Diflunisal and Amitriptyline: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 2, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Amitriptyline
Diflunisal
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
You're taking amitriptyline (Elavil), a tricyclic antidepressant, along with diflunisal (Dolobid), an anti-inflammatory pain reliever similar to ibuprofen. When these two are used together, they can raise your risk of bleeding. In rare cases this can include serious bleeding, such as bleeding in the brain.
This doesn't mean you can't take both, but it's something your care team keeps an eye on. Watch for warning signs like unusual bruising, bleeding gums, nosebleeds, blood in your stool or urine, or a sudden bad headache. Let your pharmacist or doctor know you take both so they can watch out for you and adjust things if needed.
Effect: Concurrent NSAID (diflunisal) and TCA (amitriptyline) use is associated with an increased bleeding risk, including intracranial hemorrhage, within 30 days of coadministration.
- Direction: Additive bleeding risk (increased effect).
- Mechanism: Unknown; NSAIDs impair platelet aggregation and cause GI mucosal injury, while TCAs may affect serotonin-mediated platelet function.
- Evidence: Established. Severity major. Onset unspecified.
- Management: Use caution; monitor for signs of bleeding (GI bleed, bruising, neurologic changes). Consider gastroprotection or alternative analgesia if risk is high.
Neither agent's activation is a limiting factor here; this is a pharmacodynamic additive-risk interaction.
What happens
An increased risk of bleeding
Interaction Deep Dive
Caution is warranted when NSAIDs are given together with tricyclic antidepressants, because the combination may raise the likelihood of bleeding events, such as intracranial hemorrhage occurring within 30 days of using them together1. During concurrent therapy with these two drug classes, watch the patient for indications of heightened bleeding.
Why it happens (mechanism)
Unknown
How to manage this interaction
The good news is that this is manageable, and many people safely take both under supervision.
- Keep taking both as prescribed unless your prescriber tells you otherwise.
- Your care team may monitor you more closely for signs of bleeding, especially in the first weeks.
- They may consider a stomach-protecting medicine or a different pain reliever if your bleeding risk is higher.
- Call your doctor promptly if you notice black or bloody stools, vomiting blood, easy bruising, or a sudden severe headache.
Ask your pharmacist to review all your medicines, including over-the-counter ones, since other blood thinners can add to this risk.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) The combined use of NSAIDs and antidepressants, including tricyclic antidepressants, SSRIs, serotonin-norepinephrine reuptake inhibitors, and MAOIs, led to a higher risk of intracranial hemorrhage within 30 days of concurrent use when compared to using an antidepressant by itself. No significant difference in the increased risk was observed among the different antidepressant drug classes; nevertheless, an elevated risk was associated with male patients relative to female patients 1.
Common questions
Can I take Diflunisal and Amitriptyline together?
Taking amitriptyline with diflunisal can raise your risk of bleeding, so watch for bruising or bleeding signs and tell your care team you use both. Keep taking them as prescribed unless your doctor advises a change. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Diflunisal and Amitriptyline interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How is the Diflunisal and Amitriptyline interaction managed?
The good news is that this is manageable, and many people safely take both under supervision. Keep taking both as prescribed unless your prescriber tells you otherwise. Your care team may monitor you more closely for signs of bleeding, especially in the first weeks. They may consider a stomach-protecting medicine or a different pain reliever if your bleeding risk is higher. Call your doctor prompt… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "established". Well documented — supported by controlled studies or strong clinical data.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Diflunisal or Amitriptyline need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (1)
- Shin JY, Park MJ, Lee SH, et al: Risk of intracranial haemorrhage in antidepressant users with concurrent use of non-steroidal anti-inflammatory drugs: nationwide propensity score matched study. BMJ 2015; 351:h3517. PubMed
Keep reading about Amitriptyline
Keep reading about Diflunisal
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