What are the potential interactions between Selective Serotonin Reuptake Inhibitors (SSRI) and Ketorolac (Toradol)?

SSRI and Ketorolac (Toradol) Interaction

The combination of SSRIs and ketorolac (Toradol) significantly increases the risk of gastrointestinal bleeding and should be avoided or used with extreme caution only in patients without bleeding risk factors. 1

Primary Mechanism of Interaction

The interaction between SSRIs and ketorolac creates a synergistic bleeding risk through two distinct mechanisms:

• SSRIs deplete platelet serotonin stores, impairing platelet aggregation and hemostatic function, which increases baseline bleeding risk 2, 3
• Ketorolac inhibits prostaglandin synthesis and platelet function through COX inhibition, independently increasing bleeding risk 1
• The FDA drug label explicitly warns that there is an increased risk of gastrointestinal bleeding when SSRIs are combined with NSAIDs like ketorolac, and caution should be used when these medications are administered concomitantly 1

Quantified Bleeding Risk

The magnitude of bleeding risk with this combination is substantial:

• SSRIs alone increase upper GI bleeding risk with an odds ratio of 1.66 (95% CI: 1.44-1.92) 2
• Combined SSRI and NSAID use increases upper GI bleeding risk with an odds ratio of 4.25 (95% CI: 2.82-6.42), representing more than a 4-fold increased risk 2
• This represents a synergistic rather than additive effect, meaning the combined risk exceeds what would be expected from simply adding the individual risks together 2, 3

Clinical Decision Algorithm

When SSRI and ketorolac combination is being considered:

High-Risk Patients (Avoid Combination)

• History of peptic ulcer disease or previous GI bleeding 3
• Concurrent use of anticoagulants (warfarin, heparin, DOACs) 1, 4
• Concurrent use of antiplatelet agents (aspirin, clopidogrel) 1, 3
• Cirrhosis or liver failure 3
• Age >65 years with multiple comorbidities 2
• History of bleeding disorders 5

If Combination Cannot Be Avoided

• Limit ketorolac duration to ≤5 days maximum (per standard ketorolac prescribing guidelines) 1
• Add proton pump inhibitor (PPI) prophylaxis, which decreases SSRI-associated GI bleeding risk 2, 3
• Use the lowest effective dose of ketorolac 1
• Consider alternative SSRIs with lower bleeding risk: sertraline and citalopram/escitalopram have more favorable profiles compared to fluoxetine and fluvoxamine 6
• Monitor closely for signs of bleeding (melena, hematemesis, unexplained anemia, bruising) 5

Alternative Pain Management Strategies

Safer alternatives to ketorolac in patients on SSRIs:

• Acetaminophen as first-line analgesic (no platelet or GI bleeding effects) 6
• Topical NSAIDs (diclofenac gel/patch) have lower systemic absorption and reduced GI bleeding risk 6
• Opioid analgesics if pain severity warrants, though monitor for serotonin syndrome risk with tramadol specifically 6
• Adjuvant analgesics such as gabapentin or pregabalin for neuropathic pain components 6

Critical Pitfalls to Avoid

• Underestimating the synergistic nature of this interaction—the risk is not simply additive but multiplicative 2
• Failing to obtain bleeding history before prescribing this combination 5, 3
• Not considering over-the-counter NSAID use—patients may be taking additional ibuprofen or aspirin without reporting it 3
• Assuming short-term ketorolac use is safe—even brief exposure (3-5 days) carries significant bleeding risk in combination with SSRIs 1, 2
• Neglecting PPI prophylaxis in patients who must receive both medications 2, 3

Additional Bleeding Sites

While upper GI bleeding is the most common and well-documented complication 2, 3, the evidence does not support increased risk of:

• Intracerebral hemorrhage with SSRI-NSAID combination 5
• Hemorrhagic stroke (data too limited for definitive conclusions) 3

However, any site bleeding (epistaxis, ecchymosis, petechiae, hematoma) can occur and warrants medication review 6

Special Considerations for Anticoagulated Patients

The combination of SSRI + ketorolac + anticoagulant creates particularly high bleeding risk:

• Warfarin plus SSRI more than doubles bleeding risk compared to warfarin alone 6
• Adding an NSAID to this combination is generally contraindicated 6, 1
• If anticoagulation is present, oral NSAIDs should be avoided entirely; consider topical NSAIDs only 6
• DOACs combined with SSRIs show increased major bleeding (HR 1.47,95% CI: 1.03-2.10) 4