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.

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