Phosphodiesterase-5 inhibitors for premature ejaculation: a systematic review and meta-analysis

CONTEXT: Phosphodiesterase-5 inhibitors (PDE5is) are prescribed off-label for the treatment of premature ejaculation (PE). OBJECTIVE: To systematically review the evidence from randomised controlled trials (RCTs) for PDE5is in the management of PE. EVIDENCE ACQUISITION: MEDLINE and other databases were searched to September 2015. Quality of RCTs was assessed. Intra-vaginal ejaculatory latency time (IELT) data were pooled in a meta-analysis. Heterogeneity was assessed. EVIDENCE SYNTHESIS: Fifteen RCTs were included. The majority were of unclear methodological quality. Pooled IELT evidence suggests: PDE5is are significantly more effective than placebo (231 participants, p<0.00001); there is no difference between PDE5is and selective serotonin reuptake inhibitors (SSRIs) (405 participants, p=0.50); and that PDE5is combined with an SSRI are significantly more effective than SSRIs alone (521 participants, p=0.001). However, high levels of statistical heterogeneity are evident (I(2)≥40%). Single RCT evidence suggests that sildenafil is significantly more effective than the squeeze technique; but both lidocaine gel and tramadol are significantly more effective than sildenafil. Sildenafil combined with behavioural therapy is significantly more effective than behavioural therapy alone. Sexual satisfaction and ejaculatory control appear better with PDE5is compared with placebo and with PDE5is combined with an SSRI compared with an SSRI alone. Adverse events are reported with both PDE5is and other agents. CONCLUSIONS: PDE5is are significantly more effective than placebo and PDE5is combined with an SSRI are significantly more effective than SSRIs alone at increasing IELT and improvement in other effectiveness outcomes. However, heterogeneity is evident across RCTs. The methodological quality of the majority of RCTs is unclear. PATIENT SUMMARY: We reviewed PDE5is for treating premature ejaculation. We found evidence to suggest that PDE5is are effective compared with placebo and that PDE5is combined with an SSRI are better than an SSRI alone. Adverse events are reported with PDE5is and other agents. However, the quality of the evidence is uncertain. PROSPERO registration number: CRD42013005289

Interventions to treat premature ejaculation: a systematic review short report

Background: Premature ejaculation (PE) is commonly defined as ejaculation with minimal sexual stimulation before, on or shortly after penetration and before the person wishes it. PE can be either lifelong and present since first sexual experiences (primary), or acquired (secondary), beginning later (Godpodinoff ML. Premature ejaculation: clinical subgroups and etiology. J Sex Marital Ther 1989;15:130–4). Treatments include behavioural and pharmacological interventions. Objective: To systematically review evidence for clinical effectiveness of behavioural, topical and systemic treatments for PE. Data sources: The following databases were searched from inception to 6 August 2013 for published and unpublished research evidence: MEDLINE; EMBASE; Cumulative Index to Nursing and Allied Health Literature; The Cochrane Library including the Cochrane Systematic Reviews Database, Cochrane Controlled Trials Register, Database of Abstracts of Reviews of Effects and the Health Technology Assessment database; ISI Web of Science, including Science Citation Index, and the Conference Proceedings Citation Index-Science. The US Food and Drug Administration website and the European Medicines Agency (EMA) website were also searched. Methods: Randomised controlled trials (RCTs) in adult men with PE were eligible (or non-RCTs in the absence of RCTs). RCT data were extrapolated from review articles when available. The primary outcome was intravaginal ejaculatory latency time (IELT). Data were meta-analysed when possible. Other outcomes included sexual satisfaction, control over ejaculation, relationship satisfaction, self-esteem, quality of life, treatment acceptability and adverse events (AEs). Results: A total of 103 studies (102 RCTs, 65 from reviews) were included. RCTs were available for all interventions except yoga. The following interventions demonstrated significant improvements (p < 0.05) in arithmetic mean difference in IELT compared with placebo: topical anaesthetics – eutectic mixture of local anaesthetics (EMLA®, AstraZeneca), topical eutectic mixture for PE (Plethora Solutions Ltd) spray; selective serotonin reuptake inhibitors (SSRIs) – citalopram (Cipramil®, Lundbeck), escitalopram (Cipralex®, Lundbeck), fluoxetine, paroxetine, sertraline, dapoxetine (Priligy®, Menarini), 30 mg or 60 mg; serotonin–noradrenaline reuptake inhibitors – duloxetine (Cymbalta®, Eli Lilly & Co Ltd); tricyclic antidepressants – inhaled clomipramine 4 mg; phosphodiesterase-5 (PDE5) inhibitors – vardenafil (Levitra®, Bayer), tadalafil (Cialis®, Eli Lilly & Co Ltd); opioid analgesics – tramadol (Zydol SR®, Grünenthal). Improvements in sexual satisfaction and other outcomes compared with placebo were evident for SSRIs, PDE5 inhibitors and tramadol. Outcomes for interventions not compared with placebo were as follows: behavioural therapies – improvements over wait list control in IELT and other outcomes, behavioural therapy plus pharmacotherapy better than either therapy alone; alpha blockers – terazosin (Hytrin®, AMCO) not significantly different to antidepressants in ejaculation control; acupuncture – improvements over sham acupuncture in IELT, conflicting results for comparisons with SSRIs; Chinese medicine – improvements over treatment as usual; delay device – improvements in IELT when added to stop–start technique; yoga – improved IELT over baseline, fluoxetine better than yoga. Treatment-related AEs were evident with most pharmacological interventions. Limitations: Although data extraction from reviews was optimised when more than one review reported data for the same RCT, the reliability of the data extraction within these reviews cannot be guaranteed by this assessment report. Conclusions: Several interventions significantly improved IELT. Many interventions also improved sexual satisfaction and other outcomes. However, assessment of longer-term safety and effectiveness is required to evaluate whether or not initial treatment effects are maintained long term, whether or not dose escalation is required, how soon treatment effects end following treatment cessation and whether or not treatments can be stopped and resumed at a later time. In addition, assessment of the AEs associated with long-term treatment and whether or not different doses have differing AE profiles is required