Don’t Light the Fuse of Restless Legs Syndrome with Dopamine Agonists

Twenty percent of restless legs syndrome patients are already on higher-than-recommended doses of dopamine agonists, says John Winkelman, MD, PhD.

By Bushraa Khatib

Starting a dopamine agonist to treat restless legs syndrome (RLS) is like lighting a fuse, with the near certainty that at some point in the future, the medication will cause RLS symptoms to explode, says John Winkelman, MD, PhD, professor of psychiatry at Harvard Medical School and chief of the Sleep Disorders Clinical Research Program at Massachusetts General Hospital.

Although dopamine agonists (DAs) have excellent short-term efficacy for RLS patients and relatively few side effects, Winkelman says, they are also associated with a long-term overall worsening of RLS symptoms, with earlier appearance during the day, extension of symptoms to upper extremities, shorter duration of medication benefit, and shorter time to symptom onset with immobility—a complication known as augmentation. Winkelman often sees patients on high dopamine agonist doses who have symptoms 12-plus hours per day, are unable to sit, work, or eat without having symptoms, and who sleep for less than five hours a night.

“Awareness of augmentation is unfortunately very low in the general medical community and these medications are considered beneficial by many prescribers in the context of RLS,” he says. His current research attempts to raise awareness among prescribers of long-term complications of using dopamine agonists for RLS.

Winkelman and his team used the National Prescription Audit database to identify 670,000+ patients in the United States receiving prescribed medications to treat RLS. Winkelman was unsurprised to find that nearly 20% of the roughly 400,000 individuals receiving DAs for RLS were taking doses above, and (in half of those) often well above, the maximum dose recommended by the FDA and published treatment guidelines.1

Winkelman discussed the study with Sleep Review over email. The transcript has been lightly edited for clarity and style.

John Winkelman, MD, PhD. Headshot courtesy of Massachusetts General Hospital.

What are the clinical implications of your research?

JW: Treatment guidelines are now unequivocal that DAs should not be first-line treatment for RLS.2 In certain cases, where patients have contraindications to alternative approaches, these medications can be used, as long as there is frequent clinical contact and vigilance for development of augmentation. Doses of DAs for RLS should certainly be maintained below the upper limit of treatment and FDA guidelines.

What are alternative medications to dopamine agonists?

JW: The first step in treating RLS is to address contributing factors to symptom development, most importantly iron deficiency, renal insufficiency or failure, use of serotonergic antidepressants or dopamine antagonists, and obstructive sleep apnea. Besides DAs, there are two other approaches for treating RLS: A2D calcium channel ligands (gabapentin, pregabalin, gabapentin enacarbil), which are efficacious for RLS but have potential side effects including sedation, dizziness, and weight gain, but do not produce augmentation. Similarly, opioids are very efficacious for RLS, but have potential side effects of constipation and sedation, and are highly controlled agents due to the potential for misuse/abuse.

What are treatment options for RLS patients already receiving DA doses?

JW: The ultimate goal in such patients is to discontinue the DA. However, even small reductions in DA doses produces dramatic rebound in RLS symptoms. The usual approach is to add an additional RLS treatment to the DA (such as iron, an A2D agent, or an opioid) and then very gradually (over a period of many months) reduce the dose of the DA, expecting that symptoms will temporarily flare up each time the DA dose is reduced.

Any insights on prescribers who were more likely to prescribe high-dose DAs?

JW: Neurologists had double the likelihood of prescribing high dose DAs for RLS, much higher even than of sleep specialists. I suspect that this is not because neurologists see more severe RLS patients, but rather that they are familiar and comfortable with such high doses of DAs in the context of Parkinson’s disease (PD). However, just as PD and RLS are very distinct disorders, optimal and safe doses of DAs in PD and in RLS are very different, as the risks of high dose prescribing in RLS are so substantial.

What does outreach to prescribers look like to address the problem?

JW: I often ask myself this question. It is unclear what’s the best way to reach the millions of prescribers treating RLS. However, documentation of high rates of augmentation in published articles, and including a discussion about augmentation in all lectures about RLS treatment at all levels, from medical and nursing schools to post-graduate lectures, is essential. Finally, there are important resources online that discuss optimal treatment of RLS and the features of augmentation through the Restless Legs Syndrome Foundation (rls.org) and the International Restless Legs Syndrome Study Group (irlssg.org).

What further research should be done?

JW: We need new and better treatment options for RLS. Understanding the underlying neurobiology of RLS is the path to such better treatments. In the short term, each of the established efficacious approaches has limitations. As a means to mitigate these limitations, methods to predict treatment responsiveness, either to iron treatment or to limit the development of augmentation to DAs, would be of great value.

References

1. Winkelman JW. High national rates of high-dose dopamine agonist prescribing for restless legs syndrome. Sleep. 2022 Feb 14;45(2):zsab212.

2. Silber MH, Buchfuhrer MJ, Christopher JE, et al. The management of restless legs syndrome: an updated algorithm. Mayo Clin Proc. 2021;96(7):1921-37.

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