Knee osteoarthritis (KOA) is one of the leading causes of chronic pain and disability worldwide, affecting over 30% of older adults. It 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 body mass index (BMI). Surgery is often employed to treat KOA, but it 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. However, standalone conservative treatments including non-opioid medications and joint injections provide only limited pain relief and functional improvement in a subset of knee OA sufferers. This has led to a high rate of opioid use and disability in this population. 

The overarching goal of this study is to conduct a sequential parallel group randomized controlled trial (RCT) to evaluate the comparative effectiveness of conservative behavioral and non-opioid pharmacological treatments (Phase 1) and, among those that indicate interest in obtaining further treatment and those inappropriate for conservative treatment, the benefits of procedural interventions (Phase 2). This study will also evaluate whether clinical and psychosocial phenotypes predict short- and longer-term treatment response. 

The results of this study, which will follow pragmatic principles in order to maximize the information provided to stakeholders, will examine not only the effectiveness of each tested intervention but also provide meaningful information regarding effectiveness across key subgroups of participants. The knowledge gained will contribute to the development of translatable therapeutic strategies for the treatment of KOA pain that will lead to opioid sparing.