American Academy of Sleep Medicine Guidelines Update: Restless Leg Syndrome

The American Academy of Sleep Medicine (AASM) released a clinical practice guideline (CPG) update in the Journal of Sleep Medicine about the treatment of restless leg syndrome and periodic limb movement disorder in adult and pediatric patients.

Restless leg syndrome (RLS) is a sleep-related movement disorder that can range in severity from occasional leg discomfort during periods of inactivity, typically in the evening or at night, to daily, seemingly constant discomfort and the need to move. Clinical RLS is defined as occurring more than twice per week, accompanied by at least moderate distress.

Periodic limb movements during sleep occur every 15 to 30 seconds in people with RLS. Periodic limb movement disorder is diagnosed when these movements occur at a frequency of more than 15 (adults) or 5 (children) movements per hour.

Neurology Advisor spoke to John W Winkelman, MD, PhD, a psychiatrist at Massachusetts General Hospital and professor of psychiatry at Harvard Medical School, as well as the primary author of AASM’s CPG regarding developments made in the clinical understanding of RLS.

“We’ve made tremendous advances in understanding the pathophysiology of RLS over the last 25 years. At this point, there are 2 clear pieces to understanding what is going on. One is that there is clearly a strong genetic influence. […] The second part of pathophysiology has to do with brain iron deficiency, […] even though serum iron indices are usually normal in people with RLS. So, it appears as if there is some abnormality in the transport of iron into the brain,” Dr Winkelman noted.

The AASM guidelines task force formed recommendations based on a systematic literature review and assessed evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The task force considered RLS efficacy, sleep, quality of life, augmentation (defined as the gradual worsening of RLS symptom intensity), and adverse effects in its treatment recommendations.

Treating RLS Adults, Children, and Special Populations

This 2024 CPG is an update to the 2012 AASM practice parameter and comprises 28 recommendations for treating RLS in adults, children, and special populations, as well as for treating periodic limb movement disorder in adults.

“There are some big changes [in these guidelines], and they may be a surprise to your readership. I think the one that is most important […] is that although dopaminergic medications demonstrated extraordinary efficacy in the short-term clinical trials, it has now become clear that over the long term, these medications, due to plasticity in the dopaminergic system, worsen the underlying RLS,” said Dr Winkelman. “The last thing that any clinician wants to do is provide something to their patient that makes them worse, even if it makes them a lot better in the short term.”

Medications for Long-Term Treatment of RLS

In contrast to the 2012 AASM practice parameter, the 2024 AASM CPG conditionally recommends against the standard use of the dopaminergic agents ropinirole, pramipexole, rotigotine, and levodopa for the long-term treatment of RLS due to the high risk for augmentation that is associated with extended durations of use.

In addition, the AASM conditionally recommends against the use of bupropion, carbamazepine, clonazepam, valerian, and valproic acid, as these interventions failed to demonstrate clinically meaningful improvement in RLS.

The AASM now recommends the use of gabapentin enacarbil, gabapentin, or pregabalin for adults with RLS. These recommendations were graded as strong and were based on data from 13 randomized controlled trials (RCTs) and 7 observational studies. These 3 agents were associated with clinically significant improvement in disease severity and pooled adverse event (AE) estimates did not exceed clinical significance.

RLS Management: Testing of Serum Iron Indices

A key good practice in RLS management is prompt and routine testing of serum iron indices. An iron assessment should occur in the morning after avoiding all iron-containing foods and supplements for a 24-hour period and include measurements of ferritin, iron, and total iron binding capacity. The AASM recommends the use of intravenous (IV) ferric carboxymaltose for patients with a serum ferritin level lower than 100 μg/L, which is well above the usual cutoff for low ferritin. This recommendation was graded as strong and based on data from 5 RCTs, which demonstrated a clinically significant improvement in disease severity with IV ferric carboxymaltose in patients with low ferritin.

“Beyond the strongly recommended [interventions], there are the conditionally recommended agents. So, we have other options [for patients],” said Dr Winkelman.

Conditionally Recommended Agents for RLS

The conditional recommendations regard the use of dipyridamole, extended-release oxycodone or other mu-opioid agonists, or bilateral high-frequency peroneal nerve stimulation. These recommendations are conditional because they each were based on only 1 or 2 RCTs. However, the 3 interventions demonstrated clinically significant improvement in disease severity. There were no clinically significant safety issues for dipyridamole or peroneal nerve stimulation. The pooled estimates of AEs associated with opioids, however, met clinical significance and clinicians should consider patients’ risk for abuse.

Other conditionally recommended iron supplementation options for patients with low ferritin include IV low molecular weight iron dextran, IV ferumoxytol, and ferrous sulfate. These iron supplementation approaches were conditionally recommended due to a paucity of data. However, IV low molecular weight iron dextran, IV ferumoxytol, and ferrous sulfate were associated with significant improvements in disease severity.

Future CPG Updates for RLS

“Two-thirds of people with RLS in the US who are treated with a medication are on a dopamine agent. There is little data on how to switch people who are on these agents to our strongly recommended agents. Thus, these new guidelines refer only to starting medications for people with RLS,” informed Dr Winkelman.

The areas of research needed to inform future CPG updates for RLS include how best to transition patients on dopaminergic agents to recommended interventions while maintaining disease control and lowering risk for augmentation, how to identify patients who would respond to iron supplementation alone, how to approach RLS treatment in special populations, and best practices for managing periodic limb movement disorder.

“These are guidelines. They are not requirements and they are not prohibitions. These are what we consider best practices. If you have evaluated your patient appropriately, warned them about the risk for augmentation, as well as the benefits and side effects of alternative medications, it is the patient who will be making the decision about what they think is best for them. It is a collaborative decision-making process with our patients. That’s really what doctoring is about. No requirements, no prohibitions, just what we consider [to be best practices],” concluded Dr Winkelman.