This is a pilot study with a 4-period double-cross-over design evaluating a treatment with non-steroidal anti-inflammatory drugs (NSAIDs) in people with painful knee osteoarthritis.

Once screened and found eligible, participants will be entered into an initial blinded 2-week treatment period of either naproxen or placebo and then entered into an open washout period of 2 weeks. At the end of this washout, participants will then receive either naproxen or placebo for a further 2 week period followed again by a 2 week washout. This sequence will then be repeated (total of 4 treatment periods) such that all participants receive naproxen for 2 treatment periods and placebo for 2 treatment periods. The order of treatment will be randomized.

Inclusion Criteria:

1. Male or female >40 years of age
2. Meet ACR criteria for knee OA
3. Able and willing to provide informed consent
4. Average weekly pain in the index knee based on daily pain assessments of ≥ 4/10 and <9/10 on an 11-point NRS scale
5. Willing to discontinue current medications taken for OA pain
6. For women of child-bearing potential, willing to utilize some form of birth control or abstinence during the course of the study
7. If taking cannabinoids, have to be on a stable dose and have this maintained for the duration of the study
8. If receiving physical therapy or any non-pharmacologic modality(ies) for OA, these need to continue and remain stable for the duration of the study
9. Ambulatory
10. Have a cellphone and/or access to a computer and be able to utilize the eDiary as directed
11. Use of medications for knee OA pain on at least 4 out of 7 days per week
12. eDiary entries on at least 4 out 7 days per week during the observation period
13. Sub-Group Criterion (≥12 participants): Variability of average daily pain in the index knee during the observation period of ≥ 2 points on the NRS scale on at least 4 occasions

Exclusion criteria:

1. History of intolerance or allergic reaction to NSAIDs
2. Previous history of GI bleed
3. Renal insufficiency resulting in serum creatinine > 1.5 mg/dL
4. History of myocardial infarction in last 6 months
5. Coexisting congestive heart failure or symptomatic atherosclerotic heart disease
6. Use of oral anticoagulants other than aspirin ≤ 325 mg for cardiac prophylaxis
7. Use of heparin or injectable anticoagulant
8. Uncontrolled hypertension
9. Any medical condition which in the judgement of the investigator would make it inappropriate for the participant to enroll in the study
10. Use of recreational drugs
11. Fibromyalgia
12. Inflammatory arthropathies of any sort
13. Chronic back pain in which pain level is greater than the OA pain
14. Participation in another clinical trial other than one for covid or an observational and non-interventional study
15. Use of walker or other aid for walking other than a single cane
16. Hip pain on the ipsilateral side equal to or greater than the knee pain in the index joint
17. Index knee cannot have had previous joint replacement surgery
18. Arthroscopy within the past 6 months
19. Injection of hyaluronate in the index knee in the past 6 months
20. Corticosteroid injection in the index knee in the past 3 months
21. Injection of any biologic agent in the index in the past 12 months
22. Nerve ablation for the treatment of pain in the index knee
23. Any acute or chronic pain condition which would interfere with the evaluation of knee pain.
24. Pregnant, nursing or planning to become pregnant during length of study

All medication will be prepared in capsules identical in appearance and weight.