Achilles tendinopathy (AT) pain leads to decreased function and participation in work and recreation activities [1,2]. However, factors that contribute to the development and persistence of AT pain are not well understood. Recent evidence suggests that neurobiological pain processes in the peripheral and central nervous systems (CNS) contribute to chronic AT pain [3-7]. Factors that have been associated with AT include centrally mediated mechanisms such as elevated pain, psychological factors (fear of movement and pain catastrophizing) [5,8], and motor dysfunction (heel raise repetitions reduced by pain) [5]. However, this relationship is complex and bidirectional, as pain can also reduce function. In addition, there is mixed evidence for the presence of altered CNS regulation of nociceptive processing contributing to AT pain [4,5], with some studies indicating reduced conditioned pain modulation (CPM) and/or widespread decrease in pressure pain [6,7], whereas other studies indicate no difference compared with controls [4,5]. Peripheral mechanisms include nociceptive input, as evidenced by decreased pain pressure threshold (PPT) at the site of pain relative to multiple proximal and contralateral areas [4,5,7]. An improved understanding of how different physical therapy treatment approaches affect these mechanisms of AT pain could inform clinical practice.

Chronic musculoskeletal pain conditions, such as AT, can be associated with elevated levels of kinesiophobia and catastrophizing [9]. Given the frequent chronic duration of AT symptoms, fear avoidance and negative beliefs about movement and exercise may negatively impact patient compliance and outcomes of tendon loading exercises [10]. Pain education as part of physical therapy, with a biopsychosocial approach, has recently emerged as a promising component of care for many chronic musculoskeletal pain conditions. Greater patient understanding of their condition facilitates improved self-efficacy and management of symptoms while decreasing kinesiophobia and pain catastrophizing [9]. The standard of care for AT includes progress in tendon loading exercises, based on a high level of evidence [8,10-13]. In contrast, no clinical trials have evaluated the effects of pain education on pain and function in patients with Achilles tendon pain [14]. We hypothesize that a biopsychosocial approach to patient education, which addresses pain-related psychological factors and provides accurate information on adaptation, biology, and central pain mechanisms, will decrease movement-evoked pain and improve self-reported function at 8 weeks more than standard care for patients with AT, which is usually based on a pathoanatomical educational approach.

Tendinopathy Education on the Achilles (TEAch; NCT 04059146) is a randomized, double-blind, placebo-controlled trial for individuals with chronic AT. The primary outcomes of movement-evoked pain and self-reported function will be represented as a change from baseline to 8-week follow-up (Figure 1). All participants will receive a progressive tendon loading exercise program and be assigned to either a pain education program or a pathoanatomical education program on AT pathology. The TEAch study has 2 primary aims and 2 exploratory aims. The first aim is to determine if an 8-week progressive tendon loading exercise program combined with pain education on AT is more effective at reducing movement-evoked pain and self-reported function than pathoanatomical education on AT. The second aim is to identify processes (altered CNS regulation of nociceptive input, changes in fear or pain beliefs, and improved motor function) that change over time with the intervention, regardless of education type. Our first exploratory aim is to identify if improvements in pain mechanism knowledge related to AT are associated with an improvement in pain and function. The second exploratory aim will identify if improvements in pain processes (altered CNS regulation of nociceptive input, changes in fear or pain beliefs, and improved motor function) are associated with an improvement in pain and function. In addition, a feasibility aim will gather information (recruitment, treatment fidelity, outcome capture rate, and adverse events [AEs]) to inform future clinical trials through both in-person and telehealth delivery of interventions on the outcomes of pain and function.

Participants will be recruited through the University of Iowa and local community using mass emails, databases of participants previously enrolled in research studies, referrals from participants and collaborators in the Department of Orthopedics and Rehabilitation, and review of electronic medical records. All participants will be screened through a web-based survey and review of the medical records, if available, for inclusion and exclusion criteria (Textbox 1). Potential participants will be contacted via email and/or phone by the study coordinator. Participants will be consented at their first evaluation session, including a review of the purpose of the study, risks and benefits, procedures including confidentiality and interventions, and opportunity for participants’ questions. After informed consent, an experienced physical therapist will confirm a diagnosis of AT by clinical exam and ensure that all inclusion criteria are met (Textbox 1). Participants who do not meet the eligibility criteria at evaluation session 1 will be excluded from randomization to the treatment group. Participants will be compensated for completion of evaluation sessions and travel and parking for evaluation and treatment visits. The protocol was reviewed and approved by the Institutional Review Board (IRB) at the University of Iowa.

