Pharmacological Treatment Of Premature Ejaculation Research Articles

Physiology and Pharmacology of Ejaculation.

Ejaculation is the final stage of coitus in mammalian male and is mandatory for natural procreation. Two synchronized phases, emission and expulsion, form the ejaculatory response and involve specific organs and anatomical structures. The peripheral events leading to ejaculation are commanded by autonomic (sympathetic and parasympathetic) and somatic divisions of the nervous system. The autonomic and somatic motor efferents originate in spinal nuclei located in thoracolumbar and lumbosacral segments. Co-ordinated activation of autonomic and somatic spinal nuclei is orchestrated by a group of lumbar spinal interneurons defined as the spinal generator of ejaculation. The generator of ejaculation together with the autonomic and somatic spinal nuclei constitutes a spinal network that is under the strong influence of stimulating or inhibiting genital sensory and supraspinal inputs. A brain circuitry dedicated to ejaculation has been delineated that is part of a more global network controlling other aspects of the sexual response. This circuitry includes discrete neuronal populations distributed in all divisions of the brain. The corollary to the expanded CNS network is the variety of neurotransmitter systems participating in the ejaculatory process. Among them, serotonin neurotransmission plays a key role and its targeting led to the development of the first registered pharmacological treatment of premature ejaculation in human beings. Critical gaps remain in the understanding of neurophysiopharmacology of ejaculation and management of ejaculatory disorders in human beings needs improvement. Because the ejaculatory response in laboratory animals and in human beings shares many similarities, the use of animal models will certainly provide further advances in the field.

The characterization, current medications, and promising therapeutics targets for premature ejaculation.

Premature ejaculation (PE) is the most prevalent male sexual dysfunction. This is associated with negative personal and interpersonal psychological outcomes. The pharmacologic treatment of PE includes the use of antidepressants, local anesthetic agents, and phosphodiesterase type 5 inhibitors. While numerous treatments can control PE, only antidepressants and topical anesthetic creams and sprays have recently been shown to be more effective. This review focuses on the physiology and pharmacology of ejaculation, the pathophysiology of PE and the most effective pharmacological treatment of PE. Pharmacotherapy of PE with off-label short-acting selective serotonin reuptake inhibitors (SSRIs) is common, effective, and safe. Dapoxetine, a SSRI with a short half-life, has been recently evaluated for the treatment of PE by several countries and results are promising. In clinical practice, follow-up side effects are an important part of the management strategy for PE. The understanding of etiology, pathophysiology, and treatment modalities of PE would be beneficial to clinician in helping patients with this disappointing sexual problem.

Exposure of Human Seminal Vesicle Tissue to Phosphodiesterase (PDE) Inhibitors Antagonizes the Contraction Induced by Norepinephrine and Increases Production of Cyclic Nucleotides

To investigate further the role of phosphodiesterase (PDE) isoenzymes in the control of human seminal vesicle (SV) smooth muscle contractility, we examined the functional responses of isolated SV tissue to various PDE inhibitors. It has been suggested that the application of inhibitors of the PDE type 5 may facilitate SV smooth muscle relaxation and, subsequently, retard ejaculatory response. Using the organ bath technique, strip preparations of human SV were exposed for 5 minutes to 1 μM of the PDE inhibitors milrinone (PDE3 inhibitor), rolipram, Ro 20-1724 (PDE4 inhibitors), and sildenafil (PDE5 inhibitor). Norepinephrine (NE, alpha agonist) was then added (0,1 μM, 1 μM, and 10 μM) and isometric responses were recorded. A contraction-response curve to NE in the absence of PDE inhibitors was also generated. Drug effects on the production of cyclic adenosine monophosphate (AMP) and cyclic guanosine monophosphate (GMP) were measured by means of radioimmunometric assays. The contraction induced by NE was effectively antagonized by 1 μM of rolipram (83.3% inhibition), Ro 20-1724 (72.3% inhibition), sildenafil (41.6% inhibition), and milrinone (37.5% inhibition). The inhibition of force generation was paralleled by a 1.6-fold to 2.8-fold increase in tissue cyclic AMP (induced by milrinone, rolipram, Ro 20-1724), and a 12-fold rise in cyclic GMP (induced by sildenafil). The findings demonstrate that PDE inhibitors can counteract the contraction of human SV mediated by alpha-adrenergic receptors and enhance levels of cyclic nucleotides. This might be of importance with regard to the identification of new options for the pharmacological treatment of premature ejaculation.

