Benadryl With Tramadol Interaction

Use caution when using Benadryl with tramadol.


My doctor recently prescribed me tramadol. I take Benadryl to help me sleep every now and then. Are they safe together?

Asked by Top On Sep 22, 2022

Answered by
Medical Content Reviewed By HelloPharmacist Staff

Published Sep 22, 2022
Last updated Sep 22, 2022

Key points

  • Taking Benadryl (diphenhydramine) with tramadol can result in additive side effects, such as drowsiness, dizziness and memory impairment.

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The use of Benadryl (diphenhydramine) and tramadol together can cause additive side effects and therefore, caution is recommended when combining them. These potential side effects include:

  • Sedation
  • Drowsiness
  • Decreased motor function
  • Memory impairment

How Long To Wait Between Dosing

While tramadol and Benadryl generally shouldn't be taken together due to the additive side effects, in most cases they can be taken on the same day, as long as they are separated by an appropriate amount of time.

  • Tramadol has a duration of action of around 6 hours, with peak effects occurring about 1.5-2 hours after taking a dose by mouth.
  • Benadryl has a duration of action of around 4 to 6 hours. This can be prolonged in certain individuals, such as those with liver dysfunction or the elderly.

Based on how long each drug lasts, you should wait at least 6 hours after taking tramadol to take Benadryl to lessen the risk of additive effects. Similarly, you should wait at least 6 hours after taking Benadryl to take tramadol.

It is important to note that tramadol is the active ingredient in a variety of prescription products, many of them 'extended release'. These products include:

  • Ryzolt
  • Ultram ER
  • ConZip

If you are taking any of the extended-release tramadol products, you will need to wait longer than 6 hours to avoid additive effects. To be safe, you may want to hold off on taking Benadryl the same day.

Other Recommendations

The above recommendations stem from how long the noticeable effects of each drug last. It takes considerably longer than the duration of action for them to be completely metabolized and eliminated from the body. If you wish to avoid having the two drugs in your system at the same time, you have to consider other characteristics, such as half-life.

The half-life of tramadol is around 6-7 hours for the immediate release dosage forms (e.g. Ultram). As it generally takes around 5-6 half-lives to be completely eliminated from the body, this correlates to 1 to 2 days.

The half-life of Benadryl is shorter than tramadol, around 2 to 3 hours for most individuals (although this is prolonged in certain populations) and nearly 100% of the drug is metabolized and eliminated within 24 hours.

Therefore, based on the half-lives for each drug, you will need to wait 1 to 2 days in most cases to avoid having both drugs in your body at the same time.

Final Words

Thanks for reaching out to us. I hope the information provided here was helpful!


  • Clinical pharmacokinetics of H1-receptor antagonists (the antihistamines), PubMed
  • Ultram Prescribing Information, Janssen
  • Pharmacokinetics of Diphenhydramine and a Demethylated Metabolite Following Intravenous And Oral Administration, ACCP
  • Diphenhydramine kinetics following intravenous, oral, and sublingual dimenhydrinate administration, Wiley Online Library
  • Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an 'atypical' opioid analgesic, ASPET
  • Potential interactions of central nervous system drugs used in the elderly population, BJPS

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