Acetaminophen And Codeine and Trimeprazine: 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
Trimeprazine
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.
Your pain medicine contains codeine, an opioid, along with acetaminophen (Tylenol). Trimeprazine is an antihistamine that also causes drowsiness. When you take both, their sleepy, calming effects can add up. This can make you very drowsy and, in the worst cases, slow your breathing down too much, which can be dangerous.
The good news is that your care team can manage this. They may use the lowest dose needed, watch you more closely, and keep the treatment as short as possible. Please don't start, stop, or change either medicine on your own. Talk with your pharmacist or doctor, and get help right away if you feel unusually sleepy or short of breath.
Interaction: additive CNS depression when codeine (opioid, in the acetaminophen/codeine product) is combined with trimeprazine, a sedating phenothiazine antihistamine.
- Direction/effect: pharmacodynamic additive effect increasing risk of hypotension, profound sedation, respiratory depression, coma, and death.
- Mechanism: additive CNS/respiratory depressant activity (not a CYP interaction; codeine is a prodrug activated by CYP2D6, but that pathway is not the concern here).
- Onset: unspecified. Evidence: theoretical, severity rated major.
- Management: avoid if possible; reserve for inadequate alternatives; use lowest dose and shortest duration; monitor sedation and respiratory status; consider naloxone.
What happens
An increased risk of respiratory and CNS depression
Interaction Deep Dive
Opioid-based cough preparations should not be taken together with CNS depressants. Combining opioid analgesics and benzodiazepines has been linked to higher rates of emergency department visits and deaths from overdose2. When codeine is used alongside CNS depressants, the likelihood of hypotension, respiratory depression, profound sedation, coma, and death rises. Prescribing these agents together should be limited to patients in whom other treatment options prove inadequate. Keep doses and treatment periods as low as possible. Monitor patients carefully for indications of sedation and respiratory depression. Should combined use be justified, naloxone may be prescribed to allow emergency management of opioid overdose341.
Why it happens (mechanism)
Additive CNS depression
How to manage this interaction
Your prescriber knows this combination adds up two sedating medicines, and they can manage it safely.
- Keep taking both exactly as prescribed unless your care team tells you otherwise.
- Your team may prescribe the lowest effective dose for the shortest time needed, and they may lower the dose of one medicine.
- They may monitor you more closely for heavy sedation and slowed breathing.
- In some cases your provider may prescribe naloxone as a safety backup.
Ask your pharmacist or doctor before adding any other sedating product (alcohol, sleep aids, other opioids). Get emergency help for extreme drowsiness, confusion, or trouble breathing.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
4 reports — tap to read
a) In one study, emergency department visits related to nonmedical use that occurred 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 attributable 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 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 associated 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 in patients taking opioid analgesics who had a history of a benzodiazepine prescription, and rose by 3.86 fold in 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 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 concurrently with opioid analgesics 34.
Common questions
Can I take Acetaminophen And Codeine and Trimeprazine together?
Combining codeine (in your acetaminophen/codeine product) with trimeprazine can add up their sedating effects and dangerously slow breathing, so use only if your care team says it's needed, at the lowest dose and shortest time, with close monitoring. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Trimeprazine 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 Trimeprazine interaction managed?
Your prescriber knows this combination adds up two sedating medicines, and they can manage it safely. Keep taking both exactly as prescribed unless your care team tells you otherwise. Your team may prescribe the lowest effective dose for the shortest time needed, and they may lower the dose of one medicine. They may monitor you more closely for heavy sedation and slowed breathing. In some cases yo… 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 Trimeprazine 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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