Inclusion Criteria:
1. Male or female, age greater than 40 years, with no racial/ethnic restrictions;
2. Meet American College of Radiology (ACR) criteria for knee osteoarthritis (OA) based on radiographic evidence;
3. Knee pain most days of the week for the past month at screening;
4. Must have average pain score for the week prior to baseline of ≥ 4 (on a 0 to 10 NRS)
5. Must complete pain ratings on at least 4 out of 7 days prior to baseline
6. Must be able to read and speak English and be willing to read and understand instructions as well as questionnaires;
7. Must be in generally stable health;
8. Must be able to return for all clinic visits;
9. Willing to remain stable on any concomitant therapies (TENs unit, ice, glucosamine chondroitin, cannabinoids, etc.)
10. Must sign an informed consent document after complete explanation of the study documenting that they understand the purpose of the study, procedures to be undertaken, possible benefits, potential risks, and are willing to participate.
11. Ambulatory with or without a cane, brace(s), or walking stick (use of walker or wheelchair will be exclusionary)
Exclusion Criteria:
1. Evidence of rheumatoid arthritis, ankylosing spondylitis, other inflammatory arthropathy;
2. Functional class IV congestive heart failure;
3. Significant other medical disease such as uncontrolled hypertension, untreated diabetes mellitus, coronary or peripheral vascular disease, chronic obstructive lung disease, liver disease (Liver Function Tests \>3x Upper limit of normal) or malignancy;
4. Current use of illicit drugs or history (in last 12 months) of alcohol or drug abuse;
5. Current cannabinoid use for knee pain;
6. High dose opioid use, as defined as \> 50mg morphine equivalent/day;
7. Any medical condition that in the investigator's judgment may prevent the individual from completing the study or put the individual at undue risk;
8. In the judgment of the investigator, unable or unwilling to follow protocol and instructions;
9. Intra-axial implants (e.g., spinal cord stimulators or pumps);
10. All exclusion criteria for Magnetic Resonance Imaging (MRI) safety: any metallic implants, brain or skull abnormalities, tattoos on large body parts, and claustrophobia;
11. Currently breastfeeding, pregnant, or planning to become pregnant during the study;
12. Chronic neurologic conditions, e.g., Parkinson's;
13. Renal insufficiency (creatinine \>1.5 mg/dl)
14. Previous history of peptic ulcer or gastrointestinal bleeding
15. Current use of anticoagulants or platelet inhibitors other than aspirin (ASA) at ≤325 mg/day
16. Allergy to sulfonamide drugs, duloxetine, NSAIDs, or acetaminophen
17. Acute myocardial infarction or coronary artery bypass graft surgery, in the past 12 months
18. Recent injection into the index knee of hyaluronic acid or other substance in the last 6 months, or steroid in the last 90 days.
19. Severe lactose intolerance
20. Current use of selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and/or tricyclic antidepressants (TCAs) at a therapeutic dose. Occasional use of these medications as a sleep aid will be allowed; however, participants will need to agree to remain on a stable dose of the medication while in the study.
21. Uncontrolled narrow-angle glaucoma
