Do randomized clinical trials with inadequate blinding report enhanced placebo effects for intervention groups and nocebo effects for placebo groups? A protocol for a meta-epidemiological study of PDE-5 inhibitors

Abstract

BackgroundPatients’ expectations of treatment effects may contribute to positive (placebo) and negative (nocebo) outcomes. The effect of patient expectations may be pronounced in subjectively assessed conditions, such as male erectile dysfunction. The aim of this project is to examine the magnitude of expectancy in trials of phosphodiesterase-5 inhibitors. We hypothesize that randomized controlled trials with inadequate blinding will report enhanced placebo effects for intervention groups and nocebo effects for placebo groups, compared with adequately blinded studies.Methods/designWe will quantify the magnitude of expectancy by comparing the effect estimates of trials with inadequate and adequate blinding. Blinding will be assessed using four domains from the Cochrane ‘risk-of-bias’ tool: allocation concealment; blinding of patient; caregiver; and outcome assessor. Our secondary aim is to identify factors that can modify expectations, such as prior experience with the intervention and drug side effects.We will perform an electronic search using a combination of controlled vocabulary and free text words in the following databases: MEDLINE, EMBASE, CENTRAL, and a clinical trials register. We will include randomized controlled trials, with either parallel or crossover design, that compare one phosphodiesterase-5 inhibitor with a placebo. The study’s primary aim should be to investigate the efficacy of phosphodiesterase-5 inhibitors for treating male erectile dysfunction. Screening will take place at two levels: abstracts and titles, followed by full text reports. Two reviewers will independently extract data on the primary outcome and assess risk of bias.We will meta-analyze treatment effects, if appropriate, to assess the magnitude of enhanced placebo effects and nocebo effects in intervention and placebo groups, respectively. We will explore possible mediators of placebo and nocebo effects with subgroup and meta-regression analyses.DiscussionTreatments may confer significant costs and risk of adverse effects; it is important, therefore, to determine whether the effects of treatments are larger than expectancy alone. If treatment expectations can be used in a non-deceptive way to produce clinically advantageous outcomes, then it may be possible to incorporate such mechanisms into evidence-based healthcare decision-making.

The nocebo effect of drugs

“…Feys et al. () hypothesize that randomized controlled trials with inadequate blinding report enhanced placebo effects for intervention groups and nocebo effects for placebo groups, compared with adequately blinded studies.…”

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“…In publishing this protocol we are following the lead of others who have encouraged the pre-specification and transparent reporting of the objectives and design of methodological studies [39-43]. …”

Efficacy and Safety of Flibanserin for the Treatment of Hypoactive Sexual Desire Disorder in Women

“…For inadequately blinded studies, we presented outcomes for flibanserin and placebo groups separately. 22,23 In cases of missing data for the number in analysis or standard error (SE), for efficacy outcomes the number of study completers and the largest outcome-specific SE from the other studies were imputed, respectively; a conservative approach given its modest effect on study size, weighting, and precision estimates. For safety outcomes, the number of study starters was used, given that dropout, among other reasons, was likely to be related to AEs.…”