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Fred Burbank Salt Creek International Women's Health Foundation, San Clemente, CA, USA Purpose: To determine whether sham pads used as controls in randomized clinical trials of vibratory stimulation to treat patients with sleep loss associated with restless legs syndrome perform differently than placebo pills used in comparable restless legs syndrome drug trials. Patients and methods: Sham pad effect sizes from 66 control patients in two randomized clinical trials of vibratory stimulation were compared with placebo responses from 1,024 control patients in 12 randomized clinical drug trials reporting subjective sleep measurement scales. Control patient responses were measured as the standardized difference in means corrected for correlation between beginning and ending scores and for small sample sizes. Results: For parallel randomized clinical trials, sham effects in vibratory stimulation trials were not significantly different from placebo effects in drug trials (0.37 and 0.31, respectively, Qbetween subgroups =0.25, PQ≥0.62). Placebo effect sizes were significantly smaller in crossover drug trials than sham effect sizes in parallel vibratory stimulation trials (0.07 versus 0.37, respectively, Qbetween subgroups =4.59, PQ≤0.03) and placebo effect sizes in parallel drug trials (0.07 versus 0.31, respectively, Qbetween subgroups =5.50, PQ≤0.02). Conclusion: For subjective sleep loss assessments in parallel trials, sham pads in vibratory stimulation trials performed similarly to placebo pills in drug trials. Trial design (parallel versus crossover) had a large influence on control effect sizes. Placebo pills in crossover drug trials had significantly smaller effect sizes than sham pads in parallel vibratory stimulation trials or placebo pills in parallel drug trials. Keywords: sham effect, placebo effect, trial design, crossover study, parallel study, counterstimulation

Fred Burbank Director, Salt Creek International Women's Health Foundation, San Clemente, CA, USA Purpose: Two parallel-design, randomized, sham-controlled clinical trials were conducted to study the safety and efficacy of vibratory stimulation (VS) on restless legs syndrome (RLS) patients (Part I of this series of articles). Pooled data from the two studies was retroactively analyzed to compare the relative effects of actual pad assignment with therapeutic pad assignment belief on sleep improvement for patients with RLS. Patients and methods: One hundred fifty-eight patients with at least moderately severe RLS, as measured by a score of 15 points or greater on the International Restless Legs Syndrome Study Group rating scale (IRLS), were enrolled in the study. Patients were randomly assigned to treatment (patient-controlled vibration) or sham (patient-controlled sound or light-emitting) pads. Patients and clinicians were blinded to pad assignment. The pad was placed under the patient's legs while in bed at night and activated during an RLS episode. Improvements in Medical Outcomes Study Sleep Problems Index II (MOS-II) scores from baseline to week 4 were examined as a function of pad assignment (independent variable) and therapeutic pad assignment belief held by each patient (mediator variable) through mediation analysis. Results: Therapeutic pad assignment belief influenced change in MOS-II scores more than actual pad assignment. Patients who believed they had been assigned a therapeutic pad had substantially greater sleep improvement than those who concluded the opposite. When a patient believed that a therapeutic pad had been assigned, sleep improvement was comparable in magnitude, independent of the type of pad assigned (vibrating or sham). Patients assigned vibrating pads believed that they had been assigned a therapeutic pad 2.6 times more frequently than patients assigned sham pads. Consequently, vibrating pads were more efficient at improving sleep than sham pads. Similarity of sleep improvement for those who believed that they had been assigned a therapeutic pad among vibrating, sound, and light pad patients suggests a common counter-stimulation therapeutic mechanism of action within the brain. Conclusion: Therapeutic pad assignment belief influenced improvement in MOS-II scores more strongly than actual pad assignment. Therapeutic pad assignment belief was more commonly associated with vibrating pads than sham pads. These results may have implications for the type of shams used in future device studies. Keywords: restless legs syndrome, placebo effect, mediator variable, sleep, counterstimulation

