By Alyx Arnett
Dopamine agonists constitute three of the four medications for restless legs syndrome (RLS) that have received approval from the United States Food and Drug Administration (FDA). These medications have become the drugs most commonly prescribed to patients suffering from RLS.1 In a significant shift, the American Academy of Sleep Medicine (AASM) now recommends against their use as first-line treatments for this condition.
“Whatever part I played in initially promoting these medications as first-line therapies, I now feel a strong responsibility to communicate these new guidelines,” asserts John W. Winkelman, MD, PhD, the lead author of the AASM’s 2024 guidelines.
“I was naive in my previous assessments,” admits Winkelman, who serves as the chief of the Sleep Disorders Clinical Research Program in the Department of Psychiatry at Massachusetts General Hospital. He reflects on the limitations of previous 12-week trials, stating, “These timeframes are far from adequate for disorders that can persist for a lifetime, such as RLS.”
Augmentation, a concerning phenomenon that can exacerbate RLS symptoms, is now estimated to occur in approximately 40% to 70% of patients using pramipexole and ropinirole over a decade. Though the rotigotine patch is reported to have a slightly lower augmentation rate—around 36% after five years—these figures highlight the risks associated with these medications.
First-Line Therapy Drugs for RLS
The AASM now designates alpha-2-delta ligand medications, including gabapentin enacarbil—the sole FDA-approved drug for RLS—as the first-line therapy. Additionally, gabapentin and pregabalin, the latter two often prescribed off-label, are recommended. The new guidelines strongly advise against the use of three FDA-approved dopamine agonists: pramipexole, rotigotine, and ropinirole, as well as the dopaminergic agent levodopa.
Additionally, the guidelines advocate for intravenous iron treatment (specifically ferric carboxymaltose) for RLS patients with low iron stores, underlining a crucial shift from previous guidelines that largely neglected iron deficiency. This emphasizes the necessity for healthcare providers to routinely screen for iron levels, including ferritin and transferrin saturation, to ensure comprehensive patient care.
Andy Berkowski, MD, a neurologist specializing in sleep medicine and co-author of the AASM guidelines, describes this updated stance as “almost the exact opposite” of earlier recommendations. However, he notes that some previous consensus guidelines, produced by a task force from the International Restless Legs Syndrome Study Group, the European Restless Legs Syndrome Study Group, and the RLS Foundation in 2016, suggested beginning treatment with an alpha-2-delta ligand to mitigate augmentation risks.
The RLS Foundation previously published an updated algorithm in 2021, which also prioritized alpha-2-delta ligands as the first-line treatment option, relegating dopamine agonists to a second-line role. Despite this foundational change, Berkowski observes that the medical community has been slow to abandon dopamine agonists, with a significant number of clinicians continuing to prescribe medications that are no longer recommended. Notably, a 2022 drug utilization study carried out by Winkelman revealed that nearly 60% of RLS patients—approximately 400,000 individuals—remained on dopamine agonists.
Creating a New Generation of Patients Without Augmentation
Berkowski expresses optimism that the updated guidelines, aimed particularly at newly diagnosed patients, “will foster a new generation of individuals living with restless legs who avoid the severe complications associated with current treatments.”
He emphasizes the importance of clinicians contemplating iron deficiency before “reflexively prescribing dopamine agonists.” Recent findings suggest that brain iron deficiency plays a significant role in triggering RLS symptoms. Unfortunately, this understanding appears to be “still lacking among clinicians and third-party payers,” according to the newly established guidelines. Berkowski also highlights a prevailing hesitance toward iron treatments, attributing it to misconceptions about adverse effects, even though “they are likely the safest treatment option available.”
“We have an alarming number of individuals who are iron deficient, and their condition could have been completely alleviated with an iron supplement or infusion,” he points out. “Instead, they have been prescribed medications that have the potential to make their condition significantly worse for the rest of their lives.”
Following an iron assessment, Berkowski advocates for considering alpha-2-delta ligands as a primary treatment choice, asserting that “the vast majority of patients should never commence treatment with dopamine agonists.”
What About Patients Already on Dopamine Agonists?
