Abstract Introduction Refractory restless legs syndrome (RLS) presents significant management challenges, particularly when patients fail first-line dopaminergic agents, α-2-δ ligands, and combination therapy. Opioid therapy is recognized as an evidence-based option in severe refractory cases, yet long-term outcomes remain underreported. We present a case of complex, refractory RLS successfully managed with methadone after extensive medication intolerance and augmentation. Report of case(s) A 56-year-old woman with chronic refractory RLS, chronic migraines, trigeminal neuralgia, hypertension, depression, ADHD, and insomnia had experienced years of disabling symptoms involving both nighttime and daytime periods. She previously failed all dopamine agonists, gabapentin, pregabalin, and experienced only partial relief with short-acting opioids. Kratom provided transient symptom reduction but caused limiting constipation. In April 2022, methadone was initiated after all standard therapies had been exhausted. Symptoms persisted with significant sleep disruption and severe daytime sleepiness (Epworth Sleepiness Scale ESS 23). By September 2023, her regimen was titrated to methadone 20 mg/day in divided doses plus gabapentin 1200 mg QHS during recovery from microvascular decompression for trigeminal neuralgia. Her RLS worsened markedly following knee surgery in September 2024, consistent with known postoperative exacerbations. She briefly used oxycodone for postoperative pain. Methadone was increased to 30 mg/day (10 mg evening, 20 mg bedtime), and gabapentin continued at 600 mg QHS and 300 mg QAM. She was counseled extensively on opioid safety and maintained naloxone at home. By July 2025, she reported a dramatic improvement. She slept over seven hours nightly—consistent for the first time in years—and no longer experienced daytime RLS symptoms. ESS improved to 7. She remained stable on methadone 10 mg QAM/20 mg QHS and gabapentin 300 mg QAM/600 mg QHS with excellent adherence confirmed by prescription monitoring. Her quality of life and functional status significantly improved, and she tolerated the regimen well. Conclusion This case demonstrates that methadone can provide substantial, sustained benefit in severe refractory RLS when other treatments fail. Careful titration, safety counseling, and ongoing monitoring enabled significant improvement in sleep, daytime function, and overall quality of life. Support (if any) No external funding or support was received for this case report.
Miranda et al. (Fri,) studied this question.