Skip to Content
Looking to save on your medications?  Find out how 

7 Interactions found for:

Benadryl and tramadol
Interactions Summary
  • 4 Major
  • 2 Moderate
  • 1 Minor
  • Benadryl
  • tramadol

Drug Interactions

Moderate
Benadryl + Tramadol

The following applies to the ingredients: Diphenhydramine (found in Benadryl) and Tramadol

MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

References

  1. Hamilton MJ, Bush M, Smith P, Peck AW "The effects of bupropion, a new antidepressant drug, and diazepam, and their interaction in man." Br J Clin Pharmacol 14 (1982): 791-7
  2. Stambaugh JE, Lane C "Analgesic efficacy and pharmacokinetic evaluation of meperidine and hydroxyzine, alone and in combination." Cancer Invest 1 (1983): 111-7
  3. Sotaniemi EA, Anttila M, Rautio A, et al. "Propranolol and sotalol metabolism after a drinking party." Clin Pharmacol Ther 29 (1981): 705-10
  4. Grabowski BS, Cady WJ, Young WW, Emery JF "Effects of acute alcohol administration on propranolol absorption." Int J Clin Pharmacol Ther Toxicol 18 (1980): 317-9
  5. Lemberger L, Rowe H, Bosomworth JC, Tenbarge JB, Bergstrom RF "The effect of fluoxetine on the pharmacokinetics and psychomotor responses of diazepam." Clin Pharmacol Ther 43 (1988): 412-9
  6. MacLeod SM, Giles HG, Patzalek G, Thiessen JJ, Sellers EM "Diazepam actions and plasma concentrations following ethanol ingestion." Eur J Clin Pharmacol 11 (1977): 345-9
  7. Divoll M, Greenblatt DJ, Lacasse Y, Shader RI "Benzodiazepine overdosage: plasma concentrations and clinical outcome." Psychopharmacology (Berl) 73 (1981): 381-3
  8. Naylor GJ, McHarg A "Profound hypothermia on combined lithium carbonate and diazepam treatment." Br Med J 2 (1977): 22
  9. Stovner J, Endresen R "Intravenous anaesthesia with diazepam." Acta Anaesthesiol Scand 24 (1965): 223-7
  10. Driessen JJ, Vree TB, Booij LH, van der Pol FM, Crul JF "Effect of some benzodiazepines on peripheral neuromuscular function in the rat in-vitro hemidiaphragm preparation." J Pharm Pharmacol 36 (1984): 244-7
  11. Feldman SA, Crawley BE "Interaction of diazepam with the muscle-relaxant drugs." Br Med J 1 (1970): 336-8
  12. Ochs HR, Greenblatt DJ, Verburg-Ochs B "Propranolol interactions with diazepam, lorazepam and alprazolam." Clin Pharmacol Ther 36 (1984): 451-5
  13. Desager JP, Hulhoven R, Harvengt C, Hermann P, Guillet P, Thiercelin JF "Possible interactions between zolpidem, a new sleep inducer and chlorpromazine, a phenothiazine neuroleptic." Psychopharmacology (Berl) 96 (1988): 63-6
  14. Tverskoy M, Fleyshman G, Ezry J, Bradley EL, Jr Kissin I "Midazolam-morphine sedative interaction in patients." Anesth Analg 68 (1989): 282-5
  15. "Product Information. Iopidine (apraclonidine ophthalmic)." Alcon Laboratories Inc PROD
  16. Greiff JMC, Rowbotham D "Pharmacokinetic drug interactions with gastrointestinal motility modifying agents." Clin Pharmacokinet 27 (1994): 447-61
  17. Greb WH, Buscher G, Dierdorf HD, Koster FE, Wolf D, Mellows G "The effect of liver enzyme inhibition by cimetidine and enzyme induction by phenobarbitone on the pharmacokinetics of paroxetine." Acta Psychiatr Scand 80 Suppl (1989): 95-8
  18. Markowitz JS, Wells BG, Carson WH "Interactions between antipsychotic and antihypertensive drugs." Ann Pharmacother 29 (1995): 603-9
  19. "Product Information. Ultram (tramadol)." McNeil Pharmaceutical PROD (2001):
  20. "Product Information. Artane (trihexyphenidyl)." Lederle Laboratories PROD (2001):
  21. "Product Information. Ultiva (remifentanil)." Mylan Institutional (formally Bioniche Pharma USA Inc) PROD (2001):
  22. "Product Information. Seroquel (quetiapine)." Astra-Zeneca Pharmaceuticals PROD (2001):
  23. "Product Information. Meridia (sibutramine)." Knoll Pharmaceutical Company PROD (2001):
  24. "Product Information. Tasmar (tolcapone)." Valeant Pharmaceuticals PROD (2001):
  25. Miller LG "Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions." Arch Intern Med 158 (1998): 2200-11
  26. "Product Information. Precedex (dexmedetomidine)." Abbott Pharmaceutical PROD (2001):
  27. "Product Information. Trileptal (oxcarbazepine)." Novartis Pharmaceuticals PROD (2001):
  28. Ferslew KE, Hagardorn AN, McCormick WF "A fatal interaction of methocarbamol and ethanol in an accidental poisoning." J Forensic Sci 35 (1990): 477-82
  29. Plushner SL "Valerian: valeriana officinalis." Am J Health Syst Pharm 57 (2000): 328-35
  30. "Product Information. Xatral (alfuzosin)." Sanofi-Synthelabo Canada Inc (2002):
  31. "Product Information. Lexapro (escitalopram)." Forest Pharmaceuticals (2002):
  32. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  33. Cerner Multum, Inc. "Australian Product Information." O 0
  34. "Product Information. Fycompa (perampanel)." Eisai Inc (2012):
  35. "Product Information. Belsomra (suvorexant)." Merck & Co., Inc (2014):
  36. "Product Information. Rexulti (brexpiprazole)." Otsuka American Pharmaceuticals Inc (2015):

