Efficacy and safety of pharmacological treatments in patients with premature ejaculation: an umbrella review of meta-analyses of randomized controlled trials

Abstract

Introduction: Premature ejaculation (PE) is a common male sexual dysfunction characterized by short ejaculatory latency with minimal stimulation, an inability to delay or control ejaculation, and distress or dissatisfaction due to the condition. Pharmacological therapy is central to PE management, with dapoxetine as the only approved selective serotonin reuptake inhibitor (SSRI). Off-label options, including long-acting selective serotonin reuptake inhibitors (SSRIs) (eg, paroxetine), topical anesthetics, phosphodiesterase type 5 inhibitors (eg, sildenafil), and tramadol, have also been explored. Despite numerous systematic reviews on its treatment, challenges remain due to methodological heterogeneity, variability in outcome measures, and inconsistencies in trial quality, making it difficult to draw reliable conclusions.

Objectives: This umbrella review of systematic reviews and meta-analyses (SR-MAs) of randomized controlled trials (RCTs) examined the efficacy of pharmacological treatments in prolonging intravaginal ejaculatory latency time (IELT) and their safety by analyzing associated adverse events in adults with PE.

Methods: A comprehensive search of SR-MAs ranging from 1990 to 2024 was performed. Two reviewers independently screened articles, extracted data, and assessed quality of previous SR-MAs using the A Measurement Tool to Assess Systematic Reviews version 2 (AMSTAR-2) tool and the risk of bias of RCTs using Cochrane's risk-of-bias tool for randomized trials. The primary outcome of interest was IELT. Effect sizes from primary studies of all SR-MAs were extracted, and after removing overlapping RCTs, a re-meta-analysis was conducted. We appraised evidence certainty using the Grading of recommendations, Assessment, Development, and Evaluations scoring system (GRADE).

Results: This review included 44 SR-MAs covering 65 RCTs. Only two SR-MAs rated as moderate to high quality in the AMSTAR-2 assessment. Additionally, only six out of 65 RCTs had a low risk of bias. The median follow-up for included RCTs was 7.9 months. These treatments significantly improved IELT compared to placebo, with paroxetine achieving the largest mean difference (5.64 min; 95% confidence interval [CI]: 3.50 to 9.07). However, all pharmacological treatments were associated with adverse events, with paroxetine having the lowest risk (RR: 1.5; 95% CI: 0.3 to 7.3), while risk ratios were higher for other treatments, including 4.1 for topical anesthetics, 2.4 for tramadol, and 1.8 for dapoxetine. Only topical anesthetics and paroxetine demonstrated a moderate to high rating in the GRADE assessment.

Conclusion: Topical anesthetics, tramadol, and SSRIs significantly increase IELT. However, substantial heterogeneity among meta-analyses may limit the robustness of these findings. Future RCTs should include extended follow-up periods to better assess the long-term efficacy and safety of these treatments.

Prospero registration number: CRD 42024561480.

Keywords: drug therapy; meta-analysis; premature ejaculation; umbrella review.