Meperidine and Diphenhydramine Topical: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Diphenhydramine Topical
Meperidine
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 respiratory and CNS depression and an increased risk of paralytic ileus
Interaction Deep Dive
Concomitant use of meperidine and a CNS depressant may increase the risk of respiratory depression, profound sedation, hypotension, coma and opioid overdose. Additionally, concomitant use of meperidine with anticholinergics may increase the risk of urinary retention and/or severe constipation, which can lead to paralytic ileus. Reserve the concomitant use of meperidine and anticholinergic 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. In patients already receiving meperidine, prescribe a lower initial dose of the other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If meperidine is initiated in a patient already taking other CNS depressant, prescribe a lower initial dose of meperidine, and titrate based on clinical response. Monitor for urinary retention or reduced gastric motility, severe constipation, sedation, and respiratory depression12. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose 3.
Why it happens (mechanism)
Additive CNS depression; additive effects on gastric motility
Literature reports
1 report — tap to read
a) The pharmacokinetics of meperidine were not significantly altered when chlorproMAZINE was administered concomitantly in a two-way crossover study of 10 healthy patients. Subjects were given meperidine (26 mg per meter squared) with either chlorproMAZINE (30 mg per meter squared) or placebo. The effect of chlorproMAZINE on the serum concentration-time curve and metabolism of meperidine was investigated in order to determine if concomitant administration of a phenothiazine and meperidine alters the metabolism of meperidine, resulting in additive CNS and respiratory depression. When the two drugs were combined, N-demethylation activity was increased as evidenced by elevated urinary excretion of normeperidine (a toxic metabolite) and normeperidinic acid. Excretion of normeperidine is slower than that of meperidine, thus repeated dosing of the combination (chlorproMAZINE and meperidine) could lead to increased cardiac and central nervous system toxicity 4.
Common questions
Can I take Meperidine and Diphenhydramine Topical together?
Increased risk of respiratory and CNS depression and an increased risk of paralytic ileus Always confirm with your pharmacist or prescriber before making any change.
How serious is the Meperidine and Diphenhydramine Topical 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 Meperidine or Diphenhydramine Topical 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: MEPERGAN intramuscular, intravenous injection, meperidine HCl, promethazine HCl intramuscular, intravenous injection. West-Ward Pharmaceuticals Corp (per FDA), Eatontown, NJ, 2023.
- Product Information: Demerol(TM) intramuscular, subcutaneous, intravenous injection, meperidine HCl intramuscular, subcutaneous, intravenous injection. Hospira Inc (per FDA), Lake Forest, IL, 2022.
- Product Information: DEMEROL(R) oral tablets, oral solution, meperidine HCl oral tablets, oral solution. Validus Pharmaceuticals LLC (per FDA), Parsippany, NJ, 2023. DailyMed
- Stambaugh JE & Wainer IW: Drug interaction: meperidine and chlorpromazine, a toxic combination. J Clin Pharmacol 1981; 21:140-146. PubMed
Keep reading about Diphenhydramine Topical
Keep reading about Meperidine
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