The primary outcomes of this study were movement-evoked pain and self-reported function. The sample size is calculated to have sufficient statistical power for each primary outcome using a Bonferroni adjusted type I error rate of 0.025 (0.05/2 for 2 outcomes in aim 1). On the basis of findings by Moseley [15] for a randomized controlled trial (RCT) examining the effect of exercise and pain education for patients with chronic low back pain, we anticipate between-group differences with Cohen d≥0.36 for pain (between-group difference across 2 time points=0.75; 1.05 SD on the numeric pain rating scale; effect size of f=0.36; correlation between repeated measures=0.5) and self-reported function (between-group difference across 2 time points=1.95; 2.33 SD on low back pain–specific measure; effect size of f=0.42; correlation between repeated measures=0.5) [15]. Using these estimates, a sample size of 30 patients per group is needed to reach 80% power for the time-averaged difference between two group means in a repeated measures design with =.025 to detect a between-group effect size of 0.36. A final sample size of 60 is sufficient to detect estimated effect sizes for the outcome measures based on previously published differences or clinically meaningful minimal clinical difference/minimal clinically important difference and SD for the AT population (Table 1). We will consent 110 participants, estimating a 40% ineligibility rate after screening and 10% attrition rate between the first and second evaluation visits, to achieve a total of 66 participants consented and randomized.

This is a randomized, double-blind, placebo-controlled trial with individuals who have chronic AT. Participants will be randomized to 1 of 2 groups: pain education or pathoanatomic education. All participants will receive the same progressive tendon loading exercise intervention. Each participant will complete 2 evaluation sessions where primary outcomes will be collected at baseline and 8-week follow-up, 6-7 treatment sessions with a physical therapist, and 1 evaluation session at 12-week follow-up with self-reported measures (Figure 1).

Participants will be randomized using a permuted block design with variable block sizes. Randomization will be stratified by sex and AT location (insertional and midportion). Randomization codes will be stored electronically and printed by a lab assistant and placed into opaque envelopes and sealed. Each envelope will be numbered in sequential order and stored separately from the recruiter, outcome assessor, and treating physical therapist. Immediately before each participant’s first treatment session, the treating physical therapist will either open an envelope or receive an email with the participant’s group allocation. Thus, randomization will occur after baseline assessment and remain concealed from participants for the duration of the study. Following all outcome collections, participants’ planned unmasking will be completed at 12 weeks, where participants will be informed of their group allocation by providing references and resources used for both education groups. Following completion of the study, participants will be offered the option of being sent a copy of the published findings, quarterly newsletters on study progress, and provided with any preliminary findings after study completion.

The intervention will occur over 12 weeks. The educational component will take place over the first 8 weeks during individualized treatment visits. The last 4 weeks will include maintenance of a home exercise program (HEP) with a phone call and email follow-up, if not reached by phone, from the physical therapist at 10 weeks to address any questions regarding exercise progression. The education and exercise treatments will be provided to both groups by the same unblinded physical therapist. Although a single treatment provider minimizes confounding social effects between physical therapists, an unblinded provider does allow for the potential of a bias in exercise progression between groups. The education programs, including videos, handouts, and review questions, are similar in length, style, and presentation of content, including the use of a script by a physical therapist to maximize consistency. All educational materials including handouts, weekly exercise records, and questionnaires will be provided through email and completed electronically by participants through an electronic data management system (REDCap). The education programs address participant knowledge on the causes of their pain as well as the overall importance of exercise to address tendon pathology. The main differentiating component will be based on the proposed mechanisms of pain. The pain education group will receive information that addresses concerns about fear of movement and pain catastrophizing, relates these psychosocial factors to their own experience with AT pain, and provides information on how tendon pathology is a potential (but not necessary) contributor to AT pain and that there is evidence that progressive loading is safe (Textbox 2). Key resources used to develop this pain education content include Explain Pain, Retrain Pain Foundation, and Cognitive Therapy for Chronic Pain [22-26]. The pathoanatomic education group will use a pathoanatomical model where Achilles tendon pathology is considered the primary contributor to pain (Textbox 3). Key resources used to develop this pathoanatomic education content include publicly available resources developed by the American Physical Therapy Association, the American Academy of Orthopaedics, and the FIFA Medical Network [14,27,28]. The fidelity of the intervention will be assessed by 2 steering committee members who will review a total of 10 recorded treatment visits and categorize them based on presumed participant group allocation and with a confidence rating of 0 (not confident at all) to 5 (completely confident) for the ability to determine participant group.