Safety and efficacy of vardenafil versus sertraline in the treatment of premature ejaculation: a randomised, prospective and crossover study

We investigated safety and efficacy of vardenafil and sertraline in premature ejaculation (PE). Seventy-two men graded their primary PE on a scale of 0-8 (0 = almost never, 8 = almost always). Intravaginal ejaculatory latency time (IELT) was measured. Patients were included if they scored their PE as 4 or greater and their IELTs were less than 1.30 min. After 6 weeks of behavioural psychosexual therapy, 49 patients still had a PE of 4 or greater and an IELT less than 1.30 min and they were randomised: 6 weeks vardenafil (10 mg) or sertraline (50 mg). After a wash-out phase for 1 week, medication was changed in a cross-over design. Initially, all 72 men with PE received behavioural therapy. Twenty-three men were satisfied with treatment and excluded. The remaining 49 men graded their PE as 5.94 +/- 1.6 and IELT was 0.59 min and patients were randomised. Four men discontinued the study. Vardenafil improved PE grading: 2.7 +/- 2.1 (P < 0.01) and IELT increased to 5.01 +/- 3.69 (P < 0.001). PE grading improved 1.92 +/- 1.32, (P < 0.01) and IELT 3.12 +/- 1.89 (P < 0.001) with sertraline. It is concluded that vardenafil and sertraline are useful agents in the pharmacological treatment of PE.

Effects of Phosphodiesterase Inhibitors on the Contractile Responses of Isolated Human Seminal Vesicle Tissue to Adrenergic Stimulation

It has been suggested that the capability of the phosphodiesterase 5 (PDE5) inhibitor sildenafil citrate (VIAGRA) to retard the ejaculatory response may include modulation of the contraction of seminal vesicle (SV) smooth muscle. In fact, it has been shown that PDE inhibitors can reverse the tension of isolated human SV tissue and enhance the production of cyclic AMP and cyclic GMP. The aim of this study was to examine the effects of selective phosphodiesterase (PDE) inhibitors on both the spontaneous and electrically induced phasic contractions of isolated human SV smooth muscle. To measure the inhibition exerted by PDE inhibitors vinpocetine (PDE1-inhibitor), rolipram (PDE4-inhibitor), sildenafil, and vardenafil (PDE5-inhibitors) on the phasic contractile response of isolated SV tissue. Using the organ bath technique, the effects of increasing concentrations of the PDE inhibitors (1 nM-10 microM) were investigated on phasic contractions of SV tissue strips either mediated by means of electrical field stimulation (EFS) or the alpha(1)-adrenoceptor agonist norepinephrine. The contractile activity in response to EFS was dose-dependently reversed by the PDE inhibitors. The rank order of efficacy was: rolipram > sildenafil >or= vardenafil > vinpocetine. Mean maximum inhibition of contraction was determined as -89.6% (rolipram), -61.3% (sildenafil), -62% (vardenafil), and -46% (vinpocetine). No differences were registered with regard to the effects of sildenafil and vardenafil on the inhibition of the contraction amplitudes. The frequency of the spontaneous contractions (amplitudes/5 minutes) was reduced by 50% in the presence of 2 microM rolipram, 5 microM sildenafil or vardenafil, and 8 microM vinpocetine. Our results demonstrate that PDE inhibitors can inhibit EFS-induced and spontaneous contractile activity of isolated human SV tissue. These findings might be of importance with regard to the pharmacological treatment of premature ejaculation.

The pharmacological treatment of premature ejaculation

Premature ejaculation (PE) is a common sexual dysfunction in men that is characterized by a short time to ejaculation, and a lack of control over ejaculation, and is associated with distress for men and their partners. Lack of knowledge about the aetiology of PE and lack of approved treatments might contribute to its under-diagnosis and under-treatment. The organic factors involved in PE are not well understood but serotonin (5-hydroxytryptamine, 5-HT) is important at the level of the central nervous system in the complex regulatory mechanisms involved in ejaculation. Selective serotonin reuptake inhibitor (SSRI) antidepressants (paroxetine, fluoxetine and sertraline) and the tricyclic antidepressant clomipramine increase ejaculatory control and delay ejaculation in men with PE, suggesting that pharmacological intervention might be useful for PE. These agents are intended for chronic dosing for treating psychiatric disorders because of their pharmacokinetic profile and pharmacodynamic activity, which might result in limitations when used for treating PE. Indeed, these properties might limit the utility of these drugs, whether administered on-demand or chronically, for the episodic treatment requirements of PE. Elevated synaptic 5-HT levels achieved with acute SSRI treatment might be self-limiting because of activation of presynaptic 5-HT(1A) autoreceptors, and chronic 5-HT(1A) autoreceptor desensitization might contribute to an increase in side-effects and withdrawal symptoms. Short-acting SSRIs such as dapoxetine, currently under development for the on-demand treatment of PE, might circumvent these limitations and offer better ejaculatory control and sexual satisfaction for men with PE. Phosphodiesterase-5 inhibitors have also been evaluated for treating PE, as have topical anaesthetics and the narcotic analgesic tramadol.

