Acetaminophen And Codeine and Sufentanil: 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
Sufentanil
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 are both opioids. Acetaminophen with codeine (like Tylenol #3) and sufentanil (Dsuvia) both slow down your brain and your breathing. When you take two opioids together, those effects add up. That can make you very sleepy, slow your breathing, or in serious cases make breathing dangerously slow.
There is also a smaller chance of serotonin syndrome, where the body gets too much of a chemical called serotonin (signs include shakiness, sweating, fast heartbeat, or confusion). The good news: your care team knows how to handle this. They can pick the lowest doses, watch you closely, and often keep a rescue medicine called naloxone on hand just in case. Never stop or change either drug on your own, just talk with your pharmacist or doctor.
Effect: Additive CNS and respiratory depression from combining two opioid agonists (codeine plus sufentanil), with a theoretical additive serotonergic risk (serotonin syndrome).
- Mechanism: Additive mu-opioid CNS depression; additive serotonergic effects.
- Direction: Increased opioid burden. Note codeine is a prodrug activated by CYP2D6 to morphine, but this is a pharmacodynamic (additive), not metabolic, interaction.
- Evidence/onset: Theoretical; onset unspecified.
- Management: Avoid opioid cough formulations with CNS depressants; reserve non-cough codeine plus depressants for when alternatives are inadequate. Use lowest effective dose and shortest duration. Monitor for sedation, respiratory depression, and serotonin syndrome, especially at initiation/titration. Consider naloxone. Discontinue codeine if serotonin syndrome is suspected.
What happens
Increased risk of respiratory and CNS depression and an increased risk of serotonin syndrome
Interaction Deep Dive
Do not combine opioid cough medication products with CNS depressants2. When codeine products that are not for cough are involved, limit combined use with CNS depressants to those patients in whom other options are insufficient. Should combined use be required, apply the smallest dose and the briefest duration needed to reach treatment objectives. A reduced dose of either codeine or the CNS depressant may be considered, with careful monitoring for sedation, respiratory depression, and the signs and symptoms of serotonin syndrome. Furthermore, using opioids together with serotonergic agents has led to serotonin syndrome. If such combined use is required, observe the patient closely, especially when starting therapy and when adjusting the dose. Prescribing naloxone for the emergency management of opioid overdose may be considered. Should serotonin syndrome be suspected, stop codeine 134.
Why it happens (mechanism)
Additive CNS depression; additive serotonergic effects
How to manage this interaction
What your care team may do:
- Avoid combining them when a safer option exists, or reserve the combination for when alternatives aren't enough.
- Use the lowest effective dose for the shortest time, and individualize dosing to you.
- Watch you more closely for heavy sedation, slowed breathing, or signs of serotonin syndrome (agitation, sweating, tremor, fast heartbeat), especially when starting or changing doses.
- Possibly prescribe naloxone as an emergency rescue.
What you should do: Keep taking both exactly as prescribed unless told otherwise. Tell your pharmacist or prescriber about all sedatives you take, and get help right away if you feel very drowsy or hard to wake.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
5 reports — tap to read
a) One study found that emergency department visits related to nonmedical use that took place between 2004 and 2011 and involved both opioid analgesics and benzodiazepines rose significantly, from 11 to 34.2 per 100,000. Deaths from drug overdose attributed 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 attributed to benzodiazepines rose significantly from 18% to 31% 2.
b) In a prospective cohort study, the rate of overdose deaths involving the dispensing of both opioid analgesics and benzodiazepines was 10 times greater than that seen with 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, compared with patients taking opioid analgesics who had no history of a benzodiazepine prescription. The risk of drug overdose deaths grew as the daily dose 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, it is reasonable to anticipate a similar risk when other CNS depressant drugs are used together with opioid analgesics 34.
e) Instances of serotonin syndrome, a condition that can be life-threatening, have been reported when opioids are used together with serotonergic drugs 34.
Common questions
Can I take Acetaminophen And Codeine and Sufentanil together?
Taking codeine and sufentanil together stacks two opioids, raising the risk of dangerous sedation and slowed breathing (plus a smaller serotonin syndrome risk); your care team can manage this with the lowest doses, close monitoring, and possibly naloxone, so do not change anything on your own. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Sufentanil 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 Sufentanil interaction managed?
What your care team may do: Avoid combining them when a safer option exists, or reserve the combination for when alternatives aren't enough. Use the lowest effective dose for the shortest time, and individualize dosing to you. Watch you more closely for heavy sedation, slowed breathing, or signs of serotonin syndrome (agitation, sweating, tremor, fast heartbeat), especially when starting or changi… 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 Sufentanil 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 Sufentanil
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