The introduction of effective oral agents for the treatment of erectile dysfunction (ED) has heightened the awareness and interest of both the lay public and healthcare professionals on the topic of sexual dysfunction. Along the same lines, the observation of delayed ejaculation as a consequence of some serotonergic antidepressant medications has stimulated increased interest in the use of this class of agents for the treatment of premature ejaculation (PE).

Premature ejaculation was long thought to be a learned behaviour or conditioned response resulting from early sexual experiences that were rushed and associated with anxiety. Anxiety activates the sympathetic nervous system, lowers the ejaculatory threshold, and increases the release of adrenalin, which further contracts the smooth muscle of the penis and causes secondary erectile dysfunction. Early behavioural strategies instituted by psychologists and sex therapists included psychoanalysis, the Semans "stop-start" method, and Masters & Johnson's "squeeze" technique. Efficacy rates were originally reported as 60% to 95%; however, clinical research over time revealed success rates declining to less than 25% at 3 years after treatment cessation. Disadvantages of behavioural therapy include cost, time-consuming sessions, commitment by the partner, and stability of the relationship.

Premature ejaculation and the consequences of ejaculating too soon have been referenced in the literature for many years. In a study to evaluate the impact of premature ejaculation on men's self-confidence, self-esteem, and relationship satisfaction, the 14-item validated Self-Esteem & Relationship (SEAR) questionnaire was administered to 207 men diagnosed with premature ejaculation and 1,380 men without premature ejaculation at different time points. SEAR subscales included sexual relationship (8 items); self-esteem (3 items); confidence (6 items); and overall relationship (2 items). Overall results revealed those men with premature ejaculation exhibit significantly lower self-esteem and confidence, and more sexual and overall relationship difficulties than men without premature ejaculation.

Over the past 3 decades, clinical investigators have attempted to establish a standardized definition of premature ejaculation to use in studies on the prevalence, etiology, and impact of premature ejaculation on quality-of-life for both patient and partner. The American Urological Association (AUA) guideline committee provides the following succinct working definition:

"Premature ejaculation is ejaculation that occurs sooner than desired, either before or shortly after penetration, causing distress to either one or both partners."

Diagnosis
There are no specific medical laboratory tests for premature ejaculation. The only objective criterion for PE that has been globally accepted is a nonexistent or severely shortened intravaginal ejaculatory latency time (IELT). This translates simply into ejaculation that occurs after intromission and "too soon." Subjective criteria have focused on 3 parameters: (1) reduced control over ejaculation; (2) decreased patient and/or partner satisfaction with intercourse, and (3) patient and/or partner distress or bother about the condition. Few men and/or their partners can define a "normal" time to ejaculation. In one 4-week, multicenter, US observational study in males at least 18 years of age with and without premature ejaculation, data was collected from both men and their partners, including IELT, using a stopwatch and subjective patient-reported outcome measures. This study included 207 men with premature ejaculation diagnosed using the DSM-IV TR criteria and 1380 men without premature ejaculation. Stepwise logistic regression analysis was used to determine the significant factors associated with the diagnosis of premature ejaculation and were identified as: control over ejaculation, personal distress, and IELT less than 2 minutes. While IELT does discriminate between men with and without premature ejaculation, substantial overlap between these groups exists when IELT is used alone. Discrimination between men with and without premature ejaculation is enhanced substantially when the 2 subject-reported measures (control of ejaculation and personal distress) are used in combination with IELT in a clinical evaluation.

While stopwatch IELT is mandated for use in clinical trials, estimated IELT is more commonly used in clinical practice. A study was performed to determine the how closely objective measurement of IELT matches estimated IELT. From observations of 207 men with premature ejaculation and 1380 men without premature ejaculation, each subject was asked to estimate his IELT at the first study visit. Following this visit, subjects and partners were provided with a stopwatch and event log. The IELT of each episode of sexual intercourse during the ensuing 2-week study interval was measured and recorded by the female partner. The results showed both premature ejaculation and non-premature ejaculation subjects slightly overestimated their IELT compared with the stopwatch-recorded IELT. For subjects with premature ejaculation, the mean measured value of IELT was 1.8 minutes and the mean estimated value was 2.0 minutes. For subjects without premature ejaculation mean measured value was 7.3 minutes and estimated value was 9.0 minutes. Hence, patient-estimated IELT is generally reliable (although slightly high) and for clinical purposes a stopwatch-assessment is not mandatory.

Epidemiology
According to a number of academic and pharmaceutical-company-sponsored epidemiologic studies, premature ejaculation affects an estimated 25% to 35% of men aged 18 to 59 years. In a corresponding community practice-based study, 614 men were asked to complete 13 demographic questions and the 32-question Male Sexual Health Questionnaire (MSHQ). Premature ejaculation was the most common sexual dysfunction (32.7% of men), with erectile dysfunction (10.6%) and decreased libido (10.3%) ranked second and third. Men with premature ejaculation were found to be significantly less likely to be satisfied with their overall sexual relationship, quality of sex life, and their overall partner relationship.

Topical Treatment
Besides the behavioural approaches mentioned previously, clinicians have focused on topical and medical treatments of premature ejaculation. Topical treatments (anesthetics and SS-cream) appear to increase IELT, but are associated with mild local adverse effects (AEs), may be messy, can be indiscreet, and require partner cooperation. Frequent use can lead to anorgasmia, anejaculation, and genital numbness in the female. PDE5 inhibitors are effective in the treatment of secondary premature ejaculation when caused by mild erectile dysfunction. By improving a man's failing erections, it is hypothesized that his anxiety is reduced, thereby alleviating his secondary premature ejaculation.