Brain oxytocin receptors mediate ejaculation elicited by 7‐hydroxy‐2‐(di‐N‐propylamino) tetralin (7‐OH‐DPAT) in anaesthetized rats

The involvement of the neuropeptide oxytocin in the control of male sexual responses is documented although its exact mechanisms of action, and especially the site(s) of action, are not fully delineated. In order to clarify this issue, we tested the effects of a peptide oxytocin antagonist delivered through different routes on sexual responses elicited, in anaesthetized male rats, by i.c.v. 7-hydroxy-2-(di-N-propylamino) tetralin (7-OH-DPAT), a dopamine agonist, preferentially active on D3 receptors. Seminal vesicle pressure (SVP) and bulbospongiosus muscle (BS) electromyograms were recorded as physiological markers of emission and expulsion phases of ejaculation respectively and intracavernosal pressure (ICP) was monitored as a physiological marker of erection. When injected i.v., the oxytocin antagonist did not impair 7-OH-DPAT-induced SVP and ICP responses while BS burst frequency was diminished. When delivered i.c.v., the oxytocin antagonist dose-dependently inhibited occurrence of 7-OH-DPAT-induced sexual responses. When delivered intrathecally (i.t.) at the level of the 6th lumbar (L6) segment, but not the 13th thoracic (T13) segment, the oxytocin antagonist reduced the duration of BS responses and the occurrence of ejaculation without impairing ICP responses. Brain oxytocin receptors mediate male sexual responses elicited by i.c.v. 7-OH-DPAT in anaesthetized rats whereas L6 spinal oxytocin receptors only impair the occurrence of ejaculation. Peripheral oxytocin receptors are marginally involved in 7-OH-DPAT-induced sexual responses. These findings should be considered for the development of potential pharmacological treatment of premature ejaculation in man.

Pharmacological treatment of premature ejaculation

Premature ejaculation (PE) is currently the most common male sexual complaint. Despite its frequency, there is a lack of universally accepted definition, etiology and treatment. Recently, however, new proposals for the DSM-V classification have been proposed. In 1960’s, premature ejaculation was considered a learned behavior that had to be treated by behavioral therapy, such as the so-called stop–start technique. The efficacy of this method was questioned. Physicians have always looked for medication that could delay ejaculation. Many studies, controlled and open label, have now clearly shown that PE can be treated quickly and effectively with clomipramine and SSRI’s. Clomipramine can be given in doses of 10–50 mg daily. Paroxetine can be prescribed as 10–20 mg daily. In certain cases, combination of both medications can be prescribed to patients. Daily dosing is preferred so as to promote spontaneity in sexual relations. Guidelines for the pharmacological treatment of PE were developed.

Interview with Dr François Giuliano New Avenues in the Pharmacological Treatment of Premature Ejaculation

Interview with Dr François Giuliano New Avenues in the Pharmacological Treatment of Premature Ejaculation

The efficacy of duloxetine in the treatment of premature ejaculation

Though premature ejaculation (PE) has been overshadowed by current attention given to erectile dysfunction, it is the most widespread form of male sexual dysfunction. Delayed or inhibited ejaculation, a known side effect of selective serotonin reuptake inhibitors (SSRIs), has made SSRIs potentially useful in the treatment of this disorder. In the present study, we examined the efficacy of duloxetine, an SSRI, in the treatment of PE. The study included 20 married patients diagnosed with PE. The patients were randomly assigned to two groups, duloxetine (group I) and placebo (group II), each consisting of 10 patients. The effects on the ejaculatory function were estimated by the intravaginal ejaculation latency time. All patients were evaluated by using clinical global impression-improvement Scale (CGI-I). The increase in the intravaginal ejaculation latency time in the duloxetine group was statistically significant than that of placebo group. Of group I patients, four (40%) were considered as "very much improved" and four (40%) "much improved" by CGI-I and only one of group II patients (10%) showed "much improved". Duloxetine appears to be superior to placebo in the pharmacological treatment of PE when administered on a chronic basis.

