Are Low-Dose Opioids Safe, Effective to Treat Refractory Restless Leg Syndrome?

Patients with RLS can control their symptoms via the use of low-dose opioid medications with minimal dose escalation.

Most patients with refractory restless leg syndrome (RLS) are able to obtain adequate relief using low-dose opioids with minimal dose escalation over a period of time, according to study findings published in Neurology.

The sensorimotor neurologic disorder, RLS, occurs when an individual experiences an irresistible urge to move the legs often accompanied by leg discomfort. These symptoms are typically worse at night.

Some patients experience augmented RLS that becomes refractory to treatment with dopamine agonists over a 10-year period, often depending on low-dose opioids for symptom management.

To determine the efficacy, dose stability, and risk factors for changing opioid dosage in patients with refractory, augmented RLS, researchers at Harvard Medical School and Massachusetts General Hospital conducted a 2-year, longitudinal, observational study, obtaining relevant data from the National RLS Opioid Registry. They recruited 500 eligible participants from December 2017 to September 2019.

[L]ow dose opioids can control RLS symptoms over time with minimal dose escalation in the majority of patients with refractory, augmented RLS.

By the study’s conclusion, the researchers excluded 52 of these 500 participants due to opioid discontinuation, death, loss to follow-up, withdrawal from the study, and other reasons impacting data collection.

Of the remaining 448 participants who successfully completed all surveys during the 2-year study period, 57% were women, 98% were White, and 72% were aged 70 years or older. Most had received opioid treatment for a median ranging between 1-3 years.

Researchers collected baseline information on opioid dosage, side effects, previous and concurrent RLS treatments, and augmentation history. To assess functional and mental status as well as risk for opioid abuse, they used patient outcome measures such as the Generalized Anxiety Disorder-7 (GAD-7), Insomnia Severity Index (ISI), Patient Health Questionnaire (PHQ-9), International Restless Legs Syndrome Study Group Severity Scale (IRLS), and the Opioid Risk Tool. Patients provided information via online follow-up surveys every 6 months for 2 years.

Approximately 41.1% of these patients with refractory, augmented RLS increased their opioid dosage over 2 years, while 58.9% either decreased their dosage or maintained the same dosage. Median opioid dosage increase was around the equivalent of 10 milligrams of morphine. Approximately 8% of patients with RLS increased their opioid dosage by more than 25 morphine milligram equivalents (MMEs) and 4% by more than 50 MMEs.

Of the 12% of patients who increased their opioid intake by more than 25 MMEs, almost all of them (95%) exhibited at least 1 of the following characteristics:

  • male biological sex,
  • age younger than 45 years,
  • a change in opioid treatments,
  • discontinuation of nonopioid treatments for RLS,
  • use of opioids to manage comorbid pain, mild insomnia (at least), and/or
  • a history of depression.

“[T]he present analysis provides preliminary evidence from a large national registry that low dose opioids can control RLS symptoms over time with minimal dose escalation in the majority of patients with refractory, augmented RLS,” the researchers concluded. “Continued data collection may help in identifying those RLS patients for whom opioids continue to be effective and well tolerated at low doses,” they added.

Study limitations included the potential for recall bias on patient-reported outcome measures and lack of generalizability of results outside of a predominantly White, older, and highly educated population.

Disclosures: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see original source for full list of disclosures.

This article originally appeared on Neurology Advisor


Winkelman JW, Wipper B, Zackon J. Long-term safety, dose stability, and efficacy of opioids for patients with restless legs syndrome in the National RLS Opioid Registry. Neurology. Published online January 25, 2023. doi:10.1212/WNL.0000000000206855