (21). The Achilles tendon is innervated from three main sources: cutaneous, muscular and peritendinous nerve trunks (22). Nerve fibres cross and enter the endotenon septa at the myotendinous junction. Nerve fibres form rich plexuses in the paratenon penetrate the epitenon, although most nerve fibres do not actually enter the main body of the tendon (22). Rather, they terminate as nerve endings on its surface. Despite the scarcity of intratendinous nerves, pain receptors are abundant in the paratenon (23). Unmyelinated nerve endings act as nociceptors that sense and transmit pain (17). Both sympathetic and parasympathetic fibers are present in the tendon. (c) Nomenclature Classifications and terminology used to describe Achilles tendon disorders are not clear and definitive due to overlap in symptoms, clinical signs, and histological findings of each condition (24, 25). Schepsis et al (1994) presented a classification of Achilles tendon disorders modified from one set forth by Puddu et al (1976) (26). Achilles disorders were classified as being paratenonitis, paratenonitis with tendinosis, tendinosis, insertional tendonitis, partial rupture and retrocalcaneal bursitis (1, 25, 26). Paratenonitis occurs as diffuse discomfort around the tendon (18). The tendon appears swollen, edematous, and crepitation is often noted in acute cases. The term includes what was previously referred to as peritendinitis, tenosynovitis (single layer of areolar tissue covering the tendon), and tenovaginitis (double-layer tendon sheath) (27).

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Inflammation and thickening of paratenon with adherence to the underlying tendons is present in chronic cases (25). Clinically, there is diffuse and sometimes localized thickening within the paratenon with palpable tenderness on both sides of the tendon, usually the medial side more than lateral (1). Tender nodules form in some cases within the paratenon representing localized hypertrophy and connective tissue proliferation (1). Tendinosis refers to intratendinous degeneration commonly due to aging, microtrauma, and vascular compromise (25, 27). It is associated with chronic intratendinous degeneration and alteration of tendon architecture, with histological findings of fibre disorientation, scattered vascular ingrowth, hypocellularity, noninflammatory collagen degeneration, and sometimes calcification or local necrosis (18). Tendinosis may be symptomatic on its own, histologically representing a large area of mucoid degeneration within the tendon with a gradual onset of symptoms (1). An acute partial rupture through the region of tendon degeneration can result in an asymptomatic area of tendinosis becoming symptomatic, indicated by the acute onset of pain within the tendon (1, 18). Tendinitis (also in the literature as tendonitis) is a condition with symptomatic degeneration of the tendon with vascular disruption and inflammatory repair response (18, 25). Often misused clinically to refer to conditions more appropriately coinciding with the definitions for tendinosis and paratenonitis, it has been suggested that the term tendinitis be removed from the context of tendon overuse injuries (24, 28). Misuse of the term tendinitis can cause incorrect diagnosis, but may also underestimate the implications of the condition leading to poor treatment and unrealistic treatment expectations (18, 27). Often associated with calcification within the tendon just above its insertion, these

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patients have direct tenderness over the Achilles tendon (1). The inflammatory changes within the tendon may be seen in conjunction with retrocalcaneal bursitis in some cases (1). The result of a distinct episode or series of episodes usually occurs in a partial rupture (1). Cumulative microtrauma in an area of degeneration within the tendon or shear stresses can result in this tendon overload (1). Physicians can be alerted to the possible presence of a partial rupture through history of transient sharp pain or repeated episodes of sharp pain within the tendon during tendon loading activities (such as running) (1). Patients will have a palpable nodule within the tendon or have localized fusiform thickening (1). There is often limited dorsiflexion and pain is usually exacerbated by loaded dorsiflexion of the foot (1). Retrocalcaneal bursitis is identified by pain that is anterior to the tendon, just superior to its insertion on the calcaneus (1). The retrocalcaneal bursa becomes hypertrophied, inflamed, and adherent to the underlying tendon (1). A positive twofinger squeeze test can be obtained by these patients (1). Pain is elicited by applying pressure both lateral and medially with two fingers just anterior and superior to the Achilles insertion at about the level of the posterosuperior angle of the calcaneus (1). This should be differentiated from inflammation of the subcutaneous tendon-Achilles bursa lying between the skin that occurs secondary to an abrasive heel counter or highheeled shoes, and the posterior aspect of the tendon (1). From these categories evolved the most common implications for clinical use: tendinitis (implying inflammation), tendinosis (degenerative tendon change within the tendon without accompanying inflammation) and tendinopathy (no implication for

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pathology), bursitis and rupture (1). However, the first three terms have been used inconsistently and at times inappropriately based on research into the pathophysiology of Achilles tendinopathy (27). Due to overlap in the terms, Maffuli et al (1998) advocated the use of the term tendinopathy in a clinical setting to describe any painful condition of the tendon: tendonitis, paratenonitis, tendinosis or any combination thereof. In a clinical setting this may be the most appropriate as tendinopathy makes no assumption as to the underlying pathological process that is still largely under debate in the literature (1). The terminology was subsequently updated recently to include: mid-portion Achilles tendinopathy, Achilles paratendinopathy, insertional Achilles tendinopathy, retrocalcaneal bursitis, and superficial calcaneal bursitis (29). This dissertation will refer to all Achilles tendon disorders as Achilles tendinopathy. From this, Achilles enthesopathy (insertional Achilles tendinopathy) will refer to pain occurring at or around the most distal portion of the Achilles at its attachment on the calcaneal tuberosity. Midportion Achilles tendinopathy (non-insertional Achilles tendinopathy) will refer to pain that involves the area of the tendon two to seven cm proximal to the calcaneal insertion. In the literature, there is also no standard use for the terms chronic and acute. However, this study will use the term acute to refer to symptoms experienced for less than 2 weeks; subacute will refer to symptoms experience for two to 12 weeks and chronic will refer to problems experienced 12 weeks or greater. (d) Aetiology and Pathophysiology Khan and Maffulli in 1998 stated that “the aetiology and pathophysiology of tendon ailments is not clear” (30). Over ten years later, the aetiology and

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pathophysiology of Achilles tendinopathy is still in question. Historically there were two main theories on the causes of tendon degeneration and subsequent rupture: mechanical theory and vascular theory (1, 17, 31). However, a neural theory has emerged and is being explored (1, 17, 31, 32). The mechanical theory argues that repeated loading within the normal physiological stress range of a tendon causes fatigue and eventual tendon failure (1, 16, 22, 33-37). Achilles tendon overuse injuries normally occur from work-induced or sports-induced repetitive over-loading of the muscle tendon unit (25). Jozsa and Kannus (1997) state that an overuse tendon injury is caused by a repetitive strain of the affected tendon so that the tendon is unable to further endure tension and stress, its structure begins to disrupt microscopically, and inflammation, edema, and pain result. When a tendon has been strained repeatedly to 3% to 8% of its original length, it is unable to endure further tension thus causing injury. Repetitive dysfunctional and mircrotraumatic processes overwhelm the basal reparative ability (the ability of the tenoblasts and tenocytes to repair the fibre damage) resulting in fatigue of the tendinous tissue (16, 22, 25, 33-37). This repetitive strain disrupts the structure of the tendon causing collagen fibres to slide past one another thus breaking their cross-links and causing tissue denaturation resulting in an overuse injury (16, 22, 33-37). The triphasic response of inflammation, proliferation and maturation is the standard response for acute tendon injuries, but it is unclear why overuse tendinopathy does not respond the same way (33). The majority of the collagen in healthy tendons is type 1, whereas there is significantly more type 3 collagen and less type 1 collagen in degenerate tendons (38). As type 3 collagen is a major collagen

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synthesized during tendon healing after injury, it would appear that tendon degeneration is perhaps the result of an incomplete repair process (38). This theory offers an explanation on how chronic repetitive damage to tendon can accumulate over time, and why tendinopathy is degenerative rather than inflammatory (1, 16, 22, 33-37). However, this theory does not adequately explain why exercise can improve diseased tendons, why certain tendons are more susceptible than others, and how spontaneous ruptures and tendinopathy occur in patients with lack of exercise history (1, 16, 22, 33-37). The vascular theory suggests that tendons, or parts of the tendon, have poor blood supply and are prone to vascular insufficiency (1, 31-34, 39). Tendon injury could occur if tendons with poor blood supply undergo a heavy training or functional overload (34, 39). This theory offers an explanation on why the mid portion of the tendon appears to be the most susceptible to both degenerative change and neovascularisation (1, 31-34, 39). However, this theory does not adequately explain why exercise (eccentric loading) can improve the health of the tendon (1, 40). Also, there is no convincing evidence of vascular compromise in healthy individuals and the role of neovascularisation remains unclear (1, 41, 42). Lastly, there are studies describing the lack of uniform blood flow and the increase in the appearance of new vessels that are thick walled, tortuous with a small lumen that does not appear to be part of the repair response (31-33). These studies differ from those that suggest there is uniform blood flow and question the role of neovascularisation (34, 39). The neural theory was developed as a collection of observations rather than a true theory (1, 43). However, in conjunction with the findings of local neurovascular in-

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growth and promising results of sclerotherapy there is growing sentiment that the vascular and neural theories are associated. Observations related to the neural theory include tissue hypoxia and consequent changes in the tendon induced by free radicals due to ischemia-reperfusion injury, and exercise-induced hyperthermia (44, 45). Also, in normal tendon samples level of type-I and type-III collagen mRNA have been found to be significantly lower than in the tendinopathic samples (46). Glutamate, a common excitatory neurotransmitter and modulator of pain, is found in high levels in painful tendons and not in normal tendons (47). Also, research has found substance P (neuropeptide) nerves and Neurokinin-1 receptors in the vascular wall, and calcitonin gene related peptide (CGRP) nerves close to the wall (47). What all these observations suggest is that tendons are innervated and alterations to neural homeostasis may lead to tendon pathology (1). However, morphologically pathologic tendons are not always painful and the neural theory at this time has no explanation (39). The aetiology of tendinopathy is likely a result of a combination of these three theories, but further possibilities also need to be explored. Any successful theory needs to incorporate an explanation for the cause of pain in tendinopathy. As tendinopathies likely have a multifactorial origin, interaction between intrinsic and extrinsic factors is common and maybe crucial for both the initiation and propagation of an injury (1, 17). Possible common intrinsic factors believed to be associated with the development of tendinopathy include age, gender, biomechanics (including range of motion), and presence of systemic diseases (diabetes mellitus, systemic lupus erythematosus, chronic renal failure, rheumatoid arthritis, thyroid disorders, parathyroid disorders, collagen deficiencies and infectious diseases) (1, 22, 34, 35, 38, 39, 48).

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Possible common extrinsic factors believe to be associated with the development of tendinopathy include the environment (for example equipment, footwear, and working environment), physical load on a tendon (load and frequency), changes in training pattern, poor technique, and previous injury (1). Some studies have also reported an increased incidence of Achilles tendon injuries in the ABO blood group patients, and an association between the alpha 1 type V collagen (COL5A1) gene and Achilles tendinopathy (49-52). (e) Pain and Histology Histological studies of chronic cases consistently find either absence or minimal inflammation, with the predominant lesion being one of degenerative change (53, 54). Histopathological evidence is derived from samples in chronic cases at the point where surgery is necessary (1). Animal models suggest that an inflammatory reaction is present in acute situations but that degenerative process soon supersedes this response (55, 56). It is therefore possible that inflammation is involved at the initiation of the degenerative process in humans (1). Imaging techniques have recognized degenerative changes (for example, localised widening of the tendon with focal hypoechoic areas on ultrasound) in asymptomatic and symptomatic populations (57). Consequently, it is probable that in early symptomatic cases the pathological process may be present for much longer. Studies have reported a decreased recovery time and better clinical outcome in tendons without hypoechoic lesions and enlargement (58, 59). Also, studies suggest that neovascularisation is associated with pain and removal of neovascularisation can lead to pain relief and improved function (60-63). Neovascularisation is identified in painful tendons both histologically and with the use of ultrasound, and is consistently found to be

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the most pronounced in the ventral side of the thickened tendon (60, 64-66). Previously, neovascularisation was considered to be a positive part of the healing process (67-69). However, neovascularisation was present in all patients with a long duration of pain symptoms (69). If neovascularisation was a part of the normal healing response a decrease in symptoms or a trend towards improvement should be apparent instead of absent (69). Although this neovascularisation may be associated with pain in chronic cases, the clinical relevance of neovascularisation is unclear due to inconsistent reports of the prevalence of neovascularisation in painful Achilles tendons (42, 60, 70, 71). One study found neovascularisation in 26 of 40 tendon specimens from painful Achilles tendons, and in a different study neovascularisation was present in 30 of 55 painful tendons (42, 54). This was not consistent with results of other studies in which all patients with chronic Achilles tendon pain demonstrated neovascularisation (60-63). A few hypotheses exist for these differing results including that there was a difference in the classification of patient groups between these studies (71). In the study where all patients with Achilles tendon pain had local neovascularisation present on ultrasound, they also had structural tendon changes on ultrasound (degenerative tendon characteristics such as localised widening of the tendon with focal hypoechoic areas) whereas only about 60% of the tendons in the other studies had structural changes in the tendon (42, 60, 70, 71). As degenerative change on ultrasound is possibly a predominant factor in tendinopathy, inconsistent use of imaging techniques with the studies whose results did not show 100% of painful tendons with degenerative characteristics is possible (71). Neovascularisation maybe a dynamic finding that is most pronounced during exacerbation of pain, or perhaps something in the region with tendinosis is triggering

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vascular growth (42, 71). The latter suggestion has led to a hypothesis that alterations to neural homeostasis may lead to tendon pathology (1, 71). For example, the high concentrations of glutamate demonstrated in chronic painful Achilles tendons might possibly be a trigger for vascular growth (71). Although neovascularisation appears to be associated with pain, its prevalence in Achilles tendinopathy needs to be clarified (42). As the choice of treatment for a patient is related to understanding the pathology, the importance of neovascularisation requires further exploration. (f) Epidemiology Very little reporting of incidence and prevalence of Achilles tendon injuries exists in the literature, and when reported it is limited in scope and generalizability. There have only been a handful of studies performed, most having a sample population that were limited to running clubs or competitive athletes. Although many studies were performed 5-20 years ago and do not provide exact incidence or prevalence data, their results continue to be used by present research to explain the plight of Achilles tendon disorders. Johansson (1986), Lysholm and Wiklander (1987), and Clement et al (1981) reported annual prevalence of Achilles disorders between 6% and 9% in elite orienteer and elite runners. All studies were performed as prospective cohorts over a one to two year period, and all defined an Achilles disorder as a clinical diagnosis of Achilles tendinitis or Achilles peritendinitis. The majority of participants were male and the majority of Achilles disorders were found in the male athletes. The studies propose that this was due to differences in the way each gender trained; however the studies were not sufficiently powered to draw sufficient conclusions. The prevalence rates from these

