Can ketorolac be given to a patient taking methotrexate?

Can Ketorolac IM Be Given to a Person on Methotrexate?

No, ketorolac should not be given to patients taking methotrexate due to the serious risk of life-threatening methotrexate toxicity from reduced renal clearance.

Critical Drug Interaction Mechanism

• NSAIDs, including ketorolac, reduce renal elimination of methotrexate, leading to elevated drug levels and increased toxicity risk 1
• Methotrexate is 85% renally excreted, making any interference with renal clearance particularly dangerous 1
• NSAIDs compete with methotrexate at the renal tubular secretion pathway, prolonging methotrexate exposure and dramatically increasing toxicity risk 2

Evidence of Life-Threatening Toxicity

• A retrospective analysis of ketoprofen (another NSAID) with high-dose methotrexate found severe toxicity in all 4 cases where they were co-administered, with 3 of 4 cases resulting in death 2
• The study demonstrated prolonged and striking enhancement of serum methotrexate levels when NSAIDs were given concurrently 2
• The authors explicitly stated that "this high-risk association between methotrexate toxicity and ketoprofen may also apply to other non-steroidal anti-inflammatory drugs" 2

Guideline Recommendations

• The American Academy of Dermatology identifies NSAIDs as high-risk drug interactions that decrease methotrexate binding to albumin or reduce renal tubular excretion 1
• Drug interactions with NSAIDs are listed as a primary risk factor for methotrexate toxicity 1
• The American College of Medical Toxicology specifically identifies NSAIDs as reducing renal elimination of methotrexate, which is "particularly dangerous with any dose of methotrexate" 1

Important Context: Low-Dose vs High-Dose Methotrexate

While the most dramatic evidence comes from high-dose methotrexate cases 2, there is an important distinction for clinical practice:

• For low-dose weekly methotrexate (as used in rheumatoid arthritis and psoriasis), a Cochrane systematic review found that concurrent NSAID use appears to be safe with appropriate monitoring 3
• This review included 13 studies examining NSAIDs with methotrexate in rheumatoid arthritis patients, with mean study durations of 2182.9 days 3
• The studies showed no increase in methotrexate withdrawal, no adverse effect on liver or renal function, and no increase in major toxic reactions 3
• However, one study did demonstrate transient thrombocytopenia specifically when NSAIDs were taken on the same weekday as methotrexate 3

Clinical Decision Algorithm

For patients on low-dose weekly methotrexate (≤25 mg/week for inflammatory arthritis):

• Ketorolac can be considered with extreme caution and enhanced monitoring 3
• Avoid administering ketorolac on the same day as methotrexate to minimize risk of thrombocytopenia 3
• Limit duration to the shortest possible period (ideally <5 days) 4
• Monitor CBC, renal function, and liver function more frequently than usual 3

For patients on high-dose methotrexate or with risk factors:

• Absolutely avoid ketorolac 2
• Risk factors include: renal insufficiency, advanced age, lack of folate supplementation, or hypoalbuminemia 1

Safer Alternatives

• Consider non-NSAID analgesics such as acetaminophen (paracetamol) for pain management 3
• If NSAID use is absolutely necessary, ensure it is given at least 12 hours after methotrexate administration 2
• Ensure mandatory folic acid supplementation (at least 5 mg weekly) is in place 1

Common Pitfall to Avoid

Do not assume that because the patient has been on methotrexate for a long time without problems, adding ketorolac is safe. The interaction is pharmacokinetic and can occur at any time, particularly if renal function has declined or other risk factors have developed 1, 2.