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."
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.
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.
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.
New Findings in Treatment Options of Premature Ejaculation