Perceived control over ejaculation is central to treatment benefit in men with premature ejaculation: results from phase III trials with dapoxetine

OBJECTIVES

To assess the utility of perceived control over ejaculation (‘control’) in the evaluation of treatment benefit in men with premature ejaculation (PE), and to compare effects associated with a two‐category or greater increase in this variable between men receiving dapoxetine and placebo.

PATIENTS AND METHODS

This subanalysis used combined data from all treatment groups in an integrated analysis of two identically designed, 12‐week, double‐blind, randomized, placebo‐controlled trials of dapoxetine. Men (2614) met the Diagnostic and Statistical Manual of Mental Disorders (fourth edition, text revision) criteria for PE, had a stopwatch‐measured intravaginal ejaculatory latency time (IELT) of ≤2 min in ≥75% of events in a 2‐week baseline period, and self‐reported moderate or severe PE. Men received placebo or dapoxetine 30 or 60 mg, 1–3 h before intercourse. The stopwatch‐measured IELT was recorded for each episode; the patient‐reported global impression of change (PGI; 7‐point scale, ‘much worse’ to ‘much better’), control and satisfaction with sexual intercourse (5‐point scales, ‘very poor’ to ‘very good’) were assessed monthly. The utility of a two‐category or greater increase in control was evaluated by examining the relationship of this variable with IELT and satisfaction with sexual intercourse.

RESULTS

Of 2341 men with baseline and endpoint assessments, 96.8% reported ‘very poor’ or ‘poor’ control at baseline, and 748 (32%) reported a two‐category or greater increase in control after treatment. More than 95% of those men rated their PE as ‘slightly better’, ‘better’, or ‘much better’ on the PGI; 67.1% gave ratings of ‘better’ or ‘much better.’ They also had greater improvements in IELT than men with less than a two‐category increase in control, with a mean (sd ) change from baseline of 3.7 (4.3) vs 0.77 (1.8) min, respectively, and a greater percentage reported good or very good satisfaction with sexual intercourse than men with less than a two‐category increase in control (74% vs 19%, respectively). Nausea, headache and upper respiratory tract infection were the most common adverse events reported by men with a two‐category or greater increase in control (15.8%, 7.4% and 6.6%, respectively) and those without (8.5%, 5.5% and 6.5%, respectively). The proportions of men with a two‐category or greater increase in control with dapoxetine 30 and 60 mg were 36.3% and 44.5%, respectively (vs 15% with placebo).

CONCLUSIONS

A two‐category or greater increase in control (5‐point scale) is useful for assessing the treatment benefit in men with PE; it corresponds with improvements in the man’s perception of his condition, substantially greater prolongation of IELT, and higher levels of satisfaction with sexual intercourse.     

The Premature Ejaculation Profile: validation of self-reported outcome measures for research and practice

OBJECTIVE

To evaluate the reliability and validity of the Premature Ejaculation Profile (PEP), a self‐reported outcome instrument for evaluating domains of PE and its treatment, comprised of four single‐item measures, a profile, and an index score.

SUBJECTS AND METHODS

Data were from men participating in observational studies in the USA (PE, 207 men; non‐PE, 1380) and Europe (PE, 201; non‐PE, 914) and from men with PE (1238) participating in a phase III randomized, placebo‐controlled clinical trial of dapoxetine. The PEP contains four measures: perceived control over ejaculation, personal distress related to ejaculation, satisfaction with sexual intercourse, and interpersonal difficulty related to ejaculation, each assessed on five‐point response scales. Test‐retest reliability, known‐groups validity, and ability to detect a patient‐reported global impression of change (PGI) in condition were evaluated for the individual PEP measures and a PEP index score (the mean of all four measures). Profile analysis was conducted using multivariate analysis of variance.