Pharmacologic Treatment
Selective serotonin reuptake inhibitors (SSRIs), which were found to delay ejaculation, have been used off-label for the treatment of premature ejaculation for the last 1 to 2 decades. The optimal dose and regimens for these agents for the treatment of premature ejaculation have not been established; however, data show greater success with chronic vs on-demand (PRN) dosing. However, chronic use of SSRIs is associated with a variety of AEs, including dry mouth, nervousness, gastrointestinal upset, diarrhea, headache, drowsiness, and restlessness.

The ideal drug for premature ejaculation should have a number of characteristics: (1) its use should be discreet, preferably oral; (2) it would have a rapid onset of action (< 1 hour), rapid elimination, and minimal accumulation; (3) it should have good tolerability with few AEs; (4) it should be effective on demand, without requiring chronic use or a loading dose; and (5) it should have demonstrated efficacy on IELT and patient-related outcomes in large-scale, long-term, placebo-controlled trials.

In a community-based practice study 32.7% (201/614) of men reported premature ejaculation. None of the men with self-declared PE in this study were currently seeking a treatment, but most (80%) reported that if they sought treatment for PE, their primary goal would be sexual satisfaction for both themselves and their partner. Eighty-one percent reported that a pill to prolong IELT would be their treatment of choice.

Dapoxetine
Dapoxetine hydrochloride is the first oral compound developed specifically for the treatment of premature ejaculation. In preclinical studies, dapoxetine was found to be a potent inhibitor of serotonin reuptake and is considered by authorities in the field to be a serotonin transporter inhibitor.

In experimental animal studies, researchers from Paris, France, evaluated the emission and expulsion phases of ejaculation using p-chloroamphetamine-induced ejaculation in anesthetized rats. Different doses of intravenous dapoxetine reduced both the emission and expulsion phases in a dose-dependent manner. Similar experiments in the same anesthetized-rat model were conducted to elucidate the drug's mechanism of action. These studies revealed that dapoxetine worked by increasing the pudendal motor neuron reflex latency period.

Dapoxetine has previously demonstrated its efficacy in the treatment of premature ejaculation in 2 identically designed, double-blind, randomized, placebo-controlled, 12-week phase III trials. An open-label, long-term (1 year) on-demand study of dapoxetine efficacy was presented. Of the 1774 men enrolled in the 3-month studies (placebo, dapoxetine 30 mg and 60 mg) all were provided with dapoxetine 60 mg to be taken as needed 1 to 3 hours before sexual intercourse. Patients were evaluated at 1, 2, 3, 6, and 9 months in this extension study. The final results showed that the improvements in satisfaction with sexual intercourse, control of ejaculation, symptom severity, and benefit from the medication were maintained through the duration of the study.

Further analysis of the data sets from different groups of researchers revealed that dapoxetine equally improved IELT in men with both acquired and lifelong premature ejaculation. Additionally, men with premature ejaculation who had the lowest IELTs appeared to benefit most. Men with a baseline IELT < 30 seconds had a 6.8-fold increase; those with a baseline IELT > 30 seconds and < 1 minute had a 4.4-fold increase; and those with baseline IELT > 1 minute and = 2 minutes had a 3.2-fold increase.

Additional studies involving dapoxetine showed minimal food effects. Mean maximal plasma concentrations of dapoxetine decreased slightly after a high-fat meal, from 443 ng/mL (fasted) to 398 ng/mL (fed), and were delayed by approximately 0.5 hours following a high-fat meal (1.3 hours fasted, 1.63 hours fed). There was no effect of food on elimination of this agent, with < 5% of peak plasma concentration being present 24 hours after oral administration. Interestingly, the most frequent AE with dapoxetine is nausea, which was decreased after a high-fat meal (24% of fasted and 14% of fed subjects). Perhaps a complete steak dinner will be required with this medication for the patients who complain of nausea.

The question of daily dosing and accumulation was reported in a study of 42 healthy males. Dapoxetine was rapidly absorbed with mean maximal plasma concentrations achieved at 1.01 and 1.27 hours after single doses of dapoxetine 30 and 60 mg. With repeated daily dosing, steady-state plasma concentrations were reached within 4 days, with modest accumulation (1.5-fold). Elimination of dapoxetine was rapid and biphasic, with initial and terminal half-lives of 1.4 and 20 hours. The authors concluded that the pharmacokinetic profile of dapoxetine is ideally suited to an on-demand oral therapy for premature ejaculation.

Educational Need
Even though premature ejaculation is the most common male sexual dysfunction, it seems to be under-reported by patients and underestimated by physicians. There have been 2 large surveys conducted -- one that looked at the prevalence and attitudes regarding premature ejaculation among 11,543 men from the United States, Germany, and Italy, and another querying 271 physicians (primary care physicians, urologists, and psychiatrists) from the United States, Germany, Italy, and Mexico.. Seventy-two percent of men with self-reported PE claimed significant worry about their ability to last during intercourse, with 59% reporting frustration at climaxing too soon. In contrast, > 90% of physicians thought that premature ejaculation caused only minor or no distress to their patients. Approximately 12% of men stated that they had consulted a physician for this condition, with 80% claiming to have initiated the conversation and 85% reporting little or no improvement from this medical interaction. Obviously medical enlightenment is needed.