What are the treatment options for osteoarthritis (OA) pain that is resistant to nonsteroidal anti-inflammatory drugs (NSAIDs)?

Treatment Options for Osteoarthritis Pain Resistant to NSAIDs

For patients with osteoarthritis pain that is resistant to NSAIDs, duloxetine should be considered the next treatment option due to its demonstrated efficacy when used alone or in combination with NSAIDs. 1

Pharmacologic Treatment Algorithm

First-line alternatives after NSAID failure:

• Duloxetine (60mg daily) - Conditionally recommended for knee, hip, and hand OA with demonstrated efficacy when used alone or in combination with NSAIDs 1
• Intra-articular corticosteroid injections - Strongly recommended for patients who have not responded to oral/topical NSAIDs, particularly for knee OA 1
• Topical NSAIDs - For patients ≥75 years old, topical NSAIDs are strongly recommended over oral NSAIDs to minimize systemic side effects 1

Second-line options:

• Tramadol - Conditionally recommended when duloxetine and other options have failed, though benefits are modest with potential for adverse effects 1
• Acetaminophen - While traditionally considered first-line, recent evidence shows limited efficacy with effect sizes described as "very small" 1, 2
• Combination therapy - Adding tramadol/acetaminophen to COX-2 NSAIDs has shown efficacy for inadequately controlled OA pain 3

Not recommended:

• Non-tramadol opioids - Conditionally recommended against due to modest benefits and high risk of toxicity and dependence 1
• Nutritional supplements (chondroitin sulfate, glucosamine) - Conditionally recommended against due to lack of efficacy 1
• Fish oil and colchicine - Conditionally recommended against 1

Non-Pharmacologic Interventions

When NSAIDs fail, these non-pharmacologic approaches should be emphasized:

• Exercise therapy - Strongly recommended for all patients with OA, including strengthening exercises and low-impact aerobic activities 1
• Physical therapy - Recommended as part of comprehensive management, can be delivered via individual sessions, group visits, or telehealth 1
• Aquatic therapy - Pool exercises in warm water (86°F) provide analgesia, reduce joint loading, and may help with depression and isolation 1
• Weight management - For overweight patients, weight reduction is strongly recommended 1
• Thermal agents - Application of heat or cold can provide symptomatic relief 1

Special Considerations

For elderly patients (≥75 years):

• Strongly prefer topical NSAIDs over oral NSAIDs 1
• Use lower doses of tramadol if needed due to risk of drug accumulation 4
• Monitor for hepatotoxicity with regular acetaminophen use 1

For patients with GI risk factors:

• If oral NSAIDs must be used, combine with a proton-pump inhibitor 1
• For patients with history of symptomatic or complicated upper GI ulcer, use either a COX-2 selective inhibitor or a nonselective NSAID with a proton-pump inhibitor 1
• For patients with history of upper GI bleed within the past year who still require an NSAID, use a COX-2 selective inhibitor with a proton-pump inhibitor 1

Important Caveats

• Duloxetine should be taken daily (not as needed) and discontinued only after consultation with the prescribing provider 1
• When discontinuing duloxetine, taper over 2-4 weeks for those treated longer than 3 weeks 1
• Tramadol has addiction potential, though less than traditional opioids, and should be used at the lowest effective dose for the shortest duration 1, 4
• Intra-articular corticosteroid injections should be avoided for 3 months preceding joint replacement surgery 1
• Corticosteroid injections for the hip should be image-guided 1