RESULTS

All PEP measures showed acceptable reliability (intraclass correlation coefficients ranged from 0.66 to 0.83) and mean scores for all measures differed significantly between PE and non‐PE groups (P < 0.001). Men who reported a reduction in PE with treatment in the phase III trial had significantly greater scores on each of the four measures. The PEP profiles of men with and without PE differed significantly (P < 0.001) in both observational studies; higher levels of PGI were associated with higher PEP profiles (P < 0.001). The PEP index score also showed acceptable reliability and was significantly different between the PE and non‐PE groups (P < 0.001). Men who reported an improvement in PE with treatment in the phase III trial had significantly greater PEP index scores. In the phase III trial, nausea was the most common adverse event with dapoxetine.

CONCLUSION

The PEP provides a reliable, valid, and interpretable measure for use in monitoring outcomes of men with PE.     

An evidence-based definition of lifelong premature ejaculation: report of the International Society for Sexual Medicine Ad Hoc Committee for the Definition of Premature Ejaculation

OBJECTIVE

To develop a contemporary, evidence‐based definition of premature ejaculation (PE).

METHODS

There are several definitions of PE; the most commonly quoted, the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders – 4th Edition – Text Revision, and other definitions of PE, are all authority‐based rather than evidence‐based, and have no support from controlled clinical and/or epidemiological studies. Thus in August 2007, the International Society for Sexual Medicine (ISSM) appointed several international experts in PE to an Ad Hoc Committee for the Definition of PE. The committee met in Amsterdam in October 2007 to evaluate the strengths and weaknesses of current definitions of PE, to critically assess the evidence in support of the constructs of ejaculatory latency, ejaculatory control, sexual satisfaction and personal/interpersonal distress, and to propose a new evidence‐based definition of PE.

RESULTS

The Committee unanimously agreed that the constructs which are necessary to define PE are rapidity of ejaculation, perceived self‐efficacy, and control and negative personal consequences from PE. The Committee proposed that lifelong PE be defined as a male sexual dysfunction characterized by ejaculation which always or nearly always occurs before or within about one minute of vaginal penetration, and the inability to delay ejaculation on all or nearly all vaginal penetrations, and negative personal consequences, such as distress, bother, frustration and/or the avoidance of sexual intimacy. This definition is limited to men with lifelong PE who engage in vaginal intercourse. The panel concluded that there are insufficient published objective data to propose an evidence‐based definition of acquired PE.

CONCLUSION

The ISSM definition of lifelong PE represents the first evidence‐based definition of PE. This definition will hopefully lead to the development of new tools and patient‐reported outcome measures for diagnosing and assessing the efficacy of treatment interventions, and encourage ongoing research into the true prevalence of this disorder, and the efficacy of new pharmacological and psychological treatments.     

Premature ejaculation: results from a five-country European observational study

OBJECTIVES: To characterize premature ejaculation (PE) in five European countries using intravaginal ejaculatory latency time (IELT) and the Premature Ejaculation Profile (PEP). METHODS: This 8-wk, multicenter, observational study enrolled men >or=18 yr of age and their female partners. Clinicians diagnosed PE using the DSM-IV-TR criteria and at least moderate, subject-reported, ejaculation-related personal distress or interpersonal difficulty. The PEP was administered at baseline and weeks 4 and 8. Partners measured IELT; the average stopwatch-measured IELT for each 4-wk period was calculated and compared with the man's screening-estimated IELT. Relationships between individual PEP measures and IELT were assessed with path analysis. RESULTS: PE was diagnosed in 201 of 1115 men. Findings were similar to those in a similarly conducted US study. Mean IELT was lower in the PE versus the non-PE group (3.3 vs. 10.0min, respectively), but substantial overlap was observed. Men with PE and their partners reported significantly worse control over ejaculation, ejaculation-related personal distress, satisfaction with sexual intercourse, and ejaculation-related interpersonal difficulty than men without PE and their partners. Path analysis showed that perceived control over ejaculation had a significant effect on ejaculation-related personal distress and satisfaction with sexual intercourse; IELT had an effect on control over ejaculation, no direct effect on satisfaction with sexual intercourse, and a small direct effect on ejaculation-related personal distress. CONCLUSIONS: No major cultural differences existed between EU and US men with and without PE and their female partners. These results emphasize the importance of the PEP measures, especially perceived control over ejaculation, in characterizing PE.     

