Acetaminophen And Codeine and Perphenazine: 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
Perphenazine
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.
You've been prescribed acetaminophen with codeine (a pain and cough medicine) along with perphenazine (a medicine used for certain mental health conditions or severe nausea). Taken together, both can slow down your brain and breathing, which may make you very sleepy, dizzy, or short of breath. They can also both slow your gut, which can cause bad constipation and, rarely, a blockage in the bowel. Perphenazine can also make it harder to empty your bladder.
Please don't stop either medicine on your own. Your care team can manage this safely by choosing the lowest doses that work and watching you closely. Tell them right away if you feel unusually drowsy, can't pee, or have trouble breathing.
Effect: Additive CNS and respiratory depression, plus additive slowing of GI motility with risk of severe constipation and paralytic ileus; perphenazine's anticholinergic activity adds urinary retention risk.
Mechanism: Codeine (an opioid; also a prodrug activated via CYP2D6 to morphine) and perphenazine both depress the CNS; combined opioid and anticholinergic effects reduce gastric motility and bladder emptying. This is pharmacodynamic, not PK-based.
Evidence: Theoretical. Severity: Major. Onset: Unspecified.
- Reserve co-use for when alternatives are inadequate; use lowest effective dose, shortest duration.
- Monitor sedation, respiratory rate, bowel/bladder function.
- Consider a lower dose of either agent; consider prescribing naloxone.
What happens
Increased risk of paralytic ileus and an increased risk of respiratory and CNS depression
Interaction Deep Dive
Do not combine opioid-based cough preparations with CNS depressants2. Pairing codeine with CNS depressants should be limited to patients whose alternative options prove insufficient. When such combined therapy cannot be avoided, employ the smallest dose and briefest duration required to meet therapeutic objectives. Furthermore, giving codeine together with anticholinergics can heighten the likelihood of urinary retention and/or severe constipation, potentially progressing to paralytic ileus. It may be appropriate to lower the dose of either codeine or the CNS depressant while carefully watching for urinary retention, diminished gastric motility, sedation, and respiratory depression. Should concurrent administration be justified, consider prescribing naloxone for emergency management of opioid overdose 134.
Why it happens (mechanism)
Additive effects on gastric motility; additive CNS depression
How to manage this interaction
Keep taking both medicines as prescribed unless your prescriber tells you otherwise. This combination can be used when needed, with some care.
- Your team may use the lowest effective dose of the codeine, the perphenazine, or both, for the shortest time needed.
- They may monitor you more closely for heavy drowsiness, slowed breathing, constipation, and trouble urinating.
- Your prescriber may consider having naloxone on hand as a safety measure.
Call your pharmacist or doctor promptly if you notice severe constipation, belly pain and bloating, trouble passing urine, extreme sleepiness, or slow or shallow breathing.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
4 reports — tap to read
a) In one study, the rate of emergency department visits related to nonmedical use that occurred between 2004 and 2011 and involved opioid analgesics along with 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 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 associated with the dispensing of opioid analgesics alone (7 vs 0.7 per 10,000 person years) 2.
c) In a cohort study drawing on 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, when compared with patients taking opioid analgesics without any 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 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 Perphenazine together?
Combining acetaminophen/codeine with perphenazine can stack up sedation, breathing suppression, constipation, and urinary retention, so use the lowest doses for the shortest time and watch closely. Keep taking both as prescribed and report severe drowsiness, breathing trouble, constipation, or inability to urinate to your care team. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Perphenazine 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 Perphenazine interaction managed?
Keep taking both medicines as prescribed unless your prescriber tells you otherwise. This combination can be used when needed, with some care. Your team may use the lowest effective dose of the codeine, the perphenazine, or both, for the shortest time needed. They may monitor you more closely for heavy drowsiness, slowed breathing, constipation, and trouble urinating. Your prescriber may consider… 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 Perphenazine 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 Perphenazine
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