In many relationships, PE causes few if any problems. In others, the couple may reach an accommodation of the problem through various strategies—young men with a short refractory period may often experience a second and more controlled ejaculation during a subsequent episode of lovemaking. Frequently, however, PE eventually leads to significant relationship problems with partners regarding the man as selfish and developing a pattern of sexual avoidance. This only worsens the severity of the prematurity on the occasions when intercourse does occur.

The cornerstones of behavioural treatment are the Seman’s “stop-start” manoeuvre and its modification proposed by Masters and Johnson, the squeeze technique. Both are based on the theory that PE occurs because the man fails to pay sufficient attention to preorgasmic levels of sexual tension. As most men with PE are aware of their anxiety, the sources of such anxiety being relatively superficial, treatment success with these behavioural approaches is relatively good in the short term though convincing long-term treatment outcome data is absent.

Pharmacological modulation of ejaculatory threshold represents a novel and refreshing approach to the treatment of PE and a radical departure from the psychosexual model of treatment, previously regarded as the cornerstone of treatment. The introduction of SSRIs has revolutionized the approach to and treatment of PE. SSRIs consist of five compounds (citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline) with a similar pharmacological mechanism of action. Although the methodology of the initial drug treatment studies was rather poor, later double-blind and placebo-controlled studies replicated the genuine effect of clomipramine and SSRIs to delay ejaculation. In spite of an increasing inclination towards research into more evidence-based drug treatment, the majority of studies still lack adequate design and methodology. A recent meta-analysis of all drug treatment studies demonstrated that only 14.4 % had been performed according to the established criteria of evidence-based medicine. Open-design studies and studies using subjective reporting or questionnaires showed a higher variability in ejaculation delay than double-blind studies in which the ejaculation delay was prospectively assessed with a stopwatch.

Paroxetine 20–40 mg, clomipramine 10–50 mg, sertraline 50–100 mg and fluoxetine 20–40 mg can be used for daily treatment. Paroxetine appears to exert the strongest ejaculation delay, increasing IELT approximately 8.8-fold over baseline. Ejaculation delay usually occurs within 5–10 days but may occur earlier. Adverse effects are usually minor, start in the first week of treatment, gradually disappear within 2–3 weeks and include fatigue, yawning, mild nausea, loose stools or perspiration. Diminished libido or mild ED is not reported frequently. Significant agitation is reported by a small number of patients and treatment with SSRIs should be avoided in men with a history of bipolar depression.

Administration of clomipramine, paroxetine, sertraline and fluoxetine 4–6 h before intercourse is efficacious and well tolerated but is associated with less ejaculatory delay than with daily treatment. Daily administration of an SSRI is associated with superior fold increases in IELT compared to on-demand administration. This is due to greatly enhanced 5-HT neurotransmission resulting from several adaptive processes which may include presynaptic 5-HT1a and 5-HT1b/1d receptor desensitization. On-demand treatment may be combined with either an initial trial of daily treatment or concomitant low-dose daily treatment.

A number of rapid-acting, short half-life SSRIs are under investigation as on-demand treatments for PE. Dapoxetine hydrochloride (Priligy; Janssen Pharmaceutica NV, Beerse, Belgium), a selective serotonin reuptake inhibitor (SSRI), was the first drug originally approved for the on-demand treatment of premature ejaculation (PE) by seven European countries (Austria, Finland, Germany, Italy, Portugal, Spain and Sweden) in 2008. Since then, it has received marketing authorization in 59 countries worldwide.

An integrated analysis from five phase-three trials concluded that dapoxetine 30 and 60 mg significantly improved all aspects of PE compared to placebo, including intravaginal ejaculatory latency time, PE profile questionnaire items and Clinical Global Impression of Change in PE (Althof et al. 2014). The geometric mean fold increases were 2.5, 3.0 and 1.6 with dapoxetine 30, dapoxetine 60 mg and placebo, respectively.

The safety profile of antidepressant SSRIs has never been comprehensively studied in men with PE. It consists only of safety data from clinical studies and spontaneously reported adverse events in men with psychiatric disorders. Although dapoxetine differs from other drugs within the SSRI class, due to its rapid onset of action and elimination profile enabling on-demand use, its mechanism of action theoretically could result in adverse events similar to other available SSRIs. The safety assessment currently available for dapoxetine is based on data from the clinical development programme that included >6,000 patients. In phase 3 studies, several well-recognized side effects of SSRIs (i.e. akathisia, withdrawal syndrome and mood-related changes) were not reported for dapoxetine use. A low rate of vasovagal syncope was reported in phase 3 studies, and the premarketing safety profile did not show evidence of serious cardiovascular (CV) events or arrhythmias. The primary objectives of this study were to characterize the safety profile of dapoxetine when used to treat men with PE in routine clinical practice and to report the incidence, severity and type of adverse events (serious adverse events and/or adverse events of special clinical interest). Dapoxetine is a potent SSRI (pKi = 8 nM), which is structurally similar to fluoxetine. Equilibrium radioligand-binding studies using human cells demonstrate that dapoxetine binds to 5-HT, norepinephrine (NE) and dopamine (DA) reuptake transporters and inhibits uptake in the following rank order of potency: NE < 5-HT >> DA. Brain PET studies have demonstrated significant displaceable binding of radiolabelled dapoxetine in the cerebral cortex and subcortical grey matter.