A comprehensive assessment of genetic variation in serotonin transporter gene (5-HTTLPR+rs25531) and the response to dapoxetine in Chinese patients with premature ejaculation

This study was to explore whether serotonin transporter gene-linked polymorphic region polymorphisms (5-HTTLPR+rs25531) influence the response to dapoxetine treatment in a Chinese population with premature ejaculation (PE). 112 patients with PE re-enrolled from our previous study received dapoxetine monotherapy. At the endpoint, patients with S’S’ had a significant increased risk of nonresponse compared with L’ carriers (p < .001). The improvement in S’S’ genotype was significantly lower in premature ejaculation profile (PEP) items of ‘control over ejaculation’ (p = .035) and ‘distress related to ejaculation’ (p = .017) than that in L’ carriers. As to clinical global impression of change (CGIC), results in S’S’ subjects showed significantly lower scores (p = .008) and a less satisfaction rate reporting at least ‘better’ (p = .020) compared with L’ carriers. Moreover, our findings suggested that patients with S’S’ were more likely to develop adverse effects (AEs) compared with L’ carriers (p = .040). This study suggests that PE patients bearing the S’S’ genotype have an inferior comprehensive efficacy and safety of dapoxetine treatment, which consist of poorer response in IELTs, less improvement in patient-reported outcome (PRO) measures and greater incidence of AEs, than L’ carriers. Variants of triallelic 5-HTTLPR may play a major role as a predictor of treatment response to dapoxetine.     

Identifying constructs and criteria for the diagnosis of premature ejaculation: implication for making errors of classification

OBJECTIVES

To review the many definitions of premature ejaculation (PE), determine the essential elements that best define PE, and examine and discuss the consequences of errors of inclusion and exclusion in the diagnosis of PE.

METHODS

We reviewed recent evidenced‐based studies that delineate the variables that best define PE, and the relationships between these factors. We then assessed the consequences of errors of measurement, inclusion and exclusion for setting the thresholds for the three variables.

RESULTS

PE can best be defined by a multidimensional set of criteria composed of three essential elements: (i) intravaginal ejaculatory latency time (IELT); (ii) a lack of perceived self‐efficacy or control about the timing of ejaculation; and (iii) distress and interpersonal difficulty related to the ejaculatory dysfunction. After delineating the variables, thresholds for each variable need to be determined. Carefully constructed thresholds attempt to minimize errors of inclusion and exclusion. However, even the best criteria cannot eliminate all error. The two types of errors in classification are, to some extent, inversely related: the more restrictive the criteria, the more likely that there will be errors of exclusion, whereas the more lenient the criteria the more likely there will be errors of inclusion.

CONCLUSION

Research and treatment protocols might use different threshold values for classification, as their goals might be different. For a PE research protocol, we suggest erring on the side of a more narrow definition as it would: (i) provide a more conservative, and we think, realistic prevalence of the disorder; (ii) help to establish PE as a bona fide sexual dysfunction rather than a ‘life‐style’ issue for men seeking to enhance their sexual life; (iii) ensure greater confidence in the efficacy of existing and new treatment approaches; and (iv) strengthen the likelihood of acceptance by the regulatory authorities. Conversely, standard treatment protocols for PE might use more lenient criteria if the treatment has minimal adverse events and the degree of distress of the sufferer is high.     

Dapoxetine for the Treatment of Premature Ejaculation: Results from a Randomized,Double-Blind,Placebo-Controlled Phase 3 Trial in 22 Countries

Background

Dapoxetine is being developed for the on-demand treatment of premature ejaculation (PE). Previous clinical trials have demonstrated its safety and efficacy.

Objective

To evaluate the long-term efficacy and safety of dapoxetine in men with PE.

Design, setting, and participants

This randomized, double-blind, parallel-group, placebo-controlled, phase 3 trial, conducted in 22 countries, enrolled men (N = 1162) ≥18 yr of age who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision criteria for PE for ≥6 mo, with an intravaginal ejaculatory latency time (IELT) ≤2 min in ≥75% of intercourse episodes at baseline.

