Personalized Analgesia Through Central Nervous System Engagement to Unlock Performance

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 \<=30 mg OME does not exclude the participant).
* New treatment that may help knee osteoarthritis (including medication, exercise, behavioral, or complementary and integrative treatments) started in the last month. Stable use of treatments for greater than 1 month does not exclude the participant.
* Unwillingness to maintain current knee osteoarthritis treatments for the duration of the study. This means that eligible participants must plan for the following: medications and dietary supplements should not change substantially in frequency or dose; behavioral therapy, exercise therapy, and complementary and integrative therapies should be consistent; and there should be no interventional treatments planned for lower extremity musculoskeletal conditions (e.g. joint steroid injections, knee radiofrequency ablation, knee replacement surgery).
* Recent knee intra-articular injection of steroid or other agent (greater than 1 month does not exclude the participant)
* Recent knee radiofrequency ablation (greater than 3 months does not exclude the participant)
* Recent knee arthroscopic surgery (greater than 3 months does not exclude the participant)
* History of knee replacement or open knee surgery on the index knee, defined as the more painful knee on average over the last month.
* Inability to walk or climb stairs without significant assistance (e.g. a one-person assist, use a wheelchair; use of a cane does not exclude the participant).
* Inability to participate in study procedures (e.g. cognitive impairment limiting ability to understand directions, inability to understand and read English)
* Uncontrolled or unstable medical disorder preventing participation in study procedures
* History of brain surgery
* Tattoos on sensory testing sites
* Pregnancy
* History of severe renal impairment defined by GFR \< 30 ml/min or, if renal function testing is not available on EMR review, patient-reported history of acute or chronic kidney disease of any severity
* History of chronic liver disease or cirrhosis
* History of angle-closure glaucoma