Acetaminophen And Codeine and Orphenadrine: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jun 30, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Acetaminophen And Codeine
Orphenadrine
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 these medicines can slow you down. Your acetaminophen with codeine is a pain reliever that contains an opioid, and orphenadrine is a muscle relaxer. Both can make you very drowsy, slow your breathing, and cause constipation and trouble urinating. Taken together, these effects can stack up.
The bigger worries are very deep sleepiness, dangerously slow breathing, and severe constipation. This is a theoretical concern based on how the drugs work, not a guarantee it will happen to you. The good news is your care team can manage this safely by using the lowest helpful dose and watching you closely. Call your doctor if you feel unusually sleepy, confused, or short of breath.
Additive CNS and anticholinergic effects. Codeine (an opioid; note it is a prodrug activated via CYP2D6 to morphine) combined with orphenadrine (a muscle relaxant with CNS-depressant and anticholinergic activity) produces additive depression of the CNS and respiratory drive, plus compounded anticholinergic burden.
- Direction: increased sedation, respiratory depression, hypotension, and additive constipation/urinary retention (risk of paralytic ileus).
- Evidence: theoretical; mechanism-based.
- Onset: unspecified.
- Management: reserve for when alternatives are inadequate; use lowest effective dose and shortest duration; monitor sedation, respiratory rate, bowel/bladder function; adjust opioid and/or relaxant dose; consider naloxone.
What happens
Increased risk of urinary retention and/or severe constipation leading to paralytic ileus, increased risk of profound sedation, respiratory depression, coma and death
Interaction Deep Dive
Taking dihydrocodeine together with skeletal muscle relaxants and CNS depressants may raise the likelihood of hypotension, respiratory depression, profound sedation, coma, and death. Combining dihydrocodeine with CNS depressants should be limited to patients for whom other options are insufficient. When such combined use cannot be avoided, employ the lowest dose over the shortest period needed to meet therapeutic objectives. Co-administration may also heighten the risk of urinary retention and/or severe constipation, potentially progressing to paralytic ileus. Watch for indications of urinary retention, decreased gastric motility, respiratory depression, and sedation. Because respiratory depression can exceed what would ordinarily be anticipated when a muscle relaxant is used concurrently, reduce the dose of dihydrocodeine and/or the muscle relaxant as required. Advise patients and caregivers about this possible interaction and teach them to recognize the signs and symptoms of respiratory depression (sedation included). Where concomitant use is justified, consider prescribing naloxone for emergency management of opioid overdose12.
Why it happens (mechanism)
Enhanced neuromuscular blockade; additive CNS depression
How to manage this interaction
Keep taking both as prescribed unless your care team tells you otherwise. This combination is used when it is truly needed, at the lowest helpful dose for the shortest time.
- Your team may adjust the dose of one or both medicines and monitor you more closely.
- Watch for very slow or shallow breathing, extreme drowsiness, confusion, constipation, or trouble passing urine, and report these promptly.
- Avoid alcohol and other sedating substances.
- Ask your prescriber whether naloxone (an opioid rescue medicine) is appropriate to have on hand.
Bring any concerns to your pharmacist or doctor so they can tailor your plan.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) Observational research has shown that using opioid analgesics together with benzodiazepines raises the likelihood of drug-related death when compared with taking opioid analgesics by themselves. Given the comparable pharmacological characteristics, it is reasonable to anticipate a similar risk when other CNS depressant medications are combined with opioid analgesics 12.
Common questions
Can I take Acetaminophen And Codeine and Orphenadrine together?
Combining acetaminophen with codeine and orphenadrine can add up to dangerous drowsiness, slowed breathing, and severe constipation, so use the lowest effective dose and watch closely. Contact your care team if you feel unusually sedated or short of breath. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Orphenadrine 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 Orphenadrine interaction managed?
Keep taking both as prescribed unless your care team tells you otherwise. This combination is used when it is truly needed, at the lowest helpful dose for the shortest time. Your team may adjust the dose of one or both medicines and monitor you more closely. Watch for very slow or shallow breathing, extreme drowsiness, confusion, constipation, or trouble passing urine, and report these promptly. A… 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 Orphenadrine 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 (2)
- 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 Orphenadrine
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