The goal of this clinical trial is to understand the patient and clinic visit characteristics that affect health outcomes for individuals with knee osteoarthritis (OA) pain using topical diclofenac gel. The main questions it aims to answer are:

• What baseline patient characteristics predict response to topical diclofenac?
• Does patient physiology during the study visit predict response to topical diclofenac?
• Do study visit characteristics predict response to topical diclofenac?

Participants will:

• attend 2 study visits to complete study questionnaires and have blood drawn
• apply topical diclofenac to their knee for 8 weeks
• complete biweekly questions about knee pain and diclofenac use between study visits

220 older adults with symptomatic knee OA will attend a single research clinic visit (one of four different types of study visits) with a study clinician. The investigators will video record the visits and measure participant heart rate and skin conductance during the visit. Participants will complete baseline questionnaires immediately prior to the study visit. All participants will receive diclofenac gel (a topical over-the-counter non-steroidal anti-inflammatory drug [NSAID]), a guideline recommended treatment for knee OA-related pain at the end of the first study visit. Participants will identify an "index" knee (worst pain, right or left) that they will treat and follow during the study. Between study visit 1 and the 8-week follow-up visit, participants will receive an every other week text message asking them to report on pain and diclofenac use to better understand changes in pain over time. Final questionnaires will be completed at the second study visit at week 8.

Inclusion Criteria:

• English-speaking
• 50 years of age or older
• Radiographically confirmed knee OA of K/L grade 2 or higher within the past 2 years
• Knee pain at least 15 days/month.
• Average worst daily pain 3/10 or higher over a two-week period.

Exclusion Criteria:

• Medical contraindication to taking NSAIDs such as: history of coronary artery bypass graft, myocardial infarction, coronary artery stent placement, or stroke within the past 6 months; systolic heart failure with ejection fraction <45%; chronic kidney disease stage ≥4; severe gastrointestinal bleed or stomach ulcer within the past 6 months; current pregnancy; cirrhosis; currently taking blood thinners (aspirin 81 mg daily is okay); allergy to NSAIDs or aspirin; or any other medical contraindication to using topical NSAIDs.
• Inflammatory arthritis
• Partial or total knee replacement of the index knee
• Recent therapeutic injection of the index knee (less than 12 weeks)
• Planned knee/lower limb surgery during the two-month study period
• Active cancer treatment not in remission or life expectancy less than 6 months
• Inability to provide informed consent (e.g. dementia)
• Current use of topical or oral NSAIDs more than 3 days per week.
• Inability to receive text messages or emails to complete questionnaires between study visits.
• Unable to follow the study protocol.

De-identified questionnaire and COMT genotype data will be available upon reasonable written request after publication and upon completing a data transfer agreement. Raw video and physiologic data will not be shared due to participant confidentiality/privacy.

Data will be available following publication of those data.

Completion of a data transfer agreement.