Soothing the signs of restless legs syndrome

Patients who report trouble falling or staying asleep may be suffering from restless legs syndrome (RLS), but physicians may not recognize it unless they ask targeted questions.

“The mnemonic to keep in mind for the diagnosis is URGE: an Urge to move the legs that is worse at Rest, Gets better with movement, and occurs in the Evening or at night,” said John Winkelman, MD, PhD, a professor of sleep medicine at Harvard Medical School in Boston and first author on an updated clinical practice guideline on RLS from the American Academy of Sleep Medicine (AASM), published by the Journal of Sleep Medicine in January.

Restless legs syndrome is far from rare. Clinically significant symptoms, defined as occurring at least twice a week and causing moderate distress, affect about 3% of adults, according to the AASM guideline. Prevalence rises steadily with age, reaching about 6% to 7% in adults older than age 65 years, and the disorder is roughly twice as common in women as in men.

Despite its prevalence, RLS remains challenging to recognize. “Sometimes restless legs is mistaken for neuropathy, peripheral artery disease, or even medication side effects,” said Brian Koo, MD, director of the Yale Center for Restless Legs in New Haven, Conn. “But the key feature is the urge to move. Without that, it's not restless legs.”

More than 50% of prescriptions for RLS are written by primary care physicians, Dr. Winkelman noted, yet many clinicians may be unaware of the risks of traditional therapies. Notably, the updated AASM guideline advises against using dopamine agonists first, a major shift after two decades of widespread use, due to the recognition that these medications often produce a worsening of RLS, with earlier and earlier onset of symptoms during the day and/or extension of symptoms to the upper extremities, a process called augmentation.

“In the past, dopamine agonists were our go-to treatment, but we now know that about 80% of patients will develop augmentation after a decade on these drugs,” said Stephanie Stahl, MD, associate professor and director of the sleep medicine fellowship program at Indiana University School of Medicine in Indianapolis. “It's a temporary fix that can lead to escalating doses and worsening symptoms down the road, so we want to avoid starting them whenever possible.”

Making a diagnosis

High-risk populations for RLS include pregnant women—up to one-quarter experience RLS during the third trimester—and patients with iron deficiency, renal disease, or a family history of the condition, according to AASM.

There's no definitive test for RLS, but laboratory evaluation can help uncover contributing factors. Experts recommend checking iron levels, including ferritin and transferrin saturation, since low iron stores are closely linked to symptom severity, probably related to the brain iron deficiency observed in those with RLS.

“Iron labs, including a ferritin level, are critical when someone is describing symptoms of RLS,” said Dr. Koo. He advised ordering the tests fasting in the morning and, if possible, pausing iron supplements and avoiding iron-rich meals for several days beforehand to ensure accurate results.

Normal ferritin levels for adults are usually somewhere around 15 to 150 ng/mL for women and 30 to 400 ng/mL for men. In the context of RLS, sleep specialists typically target a minimum of over 75 to 100 ng/mL for both men and women, said Dr. Stahl.

Regarding symptoms, “the circadian pattern, worse in the evening or at night, is key,” said ACP Member Sheila Tsai, MD, a sleep medicine specialist at National Jewish Health in Denver. Patients may come in with vague sleep symptoms or leg discomfort, so it's important to ask specifically about the timing and whether movement brings relief.

Other contributors should also be considered, according to experts and the AASM guideline, including common medications such as serotonergic antidepressants, antihistamines, and antipsychotics, which can provoke or worsen symptoms. Additionally, it's not uncommon for RLS to coexist with obstructive sleep apnea; in one large study of 707 adults with OSA, published in Sleep Medicine in May 2024, 16% were also diagnosed with RLS.

“We often see patients who have both obstructive sleep apnea and restless legs, and untreated sleep apnea can make the RLS much worse,” said Dr. Tsai. “It's important to think broadly and not just focus on the legs in isolation.”

Treatment strategies

Once RLS is identified, the next step is to address potentially reversible contributors. If a patient's iron labs come back low, oral supplementation is usually tried first, said Dr. Tsai. However, IV iron is increasingly considered safe and effective when levels fail to rise or symptoms remain severe.

Physicians should also investigate whether other factors may be contributing to or worsening the patient's symptoms, said Dr. Winkelman. Besides sleep apnea and certain prescription medications, antihistamines, nicotine, caffeine, and alcohol can all aggravate symptoms.

Dr. Koo noted that reducing alcohol intake is critical before starting drug therapy, since alcohol both worsens symptoms and can interact with commonly used medications. Even patients who drink one nightly glass of wine should be advised to cut back.

“Caffeine is a big precipitant, and sometimes switching to decaf isn't enough,” added Aparajitha Verma, MD, a neurologist and sleep medicine expert with UTHealth Houston. “For some patients, completely eliminating caffeine from all sources [coffee, tea, soda, energy drinks, et cetera] may be necessary.”

