Nortriptyline and Acetaminophen And Codeine: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jun 30, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Acetaminophen And Codeine
Nortriptyline
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 pain medicine contains codeine, and nortriptyline is an antidepressant. When taken together, two things can add up. First, both can affect chemicals in the brain, and rarely this can lead to a reaction called serotonin syndrome (things like agitation, shivering, fast heartbeat, sweating, or muscle twitching). Second, both can slow down the gut and bladder, so you may notice severe constipation or trouble urinating, which in rare cases can become a serious blocked bowel.
This is a possible, theoretical concern, not a certainty. Your care team can manage it safely by watching you closely, especially when starting or changing doses. Please don't stop either medicine on your own, just talk with your pharmacist or doctor.
Effect: Additive risk of serotonin syndrome and additive anticholinergic/opioid effects on GI and bladder motility, potentially leading to severe constipation, urinary retention, or paralytic ileus.
- Mechanism: Codeine has serotonergic activity; nortriptyline is a TCA with serotonergic and anticholinergic properties. Effects are additive (PD interaction), not primarily PK.
- Direction/magnitude: Increased risk of both toxicities; magnitude not quantified.
- Evidence: Theoretical; severity rated major.
- Management: Monitor for serotonin syndrome (autonomic instability, clonus, hyperreflexia, agitation) and for urinary retention/severe constipation, particularly at initiation and dose changes. Discontinue codeine if serotonin syndrome is suspected.
What happens
Increased risk of paralytic ileus; increased risk of serotonin syndrome
Interaction Deep Dive
Serotonin syndrome has been reported when opioids like codeine are taken together with serotonergic agents. Furthermore, combining codeine with anticholinergic medications can heighten the likelihood of urinary retention and serious constipation, potentially progressing to paralytic ileus. When such combined use cannot be avoided, watch the patient carefully for urinary retention, serious constipation, and any signs and symptoms of serotonin syndrome1 as therapy begins and doses are modified. Should serotonin syndrome be suspected, stop codeine 2.
Why it happens (mechanism)
Additive effects on gastric motility; additive serotonergic effects
How to manage this interaction
If both medicines are prescribed together, the goal is to use them safely, not to fear them.
- Keep taking both as prescribed unless your prescriber tells you otherwise.
- Your care team may monitor you more closely, especially when starting or adjusting a dose, and doses may be adjusted and individualized by your team.
- Watch for and report severe constipation, belly pain or bloating, or trouble urinating.
- Seek prompt help for signs of serotonin syndrome: agitation, confusion, fast heartbeat, sweating, shivering, tremor, or muscle twitching.
Bring these symptoms to your pharmacist or doctor right away so they can guide any changes.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Nortriptyline and Acetaminophen And Codeine together?
Taking codeine (in your acetaminophen/codeine) with nortriptyline can add up to raise the risk of serotonin syndrome and serious constipation or bladder problems, so watch for those symptoms and keep in close contact with your care team, especially when doses change. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Nortriptyline and Acetaminophen And Codeine 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 Nortriptyline and Acetaminophen And Codeine interaction managed?
If both medicines are prescribed together, the goal is to use them safely, not to fear them. Keep taking both as prescribed unless your prescriber tells you otherwise. Your care team may monitor you more closely, especially when starting or adjusting a dose, and doses may be adjusted and individualized by your team. Watch for and report severe constipation, belly pain or bloating, or trouble urina… 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.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Nortriptyline or Acetaminophen And Codeine 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 (2)
- Product Information: Codeine sulfate oral tablets, codeine sulfate oral tablets. West-Ward Pharmaceuticals Corp (per DailyMed), Eatontown, NJ, 2016. DailyMed
- Product Information: CARISOPRODOL, ASPIRIN, CODEINE PHOSPHATE oral tablets, carisoprodol, aspirin, codeine phosphate oral tablets. Ingenus Pharmaceuticals LLC (per DailyMed), Orlando, FL, 2021. DailyMed
Keep reading about Acetaminophen And Codeine
Keep reading about Nortriptyline
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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.
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