Restless legs syndrome (RLS) is a common neurological disorder characterized by an uncomfortable urge to move one’s legs, often with significant impact on sleep quality and overall well-being. The American Academy of Sleep Medicine (AASM) recently released updated clinical practice guidelines for management of this prevalent disorder.1 In this article, we review RLS as a disorder relevant to not only sleep providers but also those across pulmonary medicine and provide an overview of these updated guidelines, highlighting key clinical recommendations to enhance patient care.
Background
The development of RLS appears to be driven by a mix of genetic susceptibility, iron deficiency, and dopamine dysregulation. Certain conditions including chronic kidney disease, diabetes, and pregnancy are linked to a higher prevalence of RLS. Some studies have suggested that the prevalence of RLS may also be increased among patients with certain pulmonary disorders, including COPD, asthma, cystic fibrosis, and idiopathic pulmonary fibrosis.2–6
RLS is a clinical diagnosis that is neither defined by nor requires sleep testing. Its diagnosis rests on eliciting a characteristic history of an urge to move one or both legs during rest, which is relieved with movement and predominates in the evening or nighttime. If a patient with RLS does undergo sleep testing for whatever reason, period limb movements during sleep are often observed, particularly early in the night, but this finding is neither necessary nor sufficient to make an RLS diagnosis. The severity of RLS ranges broadly in the population, with some having infrequent symptoms, occurring once every few months, while others experience symptoms on a nightly basis. Sleep disruption caused by RLS is often cited by patients as the most troublesome aspect of the disorder. At its mildest, sleep disturbance may consist of brief leg repositioning over seconds to minutes that provides sufficient relief to allow sleep. In the most severe of cases, pacing the floors in the middle of the night for hours can be required to relieve the unrelenting urge to move before a patient can finally sleep.
As might be expected given this broad severity range in RLS, not all patients need treatment. The decision to initiate therapy depends on symptom severity and patient preference. A patient with only occasional symptoms that don’t impact their ability to fall asleep may be content handling the occasional nuisance of their symptoms on their own. These patients usually do not come to medical attention, but a mild history of RLS may be discovered on a sleep intake history completed for the assessment of another sleep-related symptom. On the other hand, for patients with RLS whose nightly symptoms impede sleep initiation and who get less sleep as a result, thereby experiencing daytime impairment, a trial of therapy is clearly recommended.
Treatment options
Even before embarking on a treatment program, it is important to recognize some common RLS triggers consistent with the good clinical practice statement outlined in the AASM RLS Treatment Guidelines. Cutting down on alcohol, tobacco use, and caffeine can help better control symptoms. Several commonly used over-the-counter medications including antihistamines and antiemetics (dopamine-blocking) can precipitate or worsen RLS symptoms, and their withdrawal can improve RLS symptoms significantly. Nearly all antidepressants have the potential to worsen RLS symptoms; however, the impetus to discontinue these medications should be especially strong when RLS is severe and the antidepressant has antihistaminergic properties (mirtazapine, doxepin, or other tricyclic antidepressants).
Assessment of iron status, and repletion when appropriate, is a cornerstone of the proper evaluation and treatment of RLS. All patients should be tested for iron stores, ideally in the morning after avoidance of iron-containing supplements and meals for the prior 24 hours. Either oral or intravenous iron can be used when the ferritin levels are below 75 μg/L. Only intravenous iron is recommended when the ferritin is between 75 μg/L and 100 μg/L, based on low absorption of oral iron when ferritin is in this range. The assessment and appropriate treatment of OSA is critical in the management of RLS. OSA and RLS often co-occur, and the treatment of OSA itself may be sufficient to eliminate RLS when symptoms are infrequent. Moreover, the control of RLS is more difficult when OSA is left untreated.
If RLS symptoms persist despite addressing triggers, or if RLS symptoms are so severe that simultaneous treatment initiation is warranted, practitioners can reference the new 2024 AASM RLS Treatment Guidelines. The initial choice when medical therapy is warranted, given that iron and ferritin have been properly addressed, should almost always be a gabapentinoid.
Gabapentin enacarbil, gabapentin, and pregabalin were all given strong recommendations, based on evidence that they result in clinically significant improvement in disease severity, sleep quality, and quality of life and should be considered first-line for the treatment of RLS. Most of the supporting studies used the validated International RLS Study Group Severity Scale to quantify response to therapy. These medications do have the potential to cause somnolence and dizziness, sometimes to a point limiting their use, and patients should be counseled about these potential side effects.