All antidepressants except bupropion can worsen restless legs, and mirtazapine and tricyclics are especially problematic, said Dr. Koo. If patients are stable on a tricyclic for depression, switching to a different agent may be preferable to stopping outright, but reviewing alternatives is important.

Antipsychotics, such as risperidone and ziprasidone, and antinausea medications, such as metoclopramide, can worsen or precipitate RLS, said Dr. Verma. She stressed that assessing patients' current medications and addressing side effects are necessary first steps before adding or changing RLS-specific therapy.

If symptoms persist after addressing iron deficiency, treating comorbid sleep disorders, and adjusting contributing medications, pharmacologic therapy may be appropriate. The AASM guideline recommends gabapentinoids—gabapentin, gabapentin enacarbil, or pregabalin—as first-line treatment. The guideline noted that these agents relieve symptoms in roughly two-thirds of patients and are considered safer for long-term use than dopamine agonists, according to clinical trials.

“Gabapentin enacarbil is the only one FDA-approved for RLS, but gabapentin and pregabalin are equally effective,” Dr. Winkelman said. He added that all of these medications should be started at a low dose and titrated gradually to minimize side effects, such as sedation or dizziness.

Experts emphasized that careful management is particularly important for patients already on dopamine agonists. Dr. Verma noted that she frequently sees referrals for patients whose doses have been escalated over the years, only to experience augmentation, with their symptoms starting earlier in the day or spreading beyond the legs.

To stop dopamine agonist therapy, Dr. Verma recommended a very gradual taper, sometimes reducing by just 0.125 mg every week or two while adding a gabapentinoid and optimizing iron.

Dr. Stahl agreed, cautioning that withdrawal from dopamine agonists can be miserable if therapy is stopped too quickly. She recommended reducing the dose no faster than every three weeks, sometimes over many months, to minimize rebound symptoms while transitioning patients to the currently recommended first-line choices, including gabapentin, gabapentin enacarbil, or pregabalin.

Treatment decisions should also reflect the patient's preferences, Dr. Koo noted.

“There isn't a hard rule that a certain severity requires medication,” he said. “Some patients with very severe restless legs don't want to take medicine, while others with moderate symptoms do. It's really a shared decision, but if patients have nightly symptoms that prevent sleep, they usually need consistent therapy.”

Nonpharmacologic strategies also play a role in reducing symptoms, including moderate exercise and regular sleep schedules, massage, stretching, or warm baths before bed, experts said.

Follow-up, monitoring

Managing RLS is rarely a one-and-done prescription. Because symptoms fluctuate and treatments carry unique risks, ongoing follow-up is critical.

“We usually recheck iron studies every three to six months while on iron supplementation, depending on how low the levels were to begin with,” said Dr. Tsai. “It can take a while for iron stores to build back up, and patients need to know that improvement may be gradual.”

For patients on pharmacologic therapy, follow-up often comes sooner. “If we start someone on gabapentin or pregabalin, I like to see them back within one to three months,” Dr. Stahl said. “That allows us to assess whether they're responding, titrate the dose if needed, and monitor for side effects.”

While most cases can be managed effectively in primary care, specialty involvement is often appropriate for difficult cases, said Dr. Winkelman. “If a patient is on a dopamine agonist and showing signs of augmentation or if they aren't responding to first-line treatments, that's when specialist involvement can help.”

In those patients, next steps may include low-dose opioids, peroneal nerve stimulation devices, or combination regimens.

“Occasionally, we use low-dose opioids like methadone or oxycodone when other strategies fail,” said Dr. Verma. “These must be carefully monitored and often combined with a gabapentinoid.”

She also noted that peroneal nerve stimulation devices, which are worn around the knee, are emerging as a nondrug option for refractory cases.

Managing refractory cases often requires persistence, said Dr. Koo, who emphasized the importance of setting realistic expectations.

“We may need to try several strategies—adjusting iron, tapering dopamine agonists, combining medications—before symptoms are under control,” he said. “The key is not to give up, because there are effective options even for severe cases.”

For primary care physicians, the new AASM guideline underscores a few straightforward but powerful changes in practice: Recognize RLS when patients present with sleep symptoms, check iron stores, avoid dopamine agonists as first-line therapy, and follow patients closely.

“Restless legs isn't complicated to diagnose, but it is easy to miss if you don't ask the right questions,” said Dr. Winkelman. “One simple screening question, ‘Do your legs bother you at night?,’ can make all the difference.”

When cases become more complicated, resources are available, he added.

For example, a free, online, commercial-free, HIPAA-compliant, clinician-only forum, developed by Dr. Winkelman with support from the Baszucki Group and available at RLSCurbside.org, offers curbside-style consults on difficult cases. Additionally, the Restless Legs Syndrome Foundation (rls.org) designates quality care centers across the United States for specialty referrals and provides patient education and support groups, helping bridge gaps in awareness and care.

“Primary care really is the frontline,” Dr. Verma said. “With the right tools and awareness, physicians can relieve a huge burden for patients whose symptoms often go unrecognized for years.”