Immune mechanisms of Vitamin D in a randomized controlled trial to reduce chronic pain after burn.

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Project Summary/Abstract Each year in the US ~500,000 individuals seek care after burn injury, and ~40,000 sustain major thermal burn injury (MThBI) requiring hospitalization. Approximately three-quarters of hospitalized MThBI survivors require skin grafting, a surgical procedure in which skin or another material is applied to the burn injury site (graft site). More than half of individuals who receive a skin grafts develop severe unremitting graft site pain. New non-opioid interventions to improve pain outcomes in MThBI survivors receiving skin graft are urgently needed. Importantly, the scientific community has increasingly recognized that investing millions in traditional RCTs, that provide only a “thumbs up or down” result, is a poor scientific investment. RCTs provide far greater value when (1) interventions have been shown to effectively engage targeted biological mechanisms are tested, and (2) the trial assesses whether hypothesized mechanisms mediate any observed therapeutic effect. During my K12 award, I gained valuable skills and training in the conduct and analysis of traditional randomized controlled trials (RCTs), and experience conducting research in the MThBI population. In addition, data obtained from my pilot intervention trial testing the ability of vitamin D (vit D) to improve MThBI pain outcomes support the safety, feasibility, and exciting potential of this natural product intervention to reduce or prevent chronic pain after MThBI. Vit D is a promising, low-cost, widely available intervention with potent anti-inflammatory and neuroprotective properties. Vit D has been shown to have powerful effects on immune cell populations, and has been demonstrated to improve pain and related outcomes across a range of neuro/inflammatory disorders. This 3-year NCCIH K23 will build upon my K12 training, and will provide me with the necessary skills and experience to conduct a “state-of-the-art” mechanistic trial of vit D in MThBI survivors. Specifically, during the K23 I will learn to apply the latest mass cytometry methods to serial blood samples obtained from RCT participants to evaluate the degree to which increases in circulating vit D levels result in (1) increases in anti-inflammatory monocyte phenotypes and regulatory T cells, and (2) reduction in pro-inflammatory toll-like receptor 4 signaling and effector T-cells (e.g., Th1 and Th17 cells). In addition, I will learn to use advanced statistical methods (elastic net algorithms and multiple parallel mediation models) to evaluate whether these immune cell changes mediate treatment effects, adjusting for any baseline differences in key psychosocial factors. The study of immune mechanisms of chronic pain development is a rich, exciting, burgeoning area of science. Proposed K23 activities are not only ideal for evaluating vit D target engagement and mechanistic hypotheses in MThBI survivors, but will also provide me with an excellent foundation of skills for a career as an NIH-funded chronic pain researcher and clinical trialist. In sum, the skills and training obtained during my 3-year NCCIH K23 will transition me from a “thumbs up or down” clinical trialist to one capable of interrogating engagement of immune mechanisms and testing specific hypotheses regarding innate and adaptive immunity.