Changes in Restless Legs Syndrome Treatment Recommendations

John W. Winkelman, MD, PhD, Chief of the Sleep Disorders Clinical Research Program in the Department of Psychiatry at Massachusetts General Hospital

Restless Legs Syndrome (RLS) is a neurological disorder that affects sleep, as the symptoms include an intense urge to move the legs, often with uncomfortable dysesthesias, which occur with immobility and are most pronounced at night. RLS is present to a clinically significant extent in 2-3% of adults.

RLS commonly runs in families, is more prevalent with age, and is twice as common in women as men. Symptom intensity does wax and wane but is usually chronic and unremitting in those with moderate to severe RLS.

For patients suffering from RLS, dopamine agonists have long been the widely used standard of care. These medications often have remarkable efficacy in reducing RLS symptoms in the short term. However, an increasing body of evidence has led to concerns about their long-term use and a reappraisal of how we treat RLS.

Recently, the American Academy of Sleep Medicine (AASM) made significant changes to RLS guidelines, which now conditionally recommend against the standard use of dopamine agonists as a first-line treatment option. These updated recommendations are based on a review and meta-analysis of clinical trials and large longitudinal cohort studies over the past 25 years.1

Long-term Use of Dopamine Agonists and RLS Symptom Augmentation

While dopamine agonists often reduce RLS symptoms when first prescribed, over years of treatment, clinical research shows that these medicines often do not simply lose their efficacy but can make RLS worse, known as augmentation.1 This can result in both an earlier daily onset of RLS symptoms, as well as anatomical expansion of symptoms, with discomfort extending from the legs to the upper extremities.2 This augmentation is often then exacerbated when, in response to diminishing benefit, doses of dopamine agonists are increased, leading to a vicious cycle of iatrogenic symptom worsening.2

Since this augmentation of RLS symptoms emerges with the use of dopamine antagonists after years, not months, of use, the initial pivotal clinical trials for FDA approval of these medications did not demonstrate this long-term complication.

Additionally, beyond concerns about augmentation, there is evidence of an association of impulse control disorders in patients who are treated with dopamine agonists, even at the low doses used for RLS, raising more concerns about the long-term use of these medications.3

A Critical Change in RLS Guidelines

As a result of these concerns, the AASM recently updated the Clinical Practice Guidelines for the treatment of RLS.

One of the significant changes in these guidelines is a recommendation that physicians check serum iron indices in patients with RLS, as brain iron deficiency has been documented in RLS through a variety of imaging methods. The guidelines include a strong recommendation for intravenous iron therapy in individuals whose ferritin levels are < 100 or whose transferrin saturation is < 20%, as well as conditional recommendations for oral iron.2

Based on additional evidence over the last 10 years of their efficacy for RLS, these new guidelines also have a strong recommendation for the alpha-2-delta calcium channel ligands, which include gabapentin, gabapentin enacarbil, and pregabalin.

The 2024 AASM RLS clinical practice guidelines recommend against dopaminergic medications, the most commonly prescribed agents for RLS, due to their long-term risk of augmentation of RLS symptoms. The good news is that the guidelines have provided strong recommendations for several treatment options that should provide relief of both RLS symptoms and improved sleep.

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References

1. Winkelman JW, Berkowski JA, DelRosso LM, et al. Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. Published online September 26, 2024. doi:10.5664/jcsm.11390
2. Dang D, Cunnington D, Swieca J. The emergence of devastating impulse control disorders during 883 dopamine agonist therapy of the restless legs syndrome. Clin Neuropharmacol. 2011;34(2):66-70.
3. Cornelius JR, Tippmann-Peikert M, Slocumb NL, Frerichs CF, Silber MH. Impulse control disorders with the use of dopaminergic agents in restless legs syndrome: a case-control study. Sleep. 2010;33(1):81-7.