Drug and Food Interactions

Major
Tramadol + Food

The following applies to the ingredients: Tramadol

GENERALLY AVOID: Alcohol may potentiate the central nervous system (CNS) depressant effects of opioid analgesics. Concomitant use may result in additive CNS depression and impairment of judgment, thinking, and psychomotor skills. In more severe cases, hypotension, respiratory depression, profound sedation, coma, or even death may occur. In addition, alcohol may affect opioid release from sustained-release formulations.

GENERALLY AVOID: Grapefruit or grapefruit juice may increase the plasma concentrations of opioid analgesics by inhibiting CYP450 3A4-mediated metabolism of these agents, although the interaction has not been studied. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients should not consume alcoholic beverages or use drug products that contain alcohol during treatment with opioid analgesics. Any history of alcohol or illicit drug use should be considered when prescribing an opioid analgesic, and therapy initiated at a lower dosage if necessary. Patients should be closely monitored for signs and symptoms of sedation, respiratory depression, and hypotension. Due to a high degree of interpatient variability with respect to grapefruit juice interactions, patients treated with opioid analgesics should preferably avoid the consumption of grapefruit and grapefruit juice.

References

  1. "Product Information. Alfentanil Hydrochloride (alfentanil)." Akorn Inc (2017):
  2. "Product Information. TraMADol Hydrochloride (traMADol)." Advagen Pharma Ltd (2024):
  3. "Product Information. Jamp Tramadol (tramadol)." Jamp Pharma Corporation (2024):
  4. "Product Information. Tramadol (tramadol)." Sigma Pharmaceuticals Plc (2025):
  5. "Product Information. Tramedo (tRAMadol)." Alphapharm Pty Ltd (2024):
  6. "Product Information. Alfentanil (alfentanil)." Hameln Pharma Ltd (2022):
  7. "Product Information. Butorphanol Tartrate (butorphanol)." Apotex Corporation (2024):
  8. "Product Information. Codeine Sulfate (codeine)." Lannett Company Inc (2024):
  9. "Product Information. Meperidine Hydrochloride (meperidine)." Genus Lifesciences Inc. (2024):
  10. "Product Information. Dsuvia (SUFentanil)." AcelRx Pharmaceuticals (2023):
  11. "Product Information. Dzuveo (sufentanil)." Aguettant Ltd (2024):
  12. "Product Information. Pethidine (pethidine)." Martindale Pharmaceuticals Ltd (2025):
  13. "Product Information. Meperidine Hydrochloride (meperidine)." Sandoz Canada Incorporated (2023):
  14. "Product Information. Pethidine (Juno) (pethidine)." Juno Pharmaceuticals Pty Ltd (2024):
  15. Cherrier MM, Shen DD, Shireman L, et al. "Elevated customary alcohol consumption attenuates opioid effects." Pharmacol Biochem Behav 4 (2021): 1-27
  16. Fuhr LM, Marok FZ, Fuhr U, Selzer D, Lehr T "Physiologically based pharmacokinetic modeling of bergamottin and 6,7-dihydroxybergamottin to describe CYP3A4 mediated grapefruit-drug interactions." Clin Pharmacol Ther 114 (2023): 470-82
  17. "Product Information. TraMADol Hydrochloride ER (traMADol)." Trigen Laboratories Inc (2025):
  18. "Product Information. Codeine Contin (codeine)." Purdue Pharma (2025):

