Acetaminophen And Codeine and Isoflurane: 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
Isoflurane
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.
These two medicines both slow down your brain and breathing. The codeine in your pain pill is an opioid, and isoflurane is a gas used to put you to sleep for surgery. When they are used together, their calming effects add up. That can make you very sleepy, drop your blood pressure, and slow your breathing more than either one would alone.
The good news is that this is something your care team plans for. During surgery you are watched very closely, and your doctors can adjust doses to keep you safe. Always tell your anesthesia team and pharmacist about every medicine you take, including pain pills with codeine.
Additive CNS and respiratory depression between codeine (an opioid analgesic, also a CYP2D6 prodrug converted to morphine) and isoflurane (a volatile anesthetic and CNS depressant). This is a pharmacodynamic interaction, not pharmacokinetic; effects on sedation, hypotension, and respiratory drive are additive.
- Direction: increased CNS/respiratory depression risk
- Evidence: theoretical; extrapolated from opioid plus CNS-depressant combinations
- Onset: unspecified (expected perioperatively)
- Management: reserve concomitant use for when alternatives are inadequate, use lowest effective doses and shortest duration, and monitor closely for sedation, hypotension, and respiratory depression. Consider naloxone availability.
What happens
An increased risk of respiratory and CNS depression
Interaction Deep Dive
Do not combine opioid cough preparations with agents that depress the CNS. Emergency department visits and fatal overdoses have occurred more frequently when opioid analgesics are taken together with benzodiazepines2. 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 in whom other treatment options fall short. Keep both the dose and the length of therapy to the lowest amount needed, and monitor patients closely for evidence of sedation and respiratory depression. When such combined use is justified, consider providing naloxone to allow emergency management of an opioid overdose341.
Why it happens (mechanism)
Additive CNS depression
How to manage this interaction
Keep taking your medicines as prescribed and let your surgical and anesthesia team know you use a codeine-containing product before any procedure. This combination is usually reserved for when other options are not enough.
- Your team may use the lowest dose and shortest duration needed and may lower the dose of one or both medicines.
- You will be monitored closely for heavy sedation, low blood pressure, and slowed breathing.
- In some cases, your provider may make naloxone available as a safety measure.
Raise any concerns about drowsiness or breathing with your pharmacist or prescriber.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
4 reports — tap to read
a) In one study, emergency department visits related to nonmedical use that occurred between 2004 and 2011 and involved both opioid analgesics and benzodiazepines rose significantly, from 11 to 34.2 per 100,000. Drug overdose deaths attributable to prescribed and above-prescribed doses of both drug classes likewise 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 associated with dispensing opioid analgesics alone (7 vs 0.7 per 10,000 person years) 2.
c) In a cohort study using data spanning 2004 to 2009, the risk of fatal overdose rose significantly by 2.33 fold in patients receiving opioid analgesics who had a prior benzodiazepine prescription, and rose by 3.86 fold in those with a current benzodiazepine prescription, relative to patients taking opioid analgesics with 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 the comparable pharmacological properties, 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 Acetaminophen And Codeine and Isoflurane together?
Combining codeine with isoflurane adds up their sedating and breathing-slowing effects, so use only when needed, 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 Isoflurane 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 Isoflurane interaction managed?
Keep taking your medicines as prescribed and let your surgical and anesthesia team know you use a codeine-containing product before any procedure. This combination is usually reserved for when other options are not enough. Your team may use the lowest dose and shortest duration needed and may lower the dose of one or both medicines. You will be monitored closely for heavy sedation, low blood press… 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 Isoflurane 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 Isoflurane
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