This is a clinical trial of people who have pain due to knee osteoarthritis at Northwestern University Feinberg School of Medicine. The study will last for about 20 weeks. 180 qualified participants will be randomly assigned in a 1:1:1 ratio (60 participants per group) to one of three treatment groups: duloxetine, celecoxib, or placebo. Participants will have a knee Xray, (optional) MRIs of the brain and knee, blood draws, pain sensitivity testing, and asked to fill out questionnaires. The purpose of this study is to try to predict which participants will respond to the treatment.

This longitudinal study will screen and enroll 180 participants diagnosed with knee osteoarthritis at Northwestern University Feinberg School of Medicine. The study will last for about 20 weeks' duration with a repeat-treatment design. An equal number of participants (60 per group) will be randomly assigned in a 1:1:1 ratio, stratified by sex and current opioid use, to one of three treatment groups after they qualify to enter the study. The treatment groups will celecoxib (200 mg qd), duloxetine (60 mg qd, with an initial and final 7-day titration at 30 mg qd), or matching placebo (one capsule qd). This aim of this study is to identify specific biomarkers in individual people with knee osteoarthritis pain that will allow definition of responder phenotypes distinct for different therapeutic interventions.

Inclusion Criteria:

1. Male or female, age greater than 40 years, with no racial/ethnic restrictions;
2. Meet American College of Radiology 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 ≥ 4.0 (on a 0 to 10 Numeric Rating Scale)
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 (Transcutaneous Electrical Nerve Stimulation (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);
12. Glucagon-like peptide 1 (GLP-1) agonists or other weight-loss treatment permitted if started more than 3 months prior to screening with no significant change in weight (+/- 11 lbs) over the past 30 days;

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, or liver disease (liver function tests > upper limit of normal);
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. Currently breastfeeding, pregnant, or planning to become pregnant during the study;
11. Chronic neurologic conditions, e.g., Parkinson's;
12. Renal insufficiency (creatinine >1.5 mg/dl);
13. Previous history of peptic ulcer or gastrointestinal bleeding;
14. Current use of anticoagulants or platelet inhibitors other than aspirin at ≤325 mg/day;
15. Allergy to sulfonamide drugs, duloxetine, nonsteroidal anti-inflammatory drugs (NSAIDs), or acetaminophen;
16. Acute myocardial infarction or coronary artery bypass graft surgery, in the past 12 months;
17. Recent injection into the index knee of hyaluronic acid or other substance in the last 6 months, or steroid in the last 90 days;
18. Lactose allergy;
19. 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;
20. Uncontrolled narrow-angle glaucoma;
21. Malignancy within 2 years of screening, with the exception of squamous cell carcinoma, basal cell carcinoma and prostate cancer (grade group 1);
22. Active treatment for cancer other than superficial skin cancer; or
23. Nerve ablation performed on the index knee within 12 months of screening.