Acetaminophen And Codeine and Dextromethorphan: 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
Dextromethorphan
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 given a medicine that combines acetaminophen with codeine, and you're also taking dextromethorphan (the cough medicine in Delsym). Both of these can gently raise a brain chemical called serotonin. When two medicines do that at the same time, there's a small chance serotonin can build up too much, causing something called serotonin syndrome.
Signs to watch for include feeling agitated or restless, shivering, sweating, a fast heartbeat, muscle twitching, or confusion. This is uncommon, and the risk is mostly a theoretical concern. Your care team can manage it easily by keeping an eye on you, especially when you first start or change doses. If anything feels off, call your pharmacist or doctor.
Effect: Additive serotonergic activity, increasing the theoretical risk of serotonin syndrome. Both codeine (an opioid with weak serotonergic properties) and dextromethorphan (a serotonin reuptake inhibitor at higher exposures) contribute to central serotonin.
- Mechanism: Pharmacodynamic, additive serotonergic effects (not a PK interaction).
- Direction: Increased serotonergic tone.
- Onset: Unspecified; highest vigilance at initiation and dose escalation.
- Evidence: Theoretical; case-report based for opioid plus serotonergic combinations.
- Management: If co-use is needed, monitor for autonomic instability, neuromuscular findings (clonus, hyperreflexia), and mental status changes. 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
The good news is this combination can usually be managed safely by your care team. Here is what typically happens and what you can do:
- Keep taking both as prescribed unless your prescriber tells you otherwise.
- Your team may watch you more closely, especially when you start either medicine or change a dose.
- Doses can be individualized by your care team if needed.
- Tell your pharmacist or doctor about all serotonergic medicines you take (including antidepressants and other cough or cold products).
Seek prompt care if you notice agitation, shivering, sweating, fast heartbeat, muscle twitching, or confusion.
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 Dextromethorphan together?
Taking acetaminophen/codeine with dextromethorphan slightly raises the theoretical risk of serotonin syndrome, so watch for agitation, shivering, sweating, fast heartbeat, or muscle twitching, especially when starting or changing doses, and contact your care team if these occur. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Dextromethorphan 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 Dextromethorphan interaction managed?
The good news is this combination can usually be managed safely by your care team. Here is what typically happens and what you can do: Keep taking both as prescribed unless your prescriber tells you otherwise. Your team may watch you more closely, especially when you start either medicine or change a dose. Doses can be individualized by your care team if needed. Tell your pharmacist or doctor abou… 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 Acetaminophen And Codeine or Dextromethorphan 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 Dextromethorphan
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