Progressive development of augmentation during long-term treatment with levodopa in restless legs syndrome: results of a prospective multi-center study
Birgit Hogl
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Diego Garca-Borreguero
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Ralf Kohnen
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Luigi Ferini-Strambi
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Georgios Hadjigeorgiou
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Magdolna Hornyak
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Al de Weerd
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Svenja Happe
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Karin Stiasny-Kolster
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Viola Gschliesser
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Renata Egatz
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Birgit Frauscher
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Heike Benes
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Claudia Trenkwalder
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Wayne A. Hening
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Richard P. Allen
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Wayne A. Hening: Deceased.
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R. Kohnen Research Pharmaceutical Services (RPS)
, Nuremberg,
Germany
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H. Benes Somnibene Institute for Medical Research and Sleep Medicine
, Schwerin,
Germany
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D. Garca-Borreguero R. Egatz Sleep Research Institute
,
Madrid, Spain
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K. Stiasny-Kolster Department of Neurology, Philipps University
, Marburg,
Germany
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C. Trenkwalder Paracelsus-Elena Hospital
, Kassel,
Germany
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B. Hogl (&) V. Gschliesser B. Frauscher Department of Neurology, Innsbruck Medical University
, Anichstr. 35, 6020 Innsbruck,
Austria
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H. Benes Neurology Department, University of Rostock
, Rostock,
Germany
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S. Happe University of Goettingen
, Goettingen,
Germany
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S. Happe Department of Clinical Neurophysiology
, Klinikum Bremen-Ost, Bremen,
Germany
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A. de Weerd Sleep Center SEIN Zwolle
, Zwolle,
The Netherlands
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W. A. Hening UMDNJ-RW Johnson Medical School
, New Brunswick,
NJ, USA
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M. Hornyak Department of Psychiatry and Interdisciplinary Pain Centre, University of Freiburg
,
Freiburg, Germany
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C. Trenkwalder University of Goettingen
, Goettingen,
Germany
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G. Hadjigeorgiou Department of Neurology, Medical School, University of Thessaly
, Larissa,
Greece
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L. Ferini-Strambi Sleep Disorders Center, University Vita-Salute San Raffaele
,
Milan, Italy
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R. P. Allen Neurology and Sleep Medicine, Johns Hopkins University
,
Baltimore, MD, USA
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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.
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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)