Oxycodone 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
Oxycodone
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.
Both of these medicines are opioid pain relievers. Your acetaminophen and codeine product contains codeine, and the other product contains oxycodone. When you take two opioids together, their effects add up. That can mean stronger drowsiness, slower breathing, and in serious cases very deep sedation. There is also a smaller, more theoretical chance of a reaction called serotonin syndrome (things like agitation, sweating, fast heartbeat, or shakiness).
The good news is your care team can manage this by using the lowest dose that works for the shortest time and by watching you closely. Please talk with your doctor or pharmacist before combining these, and never adjust doses on your own.
Effect: Additive CNS and respiratory depression with these two opioids (codeine plus oxycodone); a theoretical additive serotonergic risk (serotonin syndrome) is also cited.
- Mechanism: Additive mu-opioid CNS depression; additive serotonergic effects.
- Direction: Increased sedative and respiratory-depressant burden.
- Evidence/onset: Theoretical; onset unspecified.
- Management: Reserve for patients without adequate alternatives. Use lowest effective dose and shortest duration. Monitor for sedation, respiratory depression, and serotonin syndrome, especially at initiation and dose changes. For oxycodone ER/oxycodone-naloxone start at 1/3 to 1/2 usual dose; oxycodone/acetaminophen ER at 1 tablet q12h. Consider co-prescribing naloxone. Discontinue oxycodone if serotonin syndrome is suspected.
What happens
Increased risk of respiratory and CNS depression and an increased risk of serotonin syndrome
Interaction Deep Dive
When oxyCODONE is given together with a serotonergic CNS depressant, the combination can lead to serotonin syndrome as well as cumulative CNS depression, raising the likelihood of respiratory depression, deep sedation, coma, and fatal outcomes. Such combined prescribing should be limited to patients whose alternative treatment options prove insufficient. Should concurrent therapy be required, employ the smallest effective dose for the shortest possible time. Watch patients closely for signs of serotonin syndrome, sedation, and respiratory depression, especially when starting treatment and when adjusting the dose. If serotonin syndrome is suspected, stop oxyCODONE. Prescribing naloxone for emergency management of opioid overdose should be considered1. Begin oxyCODONE extended-release tablets and the oxyCODONE/naloxone combination at one-third to one-half of the standard starting dose23, and start oxyCODONE/acetaminophen extended-release tablets at the lowered dose of 1 tablet every 12 hours4.
Why it happens (mechanism)
Additive CNS depression; additive serotonergic effects
How to manage this interaction
Keep taking both only as prescribed and do not change doses yourself. Because these are two opioids, your care team will typically:
- Use the lowest effective dose for the shortest time, and often start oxycodone at a reduced dose.
- Monitor you more closely for excess drowsiness, slow or shallow breathing, and signs of serotonin syndrome (agitation, sweating, fast heartbeat, shakiness), especially when starting or adjusting.
- Consider prescribing naloxone for emergency use.
Call your prescriber or pharmacist right away if you feel unusually sedated, hard to wake, or have trouble breathing. Your dose may need to be adjusted and individualized by your care team.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) Observational research has shown that using opioid analgesics together with benzodiazepines raises the risk of drug-related death when compared with using opioid analgesics by themselves. Given the comparable pharmacological characteristics, it is reasonable to anticipate a similar risk when other CNS depressant medications are used together with opioid analgesics 3.
Common questions
Can I take Oxycodone and Acetaminophen And Codeine together?
Taking codeine and oxycodone together stacks two opioids, raising the risk of dangerous drowsiness and slowed breathing, so use only under close medical supervision at the lowest effective dose, and ask about having naloxone on hand. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Oxycodone 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 Oxycodone and Acetaminophen And Codeine interaction managed?
Keep taking both only as prescribed and do not change doses yourself. Because these are two opioids, your care team will typically: Use the lowest effective dose for the shortest time, and often start oxycodone at a reduced dose. Monitor you more closely for excess drowsiness, slow or shallow breathing, and signs of serotonin syndrome (agitation, sweating, fast heartbeat, shakiness), especially wh… 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 Oxycodone 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 (4)
- Product Information: Oxycodone HCl acetaminophen oral tablets, oxycodone HCl acetaminophen oral tablets. Mayne Pharma (per DailyMed), Greenville, NC, 2021.
- Product Information: TARGINIQ(TM) ER oral extended release tablets, oxycodone HCl naloxone HCl oral extended release tablets. Purdue Pharma LP (per FDA), Stamford, CT, 2016.
- Product Information: OXYCONTIN(R) oral extended-release tablets, oxycodone HCl oral extended-release tablets. Purdue Pharma LP (per FDA), Stamford, CT, 2023. DailyMed
- Product Information: XARTEMIS(TM) XR oral extended-release tablets, oxycodone HCl acetaminophen oral extended-release tablets. Mallinckrodt Brand Pharmaceuticals, Inc. (per FDA), Hazelwood, MO, 2016.
Keep reading about Acetaminophen And Codeine
Keep reading about Oxycodone
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.
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