Summary of new clinical practice guideline for RLS and PLMD

By J. Andrew Berkowski, MD, and John W. Winkelman, MD, PhD

The AASM recently released an updated version of its clinical practice guideline (CPG) for the treatment of restless legs syndrome (RLS) and periodic limb movement disorder (PLMD). New high-quality evidence for the benefits and risks of RLS treatments has emerged since the AASM’s last CPG in 2012 and is now represented in the Journal of Clinical Sleep Medicine, alongside a systematic review and meta-analysis.

RLS is a neurological condition producing clinically significant symptoms in at least 2% to 3% of adults and up to 1% of children. It is characterized by an urge to move one’s legs, often with unpleasant leg sensations, which can cause not only distress from the symptoms but also severe sleep disruption. The AASM commissioned a task force of seven RLS specialists and other staff and physicians assisting in the process who worked on the new CPG from 2019–2024 to complete this project. The CPG utilized the rigorous GRADE methodology and systematically assembled high-quality research studies to determine the overall balance of benefits and harms of RLS treatments. The result of the process places treatments with sufficient high-quality research evidence into categories STRONG and CONDITIONAL, both FOR and AGAINST the treatments compared to not using the treatment.

The dopamine agonist medication class, including pramipexole, ropinirole, rotigotine and the dopamine precursor levodopa, were some of the strongest recommended treatments in the 2012 CPG and have been the gold standard medications for RLS for the past 20 years. However, as a result of increasing evidence of high long-term rates of augmentation with these agents, these agents are now conditionally recommended against in the 2024 CPG. RLS augmentation describes an insidious and progressive iatrogenic worsening of symptoms due to dopaminergic medications: progressively earlier symptom onset, extension of symptoms to areas of the body not previously affected, and overall increased severity of symptoms. Augmentation occurs slowly after months and years of use; thus the phenomenon was not captured by the initial clinical trials for drug approval, which were only a few weeks or months duration. With the addition of augmentation as a key critical outcome in the CPG, the balance of effects for dopaminergic agents became more heavily weighted to the harms, particularly over the long-term, which is why they are now conditionally recommended against for most individuals with RLS.

With the downgrade of the dopaminergics to conditionally against, clinicians may be concerned that the CPG has not provided guidance for recommended treatments of RLS. In fact, due to new evidence since the 2012 CPG, four treatments are now strongly recommended for RLS, three of which are from the same pharmacological class, known as alpha-2-delta ligand calcium channel blockers, and include gabapentin, pregabalin and gabapentin enacarbil. The latter is the only remaining FDA-approved medication for RLS recommended in the CPG. Although these medications can have adverse effects, including sedation and gait instability, their benefits for RLS were considered to outweigh these concerns.

Among the other biggest changes in the new CPG is the elevation of the importance of iron evaluation in everyone with RLS and, depending on iron indices, the recommendation for iron supplementation. These recommendations are consistent with evidence that low brain iron is thought to be an important underlying cause of RLS. The CPG contains a good practice statement for clinicians treating RLS that iron studies should be performed regularly, and that serum levels for RLS often need to be higher than those in the general population. In adults with RLS, three formulations of IV iron and one formulation of oral iron were recommended for treatment, including evidence to support IV ferric carboxymaltose as a strongly recommended treatment.

Extended-release oxycodone and — by extension of a clear class effect — other opioids are conditionally recommended for the treatment of RLS in adults. This medication class has demonstrated efficacy for RLS, though the risks associated with opioid use are well described in the CPG, and these should be prescribed with caution. Other conditionally recommended treatments include dipyridamole and the newest treatment, bilateral, high-frequency peroneal nerve stimulation.

In addition to dopaminergic treatments, another previously common treatment for RLS, clonazepam, was conditionally recommended against, as there was little evidence supporting its efficacy, which was outweighed by risks of sedation and cognitive impairment.

Other categories of CPG recommendations included PLMD, which resulted in two treatments in adults with recommendations against their use and no evidence found for children with PLMD. In the discussion, the CPG focuses on the need to define more accurately the phenomenon of PLMD, which may then enable better approaches to treatment.

Very little research was found in children with RLS, with ferrous sulfate being the only recommended treatment. Further research into RLS treatment for children, special populations of adults with RLS including those who are pregnant and those specifically with dopaminergic augmentation, are noted as future aspirations in this rapidly changing area of sleep medicine.

Andy Berkowski, MD, is a sleep neurologist and founder of ReLACS Health, a direct specialty care sleep clinic specializing in the management of RLS and complex sleep disorders. He is the vice chair of the Treatment of Restless Legs Syndrome and Periodic Limb Movement Disorder Task Force.

John W. Winkelman, MD, PhD, is chief of the sleep disorders clinical research program at Massachusetts General Hospital. He is the chair of the Treatment of Restless Legs Syndrome and Periodic Limb Movement Disorder Task Force.