Personalized Analgesia Through Central Nervous System Engagement to Unlock Performance

The goal of this clinical trial is to examine the effects of duloxetine on walking ability and physical activity in patients with knee osteoarthritis. Researchers will compare duloxetine to a placebo (a look-alike substance that contains no drug) to see if duloxetine works to improve walking ability in patients with knee osteoarthritis. At study visits, participants will complete surveys, perform physical function tasks, undergo non-invasive brain imaging, and undergo sensory testing.

Inclusion Criteria: * Knee pain for greater than 6 months. * Moderate-to-severe knee pain (\>3/10) due to osteoarthritis, as defined by American College of Rheumatology and EULAR diagnostic criteria (Zhang 2010, Altman 1986) on \>50% of days in the past month. * KL grade 2-4 (Kellgren and Lawrence 1957) indicating significant degenerative changes on knee X-ray. This will be determined on evaluation of weight-bearing clinical X-rays on review of medical records. In the infrequent situation that the patient does not have an X-ray on review of their medical records, then the patient will obtain weight-bearing knee X-rays as part of the Screening Visit. * Age: 45-80 years old * Gender: Males and females will be recruited. * Language: only English-speaking subjects will be included. Exclusion Criteria: * Inflammatory arthritis (e.g. rheumatoid arthritis). * More intense pain due to another chronic pain syndrome (e.g. fibromyalgia, hip osteoarthritis) * Significant pain or weakness in the lower extremities due to a neurological condition (e.g. lumbar radiculopathy, paresis due to stroke) * New, ongoing acute pain * Recent use of duloxetine defined as any use within the last 3 months * Current use of antidepressants or tramadol * Current routine use of more than 30 mg oral morphine equivalents per day (use of \