Discussion
tolerance and dependency, primary RLS, epilepsy, medication-refractory, difficult-to-treat, RLS
RECRUITMENT, PATHOPHYSIOLOGY, EPILEPSY
TOMAC remained efficacious over an additional 24 weeks of treatment across all outcomes, with a trend toward further improvement with continued TOMAC usage. By the completion of treatment at 24 weeks, nearly three-quarters of participants in the treatment group were CGI-I responders and the mean reduction in IRLS total score was 11.3 points, which was more than double the reduction seen in control group and almost fourfold higher than the minimal clinically significant change of 3 points [Study findings suggest that there are persistent benefits of TOMAC that gradually build over many weeks of treatment and do not fully revert even after 24 weeks without TOMAC. The treatment group showed a trend towards an increased response for each outcome measure from extension study entry to week 24. Cessation of TOMAC resulted in gradual and partial reversion of improvement without evidence of rebound or withdrawal. In contrast, DAs, the most common RLS treatment, have high initial efficacy but often result in symptoms of tolerance and dependency (augmentation) [Long-term TOMAC treatment led to a substantial reduction in the frequency of RLS symptoms. Average frequency of symptoms was reduced from 5.9 to 3.2 days per week, meaning that the number of symptom-free days per week increased from 1.1 to 3.8, a 3.5-fold increase. Importantly, the reduction in the frequency of RLS symptoms conferred by TOMAC continued to improve over each consecutive 8-week period of TOMAC treatment (There are two compelling hypotheses that could explain the reduction in RLS symptoms frequency with long-term TOMAC treatment. First, long-term TOMAC treatment applied when RLS symptoms are present could result in neural plasticity at the spinal or brain level that inhibits or reverses RLS pathophysiology. This phenomenon may be consistent across multiple neurostimulation therapies; implanted neurostimulation therapies for epilepsy result in a similar trend toward increased responder rate with longer-term treatment [The results presented here establish the long-term benefits of TOMAC for reducing subjective RLS symptoms and subjective sleep quality. Whereas subjective rating scales are the gold standard for evaluating RLS [Whereas the treatment group represents a typical open-label extension study design, there are limitations to consider when comparing the results between treatment and control groups. The control group was not a “no treatment” group but represented the current standard of care for refractory RLS; participants in the control group had no restrictions on their RLS medication and were permitted to increase dosage or add medications. This allowance was intended to minimize barriers to enrollment in the control group, which was necessary because the recruitment pool was limited to RESTFUL study completers. Notably, control group participants who changed medication did not show improved RLS symptoms relative to those who continued stable medication. This reflects the “refractory” nature of the patient population in this study and reinforces the substantial unmet need for these patients. Additionally, participants were assigned to groups based on timing of RESTFUL study completion as opposed to randomization. This did not lead to any significant differences in participant characteristics between the treatment and control groups (In summary, these results indicate that TOMAC is a promising, noninvasive long-term treatment for medication-refractory moderate-to-severe primary RLS. TOMAC has the potential to provide strong and durable efficacy at very low risk to this difficult-to-treat patient population and serve as a favorable alternative to off-label opioids.