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studies, performed almost 20 years ago, are still being quoted as the prevalence of Achilles tendon disorders even though these rates are specific to elite athletes (72, 73) (74). A cohort study by Kujala et al (1999) had an eleven-year follow-up. The study reported that of the 269 male orienteering runners, 29% reported Achilles tendon overuse injuries on a questionnaire. In comparison, 7 of the 188 controls (4%) reported Achilles tendon overuse injuries giving an age-adjusted odds ratio of 10 (the odds of a runner having an Achilles tendon overuse injury compared to a non-runner was 10) (75). The study was limited in scope and generalizability to male master orienteering runners who had previously been placed among the best in the world (75). The study also used a selfreporting system (participants were required to state whether they had an Achilles tendon injury on a questionnaire) rather than a direct diagnosis by a physician for its primary outcome measure introducing the possibility for misclassification bias. A more recent study by Kujala et al (2005) used a clinical definition of Achilles tendinopathy to study the cumulative incidence of Achilles tendon rupture and tendinopathy among former top-level athletes (76). The definition of an athlete was not restricted by sport, and the controls were selected from among men who had been classified as completely healthy and matched for birth cohort and area of residence with the athletes (76). The projected cumulative incidence of Achilles tendinopathy in all athletes over their lifetime (54 to 97 years) was 23.9% (n = 785) and in controls (56 to 94 years) was 5.9% (n = 416) (76). The top five projected lifetime cumulative incidences were: 52% in middle and long-distance runners (n = 99), 31% in short-distance runners (n = 94), 23% in soccer players (n = 104), 18% in track and field participants (n = 74), and

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16% in basketball players (n = 53) (76). The main limitation of the study was that the data was collected retrospectively using a questionnaire, allowing for the possibility of recall bias. Kvist (1991, 1994) studied the epidemiologic factors of Achilles tendon disorders in competitive and recreational athletes. During 1976-1986, 455 (14%) of the 3336 athletes that consulted the Turku Sports Clinic were found to have Achilles tendon injuries. The majority of patients in the studies were males (89%). Running was the primary sport of patients who had an Achilles tendon disorder (53%) and 27% of patients participated in sports that involved running. Biomechanical abnormalities (for example, weakness, muscle inflexibilities and imbalances causing inefficient mechanics) were present in 60% of the patients with Achilles tendon disorders. Although running was found to be the primary sport of patients, this study showed the importance of broadening the breadth of the disease to include other activities. Unfortunately, the Turku Sports Clinic is referral based and exclusive to athletes. Therefore, generalizing the results to the general public was not possible. In addition, the medical problems of the athletes in the Turku area are treated at several places. There is a need for a more generalized estimate of the prevalence of Achilles tendon disorders. (g) Evaluation: Diagnosis, Imaging and Outcome Assessment (i) History and Clinical Examination The majority of information used to diagnose Achilles tendinopathy should be provided by the patient’s history (25). Many patients with Achilles tendinopathy have reported increasing the intensity of current activities or engaging in a new activity before

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the inception of their symptoms (4). The cardinal symptom of Achilles tendinopathy that causes a patient to seek medical help is pain (16). Pain presenting at 2 cm to 6 cm proximal to the tendon insertion after activity or exercise occurs in mild Achilles tendinopathy (77). As the condition worsens, pain may occur during activity or exercise, and in severe and chronic cases the pain interferes with the activities of daily living (35, 77). Morning pain is a trademark of Achilles tendinopathy whereby the degree and time of stiffness are considered good indicators of tendon health and recovery from injury (78). However, rest from activity and training can also decrease morning stiffness, but frequently it returns upon the patients return to usual activity levels (78). It is reported that clinical examinations should start with the patient standing then prone with both legs exposed from just above the knee down (35, 77). The classic orthopaedic scheme of “look, feel, and move” is typical for physical examination (25). The heel and foot should be inspected for any deformities, obvious asymmetry in the tendon size, malalignment, localized thickening, Haglund heel, and any previous scars. Inspection and palpation will provide information on tenderness, increased local temperature, thickening, nodules, and crepitation (25, 35, 77). Passive and active movements of the joint should be checked within the limits of pain. Resisted active movements have been cited as perhaps the most important part of the clinical examination as resistance can aggravate the pain (25). Lastly, an examination for biomechanical deficits should occur as they could eventually result in the development of Achilles tendinopathy by placing excess stress on the tendon (79).

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(ii) Imaging Methods Plain-film radiography may reveal bony abnormalities that can cause symptoms of Achilles tendinopathy but is unable to demonstrate any soft-tissue changes (4). For preoperative evaluation or in the event of recalcitrant pain despite conservative management, ultrasonography and magnetic resonance imaging (MRI) are sensitive in detecting abnormalities with Achilles tendon pathology thereby alleviating gaps from clinical examination and patient history. Ultrasonography has been established as an accurate and cost-effective method of Achilles tendon evaluation (80-82). Doppler ultrasonography enables an estimation of tissue vascularity. Color Doppler and Power Doppler Ultrasonography (PDU) provide the clinician with the possibility of detecting regions of hypoechogenicity and neovascularisation in Achilles tendinopathy (82-84). Also, it has been hypothesized that if ultrasonography were obligatory in the diagnosis of Achilles tendinopathy the heterogeneity of the included patients would be reduced (85). As well, ultrasonography and pressure algometry have been evaluated as objective methods for monitoring the effect of treatment (85). Using ultrasound to evaluate Achilles tendinopathy before and during treatment is a relatively inexpensive process (86). Ultrasound also has the advantage of speed (shorter wait times) for patients over MRI. However, it requires meticulously performed examinations (86). Magnetic resonance imaging (MRI) gives excellent soft tissue contrast, high spatial resolution, and multiplanar capability thus making it superior to other examination modalities for depiction of tendon anatomy and pathological changes (86).

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Although much of the recent progress in understanding the pathology of tendinopathy is due to advancements in imaging technologies, the opinion of its importance to the management of Achilles tendinopathy is not consistent. Results of a two year prospective study by Khan et al (2003) show only moderate correlation with clinical assessment of chronic Achilles tendinopathy with ultrasound and magnetic resonance imaging (MRI) (70). In their study, tendon imaging abnormalities persisted even when patients made good functional recovery (70). This suggested that imaging appearance should not be used to guide severity of Achilles tendinopathy or guide a treatment protocol, suggestions that were similar to those found in earlier studies by Astrom et al (1996) and Marcus et al (1989) (70, 81, 87). However, this is in contrast to the results of many other studies that support the use of imaging methods to assess the tendon’s response to therapy, confirm diagnosis and progress of the disease (42, 58, 59, 82, 88-92). Many of the studies that acknowledge ultrasound as playing an important role in the management of Achilles tendinopathy describe a clear direction and purpose for its use (42, 58, 60, 82, 89-92). For example, the process of having an experienced radiologist use ultrasound to find degenerative changes or neovascularisation has been consistent (42, 58, 60, 82, 89-93). However, consistency between studies is difficult to assess due to the lack of a uniform standard of reporting image findings. A few ultrasound grading systems exist for tendon appearance and neovascularisation; however their appropriateness, validity, reliability and responsiveness to Achilles tendinopathy have not been reported (58, 94-98).

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Developing consistent theories for the pathology of Achilles tendinopathy will allow current treatments to be modified to better suit the disease and patient, or will create new treatments specific to a part of the disease that was poorly or not understood. As the use of imaging continues to assist this development, the current ultrasound grading systems need to be further evaluated and explored to introduce consistency to the research area. If the current systems are not appropriate, an existing system may have to be modified to address the requirements or a new system may need to be developed. (iii) Outcome Assessment With the use of imaging techniques relatively new and lacking a quantitative option to assess images (i.e. lack of a neovascularisation or tendon inhomogeneity grading scale) subjective scales evaluating pain and function are commonly used. While a number of different scales are available, there is no generally accepted gold standard for Achilles tendinopathy. Previous studies have cited this lack of a gold standard as a major limitation to Achilles tendinopathy research (30). While the treatment options for Achilles tendinopathy varies, so do the outcome measures and scales. Achilles tendinopathy typically causes pain and a loss of normal function. Interventions concerned primarily with pain have often used outcome measures like the visual analogue scale (VAS) or numeric rating scale (NRS). However, incorporating both pain and function into the assessment of Achilles tendinopathy has resulted in the increased use of tiered measures like the Achilles tendinopathy specific Victorian Institute of Sports Assessment – Achilles (VISA-A) or performance measures like strength and range of motion. Some intervention studies use return to activity as their primary outcome and others use a Likert scale or global outcome measure such as

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excellent-good-poor. However, there is sparse data on the validity and reliability of many of these measures and scales in regards to Achilles tendinopathy specifically except for the VISA-A. The assessment procedure for reliability and validity testing of outcome measures is not reported in the majority of published studies and that makes it difficult to compare studies. Most outcome measures depend on the participants’ perceptions of what was good and bad, painful and not painful. Therefore, studies require an assessment system where the participants are not influenced by the investigator, whether that be in posture, tone of voice or general attitude (99). There is a lack of understanding for the relevant significance of the output for each outcome measure. Studies have not made clear distinctions between the difference in severity between a five centimetre change versus a two centimetre change in VAS score or a fifty versus seventy VISA-A score. For clarity, the gradient of each outcome measure should be reported. A number of studies use a pain measure (like the VAS) as the primary outcome measure for Achilles tendinopathy (40, 60-63, 100-103). This could be due to the inconsistency of the other functional measures that incorporate pain, performance and return to activity. Visual analog scales are a form of cross-modality matching (CMM) in which line length as the response continuum has been reported as a valid and reliable measure for the intensity of pain (104-108). The VAS consists of a 10-cm line, with anchors at either end where typically one end is marked “no pain” and the other end is marked “pain as bad as it could be” or “the worst imaginable pain.” The participant marks the place on the line to indicate his or her pain intensity. The line is measured with a ruler and is

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assigned a score. Visual analog scales have been found to be superior to discontinuous verbal or numerical descriptions (107), but patients appear to differ considerably in their ability to use the VAS reliably (105). Therefore when assessing efficacy of treatment, attention should be paid to several complementary indices of pain relief as well as to the individual’s tendency to bias his estimates (107). The VAS has been used in many studies and has been found superior when compared to other subject reported questionnaires including the verbal pain scale (VP) and Borg’s Category Scale for Ratings of Perceived Pain (BRPP) (109, 110). The NRS is a commonly used and modified rating scale. Typically, patients rate their pain on a 0-to-10 scale or a 0-to-5 scale, with 0 representing “no pain at all” and 10 or 5 representing “the worst imaginable pain.” Most protocols call for pain intensity levels to be measured at the initial encounter, following treatment, and periodically, as suggested by guidelines and the clinical situation. While VAS and NRS have been proven in some cases to be valid and reliable pain measures (111-113), they remain subjective measures. Using these measures without evidence of their validity and reliability as a primary outcome measure can introduce bias into a study. These measures are symptom specific and not disease specific. Little is known about the significance of any change in each of the scales to pain (113), let alone change in each of the scales relating to pain from musculoskeletal disease. Perhaps treatment of pain and not treatment of the disease in Achilles tendinopathy is the primary focus, making the use of the VAS and NRS a logical choice. These details need to be specifically addressed in studies that choose to use or incorporate the VAS or NRS as part of their outcome measures strategy.

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One study by Jensen et al (2003) attempted to interpret and specify reasonable changes in VAS score (106). Study findings suggested that a 33% decrease in the VAS represents a reasonable standard for determining that a change in pain is meaningful from individual patient perspectives. Although this provides a guide for the use of the VAS, the study results are limited in generalizability as the study only reviewed two clinical trials on postoperative pain. Therefore, further research can use the results as a guide but this does not provide sufficient evidence for a gold standard representation that change is meaningful from the patient’s perspective. The Foot and Ankle Outcome Score (FAOS) has been used to determine patient opinions about foot and ankle related problems including Achilles tendinosis (114). The FAOS assesses patient-relevant outcomes in five separate subjects as a 42-item questionnaire. Although it appears to be useful for the evaluation of patient-relevant outcomes related to ankle reconstruction (114), its ability to accurately measure Achilles tendinopathy has not been established. Performance tests and muscle measurements have been used or incorporated by some studies to give a clearer picture of the effect of treatment. A performance test protocol and scoring scale developed by Kaikkonen et al. (1994) for evaluating ankle injuries consists of subjective assessment of the affected ankle, four functional tests, and clinical evaluation of the range of motion and stability. The protocol is made up of nine questions that produce a final score between zero and 100 where a score between 85-100 is excellent, 70-80 is good, 55-65 is fair and a score less than 50 is poor. This protocol was developed for evaluating the functional recovery after an ankle injury and not specifically Achilles tendinopathy; however, it has been used in two Achilles

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tendinopathy studies (115, 116). Reproducibility of the protocol was tested (inter-rater reliability) in a population of 100 healthy individuals with no history of previous ankle problems. A team of one physician and four physical therapists tested the group twice within an interval of one to four weeks. The results showed strong inter-rater reliability with no statistical difference between mean values of each test (P < 0.001) (117). An attempt was made by Kaikkonen et al. (1994) to prove construct validity for the measure by comparing the performance of each individual in each part of the measure with the total score. However, this procedure is not sufficient in providing evidence for construct validity – the measure should have been compared to other previously validated or gold standard measures. The relative importance of quality of life (QOL) measures to Achilles tendinopathy has yet to be addressed. Validity and reliability studies of measures like the EQ-5D and SF-36 have been performed; however, data relating their outcomes to that of disease specific measures (specifically Achilles tendinopathy) is not available. Without such information and with the knowledge that pain is considered of primary importance to Achilles tendinopathy, the use of QOL measures as the primary outcome should be discouraged. However, secondary and tertiary data provided by these measures can help provide a holistic picture of the patient. The 12-item short-form (SF-12) health survey is based on the 36-item short-form (SF-36) health survey. It has undergone tests for reliability and validity and has been recommended over the SF-36 for studies on patientbased assessments of physical and mental health (118-120). A comparison between the EQ-5D and SF-12 showed that the SF-12 appeared to be more sensitive to differences in health status for people with less severe morbidity (121). However, the results also

