Tramadol and Diphenhydramine Injection: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Tramadol
Diphenhydramine 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, an increased risk of seizure, an increased risk of CNS depression, an increased traMADol exposure and increased risk of traMADol-related adverse reactions
Interaction Deep Dive
Concomitant use of traMADol with diphenhydrAMINE (anticholinergic seizure threshold lowering agent, CYP2D6 inhibitor and CNS depressant) may increase traMADol exposure, and reduce exposure of M1, the active metabolite of traMADol and reduce in M1 exposure, particularly when an inhibitor is added after a stable dose of traMADol is achieved, increase risk of risk of seizure, respiratory depression, profound sedation, coma, and death, urinary retention and/or severe constipation, which may lead to paralytic ileus. Reserve concomitant use to patients for whom alternatives are inadequate. Consider using a lower dose of traMADol or diphenhydrAMINE and titrate the dose based on clinical response. Reduced M1 exposure could result in reduced therapeutic effects, and may result in signs and symptoms of opioid withdrawal and reduced efficacy while an increase in traMADol exposure can increase the risk of seizures and serotonin syndrome. After stopping diphenhydrAMINE, as the effects of the inhibitor decline, the traMADol exposure will reduce and the M1 exposure will increase. This could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, such as potentially fatal respiratory depression. Monitor patients for adverse reactions. When discontinuing diphenhydrAMINE in a patient receiving traMADol1.
Why it happens (mechanism)
Unknown; additive lowering of seizure threshold
Common questions
Can I take Tramadol and Diphenhydramine Injection together?
Increased risk of urinary retention and/or severe constipation leading to paralytic ileus, an increased risk of seizure, an increased risk of CNS depression, an increased traMADol exposure and increased risk of traMADol-related adverse reactions Always confirm with your pharmacist or prescriber before making any change.
How serious is the Tramadol 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.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Tramadol 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 (1)
- Product Information: Tramadol hydrochloride oral tablets, tramadol hydrochloride oral tablets. Strides Pharma, Inc (per DailyMed), East Brunswick, NJ, 2025. DailyMed
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