Research

Total knee arthroplasty (TKA) is an increasingly common surgical procedure in older adults. Although effective for many patients, 15% or more experience unsatisfactory pain outcomes. While limited to post- surgical chronic pain in some patients, others also develop regional allodynia and hyperalgesia, edema, and autonomic features indicating Complex Regional Pain Syndrome (CRPS), a particularly difficult to treat chronic pain condition. The mechanisms of post-TKA chronic pain and CRPS are not well understood. The most common TKA procedure involves application of a tourniquet to the operated limb for extended periods (up to ≈2 hours). Animal models indicate that extended tourniquet application followed by reperfusion when the tourniquet is removed leads to ischemic reperfusion injury, which via increased oxidative stress, can result in prolonged neuropathic pain and clinical features of CRPS. One key objective of this project is to examine for the first time in humans the impact of baseline and perioperative oxidative stress, as indexed by F2- isoprostanes, on long-term pain, CRPS, and functional outcomes following TKA. One known predictor of post- TKA chronic pain is greater preoperative negative affect (specifically, depression and anxiety). Emerging literature suggests that elevated depression and anxiety may be associated with elevated oxidative stress levels. This project tests a novel theoretical model that integrates these disparate research areas by determining whether the influence of depression and anxiety on post-TKA chronic pain outcomes is conveyed in part through oxidative stress mechanisms. If hypotheses are supported, results will highlight a novel mechanism of post-surgical chronic pain and CRPS that is potentially amenable to pre-emptive intervention, and enhance understanding of mechanisms through which psychosocial factors impact on subsequent postsurgical pain-related and functional outcomes. The project team is comprised of investigators with complementary multidisciplinary expertise in chronic pain, CRPS, measurement and health effects of oxidative stress, TKA procedures, and prospective study designs. This study aims to enroll 150 unilateral TKA patients all experiencing similar tissue trauma during the course of surgery. Pain, CRPS symptomatology (using a validated continuous CRPS severity score), depression and anxiety symptoms, function, and plasma levels of F2-isoprostanes will be systematically assessed at pre-TKA baseline, intraoperatively, for two days post-surgically, and at 6 week and 6 month follow-up. Analyses will utilize the prospective nature of the data to examine the impact of baseline and perioperative oxidative stress on subsequent chronic pain, CRPS, and functional outcomes. Mediation analyses will be used to test whether depression and anxiety impact on long-term post-TKA pain, CRPS, and function in part via oxidative stress mechanisms. Results have the potential to enhance understanding of the mechanisms of post-surgical chronic pain and CRPS, and guide development of mechanism-based preventive interventions for both.

Chronic low back pain (CLBP) is a major public health concern. Complementary/integrative (C/I) chronic pain interventions have proliferated (eg, Mindfulness Training [MT], spinal manipulation therapy [SMT]), and some approaches have strong support for efficacy. Most research has focused on questions regarding treatment efficacy. However, important questions regarding treatment mechanisms have been neglected. A parsimonious approach to uncovering C/I treatment mechanisms may start from the hypothesis that C/I treatments work to a large extent via non-specific mechanisms that may be shared across treatments. Candidate non-specific mechanisms can be grouped into at least 3 categories: endogenous pain inhibitory systems (endogenous opioid function; conditioned pain modulation), pain-related cognition (pain catastrophizing; self-efficacy), and therapy factors (therapeutic relationship, patient expectations). The general hypothesis is that treatment-induced changes in these non-specific mechanisms will predict outcomes across different C/I interventions. At the same time, the contribution of specific mechanisms must be addressed. For MT, this would be changes in mindfulness, whereas for SMT, this would be changes in spinal stiffness. The proposed study will compare the degree to which MT and SMT activate specific and non-specific mechanisms, and the degree to which these mechanisms affect pain-related outcomes. Comparing the activation and effects of mechanisms in these 2 interventions in a single trial will allow us to test the degree to which effects of certain mechanisms are shared across treatments or are unique to a given treatment. 240 people with CLBP will be randomly assigned to MT, or SMT. All mechanism and outcome measures will be assessed frequently across all treatments. We expect the 2 treatments to produce significant changes in pain, mood and function. Aim 1 will test to what degree MT and SMT produce changes in non-specific mechanisms. Aim 2 will test to what degree MT and SMT produce changes in treatment-specific mechanisms (MT: mindfulness; SMT: spinal stiffness). Aim 3 will test to what degree changes in non-specific and specific mechanisms predict changes in pain, mood and function, and whether these relationships depend on the treatment received, and the degree to which changes in non-specific and specific mechanisms account for unique and shared variance in predicting outcomes. Addressing questions of mechanism is critical to the science and practice of C/I pain interventions because it: (1) tests theory validity, (2) provides empirically-supported rationale for asking people with pain to devote the resources needed to participate in treatment, (3) identifies the effective mechanisms of pain treatments and reveals those that may be redundant or inert, and (4) provides theoretical and empirical principles by which to enhance those C/I mechanisms that are most closely linked to the largest benefits.