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provided support for the validity of both instruments as descriptive measures of health status (121). For the purpose of economic analysis and health resource allocation, further study of these measures in the field of Achilles tendinopathy would be beneficial. The Lower Extremity Functional Scale (LEFS) is easy to administer and score and is applicable to a wide range of disability levels and conditions and all lowerextremity sites. It consists of 20 items, each with a maximum score of 4 with the total possible score of 80 indicating a high functional level (122). The scale is one page, can be completed by most patients in less than 2 minutes, and is scored by tallying the responses for all of the items (122). The scope of use for LEFS is limited and it has not been administered to an Achilles tendinopathy patient population. Without a standardized outcome measure for treatment of Achilles tendinopathy, response formats like a Likert scale or global measure of assessment is used in many studies. This type of format is widely used in various intervention and treatment studies, and commonly used as an assessment tool of injury specific outcome measures (117, 123, 124). A limitation of only using a global measure is that it is one-dimensional and may limit specificity (105). In the Roles and Maudsley method the respondent is asked to check one of four possible answers to each of a series of statements (125). This is a version of the Likert scale specific to pain and function. Cut-off for pain and function based on this scale is study specific with many studies choosing scores of one and two for successful treatment. The choices preceded by their perspective weights could be as follows: 1) Excellent (No pain, full movement, full activity), 2) Good (Occasional discomfort, full movement, and full activity), 3) Fair (Some discomfort after prolonged activity, need for further

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treatment) and 4) Poor (Pain limiting activities, need for further treatment). The Roles and Maudsley scale has not undergone any validity, reliability, responsiveness, or comparison testing yet it has been modified and used, in some cases for over 30 years. Also, stratification into only 4 levels of severity, lacks sensitivity to document changes in clinical condition. The use of a global measure of assessment as the evaluation tool for validity and reliability testing of disease specific outcome measures is common. Some of the measures, like the “Performance Test Protocol and Scoring Scale” by Kaikkonene et al. (1994) used by Paavola et al. (2000) and FAOS by Roos et al. (2001), are not specific to the Achilles tendon or Achilles tendinopathy which could limit their appropriateness. A critical review of surgery outcomes for Achilles tendinopathy by Tallon et al (2001) suggested a two-tier approach to outcome assessment: sporting success and one for symptomatic benefit. Using this approach, patients could assess pain (the leading symptom) and activity level. Although the review was specific to surgical interventions of Achilles tendinopathy, the two tier idea has been incorporated for non-surgical interventions in the form of the VISA-A. The VISA-A is comprised of eight questions that assess the domains of pain, function in daily living, and sporting activity with results ranging from 0 to 100, where 100 represents the perfect score (123). As the visual analogue scale is found to be more accurate and sensitive than categorical verbal scales, the first six questions of the VISA-A uses VAS so that patients may report magnitude on a continuum of subjective symptoms. The research team assessed that activity is best measured using a categorical rating system based on an incremental range of values therefore the final two questions use a

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categorical rating scale (126). The intent of the VISA-A questionnaire is to be a questionnaire-based instrument that would serve as an index of the severity of a clinically diagnosed condition of Achilles tendinopathy. The VISA-A questionnaire has undergone reliability and construct validity testing as well as cross cultural adaptations (123, 124, 127-129). Strong evidence for test-retest reliability was found as there was no difference in scores between tests (groups were tested at the first visit and second visit approximately one week apart). Construct validity was tested by comparing the VISA-A to the Percy and Gonochie grading system, the Curwin and Stanish grading system, and by comparing the score among groups of participants where the severity of the score could be clinically determined (123). While Robinson et al. concluded that the VISA-A questionnaire displayed construct validity and compared favourably with the two tendon grading systems, the authors also express that there is no published validation or reliability data for either of the two tendon grading scales. However, as similar results were shown between all three testing protocols this provides convergent evidence for measurement validity (130). Test-retest reliability was analyzed using the Pearson correlation coefficient. However, the correlation coefficient measures the degree of association between two quantities and does not measure how closely they agree. The cross-cultural adaptation by Silbernagel et al (2005) was in part a cross validation study that provided evidence that items on the VISA-A were not being scored simply by chance. Charlson et al (1991) describes three types of scales: predictive scales, evaluative scales and descriptive scales (131). Both evaluative and predictive scales imply that status of patients will be observed at two points in time; predictive scales must correctly

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predict how the patient will do, and evaluative scales must be able to differentiate patients who have changed clinically from those who have not (131). Scales designed to characterize patients at a single point in time are descriptive (131). The type of scale required differs depending on how it will be used. As this study deals with the effect of interventions, evaluative scales are the most appropriate (131). An evaluative scale must focus on the elements relevant to the outcomes of interest, and must have been designed and evaluated for reproducibility, validity, and responsiveness (131). If these criteria are not met, an existing scale may have to be modified to address these requirements or a new scale may need to be developed (131). Achilles tendinopathy typically causes pain, and often a reduction in normal activity level can ensue if left untreated (132). As previously mentioned a two tier approach for assessment of Achilles tendinopathy has been suggested consisting of symptomatic (pain) relief and sporting (activity level) success (99). Currently the VISA-A (Victorian Institute of Sports Assessment – Achilles) is the only Achilles specific scale that assesses pain and activity level (124, 133). The content of each question was developed through a review of the literature and consultations from individuals with expertise in the area of Achilles tendinopathy (133). The scale was tested on various populations (healthy individuals, surgical patients, pre-surgical patients, and recreational runners) and has successfully undergone a cross-cultural adaptation (124, 133). How it responds or changes to various disease states and treatment has yet to be published. A major factor in determining relevance of treatment in a clinical setting and in many studies is patient satisfaction – satisfied or unsatisfied with treatment (1, 31, 100,

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134-136). Although it has been suggested that a change of 25 points is considered clinically significant when using the VISA-A, change in the continuous scale and its relevance to the discrete state of satisfied or unsatisfied with treatment has not been explored in a prospective randomised controlled trial (70, 124, 133). In a clinical setting, this would be useful in assessing success or failure of treatment. The choice of outcome or scale is important to the consistency of reporting and interpreting study results. As the only Achilles tendinopathy specific scale, the VISA-A needs to be further used and explored. As such, it was used as the primary outcome measure for the RCT (Chapter 4) and was included as an outcome measure in the other parts of the study. (h) Management Strategies The literature suggest that somewhere between 24% and 44% of Achilles tendinopathy patients fail conservative management (non-surgical treatments) requiring either significant activity modification or surgical interventions (137, 138). However, new research in the realm of non-surgical treatments has aimed at significantly reducing that possibility. (i) Non-Surgical Treatments Chapter 2 Table 1: Summary of studies included in the critical review of nonsurgical treatments of Achilles tendinopathy Intervention

Impression of Efficacy/Effectiveness

Study

Level of Evidence

Oxford Scale

Study Participants

Outcome Measures

NSAIDs

Not efficacious

Level 2

3

50M, 20F

VAS

ESWT

Insufficient evidence

Astrom and Westlin (139) Rompe et al (140)

Level 2

3

30M, 38F

VISA-A, Likert scale, Pain (NRS), VAS

Rompe et al (141)

Level 2

3

29M, 46F

Costa et al (142)

Level 2

3

21M, 28F

Rasmussen et al

Level 2

3

20M, 28F

VISA-A, Likert scale, Pain (NRS) VAS, FIL, EQol, Ankle ROM, calf muscle circumfernce, tendon diameter AOFAS

33

Physiotherapy, Orthotics, Night Splints and Other Treatment Modalities Glyceryl Trinitrate

Not efficacious

Eccentric Exercise

Injection Therapies

(143) Mayer et al (144)

Level 2

2

21M

Knobloch et al (145) Petersen et al (146)

Level 2

3

63M, 34F

Pain Disability Index, Pain Experience Scale VAS

Level 2

3

60M, 40F

FAOS

Not efficacious

Paoloni et al (147) Kane et al (148)

Level 2 Level 2

4 4

Pain (NRS) AOS

Efficacious but insufficient evidence on effectivness

Stanish et al (149)

Level 4

n/a

Mafi et al (150) Silbernagel et al (151) Roos et al (114) Rompe et al (140)

Level 2 Level 2

3 1

40M, 12F 40 (gender not provided) 57 (gender not available) 24M, 20F 36M, 13F

Level 2 Level 2

2 3

21M, 23F 30M, 38F

Rompe et al (141)

Level 2

3

29M, 46F

De Jonge et al (152)

Level 2

3

Fahlstrom et al (153) Jonsson et al (154)

Level 4

n/a

70 (gender not provided) 92M, 40F

Level 4

n/a

12M, 15W

Fedberg et al (85)

Level 2

3

15M, 9F

Brown et al (155) De Vos et al (156)

Level 2 Level 2

3 5

17M, 9F 26M, 28F

Yelland et al (157)

Level 2

3

43 (gender not provided) 7M, 3W

Not efficacious (corticosteroid, aprotinin, platelet-rich plasma). Efficacious (Prolotherapy with dextrose, sclerotherapy with Polidocanol)

Subjective assessment of symptoms VAS VAS, ROM, jumping test, toe-raise test FAOS VISA-A, Likert scale, Pain (NRS), VAS VISA-A, Likert scale, Pain (NRS) VISA-A, Subjective patient satisfaction, neovascularisation VAS VAS, Subjective patient satisfaction Pain NRS

VISA-A VISA-A, Subjective patient satisfaction, Subjective return to sports level VISA-A, Likert scale, PGIC scale, economic aanalysis VAS

Ohberg and Level 4 n/a Alfredson (61) Ohberg and Level 4 n/a 9M, 2W VAS Alfredson (62) Ohberg and Level 4 n/a 22M, 8W VAS Alfredson (158) Alfredson and Level 2 5 9M, 11W VAS, Subjective patient Ohberg (159) satisfaction Note: NSAIDs = nonsteroidal anti-inflammatory drugs, ESWT = extracorporeal shock wave therapy, M = male, F = female, VAS = Visual Analogue Scale, VISA-A = Victorian Institute of Sports Assessment-Achilles, QOL = Quality of Life, NRS = Numeric Rating Scale, AOFAS = American Orthopaedic Foot and Ankle Society, FAOS = Foot and Ankle Outcome Score, AOS = Ankle Osteoarthritis Scale, ROM = Range of Motion, PGIC = Patient Global Impression of Change

Non-surgical or conservative treatment regimes for chronic Achilles tendinopathy have rarely been compared in randomized, prospective studies even though conservative

34

management is recommended as the preliminary strategy for treatment (25, 101, 135, 136, 160). There are numerous conservative treatment options that have been suggested to provide relief from the symptoms of Achilles tendinopathy, or to cure the disease itself, including: nonsteroidal anti-inflammatory drugs, extracorporeal shock wave therapy, physiotherapy, glyercyl trinitrate, exercise, and various injection therapies. The objective was to critically review the evidence found in randomized controlled trials for conservative treatment of chronic Achilles tendinopathy. However, information from non-randomized, uncontrolled studies involving sclerotherapy was also included as this was considered important for the primary and secondary research questions. A summary of articles is provided in Chapter 2 Table 1. Nonsteroidal Anti-inflammatory Drugs Nonsteroidal anti-inflammatory drugs (NSAIDs) are often used as part of the initial treatment despite lack of evidence for an ongoing chemical inflammation (65, 136). A systematic review by McLauchlan and Handoll (2004) showed that administering NSAIDs, at best, provides a modest change on acute symptoms in the short term. A randomized, double blind, placebo-controlled study by Astrom and Westlin (1992) found evidence that the effect of oral piroxicam (oral NSAID) was similar to that of placebo. This study included patients with acute Achilles tendinopathy and did not provide enough information for a stratified assessment of only chronic patients. NSAID use for chronic Achilles tendinopathy cannot be recommended at this time. Extracorporeal Shock Wave Therapy Extracorporeal shock wave therapy (ESWT) has been performed in a handful of non-randomized and randomized studies; however the evidence for its use is

35

inconclusive. It involves the application of acoustic shock waves to the site of maximal discomfort. Applications are done at weekly intervals for three to four applications, and patients are followed for at least 3–4 months after last application. Four RCTs were identified for inclusion in this review. A randomized controlled trials by Rompe et al (2007) compared ESWT to eccentric loading and a wait and see approach with the primary follow-up occurring after 12 weeks. VISA-A, Likert scale and pain were used as the outcome measures. For all outcome measures, there was no statistically significant difference between ESWT and eccentric loading, although both showed significantly better results to the wait and see approach (140). A second trial by Rompe et al (2009) investigated the adjunctive use of ESWT with eccentric exercise. VISA-A, Likert scale and pain were used as the outcome measures. At four months, the magnitude of change from baseline for the ESWT plus eccentric group was greater than the eccentric group alone (1.5/10 improvement on VAS and 13.5/100 improvement on VISA-A) (141). Although the clinical significance of this improvement is likely not adequate, the second trial by Rompe et al (2009) does provide some thought that perhaps ESWT is useful as an additive treatment with eccentric exercises. The trial by Costa et al (2005) reported a non-statistically significant decrease in pain between the ESWT and placebo groups. The trial included mid-portion and insertional Achilles tendinopathy patients treated for three months and assessed using a VAS. The authors state that ‘‘the confidence intervals include the potential for a clinically relevant treatment effect’’ which raises the possibility of type II error (142).

