Revealing the Progression of Pain Pathways and Identifying Chronification Of Pain Predictors After an Isolated Lateral Ankle Sprain: Project RECOIL

TITLE: REvealing the Progression of Pain Pathways and Identifying Chronification Of Pain Predictors After an Isolated Lateral Ankle Sprain: Project RECOIL Alignment to CPMRP Intent A lateral ankle sprain (LAS) is one of the most pervasive musculoskeletal conditions within the United States Military that limits the operational readiness of active-duty Service members and increases the risk for early separation from service.1 Our clinically oriented study will address the FY22 Chronic Pain Management Research Program (CPMRP) Investigator Initiated Research Award (IIRA) Focus Area of Chronification of Pain by 1) identifying risk or protective factors for a military population susceptible to pain chronification, and 2) investigate the relationship between pain and co-morbidities that contribute to pain chronification. Our study meets the intent of the FY22 CPMRR IIRA because it 1) impacts the understanding of more than one Focus Area, 2) is innovative by looking at an existing problem from new a perspective, 3) includes preliminary data, 4) involves a multidisciplinary team constructed from both military & non-military investigators, 5) is relevant to military health by collaborating with a Military Treatment Facility to focus on a highly prevalent condition and, 6) considers stakeholder engagement through patient-reported outcomes (PROs). Scientific Rationale and Approach A. Pressure Pain Thresholds Across the B. The Star Excursion Balance Test A LAS was the number one reason for lost duty days Anterior Talofibular Ligament of the Affect Pain Pressure Threshold (kg/cm2) Percent Leg Length (%LL) 100 p = 0.045 p = 0.041 within the United States Military between 2017 and 2018.2 The Limb 90 p 0.287 best available data indicates that 40% of Service members report persistent pain 6-months post-LAS,3 which mimics civilian- 5 p = 0.013 based estimates.4 Individuals who develop persistent ankle pain 4 80 report moderate intensity levels that interfere with walking, running, and vigorous activities.4 As a result, retrospective data 70 have suggested persistent pain is the leading symptom that limits 3 60 operational readiness post-LAS and is a primary reason for early separation from service.1 Our data builds upon these findings by 50 showing chronic ankle pain is associated with prolonged levels 2 40 of peripheral sensitization (Figure 1A). Also, our data shows chronic ankle pain leads to abnormal walking mechanics (not 30 pictured), decreased balance (Figure 1B), and worse fear of 1 20 injury, physical health, and emotional well-being (Figure 1C). 10 Yet, significant gaps in knowledge exist for the basic epidemiology of chronic ankle pain, the evolution of pain 0 0 Chronic Pain (n = 6) No Pain Anterior Posteromedial Posterolateral (n = 7) Chronic Pain No Pain (n = 9) (n = 13) C. The Fear-Avoidance Belief Questionnaire (FABQ) and the modified Disability in the Physical Active (mDPA) p = 0.034 50 p = 0.006 45 40 Total Sum 35 30 25 p = 0.004 20 15 10 5 0 Chronic Pain No Pain Chronic Pain No Pain Chronic Pain No Pain (n = 23) (n = 20) (n = 23) (n = 20) (n = 23) (n = 20) FABQ mDPA Physical mDPA Mental Figure 1. Preliminary data showing the tissue responsible for (A.) generating chronic ankle pain, and its (B.) effect on dynamic balance and (C.) quality of life. generating pathways post-LAS, or how changes in clinician and patient outcomes after a LAS interact with co- morbidities and contribute to the chronification of ankle pain. Prospectively evaluating such outcomes can yield valuable insight for identifying risk or protective factors for patients who are susceptible to chronification – a vital component to developing personalized therapies at critical windows of opportunity. The long-term goal for our multidisciplinary team is to improve the quality of life and level of function for all Americans by reducing pain and disability after a LAS through rehabilitation. The overall objectives of this application are to use the Heuristic Model of Pain as an established model for pain assessment to 1) quantify the prevalence rate of chronic ankle pain and the healthcare utilization patterns after a LAS, 2) assess the trajectory of clinically oriented pain pathways, and 3) examine the relationships between chronic ankle pain, co-morbidities, clinician outcomes, and PROs. Our central hypothesis is those who report chronic pain at 6- and 12-months after a LAS will have received less healthcare services, have prolonged levels of high pain facilitation, and a greater number of comorbid conditions, functional deficits and lower PROs will be predictive of chronic pain. The following Specific Aims of this prospective study will be met: Specific Aim #1: Quantify the prevalence rate of chronic ankle pain and healthcare utilization patterns at 6- months and 12-months after a LAS. Prevalence of chronic pain will be determined by the number of participants who experience ankle pain on at least half of the days for 6-months. Healthcare utilization will be quantified according to the number of physical rehabilitation visits linked to the initial injury. Hypothesis 1.1: At 6-months, 30% of participants will self-report chronic ankle pain. At 12-months, 25% of participants will self-report chronic ankle pain. Hypothesis 1.2: Less healthcare utilization will be associated with the