Chronic pain (CP) affects up to 100 million individuals in the U.S. alone. Management of CP has increasingly relied upon high-dose chronic opioid therapy, with this change paralleled by increasing numbers of individuals affected by opioid abuse, and dramatic rises in opioid-related overdose and death. While providing effective pain relief for many, approaches proven to reduce reliance upon high-dose chronic opioids are sorely needed. We have recently identified links between endogenous opioid (EO) function and responses to opioid analgesic medications. Our findings are consistent with an Opioid Supplement Model, in which opioid analgesic medications may serve to supplement natural EO levels to maximize opioid receptor-related pain inhibition. This model has important clinical implications, as it suggests that desired levels of pain relief might be achieved not by high-dose opioid analgesics alone, but rather by a combination of nonpharmacological strategies that enhance EO function with lower dosages of opioid analgesics, potentially mitigating side effects and risks associated with opioid analgesics. This project seeks for the first time to directly test the Opioid Supplement Model in 116 individuals with chronic low back pain. Specific aims are: 1) determine whether an aerobic exercise manipulation reduces evoked and chronic pain responsiveness via enhanced EO function, 2) determine whether this exercise manipulation permits achieving targeted levels of pain relief at lower opioid analgesic dosages through its effects on enhanced EO function, and 3) whether changes in Aim 2 are associated with reduced side effects and abuse-relevant drug effects (drug liking, high, euphoria, etc.). This project will incorporate a unique combination of expertise and methodologies to achieve these aims, including a randomized, controlled 6 week aerobic exercise training manipulation, assessment of pre- to post- manipulation changes in daily chronic back pain intensity based on electronic diaries, and controlled laboratory assessment of pre- to post-manipulation changes in EO function (indexed by effects of opioid blockade on evoked pain responses relative to placebo condition) and opioid analgesic responsiveness (to a series of incremental morphine doses). If hypotheses are confirmed, results could substantially alter CP management by facilitating mechanism-based strategic combinations of nonpharmacological and pharmacological pain therapies to achieve acceptable pain relief with fewer side effects and reduced abuse risk. Findings would also add important knowledge to the sparse human literature regarding links between CP, EO function, and responses to opioid analgesics, knowledge with important implications for achieving the goal of personalized pain medicine. Project results would potentially lead to changes in clinical practice with significant population level benefits, given he frequency with which chronic high-dose opioids are currently used and their increasingly recognized negative sequelae.

Dr. Stone has several ongoing projects and collaborations evaluating pain and opioid use outcomes in children following routine tonsillectomy and adenoidectomy (T&A) procedures. Currently, we are trying to better understand what factors influence parents' decisions regarding pain management strategies (e.g., complementary and alternative medicine, prescription pain medicine, over the counter medications). Ultimately, the goal of this line of research is to develop tools to help improve at home pain management following pediatric surgery.

This study will prospectively evaluate mechanisms of intergenerational transmission of risk for chronic pain by extending a landmark database of pediatric patients with functional abdominal pain and pain-free youth followed from childhood into early adulthood (Vanderbilt FAP Cohort, established by Lynn Walker, Ph.D.) to include data from participants who have become parents in the years since their previous assessment. Participants who participated in the 10-year follow-up study (n = 583) now average 30 years of age. Those with children will be invited to participate in a third wave of data collection. This project was recently funded by a 2019 IASP Early Career Grant.