Diphenhydramine 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
Diphenhydramine
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 pain medicine has codeine, an opioid, combined with acetaminophen (Tylenol). Diphenhydramine is the ingredient in Benadryl and many nighttime cold or sleep products. Both can make you very drowsy, slow your breathing, and slow down your gut and bladder.
Taken together, these effects can add up. That means more sleepiness, dizziness, trouble peeing, or serious constipation, and in bigger doses, dangerously slow breathing. This is a caution based on how the drugs work, not a common everyday event. Please don't stop either medicine on your own. Talk with your pharmacist or doctor, who can adjust doses and keep a close eye on you so you stay safe.
Additive CNS and anticholinergic effects between codeine (an opioid; note it is a prodrug activated by CYP2D6 to morphine) and diphenhydramine (sedating H1 antihistamine with anticholinergic activity). This is a pharmacodynamic interaction, not pharmacokinetic.
- Direction/effect: increased sedation, additive respiratory depression, and reduced GI motility plus urinary retention (risk of severe constipation/paralytic ileus).
- Severity/evidence: major; theoretical mechanism-based.
- Onset: unspecified.
- Management: avoid if possible; reserve for inadequate alternatives. Use lowest effective dose and shortest duration. Monitor sedation, respiratory rate, urinary retention, and bowel function. Consider prescribing naloxone.
What happens
Increased risk of paralytic ileus and an increased risk of respiratory and CNS depression
Interaction Deep Dive
Avoid concomitant use of opioid cough medication formulations and CNS depressants2. Reserve the concomitant use of codeine 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. Additionally, coadministration of codeine with anticholinergics may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Consider using a lower dose of codeine or the CNS depressant and closely monitor for urinary retention, reduced gastric motility, sedation, and respiratory depression. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose 134.
Why it happens (mechanism)
Additive effects on gastric motility; additive CNS depression
How to manage this interaction
The good news is your care team can manage this safely.
- Keep taking both exactly as prescribed unless your prescriber or pharmacist tells you otherwise.
- Your team may choose the lowest dose and shortest duration that works, or pick a non-drowsy alternative to the diphenhydramine.
- Doses of the codeine product or the diphenhydramine may be adjusted and individualized by your care team, and they may monitor you more closely.
- Watch for and report heavy drowsiness, slow or shallow breathing, trouble urinating, or severe constipation.
- Your prescriber may also give you naloxone to keep on hand as a safety measure.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
4 reports — tap to read
a) A study found that between 2004 and 2011, the rate of emergency department visits related to nonmedical use involving opioid analgesics and benzodiazepines rose significantly from 11 to 34.2 per 100,000. Drug overdose deaths attributed to prescribed and above-prescribed doses of both drug classes also rose significantly from 0.6 to 1.7 per 100,000, and overdose deaths attributed 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 associated with dispensing 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 increased significantly by 2.33 fold among patients taking opioid analgesics who had a history of a benzodiazepine prescription, and increased by 3.86 fold in those with a current benzodiazepine prescription, compared with those taking opioid analgesics without a history of a benzodiazepine prescription. The risk of drug overdose deaths rose 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 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 Diphenhydramine and Acetaminophen And Codeine together?
Combining codeine (in your acetaminophen-codeine pain pill) with diphenhydramine can stack up sedation, slowed breathing, constipation, and trouble urinating, so use them together only under your care team's guidance and report severe drowsiness, breathing changes, or bowel and bladder problems. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Diphenhydramine 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 Diphenhydramine and Acetaminophen And Codeine interaction managed?
The good news is your care team can manage this safely. Keep taking both exactly as prescribed unless your prescriber or pharmacist tells you otherwise. Your team may choose the lowest dose and shortest duration that works, or pick a non-drowsy alternative to the diphenhydramine. Doses of the codeine product or the diphenhydramine may be adjusted and individualized by your care team, and they may… 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.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Diphenhydramine 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 Diphenhydramine
These medications also interact with supplements
Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
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