By Rivka Sachdev, MD
Assistant Professor of Clinical Neurology, Weill Cornell Medical College
SYNOPSIS: A review of two-year longitudinal data regarding efficacy and dose stability in refractory restless legs syndrome (RLS) patients treated with low-dose opioids shows that patients do not escalate their opiate dosage and that there is clinical and therapeutic stability in the treatment of RLS with this therapeutic regimen. Methadone is the preferred opiate for the treatment of RLS because of its single-dose, long-acting profile and lack of euphoric effects.
SOURCE: 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 2023; Jan 25. doi: 10.1212/WNL.0000000000206855. [Online ahead of print].
Medical treatment of restless legs syndrome (RLS), a neurological disorder characterized by an irresistible urge to move the legs caused by nocturnal dysesthesias in the legs when at rest, typically involves use of alpha-2-delta calcium channel ligand agents (gabapentin, gabapentin enacarbil, pregabalin) or dopamine agonists (pramipexole, ropinirole, rotigotine) as first-line options. Dopamine agonists work well initially, but long-term use is limited by the development of augmentation symptoms that are associated with this particular class of medications. For cases of augmented RLS, discontinuing the dopamine agonist is recommended, and patients then often are switched to an alpha-2-delta calcium channel ligand agent (with or without supplemental iron). If symptoms still are not adequately controlled, in severe/refractory cases, treatment with low-dose opioids then is considered.
Controlled trials already have demonstrated that efficacious opioid doses for refractory or augmented RLS are low compared to doses in chronic opioid use for noncancer-related pain. But because of rising rates of opioid misuse, addiction, and fatal overdoses on a national level, it is important to determine the risk/benefit ratio of using even low-dose opioids long term for patients with severe RLS.
The authors of this paper discuss the two-year results from the National RLS Opioid Registry, an observational longitudinal study involving patients who are taking prescribed opioids for the treatment of RLS. The majority of registry participants already had been receiving dopamine agonists but developed augmentation. This article reviews the results from two years of data, with particular focus on long-term efficacy and opioid dose stability.
Study participants were recruited from December 2017 to September 2019. To be eligible, patients were required to have a previous therapeutic response to a dopamine agonist for RLS and had to be currently on an opioid medication prescribed for their RLS symptoms. Baseline information regarding other RLS medications tried in the past, RLS severity, current opioid dose, opioid side effects, psychiatric symptoms/mood, and opioid abuse risk factors were obtained using rating scales administered during phone interviews.
Scales used were the International Restless Legs Syndrome Study Group Severity Scale (IRLS), the Patient Health Questionnaire (PHQ-9), the Generalized Anxiety Disorder-7 (GAD 7), the Insomnia Severity Index (ISI), and the Opioid Risk Tool (ORT). Patients then completed online surveys every six months for ongoing data collection. At two-year follow-up, median daily morphine milligram equivalent (MME) was 30.0 (methadone = 7.5 mg, oxycodone = 20 mg). Data were collected on 448 patients. All opioid doses were converted to MME. Results showed that methadone was the most prescribed opioid among participants (perhaps because of its long half-life, which is needed for managing the prolonged symptoms in augmented RLS patients, the ease of once-daily dosing, and the lack of euphoric effects). At two-year follow-up, median daily MME was 30.0 (methadone = 7.5 mg, oxycodone = 20 mg). The median opioid dose change was 0 MME and the RLS symptom severity was unchanged from baseline to two years overall in this cohort. This suggests that the prescribed opioid medication controlled RLS symptoms adequately over two years without dose escalations.
Although the majority of patients did not increase their opioid dose during the two-year follow-up period, a minority of participants did, and the authors noted that attention to this minority is important because higher doses raise the risk for adverse events, such as dangerous side effects and overdoses. Specific factors appear to account for individuals with opioid dose increases and include discontinuation of a non-opioid RLS medication, use of the opioid to additionally treat a separate non-RLS comorbid pain condition, history of depression, history of insomnia, switching from one opioid to another, male sex, and age younger than 45 years.
COMMENTARY
The authors acknowledged that, since the majority of the study participants were white, female, and older than age 60 years, there is limited “generalizability” to the overall population of patients with severe RLS. Still, these results provide some preliminary evidence that low-dose opioids can adequately control RLS symptoms with little dose increase over time in many patients with refractory, augmented RLS. Continued observation will provide more insight on long-term safety and efficacy.