The task force was not assigned the responsibility of determining the course of treatment for patients already on dopamine agonists; however, Berkowski provides a clinical perspective encouraging stable patients on lower doses of these medications to consider discontinuation. For those on higher doses or experiencing adverse effects, he stresses the necessity of transitioning to alternative treatments while gradually tapering off dopamine agonist therapy.
Winkelman adds that ultimately, the decision should rest with the patient since “they are the ones who will undergo what I refer to as the ‘detox’ process.”
William Ondo, MD, who directs the Movement Disorders Clinic at the Houston Methodist Neurological Institute, primarily treats patients who are already experiencing augmentation from dopamine agonists. He collaborates with these patients to develop a strategy for discontinuing their medications. Although no standardized protocol exists for stopping the drugs, Ondo typically advises patients to choose a period when they can handle several nights of intensified symptoms.
Initially, he administers intravenous iron treatments. Following this, he generally starts patients on opioid medications, such as methadone or buprenorphine, a day or two before discontinuing the dopamine medications. While some experts advocate for a more gradual tapering process, Ondo favors an accelerated approach to discontinue the medications and shorten the period of exacerbated symptoms. “There is ongoing debate on this approach,” he acknowledges, “but I believe a faster discontinuation often benefits patients more in the long run.”
He notes that simply adding an alpha-2-delta ligand or an opioid for patients experiencing augmentation typically does not yield favorable results. However, after patients cease dopamine agonist treatment and no longer experience augmentation, “these alternative medications often become highly effective,” he explains, even though he had no role in establishing the new guidelines.
‘Too Strongly Worded’ Approach
Ondo has voiced his reservations regarding the “strongly worded” recommendation against dopamine agonists, indicating that he is “somewhat opposed” to the outright dismissal of these treatments. His views align more closely with the RLS Foundation’s algorithm, which emphasizes alpha-2-delta ligands as first-line treatment while positioning dopamine agonists as a second-line alternative.
“We consistently opt for gabapentin medications first. If they provide insufficient relief or are poorly tolerated—which occurs with some frequency—then I resort to dopamine medications,” Ondo explains. He estimates that for every five patients he successfully transitions off a dopamine agonist, he prescribes the medication to only one new patient. These instances may include those at lower risk of augmentation, such as elderly patients, for whom long-term complications are less likely.
Since the rollout of the new guidelines, Winkelman has received feedback from clinicians expressing concern about the potential legal repercussions of prescribing dopamine agonists. “I remind them that these are guidelines—not mandates. They are not prohibitive. We are simply recommending what constitutes best practice,” he clarifies.
The guidelines underscore a notable caveat: Dopamine agonists “may be used to treat RLS in patients who prioritize short-term relief of symptoms over the potential for adverse effects, especially augmentation, associated with long-term use.”
Despite the allowance for ongoing prescriptions, Winkelman emphasizes that practitioners must adequately communicate the risks of augmentation associated with these drugs, ensuring that patients remain well-informed. Berkowski underscores the importance of clinical judgement in tailoring treatment plans to meet the unique needs of individual patients.
Jacob Teitelbaum, MD, a board-certified internist and renowned authority on pain and sleep, expresses satisfaction that the latest AASM guidelines resonate with the protocols he has endorsed throughout his clinical practice and research over the past 25 years. “It is gratifying to see the AASM’s guidelines aligning more closely with recommendations I have advocated for throughout my career,” he comments.
Karla Dzienkowski, RN, BSN, executive director of the RLS Foundation, states that the organization has yet to take an official stance on the newly introduced guidelines.
Non-Pharmacological Treatment Option
In a significant development for RLS patients, as of last year, a non-pharmacological treatment option has received FDA clearance. The Nidra tonic motor activation (TOMAC) system by Noctrix Health offers a new avenue for alleviating symptoms and has received a conditional recommendation in the guidelines due to its effectiveness in mitigating symptom severity for RLS patients.
This novel prescription therapy entails the use of two devices worn on the lower legs, which stimulate the peroneal nerves bilaterally to create tonic muscle activation, thereby suppressing RLS symptoms. Shriram Raghunathan, PhD, president and CEO of Noctrix Health, emphasizes that being included in the guidelines provides additional validation and is likely to facilitate wider patient access to this therapy.
