Opioid dose reduction
RLS
DISEASE
Participants recorded daily opioid use using a written diary. For each participant, the opioid dose was reduced iteratively until the participant completed three consecutive step-downs, there was an unsuccessful step-down, or the investigator decided that additional reductions were not likely to be tolerated. A step-down was considered successful if all the following criteria were met: (1) Clinician Global Impression of Improvement (CGI-I) score ≤ 5 during final week of step-down (assessment week), (2) actual percent MME reduction during the assessment period exceeded protocol-specified thresholds (see below), (3) actual percent reduction during the assessment period was greater than the previous step-down, and (4) participant completed the step-down without participant- or investigator-initiated discontinuation.In step-down 1, the opioid dose was reduced by ≥ 20% of the baseline dose; in step-down 2, the opioid dose was additionally reduced to ≥ 33% of the baseline dose. Step-down 3 involved a further reduction in opioid dose at the discretion of the investigator. Additionally, the minimum unit of dose reduction was ½ of the opioid pill size; for methadone, this was 2.5 mg, and thus a participant starting at 10 mg would have a step-down 1 reduction of 25% and a participant starting at 5 mg would have a step-down 1 reduction of 50%. Participants were permitted to take rescue doses of their prescribed opioid on nights when TOMAC treatment was insufficient to relieve RLS symptoms. In cases when the actual opioid dose did not match the instructed dose, the actual dose was used for efficacy endpoint evaluation and for deciding whether to continue to the next step-down. Baseline, instructed, and actual step-down opioid doses were calculated as daily MME averaged over a 1-week period. Conversion to MME followed the 2016 guidelines of the United States Centers for Disease Control and Prevention (CDC) [Opioid withdrawal symptoms were assessed on a weekly basis and the investigator was permitted to discontinue the participant at any point based on clinical judgement. Each step-down included a 1–2-week run-in period followed by a 1-week assessment period during which time the opioid dose was stable. Efficacy endpoints (CGI-I and dose reduction) were evaluated based on data from assessment periods. Run-in periods provided opportunity for the investigator to adjust timing of TOMAC or opioid dosing (e.g., changing opioid dose timing from 6 to 9 pm) and for resolving any opioid withdrawal symptoms unrelated to RLS; a second run-in week was permitted if additional time was needed for either of these activities.