May 5, 2014
Allen, R. P., Chen, C., Garcia-Borreguero, D., Polo, O., DuBrava, S., Miceli, J., Knapp, L., and Winkelman, J. W. Comparison of pregabalin with pramipexole for restless legs syndrome. New England Journal of Medicine. 2014: 370, 621-631.
Personal Commentary by Dr. Christopher J. Earley
0 The focus of this paper is based on two long-standing issues in the annals of RLS treatment. First, the assumed primary nature of RLS being strictly a dopaminergic process thus dopaminergic agents should be the primary treatment option. This concept has driven the Pharmaceutical industry to focus, on developing dopaminergic drugs, almost to the exclusion of alternative agents. The second and equally relevant issue, which this study tackles, is drug-induced, progressive symptomatic worsening of RLS which has been coined “augmentation”. It is the leading cause of the failure of dopaminergic agents and has been recognized as such for nearly 20 years. It acceptance as an important clinical concern but also the controversy as to its prevalence was discussed by the authors in the Introduction. This discussion does not even touch on the bigger issue which is the unfortunate lack of knowledge about augmentation and its consequences in the general medical practice community where dopaminergic drugs are used with impunity as first line treatment for RLS.
One of the greatest problems of nearly all of the RLS treatment trials to date has been faulty design issues: diagnosis, drug implementation schedules, side-effect definitions, study duration and endpoints. But maybe it takes a decade of making all those mistakes before someone to finally gets it right. And this study gets its right. Hopefully, this study will be used as the “gold standard” on how to carry out an effective treatment trial in RLS. This study not only attempts to address two long-standing issues but succeeded admirably.
This study is the first clinically meaningful and methodologically excellent randomized trial of its kind in RLS history. It uses an approach, which truly allows a comparison between a “Goliath” in the RLS treatment armament (pramipexole) and an underappreciated “David” (pregabalin). I say this because pregabalin has been used for years in the USA as an “off-license” treatment option by many of those who regularly treat RLS patients. Prior to this study, if asked as to how pregabalin would stack up against pramipexole, I believe a large majority of those regularly treating RLS would have said pramipexole would be superior. Thus even among the “experts” (including myself) there has been a strong belief bias in favor of dopaminergic drug superiority. By using a two-drug comparison this study also allowed for a extend evaluation (52 weeks) rather than just another one-month trial versus placebo or 3-year open label follow up. This extended-period design then allowed for an assessment of augmentation as a primary endpoint. An equally important factor in the decision to use augmentation as an endpoint is the methodological rigor in the design that was implemented in order to insure a relatively accurate diagnosis of augmentation. Again, this study did it right and on this account alone, stands as a superior study to any study to date.
The results in this study speak for themselves and do so with great confidence because they flow out of a well-though out and rigorously design approach. Pregabalin, as the “experts” might not have expect (including myself) was not inferior to pramipexole but as good as if not better. There is tremendous amount of secondary data on sleep and quality of life which again place pregabalin at least equal to pramipexole. Another important outcome of this study is the issue of augmentation. Not surprising to me is that within 52 weeks nearly 10% of those on pramipexole have shown symptoms of drug-induced worsening (augmentation) at a dose (0.5 mg), which in the USA is well within the usual treatment protocol. Of note is that the 0.5 mg dose tended to have greater efficacy than 0.25 mg but clearly at a cost of developing augmentation. Nine percent augmentation after one year does not seem all that meaningful until one realizes that RLS is a chronic disease, requiring long-term treatment, and that augmentation does not stop at the first year, but will continue to afflict others at a similar rate unabated for the time of use. So an incidence of new augmentation cases of 9% per year can be expected if the 0.5 mg of pramipexole is used to chronic treatment RLS patients. What does not appear in any data sets are the true clinical consequences of what is referred to as “augmentation”. Hopefully, these results will make their way to the general medical practices, so they can see that there is a well-tested alternative treatment option 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.
Personal Commentary by Dr. Christopher Earley
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.|