Hydrocodone 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
Hydrocodone
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 opioids. Codeine (combined with acetaminophen) and hydrocodone both work in the same way in your body. Taking them together adds up their effects, which can make you very sleepy and, more importantly, can slow your breathing down to a dangerous level. There is also a smaller chance of a reaction called serotonin syndrome, which can cause agitation, a fast heartbeat, sweating, and shivering.
The good news is your care team can manage this. Please don't stop either medicine on your own. Talk with your doctor or pharmacist so they can decide the safest plan for you.
Two opioid agonists (codeine, a CYP2D6 prodrug for morphine, plus hydrocodone) produce additive CNS and respiratory depression. Hydrocodone also carries serotonergic activity, so combined use adds a theoretical serotonin syndrome risk.
- Direction/mechanism: additive PD effect (sedation, hypoventilation) plus additive serotonergic effect.
- Evidence: theoretical; severity major.
- Management: avoid combined opioid use where possible; if warranted, use the lowest effective dose and shortest duration. Consider reducing the dose of one agent. Monitor for sedation, respiratory depression, and serotonin syndrome. Discontinue hydrocodone if serotonin syndrome is suspected. Consider co-prescribing naloxone.
What happens
Increased risk of respiratory and CNS depression and an increased risk of serotonin syndrome
Interaction Deep Dive
Avoid concomitant use of opioid cough medication formulations and CNS depressants1. Also, concomitant use of HYDROcodone, with serotonergic drugs has resulted in serotonin syndrome. Reserve the concomitant use of non-cough HYDROcodone products and CNS depressants to patients for whom alternatives are inadequate. If concomitant use is necessary, use the lowest dose and shortest duration necessary to achieve treatment goals. Consider using a lower dose of HYDROcodone or the CNS depressant and closely monitor for sedation, respiratory depression, and signs and symptoms of serotonin syndrome. Discontinue HYDROcodone if serotonin syndrome is suspected 234. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose 56.
Why it happens (mechanism)
Additive CNS depression; additive serotonergic effects
How to manage this interaction
Because both drugs are opioids, care teams usually try to avoid using them together when a safer option exists. If both are truly needed, your team will typically:
- Use the lowest dose for the shortest time needed.
- Possibly lower the dose of one medicine, tailored to you.
- Monitor you more closely for heavy sedation and slowed breathing.
- Consider prescribing naloxone for emergencies.
Keep taking both exactly as prescribed for now. Learn the warning signs (extreme drowsiness, slow or shallow breathing, agitation, fast heartbeat, sweating), and contact your pharmacist or prescriber before making any changes.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
Common questions
Can I take Hydrocodone and Acetaminophen And Codeine together?
Combining these two opioids adds up their sedating effects and can dangerously slow breathing, so this pairing is generally avoided. Don't change anything on your own; talk with your doctor or pharmacist about the safest plan. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Hydrocodone 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 Hydrocodone and Acetaminophen And Codeine interaction managed?
Because both drugs are opioids, care teams usually try to avoid using them together when a safer option exists. If both are truly needed, your team will typically: Use the lowest dose for the shortest time needed. Possibly lower the dose of one medicine, tailored to you. Monitor you more closely for heavy sedation and slowed breathing. Consider prescribing naloxone for emergencies. Keep taking bot… 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 Hydrocodone 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 (6)
- Product Information: VITUZ(R) oral solution, hydrocodone bitartrate chlorpheniramine maleate oral solution. Hawthorn Pharmaceuticals, Inc. (per FDA), Morristown, NJ, 2017.
- Product Information: ZOHYDRO(R) ER oral extended-release capsules, hydrocodone bitartrate oral extended-release capsules. Pernix Therapeutics, LLC. (per FDA), Morristown, NJ, 2016. DailyMed
- Product Information: NORCO 5/325 oral tablets, hydrocodone bitartrate acetaminophen oral tablets. Allergan USA, Inc. (per DailyMed), Irvine, CA, 2016.
- Product Information: VANTRELA(TM) ER oral extended-release tablets, hydrocodone bitartrate oral extended-release tablets. Teva Pharmaceuticals USA, Inc (per manufacturer), North Wales, PA, 2017. DailyMed
- Product Information: HYSINGLA(R) ER oral extended-release tablets, hydrocodone bitartrate oral extended-release tablets. Purdue Pharma LP (per FDA), Stamford, CT, 2023. DailyMed
- Product Information: APADAZ(R) oral tablets, benzhydrocodone acetaminophen oral tablets. Zevra Therapeutics, Inc. (per FDA), Celebration, FL, 2023. DailyMed
Keep reading about Acetaminophen And Codeine
Keep reading about Hydrocodone
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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