Study on the Efficacy of Spinal Cord Stimulation in Patients With Severe Refractory Primary or Secondary RLS

A Double-Blind, Randomized, Sham-Controlled, Crossover Study on the Efficacy of Burst Spinal Cord Stimulation in Patients With Severe Refractory Primary or Secondary RLS: the REST-SCS Study

A Double-Blind Randomized Controlled Crossover Study to compare the short-efficacy of Burst-SCS with Sham Stimulation, in patients with severe to very severe RLS refractory or intolerant to standard available treatments and/or patients in augmentation, with a two-period-alternating treatment design.

Restless Legs Syndrome (RLS) is a common chronic sleep disorder characterized by an irresistible urge to move the legs, often accompanied by unpleasant sensations that worsens during rest, particularly at night, and improves with movement. Affecting around 5% of the population, moderate to severe RLS can lead to insomnia, involuntary leg movements during sleep (PLMS), depression, and increased cardiovascular risk, significantly impacting sleep and quality of life and typically requiring long-term treatment.

While the exact cause of RLS is unknown, genetic factors, dopamine system alterations, iron deficiency in the brain, and opioid pathways are suspected contributors. It's mainly classified as primary (unknown cause), with secondary RLS linked to other conditions.

Current first-line treatments involve dopamine agonists (DAs) and alpha-2-delta ligands, which are generally effective but can have long-term limitations. A major issue with DAs is "augmentation," a worsening of RLS symptoms that often leads to treatment discontinuation. DAs are also less effective for insomnia, often requiring combination with sedatives. Opioids are effective but are second-line due to side effects and addiction risk. Importantly, while DAs help with sensory symptoms, they often don't significantly improve sleep quality.

Emerging as a promising non-pharmacological approach is electrical neuromodulation, particularly spinal cord stimulation (SCS). Case studies have shown that SCS can improve RLS symptoms, reduce PLMS, and enhance sleep quality, although long-term efficacy has been variable. The potential mechanism of SCS involves activating sensory fibers and inhibitory interneurons in the spinal cord, influencing pain pathways, and modulating brain regions involved in motor control and sleep regulation. This multilevel action may explain the potential benefits of SCS across the sensory, sleep, and motor aspects of RLS.

SCS, typically used for chronic intractable pain, is being investigated as a potential treatment for severe RLS due to overlapping characteristics between the two conditions. RLS has a sensory component that can include pain, and there's evidence suggesting a link between RLS and chronic pain based on high comorbidity, similar sensory processing abnormalities, the effectiveness of certain medications (opioids and α2δ ligands), and a shared hyperexcitable state in the central nervous system. Notably, some patients receiving SCS for chronic pain have also experienced improvement in their RLS symptoms.

This double-blind randomized controlled crossover study aims at comparing the short-efficacy of SCS with Sham Stimulation, in patients with primary or secondary intractable severe or very severe RLS, with a two-period-alternating treatment design. Burst SCS, a specific spinal cord stimulation waveform that delivers pulses in clusters separated by brief periods without stimulation, is chosen over other modalities due to its demonstrated ability to modulate both the sensory and affective components of pain and discomfort. Unlike traditional tonic stimulation, Burst SCS delivers stimulation patterns that more closely resemble natural neuronal firing, and may provide effective symptom relief without inducing paresthesia. Although specific evidence for RLS is still limited, Burst SCS has shown promising results in related neuropathic conditions and is currently considered one of the most advanced and effective neuromodulation techniques available.

Inclusion Criteria:

• Male and female (all sexes) aged 18 years or older, inclusive;
• Diagnosis of primary or secondary RLS;
• Severe to very severe RLS defined as IRLS-RS score > 20;
• Duration of RSL symptoms ≥ 6 months;
• Insufficient symptom control achieved by and/or intolerance to established mono- or combination therapy of standard pharmacological treatment incl. patients in augmentation;
• Stable pharmacologic therapy for RLS for at least 1 month;
• A stable pattern of neurological symptoms;
• Patients who are legally competent and able to understand the nature, scope and aim of the clinical trial;
• Signed informed subject consent form

Exclusion Criteria:

• Known hypersensitivity or allergy to the materials of the device;
• Concomitant use of psychoactive-drugs (e.g. benzodiazepines, antidepressants; wash-out period: at least 7 days or longer depending on half-life);
• Co-morbid sleep disorders influencing sleep structure and nocturnal motor pattern (e.g. Narcolepsy, REM sleep behaviour disorder etc.);
• Coagulopathy or oral anticoagulant therapy (except low-dose acetylsalicylic acid) in conditions that do not allow for a temporary discontinuation;
• Active infection, systemic or localized;
• Known immune deficiency;
• Presence of spinal cord or peripheral nerve stimulators;
• Any disease process or condition that may make the effect of the treatment difficult to evaluate (e.g. cancer with low life expectancy);
• Severe psychiatric disorders (including substance abuse, major depression, and similar severe disorders known or suspected non-compliance) which could have a negative influence on successful treatment;
• Inability to follow the procedures of the study, e.g. due to language problems, dementia, etc. of the participant;
• Women who are pregnant or breast feeding;
• Intention to become pregnant during the course of the study;