Acetaminophen And Codeine and Tapentadol: 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
Tapentadol
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 your medicines are opioid pain relievers. Codeine (in your acetaminophen-codeine product) and tapentadol (Nucynta) both slow down the brain and breathing. Taking them together can make you very sleepy, slow your breathing, and lower your alertness more than either one alone.
They can also raise the level of a brain chemical called serotonin. Rarely, too much serotonin causes a problem called serotonin syndrome, with symptoms like agitation, shaking, sweating, a fast heartbeat, or confusion. This warning is based on theory and how these drugs work, not hard proof, but it is worth taking seriously. Please talk with your pharmacist or doctor before combining them. Your care team can manage this safely.
Effect: Additive CNS and respiratory depression plus additive serotonergic risk (serotonin syndrome) when combining codeine (with acetaminophen) and tapentadol. Both are opioids; tapentadol also has serotonin-norepinephrine reuptake activity.
- Direction: Both agents increase sedation/respiratory depression; effects are additive, not PK-driven.
- Evidence: Theoretical; severity rated major.
- Onset: Unspecified; highest risk at initiation and dose changes.
- Management: Avoid opioid cough formulations with CNS depressants. Reserve non-cough codeine use for when alternatives are inadequate; use lowest effective dose, shortest duration. Consider lower dose of codeine or tapentadol. Monitor for sedation, respiratory depression, serotonin syndrome. Consider naloxone. Discontinue codeine if serotonin syndrome suspected.
What happens
Increased risk of respiratory and CNS depression and an increased risk of serotonin syndrome
Interaction Deep Dive
Combining opioid-based cough preparations with CNS depressants should be avoided 2. In the case of codeine products not intended for cough, restrict concurrent use with CNS depressants to those patients for whom other options are insufficient. When such combined use cannot be avoided, employ the lowest effective dose over the briefest duration required to meet therapeutic objectives. A reduced dose of either codeine or the CNS depressant may be considered, along with vigilant monitoring for sedation, respiratory depression, and any signs or symptoms indicating serotonin syndrome. Serotonin syndrome has also occurred when opioids are taken together with serotonergic agents. Should concurrent therapy be required, observe the patient closely, especially when initiating treatment and when adjusting the dose. Prescribing naloxone for the 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
Your care team can manage this by tailoring your doses and watching you closely, especially when starting either drug or changing a dose.
- Keep taking both as prescribed unless your doctor or pharmacist tells you otherwise.
- Your team may use the lowest dose for the shortest time, or lower the dose of one medicine.
- Ask whether a take-home naloxone rescue kit is right for you.
- Get help right away for very slow or shallow breathing, extreme sleepiness, or signs of serotonin syndrome (agitation, shivering, sweating, fast heartbeat, confusion).
Raise any daytime drowsiness or breathing concerns with your pharmacist or prescriber.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
5 reports — tap to read
a) One study found that the rate of emergency department visits related to nonmedical use between 2004 and 2011 involving 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 also 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 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 daily benzodiazepine doses increased 2.
d) Observational studies have shown that using opioid analgesics together with benzodiazepines raises the risk of drug-related mortality compared with using opioid analgesics alone. Owing to comparable pharmacological properties, a similar risk can reasonably be anticipated when other CNS depressant drugs are used concurrently 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 Tapentadol together?
Taking codeine (with acetaminophen) and tapentadol together adds up their effects and can cause dangerous drowsiness, slowed breathing, and rarely serotonin syndrome, so use only if truly needed and under close medical supervision. Do not change either medicine on your own; talk with your pharmacist or doctor. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Tapentadol 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 Tapentadol interaction managed?
Your care team can manage this by tailoring your doses and watching you closely, especially when starting either drug or changing a dose. Keep taking both as prescribed unless your doctor or pharmacist tells you otherwise. Your team may use the lowest dose for the shortest time, or lower the dose of one medicine. Ask whether a take-home naloxone rescue kit is right for you. Get help right away for… 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 Tapentadol 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 Tapentadol
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