Acetaminophen And Codeine and Nafcillin: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 1, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Acetaminophen And Codeine
Nafcillin
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.
You're taking a codeine pain medicine (combined with acetaminophen) along with the antibiotic nafcillin. Here's the thing worth knowing: codeine has to be broken down in your body into an active form to relieve pain. Nafcillin can speed up the liver enzyme that handles codeine, so your body may clear it faster and turn less of it into the pain-relieving form.
What that can mean for you is less pain relief than expected, and if you already take codeine regularly, you might feel early withdrawal symptoms like restlessness, sweating, or an upset stomach. This is a manageable situation. Your care team can adjust your dose and watch how you're doing, so let your pharmacist or doctor know if your pain isn't controlled.
Effect: Nafcillin, a CYP3A4 inducer, may reduce codeine exposure with resultant decreased opioid efficacy and possible precipitation of withdrawal in physically dependent patients.
- Mechanism: Induction of CYP3A4 shifts codeine metabolism toward norcodeine, leaving less substrate for CYP2D6-mediated conversion to morphine (the active analgesic metabolite), lowering morphine levels.
- Direction: Reduced active opioid effect (treatment failure/withdrawal).
- Evidence: Theoretical. Onset unspecified.
- Management: Monitor for reduced analgesia and withdrawal signs; codeine dose may be increased and individualized. If nafcillin is discontinued, anticipate rising codeine effect, consider dose reduction, and monitor for sedation/respiratory depression.
What happens
Reduced codeine and morphine exposure, reduced opioid efficacy and precipitation of opioid withdrawal
Interaction Deep Dive
When codeine is taken alongside CYP3A4 inducers, the outcome may be lower codeine concentrations, elevated norcodeine concentrations, and diminished CYP2D6-mediated metabolism, which in turn yields reduced morphine levels. This can translate into weaker efficacy or trigger a withdrawal syndrome in individuals who have become physically dependent. Should this combination be required, patients should be watched carefully for reduced efficacy or indications of opioid withdrawal syndrome, and raising the codeine dose should be considered when warranted. When a CYP3A4 inducer is being stopped, a reduction in codeine dose should be considered, along with close observation of patients for evidence of sedation or respiratory depression12.
Why it happens (mechanism)
Induction of CYP3A4-mediated codeine metabolism
How to manage this interaction
Keep taking both medications as prescribed unless your care team tells you otherwise. This interaction is manageable.
- Watch for less pain relief than usual, or signs of opioid withdrawal (restlessness, sweating, chills, stomach cramps, runny nose) if you take codeine regularly.
- Your codeine dose may need to be adjusted and individualized by your care team, and they may monitor you more closely while you're on both.
- If nafcillin is later stopped, tell your team, because your codeine dose may need to be lowered and you should watch for extra sleepiness or slowed breathing.
- Report any changes to your pharmacist or prescriber rather than adjusting doses yourself.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Acetaminophen And Codeine and Nafcillin together?
Nafcillin can speed up how your body handles codeine, which may weaken its pain relief and, in regular users, trigger withdrawal. Tell your pharmacist or doctor if your pain isn't controlled, since your dose can be adjusted and monitored. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Nafcillin 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 Nafcillin interaction managed?
Keep taking both medications as prescribed unless your care team tells you otherwise. This interaction is manageable. Watch for less pain relief than usual, or signs of opioid withdrawal (restlessness, sweating, chills, stomach cramps, runny nose) if you take codeine regularly. Your codeine dose may need to be adjusted and individualized by your care team, and they may monitor you more closely whi… 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 Nafcillin 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 Nafcillin
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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