Discussion
nausea, fatigue, daytime sleepiness, constipation, RLS
These results indicate that TOMAC treatment can provide sufficient relief of RLS symptoms to allow opioid dose reduction in treatment of refractory RLS. The average percent opioid reduction with a CGI-I score of ≤ 5 was 29.9% (SD 23.7%) from 39.0 to 26.8 MME per day. Consistent with prior evaluations, TOMAC was safe and tolerable; there were no moderate or severe device-related AEs and no participants discontinued for reasons related to TOMAC tolerability. Participants were adherent to TOMAC treatment, using TOMAC on 85% of days with RLS symptoms. In summary, these results suggest that TOMAC is a low-risk treatment that can allow opioid dose reduction in a substantial number of RLS patients chronically treated with opioids.The participants in this study represent some of the hardest to treat RLS patients. Most of these patients had been referred to the study investigators after they had developed severe augmentation and failed both DAs and alpha-2-delta ligands, the only two US Food and Drug Administration approved classes of RLS medication. In addition, participants had been taking a stable opioid dose for an average of 5.3 years. Data from the opioid registry indicate that reductions to opioid dose for RLS are rare in clinical practice (16% over 2 years) [The objective of this study was to determine feasibility of reducing opioid dosage with TOMAC as opposed to reducing RLS severity, which has been demonstrated previously [The magnitude of opioid dose reduction observed in this study has the potential to reduce the side effects and risks of opioid therapy for RLS. Common dose-related side effects of opioids include constipation, nausea, fatigue, and daytime sleepiness [Variation in opioid reduction among participants was associated with acute response to TOMAC treatment sessions. In clinical practice, this presents the possibility of individualizing opioid dose reduction based on acute response to TOMAC. For example, participants with a stronger acute response to TOMAC could be prescribed a more rapid reduction in opioid dose. Conversely, opioid dose reduction might be reconsidered for a patient with minimal acute response to TOMAC following proper training and calibration.The patients in this study were representative of the opioid-treated refractory RLS population. Baseline participant characteristics were consistent with the profile of patients in the National RLS Opioid Registry [Successful dose reduction in this study was defined based on a combination of investigator and participant feedback. Based on their clinical judgement, investigators evaluated changes to RLS severity on the CGI-I, determined specific dose reductions that would be attempted during each step-down, and discontinued participants if further dose reductions were unlikely to be successful. Participants had the ability to add opioid rescue doses or discontinue from the study if opioid dose reduction was not tolerable or they did not wish to continue. An alternative approach would have been to focus more heavily on participant feedback, by using the participant-rated IRLS score to evaluate RLS severity, which is a more common endpoint than the investigator-rated CGI-I in clinical trials. We conducted sensitivity analysis with an IRLS-based success metric and found similar results of a 60% success rate and 26.4% opioid dose reduction with an 80% agreement rate between metrics. This suggests that the results were robust to relying more heavily on participant feedback.Limitations to this study include its small sample size, open-label, single-arm design, and short duration. Future work should be focused at addressing these limitations, most notably the absence of a control arm. The single-arm open-label design was selected for this study due to the risks and ethical considerations associated with opioid dose reduction in the absence of adjunctive treatment. However, this design meant that investigators and participants knew TOMAC treatment was being administered, raising the possibility of a placebo effect and bias in patient assessments. The promising results of this open-label study motivate a future randomized sham-controlled trial to directly address these limitations. A sham-controlled trial could incorporate the same sham design that was used successfully in a previous randomized controlled trial of TOMAC with stable medications [