Noninvasive neuromodulation reduces symptoms of restless legs syndrome

Buchfuhrer, Mark J.; Baker, Fiona C.; Singh, Haramandeep; Kolotovska, Viktoriia; Adlou, Bahman; Anand, Harnadar; Zambotti, Massimiliano de; Ismail, M; Raghunathan, Shriram; Charlesworth, Jonathan D.

doi:10.5664/jcsm.9404

Cited by 18 publications

(8 citation statements)

References 49 publications

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“…The planned enrollment—prespecified in the protocol—was 132 participants (66 per treatment group); this was intended to yield 112 subjects with completed data assuming a 15% drop-out rate. The sample size was chosen to provide 85% power to detect a statistically significant difference between treatment groups at a one-sided alpha level of 0.025, based on effect sizes for CGI-I and IRLS from a previous proof-of-concept study [ 15 ]. The only specified early stopping rule was in the case of an unanticipated serious adverse device effect; no such event occurred in the study.…”

Section: Methodsmentioning

confidence: 99%

“…Through this established mechanism, TOMAC engages similar neuromuscular circuitry as voluntary leg movements such as walking or standing, which are known to suppress RLS symptoms, while remaining compatible with sleep [ 13 , 14 ]. An earlier prototype of the TOMAC system showed promising results in a single-blind proof-of-concept study with a mixed population of 12 medication-naïve and 20 medication-refractory RLS patients [ 15 ]; in that study, 30-minute TOMAC stimulation sessions resulted in relief of RLS symptoms that began during stimulation and persisted after stimulation [ 15 ]. The purpose of the RESTFUL study, a multicenter, double-blind, sham-controlled, randomized trial, was to assess the efficacy and safety/tolerability of tonic motor activation (TOMAC) in medication-refractory RLS patients.…”

Section: Introductionmentioning

confidence: 99%

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Efficacy and safety of tonic motor activation (TOMAC) for medication-refractory restless legs syndrome: a randomized clinical trial

Bogan¹,

Roy

Kram

et al. 2023

Sleep

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Study Objectives The purpose of this study was to evaluate the efficacy and safety/tolerability of bilateral high-frequency tonic motor activation (TOMAC) in patients with medication-refractory restless legs syndrome (RLS). Methods RESTFUL was a multicenter, randomized, double-blind, sham-controlled trial in adults with medication-refractory moderate-to-severe primary RLS. Participants were randomized 1:1 to active or sham TOMAC for a double-blind, 4-week stage 1 and all received active TOMAC during open-label, 4-week stage 2. The primary endpoint was the Clinical Global Impressions-Improvement (CGI-I) responder rate at the end of stage 1. Key secondary endpoints included change to International RLS Study Group (IRLS) total score from study entry to the end of stage 1. Results A total of 133 participants were enrolled. CGI-I responder rate at the end of stage 1 was significantly greater for the active versus sham group (45% vs. 16%; Difference = 28%; 95% CI 14% to 43%; p = 0.00011). At the end of stage 2, CGI-I responder rate further increased to 61% for the active group. IRLS change at the end of stage 1 improved for the active versus sham group (-7.2 vs. -3.8; difference = -3.4; 95% CI -1.4 to -5.4; p = 0.00093). There were no severe or serious device-related adverse events (AEs). The most common AEs were mild discomfort and mild administration site irritation which resolved rapidly and reduced in prevalence over time. Conclusions TOMAC was safe, well tolerated, and reduced symptoms of RLS in medication-refractory patients. TOMAC is a promising new treatment for this population.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of tonic motor activation (TOMAC) for medication-refractory restless legs syndrome: a randomized clinical trial

Bogan¹,

Roy

Kram

et al. 2023

Sleep

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“…Non-pharmacological treatments that can be helpful for RLS include massage, stretching, walking, cognitive distraction, or warm or cold baths. [ 50 ] Although these measures are generally tolerable and safe for all patients with RLS, the benefits of non-drug treatments are often short-lived and lack conclusive evidence. There are low-level evidence trials on measures such as exercise, [ 51 ] yoga, [ 52 ] and lavender oil massage.…”

Section: Therapeuticsmentioning

confidence: 99%

“…Most importantly, enhancement syndrome occurs in a significant proportion of RLS patients treated with excessive dopaminergic therapy, with a morbidity rate of approximately 8% per year. [ 50 ] As previously mentioned, potentiation syndrome represents the progression of RLS symptoms in time and space, with symptoms occurring earlier and tending to last a day; symptoms of increasing intensity occur at shorter latencies, become highly sleep disordered, and involve varying degrees of spread of symptoms from the legs to other areas of the body, particularly the arms. Another important concern with dopamine drugs is the frequency of impulse control disorder symptoms, which occur in approximately 15% of patients (compared to 6%–8% in patients with sleep disorders not treated with dopamine agonists), including a range of undesirable behaviors, such as compulsive and financially disruptive shopping, gambling, mischief, and other quasi-addictive behaviors.…”

