Acetaminophen And Codeine and Pentobarbital: 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
Pentobarbital
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, an opioid, and it's paired here with pentobarbital, a barbiturate that also calms the nervous system. Both of these medicines slow down your brain and your breathing. When you take them together, those slowing effects add up, which can lead to very deep drowsiness, dangerously slow breathing, low blood pressure, or in serious cases, not waking up.
This doesn't mean you can never use both, but it does need care. Please talk with your pharmacist or doctor before combining them. Your care team can pick the lowest doses needed, watch you closely, and keep you safe.
Effect: Additive CNS and respiratory depression from combining codeine (opioid) with pentobarbital (barbiturate CNS depressant).
- Mechanism: Additive pharmacodynamic CNS depression; both agents depress respiratory drive and consciousness.
- Direction: Increased risk of hypotension, profound sedation, respiratory depression, coma, death.
- Onset: Unspecified; evidence is theoretical but severity is major.
- Management: Avoid where possible. Reserve for patients lacking adequate alternatives. Use lowest effective dose and shortest duration; consider reducing dose of either agent. Monitor closely for sedation and respiratory depression. Consider prescribing naloxone.
What happens
An increased risk of respiratory and CNS depression
Interaction Deep Dive
Do not combine opioid-containing cough preparations with agents that depress the CNS. Rates of emergency department visits and deadly overdose have risen when opioid analgesics are taken together with benzodiazepines2. Taking codeine alongside CNS depressants can heighten the likelihood of hypotension, respiratory depression, deep sedation, coma, and death. Only prescribe these medications together in patients whose alternative treatment choices prove inadequate. Restrict both the doses and the treatment periods to the least amount necessary. Monitor patients carefully for indications of sedation and respiratory depression. When simultaneous use is justified, consider providing naloxone so that opioid overdose can be treated emergently341.
Why it happens (mechanism)
Additive CNS depression
How to manage this interaction
Keep taking both exactly as prescribed unless your care team tells you otherwise. This combination is best avoided when possible, so your team may look for an alternative to one of the medicines.
- If both are needed, your team will typically use the lowest dose and shortest duration possible, and may lower the dose of the codeine or the pentobarbital.
- They may monitor you more closely for heavy sedation and slowed breathing.
- Your prescriber may also give you naloxone as a rescue medicine, just in case.
Call for help right away if you notice extreme drowsiness, confusion, or slow or shallow breathing. Raise any questions with your pharmacist or doctor.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
4 reports — tap to read
a) One study found that between 2004 and 2011 the rate of emergency department visits related to nonmedical use involving opioid analgesics together with benzodiazepines rose significantly from 11 to 34.2 per 100,000. Deaths from drug overdose attributed to both prescribed and above-prescribed doses of these two drug classes also rose significantly from 0.6 to 1.7 per 100,000, and overdose deaths attributable to benzodiazepines rose significantly from 18% to 31% 2.
b) In a prospective cohort study, the rate of overdose deaths associated with the dispensing of both opioid analgesics and benzodiazepines was 10 times greater than that seen with the dispensing of opioid analgesics alone (7 versus 0.7 per 10,000 person years) 2.
c) In a cohort study using data from 2004 to 2009, the risk of fatal overdose rose significantly by 2.33 fold among patients taking opioid analgesics who had a history of a benzodiazepine prescription, and rose by 3.86 fold among those with a current benzodiazepine prescription, when compared with patients taking opioid analgesics who had no history of a benzodiazepine prescription. The risk of drug overdose deaths grew as the daily doses of benzodiazepines increased 2.
d) Observational studies have shown that using opioid analgesics and benzodiazepines together raises the risk of drug-related mortality compared with using opioid analgesics alone. Given their comparable pharmacological properties, a similar risk can reasonably be anticipated when other CNS depressant drugs are combined with opioid analgesics 34.
Common questions
Can I take Acetaminophen And Codeine and Pentobarbital together?
Codeine and pentobarbital both depress the brain and breathing, and together that risk adds up, so this combination should be avoided when possible and used only under close medical supervision at the lowest doses. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Pentobarbital 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 Pentobarbital interaction managed?
Keep taking both exactly as prescribed unless your care team tells you otherwise. This combination is best avoided when possible, so your team may look for an alternative to one of the medicines. If both are needed, your team will typically use the lowest dose and shortest duration possible, and may lower the dose of the codeine or the pentobarbital. They may monitor you more closely for heavy sed… 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 Pentobarbital 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 (4)
- Product Information: CARISOPRODOL, ASPIRIN, CODEINE PHOSPHATE oral tablets, carisoprodol, aspirin, codeine phosphate oral tablets. Ingenus Pharmaceuticals LLC (per DailyMed), Orlando, FL, 2021. DailyMed
- US Food and Drug Administration (FDA): Drug Safety Communications: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning. US Food and Drug Administration (FDA). Silver Spring, MD. 2016.
- 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 Pentobarbital
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