What medications interact with ketorolac (Nonsteroidal Anti-Inflammatory Drug, NSAID)?

Medications That Interact with Ketorolac

Ketorolac should not be used concurrently with anticoagulants, other NSAIDs, aspirin, or SSRIs due to significantly increased bleeding risk. 1, 2

Major Drug Interactions

Anticoagulants

• Warfarin/Heparin: Significantly increases bleeding risk (3-6 times higher risk of GI bleeding) 2, 1
  • Although pharmacokinetic studies show minimal changes to warfarin levels, the combined effect on bleeding risk is synergistic
  • Monitor INR closely if combination cannot be avoided
  • Consider alternative pain management strategies

Other NSAIDs and Aspirin

• NSAIDs/Aspirin: Concurrent use increases GI bleeding risk and reduces cardioprotective effects 1, 2
  • Avoid concurrent use with other NSAIDs or aspirin
  • If aspirin is needed for cardiovascular protection, consider alternative analgesics
  • Ibuprofen specifically may interfere with aspirin's cardioprotective effects 2

Antiplatelet Agents

• Clopidogrel/Ticlopidine: Increased bleeding risk 2
  • Avoid concurrent use, especially within 12 months of coronary stent placement 2

Renal-Affecting Medications

• ACE Inhibitors/ARBs: Increased risk of renal impairment, especially in volume-depleted patients 1

  • May diminish antihypertensive effects
  • Monitor renal function and blood pressure

• Diuretics: Ketorolac can reduce the natriuretic effect of furosemide and thiazides 1

  • Monitor for signs of renal failure and diuretic efficacy

Other Significant Interactions

• Probenecid: Decreases clearance of ketorolac, increasing plasma levels three-fold 1

  • Concomitant use is contraindicated

• Lithium: NSAIDs increase plasma lithium levels and reduce renal lithium clearance 1

  • Monitor for signs of lithium toxicity

• Methotrexate: NSAIDs may enhance methotrexate toxicity 1

  • Use with caution and monitor closely

• SSRIs: Increased risk of GI bleeding when combined with ketorolac 1, 2

  • Avoid concurrent use if possible

• Pentoxifylline: Increased tendency for bleeding 1

  • Avoid concurrent use

• Corticosteroids: Approximately doubles the risk of GI events 2

  • Consider gastroprotection with PPI if combination necessary

Special Considerations

High-Risk Patients

• Elderly patients: Higher risk of adverse effects, especially GI bleeding
• Patients with renal impairment: Increased risk of ketorolac toxicity
• Patients on multiple medications: Higher risk of drug-drug interactions

Rare but Reported Interactions

• Antiepileptic drugs (phenytoin, carbamazepine): Sporadic cases of seizures reported 1
• Psychoactive drugs (fluoxetine, thiothixene, alprazolam): Hallucinations reported 1
• Nondepolarizing muscle relaxants: Reports of apnea 1

Management Strategies

1. Limit duration of ketorolac use (ideally <5 days) to minimize interaction risks 2
2. Consider gastroprotection with proton pump inhibitors when ketorolac must be used with other agents that increase bleeding risk 2
3. Monitor renal function when combining with other nephrotoxic medications
4. Avoid ketorolac entirely in patients on therapeutic anticoagulation unless absolutely necessary 2

Pitfalls to Avoid

• Don't assume that normal bleeding studies mean safe concurrent use with anticoagulants
• Don't overlook the increased bleeding risk when combining with SSRIs or corticosteroids
• Don't use ketorolac for long-term pain management (>5 days) due to increasing risk of interactions and adverse effects
• One case report noted a lethal idiosyncratic reaction to ketorolac in an adult with mastocytosis 2

Remember that ketorolac has a relatively narrow therapeutic window compared to other NSAIDs, making drug interactions particularly concerning for patient safety.