Opioids are mainstay for pain therapy and used in several countries as off-label therapy in RLS after failure of first-line therapy. This study investigated the efficacy and safety of oxycodone/naloxone prolonged-release fixed-combination (OXNPR) in severely affected RLS patients (International RLS Study Group Rating Scale (IRLS) score ¡‘Ý21 at randomization) with previously insufficient RLS therapy.Patients (N=304, mean age 62.4¡‘À11.2 years) were randomized to OXNPR twice daily (mean oxycodone dose 21.9¡‘À15.0mg/day) or placebo after screening and a 7day washout period. After the 12-week double-blind (DB) phase, 197 patients participated in a 40-week open-label extension (mean oxycodone dose 18.1¡‘À10.5mg/day). The primary objective of the DB phase was to demonstrate superior efficacy of OXNPR compared with placebo in reducing RLS symptom severity using the universally accepted IRLS. Secondary endpoints included assessment of RLS severity using the RLS-6 Rating scale, and RLS- specific quality of life (QoL) using the QoL-RLS Scale.Mean IRLS total score was significantly reduced from 31.6¡‘À4.5 at randomization (indicating severe symptom load) to 15.1¡‘À10.6 after 12 weeks of OXNPR treatment. The 12-week OXNPR treatment resulted in a statistically significant reduction in symptom severity compared to placebo with a clinically relevant treatment difference of 8.15 in the mean IRLS total score (95% CIs: ¡‘°5.46; 10.85¡‘±; p<0.001; n=269). The beneficial effects of OXNPR during the night and day when at rest were maintained throughout the extension phase. The mean IRLS total score was 9.7¡‘À7.8 at end of study (n=152), representing a mild RLS symptom severity level, on average. RLS-6 scores (0–10 scale) supported the IRLS results and showed a clinically relevant decrease in RLS symptom severity for OXNPR versus placebo (reduction RLS-6 daytime at rest severity after 12 weeks: OXNPR 6.7¡‘À2.2–2.5¡‘À2.7 vs placebo 6.7¡‘À2.5–4.4¡‘À3.3). Despite a prospective augmentation assessment during the trial, no case of augmentation was verified in the DB or extension phases. OXNPR treatment was well tolerated in accordance with the expected safety profile of opioid treatment.Oxycodone/naloxone prolonged-release effectively reduces RLS symptom severity over the short- and long-term in patients with severe RLS, inadequately controlled with previous medications, with accompanying quality of life benefits.Karen Paine provided medical writing services on behalf of Mundipharma Research. (Funded by Mundipharma Research; ClinicalTrials.gov number, NCT01112644).