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The following topics will be considered during this discussion group:

1.     What are the effects of opioids on the dopaminergic system and iron utilization?

2.     Which are the advantages and drawbacks of prolonged-released oxycodone-naloxone for RLS? How to use it when managing augmentation?

3.     Are opioids or dopamine agonists the best option for those who fail first-line therapies for RLS?

4.     Are weak opioids such as tramadol also effective for the treatment of RLS?
5.     How many patients develop restless legs syndrome (RLS) during opioid withdrawal, and are certain individuals more prone to developing RLS during withdrawal due to specific clinical factors?

Discussants

Arthur Walters (United States)

John Winkelman (United States)

Yuichi Inoue (Japan)

Ravi Gupta (India)

Ambra Stefani (Austria)

Summary

The treatment of restless legs syndrome (RLS)/Willis-Ekbom disease (WED) presents one of the significant challenges in sleep medicine. Current treatment guidelines for RLS/WED clearly outline the roles of α2δ ligands, dopamine receptor agonists (DAs), and iron supplements. However, the existence of refractory cases that do not respond to standard treatments, along with the need for strong adjunctive therapies to counteract augmentation caused by long-term usage of DAs, highlights the importance of considering opioids as a valuable treatment alternative. While the effectiveness of opioids for treating RLS/WED has been acknowledged, concerns about the risk of dependency have limited systematic research in determining their role within the treatment framework for the disorder. In this discussion group, we will discuss how opioids work to alleviate RLS/WED symptoms based on findings from basic research. We will also consider the appropriate use of opioids in cases of refractory RLS/WED and in situations where augmentation has occurred. Furthermore, we will address issues related to the long-term use of opioids.
The discussion will start with an overview of the opioid pathology related to RLS/WED, referencing studies of postmortem brain findings and opioid receptor knockout mouse models. The first discussant will highlight the effects of opioids on the dopaminergic system and iron utilization, which are key factors in the disorder's pathology. The second discussant will provide an overview of opioid use in patients with RLS/WED, highlighting the risk of medication dependency and dosage changes during long-term treatment, especially in those with comorbid pain syndromes.
Prolonged-release oxycodone-naloxone is the only proven effective and safe opioid treatment for refractory RLS/WED, as established by a placebo-controlled trial and long-term study approved by the European Medicines Agency. The third discussant will cover its unique characteristics, usage across EU countries, and associated challenges, offering insights into dosage titration and management of augmentation in RLS/WED patients.
In many Asian countries, only tramadol, a low-potency opioid, is allowed for the treatment of non-cancer pain. However, the effectiveness of tramadol for treating RLS/WED has not been fully established globally. Additionally, reportedly, high-dose usage of tramadol possibly has a risk of causing augmentation. The fourth discussant will discuss the factors influencing the response to tramadol treatment among Japanese patients with RLS/WED. He will also mention the rarity of dosage escalation and the lack of augmentation risk during long-term treatment with low-dose tramadol.
The likelihood of developing or exacerbating Restless Legs Syndrome during the rapid withdrawal from opioid medication in long-term users is a significant concern that should not be overlooked. The final discussant will mention this phenomenon, its underlying mechanisms, and management strategies.
In this series of presentations, the audience will gain a clearer understanding of how opioids are used in the treatment of RLS/WED, including their indications and limitations. Furthermore, these presentations will establish a foundation for discussing future challenges, such as the criteria for initiating and discontinuing opioid treatment for RLS/WED.