Opioids Prove Effective for Restless Legs Syndrome

November 08, 2013

In a new, placebo-controlled study, prolonged-release opioid treatment with an oxycodone-naloxone combination product produced impressive relief of symptoms in patients with severe restless legs syndrome for whom other therapies had failed.

The study, published online October 18 in Lancet Neurology, was led by Claudia Trenkwalder, MD, Paracelsus-Elena Hospital, Kassel, Germany.

"We found an 8-point reduction in the mean International RLS Study Group rating scale sum score vs placebo," Dr. Trenkwalder commented to Medscape Medical News. "This is the most effective treatment response ever seen in restless legs syndrome. A reduction of more than 3 points is thought to be clinically significant. While between-study comparisons are always difficult, dopaminergic drugs ― the main agents used ― are associated with reductions of about 4 to 6 points vs placebo. A reduction of 8 points has never been seen before."

Professor Trenkwalder explained that there has been much interest in using opioids in restless legs syndrome for many years, after a small study conducted in 1993 showed a positive effect in 8 patients. This has been followed by other small case series and anecdotal reports, but there has never been a controlled clinical trial before.

"This trial is long overdue. It has taken us 20 years to get it done, largely because no one wanted to pay for it. But we eventually managed to get funding from MundiPharma and have now definitely proven that this opioid-based combination works and works very well in reducing all symptoms of restless legs syndrome ― sensory, restlessness, pain, and sleep," she said.

This trial is long overdue. Dr. Claudia Trenkwalder

She added that doctors have been using different opioids at different dosages over the years, but this study provides solid evidence in support of one combination product used at a low dosage and given twice a day.

Professor Trenkwalder noted that the inclusion of the opioid antagonist naloxone counters peripheral side effects of the oxycodone in the gastrointestinal system and so minimizes constipation, the major side effect of long-term opioid therapy. She also highlighted the importance of taking the drug combination twice a day ― morning and evening. "Some people just take medication for restless legs syndrome at night, but you then get high levels at night and a trough during the day. It is important to have stable levels of opiates in the brain to get good symptom improvement."

In an accompanying commentary, Arthur S. Walters, MD, Vanderbilt University School of Medicine, Nashville, Tennessee, says that the data are "especially convincing because the study included patients who were refractory to other treatments. Such patients would normally be much more likely to fail an alternative treatment than patients who have not had previous treatment failure."

Although he notes that no direct comparisons can be made between drugs, "the treatment difference between groups of 8.15 points is much greater than that for most approved drugs for restless legs syndrome."

For the study, Professor Trenkwalder and colleagues randomly assigned 306 patients who had had symptoms for at least 6 months and whose International RLS Study Group severity rating scale sum score was at least 15 to study drug or placebo. Study drug was oxycodone 5 mg, naloxone 2.5 mg twice daily, up-titrated according to investigator's opinion to a maximum of oxycodone 40 mg, naloxone 20 mg twice daily.

The primary outcome was mean change in severity of symptoms according to the International RLS Study Group severity rating scale sum score at the end of the 12-week double-blind phase.

Mean score at baseline was 31.6. This was reduced by 16.5 points in the oxycodone-naloxone group vs 9.4 points in the placebo group ― a difference of 8.15 points.

Primary Outcome: International RLS Study Group Severity Rating Scale Sum Score at 12 Weeks

  Oxycodone-Naloxone Placebo Treatment Difference (95% CI) P Value
Mean sum score at 12 weeks 15.1 22.1 8.15 (5.46 - 10.85) <.0001


After 12 weeks, all patients could take active treatment for the 40-week extension phase. At the end of the extension phase, the mean sum score had been reduced to 9.7.

Treatment-related adverse events occurred in 73% of patients in the oxycodone-naloxone group vs 43% in the placebo group during the double-blind phase, and in 57% of patients in the extension phase. Serious adverse effects were experienced by 5 patients (2%). These were vomiting with concurrent duodenal ulcer, constipation, subileus, ileus, and acute flank pain.

Professor Trenkwalder noted that constipation was still the most common adverse effect, occurring in 10% to 15% of patients. "But this was manageable in the vast majority, with only about 5% of patients stopping taking the medication because of side effects."

A total of 176 patients were reassessed at 4 weeks after the end of the open-label extension for signs of physical and psychological dependence to the medication, the authors note. Drug withdrawal symptoms occurred in 1 patient after 12 weeks and in 2 patients after 1 year of treatment, they note.

"There is a huge unmet need for restless legs syndrome," she added. "Opioids really do fill that gap for severely affected patients. There is a particular problem in patients with comorbidities such as diabetes and heart failure, as the dopaminergic drugs can cause edema and therefore are not recommended in these groups."

She also pointed out that dopaminergic drugs are associated with augmentation ― when symptoms can actually worsen with overuse of these drugs.

"Only low doses of dopaminergic drugs work," she said. "You have to be careful to keep the dose down. Often, if patients are not responding well, the dose may be raised, then symptoms can become worse. This was not seen with oxycodone-naloxone in our study. The beneficial effect did not wear off, and not 1 case of augmentation was seen in patients taking the combination for 1 year."

During both phases of the study, 63 patients who reported worsening symptoms were assessed for possible augmentation, the researchers note in their article; of these, 1 patient in the oxycodone-naloxone group was deemed a potential case. "A review of this patient by a national and an international augmentation expert (EPA) concluded that this patient did not have augmentation."

The oxycodone-naloxone product used in this study is already available for the management of severe pain. MundiPharma is now pursuing an indication in restless legs syndrome.

The study was funded by MundiPharma Research. Professor Trenkwalder is a consultant for MundiPharma, Dr. Walters reports that he has received research funding from MundiPharma for nonpharmacologic studies of restless legs syndrome unrelated to the study commented on here. He has also received research funding for studies of restless legs syndrome from and has served as a consultant for UCB Pharma.

Lancet Neurol. Published online October 18, 2013. Abstract, Editorial


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