Dapoxetine undergoes rapid absorption and elimination resulting in minimal accumulation and has dose-proportional pharmacokinetics, which are unaffected by multiple dosing. The pharmacokinetic profile of dapoxetine suggests that it is a candidate for on-demand treatment of PE. The pharmacokinetics of both single doses and multiple doses over 6–9 days (30, 60, 100, 140 or 160 mg) of dapoxetine have been evaluated. Dapoxetine has a T _max of 1.4–2.0 h and rapidly achieves peak plasma concentration (Cmax) following oral administration. Both plasma concentration and area under the curve (AUC) are dose dependent up to 100 mg. The mean half-life of dapoxetine after a single dose is 0.5–0.8 h and plasma concentrations rapidly decline to about 5 % of Cmax at 24 h. The pharmacokinetics of dapoxetine and its metabolites were not affected by repeated daily dosing, and steady-state plasma concentrations were reached within 4 days, with only modest accumulation of dapoxetine (approximately 1.5-fold). Food does not have a clinically significant effect on dapoxetine pharmacokinetics.

No drug-drug interactions associated with dapoxetine have been reported. Coadministration of dapoxetine with ethanol did not produce significant changes in the pharmacokinetics of dapoxetine and its metabolites. Drug interaction studies demonstrate that tadalafil, a phosphodiesterase-5 inhibitor used in the treatment of ED, did not affect the pharmacokinetics of dapoxetine, whereas sildenafil increased the dapoxetine AUC by 22 %. However, this was not regarded as clinically important. Dapoxetine did not appear to affect the pharmacokinetics of tadalafil or sildenafil.

The data from a postmarketing observational study from Mirone et al. demonstrate that dapoxetine for treatment of PE has a good safety profile and low prevalence of TEAEs in routine clinical practice. Key study design features that differed from previous phase 3 studies in the clinical development programme were a lack of strict patient-exclusion criteria (e.g. age <18 years, comorbid erectile dysfunction, psychiatric or CV disorders) and the ability of participating physicians to select the starting dose of dapoxetine and adjust the dosage during the course of the study.

An important strength of this study was the thorough and comprehensive collection of adverse event data. Compared with former studies, fewer patients were lost to follow-up (6.2 % vs. 3.9 %, respectively), and fewer patients prematurely withdrew from the study because of the onset of a side effect induced by the drug (approximately 31 % vs. approximately 11 %, respectively).

Among a total of 6,081 subjects in the phase 3 studies, of whom 4,224 subjects were treated with dapoxetine, the incidence of syncope was similar in patients receiving placebo and in those treated with dapoxetine 30 mg (0.05 % vs. 0.06 %, respectively), although greater in subjects treated with the 60 mg dose (0.23 %). In comparison, based on this large observational study of 6,128 patients treated with dapoxetine, it was observed that the incidence of syncope was zero, with the upper bound of the 95 % confidence limit around 2.0 per 1,000 person-years. One syncope case (alternative care/nondapoxetine) occurred in the context of 3,315 patients (<0.1 %) and was generally consistent with the literature reports of a background rate of vasovagal syncope of 1.31–6 per 1,000 person-years and 0.13 % per patient.

The efficacy of on-demand tramadol in the treatment of PE was recently reported. Tramadol is a centrally acting synthetic opioid analgesic with an unclear mode of action which is thought to include binding of the parent compound and M1 metabolite to μ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin. Serotonin syndrome has been reported as an adverse effect of tramadol alone or in combination with SSRI class drugs. In this double-blind, placebo-controlled study, the on-demand use of 50 mg tramadol, taken 2 h prior to intercourse, exerted a clinically relevant ejaculation delay in men with PE with a 12.7 fold increase in IELT [91]. Additional flexible dose studies and long-term follow-up studies to evaluate the risk of opioid addiction are required.

The use of topical local anaesthetics such as lignocaine and/or prilocaine as a cream, gel or spray is well established and is moderately effective in retarding ejaculation. A recent study reported that a metered-dose aerosol spray containing a eutectic mixture of lidocaine and prilocaine produced a 2.4 fold increase in baseline IELT and significant improvements in ejaculatory control and the sexual quality of life of both patients and their partners. They may be associated with significant penile hypoanaesthesia and possible transvaginal absorption, resulting in vaginal numbness and resultant female anorgasmia unless a condom is used.