Several iron formulations were given strong or conditional recommendations for the treatment of RLS. Based on five randomized clinical trials that showed efficacy, intravenous ferric carboxymaltose received a strong recommendation for the treatment of RLS. However, this formulation is often unavailable in infusion centers. Other intravenous formulations that were given conditional recommendations include low molecular weight iron dextran and ferumoxytol. It bears noting that intravenous iron has long been considered dangerous, but this is largely based on anaphylaxis associated with high molecular weight iron dextran that is no longer available in the US. In circumstances when serum ferritin is below 75 μg/L, oral ferrous sulfate can be given.
Opioid medications received a conditional recommendation for the treatment of RLS in this newest guideline. Randomized clinical trial data testing extended-release oxycodone-naloxone formed the basis of this recommendation. There is some complication here, however, as this formulation is not available in the US. Furthermore, long-acting oxycodone, while effective in treating RLS, may present resource issues for patients. Based on a class effect and overwhelming clinical experience with the use of other μ-opioid agonists, the task force felt it was warranted to extend the conditional recommendation to include other opioids. This recommendation comes with the acknowledgement of additional risks of abuse and chemical dependence, which by most accounts in RLS appear to be low.7
Deviation from 2012 guidelines
The most striking departure of the 2024 RLS treatment guidelines from the prior 2012 version relates to the use of dopamine agonists (pramipexole, ropinirole, rotigotine, and carbidopa-levodopa). Previously considered standard treatment, and indeed adopted as first-line for most patients, the current 2024 guidelines provide a conditional recommendation against the standard use of each of these medications. The rationale driving this shift relates to mounting evidence for the past decade suggesting higher rates of augmentation with these agents.8 Augmentation refers to the paradoxical, iatrogenic worsening of RLS symptoms that can occur after prolonged use of dopaminergic medications. This phenomenon is characterized by an earlier onset of RLS symptoms in the day, increased intensity, and sometimes even spread of symptoms to other body parts such as the arms. Augmentation should be considered any time a dose increase in a dopamine agonist or levodopa is being considered. When the dose is at or exceeds the maximum recommended dose for RLS (4.0 mg for ropinirole, 0.75 mg for pramipexole, 3 mg for rotigotine), then augmentation almost definitely is occurring. Treating augmentation requires that the offending dopaminergic medication be tapered to off while an alternative nondopaminergic therapy is initiated. (For details of the treatment of augmentation, please refer to other previously published recommendation statements.9,10)
Patients on dopamine agonists who are not experiencing augmentation and are on submaximum recommended doses can be safely continued on these medicines. It is important that they be monitored for signs of augmentation and development of other dopamine agonist-related adverse events such as impulse control problems. Maintaining the dose below the recommended maximum is critical. Practitioners still have the option of prescribing dopamine agonists for RLS but should do so only after following good practice and considering or trying a gabapentinoid.
Because very few clinical trials have evaluated RLS treatment in pediatric populations, recommendations were limited only to favoring the use of oral iron when stores are low. Similarly, in pregnant women, a paucity of studies led to a general recommendation to consider the safety profiles of the various medication options, without recommending a specific agent.
Updating current practices
For most clinicians, the key clinical takeaway from the new guidelines is that dopamine agonists are no longer first-line therapy for RLS and, rather, gabapentinoids should be used as primary therapy for the vast majority of patients. Although major RLS expert organizations have advocated for the use of gabapentinoids for nearly a decade, clinical practice has been slow to reflect this shift away from dopamine agonists.10 In fact, a recent retrospective analysis found that more than half of patients with RLS were being treated with dopamine agonists, and, of these, nearly 20% were on a dose exceeding the maximum recommended by the US Food and Drug Administration.11 Treatment of RLS falls within the scope of multiple specialties, including primary care, neurology, psychiatry, sleep medicine, and others. It is our hope that these guidelines will promote broad dissemination of the message that augmentation is a critical outcome in RLS—and one that we can usually avoid by steering clear of dopamine agonists.
The relevance of the guidelines for our patients is clear. RLS leads to significant distress and disrupts not only sleep but also next-day activities for a large number of patients. An emerging literature even shows increased rates of suicidal intent and self-harm.12,13 The 2024 updated clinical practice guidelines for RLS provide a robust framework for managing this complex condition. In the systematic review that accompanies the guidelines, the authors reflect upon the last 40 years with “some pride at our progress, some disappointment at our naïveté, but some optimism that continued research will translate into better treatments for RLS in the future.”14
References
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