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What's New in RLS?

February 3, 2014

Trenkwalder C, Beneš H, Grote L, 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. The Lancet Neurology 2013;12:1141-50.

The value of opiates in treating Restless Leg Syndrome (RLS) symptoms date back to the publication by Dr. Willis in 1685. In that publication he reported the benefits of opiates on what, 300 years later, would be called Restless Legs Syndrome1. Several studies in the late 1980s and early 1990, essentially reestablish the potential benefits of opiates in managing RLS symptoms2,3,4. However, in 1987 Dr Akpinar published the dramatic effects that levodopa had on RLS symptoms5, thus began the dominance of dopamine drugs as the primary treatment option for RLS. Although dopamine drugs remain an important treatment option for RLS symptoms, they have problems. Opiates still provide an alternative treatment option in RLS. Because large, high-quality clinic trials of opiates versus a placebo (i.e., no treatment) in RLS had been missing, the use of opiates for RLS has not been given the same level of support as dopamine drugs in publications of "Best Practice" guidelines for RLS 6.

The recent publication by Trenkwalder et al7 on the effects of extended-release oxycodone versus placebo in a randomized, double-blind trial in Europe, provides the first large clinical trial of an opiate for treatment of RLS and also provided a long-term assessment of benefits. To enroll in this study, patients had to have failed alternative drug treatment, which were mostly dopamine drugs. After patients had been withdrawn from other treatments half were given only on the extended-release oxycodone while the other half were on no other RLS medications (placebo) for a 12 week period. After 12 weeks, those on oxycodone had grater improvement in the RLS symptoms than those without any treatment. The effectiveness of oxycodone on RLS symptoms was similar to or greater than that seen ropinirole and pramipexole trials. The study was extended during which all participants (including those on placebo) who completed the initial 12-week study were treatment with the oxycodone for a further 40 week period. This open-label portion of the study demonstrated that the oxycodone treatment benefits persisted over the next 40 weeks. Importantly, there is no indication of significant augmentation developing as has been found in some studies with dopamine agents. Thus this study demonstrated potential long-term benefits of opiates in those with moderate to severe RLS symptoms that have failed alternative treatment.

Physicians who are not familiar with treating RLS depend upon published Reviews and "Best Practice" guidelines. Even though opiates have been considered important part of the treatment armament for RLS8, the high-quality studies aside from this one by Trenkwalder et al are lacking. Opioid use in RLS has, therefore, received limited support in the "Best Practice" publications for RLS treatment9 and thus is rarely used by most Primary Care doctors. Large clinical trials are very expensive; most opiates are generic and inexpensive. There is no money to be made with studies of generic drugs and therefore financial support for clinical trials with most opiates is unlikely. Without high-quality clinical trials with opioids, we will continue to have a knowledge-gap when it comes to the best practice approach in managing RLS.

1.Willis T. The London practice of physick. London: Bassett and Crooke; 1685.
2.Walters A, Hening W, Cote L, Fahn S. Dominantly inherited restless legs with myoclonus and periodic movements of sleep: a syndrome related to the endogenous opiates? Adv Neurol 1986;43:309-19.
3.Hening WA, Walters AS. Successful long-term therapy of the restless legs syndrome with opioid medications. Sleep Research 1989;18:241.
4.Walters AS, Wagner ML, Hening WA, et al. Successful treatment of the idiopathic restless legs syndrome in a randomized double-blind trial of oxycodone versus placebo. Sleep 1993;16:327-32.
5.Akpinar S. Restless legs syndrome treatment with dopaminergic drugs. Clin Neuropharmacol 1987;10:69-79.
6.Hening W, Allen R, Earley C, Kushida C, Picchietti D, Silber M. The treatment of restless legs syndrome and periodic limb movement disorder. An American Academy of Sleep Medicine Review. Sleep 1999;22:970-99.
7.Trenkwalder C, Beneš H, Grote L, 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. The Lancet Neurology 2013;12:1141-50.
8.Silber MH, Becker PM, Earley C, Garcia-Borreguero D, Ondo WG. Willis-ekbom disease foundation revised consensus statement on the management of restless legs syndrome. In; 2013:977-86.
9.Garcia-Borreguero D, Kohnen R, Silber MH, et al. The long-term treatment of restless legs syndrome/Willis-Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome Study Group. Sleep Medicine 2013;14:675-84.
 

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"Restless Legs Syndrome"
New England Journal of Medicine
Willis-Ekbom Disease (aka Restless Legs Syndrome) Foundation’s Educational Pamphlets and Brochures

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