36

Rasmussen et al. (2008) reported a non-statistically significant difference in pain score between the ESWT and sham therapy groups. Patients were provided treatment over 4 weeks (significantly shorter than any of the other RCTs) and assessed using the American Orthopaedic Foot and Ankle Society (AOFAS) score. Of interest, when stratified by gender women showed the best outcome. This result is not supported by other studies, and this study does not state if it had appropriate power to make any inferences based on stratification. Also, the AOFAS is not a common outcome measure for Achilles tendinopathy treatment evaluation. In the end, the Rasmussen et al. (2008) study adds little to the evidence for or against ESWT. Conclusive evidence recommending ESWT as a primary treatment for Achilles tendinopathy is lacking, but it is being suggested as an adjunct to therapy when others fail (161). Even though research with ESWT would benefit greatly from further randomised controlled trial, the logistics of incorporating ESWT as a regular treatment protocol is difficult, time consuming, and financially inefficient. In addition, interpretation of data between studies is complicated by inconsistent protocol definitions (number of treatments, low/medium/high energy, etc) which need to be corrected for future studies to make them relevant as evidence for the use of ESWT. Physiotherapy, Orthotics, Night Splints and Other Treatment Modalities The 2010 Clinical Practice Guidelines for Achilles tendinopathy from the Orthopaedic Section of the American Physical Therapy Association has recommendations for the use of various modalities including: eccentric loading, low-level laser therapy, iontophoresis, stretching, manual therapy, taping, heel lifts, night splints, and foot orthoses (162). Aside from eccentric exercises (discussed later on), the

37

recommendations for the other modalities are based on weak evidence, expert opinion and even conflicting evidence (162). Mayer et al. (2007) reported pain reduction from baseline between groups assigned to physiotherapy or orthotics in comparison to the control group. Patients were provided orthotics, physiotherapy (including ice, massage, ultrasound, and exercise) or remained without treatment over 4 weeks and were assessed using the Pain Disability Index and Pain Experience Scale (144). The physiotherapy intervention was not standardized for each patient, so they were unable to comment on which components provided pain relief, or if it the multimodal nature of the physiotherapy experience. Of interest, the orthotics did provide a reduction in pain score however it is unknown if the randomization was stratified for any identifiable malalignments or biomechanical abnormalities. Also, the pain measure was not a common outcome measures for Achilles tendinopathy treatment evaluation. In the end, the Mayer et al. (2007) study provides little evidence in favor of orthotics, only leaves further questions regarding physiotherapy. Petersen et al (2007) compared eccentric training, AirHeel brace and a combination of eccentric and brace in patients over the course of one year. VAS, AOFAS, and SF-36 were reported as the outcome measures of interest. All three groups reported similar improvements in outcome measures and there was no statistically significant difference between the treatments (146). Knobloch et al (2008) reported no statistically significant difference when they compared eccentric exercises to eccentric exercises plus the AirHeel brace. VAS and the FAOS were used to assess outcome. Although the AirHeel brace appears to provide as much success as eccentric exercises, a

38

recommendation to use the brace with eccentric exercises could not be made. However, in patients whom eccentric exercises has failed, or those that cannot perform the exercises, the AirHeel brace may provide an option for treatment. This would depend on other factors including availability and cost to the patient or health care system. Glyceryl Trinitrate An RCT by Paoloni et al (2004) compared topical glyceryl trinitrate and eccentric training to eccentric training alone over 12 weeks. The primary outcome measure was a Likert pain scale. Compared with the eccentric only group, the glycerol trinitrate group showed a statistically significant reduction in pain score after 12 weeks (147). The basis of the treatment lies in the possibility that augmentation of the concentration of nitric oxide in the affected tendon may stimulate collagen formation by fibroblasts and lead to healing of the tendon lesion (147). However, the results show that almost half (49%) of the placebo group also showed improved outcomes. Three years later, the results remain similar, with patients treated with topical glyceryl trinitrate having less Achilles tendon tenderness and improved VISA-A scores than those in the placebo group (163). However, 67% of those in the placebo group were also completely asymptomatic. Of interest, four patients were unable to complete the protocol due to headaches or skin rashes. Therefore, although its use resulted in pain reduction a similar result is possible with eccentric exercise alone without the reported possible adverse effects of glyceryl trinitrate. Kane et al (2008) provided similar results when they compared glyceryl trinitrate and eccentric exercises versus eccentric exercises and a placebo patch. The primary outcomes was the Ankle Osteoarthritis Scale (AOS) visual analog score. As with the

39

Paoloni study, Kane and colleagues reported that the average improvement in outcome was equal in both groups (148). No adverse effects were reported. Based on these two studies, there is no evidence to suggest the use of topical glyceryl trinitrate for chronic Achilles tendinopathy. Eccentric Exercise Eccentric training or loading protocols have increased in popularity following the results of successful randomized controlled trials that suggest patients perform them prior to other treatments (1, 4, 31, 134, 135). Stanish et al. (1986) hypothesized that eccentric contraction was involved in the production of tendinopathy. Realizing that the forces subjected on the tendon during activity was causing damage to the tendon microstructure at the collagen fibre level, it allowed them to design a training program to strengthen the tendon tissue (164). A pilot study involving 57 patients was performed using their 6week eccentric training program. The mean follow-up time was 16 months at which time a survey was distributed. The survey results showed that 31 patients registered complete relief of symptoms and 26 patients registered marked decrease in symptoms. Although the study showed good results, the results were not intended to be viewed as those of a controlled clinical trial but rather as descriptive data to assess general efficacy (164). A comparative study of the Alfredson eccentric training protocol required patients with chronic painful mid-portion Achilles tendinopathy to perform eccentric exercise on a daily basis for 12 weeks, while the control group performed concentric exercises (150). In the eccentric group, 82% of patients were satisfied with treatment after 12 weeks whereas only 36% were satisfied in the concentric group (150). The mean VAS score (pain during running or walking) in satisfied patients in the eccentric group decreased

40

from 69 to 12, and the mean score of unsatisfied patients in the eccentric group after 12 weeks of treatment only decreased from 69 to 44 (150). The program developed by Alfredson varied significantly from the Stanish et al. (1986) protocol. Differences occurred in the length of the program, that pain was not a contraindication to continuing exercise, that exercises should be performed when the knee is straight as well as slightly bent, and the exercises were completed single rather than double leg. An RCT by Silbernagel et al (2001) compared a closely monitored painful eccentric training program with a largely pain-free and less monitored eccentric program. Many outcome meaures were reported (including biomechanical measurements and a study questionnaire that asked about patient satisfaction) however the primary outcome was not clearly identified (151). After 12 weeks the evaluation of the two groups was similar. Although there were statistically significant differences between the groups on specific questions within their questionnaire, they did not mention if the study was sufficiently powered to provide inferences related to this differences. Although their eccentric program provided relief for many of the patients, the study was poorly designed to provide evidence for the efficacy of there treatment. If the aim was to determine effectiveness, this was not stated. Other eccentric training RCTs involved comparison with other treatment modalities. An RCT by Roos et al (2004) comparing the Alfredson eccentric training protocol to night splints conclude that patients, regardless of duration or severity of problems, should undergo an eccentric exercise program prior to considering other treatment options for mid-portion Achilles tendinopathy (114). However, the results provide evidence of very little differences during between-group comparisons – very

41

little difference in pain between the groups at any point in time (114). De Jonge et al (2008) had similar results stating that there was no significant difference in clinical outcome when an eccentric exercise programme was supplemented by the use of night splints (152). The RCT by Rompe et al (2007) provides the only evaluation of eccentric exercises versus a wait and see approach (as part of a triple arm study with the third arm being ESWT). VISA-A, Likert scale and pain were used as the outcome measures. For all measures, the eccentric group showed statistically significant improvement over the wait and see group (140). The evidence provided by this study is important as it provides unique evidence on the efficacy of eccentric exercises in comparison to providing no treatment at all. Although eccentric training appears to have a high success rate with mid-portion Achilles tendinopathy, the results have not been consistently reproduced with Achilles enthesitis patients. One study found that eccentric calf muscle training was successful in helping 32% of cases with Achilles enthesopathy and 89% of cases with mid-portion Achilles tendinopathy (153). A short-term pilot study of a new regime of painful eccentric calf-muscle training showed promising clinical results in 67% of the patients, but effectiveness and comparative results are lacking (154). Neither of these studies were randomized or controlled. Although there is a heterogeneity of treatment groups, interventions and outcome measures across the prospective trials evaluating eccentric training, the success rate being reported for mid-portion Achilles tendinopathy is between 60% and 90% (101, 114, 151,

42

153). As a result, a treatment paradigm beginning with eccentric exercises was suggested (32). However, results from systematic reviews conclude that there is poor evidence on the effectiveness of eccentric exercises due to a lack of methodologically high quality studies and significant results (165). Eccentric exercises’ success requires a high level of patient motivation and may not be suitable for elderly or frail patients (1). A study by Sayana and Maffulli (2007) also suggests that eccentric exercises has less promising results in sedentary individuals compared to active individuals (166). This critical appraisal found only one study that compared eccentric exercises to a placebo (wait and see approach), and this was part of a triple arm study. Most of the studies involving eccentric exercises are comparative and additive studies – where one group performs eccentrics alone and the other performs eccentrics along with a second intervention. These studies appear to assume that eccentric exercises is the best (meaning the most efficacious and effective) treatment option for chronic Achilles tendinopathy, and that other treatment could increase its potency. However, the effectiveness of eccentric exercises has not been established. Injection Therapies The function of systemic or local corticosteroid injections in the treatment of Achilles tendinopathy has been debated widely as there is inconsistent and insufficient evidence to determine the comparative benefits and risks (25, 85, 167). Some research suggests that intratendinous corticosteroid injections have a significant positive effect on pain and increased tendon volume (85, 168, 169). However, others have found increased incidence of ruptures with patients who underwent a corticosteroid injection (170, 171).

43

An RCT by Fredberg et al (2004) compared ultrasound guided corticosteroid injections to placebo injections. Three injections were provided and patients were followed for up to 6 months. Pressure algometry and a numerical rating scale were the outcome measures assessed. Many of the patients experienced initial improvement followed but had a relapse of symptoms at 6 months (85). Although corticosteroid injections have been shown to be efficacious in the short term in other tendinopathies, it remains to have questionable efficacy in the management of chronic Achilles tendinopathy and is therefore not recommended (16, 35, 48, 77, 134, 135, 172). Aprotinin is a broad-spectrum protease inhibitor licensed for use in open heart surgery for prophylactic reduction of blood loss (1). Results from a study performed in patients with Achilles tendon pain that injected directly to the site of the pathology (degeneration) suggested significant benefit as there was a prompt resumption of sports by 78% of patients who received aprotinin injections compared with 30% who received placebo (173). Data from uncontrolled studies suggest a success rate of about 80%, although, 2.6-11% of patients have suffered allergic reactions to the drug (155, 174). An RCT by Brown et al (2006) found that aprotinin had no statistically significant benefit over placebo as similar pain reduction and increased activity level occurred in both groups. Also, although the preliminary and uncontrolled studies suggest a high success rate, the percentage of patients suffering from an allergic reaction is much higher than that of sclerosing therapy (155). de Vos et al (2010) compared platelet-rich plasma (PRP) injections and eccentric exercise to placebo injection and eccentric exercise over 24 weeks. VISA-A was used as the primary outcome measure. The improvement in VISA-A was similar for both groups

44

(156). PRP injections do not appear to alter the treatment effect of eccentric exercises for chronic Achilles tendinopathy. Prolotherapy is a treatment involving the injection of a solution of hypertonic glucose and local anaesthetic to the painful areas of the tendon with the aim of stimulating inflammation followed by collagen deposition. A three arm randomized trial by Yelland et al (2009) compared prolotherapy, eccentric exercises and the combined treatment over 12 weeks. VISA-A was used as the primary outcome measure, but the study was unique as it also provided a cost comparison of the treatment arms. Although not statistically significant, the combined group resulted in the largest mean increase in VISA-A score (157). The eccentric exercise group was the lowest cost, but the combined group had the lowest incremental cost per additional responder (157). There is the potential for attention bias as patients undergoing prolotherapy had 2-3 times more visits. Also, a no treatment group or a wait and see group would have been preferred – however even with a multi-centre approach recruitment was difficult and adding a fourth arm would likely have made the study not feasble. Overall, this study provides evidence that prolotherapy should be considered as a treatment option for Achilles tendinopathy as it provided the same relief as eccentric exercises. Ohberg et al. (2001) used color Doppler ultrasound to evaluate the Achilles tendon. Their results revealed the presence of neovascularisation in the painful Achilles tendons of individuals with chronic Achilles tendinopathy but not in pain-free tendons. The authors also discovered that passive dorsiflexion of the ankle stopped the blood flow in these vessels – an action repeated during eccentric calf muscle training (84). Together these discoveries led to the hypothesis that neovascularisation - and perhaps the nerves

45

that accompanied them - was involved in the pain mechanism or pathway in Achilles tendinopathy. The objective of a pilot study by Ohberg and Alfredson (2002) was to determine if sclerosing therapy (hardening and closing) of these neovessels would result in decreased tendon pain. Eight out of ten patients were satisfied with the results of the treatment and could perform Achilles tendon loading activities as desired (61). The successful patients also had no remaining neovascularisation after the treatment whereas the two patients who still had pain during activity had diagnostic evidence of neovascularisation. The sclerosing therapy had no adverse effects on any of the patients and only required up to three treatments whereas the eccentric training program continued daily for six to twelve weeks. The procedure was adapted for Achilles enthesopathy and one pilot study has been performed. Ohberg and Alfredson (2003) found that by sclerosing the neovessels and accompanying nerves while not performing any treatment to the tendon, bursae, or bone resulted in satisfaction of treatment in eight of eleven patients with neovascularisation still present in two of three unsatisfied patients (62). Another pilot study by Ohberg and Alfredson (2004) investigated the occurrence of neovascularisation before and after treatment with eccentric training. A majority of the tendons (36/41) showed good clinical results after treatment with 32/36 tendons showing no remaining neovascularisation (158). All tendons with a poor clinical result had diagnostic evidence of remaining neovascularisation. Although the study did not include a control group, it showed that the majority of good clinical outcomes in the subjects completing eccentric calf-muscle exercises were a result of neovascularisation changes.

46

Alfredson and Ohberg (2005) performed a double-blind randomised controlled trial to evaluate whether there was a difference in effect between injections of a substance with an anaesthetic and a sclerosing effect (Polidocanol), with a substance that has an anaesthetic effect alone (lidocaine hydrochloride – control arm). There were a total of 20 participants (10 in each arm). After a 3 month follow-up, 5/10 patients treated with Polidocanol were satisfied with treatment and had a significantly reduced level of tendon pain (159) while no patients in the control arm were satisfied with treatment. Neovascularisation was also absent in the pain-free tendons but not the painful tendons. Upon completion of the study, treatment with Polidocanol elicited success in 10/10 participants of the Polidocanol arm and 9/10 participants of the control arm (after crossover to the Polidocanol arm. The results of all three studies suggest a reduction in pain in patients who received Polidocanol, presumably caused by the toxic effect of the sclerosant to both the neovessels and nerves (61, 62, 100). Throughout all three studies, neovascularisation was absent after treatment in the pain-free tendons whereas neovascularisation was present in the painful tendons (61, 62, 100). There are a few issues concerning this technique. The procedure requires multiple visits and ultrasound assessments by a radiologist. Also, the role of neovascularisation in Achilles tendon pain is unclear, the prevalence of neovascularisation is not uniform in all patients clinically diagnosed with painful Achilles tendons. Lastly, Polidocanol is unavailable in North America as it does not have Health Canada or FDA approval for Achilles disorders. However, sclerosing therapy had no adverse effects (6 month followup) on any of the participants in previous studies and only required a mean of three

