Sleep and Quality of Life Under Prolonged Release Oxycodone/Naloxone for Severe Restless Legs Syndrome: An Analysis of Secondary Efficacy Variables of a Double-Blind, Randomized, Placebo-Controlled Study with an Open-Label Extension

Wolfgang H Oertel, Yngve Hallström, Gerda M Saletu-Zyhlarz, Michael Hopp, Björn Bosse, Claudia Trenkwalder, RELOXYN Study Group, B Högl, C Röper, G Saletu-Zyhlarz, S Behrens, H Beneš, B Bergtholdt, R Bitter, R Bodenschatz, J Böhringer, H-J Boldt, S Braune, P Donat, I Fietze, P Franz, P Geisler, H-J Gertz, B Gestewitz, J Haan, S Happe, H Henin, M Hornyak, A Hufnagel, B-A Kallmann, G Karlbauer, J Kassubek, M Klein, J Koppai-Reiner, M Lang, R Leibinger, W Lüer, W Lünser, A Mahler, W Mattern, G Mayer, W Molt, W Oertel, I Peglau, J Peltz, E Rüttgers, K Sallach, I Schöll, A Schulze, V Schumann, V Siefjediers, A Siever, K-O Sigel, A Simonow, F Sixel-Döring, R Sloksnat, H Sommer, J Springub, T Spieker, K-C Steinwachs, K Stiasny-Kolster, A Stierstorfer, A Storch, K Tinschert, C Trenkwalder, B Veit, R Warmuth, P Young, D Zuchner, D García-Borreguero, A Iranzo de Riquer, J E Martinez Rodriguez, F J Puertas, O Romero Santo-Tomás, L Grote, Y Hallström, A Markström, Wolfgang H Oertel, Yngve Hallström, Gerda M Saletu-Zyhlarz, Michael Hopp, Björn Bosse, Claudia Trenkwalder, RELOXYN Study Group, B Högl, C Röper, G Saletu-Zyhlarz, S Behrens, H Beneš, B Bergtholdt, R Bitter, R Bodenschatz, J Böhringer, H-J Boldt, S Braune, P Donat, I Fietze, P Franz, P Geisler, H-J Gertz, B Gestewitz, J Haan, S Happe, H Henin, M Hornyak, A Hufnagel, B-A Kallmann, G Karlbauer, J Kassubek, M Klein, J Koppai-Reiner, M Lang, R Leibinger, W Lüer, W Lünser, A Mahler, W Mattern, G Mayer, W Molt, W Oertel, I Peglau, J Peltz, E Rüttgers, K Sallach, I Schöll, A Schulze, V Schumann, V Siefjediers, A Siever, K-O Sigel, A Simonow, F Sixel-Döring, R Sloksnat, H Sommer, J Springub, T Spieker, K-C Steinwachs, K Stiasny-Kolster, A Stierstorfer, A Storch, K Tinschert, C Trenkwalder, B Veit, R Warmuth, P Young, D Zuchner, D García-Borreguero, A Iranzo de Riquer, J E Martinez Rodriguez, F J Puertas, O Romero Santo-Tomás, L Grote, Y Hallström, A Markström

Abstract

Objective: The aim was to assess the effects of prolonged release oxycodone/naloxone (OXN PR) on sleep and quality of life (QoL) in patients with severe restless legs syndrome (RLS) refractory to first-line dopaminergic RLS treatment.

Methods: Sleep and QoL data from a 12-week, randomized, double-blind, placebo-controlled study with subsequent 40-week, open-label extension were analyzed. Instruments included the Medical Outcomes Study (MOS) sleep scale, RLS-6 rating scale, and RLS-QoL questionnaire.

Results: The full analysis population included 132 OXN PR and 144 placebo patients. After 12 treatment weeks, improvements in the MOS domains 'sleep disturbance' [-18.6; 95 % confidence interval (CI) -24.4 to -12.9; p < 0.0001], 'sleep adequacy' (14.9; 95 % CI 7.9-21.9; p < 0.0001), and 'sleep quantity' (0.77 h; 95 % CI 0.43-1.11; p < 0.0001) were significantly greater under OXN PR than under placebo. OXN PR also reduced symptom severity (when falling asleep and during the night) and daytime tiredness, and increased sleep satisfaction to a significantly greater extent than placebo (all p < 0.001; RLS-6). QoL improved in both treatment arms, with a significant difference of -9.02 (95 % CI -12.85 to -5.19; p < 0.001) in the mean sum score in favor of OXN PR. All sleep and QoL aspects also improved under 40 weeks of open-label OXN PR treatment.

Conclusions: OXN PR improved RLS symptom severity and sleep quantity and adequacy, resulting in greater sleep satisfaction, less daytime tiredness, and improved QoL. In appropriate patients, OXN PR should be considered as an alternative treatment option for severe RLS that cannot be controlled by first-line dopaminergic medications.

Trial registration: ClinicalTrials.gov (NCT01112644) and EudraCT (2009-011107-23).

Figures

Fig. 1
Fig. 1
Study design. OXN PR prolonged release oxycodone/naloxone, V visit
Fig. 2
Fig. 2
Study profile. Reprinted from The Lancet Neurology [12], Trenkwalder et al., 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. Pages 1141–50, copyright (2013), with permission from Elsevier
Fig. 3
Fig. 3
Mean change (SE) from baseline to end of 12-week, double-blind study phase in Medical Outcomes Study sleep scale domains (full analysis set, OXN PR n = 132, placebo n = 144). *p < 0.0001 compared with placebo. Item scores were converted to a 0–100 scale, except for sleep quantity (h), according to Spritzer and Hays [17]. Decreases in sleep disturbance and daytime somnolence and increases in sleep adequacy and sleep quantity indicate improvements. OXN PR prolonged release oxycodone/naloxone, SE standard error
Fig. 4
Fig. 4
Mean changes (+SE) in QoL (sum score) during the study. Full analysis set for the double-blind phase: OXN PR n = 132, placebo n = 144, LOCF data; baseline extension: n = 197; end of extension: n = 190. LOCF last observation carried forward, OXN PR prolonged release oxycodone/naloxone, QoL quality of life, SE standard error
Fig. 5
Fig. 5
Mean changes (+SE) in RLS-QoL dimensions at start of study and end of 12-week, double-blind phase. Full analysis set (LOCF data); *p < 0.001 compared with placebo. Dimensions: effects of RLS symptoms (items 1–4: impairment of sleep, general performance, mental health, and social activities); disturbed sleep and its effects (item 5 and 6: impairment of daily activities due to lack of sleep, impairment of well-being due to daytime tiredness); effects of other features (item 7 and 8: medication side effects, arm or leg pain); coping with RLS symptoms (items 9–11: strain of using coping strategies, avoidance of certain activities/situations, strain of lifestyle changes); and overall quality of life summary question (item 12). LOCF last observation carried forward, QoL quality of life, RLS restless legs syndrome, SE standard error

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