Sleep improvement for restless legs syndrome patients. Part III: effect of treatment assignment belief on sleep improvement in restless legs syndrome patients. A mediation analysis

Abstract

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 counterstimulation 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.

Sleep improvement for restless legs syndrome patients. Part I: pooled analysis of two prospective, double-blind, sham-controlled, multi-center, randomized clinical studies of the effects of vibrating pads on RLS symptoms

“…Sound and light shams performed comparably and may have exerted primary therapeutic effects on some patients (Part III). 43 However, vibration therapy failed to significantly improve scores on the RLS-QoL or IRLS scales. It is possible that vibration is a general aid to sleep that has no specific or unique therapeutic benefit for RLS patients.…”

“…The contribution of assignment belief (the patient's belief that he was receiving treatment) to the results is further explored in Part III of this series. 43 …”

Sleep improvement for restless legs syndrome patients. Part IV: meta-analysis comparison of effect sizes of vibratory stimulation sham pads and placebo pills

“…As previously demonstrated, 9 once RLS patients develop a belief about the type of treatment they received (active versus control), their sleep inventory scores are strongly influenced. Patients who believed they had been given a placebo reported little sleep improvement.…”

“…Pad assignment (treatment pad versus sham pad) and pad assignment belief (patient belief that a treatment or sham pad was assigned) both influenced improvement in Medical Outcomes Study Sleep Problems Index II (MOS-II) 6-8 sleep scores; however, pad assignment belief was more influential. 9 Others have similarly reported the influence of patient belief on RCT outcomes. 10 Thus, we now examine inactive (control) effect sizes, comparing sham effect sizes in VS trials to placebo effect sizes in RLS drug trials.…”

Improving sleep for patients with restless legs syndrome. Part II: meta-analysis of vibration therapy and drugs approved by the FDA for treatment of restless legs syndrome

“…These patients could have focused attention on light or sound, tuned light or sound to an intensity that they felt was comforting, and diverted their attention away from RLS sensations (Part III of this report). 66 Light can be an effective counterstimulus to extremity pain. 26 Similarly, sound has been demonstrated to modulate pain, [67][68][69][70] and has been used as a counterstimulus for patients with conditions such as tinnitus and auditory hallucinations.…”