Moderate
Benadryl + Food

The following applies to the ingredients: Diphenhydramine (found in Benadryl)

GENERALLY AVOID: Use of anticholinergic agents with alcohol may result in sufficient impairment of attention so as to render driving and operating machinery more hazardous. In addition, the potential for abuse may be increased with the combination. The mechanism of interaction is not established but may involve additive depressant effects on the central nervous system. No effect of oral propantheline or atropine on blood alcohol levels was observed in healthy volunteers when administered before ingestion of a standard ethanol load. However, one study found impairment of attention in subjects given atropine 0.5 mg or glycopyrrolate 1 mg in combination with alcohol.

MANAGEMENT: Alcohol should generally be avoided during therapy with anticholinergic agents. Patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them.

References

  1. Linnoila M "Drug effects on psychomotor skills related to driving: interaction of atropine, glycopyrrhonium and alcohol." Eur J Clin Pharmacol 6 (1973): 107-12

Drug and Pregnancy Interactions

The following applies to the ingredients: Tramadol

According to some authorities: Use is not recommended.

AU TGA pregnancy category: C
US FDA pregnancy category: Not Assigned

Risk Summary: Insufficient data are available in humans to inform a drug-related risk; however, prolonged use of opioids during pregnancy for medical or nonmedical purposes can result in respiratory depression and physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Comments:
-Use is not recommended in pregnant women immediately prior to or during labor when other analgesic techniques are more appropriate.
-If prolonged use is required in a pregnant woman, advise the patient of the risk for neonatal opioid withdrawal syndrome, which could be life-threatening if not recognized and treated, and ensure appropriate monitoring and treatment will be available.
-Monitor newborns exposed to this drug for signs of excess sedation, respiratory depression, and neonatal opioid withdrawal syndrome and manage accordingly. An opioid overdose reversal agent must be available for reversal of opioid-induced respiratory depression in the neonate.

Animal studies have revealed decreased fetal weights, reduced ossification, and structural abnormalities in the brains of fetuses. This drug has been shown to cross the placental barrier with an umbilical vein to maternal vein serum concentration ratio of 0.83. There are no controlled data in human pregnancy; however, there have been postmarketing reports of neonatal seizures, neonatal withdrawal syndrome, fetal death, and still birth.

Chronic use of opioids may cause reduced fertility in females and males; however, it is unknown whether these effects are reversible.

AU TGA pregnancy category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.

US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

References

  1. "Product Information. TraMADol Hydrochloride (traMADol)." Advagen Pharma Limited (2026):
  2. "Product Information. TraMADol Hydrochloride ER (traMADol)." Trigen Laboratories Inc (2026):
  3. "Product Information. TraMADol Hydrochloride ER (traMADol)." Lupin Pharmaceuticals Inc (2025):
  4. "Product Information. TraMADol Hydrochloride (traMADol)." TruPharma LLC (2023):
  5. "Product Information. Tramal (tRAMadol)." Seqirus Pty Ltd (2025):
  6. "Product Information. Zamadol SR (tramadol)." Viatris UK Healthcare Ltd (2026):
  7. "Product Information. Brimisol PR (tramadol)." Bristol Laboratories Ltd (2025):
  8. "Product Information. Zydol SR (tramadol)." Grunenthal Ltd (2025):
  9. "Product Information. Zydol XL (tramadol)." Grunenthal Ltd (2025):
  10. "Product Information. Tramadol Hydrochloride (tramadol)." Brown & Burk UK Ltd (2025):
  11. "Product Information. Zydol (tramadol)." Grunenthal Ltd (2025):
  12. "Product Information. Zamadol Melt (tramadol)." Viatris UK Healthcare Ltd (2026):
  13. "Product Information. Tramadol Hydrochloride (tramadol)." Hameln Pharma Ltd (2025):

The following applies to the ingredients: Diphenhydramine (found in Benadryl)

Use is recommended only if clearly needed and the benefit outweighs the risk.

