Acetaminophen And Codeine and Amitriptylinoxide: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 1, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Acetaminophen And Codeine
Amitriptylinoxide
No brand names on record
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.
Your two medicines can each nudge up serotonin, a natural chemical in your brain and body. Amitriptylinoxide is an antidepressant, and codeine (the pain reliever paired with acetaminophen) can also add to serotonin activity. Taken together, there is a small chance of too much serotonin, called serotonin syndrome.
This is mostly a theoretical concern, but it is worth knowing the warning signs: agitation, a fast heartbeat, sweating, shivering, muscle twitching, or feeling confused. These are most likely when you first start or when a dose changes. The good news is your care team can watch for this and manage it, so keep taking both as prescribed and reach out if you feel off.
Effect: Additive serotonergic activity from codeine (a weak serotonergic opioid) plus amitriptylinoxide (a TCA with serotonergic properties) may increase risk of serotonin syndrome.
- Direction: Additive pharmacodynamic effect, not a PK enzyme interaction; risk is increased serotonergic burden.
- Evidence: Theoretical; severity rated major.
- Onset: Unspecified; highest risk at initiation and dose changes.
- Monitoring: Observe for hyperthermia, autonomic instability, neuromuscular signs (clonus, hyperreflexia, rigidity), and mental status changes.
- Management: If clinically appropriate to co-prescribe, monitor closely; discontinue codeine if serotonin syndrome is suspected.
What happens
Increased risk of serotonin syndrome
Interaction Deep Dive
Concomitant use of opioids, such as codeine, with serotonergic drugs has resulted in serotonin syndrome. If concomitant use is needed, carefully observe the patient, particularly during treatment initiation and dose adjustments. Discontinue codeine if serotonin syndrome is suspected123.
Why it happens (mechanism)
Additive serotonergic effects
How to manage this interaction
Both drugs can raise serotonin, so the main step is watchful monitoring, especially when either medicine is started or a dose is changed.
- Keep taking both exactly as prescribed unless your prescriber tells you otherwise.
- Watch for agitation, confusion, fast heart rate, high fever, heavy sweating, shivering, muscle twitching, or stiffness.
- If several of these appear, seek medical care promptly, as the codeine product may need to be stopped.
Ask your pharmacist or doctor to review your full medication list. Your dose may need to be adjusted and individualized, and your team may choose to monitor you more closely.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
Common questions
Can I take Acetaminophen And Codeine and Amitriptylinoxide together?
Combining codeine with amitriptylinoxide carries a theoretical risk of serotonin syndrome; keep taking both as prescribed but watch for agitation, fever, sweating, or muscle twitching and get medical help if these appear. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Amitriptylinoxide 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 Acetaminophen And Codeine and Amitriptylinoxide interaction managed?
Both drugs can raise serotonin, so the main step is watchful monitoring, especially when either medicine is started or a dose is changed. Keep taking both exactly as prescribed unless your prescriber tells you otherwise. Watch for agitation, confusion, fast heart rate, high fever, heavy sweating, shivering, muscle twitching, or stiffness. If several of these appear, seek medical care promptly, as… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
Questions for your pharmacist
- Does my dose of Acetaminophen And Codeine or Amitriptylinoxide 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 (3)
- Product Information: Codeine sulfate oral tablets, codeine sulfate oral tablets. West-Ward Pharmaceuticals Corp (per DailyMed), Eatontown, NJ, 2016. DailyMed
- Product Information: Codeine sulfate oral solution, codeine sulfate oral solution. Hikma Pharmaceuticals USA Inc(per FDA), Berkeley Heights, NJ, 2023. DailyMed
- Product Information: Codeine sulfate oral tablets, codeine sulfate oral tablets. Hikma Pharmaceuticals USA Inc. (per FDA), Berkeley Heights, NJ, 2023. DailyMed
Keep reading about Acetaminophen And Codeine
Keep reading about Amitriptylinoxide
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