Fred Burbank,1 Mark J Buchfuhrer,2 Branko Kopjar3 1Salt Creek International Women's Health Foundation, San Clemente, CA, 2Stanford University Center for Sleep Sciences, Downey, CA, 3Department of Health Services, University of Washington, Seattle, WA, USA Background: Vibratory stimulation pads have been shown to improve sleep in patients with restless legs syndrome (RLS) to a greater extent than sham therapy. The current gold standard of treatment is drugs approved by the US Food and Drug Administration (FDA) for use in RLS. The aim of this meta-analysis was to compare the efficacy and safety of vibratory stimulation pads, sham pads, and drugs approved by the FDA for use in RLS. Methods: We searched the PubMed, Embase, and clinical trial websites to identify the relevant randomized, double-blind, and placebo-controlled or sham-controlled studies. Fifteen studies including a combined total of 3455 patients with at least moderately severe primary RLS met our search criteria. Efficacy was defined as the standardized mean difference in sleep improvement between treatment and controls. Safety was assessed by comparing the odds ratios of any adverse events and adverse events leading to study withdrawal between treatment and control subjects. Results: Improvement in Medical Outcomes Study (MOS) sleep inventory scores from baseline was significantly greater in patients treated with vibratory stimulation pads than in those receiving sham pads (Hedges's g, standardized mean difference −0.39, P ≤ 0.02). There was no difference in improvement in sleep scores between patients treated with vibratory stimulation pads (−0.39) and those receiving an approved RLS drug (−0.44, P > 0.70). The risk of any adverse event or withdrawal because of an adverse event was not significantly different between patients treated with vibratory stimulation pads and those assigned to sham pads (Mantel-Haenszel odds ratio 2.16 [P > 0.14] and 1.39 [P > 0.80], respectively). The odds ratios for patients reporting any adverse events and adverse events leading to withdrawal were not significantly different between patients treated with vibratory stimulation pads (2.16 and 1.39, respectively) and those who received approved RLS drugs (2.11 [P > 0.89] and 2.07 [P > 0.82], respectively, mixed-effects model). Conclusion: For patients with moderately severe RLS, vibratory stimulation pads were more effective than sham pads for improving sleep, as effective as FDA-approved RLS drugs, and as safe as both sham pads and FDA-approved RLS drugs. Keywords: meta-analysis, restless legs syndrome, sleep, vibration, counterstimulation, drug therapy

Fred Burbank,1 Mark J Buchfuhrer,2 Branko Kopjar31Salt Creek International Women’s Health Foundation, San Clemente, CA, USA; 2Stanford University Center for Sleep Sciences, Downey, CA, USA; 3Department of Health Services, University of Washington, Seattle, WA, USAPurpose: Pooled data from two randomized, double-blind, prospective clinical trials were analyzed (i) to determine if vibratory stimulation can safely treat patients with moderately severe restless legs syndrome and (ii) to compare two types of shams.Patients and methods: One hundred and fifty-eight patients with at least moderately severe primary restless legs syndrome (a score of 15 or greater on the International Restless Legs Syndrome Study Group rating scale) were enrolled at five investigational sites, between April 20, 2009 and February 12, 2010. Patients were randomly assigned to treatment with a vibrating pad or control (sound-producing or light-emitting sham pad). Patients and investigators were blinded to pad assignment type (treatment pad or sham pad). Efficacy was measured as a change in score from baseline to week 4, on the Medical Outcomes Study Sleep Problems Index II, the Johns Hopkins Restless Legs Syndrome Quality of Life summary scale, and the International Restless Legs Syndrome Study Group rating scale. Clinicians were asked to evaluate the effectiveness of the pad assignment and to guess whether treatment or sham therapy had been assigned. Adverse events related to vibrating pad assignment were tabulated.Results: The Medical Outcomes Study Sleep Problems Index II scores improved significantly more for patients receiving a vibrating pad over those receiving a sham pad (P ≤ 0.02) even when corrected for multiplicity (P ≤ 0.04). Clinician evaluation favored patients assigned vibrating pads, and neither patients nor clinicians accurately guessed which pad was assigned. No significant difference in adverse event rates was observed between the vibrating and sham pad groups. Sound and light sham pads performed comparably with respect to safety and efficacy.Conclusion: Four weeks of treatment with vibrating pads safely improved sleep in patients with restless legs syndrome and both shams functioned comparably.Keywords: restless legs syndrome, vibration therapy, sham-controlled, double-blind, randomized clinical trial