47

treatments whereas the eccentric training program continued daily for twelve weeks (61, 62, 100, 114, 150, 151). Although dextrose is commonly used in prolotherapy procedures and varicose vein sclerotherapy, controlled data on its use in Achilles tendinopathy are unavailable. As Polidocanol is unavailable in North America and no long term side effects have been reported with dextrose use, it would be a possible substitute for use in the sclerosing procedure (175). Although dose-response data is not available, a 25% solution is common and one study suggests it is clinically more effective than a 10% solution for anterior cruciate ligament laxity (175). An uncontrolled and nonrandomised study used a 25% hyperosmolar dextrose solution during prolotherapy as a treatment for chronic tendinosis of the Achilles and reported reduction in pain at rest and during tendonloading activities (176, 177). The evidence base for most conservative treatments of chronic Achilles tendinopathy is weak based in the above review as summarized in Chapter 2 Table 1, with the exceptions being eccentric exercises, prolotherapy and sclerotherapy. Eccentric exercises appears to largely be the treatment of choice, despite differing opinions on its effectiveness and lack of placebo controlled trials. Response to treatment may need to be individualized, especially for those with a sedentary lifestyle for whom eccentric exercises may not be effective. Prolotherapy with dextrose and sclerotherapy with Polidocanol have promising results, but this has only been born out in one RCT for each procedure. Also, the unavailability of Polidocanol in Canada requires the investigation of another substance if sclerotherapy is to be an option. Sclerotherapy with a dextrose

48

sclerosant could provide much needed relief of symptoms, therefore, its potential efficacy needs to be evaluated in a randomized controlled trial. (ii) Surgical Treatments Failure of conservative treatment can result in several surgical procedures that are designed to irritate the tendon and initiate a chemically mediated healing response. There are no studies directly comparing efficacy of conservative treatment versus surgical treatment and long-standing tendinopathy has been linked with poor results after operation (178, 179). Surgical procedures can be grouped into two broad categories: percutaneous longitudinal tenotomy and open tenotomy. Open tenotomy can be further divided into open tenotomy with removal of abnormal tissue and paratenon stripped, open tenotomy with removal of abnormal tissue and paratenon not stripped, and open tenotomy with longitudinal tenotomy with or without paratenon stripping (180-183). The aim of surgery is to remove degenerated nodules, excise fibrotic adhesions, and make multiple longitudinal incisions in the tendon. Multiple longitudinal incisions in the tendon allows for the detection of intratendinous lesions, restore vascularity and stimulate the remaining viable cells to initiate cell matrix response and healing (53, 180). A systematic review by Tallon et al (2001) found poor methodology behind outcome assessment after surgical treatment of Achilles tendinopathy (99). Although most articles reported surgical success rates in over 70% of cases, this result was not reproducible in clinical practice (99). Most reports are retrospective and very few outcomes were based on objective evaluations, such as range of motion of the ankle. The

49

study suggests that methodology may influence reported surgical outcome and recommends guidelines for clinical research in the area of surgical interventions (99). Studies that incorporated subjective, clinical and functional tests as outcome criteria found good and acceptable short-term results for surgical interventions. A study by Paavola et al (2002) had full recovery of physical activities in 28 of 42 patients (67%) with 35 patients (83%) asymptomatic or with only mild pain during strenuous activity. A study by Vulpiani and Guzzini (2003) had 76 of 86 (87%) cases able to return to sport and perform at pre-injury levels. Even with positive results, studies have shown a relatively high rate of complications associated with surgical treatment of Achilles tendinopathy (160, 179). A study by Cetti et al (1993) had an overall complication rate in 12% of the 4083 patients surgically treated for Achilles tendinopathy. Paavola et al (2002) had an overall complication rate of 19% and rate of skin complications of 14%. The most common complication reported is skin breakdown, although lesions to the sural nerve and deep vein thrombosis have been found (48). Newer techniques came from the need for a one-stage procedure that allowed a faster return to activity as well as the need for decreased complications. This has included the introduction of the mini-surgical scraping technique for Achilles and the potential for ultrasound guided arthroscopic shaving similar to what has been piloted with the patellar tendon (184, 185). The state of the literature base has changed since the time of the design of this dissertation project. However, the role of sclerotherapy in terms of the overall management of Achilles tendinopathy and its place within that management is still

50

unclear. No studies had investigated the possibility that sclerotherapy using dextrose as the sclerosant could be a successful primary therapy for Achilles tendinopathy. To date, there have not been any studies investigating the efficacy of sclerotherapy using dextrose to treat Achilles tendinopathy for which eccentric training provided little to no relief of symptoms.

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Chapter Three: THE EFFECTIVENESS OF A HOME-BASED HEAVY LOAD ECCENTRIC TRAINING PROGRAM FOR TREATMENT OF ACHILLES TENDINOPATHY The following chapter has been prepared for submission to the Scandinavian Journal of Medical, Science and Sport. Other than the references, and table and figure titles, it is formatted according to the instructions for authors of the journal.

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THE EFFECTIVENESS OF A HOME-BASED ECCENTRIC TRAINING FOR TREATMENT OF ACHILLES TENDINOPATHY R Ram1, BSc; W Meeuwisse1, 3, 4, MD, PhD; C Patel2, MD; D Wiseman2, MD; JP Wiley3, 4

, MPE, MD

1

Department of Community Health Sciences, University of Calgary, Calgary, AB,

Canada 2

Department of Diagnostic Imaging, Foothills Medical Center

3

Faculty of Kinesiology, University of Calgary, Calgary, AB, Canada

4

Sport Medicine Center, University of Calgary, Calgary, AB, Canada

Correspondence: Preston Wiley, MPE, MD University of Calgary Sport Medicine Centre 2500 University Drive NW Calgary, AB, Canada T2N 1N4 Tel: (403) 220-8276 Fax: (403) 220-9849 [email protected]

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Abstract This study evaluated the outcome of a standardized heavy load eccentric training program in adults with chronic painful Achilles tendinopathy, and the presence of neovascularisation in diseased and non-diseased adults. The hypothesis was that patient satisfaction would fall within the range of average satisfaction present in the literature of 60 to 90%. Subjects were instructed on a home based heavy load eccentric training program based on the Alfredsson protocol of straight leg followed by bent knee heel drops and raises. Patient satisfaction (satisfied or not satisfied with treatment) was recorded as the primary outcome with VISA-A, VAS, Tegner, and neovascularisation were also recorded. Patient satisfaction was significantly lower when compared to the literature as 2 patients reported that they were satisfied with the treatment while the remaining 15 reported that they were unsatisfied. Neovascularisation was present in only one participant without the disease and in all patients with the disease at the end of the study (neovascularisation was only present in 40% of patients with the disease at the beginning of the study). Although some patients’ symptoms improved over time, a home based heavy load eccentric training program did not satisfy patient expectations of treatment despite compliance with the home based program. Although a mainstay of treatment, other options need to be developed for patients who prefer a conservative but relatively non-invasive treatment option from the start. Key Words: eccentric, Achilles, tendinopathy, heel drops, neovascularisation

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Introduction Despite being one of the largest and strongest tendons in the human body, injuries frequently occur in the Achilles tendon (186-190). The incidence of Achilles tendon injuries has increased over the past two decades. A prevalence of Achilles tendinopathy has been estimated at 7-18% in runners (186-190). Lack of evidentiary support for the use of NSAIDs (non-steroidal anti-inflammatory drugs), corticosteroids, rest, ice, physical therapy and biomechanical alterations complicates treatment (191). History suggests that somewhere between 24% and 44% of Achilles tendinopathy patients fail conservative management requiring either significant activity modification or surgery (137, 138). Eccentric training or loading protocols have increased in popularity following the results of successful randomized controlled trials that suggest patients perform them prior to other treatments (1, 4, 31, 134, 135). A comparative study of the Alfredson heavy load eccentric training protocol required patients with chronic painful mid-portion Achilles tendinopathy to perform heavy load eccentric exercise on a daily basis for 12 weeks, while the control group performed concentric exercises (150). In the eccentric group, 82% of patients were satisfied with treatment after 12 weeks whereas only 36% were satisfied in the concentric group (150). Similar results have been reported from studies involving eccentric exercises both on its own and in combination with other modalities, with a success rate between 60% and 90% (101, 114, 151, 153). As a result, a treatment paradigm beginning with heavy load eccentric exercises has been suggested (32).

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However, reviews conclude that there is poor evidence on the effectiveness of eccentric exercises due to a lack of methodologically high quality studies and significant results (165). Eccentric exercises’ success requires a high level of patient motivation and may not be suitable for elderly or frail patients (1). Eccentrics also do not have a similar benefit for mid-portion and enthesopathy patients, although a recent uncontrolled and nonrandomised study suggested that chronic enthesopathy patients may respond to eccentric loading exercises without dorsiflexion to avoid impingement between tendon, bursa, and bone (154). A study by Sayana and Maffulli (2007) also suggests that eccentric exercises have less promising results in sedentary individuals compared to active individuals (166). Despite these limitations and the lack of information on its relation to pathology, eccentric exercises are still being suggested to patients with chronic Achilles tendinopathy. No studies have been performed to evaluate the effectiveness of a homebased heavy load eccentric training program for chronic painful Achilles tendinopathy in an unrestricted adult population. Therefore, this study was undertaken as part of the initial phase of an RCT investigating treatment options for Achilles tendinopathy. The hypothesis was that patient satisfaction with treatment (home based heavy load eccentric training program) would fall within the range of average satisfaction present in the literature of 60 to 90%. A secondary objective was to describe the effect of a standardized heavy load eccentric training program in adults with no prior history of Achilles tendon pain. The final objective of the study was to explore the role of neovascularisation in Achilles tendinopathy and its relationship to eccentric training.

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Material & Methods Procedure & Patients The study was part of the initial phase of a randomized controlled trial. Convenience sampling, a non-probability sampling strategy, was employed. The “definition of condition” was history of Achilles tendon pain. Through direct referrals from physicians, patients presenting at the Sport Medicine Centre at the University of Calgary, poster advertisements (in physician’s offices, fitness centres, universities and colleges), and an e-poster advertisement through the University of Calgary (Appendices B-G) participants with a history of Achilles tendon pain were recruited. Population with Achilles tendon pain was assessed using the inclusion and exclusion criteria (Appendix H). Informed consent was asked of those participants that passed the inclusion/exclusion (Appendices V-X). Participants who refused to enter the study were counselled regarding treatment options by the study sport medicine physician as per standard of care. Participants for which informed consent was received were serially enrolled into the study until an a priori sample size for the RCT was reached (n = 16). Data from studies using an eccentric training protocol reported 60-90% chance of success (101, 114, 151). Using 80% as the assumed probability of success, to end up with 16 participants in the sclerosing therapy RCT who have failed a standardized eccentric training protocol 80 participants maybe required. However, once 16 participants were enrolled in the RCT recruitment of individuals with Achilles tendon pain stopped. A cohort of normative graduate students of similar size were recruited once the final sample size of adults with chronic Achilles tendinopathy has been established. A separate distinct group was recruited consisting of patients (with no known 57

lower extremity injuries) presenting at the Sport Medicine Centre (SMC) to evaluate presence of neovascularisation. Unlike the graduate students, these individuals were not required to complete the eccentric training protocol. All normative adults needed to adhere to the inclusion/exclusion criteria of the RCT, specifically, no prior rupture and no prior injections to Achilles. All subjects were required to undergo a Doppler ultrasound (15-8 MHz linear array transducer) examination at baseline. Adults with painful chronic Achilles tendinopathy and the graduate students were instructed on a home based heavy load eccentric training program based on the Alfredsson protocol of straight leg followed by bent knee heel drops and raises (three sets of fifteen repetitions with a straight knee and three sets of fifteen repetitions with a slightly bent knee) (101). During their baseline visit, each patient completed a baseline questionnaire (Appendix J) and received personal instructions on how to complete the program (Appendix O). Clinical information related to Achilles tendinopathy was recorded by a sports medicine physician (Appendix N). During the training regimen, patient specific recreational activities were allowed if they could be performed with only mild or no discomfort, and no pain. Adults who had bilateral Achilles tendinopathy were instructed on the eccentric program for both legs; however, it was decided a priori that the worst tendon at baseline (the tendon with the lowest VISA-A score) would be used in the analysis. Outcome Measures & Analysis During the 12 week eccentric training protocol, patients and graduate students were required to attend a follow-up visit at 6 weeks. At this time, patients were required to complete a Victorian Institute of Sport Assessment – Achilles (VISA-A) (Appendix 58

K), visual analogue scales (VAS) (Appendix L), Tegner Activity Scale (Appendix M), and follow-up data questionnaire (Appendix O) that included a patient subjective question on satisfaction with treatment. Compliance of the eccentric training protocol was encouraged and monitored with logbooks (Appendix S) and reviewed at the six week follow-up visit along with participant log form for medications (Appendix Q). This was seen as a reasonable time period when a follow-up appointment in the clinical setting would occur and served to not only reinforce correct technique and progression of the program, but also to reassure patients in regards to any muscle soreness developed from completing the exercises. At 12 weeks, patients and graduate students underwent an ultrasound examination for neovascularisation and degenerative tendon characteristics, and also completed all of the outcome scores and questionnaires. The primary outcome was subjective patient satisfaction which was compared to the average satisfaction present in the literature of 60 to 90% using a binomial probability test. It was subjectively evaluated through the following questions: 1) did the current treatment you are receiving improve your ability to perform strenuous activities (e.g. running), 2) did the current treatment you are receiving improve your ability to perform activities of daily living (e.g. walking), and 3) are you satisfied with the current treatment you are receiving or do you require further treatment to alleviate the pain and other symptoms resulting from your Achilles tendon pain. The answer to question 3 was used as the primary response to assess patient satisfaction. In this case, the hypothesis was Ho: π1 = π2. As the data follows a binomial distribution, a binomial probability test was performed.

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Secondary outcomes included a 100 mm VAS pain ratings for two different situations (overall pain in Achilles during tendon loading and overall pain in Achilles during regular activities), Tegner Activity Scale (192), and VISA-A (133). Outcome measurements were assessed at baseline, 6 and 12 weeks for the adults with painful chronic Achilles tendinopathy. Semi-quantitative ultrasound grading systems of the tendon and vascularisation used modified procedures previously employed by Archambault and Boesen (58, 193) (Appendix R). An (a) and (b) designation were added to the Archambault system to describe calcification, and a Part 2 was added to the Boesen system to quantify number of neovessels. Patients were considered compliant if their log book showed that they completed at least 80% of the protocol. One patient withdrew from the study after completion of the 12 week eccentric training protocol. They were included in the unsatisfied group of patients as per their final assessment. Ethical Considerations Ethical approval (ID 20903) was granted by the Conjoint Health Research Ethics Board at the University of Calgary on May 17, 2007. Results Forty-eight adults (20 patients diagnosed with Achilles tendinopathy, 7 adults without the condition and 21 graduate students without the condition) were included in the study (Table 1). All patients had at least 3 months of pain and were not able to participate in their regular tendon loading activities because of pain. Patients with chronic painful Achilles tendinopathy were involved in a variety of activities including walking, running, basketball, soccer, skiing and other sports and had 60

tried a number of treatments including rest (20), NSAIDS (15), physiotherapy (18), acupuncture (2), ultrasound (2), orthotics (2), and night splints (1). Seventeen of 20 patients completed at least 80% of the program and were considered compliant. Although the three patients who were considered non-compliant completed over 50% of the program, they were unable to perform the exercises twice per day due to the extreme pain that resulted when performing the exercises. Satisfaction of those patients with chronic painful Achilles tendinopathy was significantly lower (2 patients reported that they were satisfied with the treatment while the remaining 18 reported that they were unsatisfied) when compared to the literature (p=0.0174). An improved VISA-A score was recorded in both satisfied and unsatisfied patients (Chapter 3 Figure 1), as well as an improved VAS and Tegner score. There was no significant difference in the change of VISA-A, VAS and Tegner scores from baseline to 12 weeks in the satisfied and not satisfied patients (Chapter 3 Table 4). With the exception of one graduate student, all of the adults without the condition had no neovascularisation visible using ultrasound, and the remainder of the graduate students had no neovascularisation during their first ultrasound. One neovessel was visible during the graduate students second ultrasound; however, the tendon appearance was considered grade 1 or a normal appearing tendon. In comparison 8/20 patients with chronic painful Achilles tendinopathy had neovascularisation visible during their first ultrasound evaluation, and 19/20 had neovascularisation visible during their second ultrasound (one being satisfied with treatment).

