Benzhydrocodone and Diphenhydramine Injection: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Benzhydrocodone
No brand names on recordDiphenhydramine Injection
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.
What happens
Increased risk of urinary retention and/or severe constipation leading to paralytic ileus and an increased risk of respiratory depression, hypotension, sedation, coma
Interaction Deep Dive
Avoid concomitant use of opioid cough medication formulations and CNS depressants1. Reserve the concomitant use of non-cough hydrocodone 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. Also, concomitant use may result in increased urinary retention or severe constipation, which may lead to paralytic ileus. Consider using a lower dose of hydrocodone or the CNS depressant and closely monitor for urinary retention, severe constipation, sedation, and respiratory depression 234. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose 56.
Why it happens (mechanism)
Additive effects on gastric motility; additive CNS depression
Literature reports
1 report — tap to read
a) A case report describes a fatal drug-drug interaction between hydrocodone and diphenhydramine. A woman in her late 50s had a longstanding prescription for hydrocodone/acetaminophen to manage chronic pain. She began taking diphenhydramine for symptoms related to upper respiratory infection. A post-mortem toxicology report detected the following drug levels: acetaminophen (14 micgrogram/mL), hydrocodone (410 nanogram (ng)/mL), dihydrocodeine (24 ng/mL), diphenhydramine (150 ng/mL), and hydromorphone (less than 1 ng/mL). All compounds were detected in therapeutic concentrations except for hydrocodone, which was present at lethal concentrations. These findings are highly suggestive of a fatal opioid overdose precipitated by a drug-drug interaction of diphenhydramine (a CYP2D6 inhibitor) and hydrocodone (a CYP2D6 substrate) 7.
Common questions
Can I take Benzhydrocodone and Diphenhydramine Injection together?
Increased risk of urinary retention and/or severe constipation leading to paralytic ileus and an increased risk of respiratory depression, hypotension, sedation, coma Always confirm with your pharmacist or prescriber before making any change.
How serious is the Benzhydrocodone and Diphenhydramine Injection 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 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 Benzhydrocodone or Diphenhydramine Injection 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 (7)
- Product Information: VITUZ(R) oral solution, hydrocodone bitartrate chlorpheniramine maleate oral solution. Hawthorn Pharmaceuticals, Inc. (per FDA), Morristown, NJ, 2017.
- Product Information: ZOHYDRO(R) ER oral extended-release capsules, hydrocodone bitartrate oral extended-release capsules. Pernix Therapeutics, LLC. (per FDA), Morristown, NJ, 2016. DailyMed
- Product Information: NORCO 5/325 oral tablets, hydrocodone bitartrate acetaminophen oral tablets. Allergan USA, Inc. (per DailyMed), Irvine, CA, 2016.
- Product Information: VANTRELA(TM) ER oral extended-release tablets, hydrocodone bitartrate oral extended-release tablets. Teva Pharmaceuticals USA, Inc (per manufacturer), North Wales, PA, 2017. DailyMed
- Product Information: HYSINGLA(R) ER oral extended-release tablets, hydrocodone bitartrate oral extended-release tablets. Purdue Pharma LP (per FDA), Stamford, CT, 2023. DailyMed
- Product Information: APADAZ(R) oral tablets, benzhydrocodone acetaminophen oral tablets. Zevra Therapeutics, Inc. (per FDA), Celebration, FL, 2023. DailyMed
- Whitt AG & Jortani SA: CYP2D6 inhibition by diphenhydramine leading to fatal hydrocodone overdose. Drug Metab Pers Ther 2024; 39(2):99-102. PubMed
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