AAN Releases First Treatment Guideline on Restless Legs Syndrome

Deborah Brauser

December 02, 2016

The American Academy of Neurology (AAN) has released its first practice guideline for the management of restless legs syndrome (RLS) in adult patients.

Medication, especially pramipexole (Mirapex, Boehringer Ingelheim), rotigotine (Neupro, UCB), and gabapentin enacarbil (Horizant, XenoPort), should be considered for treating symptoms of moderate to severe RLS in adult patients, the authors write.

A summary of the practice guideline on RLS treatment, which was published online November 16 in Neurology, notes that "strong evidence" supports the use of these three agents. Cabergoline was also given a Level A recommendation, but because of a risk of cardiac valvulopathy when the agent is used at high doses, it's "rarely used" anymore in clinical practice, report the authors.

"Moderate evidence" led to Level B recommendations for ropinirole (Requip, GlaxoSmithKline), pregabalin (Lyrica, Pfizer), and intravenous ferric carboxymaltose (Injectafer, American Reagent), and a Level C nod was given to prescribing levodopa, noting weak evidence in support of its use.

The committee also gave nonpharmacologic recommendations for treating RLS, including the use of pneumatic compression (Level B) or transcranial magnetic stimulation and near-infrared spectroscopy (both Level C). Vibrating pads were mentioned as having Level C support for improving subjective sleep concerns — but not for improving RLS symptoms themselves.

"I think what makes this so important from a clinical neurologist's perspective is that this is the first time that the AAN has done this work, which took us 8 years to do," lead author John W. Winkelman, MD, PhD, Harvard Medical School and Massachusetts General Hospital, Boston, told Medscape Medical News.

Dr John W. Winkelman

That said, Dr Winkelman, who was chair of the AAN's guideline writing subcommittee, said that the best thing a clinician can do is to take the recommendations and then figure out what's best for the individual patient — especially since there's a dearth of head-to-head studies between the various agents.

"Although all of these medications have demonstrated efficacy, one of them [cabergoline] we don't use," said Dr Winkelman. Two of the remaining three with strong evidence are dopamine agonists (pramipexole and rotigotine, as well as the B Level ropinirole), which are effective in the short term. "But in the longer term, they have the potential for actually worsening restless legs syndrome, by augmenting RLS. So you need to be cautious in using them," he added.

"I think we'd choose one medicine over another based on a patient's age, comorbid illnesses, sensitivity to side effects, prior history of taking RLS medications, and what the chief features are of their individual RLS."

2.5% of US Adults Affected

As recently reported by Medscape Medical News, several studies have shown a significant association between increased risk for stroke and sleep-wake disturbance conditions, including RLS.

The current authors note that 2.5% of adults in the United States and Northern Europe are affected by RLS. However, treatment should be considered only if symptoms of the condition are interfering with a patient's sleep or daytime functioning. And contributing factors, such as an iron deficiency, should be ruled out first, they add.

Dr Winkelman pointed out that only four agents are currently approved by the US Food and Drug Administration for treating RLS: pramipexole, gabapentin enacarbil, rotigotine, and ropinirole. "That's three of our Level A recommendations and one of our Level Bs," he said.

Although the American Academy of Sleep Medicine has created RLS guidelines, this is the first time that the AAN has tackled them.

"Restless legs syndrome is a neurological disorder. It affects sleep but it's primarily a neurological disease," said Dr Winkelman, adding that disturbed sleep isn't even one of the diagnostic criteria for RLS. "It's just kind of a byproduct, if you will, of the core features of the disorder."

He noted that because patients are going to neurologists for care of this disorder, "it seemed relevant for the AAN to address."

The guideline committee reviewed all clinical trials on RLS that had been published. "We assessed them for key components of core RLS symptoms," said Dr Winkelman. "And we used only the data with the highest level of evidence in support of clinical recommendations."

In addition to finding strong or moderate evidence supporting the use of the agents listed earlier for treating RLS, the investigators assessed evidence for pharmacologic treatments for various subconditions, as shown in the following table.

Table. Treatment Recommendations for RLS Patients With Subconditions

Condition Agent Recommendation Level
Periodic limb movements Ropinirole A
  Cabergoline B
  Rotigotine B
  Pramipexole B
  Pregabalin B
Subjective sleep measures Cabergoline A
  Gabapentin enacarbil A
  Ropinirole B
  Rotigotine B
  Pramipexole B
  Pregabalin B
Ferritin ≤75 μg/L Ferrous sulfate with vitamin C B
Comorbid anxiety Ropinirole B
Comorbid depression Ropinirole C
Overall mood Gabapentin enacarbil B


"For patients failing other treatments for RLS symptoms, clinicians may consider prescribing prolonged-release oxycodone/naloxone where available (Level C)," write the authors. However, they caution that benefits should be weighed against opioid risks.

In addition, vitamin C and E supplementation are Level B treatment recommendations for patients with RLS undergoing hemodialysis; levodopa, ropinirole, or exercise are listed as Level C recommendations.

Treatments receiving a Level U classification, symbolizing insufficient evidence toward support or nonsupport, include iron sucrose, bupropion, botulinum neurotoxin, carbamazepine, and acupuncture.

"Neurologists Are Lucky"

"I think for people who have mild symptoms of RLS, you could consider the nonpharmacologic approaches," said Dr Winkelman. "But for more frequent and severe symptoms, you're probably going to end up with a medication approach."

He added that he hopes that clinicians find having all this information laid out in one place helpful.

"Medicine is a combination of science and art. We're presenting some of the science here, but the art is in understanding your patient and understanding what vulnerabilities and sensitivities that they have. And then figuring out what's going to be most effective and best tolerated," Dr Winkelman said.

He noted that the top take-home message from the guidelines is that clinicians should ask their patients if they have problems sleeping and then ask about possible RLS.

"It's important for both doctors and patients to know that there are effective medications and even nonpharmacologic approaches that can address RLS symptoms, as well as sleep," said Dr Winkelman.

"I think neurologists in general are lucky to have these multiple treatment choices. This is not a condition that people just have to live with. It's a disturbance of the nervous system that can be specifically addressed."

The full 72-page RSL treatment guideline is available on Neurology's website.

The guideline was developed with financial support from the AAN. Dr Winkelman serves on scientific advisory boards for Merck and Flex Pharma. He has also served on scientific advisory boards for, received honoraria from, served on speakers bureaus for, and/or received research support from UCB, Impax, Pfizer, Lacrima, Luitpold Pharmaceuticals, GlaxoSmithKline, Boehringer-Ingelheim, XenoPort, Zeo Inc, Sunovion, Sepracor (now Sunovion), Insys, Takeda, Jazz, Neurogen, and Novartis; holds stock in Flex Pharma; receives publishing royalties for Foundation of Psychiatric Sleep Medicine; and has given expert testimony for legal cases representing generic manufacturers of pharmaceuticals approved for the treatment of insomnia and narcolepsy. Disclosures for the coauthors are in the paper.

Neurology. Published online November 16, 2016. Full text

Follow Deborah Brauser on Twitter: @MedscapeDeb. For more Medscape Neurology news, join us on Facebook and Twitter


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.