Diphenoxylate 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
Diphenoxylate
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 acetaminophen with codeine is an opioid pain reliever, and diphenoxylate (used to slow down diarrhea) is a close cousin of opioids. Both can calm down your brain and slow your breathing. When you take them together, those effects can stack up, which may leave you extra sleepy, dizzy, or (rarely) breathing too slowly. There is also a small, mostly theoretical chance of a reaction called serotonin syndrome.
The good news is your care team knows how to handle this. They may use the lowest doses for the shortest time and keep a closer eye on you. Please don't stop or change either medicine on your own, just check in with your pharmacist or doctor.
Effect: Additive CNS and respiratory depression from combining two opioid/opioid-like agents (codeine plus diphenoxylate), with a theoretical additive serotonergic risk.
- Mechanism: Additive CNS depression; additive serotonergic effects (PD interaction).
- Direction/magnitude: Enhanced sedation and respiratory depression; magnitude undefined.
- Onset: Unspecified; risk highest at initiation and dose changes.
- Evidence: Theoretical, severity rated major.
- Management: Avoid where possible; reserve for inadequate alternatives. Use lowest effective dose, shortest duration; consider reducing codeine or the CNS depressant. Monitor for sedation, respiratory depression, and serotonin syndrome. Consider naloxone. Discontinue codeine if serotonin syndrome is 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
Both of these medicines slow the brain and breathing, so your care team will be cautious combining them.
- Keep taking both exactly as prescribed unless your prescriber tells you otherwise.
- Your team may use the lowest dose for the shortest time and might lower the dose of one medicine. Doses may need to be adjusted and individualized by your care team.
- Expect closer monitoring for heavy drowsiness, slow or shallow breathing, and signs of serotonin syndrome (agitation, fast heartbeat, sweating, tremor, confusion).
- Ask whether naloxone is appropriate to have on hand.
- Call your pharmacist or doctor right away if you feel very sedated or hard to wake.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
5 reports — tap to read
a) One study found that emergency department visits related to nonmedical use that took place between 2004 and 2011 and involved both opioid analgesics and benzodiazepines rose significantly, going from 11 to 34.2 per 100,000. Deaths from drug overdose attributable to prescribed and higher than prescribed doses of both drug classes likewise increased significantly, from 0.6 to 1.7 per 100,000, while overdose deaths attributed 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 seen with dispensing of opioid analgesics on their own (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 among 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, when compared with patients taking opioid analgesics who had no history of a benzodiazepine prescription. The risk of overdose deaths grew as daily benzodiazepine doses increased 2.
d) Observational studies have shown that using opioid analgesics together with benzodiazepines raises the risk of drug-related mortality relative to using opioid analgesics alone. Given comparable pharmacological characteristics, 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 Diphenoxylate and Acetaminophen And Codeine together?
Combining codeine with diphenoxylate stacks two opioid-like sedatives, raising the risk of heavy sedation and slowed breathing. Take both only as prescribed, watch for excessive drowsiness, and let your care team manage the doses and monitoring. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Diphenoxylate 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 Diphenoxylate and Acetaminophen And Codeine interaction managed?
Both of these medicines slow the brain and breathing, so your care team will be cautious combining them. Keep taking both exactly as prescribed unless your prescriber tells you otherwise. Your team may use the lowest dose for the shortest time and might lower the dose of one medicine. Doses may need to be adjusted and individualized by your care team. Expect closer monitoring for heavy drowsiness,… 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 Diphenoxylate 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
Keep reading about Acetaminophen And Codeine
Keep reading about Diphenoxylate
Check another combination
Our instant two-drug interaction checker is almost here.
Still have questions about this combination?
Every question gets a real answer from a licensed pharmacist — free, and usually within a day.
Ask the pharmacist