What medication options are appropriate for an adult with uncomplicated knee pain such as osteoarthritis, strain, or mild inflammatory pain?

Medication Options for Knee Pain

Acetaminophen (up to 4000 mg daily) should be your first-line pharmacologic treatment for uncomplicated knee pain from osteoarthritis or mild inflammatory conditions, as it provides effective pain relief with the safest adverse effect profile compared to all other oral analgesics. 1, 2

First-Line Pharmacologic Treatment

• Start with acetaminophen at regular dosing intervals throughout the day (not "as needed"), with a maximum daily dose of 4000 mg, though consider limiting to 3000 mg daily in elderly patients to minimize hepatotoxicity risk. 1, 2

• Acetaminophen provides pain relief comparable to NSAIDs for mild-to-moderate osteoarthritis pain without the gastrointestinal bleeding, cardiovascular, renal, or platelet dysfunction risks associated with NSAIDs. 1, 2

• This recommendation comes from the American Geriatrics Society and represents the consensus first-line approach, though recent evidence (2022 CDC guidelines) notes that acetaminophen has limited effectiveness for osteoarthritis and is no longer considered first-line by some authorities. 1

Second-Line: Topical NSAIDs

If acetaminophen provides insufficient relief after an adequate trial (2-4 weeks at maximum dose), switch to or add topical NSAIDs (such as diclofenac gel) before considering oral NSAIDs. 1, 2

• Topical NSAIDs demonstrate clinical efficacy with minimal systemic absorption, avoiding the gastrointestinal, cardiovascular, and renal risks of oral NSAIDs. 1, 2

• Apply topical diclofenac to clean, dry skin twice daily directly over the affected knee, avoiding application for at least 30 minutes before bathing and avoiding covering the area until completely dry. 3

• Topical NSAIDs are particularly appropriate for localized knee pain affecting one or a few joints near the skin surface. 1

Third-Line: Oral NSAIDs or COX-2 Inhibitors

Only escalate to oral NSAIDs (such as naproxen, ibuprofen, or meloxicam) or COX-2 inhibitors (celecoxib) when both acetaminophen and topical NSAIDs have failed, and only after careful assessment of cardiovascular, gastrointestinal, and renal risk factors. 1, 2

• Use the lowest effective dose for the shortest possible duration—never use high doses for prolonged periods, especially in elderly patients who face substantially higher risks of serious adverse events. 1

• Mandatory co-prescription: Always prescribe a proton pump inhibitor alongside any oral NSAID for gastroprotection. 2

• Oral NSAIDs are contraindicated or require extreme caution in patients with: 1, 2

  • Cardiovascular disease (coronary artery disease, heart failure, hypertension)
  • Renal insufficiency (assess renal function before prescribing)
  • History of gastrointestinal bleeding or peptic ulcer disease
  • Hepatic disease
  • Age ≥65 years (independent risk factor for adverse outcomes)
  • Concurrent anticoagulant or corticosteroid use

• COX-2 selective inhibitors (celecoxib, rofecoxib) provide equivalent pain relief to traditional NSAIDs with reduced gastrointestinal toxicity, but still carry renal and cardiovascular risks including fluid retention. 1

Fourth-Line: Duloxetine

For patients with osteoarthritis pain inadequately controlled by NSAIDs, or in whom NSAIDs are contraindicated, consider duloxetine (SNRI antidepressant), which has small-to-moderate benefits for pain and function. 1

• Duloxetine is FDA-approved for osteoarthritis pain and demonstrates greater effectiveness in older patients (>65 years) and specifically for knee osteoarthritis. 1

• Common adverse effects include nausea and sedation; dosage reductions can mitigate some adverse events. 1

Interventional Option: Intra-Articular Corticosteroid Injection

For acute flares of knee pain, especially when accompanied by joint effusion or evidence of inflammation, intra-articular corticosteroid injection provides effective short-term pain relief lasting 2-4 weeks. 2, 4

• This intervention is particularly beneficial when baseline pain is severe and there is visible joint effusion. 4

• Corticosteroid injections should not be used as first-line treatment but are reserved for acute exacerbations or when oral medications have failed. 4

• Pain relief persists for 1-4 weeks but shows no significant difference from placebo at 12 and 24 weeks, so set realistic patient expectations. 4

Critical Contraindications and Warnings

• Never use NSAIDs immediately before or after coronary artery bypass graft (CABG) surgery. 5

• Never exceed 4000 mg daily of acetaminophen; consider 3000 mg as the upper limit in elderly patients. 2

• Never prescribe oral NSAIDs without gastroprotection (proton pump inhibitor co-prescription). 2

• Avoid NSAIDs in patients taking anticoagulants due to increased bleeding risk from platelet dysfunction. 1, 5

• NSAIDs can cause ulcers and bleeding in the stomach and intestines at any time during treatment, which can occur without warning symptoms and may cause death. 5

Essential Non-Pharmacologic Core Treatments (Mandatory)

Pharmacologic therapy is most effective only when used in conjunction with non-pharmacologic interventions, which are not optional adjuncts but essential core therapy. 1, 2

• Joint-specific strengthening exercises (quadriceps strengthening for knee OA) and general aerobic conditioning must be implemented before or concurrent with any pharmacologic management. 1, 2

• Weight reduction in overweight or obese patients directly reduces mechanical stress on the knee and improves symptoms. 2

• Patient education, local heat or cold applications, assistive devices, and shock-absorbing footwear are all evidence-based core treatments. 1, 2

• Pool exercises in warm water (86°F) provide analgesia and reduce joint loading while enhancing pain-free motion. 1

Medications to Avoid

• Do not prescribe opioids (including tramadol) for uncomplicated knee osteoarthritis—they are associated with increased medication-related adverse effects with no consistent improvement in pain and function. 1, 2

• Do not prescribe glucosamine or chondroitin—current best evidence does not support their efficacy. 2

• Do not use systemic (oral or intramuscular) corticosteroids for osteoarthritis—only intra-articular injection has proven efficacy. 4

Evidence Nuances and Controversies

The 2001 American Geriatrics Society guidelines strongly endorsed acetaminophen as first-line therapy based on comparable efficacy to NSAIDs with superior safety. 1 However, the 2022 CDC guidelines note that acetaminophen has "limited evidence for effectiveness" and is "no longer considered a first-line treatment for osteoarthritis" by some authorities. 1 A 2003 randomized controlled trial found that diclofenac was effective but acetaminophen showed no significant improvement over placebo at 2 or 12 weeks. 6 Despite this controversy, acetaminophen remains the safest initial option and should be tried first given its minimal adverse effect profile, with the understanding that many patients will require escalation to topical or oral NSAIDs for adequate pain control. 1, 2