Opioids for Restless Legs Syndrome

Summary and Comment |
November 18, 2013

Opioids for Restless Legs Syndrome

  1. Michael S. Okun, MD

Should we give opioids for RLS when conventional dopaminergics fail?

  1. Michael S. Okun, MD

Evidence has been lacking to support opioid-based therapy when dopaminergics fail to control restless legs syndrome (RLS). This study was a 55-center, 12-week, randomized, double-blind, placebo-controlled trial with a 40-week open-label extension. RLS was required to be present for at least 6 months with an International RLS Study Group severity rating scale score of 15. Active treatment was oxycodone (5 mg) plus naloxone (2.5 mg) administered twice daily and titrated to maximums of 40-mg oxycodone and 20-mg naloxone twice daily. The primary outcome variable was mean change in the total score on the International RLS Study Group severity rating scale at 12 weeks. Of 306 patients randomized, 276 were included in the primary analysis (132 assigned to oxycodone–naloxone and 144 to placebo).

The mean International RLS Study Group score change after 12 weeks was significantly better with oxycodone–naloxone than with placebo (−16.6 points vs. −9.5 points). The opioid group had more treatment-related adverse events than the placebo group (73% vs. 43%). During the open-label extension phase, 57% of 197 patients experienced treatment-related adverse events. Serious treatment-related adverse events in the opioid group (2%) were vomiting, constipation, subileus, ileus, and acute flank pain. Three patients had withdrawal symptoms after the end of oxycodone–naloxone treatment.


Restless legs syndrome is a very common issue that presents to both neurology and general medical practitioners. In most cases, dopaminergic therapy is very effective for RLS. However, some patients experience problems with medication tolerability or report augmentation (as worsening of symptoms despite dopaminergic treatment). This study emphasizes what many experts had previously discovered: That opioids are an excellent alternative to dopaminergic-resistant RLS. Adding naloxone is a clever way to combat gastrointestinal side effects, although the benefit of this addition was not specifically addressed in this study. However, the results showed a tremendous placebo effect. Neurologists and general practitioners should consider trying multiple combinations of carbidopa/levodopa, dopamine agonists, benzodiazepines, and other anticonvulsants before considering chronic opioid therapy. For many patients, RLS is adequately controlled by a bedtime single dose of whatever therapy is appropriate.

Editor Disclosures at Time of Publication

  • Disclosures for Michael S. Okun, MD at time of publication Grant / research support NIH; National Parkinson Foundation; Michael J. Fox Foundation Editorial boards Parkinsonism and Related Disorders; Tremor and Hyperkinetic Disorders Leadership positions in professional societies National Parkinson Foundation (Medical Director and Ask the Doctor Director); Tourette Syndrome Association (Medical Advisory Board)


Reader Comments (2)

John Newsome

I take 40 mg of oxycodone every 24 hours to control my restless leg syndrome. It works fine. I have an extreme case of RLS. I used to go 3 days without sleep. Now I do get enough sleep to have a good life. I am so afraid that the pills will become so controlled that I will not be able to obtain. My Dr. keeps me monitored. He gives me tests every 6 months to keep a check on my level. Should I be concerned?

Robert Brouillette Other, Charles River Laboratories

This study helps validate what is considered an alternative treatment for RLS. When patients augment on one dopamine agonist, it is not uncommon for augmentation to occur with other dopamine agonists. This often leaves physicians with no other choice but continued increasing of dopamine agonists. Many doctors are reluctant to prescribe opioids to patients for the treatment of RLS. This study could help convince them that opioids are a viable option.

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