Can You Take Benadryl (Diphenhydramine) With Oxycodone?

In our latest question and answer, the pharmacist discusses whether or not you can combine Benadryl (diphenhydramine) with oxycodone.


Can you take Benadryl with oxycodone? I have trouble sleeping.

Asked by Manu On Sep 21, 2022

Answered by
Medical Content Reviewed By HelloPharmacist Staff

Published Sep 21, 2022
Last updated Sep 21, 2022

Key points

  • Benadryl (diphenhydramine) and oxycodone generally should not be taken together due to the increased risk of side effects.


In general, it is not recommended to combine Benadryl (diphenhydramine) and oxycodone, especially if oxycodone is a new medication for you.

Increased Risk Of Side Effects

Oxycodone, by itself, can cause respiratory depression as well as depression of the CNS (Central Nervous System). Combining Benadryl (diphenhydramine), a sedating first-generation antihistamine, can enhance these effects.

There have been reports of significant drops in blood pressure, excess sedation as well as respiratory depression with the combination. Additionally, you certainly do not want to mix Benadryl (diphenhydramine), oxycodone, and alcohol together.

Having said all this, the combination of Benadryl (diphenhydramine) and oxycodone can be used in some situations.

Chronic use of oxycodone leads to tolerance to its effects.

Typically, once your level of tolerance to the depressant effects of oxycodone are appropriately assessed, your doctor may recommend combining Benadryl (diphenhydramine) for certain indications, such as insomnia. Your doctor may adjust the dose of one of the medications to get the best response in a safe way.

Final Words

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Dr. Brian Staiger, PharmD

Dr. Brian has been practicing pharmacy for over 11 years and has wide-ranging experiences in many different areas of the profession. From retail, clinical and administrative responsibilities, he's your knowledgeable and go-to source for all your pharmacy and medication-related questions! Feel free to send him an email at! You can also connect with Dr. Brian Staiger on LinkedIn.

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