The People's Perspective on Medicine

Do Drugs Like 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?
Female legs in bed, closeup. Woman body and skin care, tired legs after working day or fitness workout

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 often 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. What many health professionals don’t realize is that a number of medications including popular OTC antihistamines trigger RLS.

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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People’s Pharmacy Leg Soap
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I take Benadryl regularly for allergies, and although I don’t suffer from RLS, I have accidentally taken doses too close together at bedtime and experienced restless legs once or twice. It’s not pleasant at all.

I have RLS ,but was overwhelmed by the frequency many years ago until I realized it was connected to taking Diphenhydramine. Haven’t taken any in almost 25 years and The number of incidents was reduced drastically.

Quoting your (PP) statement above re one’s medication(s) causing RLS: “…If people have to take such medicine, RLS may be the price they have to bear”. All medication has to be started and stopped under medical supervision. But no one should be told that RLS is a price they may “have to bear”. If you make that statement, you’ve never suffered from, or witnessed the suffering of Restless Legs Syndrome.

There are either alternative medications for insomnia, allergies, nausea, depression, etc. or medications specifically for direct treatment of RLS.
Example: Zofran is an ant-nausea medication that can be used instead of Phenergan and its equivalents to avoid the side effect of RLS. Requip and other drugs formulated to treat RLS can be prescribed if one must take a drug that aggravates RLS. Other medications, such low-dose diazepam can also be prescribed off-label to treat RLS.

The Restless Legs Foundations – – can provide resources for people who suffer from the misery of RLS.

Like the original poster…I have taken Prilosec for over 20 years. Restless Leg Syndrome was a problem for years, until I read on Peoples Pharmacy about magnesium deficiency as a cause for the RSL. Added magnesium daily and the RSL basically disappeared.
Interestingly, it may have been the Prilosec PPI that caused the magnesium deficiency in the first place.

Currently finally getting off the prilosec with the use of DGL. But still taking a tylenol PM to sleep, and have noticed a little return of the RSL.

I believe this is so true! Whenever, like just in the last 3 weeks I caught a summer cold and when I have to use Nyquil or Dayquil I suffer terribly from what i call the “creepy crawlies” in my legs at night. Then I know that it is time to switch meds until its over and I’m well again.

One of the comments about RLS was to bend over and touch your feet. I do this every night before bed and haven’t had RLS since!

Add melatonin to the list of substances that aggravate my RLS.

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