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

Abstract

BackgroundStudies 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.MethodsWe 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domain score (IIEF-EF), and be published in either English, French, Dutch, or German.We searched for both published and unpublished relevant trials using PUBMED, EMBASE, the Cochrane Central Register of Controlled Trials, a clinical trials register (clinicaltrials.gov) and the Food and Drug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high risk of bias were judged to be inadequately blinded.ResultsWe included 110 studies (205 journal publications and 2 unpublished sources) that involved 23,877 participants; 93 (85%), 51 (46%), 93 (85%) and 93 (85%) studies were assessed with an unclear risk of bias for allocation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 lowe...

Better outcome from arthroscopic partial meniscectomy than skin incisions only? A sham-controlled randomised trial in patients aged 35–55 years with knee pain and an MRI-verified meniscal tear

“…Second, 36% (16/44) of patients were non-blinded in the course of the study, which may have enhanced the placebo effects in the surgery group and negatively impacted the patient-reported outcomes in the sham-surgery group through nocebo effects. 24 In our trial, 45% (10/22) of patients randomised to skin incisions only were non-blinded. Third, 8 of the 10 non-blinded patients in the skin-incision-only group crossed-over to meniscus resection, which further confounded the interpretation of the results.…”

Effect of ibuprofen on the efficacy of inferior alveolar nerve block in patients with irreversible pulpitis: A meta‐analysis

“…If an RCT is not adequately blinded, for instance participants and investigators will know who gets what type of treatment. Expectations, therefore, could become unbalanced between the treatments . In this systematic review, two studies did not report if participants and operators were blinded , which prevented us from being sure if these studies were free or not of performance bias.…”

Peer Review #3 of "Effectiveness and adequacy of blinding in the moderation of pain outcomes: Systematic review and meta-analyses of dry needling trials (v0.1)"

“…Adequacy was based on the four RoB domains that relate to blinding (allocation concealment, participant blinding, therapist blinding, and outcome assessor blinding) [adapted from Feys et al (2014)]. Trials were conservatively categorised as either 'adequately blinded' or 'inadequately blinded' based on the following rules:  Adequately blinded: low RoB across all four domains, or low RoB in the three domains excluding 'therapist blinding' if no trials attempted therapist blinding.…”