Acetaminophen And Codeine and Diltiazem: 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
Diltiazem
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 diltiazem is a blood pressure and heart medicine. Diltiazem can slow down one of the liver enzymes (CYP3A4) that helps break down codeine. When that pathway is slowed, more codeine (and the morphine your body makes from it) can build up in your system.
That can mean stronger opioid effects like heavy drowsiness, confusion, or very slow, shallow breathing, which can be dangerous. The good news: this is mostly a theoretical concern, and your care team can manage it easily by keeping an eye on how you respond and adjusting your codeine dose if needed. Keep taking both as prescribed, and let your pharmacist or doctor know if you feel unusually sleepy or short of breath.
Effect: Diltiazem, a moderate CYP3A4 inhibitor, may reduce CYP3A4-mediated metabolism of codeine, increasing codeine and morphine exposure and raising the risk of sedation and respiratory depression.
Note on direction: Codeine is a prodrug activated to morphine primarily via CYP2D6; CYP3A4 handles a competing N-demethylation pathway. CYP3A4 inhibition shifts metabolism, and per the source data the net documented effect is increased codeine and morphine concentrations.
- Onset: unspecified
- Evidence: theoretical
- Severity: major
- Management: monitor for respiratory depression and sedation; consider codeine dose reduction until stable effects seen. On diltiazem discontinuation, watch for opioid withdrawal and consider a codeine dose increase.
What happens
Increased codeine and morphine exposure
Interaction Deep Dive
Concomitant use of codeine with CYP3A4 inhibitors has resulted in increased codeine and morphine concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of codeine is achieved. If concomitant use is needed, closely monitor patients for respiratory depression and sedation, and consider dose reduction of codeine until stable drug effects have been observed. If a CYP3A4 inhibitor is being discontinued, monitor patients for signs of opioid withdrawal, and consider increasing dose of codeine until stable drug effects have been observed12.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated codeine metabolism
How to manage this interaction
This can usually be managed safely with a few simple steps by your care team:
- Keep taking both as prescribed unless your prescriber tells you otherwise.
- Your team may monitor you more closely for heavy drowsiness or slow, shallow breathing, especially when diltiazem is first added.
- Your codeine dose may need to be adjusted and individualized by your care team until they see how you respond.
- If diltiazem is later stopped, tell your team, since your codeine dose may need review to avoid withdrawal or reduced pain control.
Call your pharmacist or doctor right away if you feel unusually sedated or short of breath.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Acetaminophen And Codeine and Diltiazem together?
Diltiazem may raise codeine and morphine levels, increasing the risk of excess sedation or slowed breathing, so watch for drowsiness or breathing changes and let your care team adjust and monitor your codeine dose. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Diltiazem 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 Diltiazem interaction managed?
This can usually be managed safely with a few simple steps by your care team: Keep taking both as prescribed unless your prescriber tells you otherwise. Your team may monitor you more closely for heavy drowsiness or slow, shallow breathing, especially when diltiazem is first added. Your codeine dose may need to be adjusted and individualized by your care team until they see how you respond. If dil… 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 Diltiazem 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 Diltiazem
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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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