A review of controlled trials in the pharmacological treatment of premature ejaculation

Premature ejaculation is a common sexual problem which presents to genitourinary (GU) medicine services. Five main treatment approaches have been used in clinical trials: behavioural therapy, antidepressants, phosphodiesterase-5 (PDE5) inhibitors, topical anaesthetic agents and alpha-blockers. We have carried out a systematic review of published pharmacological trials. All antidepressants appeared to delay ejaculation to some extent at all doses. Anaesthetic creams appeared to be as successful in slowing ejaculation as antidepressants without systemic side-effects, although some patients did experience erectile problems or unpleasant local symptoms. Anecdotally, behavioural therapy is effective and appears to have long-lasting efficacy. There is a need for quality comparative trial of behavioural therapy, topical anaesthetic agents and antidepressants, including appropriate measures of relapse, follow-up and acceptability of continuing long-term treatment.

Guidelines for the pharmacotherapy of premature ejaculation

In the 1960s, premature ejaculation was considered a learned behaviour that had to be treated by behavioural therapy, such as the so-called stop-start technique. The efficacy of this method was questioned. Physicians have always looked for medication that could delay ejaculation. Many studies, controlled and open label, have now clearly shown that rapid ejaculation can be treated quickly and effectively with clomipramine and SSRIs. This article describes the guidelines for the pharmacological treatment of premature ejaculation. These guidelines were developed to ensure that medication are used when clear indications are present.

Pharmacological treatment of premature ejaculation.

Ejaculatory dysfunction is the most common male sexual disorder and premature ejaculation the most common presentation of ejaculatory dysfunction. Convincing data are lacking from controlled clinical studies to support sustainable long term efficacy of psychosexual counselling in the management of premature ejaculation. The pharmacological treatment of premature ejaculation is now receiving increased attention from both physicians with an interest in sexual medicine and from the pharmaceutical industry.

Treatment of premature ejaculation with paroxetine hydrochloride.

To evaluate the efficacy of chronic and 'on demand' administration of paroxetine hydrochloride in the drug treatment of premature ejaculation (PE). Ninety-four normally potent men, aged 18-61 y (mean 39 y) with premature ejaculation were treated between January 1996 and March 1997, with oral paroxetine hydrochloride, a selective serotonin re-uptake inhibitor (SSRI). All men were either married or in a stable relationship. Sixty-four out of ninety-four men (Group A) were initially treated with paroxetine hydrochloride 20 mg administered once daily. Those men who responded with improved ejaculatory control within four weeks, were then treated with 'on-demand' paroxetine hydrochloride (20 mg) administered 3-4 h prior to planned intercourse. The remaining 33 out of 94 men (Group B) were initially treated with 'on-demand' paroxetine hydrochloride 20 mg administered 3-4 h prior to planned intercourse. The mean pre-treatment ejaculatory latency time (ELT) of both group A and B was 0.4 min (range 0-1 min) in 205 intercourses at a frequency of 0.4 intercourses per week. In group A after four weeks of daily administration of paroxetine, the mean ELT was 4.5 min (range 1-anejac.) in 761 intercourses at a frequency of 2.4 intercourses per week. Fifty-three out of sixty-one men in group A regarded their ejaculatory control as improved and were then treated with 'on-demand' paroxetine, achieving an ELT of 3.9 min (range 0-10) in 608 intercourses at a frequency of 2.6 intercourses per week. Thirty-six men in this group of 53 regarded that they had maintained improved ejaculatory control with a mean ELT of 5.5 min (range 2-20 min) after a further four weeks of treatment (P < 0.001). The remaining 17 men reported a recurrence of poor ejaculatory control with a mean ELT of 0.7 min (range 0-2 min). In group B with initial 'on-demand' paroxetine after a mean of 4.5 weeks of treatment, the mean ELT was 1.5 min (range 0-5 min) in 298 intercourses at a frequency of 2.2 intercourses per week. Adverse effects were only recorded in men taking daily paroxetine and included anejaculation in 5 out of 61, inhibited orgasm in 3 out of 61 and reduced libido on 3 out of 61. Erectile dysfunction was not reported and 'on demand' paroxetine was not associated with any adverse effects. Paroxetine hydrochloride appears to be a useful agent in the pharmacological treatment of premature ejaculation when administered on a chronic, an 'on-demand' basis following chronic treatment or initial 'on demand' basis.

