title: Prolonged release oxycodone-naloxone for treatment of severe restless legs syndrome after failure of previous treatment: a double-blind, randomised, placebo-controlled trial with an open-label extension.
abstract: BACKGROUND
  Opioids are a potential new treatment for severe restless legs syndrome. We investigated the efficacy and safety of a fixed-dose combination of prolonged release oxycodone-naloxone for patients with severe restless legs syndrome inadequately controlled by previous, mainly dopaminergic, treatment.
  
  
  METHODS
  This multicentre study consisted of a 12-week randomised, double-blind, placebo-controlled trial and 40-week open-label extension phase done at 55 sites in Austria, Germany, Spain, and Sweden. Patients had symptoms for at least 6 months and an International RLS Study Group severity rating scale sum score of at least 15; patients with severe chronic obstructive pulmonary disease or a history of sleep apnoea syndrome were excluded. Patients were randomly assigned (1:1) to either study drug or matched placebo with a validated interactive response technology system in block sizes of four. Study drug was oxycodone 5·0 mg, naloxone 2·5 mg, twice per day, which was up-titrated according to investigator's opinion to a maximum of oxycodone 40 mg, naloxone 20 mg, twice per day; in the extension, all patients started on oxycodone 5·0 mg, naloxone 2·5 mg, twice per day, which was up-titrated to a maximum of oxycodone 40 mg, naloxone 20 mg, twice per day. The primary outcome was mean change in severity of symptoms according to the International RLS Study Group severity rating scale sum score at 12 weeks. This study is registered with ClinicalTrials.gov (number NCT01112644) and with EudraCT (number 2009-011107-23).
  
  
  RESULTS
  We screened 495 patients, of whom 306 were randomly assigned and 276 included in the primary analysis (132 to prolonged release oxycodone-naloxone vs 144 to placebo). 197 patients participated in the open-label extension. Mean International RLS Study Group rating scale sum score at randomisation was 31·6 (SD 4·5); mean change after 12 weeks was -16·5 (SD 11·3) in the prolonged release oxycodone-naloxone group and -9·4 (SD 10·9) in the placebo group (mean difference between groups at 12 weeks 8·15, 95% CI 5·46-10·85; p<0·0001). After the extension phase, mean sum score was 9·7 (SD 7·8). Treatment-related adverse events occurred in 109 of 150 (73%) patients in the prolonged release oxycodone-naloxone group and 66 of 154 (43%) in the placebo group during the double-blind phase; during the extension phase, 112 of 197 (57%) had treatment-related adverse events. Five of 306 (2%) patients had serious treatment-related adverse events when taking prolonged release oxycodone-naloxone (vomiting with concurrent duodenal ulcer, constipation, subileus, ileus, acute flank pain).
  
  
  CONCLUSIONS
  Prolonged release oxycodone-naloxone was efficacious for short-term treatment of patients with severe restless legs syndrome inadequately controlled with previous treatment and the safety profile was as expected. Our study also provides evidence of open-label long-term efficacy of this treatment. Opioids can be used to treat patients with severe restless legs syndrome who have had no benefit with first-line drugs.
  
  
  BACKGROUND
  Mundipharma Research.
authors.affiliation: Paracelsus-Elena Hospital, Kassel, Germany; Department of Neurosurgery, University of Göttingen, Göttingen, Germany. Electronic address: trenkwalder@paracelsus-kliniken.de.
authors.forename: Claudia
authors.initials: C
authors.lastname: Trenkwalder
authors.forename: Heike
authors.initials: H
authors.lastname: Beneš
authors.forename: Ludger
authors.initials: L
authors.lastname: Grote
authors.forename: Diego
authors.initials: D
authors.lastname: García-Borreguero
authors.forename: Birgit
authors.initials: B
authors.lastname: Högl
authors.forename: Michael
authors.initials: M
authors.lastname: Hopp
authors.forename: Björn
authors.initials: B
authors.lastname: Bosse
authors.forename: Alexander
authors.initials: A
authors.lastname: Oksche
authors.forename: Karen
authors.initials: K
authors.lastname: Reimer
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkelmann
authors.forename: Richard P
authors.initials: RP
authors.lastname: Allen
authors.forename: Ralf
authors.initials: R
authors.lastname: Kohnen
mesh_terms: D000368:Aged; D003692:Delayed-Action Preparations; D006970:Disorders of Excessive Somnolence / Q000209:etiology; D018491:Dopamine Agonists / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D021501:Flank Pain / Q000139:chemically induced; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D009270:Naloxone / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D010098:Oxycodone / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018579:Patient Selection; D011788:Quality of Life; D012148:Restless Legs Syndrome / Q000188:drug therapy*; D016879:Salvage Therapy; D012720:Severity of Illness Index; D012890:Sleep; D016896:Treatment Outcome
chemical_list: D003692:Delayed-Action Preparations; D018491:Dopamine Agonists; D009270:Naloxone; D010098:Oxycodone