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Discussion Overall patients’ symptoms in this study improved over time, but a home based heavy load eccentric training program did not satisfy patient expectations of treatment even with good compliance over a 12-week period. Results are consistent with recent reviews questioning the effectiveness of eccentric training for Achilles tendinopathy (39, 165, 194). Achilles tendinopathy has been attributed to a number of intrinsic and extrinsic factors including age, weight, height and BMI (1, 22, 35, 38, 39, 48, 195). A study by Longo et al (2009) suggested that there may be no influence of age, weight and height on the occurrence of Achilles tendinopathy (196). Although the population is different, age and BMI were not similar between the adults with chronic painful Achilles tendinopathy and the adults without the condition in this study. However, the causal pathway of Achilles tendinopathy remains largely unclear due to a lack of sufficient research. Decreasing vascularity, blood flow, and tensile strength of the tendon could be related to age, making it more susceptible to injury. An enhanced understanding on factors such as age and BMI and how these relate to Achilles tendinopathy would allow for new advances in prevention. The varying methods of describing and assessing the degree of neovascularisation contributes to inconsistencies in the literature, and therefore various scoring methods have been developed (197). The complexity of some ultrasound imaging forms; however, can cause the methods to become unusable. The radiologists in this study found the surface area measurement and region of interest section of the form to be cumbersome and not a realistic task to be performed in a true clinical setting. As a result, 62

this part of the form was removed and left blank for all patients. This change increased the efficiency of the procedure thereby making it more applicable to an actual clinical setting; however, it reduced the ability to use neovascularisation to assess the severity of the disease. Although the sample size is small, neovascularisation could be detected with Doppler ultrasound in all of the symptomatic and unsatisfied patients at the end of the protocol and in only one of the participants without the disease suggesting that neovascularisation has a relationship with chronic painful Achilles tendinopathy. Clinically, perhaps presence of neovascularisation can be used to confirm the diagnosis of Achilles tendinopathy, increase the accuracy of the prognosis, or be used to direct treatment – however this requires further exploration. Previous research suggested that eccentric exercises reduce the amount of neovascularisation visible by ultrasound, which in turn reduces pain associated with Achilles tendinopathy (40, 103). However, this causation model is arbitrary, for no literature circumvents the potential for neovascularisation to form as a result of eccentric exercises. After 12 weeks of performing the heavy load eccentric training program only one graduate student showed signs of neovascularisation with an otherwise asymptomatic and normal appearing tendon. This suggests that neovascularisation likely does not form as a result of eccentric exercises in healthy tendons. However, the magnitude (mean) of neovascularisation increased in the symptomatic cohort following eccentric training. The study was limited by a number of factors: it was not randomized or blinded and the sample size was small. The study was also limited by the use of the subjective outcomes measures VISA-A, VAS, and Tegner scales. The VAS scales were included to 63

compare with most of the other eccentric exercise studies that used pain measured by VAS as an outcome measure. However, pain intensity alone as a primary outcome measure has been questioned with one review stating that it would be more clinically relevant to use an outcome measure that takes into consideration the function of the Achilles tendon, patients’ activity level, and patients’ participation level (165). This was taken into consideration and accounts for the use of the VISA-A. The VISA-A is limited by its subjective nature that relies on the patient comprehending and completing the form accurately and truthfully; it also assumes that patient’s perception of pain and function can be standardized on a linear and numerical scale. One patient who was unsatisfied at 12 weeks recorded ninety-five points on the VISA-A, zero on the VAS (pain during regular daily activities) and nine on the Tegner, which is inconsistent with the recordings of the other unsatisfied patients. The log books are also a limitation, for one cannot chart if patients completed the logbooks truthfully, accurately and efficiently. More patient contact with the investigator is one method that could have improved the legitimacy of the logbooks. However, this would have altered the study from one of effectiveness to efficacy, and therefore patient contact was limited to what would be more realistic in a regular patient-physician care setting. Even with these limitations, this study adds to the growing evidence questioning the effectiveness of eccentric exercises for Achilles tendinopathy. Most of the reviews on the effectiveness of Achilles tendinopathy are consistent in their recommendations for future research: standardized Achilles specific outcome measures, long-term follow-up, adequate power, and appropriate randomization and blinding procedures (39, 165, 194). 64

The reviews also allude to a lack of efficacy stating that the results of many studies should be viewed with caution due to low methodological quality (39, 165, 194). Furthermore, they observe that the treatment regime was largely based on clinical experience rather than being derived from empirical data putting into question the optimal dosage (loading parameters, progression and frequency) of the exercises (194). Perspective While the recommendations by reviews regarding eccentrics in the literature are echoed by the results of this study, the apparent simplicity of the treatment and its conservative (non-surgical) nature may continue to make it a treatment option for many physicians . A recent case series found that a majority of patients showed improved symptoms with up to five years of treatment – too long a time frame for many patients (198). Eccentric exercises may provide adequate relief of symptoms if there is constant supervision by a healthcare professional; however, it is not effective for patients to use as a treatment otherwise. A decision/economic analysis study should be performed to study the appropriateness of eccentric exercises as a treatment for Achilles tendinopathy taking into consideration the delta benefit to the patient and health care system. Including as many of the other treatment options currently employed or suggested for clinical practice would add more to the body of evidence surrounding eccentric exercises for Achilles tendinopathy than another soundly performed RCT. Acknowledgements The authors would like to thank the Department of Radiology, University of Calgary for its expertise and assistance with ultrasound assessments.

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TABLES & FIGURES Chapter 3 Table 1: Baseline characteristics of adults diagnosed with Achilles tendinopathy, normative graduate students, and normative adults ADULTS ADULTS WITHOUT GRADUATE DIAGNOSED WITH CONDITION STUDENTS ACHILLES (n = 7) WITHOUT TENDINOPATHY CONDITION (n = 20) (n = 21) Gender Male 9/20 2/7 8/21 Female 11/20 5/7 13/21 BMI 27.2 (7.48) [19.0-51.5] 25.9 (5.83) [20.6-37.3] 23.4 (4.38) [15-34.9] Age 49.2 (9.07) [33-65] 45.9 (10.51) [30-59] 27.9 (2.93) [25-37] Bilateral 5/20 Location Midportion 16/20 Enthesitis 4/20 Other Previous 20/20 Treatments Baseline VISA-A 45.4 (18.1) [9-83] 93.4 (4.72) [90-100] 95 (6.37) [77-100] score Baseline VAS (tendon 58.95 (22.37) [15-87] 0 (0) [0] 2.05 (5.66) [0-23] loading) Baseline VAS (ADL) 35.55 (24.39) [0-78] 0 (0) [0] 0 (0) (0) Baseline Tegner score 3.5 (1.61) [2-7] 4.14 (2.03) [1-7] 5.01 (1.34) [3-7] NOTE: Results expressed as mean (SD) [range] unless specified. BMI = body mass index, VISA-A = Victorian Institute of Sports Assessment – Achilles, VAS = Visual Analogue Scale, ADL = activities of daily living.

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Chapter 3 Table 2: Ultrasound and outcome results for adults diagnosed with Achilles tendinopathy, normative graduate students, and normative adults

Neovascularisation (number of neovessels) Neovascularisation (number of neovessels) Appearance of Tendon

Baseline

ADULTS DIAGNOSED WITH ACHILLES TENDINOPATHY 3.77 (2.60) [1-10]

Visit 2

4.28 (2.67) [0-10]

Appearance of Tendon

Visit 2

VISA-A Score

Baseline

Baseline

Visit 2 VAS Score (tendon loading) VAS Score (ADL) Tegner Score

Baseline Visit 2 Baseline Visit 2 Baseline

1 2a 2b 3a 3b 1 2a 2b 3a 3b

2/20 15/20 1/20 2/20 0 3/20 14/20 0 3/20 0 58.8 (19.03) [26-90] 63.95 (19.67) [3295] 43 (23.22) [0-71] 32.79 (23.23) [0-70] 29.6 (21.09) [0-59] 25.37 (20.24) [0-58] 3.6 (1.57) [1-7]

ADULTS WITHOUT CONDITION 0 (0) [0]

GRADUATE STUDENTS WITHOUT CONDITION 0 (0) [0] 0.095 (0.301) [0-1]

7/7 0 0 0 0

93.4 (4.72) [90-100] 0 (0) (0) 0 (0) (0) 4.14 (2.03) (1-7)

21/21 0 0 0 0 21/21 0 0 0 0 95 (6.37) [77-100] 94.1 (8.37) [70100] 2.05 (5.66) [0-23] 4.52 (12.65) [0-52] 0 (0) [0] 0.62 (1.96) [0-7] 5.01 (1.34) [3-7]

Visit 2 4.11 (2.05) [1-9] 4.95 (1.53) [2-7] NOTE: Results expressed as mean (SD) [range]. VISA-A = Victorian Institute of Sports Assessment – Achilles, VAS = Visual Analogue Scale, ADL = activities of daily living.

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Chapter 3 Table 3: Characteristics of 25 tendons in 20 patients with chronic painful Achilles tendinopathy: comparison between subjects who were satisfied and not satisfied with treatment Variable Female Age

Satisfied (n=2) Not Satisfied (n=18) p-value 1/2 10/18 0.9414 44 48.88 0.4942 (1.41) [43-45] (9.62) [33-65] Height (m) 1.68 1.73 0.5238 (0.11) [1.6-1.75] (0.11) [1.57-1.98] Weight (kg) 71.44 82.36 0.5695 (11.23) [63.5-79.38] (25.82) [48.53-138.35] BMI 25.32 27.46 0.7151 [0.74, 24.8-25.8] (7.93) [18.86-51.49] Enthesitis 0/2 4/18 0.4682 Bilateral 1/2 4/18 0.4496 Neovascularisation at 12 weeks 1/2 18/18 0.0012 Baseline VISA-A Score 65 (6.36) [61-70] 43.17 (17.60) [9-83] 0.0980 Baseline VAS (tendon loading) 50.5 (28.99) [30-71] 59.89 (22.36) [15-87] 0.5872 Baseline VAS (ADL) 15 (21.21) [0-30] 37.83 (24.15) [5-78] 0.2180 Baseline Tegner Score 4 (2.83) [2-6] 3.44 (1.52) [2-7] 0.6550 12 week VISA-A Score 94 (0) [94] 60.41 (17.58) [32-95] 0.0174 12 week VAS (tendon loading) 0 (0) [0] 36.65 (21.37) [0-70] 0.0302 12 week VAS (ADL) 0 (0) [0] 28.35 (19.26) [0-58] 0.0583 12 week Tegner Score 6.5 (0.71) [6-7] 3.82 (1.98) [1-9] 0.0802 Compliance with program 2/2 15/18 0.9414 NOTE: Results expressed as mean (SD) [range]. VISA-A = Victorian Institute of Sports Assessment – Achilles, VAS = Visual Analogue Scale, ADL = activities of daily living.

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Chapter 3 Table 4: Means, 95% confidence intervals and p-values of the change in outcome measure score from baseline to 12 weeks in the satisfied and not satisfied patients with chronic painful Achilles tendinopathy Variable

Satisfied Not Satisfied p-value (n=2) (n=18) VISA-A Score 28.5 16.78 0.4533 (-28.68, 85.68) (6.31, 27.25) VAS -50.5 -22.22 0.2213 (tendon loading) (-310.98, 209.98) (-37.14, -7.30) VAS -15 -8.11 0.6837 (ADL) (-205.59, 175.59) (-19.24, 3.02) Tegner Score 2.5 0.33 0.1702 (-29.27, 34.27) (-0.62, 1.28) NOTE: VISA-A = Victorian Institute of Sports Assessment – Achilles, VAS = Visual Analogue Scale, ADL = activities of daily living.

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22 100 80 60 40 20 VAS 0 1 6 12 Weeks Satisfied Not 0 Satisfied Scale(fitted (mm) (fitted line)line) (b)

0

0

20

20

VISA-A Score 40 60

VAS Scale (mm) 40 60

80

80

100

100

22 100 80 60 40 20 VISA-A 0 1 6 12 Weeks Satisfied Not 0 Satisfied Score (fitted (fitted line)line) (a)

0

6 Weeks Satisfied (fitted line) Not Satisfied (fitted line)

12 Satisfied Not Satisfied

6 Weeks Satisfied (fitted line) Not Satisfied (fitted line)

22 100 80 60 40 20 VAS 0 1 6 12 Weeks Satisfied Not 0 Satisfied Scale(fitted (mm) (fitted line)line)

12 Satisfied Not Satisfied

Not 82 4 2 10 Tegner 0 1 6 12 Weeks Satisfied 0 Satisfied Score (fitted (fitted line)line)

10

100

(d)

0

0

2

20

Tegner Score 4 6

VAS Scale (mm) 40 60

8

80

(c)

0

0

6 Weeks Satisfied (fitted line) Not Satisfied (fitted line)

12

0

6 Weeks Satisfied (fitted line) Not Satisfied (fitted line)

Satisfied Not Satisfied

12 Satisfied Not Satisfied

Chapter 3 Figure 1: Scores during the 12-week treatment schedule for all patients with chronic painful Achilles tendinopathy. The graph illustrates the score for each patient who was either satisfied (dot) or not satisfied (circle) after 12 weeks. (a) VISA-A, (b) VAS scores (overall pain in Achilles tendon during tendon loading activity), (c) VAS scores (overall pain in Achilles tendon during regular activities of daily living), and (d) Tegner.

