Placebo Responses Among Men With Erectile Dysfunction Enrolled in Phosphodiesterase 5 Inhibitor Trials: A Systematic Review and Meta-analysis

Abstract

Importance: Placebo responses in the treatment of erectile dysfunction (ED) are poorly described in the literature to date.

Objective: To quantify the association of placebo with ED outcomes among men enrolled in placebo-controlled, phosphodiesterase 5 inhibitor (PDE5I) trials.

Data sources: For this systematic review and meta-analysis, a database search was conducted to identify double-blind, placebo-controlled studies using PDE5Is for the treatment of ED published from January 1, 1998, to December 31, 2018, within MEDLINE, Embase, Cochrane Library, and Web of Science. Only articles published in the English language were included.

Study selection: Double-blind, placebo-controlled randomized clinical trials of PDE5Is for ED were included. Studies were excluded if they did not provide distribution measures for statistical analysis. Study selection review assessments were conducted by 2 independent investigators. A total of 2215 studies were identified from the database search, and after review, 63 studies that included 12 564 men were analyzed.

Data extraction and synthesis: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed in abstracting data and assessing validity. Data were extracted from published reports by 2 independent reviewers. Quality assessment was performed using the Jadad scale. Data were pooled using a random-effects model.

Main outcomes and measures: The main outcome was improvement in the erectile function domain of the International Index of Erectile Function questionnaire in the placebo arm of the included studies. Effect size was reported as bias-corrected standardized mean difference (Hedges g). The hypothesis was formulated before data extraction.

Results: A total of 63 studies that included 12 564 men (mean [SD] age, 55 [7] years; age range, 36-68 years) were included. Erectile function was significantly improved among participants in the placebo arm, with a small to moderate effect size (Hedges g [SE], 0.35 [0.03]; P < .001). Placebo effect size was larger among participants with ED associated with posttraumatic stress disorder (Hedges g [SE], 0.78 [0.32]; P = .02) compared with the overall analysis. No significant difference was found between placebo and PDE5Is for ED after prostate surgery or radiotherapy (Hedges g [SE], 0.30 [0.17]; P = .08).

Conclusions and relevance: In this study, placebo was associated with improvement of ED, especially among men with ED-related posttraumatic stress disorder. No difference was found between placebo and PDE5I among men treated for ED after prostate surgery.

Figure 1.. Flowchart for the Trials Included in the Meta-analysis

ED indicates erectile dysfunction.

Figure 2.. Forest Plot of the Association Between Placebo and Erectile Disfunction Outcomes

Erectile dysfunction outcomes were measured using the Erectile Function Domain of the International Index of Erectile Function. A low to moderate improvement was seen in the placebo arm, as indicated by the bias-corrected standardized mean difference (Hedges g [SE], 0.35 [0.03]; P < .001).