NeuroVoices: John Winkelman, MD, PhD, on Taking a Major Shift Away From Dopamine Agonists in the Revised Guidelines for Restless Legs Syndrome Treatment

John Winkelman, MD, PhD

(Credit: Mass General Hospital)

Adequate sleep is vital for maintaining overall health, safety, and well-being, standing as one of the 3 key pillars of a healthy lifestyle alongside balanced nutrition and consistent exercise. Unfortunately, patients with restless legs syndrome (RLS) often struggle with sleep disruptions, as the discomfort associated with the condition interferes with both falling and staying asleep, which can lead to chronic sleep deprivation and daytime fatigue.¹ Over time, this lack of restful sleep can result in heightened irritability and impaired focus during daily activities.

A recent online survey by the American Academy of Sleep Medicine (AASM) revealed that 13% of 2006 respondents in the United States (US) reported a diagnosis of RLS. Additionally, another survey by the RLS Foundation, the “Patient ODYSSEY II Survey,” reported that patients with RLS experienced depression and anxiety at 4 times the rate of the general US population. These findings underscore the importance of addressing RLS with timely diagnosis and treatment to improve patients’ sleep and overall well-being.¹

More recently, a task force of experts in sleep medicine commissioned by AASM published new clinical practice recommendations for the treatment of RLS in adults and pediatric patients. Constructed by lead author John Winkelman, MD, PhD, chair of the AASM committee that revised the guidelines, and colleagues, the developed recommendations and assigned strengths were based on a systematic review of the literature and an assessment of the evidence. Published in Journal of Clinical Sleep Medicine, these revised guidelines will help clinicians in prescribing the appropriate treatment for their patients with the condition.²

In a new iteration of NeuroVoices, Winkelman, who also serves as the chief of the Sleep Disorders Clinical Research Program at Massachusetts General Hospital, provided further context about the changes and their clinical implications. He talked about what led to the decision to remove dopamine agonists from the recommended first-line treatments for RLS. Winkelman also spoke about how alpha-2-delta calcium channel ligands compare with dopamine agonists in terms of efficacy and safety for the treatment of patients with RLS. Moreover, he talked about the role of iron therapy in the updated RLS treatment guidelines, and its recommendations for usage.

NeurologyLive: Can you provide our audience with the most significant updates in the treatment guidelines for RLS?

John Winkelman, MD, PhD: There are indeed substantial changes in these guidelines compared with the last set issued by the American Academy of Sleep Medicine 12 years ago. These updates involve new data on some medications, newly introduced medications, and the most dramatic change—which I think will surprise people—is that dopamine agonists, previously considered first-line therapies for RLS, are no longer recommended as such. In fact, we now conditionally advise against their use for RLS.

The reason for this is the increasing data from the past 10 to 15 years showing the occurrence of what's called "augmentation," a worsening of RLS symptoms caused by these medications. Although they work well in the short term, over the long term, they make symptoms worse—more severe, occurring for more hours in the day, and spreading from the lower extremities to the upper extremities. Therefore, we now recommend against their use except in cases where other agents are ineffective or not well-tolerated.

The good news is that we have other effective medications for long-term use, especially the alpha-2-delta calcium channel ligands. These include gabapentin, gabapentin enacarbil, and pregabalin, which have been shown in randomized controlled trials, including head-to-head comparisons with dopamine agonists, to offer good efficacy without the risk of augmentation.

In addition, we have a strong recommendation for intravenous (IV) iron therapy in individuals whose ferritin levels are below 100 or whose transferrin saturation is less than 20%. This provides several treatment options. We also made conditional recommendations for oral iron and various forms of IV iron. Additionally, there is the use of dipyridamole, an older cardiology drug, which has shown success in treating RLS. New opioid agonists, including one large controlled trial of extended-release oxycodone, also demonstrated significant benefits for RLS. Lastly, bilateral, high-frequency peroneal nerve stimulation has proven beneficial in cases of refractory RLS.

There are many good options, but dopamine agonists are no longer considered first-line treatments, and the task force was very clear on this.

If you were speaking to a patient, how would you explain these recommendations in a way they can easily understand?

With every patient, it’s important to engage in a collaborative decision-making process. It’s not about me telling them, “You should take this.” I present the options, and the patient drives the decision while I sit beside them to guide the way. Like the task force, I balance efficacy with potential side effects or complications.

So, I tell my patients, “There are several good options for treating RLS,” and I walk them through the alpha-2-delta calcium channel ligands, explaining, “These medications have proven efficacy for moderate to severe RLS. They’re available and have specific side effects we need to consider.” I always add, “We’ll start with a low dose and adjust as needed, and most people see significant improvement.”

I also emphasize, “We need to check your iron levels because RLS is linked to brain iron deficiency. While we can’t take brain samples, we can test your blood. If iron levels are low, oral or IV iron could help.” I reassure them that iron formulations generally have few side effects, though oral iron may cause some stomach discomfort. IV iron, on the other hand, is typically well-tolerated, and the older concerns about anaphylaxis are linked to a drug no longer on the market. The real challenge is getting insurance approval, as we need to administer around 1000 milligrams for it to be effective.

When discussing dopamine agonists, I explain, “While these medications provide immediate relief and may feel like a miracle in the short term, in the long term, they can worsen your condition. If you’re someone who prioritizes short-term relief despite long-term complications, they may seem appealing, but from my perspective, they’re not the best choice.”

Is there anything else you’d like to share regarding the guidelines, perhaps specifically for populations like pregnant women or pediatric patients?

There’s a lot to cover. The task force included about 8 members, and we reviewed over 5000 papers on RLS treatments. We only extracted studies that met specific quality standards, and we conducted detailed meta-analyses on them. These recommendations are very carefully considered, balancing benefits, risks, immediate adverse effects, and long-term concerns like augmentation.

We now recommend several agents as first-line therapies, such as alpha-2-delta medications and IV iron. Others are designated as second-line therapies. However, we strongly recommend that practitioners avoid starting patients on dopamine agonists unless they are fully aware of the long-term risks of augmentation. We didn’t specifically address what to do with patients already on dopamine agonists, or those who don’t have augmentation yet, but that’s a separate question, and one I’ve written about extensively, though it’s not part of these guidelines.

Transcript edited for clarity.

REFERENCES
1. Restless legs lead to restless nights: More than one in 10 Americans report having an RLS diagnosis. News Release. American Academy of Sleep Medicine (AASM). Published September 9, 2024. Accessed October 15, 2024. https://www.newswise.com/articles/restless-legs-lead-to-restless-nights-more-than-one-in-10-americans-report-having-an-rls-diagnosis
2. 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

Editor’s Note: Winkelman has disclosed that he receives grant or research support from American Regent, Merck, RLS Foundation, National Institute of Drug Abuse. He has been a consultant for Alexza, Avadel, Azurity, Disc Medicine, Emalex, Genenttec, Haleon, Idorsia, Noctrix, and Psychogenics. Winkelman also gets financial support from the Baszucki Group and has gotten honoraria from UpTo Date and Teledoc.