Management of augmentation of restless legs syndrome with rotigotine: a 1-year observational study

Trenkwalder, Claudia; Canelo, Monica; Lang, Michael; Schroeder, Hanna; Kelling, Daniela; Berkels, Reinhard; Schollmayer, Erwin; Heidbrede, Tanja; Beneŝ, Heike

doi:10.1016/j.sleep.2015.10.006

Cited by 22 publications

(6 citation statements)

References 28 publications

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“…Both D3 and D1 receptors are expressed in the lumbar spinal cord (Zhu et al, 2007 ), and DA can up- or downregulate cellular and network functions in a dose-dependent manner (Missale et al, 1998 ; Thirumalai and Cline, 2008 ; Clemens et al, 2012 ). Current DA-based RLS treatment options center around D3 receptor agonists (Ferini-Strambi et al, 2016 ; Ferré et al, 2017 ), but their effect is reduced over time and can cause a worsening of the symptoms (augmentation) (Allen et al, 2011 ; García-Borreguero and Williams, 2011 ; Earley et al, 2017 ; Trenkwalder et al, 2017 ). While we have previously shown that D3 receptor agonists and antagonists can oppositely regulate spinal reflex amplitudes (SRAs) of WT in vitro while they do not alter SRAs in D3KO (Clemens and Hochman, 2004 ), we here wanted to test how these neuromodulators act in vivo , and how their effects compare with the Meis1KO animals (Figure 4 ).…”

Section: Discussionmentioning

confidence: 99%

Differential Dopamine D1 and D3 Receptor Modulation and Expression in the Spinal Cord of Two Mouse Models of Restless Legs Syndrome

Meneely

Dinkins

Kassai

et al. 2018

Front. Behav. Neurosci.

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Restless Legs Syndrome (RLS) is often and successfully treated with dopamine receptor agonists that target the inhibitory D3 receptor subtype, however there is no clinical evidence of a D3 receptor dysfunction in RLS patients. In contrast, genome-wide association studies in RLS patients have established that a mutation of the MEIS1 gene is associated with an increased risk in developing RLS, but the effect of MEIS1 dysfunction on sensorimotor function remain unknown. Mouse models for a dysfunctional D3 receptor (D3KO) and Meis1 (Meis1KO) were developed independently, and each animal expresses some features associated with RLS in the clinic, but they have not been compared in their responsiveness to treatment options used in the clinic. We here confirm that D3KO and Meis1KO animals show increased locomotor activities, but that only D3KO show an increased sensory excitability to thermal stimuli. Next we compared the effects of dopaminergics and opioids in both animal models, and we assessed D1 and D3 dopamine receptor expression in the spinal cord, the gateway for sensorimotor processing. We found that Meis1KO share most of the tested behavioral properties with their wild type (WT) controls, including the modulation of the thermal pain withdrawal reflex by morphine, L-DOPA and D3 receptor (D3R) agonists and antagonists. However, Meis1KO and D3KO were behaviorally more similar to each other than to WT when tested with D1 receptor (D1R) agonists and antagonists. Subsequent Western blot analyses of D1R and D3R protein expression in the spinal cord revealed a significant increase in D1R but not D3R expression in Meis1KO and D3KO over WT controls. As the D3R is mostly present in the dorsal spinal cord where it has been shown to modulate sensory pathways, while activation of the D1Rs can activate motoneurons in the ventral spinal cord, we speculate that D3KO and Meis1KO represent two complementary animal models for RLS, in which the mechanisms of sensory (D3R-mediated) and motor (D1R-mediated) dysfunctions can be differentially explored.

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Section: Discussionmentioning

confidence: 99%

Differential Dopamine D1 and D3 Receptor Modulation and Expression in the Spinal Cord of Two Mouse Models of Restless Legs Syndrome

Meneely

Dinkins

Kassai

et al. 2018

Front. Behav. Neurosci.

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“…153 Switching to an alternative dopaminergic agent Switching from one dopamine agonist to another is generally not considered useful for preventing (or treating) augmentation, except for switching from levodopa to a longer acting formulation of a licensed dopamine agonist. 157 Augmentation Augmentation, the main complication of treatment, was first described and defined in 1996 when it was reported in 73% of RLS/WED patients treated with carbidopa/ levodopa. In this report, the main feature of augmentation was identified as a worsening of symptom severity manifested by an earlier onset of symptoms in the afternoon or evening compared with before the start of treatment, which was severe enough to require modification treatment in 50% of patients.…”

