Acetaminophen And Codeine and Nefazodone: 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
Nefazodone
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 nefazodone is an antidepressant. Taking them together can raise the level of codeine and morphine (the active form) in your body. That can make you more drowsy, more sedated, and in some cases cause slower, weaker breathing.
Both medicines can also nudge up your body's serotonin. Rarely, that can cause a reaction called serotonin syndrome with agitation, shakiness, sweating, a fast heartbeat, or confusion. This concern is based on how the drugs work rather than lots of cases, so try not to worry. Please keep taking both as prescribed and let your pharmacist or doctor know you take them together so they can watch you and tailor your dose.
Effect: Nefazodone inhibits CYP3A4, reducing codeine metabolism and increasing codeine and its active metabolite morphine exposure, raising risk of sedation and respiratory depression. Both agents are serotonergic, adding risk of serotonin syndrome.
- Direction: increased opioid effect; additive serotonergic effect.
- Evidence: theoretical; severity: major; onset unspecified.
- Management: if used together, consider codeine dose reduction until stable effects seen; monitor for respiratory depression, sedation, and serotonin syndrome (autonomic instability, clonus, hyperreflexia, mental status changes).
- If nefazodone is discontinued, monitor for opioid withdrawal and consider re-titrating codeine upward.
- Discontinue codeine if serotonin syndrome is suspected.
What happens
Increased codeine and morphine exposure and an increased risk of serotonin syndrome
Interaction Deep Dive
Taking codeine together with CYP3A4 inhibitors like nefazodone has produced elevated levels of both codeine and morphine. When the combination cannot be avoided, a reduction in the codeine dose should be considered until stable drug effects are seen, with close observation for sedation, respiratory depression, and serotonin syndrome. Should the CYP3A4 inhibitor be withdrawn, watch the patient for indications of opioid withdrawal and consider raising the codeine dose until stable drug effects are achieved. Beyond this, giving opioids alongside serotonergic agents (nefazodone) has led to serotonin syndrome. If the two must be used together, monitor the patient carefully, especially when therapy is started and doses are changed. Codeine should be stopped if serotonin syndrome is suspected12.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated codeine metabolism; additive serotonergic effects
How to manage this interaction
This combination can be used safely when your care team keeps an eye on you.
- Keep taking both as prescribed unless your prescriber tells you otherwise.
- Your codeine dose may need to be adjusted and individualized, and your team may monitor you more closely, especially when starting or changing doses.
- Watch for and report unusual drowsiness, slow or shallow breathing, or signs of serotonin syndrome (agitation, sweating, shivering, tremor, fast heartbeat, confusion).
- If nefazodone is ever stopped, your codeine dose may need to be revisited, so tell your team about any changes.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Acetaminophen And Codeine and Nefazodone together?
Nefazodone can raise codeine/morphine levels and add serotonin risk, so keep taking both as prescribed but ask your care team to monitor you and tailor your codeine dose; seek help for heavy sedation, slow breathing, or agitation and tremor. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Nefazodone 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 Nefazodone interaction managed?
This combination can be used safely when your care team keeps an eye on you. Keep taking both as prescribed unless your prescriber tells you otherwise. Your codeine dose may need to be adjusted and individualized, and your team may monitor you more closely, especially when starting or changing doses. Watch for and report unusual drowsiness, slow or shallow breathing, or signs of serotonin syndrome… 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 Nefazodone 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 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 Nefazodone
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