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Do Heartburn Drugs or Antihistamines Trigger RLS (Restless Legs Syndrome)?

Restless legs syndrome can be mysterious. Most people do their best to cope with RLS. But did you know that some meds like antihistamines trigger RLS?

What causes Restless Legs Syndrome (RLS)? Check with most medical authorities and you will learn that “there’s no known cause” (Mayo Clinic). Symptoms are often blamed on a chemical imbalance in the brain. Researchers may suggest that genetics play a role. In other words, if mom and grandma suffered from creepy, crawly sensations, itching, aching or throbbing, then you too may be susceptible because of your genes. Diabetes, anemia, neuropathy and kidney disease have also been blamed. Many health professionals don’t realize that a number of medications including popular OTC antihistamines trigger RLS. Some widely-used acid-suppressing drugs may also cause trouble.

Pepcid Triggered RLS:

Q. Recently I began taking Pepcid for acid reflux and shortly developed restless leg syndrome while sleeping (or trying to sleep). Intrigued, I did some research and found that acid blockers can indeed cause RLS in susceptible individuals. Perhaps other readers might want to know about this possible reaction.

A. Restless leg syndrome (RLS) is the name doctors use when a patient reports an irresistible urge to move the legs. The cause remains mysterious. This condition (technically known as Willis-Ekbom syndrome) can interfere with sleep.

Thanks for including a reference for the recent article published in Sleep (April 2021).  The scientists looked for low iron stores among blood donors in the US and Denmark. That’s because iron deficiency has been associated with RLS (Nature Reviews. Disease Primers, Nov. 3, 2021). Although they did find that people taking acid-suppressing drugs (including proton pump inhibitors or PPIs) were more likely to suffer RLS, they discovered no link with iron levels.

A Reader Targets Benadryl:

Q. One parent and all of my siblings have restless legs syndrome. So do I.

Benadryl, specifically its primary ingredient diphenhydramine, absolutely aggravates my RLS. I avoid it and anything else that contains it, such as the PM pain medications.

Certain nausea medications also make RLS worse. The one I recall is Phenergan.

Don’t assume your physician knows this. Several doctors I spoke with knew nothing about it. As far as I’m concerned, I’m allergic to these drugs, and list them in my records accordingly.

Do Antihistamines Trigger RLS?

A. Restless legs syndrome (RLS) is characterized by an urgent feeling that you need to move your legs. Moving them alleviates sensations of crawling, itching or throbbing, but this frequently keeps people awake.

You are quite right that diphenhydramine can aggravate RLS symptoms (National Institute of Neurological Disorders and Stroke).  We think people who take PM pain relievers containing diphenhydramine should be alerted to this potential reaction.

What makes this so insidious is that there are now lots of “PM” nighttime pain medicines. These over-the-counter products include:

  • Acetaminophen PM
  • Advil PM
  • Aleve PM
  • Bayer PM
  • Excedrin PM
  • Ibuprofen PM
  • Motrin PM
  • Tylenol PM
  • Unisom PM

We suspect that most people are unaware of the possibility that diphenhydramine (“PM”) sleeping pills might lead to restless legs syndrome. If there is no warning, people may develop symptoms and receive powerful medications to combat a drug-induced side effect. If antihistamines trigger RLS, it seems counterproductive to take another medicine to counteract this complication.

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Other Drugs That May Trigger RLS:

Although millions are now taking diphenhydramine daily to get to sleep, there are other drugs that have also been associated with RLS (Worst Pills, Best Pills News, March, 2019).  They may include antidepressants such as:

Amitriptyline (Elavil)

Imipramine (Tofranil)

Citalopram (Celexa)

Escitalopram (Lexapro)

Fluoxetine (Prozac)

Paroxetine (Sertraline)

Venlafaxine (Effexor)

Antipsychotics are also on the list:

Chlorpromazine (Thorazine)

Clozapine (Clozaril)

Olanzapine (Zyprexa)

Quetiapine (Seroquel)

Risperidone (Risperdal)

The heartburn drug metoclopramine (Reglan) is also included, as is the antiepilepsy medicine topiramate (Topamax).

What to Do if Drugs Are Causing RLS?

No one should ever stop any of these medicines suddenly or without medical supervision. If people have to take such medicine, RLS may be the price they have to bear.

Learn About Treatments for RLS:

What can people do if they have restless legs syndrome? Learn about home remedies and medications such as ropinirole (Requip) and pramipexole (Mirapex) at this link:

Restless Legs Syndrome (RLS) Relieved With Soap!

Find intriguing information about:

Best Home Remedies for Restless Legs Syndrome

Traveling? RLS can be especially troublesome if you have to take a long flight or drive for many hours. Here’s a unique idea:

Soap for RLS When Taking Long Flights

Share your own RLS story in the comment section. Did antihistamines trigger RLS for you? What about other medications? Have you ever found a treatment that worked? We’d love to hear from you.

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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.”.
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