Abstract Great variation exists in opioid consumption after similar surgeries, with some patients using few opioids while others consume opioids well beyond the expected acute pain episode. Prolonged opioid use is considered one of the most common surgical complications. Recent models developed to predict the variability in postoperative opioid use focus primarily on clinical and psychological survey data, but leave a significant proportion of the variability unexplained. As it is unclear whether prolonged opioid use results from prolonged pain or other factors, this project proposes to extend the previous research by prospectively examining important pain sensitivity and biomarker predictors of pain to determine their effect on opioid use. Pain is a biopsychosocial phenomenon, so the inclusion of these important biological variables will lead to increased mechanistic understanding of postoperative opioid consumption variability and enable better management of postoperative pain by providing potential new therapeutic targets. One such understudied variable is an individual’s underlying pain sensitivity, measurable by quantitative sensory testing (QST). Use of QST to predict inpatient opioid use and pain has led to inconsistent findings, but recent studies highlight a promising role for QST to predict postoperative home opioid use. Speculation has long focused on genetic influences as a factor in variability in pain sensitivity and opioid use. Candidate gene and whole genome-wide studies have proven to be inadequate to study the complex trait of pain, resulting in small effect sizes and lack of reproducibility. Assessing gene expression is an approach that can be used to augment the research on postoperative pain. Gene expression analyses in blood have identified changes that confer vulnerability for the transition from acute to chronic low back pain, lending support to the hypothesis that changes in gene expression from preoperative to early and later postoperative time periods may identify early markers for the transition to prolonged postoperative pain. By integrating genetic and gene expression data, we will assess whether acute surgical pain leaves signatures in the blood that can be identified through gene expression which can influence postoperative pain sensitivity and subsequent opioid use. Our proposal focuses on the total knee arthroplasty (TKA) population, as this population demonstrates one of the highest variabilities in postoperative pain and opioid use, and is projected to increase 700% within the near future. This project proposes to innovatively incorporate standard demographic, clinical, and psychological variables with novel neurophysiological, genetic, and gene expression data to holistically examine the variability in postoperative pain, and ultimately opioid use through the biopsychosocial lens.