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Restless legs syndrome—current therapies and management of augmentation

Key Points

  • Treatment of restless legs syndrome (RLS) usually involves dopamine agonists, which are approved for treatment of RLS in most countries; α-2-δ ligands, such as gabapentin enacarbil and pregabalin, are also effective

  • In patients with RLS who have low levels of ferritin, iron supplementation should be the first-line therapy

  • For patients with severe RLS, opioids such as oxycodone–naloxone are an option as second-line therapy where they are approved

  • Augmentation is a major complication of long-term RLS therapy with dopaminergic agents, and is related to high doses of dopaminergics

  • International treatment guidelines recommend weighing the benefits against the risks for each drug class when initiating treatment

  • Combined treatment approaches are used on the basis of expert opinions, and are currently not evidenced-based

Abstract

Idiopathic restless legs syndrome (RLS) can severely affect quality of life and disturb sleep, so that pharmacological treatment is necessary, especially for elderly patients. Treatment guidelines recommend initiation of therapy with dopamine agonists (pramipexole, ropinirole or the rotigotine transdermal patch, all approved in most countries) or α-2-δ ligands (gabapentin enacarbil, approved in the USA and Japan), depending on the country and availability. Where approved, opioids (prolonged release oxycodone–naloxone, approved in Europe) are also recommended as a second-line therapy for severe RLS. Several iron formulations can be effective but are not yet approved for RLS therapy, whereas benzodiazepines and other anticonvulsants are not recommended or approved. Less is known about effective management of RLS that is associated with other conditions, such as uraemia or pregnancy. Furthermore, very little data are available on the management of RLS when first-line treatment fails or patients experience augmentation. In this Review, we summarize state-of-the-art therapies for RLS in the context of the diagnostic criteria and available guidelines, based on knowledge ranging from Class I evidence for the treatment of idiopathic RLS to Class IV evidence for the treatment of complications such as augmentation. We consider therapies, including combination therapies, that are used in clinical practice for long-term management of RLS, despite a lack of trials and approval, and highlight the need for practical long-term evaluation of current trials.

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Figure 1: Algorithm for the initiation of pharmacological therapy for RLS and management of augmentation.

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Acknowledgements

We thank Christine Crozier for her expertise in editing the manuscript.

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All authors researched data for the article and made substantial contributions to the discussion of content. C.T. and W.P. wrote the article. C.T., J.W., Y.I. and W.P. reviewed and/or edited the manuscript before submission.

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Correspondence to Claudia Trenkwalder.

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C.T. has acted as a consultant for Britannia, Mundipharma, Novartis, UCB and Vifor, and has received honoraria for speaking for Mundipharma and UCB. J.W. has acted as a consultant for UCB. Y.I. has acted as a consultant for Hisamitsu Pharmaceutical. W.P. has received a honorarium for speaking for Mundipharma.

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Trenkwalder, C., Winkelmann, J., Inoue, Y. et al. Restless legs syndrome—current therapies and management of augmentation. Nat Rev Neurol 11, 434–445 (2015). https://doi.org/10.1038/nrneurol.2015.122

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  • DOI: https://doi.org/10.1038/nrneurol.2015.122

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