Section: Fluctuating Rls/wed Symptomsmentioning

confidence: 99%

“…Classic features of initial augmentation are breakthrough crises during the daytime, increase in symptom frequency or symptom intensity, shorter duration of treatment effects, symptoms in previously unaffected body parts, worsening of sleep efficacy or sleep quality, increased PLMs during sleep or wakefulness, need for additional treatment, or overall decrease in therapeutic efficacy. 161 162 Implications for initial treatment and prevention and treatment of augmentation As augmentation is probably exclusively related to the specific action of the dopaminergic system, and this risk is strongly correlated with the dose and duration of treatment, [144][145][146][147][148][149][150][151][152][153][154][155][156][157][158][159][160][161][162][163] the most effective strategy to prevent augmentation would be not to use dopaminergic treatment or at least to keep the dopaminergic load as low as possible. 153 Other factors that have been reported to contribute to an increased risk of augmentation include low iron stores, greater severity of RLS/WED symptoms before starting treatment, and a family history of RLS/WED or lack of neuropathy.…”

Section: Fluctuating Rls/wed Symptomsmentioning

confidence: 99%

New concepts in the management of restless legs syndrome

Garcı́a-Borreguero¹,

Cano-Pumarega²

2017

BMJ

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Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED) is a neurological condition with an overall prevalence in adults of 5-10% in Europe and North America. It is characterised by strong feelings of restlessness and distressing paraesthesia-like sensations in the lower legs, particularly when at rest. The symptoms vary considerably in severity and frequency. RLS/WED has a variable clinical expression influenced by genetic, environmental, and medical factors. Research into the pathophysiology of RLS/WED has found that various genetic markers and existing dysfunctions in dopaminergic mechanisms and iron mechanisms play a central role. Until recently, the first line treatment of RLS/WED was with low dose dopamine agonists, with three drugs having been approved by the US Food and Drug Administration and the European Medicines Agency. However, the occurrence of dopaminergic augmentation and an overall increase in severity of symptoms during long term treatment with dopamine agonists is leading to a shift towards non-dopaminergic alternatives as initial treatments, and particularly to αδ ligands. Recent international guidelines recommend, whenever possible, to start treatment with these drugs (αδ ligands) to avoid augmentation from the start. Other (eg, glutamatergic or adenosine) neurotransmitters might also play an important role in causing RLS/WED and might thus lead to new treatments.

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“…Die Augmentation wurde also deutlich vermindert (▶Abb. 2) [14]. Das Nebenwirkungsprofil war typisch für eine dopaminerge Stimulation sowie eine transdermale Anwendung und deckte sich mit den Ergebnissen anderer Interventionsstudien zu Rotigotin in der RLS-Therapie [14].…”

Section: Therapiewechsel Bei Augmentation Erwägenunclassified

“…Nach dem Wechsel zum Rotigotin-Pflaster setzten die RLS-Symptome oftmals erst später im Tagesverlauf ein, mod. nach[14].…”

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Restless Legs Syndrom - Neue Evidenz: Leitlinie überholt? (Sponsor: UCB Pharma GmbH)

2019

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ZusammenfassungDer Leidensdruck von Menschen mit Restless Legs Syndrom (RLS) ist groß. Dennoch wird die Erkrankung oftmals unterschätzt und die Patienten stoßen nur auf eine geringe Akzeptanz. Darüber hinaus herrscht Unsicherheit bezüglich der adäquaten Behandlung: Die letzte deutsche RLS-Leitlinie stammt aus dem Jahre 2012. Inzwischen gibt es zahlreiche neue Studien, die in der Leitlinie nicht berücksichtigt wurden. So weichen z. B. die Expertenmeinungen bei dem Einsatz von L-Dopa ganz klar von der DGN-Leitlinie ab. Ist die Leitlinie also überholt? Bei einem Workshop in Stuttgart beantworteten 4 renommierte RLS-Expertinnen diese Frage und diskutierten aktuelle Therapieoptionen sowie Herausforderungen in der RLS-Behandlung vor dem Hintergrund aktueller Studiendaten.

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Management of augmentation of restless legs syndrome with rotigotine: a 1-year observational study

Cited by 22 publications

References 28 publications

Differential Dopamine D1 and D3 Receptor Modulation and Expression in the Spinal Cord of Two Mouse Models of Restless Legs Syndrome

Differential Dopamine D1 and D3 Receptor Modulation and Expression in the Spinal Cord of Two Mouse Models of Restless Legs Syndrome

New concepts in the management of restless legs syndrome

Restless Legs Syndrom - Neue Evidenz: Leitlinie überholt? (Sponsor: UCB Pharma GmbH)

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