Ketamine and Acetaminophen And Codeine: 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
Ketamine
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.
Both of these medicines can slow down your breathing and make you very sleepy. The codeine in your acetaminophen-codeine tablet is an opioid pain reliever, and ketamine is a strong sedative. When they are used together, those calming effects can add up. That can lead to very deep sleepiness, low blood pressure, and dangerously slow breathing.
Please don't stop or change either medicine on your own. This is a real safety concern, but your care team can manage it by using the lowest doses needed, keeping treatment short, and watching you closely. Always tell your pharmacist or doctor that you take both so they can keep you safe.
Additive CNS and respiratory depression from combining codeine (opioid analgesic) with ketamine (dissociative anesthetic/sedative).
- Mechanism: pharmacodynamic additive CNS depression; no prodrug reversal issue applies here.
- Effect/direction: increased risk of hypotension, profound sedation, respiratory depression, coma, and death.
- Onset: unspecified. Evidence: theoretical, but extrapolated from documented opioid plus CNS depressant harms.
- Management: reserve concurrent use for when alternatives are inadequate; use lowest effective doses and shortest duration; consider dose reduction of codeine and/or ketamine; monitor sedation and respiratory status; 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. When opioid analgesics are taken together with benzodiazepines, higher rates of emergency department visits and fatal overdose have been reported2. Taking codeine alongside CNS depressants raises the likelihood of hypotension, respiratory depression, profound sedation, coma, and death. Prescribing these medications together should be limited to patients whose alternative treatment options are insufficient. Keep both the doses and the treatment durations to the smallest amount necessary. Monitor patients carefully for indications of sedation and respiratory depression. Should combined use be justified, consider providing naloxone for emergency management of opioid overdose341.
Why it happens (mechanism)
Additive CNS depression
How to manage this interaction
Keep taking both medicines as prescribed unless your care team tells you otherwise. Here is how a care team usually handles this combination:
- Uses this combination only when other options are not enough.
- Uses the lowest dose and shortest duration that works.
- May adjust and individualize the dose of the codeine product or the ketamine, tailored to you.
- Monitors you closely for heavy sedation and slowed breathing.
- May prescribe naloxone as an emergency rescue medicine.
Tell your pharmacist or prescriber that you take both. Get emergency help right away for extreme drowsiness, confusion, or very slow or shallow breathing.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
4 reports — tap to read
a) One study found that the rate of emergency department visits linked to nonmedical use and involving both opioid analgesics and benzodiazepines rose significantly between 2004 and 2011, going from 11 to 34.2 per 100,000. Deaths from drug overdose attributable to prescribed and higher than prescribed doses of both drug classes also rose significantly from 0.6 to 1.7 per 100,000, while overdose deaths attributable to benzodiazepines rose significantly from 18% to 31% 2.
b) A prospective cohort study reported that the rate of overdose deaths involving dispensing of both opioid analgesics and benzodiazepines was 10 times greater than 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 receiving 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 daily benzodiazepine doses increased 2.
d) Observational studies have shown that using opioid analgesics and benzodiazepines together raises the risk of drug-related death compared with using opioid analgesics alone. Given comparable pharmacological characteristics, it is reasonable to anticipate a similar risk when other CNS depressant drugs are used together with opioid analgesics 34.
Common questions
Can I take Ketamine and Acetaminophen And Codeine together?
Taking acetaminophen-codeine with ketamine adds up their sedating effects and can dangerously slow your breathing, so use this combination only under close medical supervision and never adjust doses on your own. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Ketamine and Acetaminophen And Codeine 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 Ketamine and Acetaminophen And Codeine interaction managed?
Keep taking both medicines as prescribed unless your care team tells you otherwise. Here is how a care team usually handles this combination: Uses this combination only when other options are not enough. Uses the lowest dose and shortest duration that works. May adjust and individualize the dose of the codeine product or the ketamine, tailored to you. Monitors you closely for heavy sedation and sl… 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 Ketamine or Acetaminophen And Codeine 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 Ketamine
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