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Chapter Four: THE EFFICACY OF SCLEROTHERAPY WITH A SOLUTION OF DEXTROSE AND LIDOCAINE TO TREAT CHRONIC ACHILLES TENDINOPATHY: A RANDOMIZED CONTROLLED TRIAL The following chapter has been prepared for submission to the Canadian Medical Association Journal. Other than the references, and table and figure titles, it is formatted according to the instructions for authors of the journal.

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THE EFFICACY OF SCLEROTHERAPY WITH A SOLUTION OF DEXTROSE AND LIDOCAINE TO TREAT CHRONIC ACHILLES TENDINOPATHY: A RANDOMIZED CONTROLLED TRIAL R Ram1, BSc; W Meeuwisse1, 3, 4, MD, PhD; C Patel2, MD; D Wiseman2, MD; JP Wiley3, 4

, MPE, MD

1

Department of Community Health Sciences, University of Calgary, Calgary, AB,

Canada 2

Department of Diagnostic Imaging, Foothills Medical Center

3

Faculty of Kinesiology, University of Calgary, Calgary, AB, Canada

4

Sport Medicine Center, University of Calgary, Calgary, AB, Canada

Correspondence: Preston Wiley, MPE, MD University of Calgary Sport Medicine Centre 2500 University Drive NW Calgary, AB, Canada T2N 1N4 Tel: (403) 220-8276 Fax: (403) 220-9849 [email protected]

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Abstract Background: Sclerotherapy may have the potential to improve pain and function in patients with chronic Achilles tendinopathy. We conducted a triple blinded randomized controlled trial to assess its efficacy. There are no sclerotherapy studies that have administered a dextrose solution to a homogenous Achilles tendinopathy population in a prospective, controlled and randomized manner.

Method: Patients who failed a standardized heavy load eccentric training protocol were randomly allocated into two groups: one received an injection of 25% dextrose and 0.5% lidocaine (sclerosing solution) and the other received an injection of 1% lidocaine (control) for up to three injections over 12 weeks. Outcome assessment of pain and function, ultrasound examination, and subjective measurement of patient satisfaction were performed at each appointment. The primary outcome was the Victorian Institute of Sport Assessment - Achilles (VISA-A) score which is a composite score assessing pain and function. The mean difference between groups and associated 95% confidence intervals were calculated from baseline measurement to 12 weeks, and a repeated measurement ANCOVA was performed for the mean difference between groups in VISA-A.

Results: Seventeen subjects (nine females and seven males) were enrolled and randomly allocated into the active and placebo group. The mean difference (95% confidence interval) from baseline to 12 weeks in VISA-A in the active group was 15.33 (3.0, 27.7), whereas the mean difference in the placebo group was -4.1 (-11.2, 2.9). This difference is 73

considered significant when assessed using repeated measures ANCOVA (p3(months(

!

Clinically(diagnosed( Achilles(tendinopathy(

Midportion(( (266(cm(from(Calcaneus)(

Enthesopathy(

EXCLUDE:( Posterior(impingement(syndrome( Sever's(lesion((calcaneal(apophysitis(in( adolescents)( Accessory(soleus(muscle( Osteoarthritis( Neuropathy( Peripheral( Tarsal(tunnel(syndrome( Vascular(claudication(

Sclerotherapy( (up(to(5( injections)( Prolotherapy( (up(to(10( injections)(

Sclerotherapy( (up(to(5( injections)(

Deep(venous(thrombosis( Rheumatologic(disease( Cellulitis( Abscess( Osteomyelitis( Bone(cyst( Malignancy( Hematoma(

Surgery( Surgery(

Chapter 6 Figure 1: Scheme for treating Achilles tendinopathy.

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To appreciate this scheme, an example is presented on the management of Achilles tendinopathy in Figure 2. An otherwise healthy 42-year-old woman presents to a sport medicine physician with a 3-month history of pain along her Achilles tendon which she states has hindered her performance as a semi-competitive soccer player. She has a BMI of 25.3 and considers herself active engaging in soccer or other activities at least 5 days a week. There is no history of trauma or an obvious episode of strain or sprain. The pain is variable but is present throughout the day and also at night. It becomes severe immediately following a soccer game, and the pain is only mildly relieved by oral over the counter NSAIDS. There is no significant past medical history or family history. Physical examination shows a painful thickening in the midportion of the Achilles tendon, which triggers a sharp, localized pain when palpated. You discuss the treatment options available to her as per the scheme, and she is willing to wait for an ultrasound in order to proceed with sclerotherapy using 25% dextrose and lidocaine. During the ultrasound examination, moderate thickening of the Achilles tendon is evident with neovascularisation present anterior to the midportion of the tendon. She receives her first sclerotherapy injection in the area of pain and neovascularisation, and continues receiving injections every 4 weeks. During her fourth session neovascularisation is still present, but she no longer has any pain and is able to compete at the level in her soccer games that she was previously accustomed to. Injections are discontinued, and during her follow-up appointment with the sports medicine physician she is educated on the possibility of her pain returning in the future.

Chapter 6 Figure 2: Applying the scheme (fictional case) There are a number of addendums or caveats to the scheme: 1. It is unreasonable at this time to provide health care resources for extracorporeal shock wave therapy, glyceryl trinitrate, orthotics, braces, and splints given the vague or inconclusive evidence surrounding all of these treatment modalities (11, 148, 161). 2. Evidence for the effectiveness of eccentric exercises was not provided by this study. As a result, it cannot be recommended as a treatment option. 3. Although prolotherapy and eccentric exercises may be beneficial to Achilles enthesopathy patients (indeed one pilot study of eccentric exercises showed promising results in 67% of patients), there are currently no randomized controlled trials supporting its use in this patient population (154).

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4. Physiotherapy is a multimodal intervention that can include ice, transverse friction massage (and other massage and stretch techniques, therapeutic ultrasound (and other modalities) and exercise (including heavy load eccentric exercises). Physiotherapy interventions have little prospective and randomized evidence to support their use as separate distinct treatments (144). 5. Unlike previous algorithms in the literature, there is no rank order for the available interventions for mid-portion and enthesopathy. Clinical judgement, patient preference and healthcare resource availability should govern the order in which the patient proceeds as there is little to no comparative data of the interventions. However, a reasonable assumption is that any surgical interventions would proceed after other treatments have failed due to the higher risk of surgery. 6. There are a number of surgical options; however, it was beyond the scope of this thesis to evaluate and provide recommendations for each different type of surgery for Achilles tendinopathy. 7. Although the VISA-A may provide an appropriate measure of Achilles tendinopathy pain and function during research studies, at this time there are no outcome scores available for Achilles tendinopathy. Given that assessment is largely based on the patient’s subjective assessment of pain and function, finding a measure with utility for clinical practice may not be realistic. Yelland et al (2009) found that the minimum clinically important change for the VISA-A was 28 points. However, their inclusion criteria and severity index based on VISA-A scores is ambiguous and without explanation – it is unlikely at this time that patients presenting in a clinical

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scenario will be denied treatment, or that treatment will be discontinued based on their VISA-A or any other outcome measure score (157). Future research directions There are a number of things that were brought to light during the course of this thesis that need to be addressed in future research initiatives: 1. Healthcare resources are a factor in many clinical and patient decisions. The efficacy of the treatments presented in the scheme has been explored and future research in Canada should evaluate the comparative cost-effectiveness of the treatments presented in the scheme. Specifically, comparing the clinical effectiveness and cost effectiveness of prolotherapy and sclerotherapy in a multi-centre randomized clinical trial would provide unique information. 2. Further analysis of the data was limited in this study due to sample size, but other studies (even multi-centered studies) have cited available resources and slow recruitment rate as a limiting factor regarding sample size which could explain the lack of large, population based RCTs (157). Therefore, other study designs maybe required to evaluate whether the VISA-A has a role in the outpatient clinical setting. 3. Canadian clinical practice guidelines for Achilles tendinopathy that are reviewed and updated would benefit both the physician and patient and need to be developed.

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APPENDICES

117

A: Literature Search and Abstract Selection Criteria Database: CDSR, ACP Journal Club, DARE, CCTR, CLCMR, CLHTA, CLEED, Ovid MEDLINE(R), EMBASE Search Strategy: -------------------------------------------------------------------1 ("tendinopathy" or "tendinitis" or "tendinosis" or "paratenonitis").mp. [mp=ti, ab, tx, kw, ct, ot, sh, hw, nm, tn, dm, mf] (5168) 2 tendinopathy.mp. or exp Tendinopathy/ (6182) 3 exp Bursitis/ or exp Tendinopathy/ or exp Tendons/ or exp Achilles Tendon/ or exp Athletic Injuries/ or exp Tendon Injuries/ or exp Tenosynovitis/ (43857) 4 exp Calcaneus/ (4385) 5 (enthesitis or enthesopathy).mp. [mp=ti, ab, tx, kw, ct, ot, sh, hw, nm, tn, dm, mf] (1246) 6 ("shock wave" or "eccentric" or "injection" or "surgery" or "NSAID" or "glyceryl " or "laser" or "Aprotinin" or "orthotics" or "massage" or "exercise" or "cyro").mp. [mp=ti, ab, tx, kw, ct, ot, sh, hw, nm, tn, dm, mf] (1423339) 7 insertional.mp. (12020) 8 1 or 2 or 3 or 4 or 5 or 6 or 7 (1470814) 9 limit 8 to yr="1997 - 2009" [Limit not valid in DARE; records were retained] (1355979) 10 case reports.pt. (569881) 11 9 not 10 (1296799) 12 limit 11 to (english language and ("all adult (19 plus years)" or "adult (19 to 44 years)" or "middle age (45 to 64 years)" or "middle aged (45 plus years)" or "all aged (65 and over)" or "aged (80 and over)")) [Limit not valid in CDSR,ACP Journal Club,DARE,CCTR,CLCMR,EMBASE; records were retained] (878478) 13 achilles.mp. (7049) 14 12 and 13 (3462) 15 achilles.m_titl. (2834) 16 14 and 15 (1490) 17 achilles.mp. [mp=ti, ot, ab, tx, kw, ct, sh, hw, nm, tn, dm, mf] (7049) 18 remove duplicates from 14 (2692) 19 rupture.mp. [mp=ti, ot, ab, tx, kw, ct, sh, hw, nm, tn, dm, mf] (70207) 20 18 not 19 (1832) 21 15 and 20 (559) 22 from 21 keep 1-559 (559)

Database: CDSR, ACP Journal Club, DARE, Ovid MEDLINE(R), EMBASE Search Strategy: -------------------------------------------------------------------1 polidocanol.mp. [mp=ti, ot, ab, tx, kw, ct, sh, nm, hw, tn, dm, mf] (1580) 2 sclerotherapy.mp. [mp=ti, ot, ab, tx, kw, ct, sh, nm, hw, tn, dm, mf] (6450)

118

3 prolotherapy.mp. [mp=ti, ot, ab, tx, kw, ct, sh, nm, hw, tn, dm, mf] (89) 4 neovessel$.mp. [mp=ti, ot, ab, tx, kw, ct, sh, nm, hw, tn, dm, mf] (729) 5 neovasculari$.mp. [mp=ti, ot, ab, tx, kw, ct, sh, nm, hw, tn, dm, mf] (43711) 6 achilles.mp. [mp=ti, ot, ab, tx, kw, ct, sh, nm, hw, tn, dm, mf] (6828) 7 1 or 2 or 3 or 4 or 5 (51392) 8 6 and 7 (129) 9 limit 8 to english language [Limit not valid in CDSR,ACP Journal Club,DARE; records were retained] (119) 10 case reports.pt. (568553) 11 9 not 10 (116) 12 remove duplicates from 11 (92) 13 rupture.mp. [mp=ti, ot, ab, tx, kw, ct, sh, nm, hw, tn, dm, mf] (68716) 14 12 not 13 (77) 15 from 14 keep 1-77 (77)

Treatment of Achilles Tendinopathy – Abstract selection criteria Instructions: When reviewing abstracts refer to these criteria for determining whether they are in or out or flagged for later use. For each abstract, whether IN or OUT or flagged for later use, please indicate the number of the criterion used. There are five objectives for this study: a. To perform a controlled longitudinal study to evaluate the outcome of a standardized heavy load eccentric training program in adults with chronic painful Achilles tendinopathy (unilateral). Also, to describe the effect of a standardized heavy load eccentric training program in adults with no prior history of Achilles tendon pain. b. To describe the frequency of neovascularisation in adults with chronic painful Achilles tendinopathy, and in adults with no prior history of Achilles tendon pain. c. To perform a double blind randomised clinical trial to evaluate sclerosing therapy using a 25% dextrose mixed with 1% lidocaine sclerosant as a treatment option for adults with chronic painful Achilles tendinopathy with existing neovascularisation for whom a standardized heavy load eccentric training program has failed to provide pain relief. d. To describe the effect of sclerotherapy on chronic painful Achilles tendons without neovascularisation. e. To describe the sonographic changes of Achilles tendons in patients who undergo a standardized heavy load eccentric training program, and those that undergo sclerosing therapy. 119

f. To describe the responsiveness of the VISA-A and its relevance to the discrete state of satisfied and unsatisfied with treatment, the Tegner Activity Scale, and VAS scales. Papers that are IN: Regarding the human Achilles tendon: 1. Neovascularisation / Sclerotherapy / Prolotherapy 2. Eccentric training 3. Other conservative management strategies 4. Evaluation including outcome measures and imaging 5. Epidemiology and aetiology 6. Anatomy and pathology 7. Reviews / General Studies 8. Papers that are OUT • Not about Achilles tendon UNLESS about neovascularisation • About management and care before and after surgery • About Achilles tendinopathy as a result of other diseases (e.g. diabetes, psoriasis, cancer) • About management and care of Achilles rupture • About healing of Achilles tendon related to surgical interventions • Include populations under 18 years old 5. Papers to FLAG for future reference: • Include guidelines, criteria or common characteristics describing symptoms and/or measures for patients 3with Achilles tendon pain • Laboratory/animal studies that provide insight into pathology, aetiology and possible treatment modalities as related to Achilles tendinopathy • Others – please describe why selected. • Neovascularisation, sclerotherapy, or prolotherapy of other tendons

120

B: Physican Approach Letter

121

122

C: Recruitment E-poster

* Surname of Principal Investigator: Wiley * Study Title: Treatment of Achilles tendinopathy

* GRANT-ID: Study Description: We are conducting a study to determine whether sclerosing therapy will provide pain relief and improved function for chronic painful Achilles tendon. If you are 18 years of age or older with at least 3 months Achilles tendon pain you may be eligible for this study. Enrolment is conditional on diagnosis by a sport medicine physician and radiologist.

