Do randomized clinical trials with inadequate blinding report enhanced placebo effects for intervention groups and nocebo effects for placebo groups?

BACKGROUND: Studies suggest that expectations powerfully shape clinical outcomes. For subjective outcomes in adequately blinded trials, health improvements are substantial and largely explained by non-specific factors. The objective of this study was to investigate if unblinding in randomized controlled trials (RCTs) is associated with enhanced placebo effects for intervention groups and nocebo effects for placebo groups. For these effects, a secondary objective was to explore potential moderating factors. METHODS: We included RCTs that investigated the efficacy of phosphodiesterase-5 (PDE-5) inhibitors for male erectile dysfunction by comparing one PDE-5 inhibitor to placebo. In addition, to be included studies must have reported scores for change from baseline, or baseline and final International Index of Erectile Functioning-Erectile Functioning domain score (IIEF-EF), and be published in either English, French, Dutch, or German. We searched for both published and unpublished relevant trials using PUBMED, EMBASE, the Cochrane Central Register of Controlled Trials, a clinical trials register (clinicaltrials.gov) and the Food and Drug Administration clinical reviews through March 2012. We evaluated the blinding status of trials with the Cochrane Risk of Bias Tool, using the domains of allocation sequence concealment, blinding of participants, healthcare providers and outcome assessors. Across these four domains, studies that scored low risk of bias were judged to be adequately blinded and studies that scored unclear or high risk of bias were judged to be inadequately blinded. RESULTS: We included 110 studies (205 journal publications and 2 unpublished sources) that involved 23,877 participants; 93 (85%), 51 (46%), 93 (85%) and 93 (85%) studies were assessed with an unclear risk of bias for allocation concealment, blinding of participant, blinding of caregiver and blinding of outcome assessor, respectively. None of the studies reported testing of blinding. None of the 205 journal publications provided sufficient details to assess allocation concealment, blinding of participants, caregivers and outcome assessors. After contacting authors for additional information, we judged five studies to be adequately (n = 1,202) and 16 to be inadequately (n = 3,006) blinded. The IIEF-EF score for placebo groups in adequately blinded trials versus inadequately blinded trials was 1.92 points (95% CI, 0.64 to 3.20) versus 1.56 (95% CI, 0.93 to 2.20), respectively. The IIEF-EF score for intervention groups in adequately blinded trials versus inadequately blinded trials was 9.40 (95% CI, 6.96 to 11.83) versus 8.33 (95% CI, 7.29 to 9.37), respectively. In a secondary analysis, prior experience with the drug affected the scores; in placebo groups with participants naïve to the intervention the score was 2.89 (95% CI, 2.33 to 3.45) versus -0.11 (95% CI, -2.06 to 1.84) with participants having prior experience. In the intervention groups, these scores were 7.99 (95% CI, 6.85 to 9.14) versus 8.33 (95% CI, 7.51 to 9.16), respectively. Unblinding lowered placebo scores (creating a nocebo effect) by 19% (0.33 points; 95% CI, -0.96 to 1.62). Unblinding lowered intervention scores by 11% (1.0; 95% CI, -1.35 to 3.47). The results provided no conclusive evidence for nocebo or enhanced placebo effects. Patients taking a PDE-5 inhibitor for the first time experience a larger placebo effect that accounts for 35% of the total effect. CONCLUSIONS: Given the overall poor reporting of blinding in clinical trial reports and the small number of trials that could be rated as adequately or inadequately blinded, we could not draw any robust conclusions about the existence or absence of nocebo and enhanced placebo effects. A large placebo effect was found for patients taking PDE-5 inhibitors for the first time. It was not clear if previous exposure to the drug impacted trial blinding. We found clear evidence that studies assessing a subjective continuous outcome fail to report on measures taken to secure double blinding. Although we observed a trend for the presence of a nocebo effect, there was insufficient evidence to quantify its impact on expectations. RCTs with patients with no prior experience with PDE-5 inhibitors reported larger placebo effects and possibly these studies were better blinded. Future research should further investigate the factors that contribute to blinding and their impact on health outcomes in randomized trials of subjectively assessed conditions. This research is part of a PhD project and has no external funding. The authors have no competing interests to declare.