Low-Dose Opioids Show Long-Term Dose Stability, Effectiveness in Augmented Restless Legs Syndrome

A large, 5-year longitudinal analysis from the National RLS Opioid Registry evaluated opioid dose stability and long-term effectiveness in patients with restless legs syndrome (RLS) complicated by dopamine agonist augmentation. All told, the study found that opioid doses at low doses remained largely stable over this long-term period, supporting this approach as an effective long-term treatment option for patients with augmented RLS.

The study results were first presented at the 2025 SLEEP Annual Meeting, held June 8–11 in Seattle, Washington, and published recently in the journal of SLEEP. The registry initially enrolled 500 participants taking opioids for RLS, who completed baseline interviews assessing RLS symptoms, opioid medications and doses, sleep, and mental health.

In the study, participants completed online surveys every six months that measured changes in opioid dose from baseline to the 5-year follow-up. These individuals were assessed using morphine milligram equivalents (MME) and analyzed with group-based trajectory modeling, while independent predictors of dose change were evaluated using multiple logistic regression. Of note, participants taking buprenorphine were excluded from the MME dose-trajectory analysis.

Led by John W. Winkleman, MD, PhD, chief of the Sleep Disorders Clinical Research Program in the Department of Psychiatry at Massachusetts General Hospital, the 5-year follow-up included 410 participants, 46 of whom were excluded due to buprenorphine use, leaving 364 participants in the final analytic cohort. The median daily opioid dose at five years was 37.5 MME (equivalent to methadone 8.0 mg or oxycodone 25.0 mg), representing an increase of 7.5 MME from baseline.

Coming into the study, the cohort was predominantly female (57.1%) and White (98.3%), with a mean age of 64.7 years (SD, 10.6), and 88.8% of participants reported a history of dopamine agonist augmentation. Over the follow-up period, opioid doses increased in 49.5% of participants and decreased in 20.0%.

In the recently published data, group-based trajectory analysis identified four distinct groups: decrease (3.4% of participants; average MME change = -15.7 [SD, 12.4]), no/little change (66.1% of participants; average MME change = 1.5 [SD, 8.0]), small increase (23.9% of participants; average MME change = 22.0 [SD, 11.6]), and large increase (3.4% of participants; average MME change= 49.2 [SD, 18.7]). RLS severity was stable from baseline (13.3 [SD, 9.6]) to 5-years (13.1 [SD, 9.0]) according to the IRLS severity scale.

Read more: Tonic Motor Activation Effective in Treating Both Painful and Painless Restless Legs Syndrome

These findings come just months after the RLS guidelines underwent recent revisions. For context, the American Academy of Sleep Medicine (AASM) commissioned a task force of sleep medicine experts who developed the recommendations and assigned strength ratings based on a systematic review of the literature. Using Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, the task force considered factors such as certainty of evidence, the balance of benefits and harms, patient values and preferences, and resource use to formulate such recommendations.

Once complete, the final recommendations were approved by the AASM Board of Directors. The updates followed the 2012 revisions to the RLS guidelines, incorporating new studies and emerging data relevant to RLS care.²

The latest guidelines covered a broad spectrum of RLS management, beginning with diagnostic testing, treatment strategies, and symptom management, while highlighting populations in which RLS is particularly prevalent. The guidelines then provide recommendations for treating RLS, followed by specific treatment options tailored to individualized patient scenarios. These recommendations address adults, specialized adult populations, and children with RLS, as well as adults with PLMD.

REFERENCES
1. Winkelman J., Kilty A., Wipper B., Zackon J, Sherfey J. Effectiveness and dose stability of opioids in patients with restless leg syndrome: 5-year findings from the National RLS Opioid Registry. Sleep. 2026;zsag008. DOI: 10.1093/sleep/zsag008
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. 2025;21(1):137-152. doi:10.5664/jcsm.11390