* Keyword #1: Achilles Keyword #2: Pain Keyword #3: Tendinopathy Keyword #4: Treatment Keyword #5: Heal

* Contact Information: Rithesh Ram @ 837-7681 or [email protected]

123

D: Recruitment Poster

We are currently enrolling patients in a research study for people with pain in their Achilles tendon Research Study Title:

Treatment of Achilles tendinopathy Study Description:

We are conducting a study to determine whether sclerosing therapy will provide pain relief and improved function for chronic painful Achilles tendon. If you are 18 years of age or older with at least 3 months Achilles tendon pain you may be eligible for this study. Enrolment is conditional on diagnosis by a sport medicine physician and radiologist. This research is being conducted by:

Dr. Preston Wiley, MPE, MD, CCFP For additional information regarding this study, please contact:

Rithesh Ram, 403-837-7681 or [email protected]

124

E: Recruitment E-poster – Adults Without Condition

* Surname of Principal Investigator: Wiley * Study Title: Treatment of Achilles tendinopathy

* GRANT-ID: Study Description: We are conducting a study to determine the proportion of adults with neovascularisation present as measured with Doppler ultrasound who have no history of Achilles tendon pain. If you are 18 years of age or older with no history of Achilles tendon pain you may be eligible for this study. The study will involve noninvasive ultrasound imaging of both Achilles tendons. It will take approximately 20 minutes of your time

* Keyword #1: Achilles Keyword #2: Ultrasound Keyword #3: Tendinopathy Keyword #4: Treatment Keyword #5: Heal

* Contact Information: Rithesh Ram @ 837-7681 or [email protected]

125

F: Recruitment Poster – Adults Without Condition

We are currently recruiting patients for an Achilles tendon research study Research Study Title:

Treatment of Achilles tendinopathy Study Description:

We are conducting a study to determine the proportion of adults with neovascularisation present as measured with Doppler ultrasound who have no history of Achilles tendon pain If you are 18 years of age or older with no history of Achilles tendon pain you may be eligible for this study. The study will involve non-invasive ultrasound imaging of both Achilles tendons. It will take approximately 20 minutes of your time. This research is being conducted by:

Dr. Preston Wiley, MPE, MD, CCFP For additional information regarding this study, please contact:

Rithesh Ram, 403-837-7681 or [email protected] 126

G: Recruitment Poster – Athletes/Graduate Students Without Condition

We are currently recruiting patients for an Achilles tendon research study Research Study Title:

Treatment of Achilles tendinopathy Study Description:

We are conducting a study to evaluate the outcome of a standardized heavy load eccentric training program in adults with chronic painful Achilles tendinopathy, and in adults with no prior history of Achilles tendon pain. If you are a varsity athlete or graduate student, 18 years of age or older with no history of Achilles tendon pain you may be eligible for this study. The study will involve two non-invasive ultrasound imaging sessions of both Achilles tendons along with completion of a 12 week eccentric training program. The imaging sessions will take approximately 20 minutes of your time. This research is being conducted by:

Dr. Preston Wiley, MPE, MD, CCFP For additional information regarding this study, please contact:

Rithesh Ram, 403-837-7681 or [email protected]

127

H: Inclusion / Exclusion Criteria

Name: ___________________________

Date: _________________

Age: _______ Achilles tendon pain (day or night)

Y

N

Greater than 3 months since onset of symptoms

Y

N

Previous Achilles tendon rupture

Y

N

Received any type of injection in or around the Achilles tendon

Y

N

Tried at least one other treatment option

Y

N

Known allergy to dextrose based sclerosing agent or other contraindications

Y

N

Known allergy to lidocaine or other contraindications

Y

N

Known allergy to saline or other contraindications

Y

N

Physical ailments precluding them from performing the eccentric training program

Y

N

Worker’s Compensation Board (WCB)

Y

N

Elite athletes (varsity, national and professional level)

Y

N

* All data should be filled out, regardless of whether participant is excluded before the form is complete

128

Table: Inclusion and exclusion criteria Inclusion Criteria - Adults 18 years of age and older with a minimum of 3 months of clinically determinant history and symptoms (pain) consistent with unilateral Achilles tendinopathy (enthesitis or mid-portion) as diagnosed by a sport medicine physician. - Participants are not required to have tried other treatments, however, those who have tried other treatments (except injection treatments) including, but not restricted to, oral NSAIDs, topical NSAIDs, shoe modifications, and physical/athletic therapy will not be restricted from the study - Provide informed consent for the controlled longitudinal study and RCT

Exclusion Criteria - Individuals with physical ailments precluding them from performing the eccentric training program - Worker’s Compensation Board (WCB) and elite athletes (varsity, national and professional level). - Individuals younger than 18 years of age will be excluded from this trial due to the complicating factors of musculoskeletal immaturity and the lack of relevant research of Achilles tendinopathy and neovascular bundles in this population (218). - Previous Achilles tendon rupture of the tendon in question - Individuals that have received any type of injection in or around the Achilles tendon - Known allergy to dextrose based sclerosing agent or other contraindications - Known allergy to lidocaine

129

I: Sample Size Calculations Intercooled Stata 10 was used for sample size calculations. Sclerosing Therapy RCT:  Primary endpoint: Between groups difference over 3 months as measured using a VISA-A  Analysis: ANCOVA (Analysis of Co-Variance)  Type 1 error = 0.05 (two-sided)  Desired power = 0.90  Clinically important difference (CID) = 25 points in VISA-A score  Estimated standard deviation = 20 points  Number of follow-up measures: 3  Number of baseline measurements: 1 Scenario 1: no correlation between measurements (r = 0.000) . sampsi 25 0, sd1(20) sd2(20) method(ancova) pre(1) post(3) r1(0) power(0.9) Estimated sample size for two samples with repeated measures Assumptions: alpha = 0.0500 (two-sided) power = 0.9000 m1 = 25 m2 = 0 sd1 = 20 sd2 = 20 n2/n1 = 1.00 number of follow-up measurements = 3 correlation between follow-up measurements = 0.000 number of baseline measurements = 1 correlation between baseline & follow-up = 0.000 Method: ANCOVA relative efficiency adjustment to sd adjusted sd1 adjusted sd2

= = = =

3.000 0.577 11.547 11.547

Estimated required sample sizes: n1 = 5 n2 = 5 20% increase due to loss to follow-up: . display (10/(1-0.2)) 12.5 Gives 7 patients per group for a total sample size of 14.

Scenario 2: moderate correlation between measurements (r = 0.500) . sampsi 25 0, sd1(20) sd2(20) method(ancova) pre(1) post(3) r1(.5) power(0.9) Estimated sample size for two samples with repeated measures Assumptions: alpha = 0.0500 (two-sided) power = 0.9000 m1 = 25 m2 = 0 sd1 = 20

130

sd2 n2/n1 number of follow-up measurements correlation between follow-up measurements number of baseline measurements correlation between baseline & follow-up Method: ANCOVA relative efficiency adjustment to sd adjusted sd1 adjusted sd2

= = = =

= = = = = =

20 1.00 3 0.500 1 0.500

2.400 0.645 12.910 12.910

Estimated required sample sizes: n1 = 6 n2 = 6 20% increase due to loss to follow-up: . display (12/(1-0.2)) 15 Gives 8 patients per group for a total sample size of 16.

Scenario 3: strong correlation between measurements (r = 0.900) . sampsi 25 0, sd1(20) sd2(20) method(ancova) pre(1) post(3) r1(.999) power(0.9) Estimated sample size for two samples with repeated measures Assumptions: alpha = 0.0500 (two-sided) power = 0.9000 m1 = 25 m2 = 0 sd1 = 20 sd2 = 20 n2/n1 = 1.00 number of follow-up measurements = 3 correlation between follow-up measurements = 0.999 number of baseline measurements = 1 correlation between baseline & follow-up = 0.999 Method: ANCOVA relative efficiency adjustment to sd adjusted sd1 adjusted sd2

= = = =

750.563 0.037 0.730 0.730

Estimated required sample sizes: n1 = 1 n2 = 1 20% increase due to loss to follow-up: . display (2/(1-0.2)) 2.5 Gives 2 patients per group for a total sample size of 4.

131

J: Baseline Data Questionnaire Name: ______________________________________________ Date: ______________________________ Gender: ____________________________ Weight (kg / lbs): _______________ Height: ________________ BMI: _____________ Diabetic (circle one)?

YES

NO

Initial Start of Achilles Tendon Pain: _________________________________________ Previous Lower Body Injury (circle one)

YES

NO

If yes explain: ____________________________________________________________

________________________________________________________________________ Antibiotic use near the time of injury:_________________________________________

Medication Use:__________________________________________________________

________________________________________________________________________ Allergies to medication: ____________________________________________________ ________________________________________________________________________ Other medical conditions: __________________________________________________ ________________________________________________________________________ ________________________________________________________________________ SIGNATURE OF CONFIRMATION ______________________ DATE ____________ 132

K: VISA-A Questionnaire Name: _____________________________ Date: _____________________________

133

134

135

L: Visual Analog Scale Achilles Tendon Pain

Name: _____________________________ Date: ______________________________

Please indicate with an ‘X’ or a vertical line the average amount of pain in your Achilles tendon affected with tendinopathy.

Overall pain in Achilles tendon during tendon loading activity (running etc.): No Pain

Worst pain imaginable

Overall pain in Achilles tendon during regular activities of daily living (walking, shopping, etc.): No Pain

Worst pain imaginable

POST INJECTION:

Overall pain in Achilles tendon immediately after injection: No Pain

Worst pain imaginable

Overall pain in Achilles tendon 10 minutes after injection: No Pain

Worst pain imaginable

136

M: Tegner Activity Scale

137

N: History and Physical Exam Form Name: ________________________________

Date: _________________

Sport/Position: ___________________________________________________ Presence of tenderness?

Left:

Y

N

Right: Y

N

Location of tenderness: ____________________________________________ Presence of swelling?

Left:

Y

N

Right: Y

N

Location of swelling: ______________________________________________

To be completed by physician: Hx: ________________________________________________________________________ ________________________________________________________________________

Physical Exam: ________________________________________________________________________ ________________________________________________________________________

138

O: 12-week Eccentric Exercise Program * routine should be performed twice daily, seven days per week. Part I Exercises are completed on a step while in a standing position, with full bodyweight on the forefoot of your injured leg. The ankle joint of your injured leg is in plantar flexion (i.e. up on your toes) and the knee is straight. To start the exercise, begin to lower your heel and continue until your heel is beneath the level of the step. During the lowering phase, you will use only the injured leg to complete the exercise. Once the heel is lowered beneath the level of the step, place the forefoot of your uninjured leg on the step and use only this leg to return to the starting position. Complete 15 repetitions, and then rest for approximately one minute. Repeat the cycle of 15 repetitions (with rest) two additional times. Part II All elements of the routine remain the same, with the exception of the knee position of the injured leg. In part II, allow the knee to slightly bend through the entire lowering phase of the exercise. Complete 15 repetitions, and then rest for approximately one minute. Repeat the cycle of 15 repetitions (with rest) two additional times. Exercises should be painful - when there is no pain in your Achilles during training, the load should elevated to reach a new level of “painful training”. However, no training through disabling pain should occur. The load may be increased by wearing a backpack where weights or books can be added (increase at about 5 lb or 2.5 kg intervals). Please note that muscle soreness following exercise, particularly during the first 1 to 2 weeks of training is expected. If you have any questions, please contact Rithesh Ram at 837-7681.

Please complete the daily training log after each session of exercises

139

P: Follow-up Data Questionnaire Name: ______________________________________________ Date: ______________________________ Current treatment you are receiving (circle one):

Eccentric Training

Did the current treatment you are receiving improve your ability to perform strenuous activities (e.g. running) (circle one)? Did the current treatment you are receiving improve your ability to perform activities of daily living (e.g. walking) (circle one)? Are you satisfied with the current treatment you are receiving or do you require further treatment to alleviate the pain and other symptoms resulting from your Achilles tendon pain (circle one):

Injection

Yes

No

Yes

No

Satisfied

Further Treatment Required

Describe course of Achilles tendon pain since last assessment:______________________ ________________________________________________________________________

Lower body injuries since entering the study (provides date of injury and explain): ________________________________________________________________________

Antibiotic use near the time of injury:_________________________________________

Medication use since entering the study: _______________________________________

________________________________________________________________________ New medical conditions since entering the study:________________________________ ________________________________________________________________________ ________________________________________________________________________ 140

Other treatment approaches performed since entering the study (provide date and type of treatment):_______________________________________________________________ ________________________________________________________________________

141

Q: Participant Log Form Date

Medication Taken

Dosage (strength & num ber of pills)

142

Reason for Taking Medication

R: Ultrasound Imaging Form Name: _________________________________

Date: ______________________

Appearance of Achilles tendon (58): Grade 1: Normal-appearing tendon (parallel margins with homogeneous echotexture) Grade 2a: Enlarged tendon no calcification (bowed margins with homogeneous echotexture) Grade 2b: Enlarged tendon with calcification (bowed margins with homogeneous echotexture) Grade 3a: Hypoechoic area with or without tendon enlargement and no calcification (dark area within tendon, with or without bowed margins) Grade 3b: Hypoechoic area with or without tendon enlargement and calcification (dark area within tendon, with or without bowed margins) Vascularisation (94): Part 1: When Doppler activity is present, the centre with the most pronounced Doppler activity will be defined and 1 cm of the tendon in both proximal and distal directions will be used as the region of interest (ROI) (94). Grade 0: No Doppler activity Grade 1: One or two tiny color foci Grade 2: Up to 50% color inside the ROI Grade 3: 50-90% color inside the ROI Grade 4: 90-100% color inside the ROI Part 2: Number of neovessels visible under Doppler ultrasound outside of the tendon: ________ Color Doppler Ultrasound Longitudinal Image Transverse Image

Left

Power Doppler Ultrasound Longitudinal Image Transverse Image Panoramic Image 143

Right

S: Eccentric Log Book Day

Time

E.g. 1

8:30 AM

Repetitions 15

Part 1 Sets 2

1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 10 10 11 11 12 12 13 13 14 14 15 15 16 16 17 17 18 18

144

Weight No weight

Repetitions 15

Part 2 Sets 2

Weight No Weight

T: Adverse Event Report

145

U: Treatment Allocation Assessment Form Treatment Allocation Assessment

Name: _______________________ Date: ________________________ Do you believe you were randomly allocated to the placebo or active injection group (placebo/active)? ______________________ Are you satisfied with your treatment (yes/no)? ______________________ If you were randomly allocated to the placebo group, would you like to begin treatment with the active (dextrose and lidocaine) injection (yes/no)? _______________________ Please list any medications that you consumed during the last 3 months

146

V: Consent Form – Study Sample (Unilateral & Bilateral)

147

148

149

150

151

152

153

154

155

156

157

W: Consent Form – Adults Without Condition

158

159

160

X: Consent Form – Athletes/Graduate Students Without Condition

161

162

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