Guidelines for Concurrent Use of Methotrexate and NSAIDs
Key Recommendation
Caution should be used when NSAIDs and methotrexate are administered concomitantly, but the combination can be used safely in patients with normal renal function and with appropriate monitoring. 1
Mechanism of Interaction
- NSAIDs can reduce the renal elimination of methotrexate, leading to increased serum levels and potential toxicity 2, 1
- The interaction occurs primarily through competition for renal tubular secretion via organic anion transporters, particularly OAT3 3
- NSAID glucuronides may also inhibit methotrexate excretion via multidrug resistance proteins (MRP2 and MRP4), potentially more potently than parent NSAIDs 4
Safety Considerations for Combined Use
- High-dose methotrexate (as used in cancer treatment) should NOT be combined with NSAIDs due to severe risk of toxicity 1
- Low-dose methotrexate (≤15 mg/week) as used in rheumatoid arthritis can generally be combined with NSAIDs with appropriate monitoring 5, 6
- The FDA drug label specifically warns: "Concomitant administration of some NSAIDs with high-dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity" 1
Specific NSAID Considerations
- Case reports have documented toxicity particularly with naproxen, diclofenac, ibuprofen, and indomethacin when combined with methotrexate 2, 7
- COX-2 selective inhibitors like celecoxib appear to have less interaction with methotrexate 2, 6
- Anti-inflammatory doses of aspirin should be avoided with methotrexate due to potential for increased toxicity 1, 6
- Acetaminophen (paracetamol) appears to have minimal interaction with methotrexate 8, 3
Patient Risk Factors for Increased Toxicity
- Elderly patients are at higher risk due to age-related decline in renal function 7, 1
- Patients with existing renal impairment are at significantly increased risk 1
- Patients with reduced albumin levels may experience increased toxicity due to higher free methotrexate levels 1
- Dehydration can increase methotrexate levels and toxicity 1
Monitoring Recommendations
- Baseline assessment should include complete blood count with differential and platelet counts, hepatic enzymes, and renal function tests 1
- More frequent monitoring of liver function tests and renal function is recommended when methotrexate is used with NSAIDs 7, 1
- Hematology monitoring at least monthly, and renal/liver function every 1-2 months 1
- Patients should be educated to report symptoms of methotrexate toxicity promptly (mouth ulcers, unusual bruising, severe sore throat, dyspnea) 7, 1
Practical Recommendations to Minimize Risk
- Consider scheduling NSAIDs on different days than methotrexate to minimize interaction risk 7
- For patients with ankylosing spondylitis who are stable on TNF inhibitors, consider discontinuing NSAIDs if possible 2
- The British Association of Dermatologists notes that patients should have a detailed medication history taken and a detailed review of potential interactions before starting methotrexate 2
- In patients requiring both medications, use the lowest effective dose of NSAIDs for the shortest duration possible 7
Special Clinical Situations
- In stable ankylosing spondylitis patients receiving treatment with TNF inhibitors and NSAIDs, guidelines conditionally recommend continuing treatment with TNF inhibitors alone over continuing both medications 2
- For patients with rheumatoid arthritis requiring both medications, the combination can generally be used safely with appropriate monitoring 5, 6
- If antibiotics are needed for severe infection in patients on both methotrexate and NSAIDs, consider temporarily stopping methotrexate until the infection resolves and antibiotic course is complete 2
By following these guidelines and implementing appropriate monitoring, the concurrent use of methotrexate and NSAIDs can be managed safely in most patients with inflammatory arthritis.