Senior Asian woman experiences leg pain while in bed.

Solving the mystery of restless legs syndrome: Acid-blocking medicines may play role

It’s been called the most common disease nobody’s heard of – and also one of the big mysteries in medicine.

It’s restless legs syndrome (RLS), a neurological and sleep disorder that causes discomfort and sometimes pain in the legs, particularly at night. It triggers a constant urge to move the legs that makes falling asleep and staying asleep difficult. And it can lead to other serious health problems, including depression.

RLS affects about 5-15% of adults in the United States. It shows up more as people age, occurs almost twice as often in women than men, and tends to run in families. Some studies have found a higher incidence of RLS among people with iron deficiency.

Yet for all that researchers know about it, RLS can be difficult to diagnose, in part because its symptoms overlap with other common conditions, such as nighttime leg cramps. It’s also difficult to treat, as there are few effective medications or therapies for relieving the symptoms of the disorder, which has no known cure.

But a recent observational study found a link between the development of RLS and the use of certain prescription medications commonly used to reduce acid reflux. The study, published in the journal SLEEP, was funded in part by the National Heart, Lung, and Blood Institute (NHLBI).

The researchers chose to study antacids because a growing number of studies have shown a link between these drugs and iron deficiency. They hypothesized that antacid use might therefore contribute to RLS by reducing blood iron levels. The study focused on two types of potent medications that directly inhibit stomach acid secretion—proton pump inhibitors (PPI) and histamine type 2 receptor antagonists (H2A). These are different from many of the other over-the-counter antacid products that neutralize stomach acid but do not block its production. The researchers explored the use of these PPI and H2A medications and the incidence of RLS among two different populations of blood donors in the United States and Denmark.

“We found that consuming these powerful acid-blocking agents is strongly linked to a significantly higher incidence of restless legs syndrome compared to those who did not consume these medications,” said Eric J. Earley, Ph.D., a researcher at RTI International in Research Triangle Park, N.C., and lead author of the study. “This finding suggests the need to reevaluate their use in patients who experience RLS or are at high risk for developing it.”

The U.S. group included 13,403 blood donors from the NHLBI’s REDS-III program, while the group from Denmark included 50,323 donors from the Danish Blood Donor Study. The donors completed blood count measures and an RLS diagnostic questionnaire. After adjusting for age, sex, race, BMI, blood donation frequency, and other factors, the researchers found that those who regularly consumed two or more different acid-blocking drugs were about twice as likely to have RLS compared with those who took none.

While past studies by other researchers found that blood iron deficiency may play a key role in the development of RLS, the current study did not find that, Earley said. The finding suggests that there likely are other mechanisms at play that determine how acid-blocking medications like PPI and H2A are linked to RLS, he said.

“We’ve potentially revealed a new avenue in understanding the mechanism of RLS, but more studies are needed to prove the causation,” Earley said. More knowledge about the link between RLS and acid-blocking medications could lead to new therapies for RLS, including both drug and non-drug options, he said.

Marishka Brown, Ph.D., director of the NHLBI’s National Center on Sleep Disorders Research, agreed. “This study represents an important step toward solving the longstanding mystery of restless legs syndrome and its disruptive impact on sleep,” Brown said. “While more research and better treatments for RLS are still needed, we are hopeful that NHLBI-supported investigators will continue to make progress in this area.”

The study is also important for another reason. “This finding illustrates how studies in blood donors may help address important research questions that have public health impact,” said Simone Glynn M.D., M.P.H., chief of the Blood Epidemiology and Clinical Therapeutics branch of the NHLBI, and the scientific project officer for the REDS-III research program, the U.S. component of the study. “It also shows the value of establishing collaborations with other research groups to enhance the quality and size of these studies.”

Although the disorder is complex and may also involve other biological mechanisms and other medications, RTI’s Earley said he and his colleagues are optimistic about the findings. “We think this work has the potential to have a significant and rapid clinical impact on the health of patients with RLS.”

For now, he encourages anyone who thinks they may have symptoms of restless legs syndrome to see their doctor.