Another face of placebo: the lessebo effect in Parkinson disease: meta-analyses

Abstract

Objective: To study the impact of negative expectation related to receiving a placebo (the "lessebo effect") on efficacy outcome measures of symptomatic treatments in Parkinson disease (PD).

Methods: We conducted meta-analyses of double-blind randomized controlled trials (RCTs) of dopamine agonists in PD and compared the pooled mean score change of the motor section of the Unified Parkinson's Disease Rating Scale (mUPDRS) across active treatment arms according to the presence of a placebo arm or the probability of placebo assignment (0%, <50%, and 50%) of the original RCT. A mixed-effects model was used. Heterogeneity was assessed by subgroup analyses and meta-regression modeling.

Results: A total of 28 study arms were extracted from active-controlled trials (3,277 patients) and 42 from placebo-controlled trials (4,554 patients). The overall difference between groups in the pooled mean score change in the mUPDRS was 1.6 units (95% confidence interval [CI] 0.2, 3.0; p = 0.023), in favor of the active-controlled group. In subgroup analyses, this difference was of higher magnitude in the early PD group without motor fluctuations (3.3 mUPDRS units, 95% CI 1.1, 5.4; p = 0.003) and for study duration ≤ 12 weeks (4.1 mUPDRS units, 95% CI 1.0, 7.2; p = 0.009). There was no between-group difference using probability of placebo assignment as criterion.

Conclusions: This study shows that the use of a placebo can be associated with a clinically significant reduction in the magnitude of change of the mUPDRS after an active treatment in RCTs for PD. These new findings have potential implications in the development of new treatments and appraisal of current treatment options for PD and possibly for other neurologic disorders.

Figure 1. Flowchart for selection of included studies (according to PRISMA guidelines)

mUPDRS = motor section of the Unified Parkinson's Disease Rating Scale; RCT = randomized controlled trial.

Figure 2. Forest plots

(A) Forest plot of the meta-analysis for the change in the motor section of the Unified Parkinson's Disease Rating Scale (mUPDRS) after an active treatment in placebo-controlled studies in Parkinson disease (PD). (B) Forest plot of the meta-analysis for the change in the mUPDRS after an active treatment in active-controlled studies in PD. Results from individual studies and pooled results are presented. Reference numbers refer to e-references. CI = confidence interval; ES = effect estimate/mean difference; n = sample size of study arm; weight = inverse variance weighing.