In the newly minted American Urological Association and Sexual Medicine Society of North America (AUA/SMSNA) Disorders of Ejaculation Guidelines, premature ejaculation (PE) is recognized as either being either lifelong, or acquired.¹ Lifelong PE is defined as poor ejaculatory control (ejaculation occurs within 2 minutes of the initiation of penetrative intercourse) associated with bother since the patient’s first sexual encounter. Similarly, acquired PE is defined as poor ejaculatory control (ejaculatory latency during penetrative sex that is significantly reduced from prior) with associated bother. PE can cause significant distress to affected men, leading to the development of anxiety surrounding future sexual encounters.¹

Current first line recommendations for the management of PE include sexual health therapy referral, topical anesthetics, and off-label use of selective serotonin re-uptake inhibitors (SSRI) or clomipramine. These treatment modalities are not without their limitations, such as compliance (sexual therapy) and adverse effects (AEs), such as decreased libido, weight gain and the risk of developing mania (in men with undiagnosed bipolar disease).¹ Additionally, daily SSRIs can be associated with significant withdrawal if discontinued suddenly.^1,2 Topical anesthetics can be absorbed transvaginally leading to partner discomfort.¹ Second line pharmacologic treatments recommended by the AUA/SMSNA guidelines include tramadol, which is moderately successful but also has the concern for possible addiction or abuse. While the aforementioned therapies can be efficacious in up to 60% of cases, side effects often lead to discontinuation, generating a significant interest for the identification of novel therapies.¹

Dapoxetine

Dapoxetine is a rapid acting SSRI with a short half-life developed specifically as an on-demand treatment for PE.² While it is currently an approved first line agent in the guidelines, its utility has been limited by availability and thus providers may not be familiar with the drug.¹ A meta-analysis by Yue et al. included 5 placebo-controlled trials and found a significantly increased intravaginal ejaculatory latency time (IELT) with dapoxetine.² The analysis included a total of 6,576 subjects, aged >18 years, in monogamous heterosexual relationships for >6 months. Four of the trials involved subjects taking 30 mg or 60 mg on demand 1 to 3 hours prior to sexual intercourse, while one trial involved either 60 mg pm dosing or once daily. Across all studies, dapoxetine increased IELT by a weighted mean difference of 1.47 minutes (95% CI 1.22–1.71). In all 5 trials, patient reported outcomes were significantly improved in the treatment groups as compared to placebo. When comparing the 30 mg and 60 mg doses, the higher dose appeared to be more effective. Mild AEs where reported in around 50% of subjects in the treatment groups compared to 33% of the placebo groups, with the most frequent AEs being nausea (17%), dizziness (9%), headache (8%), and diarrhea (6%). Less than 1% of subjects experienced severe AEs with no reports of sexual dysfunction or suicide attempts, leading the authors to argue that dapoxetine is safer than SSRIs historically used to treat PE. While approved in over 50 countries for the treatment of PE, dapoxetine has not received marketing approval by the FDA.

Modafinil

Modafinil is a wake-promoting agent that has a complex and incompletely understood effect on the central nervous system, though it is thought to principally act on the dopaminergic and GABAergic systems.^1,3 Murine studies demonstrate that modafinil increases ejaculatory latency without suppressing sexual behavior. A recent uncontrolled proof-of-concept study involving 55 patients with lifelong PE showed positive results.³ Using patient reported IELTs the authors demonstrated that 100 mg of on-demand modafinil (taken before noon the day of anticipated sex) doubled patient reported mean IELT from 25 to 50 seconds. This was associated with significant improvements in patient reported outcomes. The authors did not report any notable AEs. While this study does suggest a potential role for modafinil in the treatment of PE, placebo-controlled trials are need.

Oxytocin Antagonists

Oxytocin has a prominent role in sexual response and is known to have a stimulatory effect on the ejaculatory process; therefore it is hypothesized that oxytocin antagonists could be used as a potential treatment for PE.⁴ Two recently published phase II randomized control trials of cligosiban, an oxytocin antagonist, have shown conflicting results.^5,6 In one study, subjects were randomized to either 400 mg cligosiban 1 to 6 hours before planned sexual activity for 8 weeks with subjects allowed to adjust their dose to 200 or 800 mg during the trial. At the conclusion of the study, IELT increased by 61 seconds in the treatment vs 16.4 seconds in the placebo group, with corresponding significant improvements in ejaculation-related personal distress scores. The same authors performed a second phase II RCT randomizing 239 patients to either a fixed dose of cligosiban (400, 800, or 1,200 mg) vs placebo. However, in this trial no significant differences were observed in either IELT or patient-reported outcomes.⁶ Both trials showed cligosiban to be generally well tolerated with no severe AEs. The reasons for the conflicting outcomes of these two studies may be explained by differences in design. First, the negative study prescribed a fixed dose rather than allowing the patients to dose titrate. Second, in the positive trial subjects with PE were selected from centers with specialists in sexual medicine, while the negative trial included subjects referred from generalist clinics and may not have been as carefully screened for true lifelong PE.⁴ Although mechanistically oxytocin antagonists show promise, more research is needed before they can be established as a viable therapy for PE.

Conclusions

While topical anesthetics and daily SSRIs remain the most established pharmacologic treatments for PE, their side effect profile can be problematic. Though the guidelines state the most efficacious strategies are likely to involve a combination of both medications and behavioral approaches, having medications with fewer AEs is of paramount importance.¹ As our understanding of the complex physiology underlying ejaculatory function improves, and our classification of men with PE becomes more standardized, it is likely that more robust clinical trials will follow. Our hope is that these advances will provide clinicians with an expanded repertoire of pharmacologic options to alleviate the distress experienced by patients with PE without unnecessary side effects.