National RLS Registry Provides Long-Term Insights Into Opioid Use for Restless Legs Syndrome

John Winkelman, MD, PhD

At the 2025 SLEEP Annual Meeting, held June 8-11 in Seattle, Washington, investigators presented new 5-year data from the National RLS Opioid Registry, a longitudinal, observational databank that tracks the efficacy, dose stability, and tolerability of opioids in patients with restless legs syndrome (RLS). Over this long-term follow-up, treatment with low-dose opioids produced stable RLS symptoms, with more than half of the 400-plus patient cohort increasing their dose.¹

The analysis comprised 410 patients who continued opioid treatment for RLS for 5 years, with methadone (53.2%) and oxycodone (16.3%) considered the most commonly used opioids. Coming into the registry, all patients had a history of therapeutic response to dopamine agonists and a majority experienced augmentation. Each patient participated in self-administered biannual surveys to track opioid dosage, adverse events (AEs), RLS severity, and other relevant factors.

Led by John Winkelman, MD, PhD, chief of the Sleep Disorders Clinical Research Program at Massachusetts General Hospital, results showed a stable mean RLS severity (baseline IRLS=13.3; 5-year IRLS=13.1) and sleep disturbance (baseline ISI=10.6, 5-year ISI=9.6) with opioid treatment over the 5-year period. During this time, the median daily opioid dose rose from 30 to 36 Morphine Milligram Equivalents (MME), with 51.0% of participants increasing their dose (median increase: 15.0 MME) and 19.3% decreasing it (median decrease: 12.5 MME).

Large dose increases of at 25-50 MME or at least 50 MME occurred in 6.8% and 6.3% of participants, respectively, with switching to buprenorphine (OR, 9.21; 95% CI, 3.23-25.54) as the most common factor. Other factors in predicting larger dose increases included switch from opioids to methadone (OR, 4.39; 95% CI, 1.95-9.68), adding dopamine agonists (OR, 4.55; 95% CI, 1.46-12.94), and use of opioids for comorbid pain condition (OR, 3.13; 95% CI, 1.13-8.10).

The study also found that higher baseline RLS severity (IRLS>20; OR, 2.79, 95% CI; 1.17-6.60), comorbid neuropathy (OR, 2.79, 95%CI; 1.14-6.62), baseline sleep disturbance (ISI>7; OR, 2.42, 95%CI; 1.18-5.4), and under 1 year on opioids at baseline (OR, 2.02, 95%CI; 1.06-3.81) were main factors for predicting larger dose increases. Notably, 100% of participants who increased their dose by at least 25 MME had at least 1 predictor.

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Winkelman and others from the American Academy of Sleep Medicine (AASM) were an integral part of the recently published updated recommendations for RLS. In this latest paper, the use of low-dose, extended-release oxycodone and other low-dose opioids received conditional recommendations of support. The authors noted that low-dose opioids have demonstrated efficacy for RLS, but opioids also have risks that require cautious use and clinical oversight.²

One of the most significant changes to the guideline was the raised importance of iron evaluation in patients with RLS. In all patients with clinically significant RLS, it was recommended that clinicians regularly test serum iron studies including ferritin and transferrin saturation. Authors noted that these tests should ideally be done in the morning to avoid all iron-containing supplements and foods at least 24 hours prior to blood drawn.

Analysis of iron studies may greatly influence the decision to use oral or intravenous iron treatment, the study authors noted. Consensus guidelines, which have not been empirically tested, suggested that supplementation of iron in adults with RLS should be instituted with oral or IV iron if serum ferritin levels are below 75 ng/mL or transferrin saturation is less than 20%. In children, supplementation or iron should be instituted for serum ferritin less than 50 ng/mL with oral or intravenous formulations.

At the 2023 SLEEP Annual Meeting, Winkelman sat down with NeurologyLive® to outline effective treatment strategies for patients with RLS, with consideration to the use of opioids. In the clip below, he provided perspective on the need to assess risks and benefits with opioids, why thorough clinical examination is important, and why ignoring potential improvements gained from opioids is a disservice to patients with the condition.

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REFERENCES
1. Winkelman J, Kilty A, Wipper B, Zackon J, Adams S. FIVE-YEAR OUTCOMES FROM THE NATIONAL RLS OPIOID REGISTRY: EFFICACY, STABILITY, AND TOLERABILITY. Presented at: 2025 SLEEP Annual Meeting; June 8-11; Seattle, Washington. ABSTRACT 0904.
2. Winkleman 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. Journal of Clin Sleep Med. Published online January 1, 2025. doi:10.5664/jcsm.11390