Raghunathan points out that Nidra has been particularly beneficial for patients experiencing augmentation. He noted during clinical trials that many patients were administered doses of dopamine agonists that exceeded FDA recommendations, which heightens the risk and severity of augmentation symptoms. “Some of the most severe patients that we have put on Nidra therapy often had undergone multiple titrations with dopamine treatments,” he adds.
Currently, Nidra is available in 14 states, and efforts are underway to further expand its reach.
Payer and Prescribing Hurdles
Several barriers prevent the effective clinical implementation of the new guidelines, including high costs and insurance coverage complications. Ironically, “the only FDA-approved drug we advocate, almost no one has ever attempted,” remarks Berkowski. “This treatment is prohibitively expensive, and insurers are often unwilling to cover it.” Moreover, iron infusion therapy for RLS is typically not included in insurance coverage.
Berkowski notes that a significant benefit of the new guidelines lies in their potential to prevent insurance companies from denying coverage for strongly advised treatments in favor of those that are no longer recommended. He expresses hope that insurers will begin to mandate patients to try gabapentin or pregabalin before requiring them to experiment with dopamine agonists first in order to qualify for coverage.
“Ferric carboxymaltose is the iron formulation strongly recommended, yet [payers] often refuse coverage unless a patient has already tried pramipexole,” he explains. “The guidelines should bring about a change in this practice, as it aligns with what is medically recommended.”
Ondo believes that a decrease in the use of dopamine agonists will likely ease the prevalence of augmentation and, consequently, reduce the complexities when discontinuing these medications. However, he raises concerns regarding the immediate treatment availability for patients suffering from RLS. “Yes, reduced dopamine agonist usage will correlate with a lower occurrence of augmentation issues, leading to fewer challenging cases of medication cessation. Yet patients might experience hurdles in effectively treating their RLS symptoms,” Ondo cautions.
This challenge is compounded by the classification of medications such as pregabalin, which is marked as a Schedule V controlled substance in the US. Gabapentin is a controlled substance in some jurisdictions, while opioids result in greater restrictions. “Doctors have to navigate a complex landscape to prescribe these alternatives as first-line options when compared to readily prescribed dopamine agonists,” Berkowski asserts. “This shift will require increased diligence and monitoring.”
Despite these hurdles, Winkelman remains hopeful that sleep specialists will take the initiative to raise awareness of the new recommendations with professionals in other medical fields. He emphasizes, “As influencers in the field, we must propagate and share this crucial information widely.”
References
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- 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. 2024 Sept 26.
- Aurora RN, Kristo DA, Bista SR, et al. The treatment of restless legs syndrome and periodic limb movement disorder in adults–an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses: an American Academy of Sleep Medicine Clinical Practice Guideline. Sleep. 2012;35(8):1039-62.
- Winkelman JW, Berkowski JA, DelRosso LM, et al. Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2024 Sept 26.
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- Winkelman JW, Johnston L. Augmentation and tolerance with long-term pramipexole treatment of restless legs syndrome (RLS). Sleep Med. 2004;5(1):9-14.
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- Silber MH, Buchfuhrer MJ, Earley CJ, et al. The management of restless legs syndrome: an updated algorithm. Mayo Clin Proc. 2021;96(7):1921-37.
- Garcia-Borreguero D, Silber MH, Winkelman JW, et al. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med. 2016;21:1-11.
- Schifano F, Chiappini S. Pregabalin: A range of misuse-related unanswered questions. CNS Neurosci Ther. 2019;25(5):659-60.
How has the introduction of the Nidra TOMAC system impacted the treatment options available for patients with Restless Legs Syndrome?
Practice guideline. Sleep. 2023;46(8):zsad071.
### Summary The treatment landscape for Restless Legs Syndrome (RLS) has shifted following the introduction of new guidelines, focusing on minimizing the use of dopamine agonists due to their association with a phenomenon known as augmentation. Physicians like Dr. William Ondo advocate for patient-centered approaches, emphasizing the importance of patient involvement in treatment decisions, especially during the medication discontinuation phase. While non-pharmacological options like the FDA-cleared Nidra TOMAC system provide alternative avenues for relief, significant barriers such as high costs and insurance limitations remain. Ongoing discussions among clinicians about these guidelines will be crucial in shaping future treatment paradigms and ensuring that patients receive the most appropriate care.