Go Ad-Free
logoThe People's Perspective on Medicine

Paradoxical Excitation from DPH Sleeping Pills

Diphenhydramine (DPH) is the antihistamine in the allergy med Benadryl. It makes many drowsy. But DPH pain relievers wake some people up!

When you think about sleeping pills, you probably imagine medications that make you drowsy. After all, the whole point of sleeping pills is to help you fall asleep easier. In recent years “PM” pain relievers have proliferated. I am talking about drugs like Advil PM, Aleve PM and Tylenol PM. These OTC pain relievers contain the antihistamine diphenhydramine (DPH). It is the antihistamine found in the allergy medicine Benadryl. These DPH sleeping pills and pain relievers are supposed to make you drowsy so you can fall asleep. But some people experience paradoxical excitation. Some readers describe the problem.

Restless Legs from DPH:

Q. I know that many people take the antihistamine diphenhydramine to help them sleep. Unlike them, I feel agitated, not drowsy, when I take it. This drug often gives me restless legs or leg cramps.

A. Researchers call your reaction to diphenhydramine (Benadryl) “paradoxical excitation.” Some have hypothesized that this could be explained by genetic differences in enzyme activity (CNS Spectrums, Feb. 2008).

Other readers have also experienced RLS (restless leg syndrome) after taking diphenhydramine (DPH). We find it disturbing that DPH is a component in most “PM” pain relievers. Using a sleep aid that might cause leg movements or agitation seems potentially counterproductive.

DPH Sleeping Pills Wake Him Up:

Q. Any product like a nighttime pain reliever that contains the antihistamine diphenhydramine (DPH) has the opposite effect on me, keeping me awake all night with jitters and restless-leg type symptoms. This is the opposite of what one would expect or want.

As a result, I have to be very careful about what I take when I can’t sleep. I would really like to understand why I have this reaction to DPH products. Also, what can I can take when I need help with sleep?

Paradoxical Excitation with DPH Sleeping Pills:

A. You are describing “paradoxical excitation on diphenhydramine.” Most people find this medication makes them drowsy. That is why it is included in so many nighttime pain relievers. Here is a partial list:

Acetaminophen PM
Advil PM
Aleve PM
Excedrin PM
Excedrin PM Headache
Ibuprofen PM
Naproxen Sodium PM
Pain Relief PM
Pain Reliever PM
Simply Sleep
Tylenol PM
Unisom PM Pain
ZzzQuil Night Pain

Pharmacologists have known for decades that some people react differently to DPH. Instead of becoming drowsy, they may become agitated or anxious. When I was a graduate student in the Department of Pharmacology at the University of Michigan over 50 years ago I learned about the paradoxical excitation associated with antihistamines like diphenhydramine. It fascinated me then and continues to fascinate me today.

Here is what the pharmacology “bible” (GOODMAN and GILLMAN’s The Pharmacological Basis of Therapeutics) has to say about this effect:

“The H1 [histamine] blockers can both stimulate and depress the CNS [central nervous system]. Stimulation is occasionally encountered in patients given conventional doses, who become restless, nervous, and unable to sleep.”

Why Do DPH Sleeping Pills Wake Some People Up?

One hypothesis is that these individuals metabolize DPH very rapidly to a stimulant compound (CNS Spectrums, Feb. 2008). In reality, though, we do not understand what makes some people super sensitive to diphenhydramine’s stimulant activity.

You would think that the FDA would require some information on the label of PM pain relievers that warns about this paradoxical excitation reaction. Imagine giving someone with a bad cold a liquid cough medicine that paradoxically makes them cough more! Crazy, right?

You would hope that there would be some mention of such a contradictory complication on the label of OTC PM sleeping pills. As far as we can tell, there is no mention of this unusual and unpleasant adverse reaction.

Natural Approaches to Insomnia?

You may find some natural sleep aids less disruptive. Valerian, passionflower, tart cherry juice, lemon balm or melatonin are popular and can sometimes be helpful. To learn more about these approaches and other strategies, you may find our eGuide to Getting a Good Night’s Sleep helpful. This online resource can be found under the Health eGuides tab.

Please share your own story of diphenhydramine. Have you tried one of the PM pain relievers? How well did it work? have you ever had a paradoxical reaction to a medication? We would be grateful if you would include your experience in the comment section below.

Rate this article
4.6- 72 ratings
About the Author
Joe Graedon is a pharmacologist who has dedicated his career to making drug information understandable to consumers. His best-selling book, The People’s Pharmacy, was published in 1976 and led to a syndicated newspaper column, syndicated public radio show and web site. In 2006, Long Island University awarded him an honorary doctorate as “one of the country's leading drug experts for the consumer.”.
Tired of the ads on our website?

Now you can browse our website completely ad-free for just $5 / month. Stay up to date on breaking health news and support our work without the distraction of advertisements.

Browse our website ad-free
  • de Leon J & Nikoloff DM, "Paradoxical excitation on diphenhydramine may be associated with being a CYP2D6 ultrarapid metabolizer: three case reports." CNS Spectrums, Feb. 2008. DOI: 10.1017/s109285290001628x
Join over 150,000 Subscribers at The People's Pharmacy

We're empowering you to make wise decisions about your own health, by providing you with essential health information about both medical and alternative treatment options.