Progressive development of augmentation during long-term treatment with levodopa in restless legs syndrome: results of a prospective multi-center study

Journal of Neurology, Feb 2010

The European Restless Legs Syndrome (RLS) Study Group performed the first multi-center, long-term study systematically evaluating RLS augmentation under levodopa treatment. This prospective, open-label 6-month study was conducted in six European countries and included 65 patients (85% treatment naive) with idiopathic RLS. Levodopa was flexibly up-titrated to a maximum dose of 600 mg/day. Presence of augmentation was diagnosed independently by two international experts using established criteria. In addition to the augmentation severity rating scale (ASRS), changes in RLS severity (International RLS severity rating scale (IRLS), clinical global impression (CGI)) were analyzed. Sixty patients provided evaluable data, 35 completed the trial and 25 dropped out. Augmentation occurred in 60% (36/60) of patients, causing 11.7% (7/60) to drop out. Median time to occurrence of augmentation was 71 days. The mean maximum dose of levodopa was 311 mg/day (SD: 105). Patients with augmentation compared to those without were significantly more likely to be on higher doses of levodopa (≥300 mg, 83 vs. 54%, P = 0.03) and to show less improvement of symptom severity (IRLS, P = 0.039). Augmentation was common with levodopa, but could be tolerated by most patients during this 6-month trial. Patients should be followed over longer periods to determine if dropout rates increase with time.

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Progressive development of augmentation during long-term treatment with levodopa in restless legs syndrome: results of a prospective multi-center study

Birgit Hogl 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Diego Garca-Borreguero 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Ralf Kohnen 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Luigi Ferini-Strambi 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Georgios Hadjigeorgiou 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Magdolna Hornyak 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Al de Weerd 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Svenja Happe 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Karin Stiasny-Kolster 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Viola Gschliesser 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Renata Egatz 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Birgit Frauscher 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Heike Benes 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Claudia Trenkwalder 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Wayne A. Hening 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Richard P. Allen 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Wayne A. Hening: Deceased. 0 R. Kohnen Research Pharmaceutical Services (RPS) , Nuremberg, Germany 1 H. Benes Somnibene Institute for Medical Research and Sleep Medicine , Schwerin, Germany 2 D. Garca-Borreguero R. Egatz Sleep Research Institute , Madrid, Spain 3 K. Stiasny-Kolster Department of Neurology, Philipps University , Marburg, Germany 4 C. Trenkwalder Paracelsus-Elena Hospital , Kassel, Germany 5 B. Hogl (&) V. Gschliesser B. Frauscher Department of Neurology, Innsbruck Medical University , Anichstr. 35, 6020 Innsbruck, Austria 6 H. Benes Neurology Department, University of Rostock , Rostock, Germany 7 S. Happe University of Goettingen , Goettingen, Germany 8 S. Happe Department of Clinical Neurophysiology , Klinikum Bremen-Ost, Bremen, Germany 9 A. de Weerd Sleep Center SEIN Zwolle , Zwolle, The Netherlands 10 W. A. Hening UMDNJ-RW Johnson Medical School , New Brunswick, NJ, USA 11 M. Hornyak Department of Psychiatry and Interdisciplinary Pain Centre, University of Freiburg , Freiburg, Germany 12 C. Trenkwalder University of Goettingen , Goettingen, Germany 13 G. Hadjigeorgiou Department of Neurology, Medical School, University of Thessaly , Larissa, Greece 14 L. Ferini-Strambi Sleep Disorders Center, University Vita-Salute San Raffaele , Milan, Italy 15 R. P. Allen Neurology and Sleep Medicine, Johns Hopkins University , Baltimore, MD, USA 16 R. Kohnen University of Erlangen-Nuremberg , Erlangen, Germany The European Restless Legs Syndrome (RLS) Study Group performed the first multi-center, long-term study systematically evaluating RLS augmentation under levodopa treatment. This prospective, open-label 6-month study was conducted in six European countries and included 65 patients (85% treatment naive) with idiopathic RLS. - impression (CGI)) were analyzed. Sixty patients provided evaluable data, 35 completed the trial and 25 dropped out. Augmentation occurred in 60% (36/60) of patients, causing 11.7% (7/60) to drop out. Median time to occurrence of augmentation was 71 days. The mean maximum dose of levodopa was 311 mg/day (SD: 105). Patients with augmentation compared to those without were significantly more likely to be on higher doses of levodopa (C300 mg, 83 vs. 54%, P = 0.03) and to show less improvement of symptom severity (IRLS, P = 0.039). Augmentation was common with levodopa, but could be tolerated by most patients during this 6-month trial. Patients should be followed over longer periods to determine if dropout rates increase with time. Levodopa was the first dopaminergic therapy investigated for the treatment of restless legs syndrome (RLS) [1, 25] and is licensed for the treatment of RLS in certain European countries. Evidence for the efficacy of levodopa was demonstrated in the first placebo-controlled short-term clinical trials of dopaminergic treatment in RLS [6, 8, 9, 14, 20]. However, more than a decade ago augmentation of RLS symptoms was noted as a serious complication of levodopa therapy [2]. Augmentation is a worsening of RLS symptom severity characterized by the occurrence of RLS symptoms earlier in the day, by a shorter latency to symptoms at rest, increased intensity of symptoms, and a spreading of RLS symptoms to previously unaffected areas of the body [3] compared to the status at start of treatment or to favourable initial response. Trenkwalder et al. [21] reported that 35% (8 of 23) of all treated patients during a 1 year open-label study of levodopa/benserazide therapy discontinued the trial prematurely due to a time-shift towards intolerable symptoms during the day. In a recent double-blind, long-term (6 months) trial comparing the dopamine agonist cabergoline to levodopa/benserazide [23], 9.8% of patients treated with levodopa developed augmentation requiring premature discontinuation. In summary, the results of previous studies suggest a substantial risk for augmentation with levodopa therapy. There has not, however, been any study specifically designed to prospectively evaluate the development of augmentation with levodopa treatment systematically by NIH (...truncated)


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Birgit Högl, Diego García-Borreguero, Ralf Kohnen, Luigi Ferini-Strambi, Georgios Hadjigeorgiou, Magdolna Hornyak, Al de Weerd, Svenja Happe, Karin Stiasny-Kolster, Viola Gschliesser, Renata Egatz, Birgit Frauscher, Heike Benes, Claudia Trenkwalder, Wayne A. Hening, Richard P. Allen. Progressive development of augmentation during long-term treatment with levodopa in restless legs syndrome: results of a prospective multi-center study, Journal of Neurology, 2010, pp. 230-237, Volume 257, Issue 2, DOI: 10.1007/s00415-009-5299-8