PROJECT SUMMARY/ABSTRACT Knee osteoarthritis (KOA) is one of the leading causes of chronic pain and disability worldwide, affecting over 30% of older adults, and represents a major global health and economic burden to individuals and society. The rates of KOA have more than doubled in the past 70 years and continue to grow sharply, given increases in life expectancy and population BMI. Surgery is often used to treat KOA, but is associated with a high rate of persistent pain and is not a permanent solution. Numerous nonsurgical therapies have been advocated to treat pain in patients with KOA. A growing literature documents enhanced central nervous system pain processing, known as central sensitization (CS), which produces widespread sensitivity, among KOA patients. Sleep disturbance is associated with CS but imparts a terrible burden on patients suffering from pain in its own right. Both CS and sleep disturbance are hallmarks of various chronic pain conditions and important treatment considerations, with both independently being associated with the initiation and maintenance of pain and heightening pain severity . The parent project, which provides the platform for the current proposal, will evaluate behavioral, pharmacologic, and procedural interventions for KOA; a step-care model that allows for multiple treatment comparisons and phenotyping to improve selection for each therapy, which is expected to refine outcomes and reduce unnecessary interventions. The results of this study, which will follow pragmatic principles in order to maximize the information provided to stakeholders, will address not only the effectiveness of each tested intervention but also provide meaningful information regarding effectiveness across key subgroups of patients. However, the parent project will not assess CS or sleep disturbance, due to the additional expertise, expense, equipment and time required. A mechanistic evaluation of these factors is required to substantiate their impact on treatment response. The current proposal seeks to substantiate whether the conceptual understanding of these factors is legitimate. The project will also evaluate whether advanced understanding of CS and sleep disturbance are important contributions on top of the more easily quantified phenotypes collected in the parent project. The knowledge gained will inform patient phenotyping to better match patients with effective interventions, ultimately reducing the substantial heterogeneity across intervention outcomes and reliance on opioid therapies.