Acetaminophen And Codeine and Levorphanol: 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
Levorphanol
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 are opioids. Your acetaminophen with codeine and levorphanol (Xyvona) both work on the brain and can slow down breathing and make you very sleepy. Taking them together adds up, so the risk of dangerously slow breathing, heavy drowsiness, and confusion goes up.
Opioids can also raise your body's serotonin levels. Rarely, when two such drugs are combined, this can lead to serotonin syndrome, with symptoms like agitation, shaking, sweating, a fast heartbeat, or a high fever. The good news is your care team can manage this by using the lowest doses needed and watching you closely. Please talk with your doctor or pharmacist before combining them.
Additive CNS and respiratory depression from two opioid agonists (codeine, a prodrug, plus levorphanol), with a theoretical additive risk of serotonin syndrome from combined serotonergic activity.
- Direction: additive PD effects, increasing sedation, respiratory depression, and serotonergic burden.
- Severity/evidence: major; evidence theoretical/mechanistic.
- Onset: unspecified; highest risk at initiation and dose titration.
- Management: avoid or reserve for when alternatives are inadequate; use lowest effective dose and shortest duration; consider reducing the dose of codeine or levorphanol; monitor for sedation, hypoventilation, and serotonin syndrome; consider prescribing 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 preparations with CNS depressants2. When codeine products intended for uses other than cough are involved, restrict their combined use with CNS depressants to those patients in whom other options are insufficient. Should combined use be required, apply the smallest dose and briefest duration that will meet the treatment objectives. A reduced dose of either codeine or the CNS depressant should be considered, along with vigilant monitoring for sedation, respiratory depression, and the signs and symptoms of serotonin syndrome. Serotonin syndrome has also occurred when opioids are used together with serotonergic agents. If such combined use is required, observe the patient closely, especially when therapy is being started and when doses are changed. Naloxone may be considered for prescription to allow emergency management of opioid overdose. Should serotonin syndrome be suspected, stop codeine 134.
Why it happens (mechanism)
Additive CNS depression; additive serotonergic effects
How to manage this interaction
Keep taking both only as prescribed and do not stop or change either one on your own.
- Your care team will generally avoid combining two opioids unless it is truly needed, and will use the lowest dose for the shortest time.
- Your dose of codeine or levorphanol may be adjusted and individualized, and your team may monitor you more closely, especially when starting or changing a dose.
- Ask whether a naloxone rescue kit is right for you.
- Seek help urgently for very slow or shallow breathing, extreme drowsiness, or agitation, shaking, sweating, fast heartbeat, or fever.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
5 reports — tap to read
a) A study found that emergency department visits linked to nonmedical use and involving both opioid analgesics and benzodiazepines between 2004 and 2011 rose significantly from 11 to 34.2 per 100,000. Drug overdose deaths attributable to prescribed and higher than 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 involving the dispensing of both opioid analgesics and benzodiazepines was 10 times greater than the rate with dispensing of opioid analgesics alone (7 vs 0.7 per 10,000 person years) 2.
c) In a cohort study drawing on data from 2004 to 2009, the risk of fatal overdose rose significantly by 2.33 fold among patients using 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 using 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 together with benzodiazepines raises the risk of drug-related death compared with using opioid analgesics on their own. Given comparable pharmacological characteristics, 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 Levorphanol together?
Combining acetaminophen with codeine and levorphanol adds two opioids together, raising the risk of slowed breathing, heavy sedation, and rarely serotonin syndrome. Only use both together under your care team's guidance, at the lowest effective doses, with close monitoring. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Levorphanol 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 Levorphanol interaction managed?
Keep taking both only as prescribed and do not stop or change either one on your own. Your care team will generally avoid combining two opioids unless it is truly needed, and will use the lowest dose for the shortest time. Your dose of codeine or levorphanol may be adjusted and individualized, and your team may monitor you more closely, especially when starting or changing a dose. Ask whether a na… 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 Levorphanol 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 Levorphanol
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