Each participant will receive the same standardized therapeutic exercise program where progression will be individualized to each participant based on pain levels, the physical therapist’s clinical judgment, and predetermined physical function criteria (Multimedia Appendix 1). The exercise intervention is based on evidence supporting the use of isometric exercise as a safe starting point for tendon loading and for pain relief as well as progressive isotonic tendon loading and restoring the spring-like function of Achilles [14,29,30]. The exercise program will consist of 4 phases with a progressive increase in tendon loading beginning with isometrics, progressing to concentric/eccentric heel raises, a functional spring phase, and a self-selected exercise routine (Figure 2). Throughout study participation, we will monitor the pain level using the 11-point verbal numeric pain rating scale. If a participant has 4/10 pain, then we will offer them to take a break or modify the activity. Blood pressure will be assessed before and after initiating aerobic activity during the spring phase with in-person visits. Participants will not be eligible for telehealth visits if they report symptoms indicating the need for in-person blood pressure monitoring, including (1) inconsistent use of hypertension medications and/or (2) any recent/current associated symptoms with uncontrolled hypertension. Exercise will be stopped according to the American College of Sports Medicine guidelines [31]. Participants will be asked to refrain from other invasive and noninvasive interventions during enrollment, including surgery, injection at the Achilles, and other forms of rehabilitation. Participants will be offered the option of follow-up visits via a telehealth format. This option will be provided to participants who are unable to attend owing to illness, limited transportation, or any other circumstance that may restrict the participants’ ability to complete in-person visits.

Outcomes are described by the specific aim and timeframe collected in Tables 2 and 3. Additional outcomes collected for exploratory aims and examining the feasibility of future clinical trials are provided in Table 4. At evaluation session 1 (0 weeks) and evaluation session 2 (8 weeks), participants will complete functional testing in the following order: walking at a self-selected pace, walking at a standardized pace (Froude 4) [32], heel raises, and hops. Participants will then complete the Tampa Scale of Kinesiophobia (TSK) and Pain Catastrophizing Scale with instruction to think about any pain or discomfort in their Achilles tendon during walking, heel raises, and hopping. Participants who complete in-person evaluation sessions will conclude the session with quantitative sensory testing.

We will use a modified intention-to-treat analysis to examine the treatment effect for all outcome measures on participants based on group randomization. Characteristic comparisons will also be completed for those patients who remained in the study versus those who dropped out to determine if data at subsequent time points were consistent with missing at random data. For aim 1, we will compare differences between education groups for changes in movement-evoked pain and self-reported function from baseline to 8 weeks (primary endpoint) and 12 weeks using a linear mixed model for repeated measures. For aim 2, we will use a linear mixed model for repeated measures for intervention effect within groups on central pain mechanisms from baseline to 8 weeks. Secondary outcomes for pain, function, altered CNS nociceptive processing, psychological factors, motor control, pain, and function will be analyzed with a linear mixed model for repeated measures. Demographics, ultrasound imaging, and treatment history will be used to describe the sample and will be covariates in the analysis if different between groups. Secondary analyses of sex will examine for potential sex-based differences to inform sample size estimates for future clinical trials. Another secondary analysis of AT type (midportion vs insertional) will also be assessed to inform recruitment strategies for future clinical trials.

