Dynamic Features of Placebo Effects Addressing Primary Insomnia

Abstract

Background: It has been accepted knowledge that placebo effects have been significant in insomnia randomized clinical trials. However, the dynamic features of placebo effects have not been clarified. Our aim was therefore to conduct a meta-analysis of placebo-controlled randomized clinical trials to characterize the dynamic features of placebo effects addressing primary insomnia. Methods: We performed a comprehensive literature search for randomized, placebo-controlled, double-blind clinical trials evaluating the efficacy of therapeutic regimens addressing primary insomnia. We pooled separate effect size estimates (Hedge's g) of placebo and regimen conditions across trials for outcome measures, and multilevel mixed-effects models was used to explore potential sources of heterogeneity. Findings: The placebo effects were significant and robust to reduce the symptoms of insomnia, and subjective measures were significantly smaller than objective measures (p<0.001), but placebo response rates were nearly identical. The overall placebo effects were influenced by publication year (p = 0.015), treatment duration (p = 0.010), sample size (p<0.001), and therapeutic regimen (p<0.001). Placebo effects showed a diphasic feature within treatment duration: initial short-term increase-to-decrease status, and subsequent long-term slow increase-to-steady status. After withdrawals, placebo effects showed a sustained decline with fast-to-slow trend. In a large-scale time span, placebo effects of a new therapeutic regimen showed a slow-decline status. Interpretation: The dynamic features of placebo effects addressing primary insomnia may lead to the development and validation of dosing strategies that require less medication exposure to maintain clinical effects. Funding Statement: The authors state: There was no funding source for this study. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement was followed for this pooled analysis.