What is the recommended pharmacologic treatment for a typical adult with osteoarthritis of the knee, hip, or hand, including options for patients with peptic ulcer disease, chronic kidney disease, or cardiovascular risk?

Pharmacologic Treatment for Osteoarthritis of the Knee, Hip, and Hand

Start with acetaminophen up to 3,000–4,000 mg daily in divided doses as first-line therapy for all patients with osteoarthritis; if pain persists after 2 weeks, add topical NSAIDs (diclofenac gel) before considering oral NSAIDs, which should be reserved for patients who fail both acetaminophen and topical agents. 1, 2

First-Line Pharmacologic Treatment

• Acetaminophen 3,000–4,000 mg daily (divided into 3–4 doses) is the initial pharmacologic choice for knee, hip, and hand osteoarthritis, providing pain relief comparable to NSAIDs in mild-to-moderate disease with a significantly safer profile. 1, 2

• The 4,000 mg daily maximum must be strictly enforced; counsel patients to avoid all other acetaminophen-containing products including over-the-counter cold remedies and combination opioid products. 1

• For elderly patients (≥75 years), consider limiting acetaminophen to 3,000 mg daily to minimize hepatotoxicity risk. 2

• Regular scheduled dosing throughout the day provides superior sustained pain control compared to "as needed" dosing. 1, 2

Second-Line: Topical NSAIDs (Before Oral NSAIDs)

• If acetaminophen provides insufficient relief after 2 weeks, add topical diclofenac gel (40 mg = 2 pump actuations to each painful knee twice daily) rather than immediately escalating to oral NSAIDs. 1, 2, 3, 4

• Topical NSAIDs achieve clinically significant pain reduction with minimal systemic absorption, avoiding gastrointestinal bleeding, cardiovascular events, and renal toxicity. 2, 3, 5

• For patients ≥75 years, topical NSAIDs are strongly recommended over oral NSAIDs. 1

• Apply to clean, dry skin; wait 30 minutes before showering; avoid skin-to-skin contact until completely dry; wash hands after application. 4

Third-Line: Oral NSAIDs (With Mandatory Gastroprotection)

• Oral NSAIDs should only be used after both acetaminophen and topical NSAIDs have failed, at the lowest effective dose for the shortest duration. 1, 2

• Every oral NSAID prescription must include a proton pump inhibitor for gastroprotection, regardless of gastrointestinal history. 1, 2

• Etoricoxib 60 mg daily or diclofenac 150 mg daily are the most effective oral NSAIDs for pain and function, though both carry increased adverse event risk. 5

• For patients ≥75 years, oral NSAIDs carry substantially higher risks of gastrointestinal bleeding, renal insufficiency, and cardiovascular complications; topical agents are strongly preferred. 1, 2

Special Population: Peptic Ulcer Disease

• If the patient has a history of symptomatic or complicated upper GI ulcer but no bleed in the past year, use either a COX-2 selective inhibitor (celecoxib) or a nonselective NSAID, both combined with a proton pump inhibitor. 1

• If the patient had an upper GI bleed within the past year, use only a COX-2 selective inhibitor (celecoxib) combined with a proton pump inhibitor if an oral NSAID is absolutely necessary. 1

• Consider adding a proton pump inhibitor to any NSAID (selective or nonselective) for chronic osteoarthritis management to reduce symptomatic or complicated upper GI events. 1

Special Population: Chronic Kidney Disease

• Oral NSAIDs are absolutely contraindicated in chronic kidney disease stage IV or V (estimated glomerular filtration rate <30 mL/min). 1

• For chronic kidney disease stage III (eGFR 30–59 mL/min), oral NSAIDs may be used only after careful individual risk-benefit assessment and with close monitoring. 1

• Topical NSAIDs are acceptable alternatives in renal impairment due to minimal systemic absorption. 2, 3

Special Population: Cardiovascular Risk or Low-Dose Aspirin

• If the patient takes low-dose aspirin (≤325 mg/day) for cardioprotection, use a nonselective NSAID other than ibuprofen combined with a proton pump inhibitor. 1

• Never use ibuprofen with low-dose aspirin—ibuprofen renders aspirin less effective for cardioprotection through pharmacodynamic interaction. 1, 6

• COX-2 selective inhibitors should not be used in patients taking low-dose aspirin for cardiovascular protection. 1

• Diclofenac and celecoxib do not demonstrate the same pharmacodynamic interaction with aspirin as ibuprofen. 1

Intra-Articular Corticosteroid Injections

• Intra-articular corticosteroid injections are strongly recommended for moderate-to-severe knee or hip pain, particularly when joint effusion is present, providing short-term relief lasting 1–3 weeks. 1, 2

• Injections are especially appropriate for elderly patients who cannot tolerate oral NSAIDs due to comorbidities. 2

Adjunct Pharmacologic Options

• Tramadol is conditionally recommended only if acetaminophen, topical NSAIDs, and oral NSAIDs have all failed or are contraindicated. 1

• Duloxetine 60 mg daily is conditionally recommended for knee osteoarthritis, particularly when neuropathic pain features are present. 1, 2

• Intra-articular hyaluronan injections are conditionally recommended only for knee osteoarthritis in patients with chronic moderate-to-severe pain who are candidates for total knee arthroplasty but are unwilling or have contraindications to surgery. 1

Opioid Analgesics (Last Resort Only)

• Opioid analgesics are strongly recommended only for patients with symptomatic knee osteoarthritis who have failed both nonpharmacologic and pharmacologic modalities and are either unwilling to undergo or are not candidates for total joint arthroplasty. 1

• The clinical benefit of opioids does not outweigh the harm in osteoarthritis patients; 83.3% of opioids had increased risk of dropouts due to adverse events and 89.5% had increased risk of any adverse event. 5

Not Recommended

• Do not use glucosamine, chondroitin sulfate, or topical capsaicin—these are conditionally recommended against due to lack of efficacy. 1, 2

Essential Non-Pharmacologic Core Treatments (Must Accompany All Pharmacologic Therapy)

• Prescribe joint-specific strengthening exercises and general aerobic fitness programs with every pharmacologic intervention; exercise produces pain-reduction effect sizes of 0.57–1.0. 1, 2

• Counsel all overweight or obese patients (BMI ≥25 kg/m²) regarding weight loss, which significantly reduces osteoarthritis symptoms and disease progression. 1, 2

• Provide patient education to counter the misconception that osteoarthritis is inevitably progressive and cannot be treated. 1, 2

• Recommend local heat or cold applications, assistive devices (walking sticks, tap turners), and shock-absorbing footwear. 1, 2, 7

Critical Safety Pitfalls to Avoid

• Never prescribe oral NSAIDs without a proton pump inhibitor, regardless of gastrointestinal history. 1, 2

• Never combine ibuprofen with low-dose aspirin for cardioprotection—it negates aspirin's antiplatelet effect. 1, 6

• Never use oral NSAIDs in chronic kidney disease stage IV–V (eGFR <30 mL/min). 1

• Never exceed 4,000 mg daily of acetaminophen; consider 3,000 mg limit in elderly patients. 1, 2

• Never use opioids as first- or second-line therapy—reserve for absolute treatment failures who are not surgical candidates. 1, 2, 5

• Assess cardiovascular, gastrointestinal, and renal risk factors before prescribing any oral NSAID, especially in patients >50 years. 2, 6