Prolonged Release Oxycodone-Naloxone for Treatment of Severe RLS
Abstract & Commentary
By Claire Henchcliffe, MD
Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College
Dr. Henchcliffe reports she is on the speakers bureau and advisory board for GE, Teva Pharmaceutical Industries, and UCB; advisory board for Allergan and USWorldmeds; receives grant/research support from Biogen and Kaneka; and does CME program development and presentation for MedIQ.
Synopsis: This 12-week, randomized, double-blind, placebo-controlled trial examined the combination of oxycodone and naloxone for treatment of severe restless legs syndrome in patients inadequately controlled by previous treatment. An open-label, 40-week extension study supported long-term efficacy of this treatment.
Source: Trenkwalder C, et al. Prolonged release oxycodone-naloxone for treatment of severe restless legs syndrome after failure of previous treatment: A double-blind, randomized, placebo-controlled trial with an open-label extension. Lancet Neurol 2013;12:1141-1150.
This 12-week, multicenter, european clinical trial used a randomized, double-blind, placebo-controlled design to assess efficacy of prolonged-release oxycodone-naloxone for treatment of patients with severe restless legs syndrome (RLS). Individuals with secondary causes of RLS and those with serum ferritin < 30 pg/mL were excluded. All subjects had onset of symptoms before 1800 h at least 4 days a week. Previous treatment failure, mostly with dopamine agonists or levodopa, was due to either lack of efficacy or intolerable side effects. All previous treatments were tapered off prior to the start of the trial, so that at randomization, subjects had not received any RLS treatment for 7 days. In the treatment and placebo arms of the study at baseline, mean age was 63.1 ± 11.4 years and 61.7 ± 11.0 years, respectively; symptom duration was approximately 10 years in each group; and the International RLS (IRLS) Study Group rating scale score was approximately 28 in each group, denoting severe symptoms (scale range is 0-40). In the treatment arm, the starting dose was oxycodone 5 mg plus naloxone 2.5 mg twice daily, which could be titrated in weekly fixed increments during the first 6 weeks up to a maximum of oxycodone 40 mg plus naloxone 20 mg. The mean daily dose of oxycodone/naloxone was 21.9/11.0 mg, and placebo oxycodone equivalent 34.4 mg/19.4 mg. Improvement in mean IRLS rating scale score at 12 weeks was significantly greater in the treatment group (-16.6 points) vs the placebo group (-9.5 points). This beneficial effect was also maintained throughout an open-label, 40-week extension phase. Treatment-related adverse events included fatigue, constipation, nausea, and headache, and serious adverse events included severe constipation in two patients, one case of ileus, and one case of vomiting. There were three cases of drug withdrawal symptoms. Most quality-of-life measures were also significantly improved with oxycodone/naloxone at the end of the double-blind phase.
This study provides strong evidence that prolonged-
release oxycodone-naloxone is effective and well tolerated in the treatment of severe RLS, in cases in which standard treatments have failed. The majority of individuals in the treatment arm experienced at least a 50% decrease in severity rating scale scores, and more than 40% achieved scores in the mild RLS range. Dopaminergic medications are generally used as first-line treatment in patients with RLS, but in the long-term can lead to loss of efficacy and augmentation of symptoms. Moreover, they are not well tolerated in some patients, and even at low doses used for RLS treatment, dopamine agonist-associated impulse control disorders have been reported. Gabapentin enacarbil is approved for RLS treatment, but again some patients experience refractory and troublesome symptoms. There remains, therefore, a critical need for alternatives. In such situations, off-label choices include gabapentin, pregabalin, benzodiazepines, and opioids such as oxycodone and methadone. Opioids have long been used for RLS, with recording of the opiate laudanum use for RLS as early as the 17th century. However, there has been very little evidence from clinical trials to support their use, and the majority of studies have been open-label. This clinical trial, therefore, adds considerably to RLS treatment, and should stimulate further studies. In particular, it would be interesting to see how the benefit of prolonged-release oxycodone-naloxone stacks up against more familiar treatment options, including dopamine agonists and gabapentin enacarbil. There are also particular challenges to using opiates for treatment. There is concern about development of tolerance, and, although the open-label extension in the study supports sustained benefit, longer-term data would be helpful. Drug dependence and addiction is another concern, although in this study only three cases in which withdrawal symptoms occurred were noted. There is the risk of opioid-related bowel dysfunction including severe constipation, but this fixed-dose combination of prolonged-release oxycodone-naloxone has been shown in previous studies for pain to be significantly more tolerable in terms of bowel function when compared to oxycodone. As yet, it remains unclear whether opioids will cause less augmentation of RLS than dopaminergic intervention, but that is a possibility which needs to be examined. In summary, this important clinical trial provides hope for carefully chosen individuals with severe RLS in which standard treatments have either not worked or not been tolerated.