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chronic pain, fracture, pain phenotype, RNA sequencing



  1. Griffioen, Mari A.
  2. Glutting, Joseph
  3. O'Toole, Robert V.
  4. Starkweather, Angela R.
  5. Lyon, Debra
  6. Dorsey, Susan G.
  7. Renn, Cynthia L.


Background: Traumatic injury is a major source of chronic pain, particularly for individuals with traumatic fracture of the fibula and/or tibia (lower extremity fracture [LEFx]). Although several factors (e.g., older age, being female, high pain intensity at time of initial injury) have been identified as risk factors for chronic pain associated with LEFx. Comprehensive biopsychosical models to predict the odds of transitioning from acute to chronic pain after LEFx are needed to better understand the underlying processes, predict risk for chronic pain, and develop personalized therapies for individuals at higher risk for developing chronic pain.


Objective: The aim of the study was to outline the study design that will be used to examine the physiological, psychological, and genetic/genomic variables-models that predict the transition from acute to chronic pain after LEFx.


Method: This prospective descriptive cohort study will enroll 240 participants with a fibula and/or tibia fracture and 40 controls with no LEFx. Data will be collected during an in-hospital baseline visit, five in-person clinic visits (6 weeks, 12 weeks, 24 weeks, 52 weeks, and 24 months), and seven online between-visit surveys (2 weeks, 4 weeks, 8 weeks, 10 weeks, 16 weeks, 20 weeks, and 18 months) from participants with LEFx and at concordant intervals from controls. Measures will consist of 19 questionnaires characterizing pain and psychological status, neurophysiological testing for peripheral sensory nerve function, and peripheral blood samples collections for RNA sequencing. Illumina standard protocols will be used to sequence RNA, and read counts will be used to measure gene expression.


Analysis: Direct-entry, multiple logistic regression will be used to produce odds ratios expressing the relative risk on each explanatory variable when controlling for other predictors/covariates in the model.


Conclusion: This study is one of the first to longitudinally characterize the biopsychosocial variables associated with a clinically relevant problem of the transition from acute to chronic posttraumatic fracture pain in individuals with LEFx. Results from this study will be used to construct predictive risk models of physiological, psychological, and genetic/genomic variables associated with increased risk for transitioning from acute to chronic pain status after LEFx. This work will lead to a better understanding of the trajectory of pain and relevant variables over time; initiate a better understanding of variables associated with risk for transitioning from acute to chronic pain; and, in the future, could provide a foundation for the identification of novel therapeutic targets to improve the outcomes of individuals with LEFx.