TREATMENT OF PREMATURE EJACULATION WITH PAROXETINE HYDROCHLORIDE AS NEEDED: 2 SINGLE-BLIND PLACEBO CONTROLLED CROSSOVER STUDIES

Purpose We evaluate the efficacy of paroxetine hydrochloride as needed for the treatment of premature ejaculation. Materials and Method Study 1 comprised 26 potent men with a mean age of 39.5 years with premature ejaculation who were randomized to receive 20 mg. oral paroxetine (group A) or placebo (group B) as needed 3 to 4 hours before planned intercourse in a controlled single-blind crossover trial. Study 2 comprised 42 potent men with a mean age of 40.5 years with premature ejaculation who were randomized to receive 10 mg. paroxetine daily for 3 weeks and then 20 mg. paroxetine as needed (group C) for 4 weeks or placebo daily for 3 weeks and then placebo as needed (group D) for 4 weeks. Results Mean pretreatment ejaculatory latency time was 0.3 minute for study 1. At 4 weeks mean ejaculatory latency time was 3.2 minutes in the paroxetine as needed and 0.45 in the placebo as needed phase for group A (p <0.001), and 0.6 in the placebo as needed and 3.5 in the paroxetine as needed phase for group B (p <0.001). There were no adverse effects with paroxetine or placebo in study 1. Mean pretreatment ejaculatory latency time was 0.5 minute for study 2. At 3 weeks mean ejaculatory latency time was 4.3 minutes in the paroxetine daily and 5.8 in the paroxetine as needed phase, and 0.9 in the placebo daily and 0.6 in the placebo as needed phase for group C (p <0.001). At 3 weeks mean ejaculatory latency time was 0.8 minutes in the placebo daily and 1.1 in the placebo as needed phase, and 3.3 in the paroxetine daily and 6.1 in the paroxetine as needed phase for group D (p <0.001). Adverse effects in 7 of 42 men (17%) given paroxetine daily included anejaculation in 3, anorexia in 1, gastrointestinal upset in 3 and reduced libido in 2. Mean ejaculatory latency time was greater in the paroxetine as needed phase of study 2 than that of study 1 (p <0.05). suggesting that ejaculatory control achieved with paroxetine as needed is significantly better if patients are initially treated with the drug daily. Conclusions Paroxetine appears to be superior to placebo in the pharmacological treatment of premature ejaculation when administered on a chronic or as needed basis.

TREATMENT OF PREMATURE EJACULATION WITH SERTRALINE HYDROCHLORIDE: A SINGLE-BLIND PLACEBO CONTROLLED CROSSOVER STUDY

Purpose The efficacy of sertraline hydrochloride for the treatment of premature ejaculation is evaluated. Materials and Methods A total of 37 potent men, 19 to 70 years old (mean age 41), with premature ejaculation were treated with 50 mg. oral sertraline and placebo in a controlled randomized single-blind crossover trial. All men were either married or in a stable relationship. None of the patients received any formal psychosexual therapy. Chronic open label treatment with sertraline was continued in 29 patients who had achieved an increase in ejaculatory latency times over pretreatment levels with active drug in the initial crossover study. In an attempt to identify which patients could maintain the improved ejaculatory control after withdrawal of the active drug, serial drug withdrawal was conducted every 4 weeks with drug initiation after a further 2 weeks if improved ejaculatory control was not maintained. Results The mean pretreatment ejaculatory latency time was 0.3 minute (range 0 to 1). The mean ejaculatory interval after 4 weeks of treatment was 3.2 minutes (range 1 minute to anejaculation) with sertraline and 0.5 minute (range 0 to 1) with placebo (p <0.001). Intravaginal ejaculation was achieved for the first time in 5 patients with primary premature ejaculation and 2 patients experienced anejaculation. One patient described minor drowsiness and anorexia, and 2 patients described mild, transient gastrointestinal upset. Staged drug withdrawal allowed 20 of the 29 patients (67%) on chronic open label treatment with sertraline to discontinue the drug after a mean interval of 7.3 months with a mean ejaculatory latency time of 4.1 minutes (range 1 to 12). Conclusions Sertraline appears to be a useful agent in the pharmacological treatment of premature ejaculation.