Immunological Contributions to the Chronification of Pain
Abstract
Chronification of Pain Knowledge Gap: This project addresses all three major priorities emphasized by CDMRP as knowledge gaps in our understanding of pain chronification. (1) Understanding mechanisms and developing models for studying the transition from acute to chronic pain following trauma either physical or psychological. Our project addresses a clear hypothesized mechanism supporting pain chronification. This mechanism is rigorously tested in a laboratory model translatable to human patient populations. (2) Development of non-opioid therapies to prevent and treat chronification. Our study preclinically evaluates two unique approaches to the prevention of pain chronification, all amenable to clinical translation. (3) Identification of risk factors or biomarkers for patients at risk of chronification including at risk sub-populations. Our project focuses on the measurement of pain-related autoantibodies as biomarkers of the risk of pain chronification. Objectives and Rationale: The chronification of pain after trauma, including military and civilian injuries, is common, results in suffering and poor functional recovery, and delays return to normal activities. It is now well-recognized that pain after surgery of many types with accompanying bone and soft tissue injuries also frequently results in pain that undergoes chronification. Trauma to the extremities is particularly common and strongly linked to poor pain and functional outcomes as are major, e.g., joint replacement, and minor, e.g., hand soft tissue, operations. Between 20% and 80% of such patients experience the chronification of their acute post-traumatic pain. Worse, the chronification of acute pain supports adverse neuropsychological outcomes of injury including depression, anxiety, and cognitive decline. The dysregulation of immune system activation after trauma is novel mechanism supporting pain chronification for which evidence is rapidly accumulating. The main objective of this research is to explore a rapidly deployable method of reducing immune system activation occurring at the time of injury to prevent the chronification of acute pain and downstream adverse outcomes. This approach may be applicable to Soldiers with battlefield injuries, Veterans and civilians suffering limb traumas, and all patients undergoing surgeries on their extremities. The specific treatments under study are diverse, allowing for the selection of the most appropriate treatment under specific circumstances. The approach less profoundly affecting immune system function (vitamin C) might be used for battlefield and other low resource environments while the more aggressive approach (dimethyl fumarate) might be selected in well-supported hospital settings. The former approach uses an inexpensive drug, and both medications would be relatively straightforward to implement without special equipment. A second sub-aim of the work uses additional drugs and tissue analyses to establish the production of antibodies directed against injured tissues as an important cause of pain persistence after trauma. By better establishing this mechanism of pain chronification, we will be in position to monitor biomarkers of the development of chronic pain and identify additional approaches to preventing such pain. Contributions to chronic pain research, patient care, and quality of life for chronic pain sufferers: The trauma-related immune activation hypothesis is a major new innovative hypothesis being pursued by leading pain research laboratories including our own. We have established some of the field’s most widely accepted trauma pain preclinical models, and we have completed both translational and clinical outcome studies in this area often using the surgical setting as our test environment. The proposed work advances our knowledgebase regarding pain chronification by focusing on mechanisms regulating immunity after trauma oriented towards discovering therapeutic a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010911
Entities
People
- David B. Clark
Organizations
- United States Army
- VA Palo Alto Health Care System