Acetaminophen And Codeine and Methadone: 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
Methadone
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 slow down your body. Acetaminophen with codeine and methadone are both opioids. Taken together, they can add up and make you very drowsy, slow your breathing, and in rare cases cause a reaction called serotonin syndrome (with things like agitation, fast heartbeat, sweating, or shivering).
The most serious concern is breathing that gets too slow or too shallow, which can be dangerous. This is a caution based on how these drugs work rather than a lot of real-world reports, but it's still taken seriously. Please don't stop or change either medicine on your own. Your care team can manage this by using the lowest doses needed and watching you closely, so talk with your doctor or pharmacist.
Additive CNS and respiratory depression; additive serotonergic risk. Codeine (an opioid; also a CYP2D6-activated prodrug for morphine) plus methadone are both mu-opioid agonists, and methadone additionally has serotonergic activity. Combined use is pharmacodynamically additive.
- Direction/effect: increased sedation, respiratory depression, and potential serotonin syndrome.
- Evidence: theoretical; severity rated major.
- Onset: unspecified; highest risk at initiation and dose changes.
- Management: avoid where alternatives exist; if needed, use lowest effective dose and shortest duration, consider reduced dose of one agent, monitor for sedation and respiratory depression, watch for serotonin syndrome, consider prescribing naloxone, and 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
Opioid cough preparations should not be taken together with CNS depressants2. For non-cough codeine products, combined use with CNS depressants should be limited to patients in whom other options are insufficient. When such combined use cannot be avoided, apply the smallest dose and briefest duration required to reach therapeutic objectives. A reduced dose of either codeine or the CNS depressant may 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 combined with serotonergic agents. Should combined use be required, monitor the patient closely, especially at the start of therapy and when doses are being changed. Prescribing naloxone for emergency management of opioid overdose may be considered. Codeine should be stopped if serotonin syndrome is suspected 134.
Why it happens (mechanism)
Additive CNS depression; additive serotonergic effects
How to manage this interaction
Keep taking both exactly as prescribed unless your care team tells you otherwise. Because these are two opioids, teams often avoid using them together when a safer option exists, or reserve the combination for when nothing else works.
- Your doctor may use the lowest dose for the shortest time and may adjust and individualize your doses.
- Expect closer monitoring for heavy drowsiness, slow or shallow breathing, and signs of serotonin syndrome (agitation, fast heartbeat, sweating, shivering, muscle twitching).
- Your prescriber may offer a naloxone rescue kit.
Call your care team or seek help right away if breathing slows or you feel these symptoms.
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 occurring between 2004 and 2011 and involving both opioid analgesics and benzodiazepines 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 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 doses of benzodiazepines increased 2.
d) Observational studies have shown that using opioid analgesics together with benzodiazepines raises the risk of drug-related mortality when compared with using opioid analgesics alone. Given the 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 Methadone together?
Combining acetaminophen/codeine with methadone stacks two opioids and can cause dangerous sedation, slowed breathing, and rarely serotonin syndrome. Don't change anything yourself; let your care team use the lowest doses and monitor you closely. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Methadone 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 Methadone interaction managed?
Keep taking both exactly as prescribed unless your care team tells you otherwise. Because these are two opioids, teams often avoid using them together when a safer option exists, or reserve the combination for when nothing else works. Your doctor may use the lowest dose for the shortest time and may adjust and individualize your doses. Expect closer monitoring for heavy drowsiness, slow or shallow… 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.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Acetaminophen And Codeine or Methadone 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 Methadone
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Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
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