Acetaminophen And Codeine and Methotrimeprazine: 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
Methotrimeprazine
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.
These two medicines can add up in a way that slows your breathing and makes you very sleepy. The codeine in your pain pill is an opioid, and methotrimeprazine is a strong sedating medicine. Taken together, they can both calm the brain and nervous system at the same time. That can lead to heavy drowsiness, low blood pressure, and slowed or shallow breathing.
The good news is that your care team can manage this. If you need both, they will usually use the lowest doses for the shortest time and watch you closely. Please don't stop or change either medicine on your own. Let your doctor or pharmacist know if you feel unusually sleepy, confused, or short of breath.
Effect: Additive CNS and respiratory depression when acetaminophen/codeine is combined with methotrimeprazine (a sedating phenothiazine).
- Mechanism: Pharmacodynamic additive CNS depression. Note codeine is a prodrug (CYP2D6 to morphine), but this interaction is PD, not PK, so overall sedative and respiratory-depressant burden increases.
- Direction/magnitude: Increased risk of hypotension, profound sedation, respiratory depression, coma, death.
- Onset: Unspecified; evidence: theoretical, but severity rated major by analogy to opioid plus CNS depressant data.
- Management: Avoid if possible; if warranted, use lowest effective doses and shortest duration, monitor sedation and respiratory rate, consider naloxone.
What happens
An increased risk of respiratory and CNS depression
Interaction Deep Dive
Do not combine opioid cough preparations with CNS depressants. Taking opioid analgesics together with benzodiazepines has been linked to higher numbers 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 whose alternative treatment options are not sufficient. Keep both doses and treatment periods as low as possible. Monitor patients carefully for indications of sedation and respiratory depression. Should concurrent use be justified, consider prescribing naloxone to treat opioid overdose on an emergency basis341.
Why it happens (mechanism)
Additive CNS depression
How to manage this interaction
Keep taking both exactly as prescribed unless your care team tells you otherwise. When these are used together, teams usually take practical steps to keep you safe.
- They may reserve the combination for when other options aren't enough.
- Doses may be adjusted and individualized, often using the lowest dose and shortest duration.
- Your team may monitor you more closely for heavy sedation and slowed breathing.
- They may consider prescribing naloxone as an emergency backup.
Call your doctor or pharmacist if you notice extreme drowsiness, confusion, dizziness, or trouble breathing. Ask them before adding any other sedating medicine or alcohol.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
4 reports — tap to read
a) In a study, the rate of emergency department visits related to nonmedical use that occurred between 2004 and 2011 and involved opioid analgesics together with 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 that seen with the 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 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 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 compared with using opioid analgesics alone. Given the similar pharmacological properties, it is reasonable to anticipate a comparable risk when other CNS depressant drugs are used concomitantly with opioid analgesics 34.
Common questions
Can I take Acetaminophen And Codeine and Methotrimeprazine together?
Combining acetaminophen/codeine with methotrimeprazine can add up to dangerous sedation and slowed breathing, so use the lowest doses for the shortest time and watch closely. Talk to your doctor or pharmacist before changing anything. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Methotrimeprazine 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 Methotrimeprazine interaction managed?
Keep taking both exactly as prescribed unless your care team tells you otherwise. When these are used together, teams usually take practical steps to keep you safe. They may reserve the combination for when other options aren't enough. Doses may be adjusted and individualized, often using the lowest dose and shortest duration. Your team may monitor you more closely for heavy sedation and slowed br… 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 Methotrimeprazine 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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