Difenoxin and Acetaminophen And Codeine: 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
Difenoxin
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 medicine Tylenol with codeine contains an opioid pain reliever, and difenoxin is an opioid used to slow down diarrhea. When two opioid-type medicines are taken together, their calming effects on the brain and body can add up. This may make you more drowsy or dizzy, and in stronger cases it can slow your breathing.
The good news is that your care team knows how to handle this. They may choose the lowest dose that works, use it for a short time, and keep a closer eye on you. If you feel unusually sleepy, confused, or short of breath, reach out to your doctor or pharmacist right away.
Effect: Additive CNS and respiratory depression from combining two opioid agents (codeine plus difenoxin). A theoretical additive serotonergic risk is also cited, though this is largely opioid-class labeling language.
- Mechanism: Additive CNS depression; potential additive serotonergic effects (PD, not PK based).
- Direction/magnitude: Enhanced sedation and hypoventilation; magnitude undefined.
- Onset: Unspecified; greatest risk at initiation and dose changes.
- Evidence: Theoretical.
- Management: Use lowest effective dose and shortest duration; monitor for sedation, respiratory depression, and serotonin syndrome; consider naloxone. Discontinue codeine if serotonin syndrome suspected.
What happens
Increased risk of respiratory and CNS depression and an increased risk of serotonin syndrome
Interaction Deep Dive
Avoid concomitant use of opioid cough medication formulations and CNS depressants2. Reserve the concomitant use of non-cough codeine products and CNS depressants to patients for whom alternatives are inadequate. If concomitant use is necessary, use the lowest dose and shortest duration necessary to achieve treatment goals. Consider using a lower dose of codeine or the CNS depressant and closely monitor for sedation, respiratory depression, and signs and symptoms of serotonin syndrome. Additionally, concomitant use of opioids with serotonergic drugs has resulted in serotonin syndrome. If concomitant use is needed, carefully observe the patient, particularly during treatment initiation and dose adjustments. Consider prescribing naloxone for the emergency treatment of opioid overdose. Discontinue codeine if serotonin syndrome is suspected 134.
Why it happens (mechanism)
Additive CNS depression; additive serotonergic effects
How to manage this interaction
Keep taking both medicines exactly as prescribed unless your care team tells you otherwise. Because both are opioid-type drugs, your team will typically:
- Use the lowest dose and shortest duration that controls your symptoms.
- Monitor you more closely, especially when starting or changing doses.
- Possibly adjust the dose of one medicine, tailored to you.
- Consider having naloxone available as a safety measure.
Tell your pharmacist or doctor if you notice heavy drowsiness, slowed or shallow breathing, confusion, or agitation, restlessness, sweating, and shivering.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
5 reports — tap to read
a) One study found that the rate of 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. Drug overdose deaths attributable to prescribed and greater than prescribed doses of both drug classes likewise increased significantly from 0.6 to 1.7 per 100,000, and overdose deaths attributable to benzodiazepines increased 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 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 taking 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 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 their comparable pharmacological properties, it is reasonable to anticipate a similar risk when other CNS depressant drugs are used concurrently with opioid analgesics 34.
e) Instances of serotonin syndrome, a condition that can be life-threatening, have been reported when opioids are used together with serotonergic drugs 34.
Common questions
Can I take Difenoxin and Acetaminophen And Codeine together?
Combining Tylenol with codeine and difenoxin stacks two opioids, which can add up to more sedation and slowed breathing, so use the lowest dose for the shortest time and watch closely for drowsiness or breathing changes. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Difenoxin and Acetaminophen And Codeine 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 Difenoxin and Acetaminophen And Codeine interaction managed?
Keep taking both medicines exactly as prescribed unless your care team tells you otherwise. Because both are opioid-type drugs, your team will typically: Use the lowest dose and shortest duration that controls your symptoms. Monitor you more closely, especially when starting or changing doses. Possibly adjust the dose of one medicine, tailored to you. Consider having naloxone available as a safety… 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 Difenoxin or Acetaminophen And Codeine 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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