Salsalate 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
Salsalate
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've been prescribed amitriptyline (an antidepressant that also helps with pain and sleep) along with salsalate (an aspirin-like pain and anti-inflammatory medicine). When these two are taken together, they can raise your risk of bleeding. In rare cases this can include serious bleeding, such as bleeding in the brain.
The good news is this is manageable. Keep taking both exactly as prescribed, and watch for warning signs like easy bruising, black or bloody stools, vomiting that looks like coffee grounds, or a sudden bad headache. If anything like that happens, get help right away. Your pharmacist or doctor can keep an eye on this and adjust things if needed.
Effect: Increased bleeding risk with concurrent salsalate (an NSAID/salicylate) and amitriptyline (a TCA), including reports of intracranial hemorrhage within 30 days of concomitant use.
Mechanism: Unknown, though additive effects on platelet function and mucosal/vascular integrity are plausible. Neither agent requires a caution about prodrug status here.
Evidence: Established. Onset: unspecified. Severity: major.
- Monitor for signs and symptoms of bleeding (GI bleeding, bruising, neurologic changes suggestive of ICH).
- Assess additional bleeding-risk factors (anticoagulants, antiplatelets, age, ulcer history).
- Consider a non-NSAID analgesic alternative where clinically appropriate.
What happens
An increased risk of bleeding
Interaction Deep Dive
Coadministering NSAIDs with tricyclic antidepressants warrants caution, since it may heighten the risk of bleeding, including intracranial hemorrhage occurring within 30 days of combined use1. If a patient receives NSAIDs and tricyclic antidepressants together, watch for indications of heightened bleeding.
Why it happens (mechanism)
Unknown
How to manage this interaction
This combination can be used with care under your care team's supervision. Here is how it is typically handled:
- Keep taking both as prescribed unless your doctor or pharmacist tells you otherwise.
- Your team may monitor you more closely for any signs of bleeding.
- They may review whether a different pain reliever is a better fit for you.
Tell your prescriber promptly if you notice unusual bruising, black or bloody stools, blood in vomit or urine, or a sudden severe headache. Also mention any blood thinners or aspirin you take, since these add to the 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 with antidepressants, including tricyclic antidepressants, SSRIs, serotonin-norepinephrine reuptake inhibitors, and MAOIs, was associated with a heightened risk of intracranial hemorrhage within 30 days of the concurrent use when compared to using an antidepressant by itself. No meaningful difference was observed among the antidepressant drug classes regarding this elevated risk; nevertheless, male patients carried a greater risk than female patients 1..
Common questions
Can I take Salsalate and Amitriptyline together?
Taking amitriptyline with salsalate can increase your bleeding risk, so keep taking both as prescribed but watch for signs of bleeding and report them right away to your pharmacist or doctor. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Salsalate 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 Salsalate and Amitriptyline interaction managed?
This combination can be used with care under your care team's supervision. Here is how it is typically handled: Keep taking both as prescribed unless your doctor or pharmacist tells you otherwise. Your team may monitor you more closely for any signs of bleeding. They may review whether a different pain reliever is a better fit for you. Tell your prescriber promptly if you notice unusual bruising,… 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 Salsalate 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 Salsalate
These medications also interact with supplements
Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
Check another combination
Our instant two-drug interaction checker is almost here.
Still have questions about this combination?
Every question gets a real answer from a licensed pharmacist — free, and usually within a day.
Ask the pharmacist