Acetaminophen And Codeine and Opium Alkaloids: 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
Opium Alkaloids
No brand names on record
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 opioids. The one with codeine is a pain and cough medicine, and opium alkaloids act in the same way. When you take two opioids together, their effects add up. That can make you very sleepy and, more seriously, can slow your breathing too much.
There is also a small chance of something called serotonin syndrome, which can cause a fast heartbeat, shakiness, sweating, or confusion. The good news is your care team can manage this by using the lowest doses needed and watching you closely. If you feel unusually drowsy or short of breath, call your pharmacist or doctor right away.
Additive CNS and respiratory depression from two opioid agents (codeine, an opioid also serotonergic, plus opium alkaloids), with a theoretical additive risk of serotonin syndrome.
- Mechanism: additive mu-opioid CNS/respiratory depression; additive serotonergic activity.
- Direction: increased opioid effect and toxicity risk.
- Evidence: theoretical; severity rated major. Onset unspecified.
- Management: avoid combination where possible; if required, use lowest effective dose and shortest duration. Monitor for sedation, respiratory depression, and serotonin syndrome, especially at initiation/titration. Consider prescribing naloxone. Discontinue codeine if serotonin syndrome is suspected.
Note: codeine is a prodrug activated via CYP2D6, but this is a pharmacodynamic (additive) interaction, not a metabolic one.
What happens
Increased risk of respiratory and CNS depression and an increased risk of serotonin syndrome
Interaction Deep Dive
Opioid cough medication formulations should not be used together with CNS depressants2. When codeine products that are not intended for cough are involved, restrict their combined use with CNS depressants to those patients in whom other options prove insufficient. Should such combined therapy be required, apply the smallest dose and briefest duration that will meet treatment objectives. A reduced dose of either codeine or the CNS depressant may be warranted, along with vigilant monitoring for sedation, respiratory depression, and the signs and symptoms of serotonin syndrome. Furthermore, taking opioids alongside serotonergic agents has produced serotonin syndrome. When this combination cannot be avoided, monitor the patient closely, especially as therapy begins and when doses are modified. Prescribing naloxone for emergency management of opioid overdose may be considered. If serotonin syndrome is suspected, stop codeine 134.
Why it happens (mechanism)
Additive CNS depression; additive serotonergic effects
How to manage this interaction
The safest approach is often to avoid taking two opioids together, so your care team may look for an alternative. If you do need both, they will use the lowest dose for the shortest time and monitor you closely.
- Keep taking both exactly as prescribed unless told otherwise. Do not start, stop, or change doses on your own.
- Your dose may be adjusted and individualized by your team, and they may watch you more closely, especially when starting or changing a dose.
- Ask whether naloxone (a rescue medicine for opioid overdose) is right to have on hand.
- Report heavy drowsiness, slow or shallow breathing, agitation, fast heartbeat, sweating, or confusion right away.
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. Deaths from drug overdose 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 involving benzodiazepines increased significantly from 18% to 31% 2.
b) In a prospective cohort study, the rate of overdose deaths associated with dispensing of both opioid analgesics and benzodiazepines was 10 times greater than with dispensing of opioid analgesics alone (7 vs 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 receiving 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 without a history of a benzodiazepine prescription. The risk of 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 opioid analgesics used alone. Given the similar pharmacological properties, it is reasonable to anticipate a comparable 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 with the concurrent use of opioids and serotonergic drugs 34.
Common questions
Can I take Acetaminophen And Codeine and Opium Alkaloids together?
Combining these two opioids adds up their sedating and breathing-slowing effects and carries a small serotonin syndrome risk, so use them together only when necessary, at the lowest dose, and under close monitoring. Ask your care team about keeping naloxone available. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Opium Alkaloids 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 Opium Alkaloids interaction managed?
The safest approach is often to avoid taking two opioids together, so your care team may look for an alternative. If you do need both, they will use the lowest dose for the shortest time and monitor you closely. Keep taking both exactly as prescribed unless told otherwise. Do not start, stop, or change doses on your own. Your dose may be adjusted and individualized by your team, and they may watch… 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 Opium Alkaloids 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
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