Acetaminophen And Codeine and Phenobarbital: 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
Phenobarbital
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've been prescribed Tylenol with codeine along with phenobarbital. There are two things to know here. First, both medicines can slow down your brain and breathing, so together they can make you very drowsy, slow your breathing, or drop your blood pressure. That's the more serious concern.
Second, phenobarbital can speed up how your body clears codeine, which may make the codeine work less well for pain. And if phenobarbital is ever stopped, the codeine level can climb back up. The good news is your care team can manage this by keeping doses low, watching you closely, and adjusting as needed. Never change either medicine on your own, but do call your doctor or pharmacist with questions.
Direction: Dual concern. (1) Additive CNS and respiratory depression (pharmacodynamic). (2) Phenobarbital is a strong CYP3A4/2C inducer that can reduce codeine exposure, lowering analgesic efficacy.
- Codeine is a prodrug (CYP2D6 to morphine); the dominant clinical risk here is additive sedation/respiratory depression rather than a clean efficacy loss.
- Onset: unspecified. Evidence: theoretical. Severity: major.
- Management: reserve for patients lacking alternatives; use lowest effective dose and shortest duration. Monitor for respiratory depression, hypotension, sedation, or opioid withdrawal.
- On discontinuation of phenobarbital, codeine concentrations may rise; watch for increased opioid effect and respiratory depression.
What happens
Increased risk of CNS depression and reduced codeine exposure
Interaction Deep Dive
Taking codeine together with phenobarbital, or its prodrug primidone, can cause hypotension, respiratory depression, and deep sedation, with the potential to progress to coma or death. This combination may also reduce the effectiveness of codeine. When these drugs must be given together, watch for indications of respiratory depression or opioid withdrawal, and weigh the need for dose adjustments. If phenobarbital or primidone is stopped, codeine plasma levels will rise, which can heighten or extend both the therapeutic and adverse effects of codeine, including the danger of serious respiratory depression2. Prescribing these agents concurrently should be reserved for patients in whom other treatment options are insufficient. Keep doses and treatment durations at the lowest level needed. Monitor patients closely for indications of sedation and respiratory depression13.
Why it happens (mechanism)
Additive CNS depression; induction of CYP3A4-mediated metabolism of codeine
How to manage this interaction
Keep taking both exactly as prescribed unless your care team tells you otherwise. This combination is usually reserved for when other options aren't enough.
- Your team will likely use the lowest dose for the shortest time and may monitor you more closely for slowed or shallow breathing, extreme drowsiness, or low blood pressure.
- Doses may need to be adjusted and individualized by your care team.
- Tell your prescriber if the codeine seems to stop controlling your pain, or if you feel withdrawal symptoms.
- Let them know before phenobarbital is stopped, since your codeine effect could get stronger and need rechecking.
Get emergency help for very slow breathing, blue lips, or being hard to wake.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Acetaminophen And Codeine and Phenobarbital together?
Combining codeine with phenobarbital adds up to dangerous sedation and slowed breathing, and phenobarbital may also weaken codeine's pain relief; use only when necessary, at the lowest dose, with close monitoring by your care team. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Phenobarbital 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 Phenobarbital interaction managed?
Keep taking both exactly as prescribed unless your care team tells you otherwise. This combination is usually reserved for when other options aren't enough. Your team will likely use the lowest dose for the shortest time and may monitor you more closely for slowed or shallow breathing, extreme drowsiness, or low blood pressure. Doses may need to be adjusted and individualized by your care team. Te… 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 Phenobarbital 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 (3)
- Product Information: CARISOPRODOL, ASPIRIN, CODEINE PHOSPHATE oral tablets, carisoprodol, aspirin, codeine phosphate oral tablets. Ingenus Pharmaceuticals LLC (per DailyMed), Orlando, FL, 2021. DailyMed
- Product Information: codeine sulfate oral tablets, codeine sulfate oral tablets. West-Ward Pharmaceuticals Corp. (per FDA), Eatontown, NJ, 2017. DailyMed
- Product Information: SEZABY(TM) intravenous injection, phenobarbital sodium intravenous injection. Sun Pharmaceutical Industries Inc (per manufacturer), Cranbury, NJ, 2022. DailyMed
Keep reading about Acetaminophen And Codeine
Keep reading about Phenobarbital
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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