AU TGA pregnancy category: A
US FDA pregnancy category: B

Comment:
-Exposure during the third trimester may result in adverse reactions in premature infants and neonates.

Animal models have failed to reveal evidence of impaired fertility or fetal harm at doses up to 5 times the human dose. There are no controlled data in human pregnancy.

AU TGA pregnancy category A: Drugs which have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed.

US FDA pregnancy category B: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.

References

  1. "Product Information. Benadryl (diphenhydramine)." Parke-Davis PROD (2002):
  2. "Product Information. Benadryl Children's Allergy Fastmelt (diphenhydrAMINE)." Pfizer U.S. Pharmaceuticals Group (2022):
  3. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  4. Cerner Multum, Inc. "Australian Product Information." O 0
  5. "Product Information. DiphenhydrAMINE Hydrochloride (diphenhydramine)." West-Ward Pharmaceuticals Corporation (previously Roxane Laboratories Inc) (2019):

Drug and Breastfeeding Interactions

The following applies to the ingredients: Diphenhydramine (found in Benadryl)

Use is not recommended.
-According to some authorities: Use is contraindicated.

Excreted into human milk: Yes

Comments:
-The effects in the nursing infant are unknown.
-This drug may affect milk production, especially at high doses given early in the postpartum period and/or when used concomitantly with a sympathomimetic drug.

References

  1. "Product Information. Benadryl (diphenhydramine)." Parke-Davis PROD (2002):
  2. "Product Information. Benadryl Children's Allergy Fastmelt (diphenhydrAMINE)." Pfizer U.S. Pharmaceuticals Group (2022):
  3. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  4. Cerner Multum, Inc. "Australian Product Information." O 0
  5. United States National Library of Medicine "Toxnet. Toxicology Data Network. http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT" (2013):

The following applies to the ingredients: Tramadol

Use is not recommended

Excreted into human milk: Yes

Comments:
-The US FDA recommends against the use of tramadol during breastfeeding due to risks of serious adverse reactions in breastfed infants; this drug is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied.
-If infants are exposed through breastmilk, they should be monitored for excess sedation and respiratory depression.

Serious adverse reactions in breastfed infants may include excess sleepiness, difficulty breastfeeding, or serious breathing problems that could result in death. Newborns have limited capacity to metabolize the active 0-desmethyltramadol.

A study in 75 mothers reported an average milk concentration of 748 mcg/L; this translates to an average infant dose of 112 mcg/kg and a maternal weight-adjusted dose of 2.24% and 0.64% for the drug and its metabolite, respectively. Reanalysis of the data using a population pharmacokinetic model showed a maternal weight adjusted dose of 2.2% for extensive metabolizers and 2.6% for poor metabolizers. The amount of drug present in breast milk represents a maximum of 2.6% of the proposed IV newborn dose. This drug can increase prolactin levels; however, the prolactin level in a mother with established lactation may not affect her ability to breastfeed.

References

  1. "Product Information. Ultram (tramadol)." McNeil Pharmaceutical PROD (2001):
  2. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  3. Cerner Multum, Inc. "Australian Product Information." O 0
  4. United States National Library of Medicine "Toxnet. Toxicology Data Network. http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT" (2013):
  5. "Product Information. Ultram ER (tramadol)." PriCara Pharmaceuticals (2015):
  6. US Food and Drug Administration (FDA) "FDA Drug Safety Communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. https://www.fda.gov/Drugs/DrugSafety/ucm549679.htm" (2017):

Therapeutic Duplication Warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

Switch to: Consumer Interactions

Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Disclaimer: This content should not be considered complete and should not be used in place of a call or visit to a healthcare professional. Use of this content is subject to our terms of use & medical disclaimer.