development of chronic pain at 6- and 12-months post-LAS. Specific Aim #2: Compare mechanical pain sensitivity levels, pain facilitation and inhibition levels between participants who do and do not develop chronic pain at 6- and 12-months after a LAS. Quantitative Sensory Testing (QST) techniques will be used to assess mechanical pain sensitivity via pressure pain thresholds, pain facilitation via temporal summation, and pain inhibition via a conditioned pain modulation response at baseline (i.e., within 2 weeks of injury), 3-months, and at 6-months post-LAS. Hypothesis 2: Participants who develop chronic pain will exhibit decreased pressure pain thresholds, elevated levels of pain facilitation, and lower levels of pain inhibition at baseline, 3-months, and 6-months post-LAS. Specific Aim #3: Identify comorbid conditions, clinician outcomes and patient-reported outcomes that are predictive of chronic ankle pain at 6-months and 12-months after a LAS. A history of physician diagnosed comorbid conditions (i.e., insomnia, sleep apnea, depression, etc.) will be recorded at baseline. Clinician (i.e., dynamic balance) and PROs (i.e., surveys assessing ankle function, pain interference in emotional and physical functioning, and pain qualities) will be collected at baseline (i.e., within 2 weeks of injury), 3-months, and 6-months post-LAS. Hypothesis 3: Greater number of comorbid conditions, worse clinician outcomes, and lower PROs post-LAS will be predictive of chronic pain at 6- and 12-months. Study Design: A prospective study design will be used to recruit University of Womack Army participants (18-45 years of age) from the University of Kentucky Kentucky Medical Center (UK) and Womack Army Medical Center (WAMC). Patients with Acute Lateral Ankle Sprain Participants: A total of 200 Service members and Civilians Prospective Data Collection Timeline diagnosed with an isolated acute LAS will be enrolled. Based on 3-Month 6-Month 12-Month Baseline billing data, ~548 patients are treated annually within the UK Specific Aim 1 • Chronic pain prevalence rate Healthcare system and ~1,030 at WAMC for an isolated ankle sprain. Specific Aim 2 • Healthcare utilization patterns Sample Size: We hypothesize 30% of participants will develop Specific Aim 3 • Pressure Pain Thresholds chronic pain at 6-months. Thus, 167 participants are needed to • Pain Facilitation Level identify predictors of chronification using 5 covariates (comorbidity • Pain Inhibition Level index, clinical outcomes, PROs). To account for 15% attrition, 200 participants will be enrolled (i.e., 100 participants at each site). • Physician Diagnosed Comorbidities • Clinician Outcomes Outcomes: The primary outcome will be pain chronification at 6- and 12-months post-LAS. Secondary outcomes will include healthcare • Star Excursion Balance Test utilization, QST techniques, history of comorbid conditions, clinician • Hop-to-Stabilization • Walking Plantar Pressure • Patient-Reported Outcomes • Foot & Ankle Disability Index • Brief Pain Inventory Scale • Defense & Veterans Rating Scale • Short-Form McGill Pain Questionnaire • Disablement in the Physically Active Scale • Fear-Avoidance Beliefs Questionnaire outcomes, and PROs (Figure 2). Our research team has extensive Figure 2. Study Design, Endpoints, & Outcomes experience collecting these outcomes,5-13 and preliminary data as supporting evidence. Impact A LAS is the most common joint injury sustained by the general public (?2 million per year)14 and military personnel during training or combat.15 Many Service members who sustain a LAS seek care up to 120 days post-injury because of pain, swelling, or loss of function.16 The financial costs of treating a Service member, Veteran, or dependent with a LAS (~$3400 per patient-year) make this injury a lead source of burden and expenditures within the Military Health System. Unfortunately, the odds of a recurrent injury,16 developing a chronic condition,17 suffering a diminished quality of life,10, 13 or experiencing functional limitations5, 12, 18 can increase if a patient fails to receive timely rehabilitation and cause added healthcare expenditures (~$1400 per episode).16 Thus, our proposed research will make a significant impact on improving the quality of life and level of function for a highly prevalent health condition in the general public and military populations. Prospective studies to identify susceptibility and resilience factors underlying the transition from acute- to-chronic pain for the most prevalent and costly conditions is a top priority listed in the Federal Pain Research Strategy. Our proposed research will generate a substantial step towards achieving this priority by prospectively evaluating pain pathways, clinician and patient-reported risk factors, and the economic impact underlying the transition from acute-to-chronic pain after a LAS. Our proposed research will immediately impact patient care and improve the quality of life for all Americans by identifying early modifiable factors that can be targeted with current treatment strategies and critical timepoints to intervene for reducing the risk of developing chronic pain. Additionally, our research will have a long-term impact by generating new avenues to test innovative impairment-based therapies that treat the whole person for quicker resolution of acute pain to improve the medical readiness of Service members, as well as the quality of life and level of function of all Americans.