Guideline Recommendations and Clinical Evidence for Opioid Use in Restless Legs Syndrome

Guideline Recommendations

The 2025 American Academy of Sleep Medicine (AASM) guidelines conditionally recommend extended‑release oxycodone as a second‑line therapy for adults with restless‑legs syndrome, with a conditional recommendation and moderate certainty of evidence. 1

Clinical trials in restless‑legs syndrome have demonstrated that oxycodone’s therapeutic benefit is primarily mediated by the parent drug rather than the CYP2D6‑derived metabolite oxymorphone, indicating that efficacy does not depend on CYP2D6 metabolic status. 2

Prior to adjusting oxycodone dosage, iron deficiency should be corrected; the relevant thresholds are ferritin ≤ 100 ng/mL or transferrin saturation < 20 %. 1

Methadone (approximately 5–10 mg daily) is the most commonly used opioid in restless‑legs syndrome registries and its effectiveness is independent of CYP2D6 activity. 2
Buprenorphine is an alternative opioid for restless‑legs syndrome that carries a lower risk of respiratory depression and is not metabolized by CYP2D6. 2

Concurrent central nervous system depressants (e.g., benzodiazepines, gabapentinoids, sedative‑hypnotics, alcohol) increase the risk of respiratory depression in patients receiving oxycodone, regardless of CYP2D6 genotype. 2
Screening for central sleep apnea and other respiratory disorders should be performed before initiating or continuing opioid therapy for restless‑legs syndrome, as these conditions represent major contraindications. 2

Opioid therapy for restless‑legs syndrome shows minimal augmentation risk, with no confirmed cases reported in the RELOXYN trial, compared with a 7–10 % annual augmentation incidence observed with dopamine agonists. 1