Section: Therapeuticsmentioning

confidence: 99%

Exploration of restless legs syndrome under the new concept: A review

2022

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Restless leg syndrome (Restless legs syndrome, RLS) is a common neurological disorder. The pathogenesis of RLS remains unknown, and recent pathophysiological developments have shown the contribution of various genetic markers, neurotransmitter dysfunction, and iron deficiency to the disease, as well as other unidentified contributing mechanisms, particularly chronic renal dysfunction. RLS enhancement syndrome is frequently observed in patients with RLS who have received long-term dopamine agonist therapy, manifesting as a worsening of RLS symptoms, usually associated with an increase in the dose of dopamine agonist. Some patients with RLS can adequately control their symptoms with non-pharmacological measures such as massage and warm baths. First-line treatment options include iron supplementation for those with evidence of reduced iron stores, or gabapentin or pregabalin, as well as dopamine agonists, such as pramipexole. Second-line therapies include opioids such as tramadol. RLS seriously affects the quality of life of patients, and because its pathogenesis is unclear, more biological evidence and treatment methods need to be explored.Abbreviations: BID = brain iron deficiency, CNS = central nervous system, GABA = gamma-aminobutyric acid, IRLSSG = International restless leg syndrome research group, PLMD = periodic limb movement disorder, PLMS = periodic leg movement in sleep, RLS = restless legs syndrome, WED = Willis-Ekbom disease.

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“…The efficacy and safety of TOMAC have been demonstrated in two randomized sham-controlled clinical trials with a maximum of 8 weeks of TOMAC treatment. The first of these trials enrolled a mixture of medication-refractory and medication-naïve adults with primary moderate-to-severe RLS who completed 2 weeks of TOMAC treatment and 2 weeks of sham control in a crossover design [ 11 ]. The second trial (RESTFUL study)—which is the parent study of this extension study—enrolled medication-refractory adults with primary moderate-to-severe RLS who were randomly assigned to 4 weeks of active or sham TOMAC treatment (stage 1) followed by 4 weeks of open-label active TOMAC (stage 2) [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Long-term efficacy and safety of tonic motor activation for treatment of medication-refractory restless legs syndrome: A 24-Week Open-Label Extension Study

Roy

Ojile

Kram

et al. 2023

Sleep

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Study Objectives To evaluate long-term efficacy and safety of tonic motor activation (TOMAC) for treatment of medication-refractory moderate-to-severe primary restless legs syndrome (RLS). Methods In the parent study (RESTFUL), adults with refractory RLS were randomized to active TOMAC or sham for 4 weeks followed by 4 weeks of open-label active TOMAC. In the extension study, earlier RESTFUL completers comprised the control group (n=59), which was followed for 24 weeks with no TOMAC intervention, and later RESTFUL completers compromised the treatment group (n=44), which received 24 additional weeks of open-label active TOMAC followed by no intervention for 8 weeks. The primary endpoint was Clinician Global Impressions-Improvement (CGI-I) responder rate at Week 24 compared to RESTFUL entry. Results CGI-I responder rate improved from 63.6% (95% CI, 49.4 to 77.9%) at RESTFUL completion to 72.7% (95% CI, 58.2 to 83.7%) at Week 24 for the treatment group versus 13.6% (95% CI, 7.0 to 24.5%) at Week 24 for the control group (p<0.0001). Mean change in International RLS Rating Scale (IRLS) score improved from -7.4 (95% CI, -5.6 to -9.2) at RESTFUL completion to -11.3 points (95% CI, -8.8 to -13.9) at Week 24 for the treatment group versus -5.4 (95% CI, -3.7 to -7.2) at Week 24 for control group (p=0.0001). All efficacy endpoints partially reverted during cessation of treatment. There were no Grade 2 or higher device-related adverse events. Conclusions TOMAC remained safe and efficacious for >24 total weeks of treatment with partial reversion of benefits upon cessation.

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Noninvasive neuromodulation reduces symptoms of restless legs syndrome

Cited by 18 publications

References 49 publications

Efficacy and safety of tonic motor activation (TOMAC) for medication-refractory restless legs syndrome: a randomized clinical trial

Efficacy and safety of tonic motor activation (TOMAC) for medication-refractory restless legs syndrome: a randomized clinical trial

Exploration of restless legs syndrome under the new concept: A review

Long-term efficacy and safety of tonic motor activation for treatment of medication-refractory restless legs syndrome: A 24-Week Open-Label Extension Study

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