Exploratory aims 1 and 2 will examine whether changes in participant knowledge of pain education and central pain mechanisms, including altered CNS regulation of nociceptive input, changes in fear or pain beliefs, and improved motor function are associated with pain and function. For exploratory aim 1, we will use Pearson correlations between changes in knowledge from baseline to final evaluation (percentage of correct responses to pain education multiple choice questions) and changes in pain and function separately. For exploratory aim 2, we will examine Pearson correlations between changes in central pain mechanisms and changes in pain and function separately.

To evaluate the feasibility of future clinical trials, we will use descriptive statistics to assess patient retention, participant recruitment numbers, treatment fidelity, and patient adherence to their exercise program. To evaluate for potential confounders of treatment effect between groups, we will assess differences in duration of treatment sessions, time spent completing their HEP, time participants spent in each phase of their exercise program, percentage of participants who believed they were receiving the education program that the research team believed to be more effective, and the highest level reached within each exercise phase (half body weight, body weight, and machine weight) using two independent samples t tests, Wilcoxon rank-sum test for continuous variables, or Chi-square or Fisher exact test for categorical variables, as appropriate.

From March 17 to July 15, 2020, in-person human subjects research was suspended in accordance with the University of Iowa policy related to COVID-19. We conferred with the Data Safety Monitoring Board (DSMB) and the safety officer on protocol changes to continue the clinical trial via telehealth. These protocol changes were approved by the IRB at University of Iowa on March 17, 2020. The intervention content and the primary outcomes of movement-evoked pain and self-reported function were not altered, yet the transition to a virtual format affected screening, evaluation, and mode of delivering treatment as outlined below. Participants who did not pass the additional virtual screening questions were categorized as delayed owing to COVID and rescreened once in-person human subjects research resumed.

All patient data will be stored in electronic records kept on a network drive of the Department of Physical Therapy and Rehabilitation Science at the University of Iowa and on REDCap. Access will be restricted to only the research team who will comply with the confidentiality of patient information consistent with the Health Insurance Portability and Accountability Act guidelines. An independent safety officer will review all AEs, serious AEs, unanticipated problems, and any protocol deviations affecting safety on a quarterly basis. The DSMB will meet yearly with the study team. The DSMB will convene annually to review the data, recruitment, and safety of subjects. This review will include a discussion of the allocation concealment process to ensure that concealment is done at the last minute and review of records to ensure that the proper random sequence was used. The review will also include reports of AEs, serious AEs, protocol deviations or violations, and unanticipated problems. Recruitment and retention will also be reviewed.

Funding for this study was provided by the National Institute of Arthritis Musculoskeletal and Skin Disease research grant R00 AR071517 and the Collaborative Research Grant from the International Association for the Study of Pain (IASP). Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR002537. These funding sources had no role in the study design, collection, analysis/interpretation of data, or decision on submission for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Institutional review board approval was obtained on March 15, 2019, and study funding began on July 1, 2019. The TEAch study began enrollment on September 17, 2019. As of March 2020, we randomized 23 out of 66 participants. In September 2020, we screened 267 individuals, consented 68 participants, and randomized 51 participants. We anticipate to complete the primary data analysis by March 2022 and will submit the results for primary outcomes no later than 1 year after the primary completion date on ClinicalTrials.gov (NCT: 04059146) and Open Science Framework (JF2XU).

In compliance with FAIR (findability, accessibility, interoperability, and reusability) data principles, data will be deposited at the University of Iowa open-access institutional repository, Iowa Research Online. The repository is open access and maintained by the Libraries at the University of Iowa for the preservation and sharing of intellectual work of faculty, students, and staff. The IPD will be available to other researchers for the primary outcomes. Data sets will be accompanied with appropriate descriptive, technical, and administrative metadata to facilitate discovery and scholarly reuse, and will be assigned unique digital object identifiers (DOIs) that can be incorporated into publications and cited in the literature. Metadata will be included in the data records in the repository through readme files and structured information following the DataCite metadata schema.