When does the placebo effect have an impact on network meta-analysis results?

Abstract

The placebo effect is the ‘effect of the simulation of treatment that occurs due to a participant’s belief or expectation that a treatment is effective’. Although the effect might be of little importance for some conditions, it can have a great role in others, mostly when the evaluated symptoms are subjective. Several characteristics that include informed consent, number of arms in a study, the occurrence of adverse events and quality of blinding may influence response to placebo and possibly bias the results of randomised controlled trials. Such a bias is inherited in systematic reviews of evidence and their quantitative components, pairwise meta-analysis (when two treatments are compared) and network meta-analysis (when more than two treatments are compared). In this paper, we aim to provide red flags as to when a placebo effect is likely to bias pairwise and network meta-analysis treatment effects. The classic paradigm has been that placebo-controlled randomised trials are focused on estimating the treatment effect. However, the magnitude of placebo effect itself may also in some instances be of interest and has also lately received attention. We use component network meta-analysis to estimate placebo effects. We apply these methods to a published network meta-analysis, examining the relative effectiveness of four psychotherapies and four control treatments for depression in 123 studies.

Placebo Effect: The Stem of Seminal Studies with Active Treatment Neurobiological Mechanisms, And Implications for Parkinson’s Disease with Deep Brain Stimulation

“…As studies of placebo analgesia, a diminution or elimination of pain after receiving placebo-induced treatment, flourished, questions whether combination of placebo and active treatment can increase the positive effect in the context of pain relief. In double-blind randomized placebo controlled trials or RCTs, the assumption of additivity states that the true effect of the treatment is determined by calculating the effect of the active treatment and subtracting the response in the placebo group (Tallarida, 2001;Adriani Nikolakopoulou et al, 2023). The three types of outcomes from the way placebo and active treatment interact are subadditivity, an instance when the combined therapeutic effect is less than the sum of the isolated effects of active treatment and placebo and superadditivity, the case when the combined effect exceeds the sum of individualized effects of active treatment and placebo which can lead to an overestimation of active treatment's efficacy in RCTs, or even a reverse reaction to the treatment (De La Fuente-Fernández et al, 2001; Rémy Boussageon et al, 2022).…”

Placebo effects in randomized trials of pharmacological and neurostimulation interventions for mental disorders: An umbrella review

“…The increased placebo response can also affect larger data synthesis approaches, such as network meta-analysis, in which assumptions about placebo responses (e.g. stability over time) might affect the validity of results [43].…”