Intervention

Dapoxetine 30 mg or dapoxetine 60 mg or placebo on demand (1–3 h before intercourse) for 24 wk.

Measurements

Stopwatch-measured IELT, Premature Ejaculation Profile (PEP), Clinical Global Impression (CGI) of change, adverse events (AEs).

Results and limitations

The study was completed by 618 men. Mean average IELT increased from 0.9 min at baseline (all groups) to 1.9 min, 3.2 min, and 3.5 min with placebo and dapoxetine 30 mg and dapoxetine 60 mg, respectively, at study end point; geometric mean IELT increased from 0.7 min at baseline to 1.1 min, 1.8 min, and 2.3 min, respectively, at study end point. All PEP measures and IELTs improved significantly with dapoxetine versus placebo at week 12 and week 24 (p < 0.001 for all). The most common AEs were nausea, dizziness, diarrhea, and headache. AEs led to discontinuation in 1.3%, 3.9%, and 8.2% of subjects with placebo and dapoxetine 30 mg and dapoxetine 60 mg, respectively. Limitations of this study included the exclusion of men who were not in long-term monogamous relationships.

Conclusions

Dapoxetine significantly improved all aspects of PE and was generally well tolerated in this broad population.     

Evolving therapeutic strategies for premature ejaculation: The search for on-demand treatment �C topical versus systemic

Premature ejaculation (PE) is a common sexual dysfunction affecting 20% to 30% of men worldwide. Definitions of PE vary, but it is typically characterized by short intravaginal ejaculatory latency time (IELT) with concomitant sexual dissatisfaction and distress. PE may be lifelong or acquired, but its etiology remains unclear. Treatment of PE typically involves pharmacotherapy, particularly when lifelong. Although there are numerous reports on the off-label use of selective serotonin reuptake inhibitors (SSRIs) and other compounds, only 2 treatments have been evaluated in randomized controlled phase 3 clinical trials: PSD502 and dapoxetine (SSRI). Both significantly improved IELT and patient-reported outcome domains of ejaculatory control, sexual satisfaction, and distress as measured by the index of premature ejaculation (IPE), compared with placebo. They constitute the focus of this review. Evidence demonstrated that PSD502, dapoxetine and other SSRIs all significantly improve the symptoms of PE. Systemic use of SSRIs presents risks associated with the known pharmacology of this class. PSD502 allows for topical on-demand treatment applied applied immediately before intercourse, and is not associated with systemic adverse events.     

Comparison of the clinical efficacy and safety of the on‐demand use of paroxetine,dapoxetine, sildenafil and combined dapoxetine with sildenafil in treatment of patients with premature ejaculation: A randomised placebo‐controlled clinical trial

The aim of the study was to compare the clinical efficacy and safety of the on‐demand use of paroxetine, dapoxetine, sildenafil and combined dapoxetine with sildenafil in treatment of patients with premature ejaculation (PE). In a single‐blind placebo‐controlled clinical study, 150 PE patients without erectile dysfunction (ED) were included during the period of March 2015 to May 2016. Patients were randomly divided into five groups (30 patients each). On demand placebo, paroxetine (30 mg), dapoxetine (30 mg), sildenafil citrate (50 mg) and combined dapoxetine (30 mg) with sildenafil citrate (50 mg) were given for patients for 6 weeks in each group respectively. All patients were instructed to record intravaginal ejaculatory latency time (IELT) and evaluated with Premature Ejaculation Diagnostic Tool (PEDT) and the patient satisfaction score before and after treatment. The mean of IELT, satisfaction score and PEDT in all groups was significantly improved after treatment (p value = .001). Combined dapoxetine with sildenafil group had the best values of IELT, satisfaction scores and PEDT in comparison with other treatment groups (p value <.001). The combined dapoxetine with sildenafil therapy could significantly improve PE patients without ED as compared to paroxetine alone or dapoxetine alone or sildenafil alone with tolerated adverse effects.     

Efficacy and safety of tadalafil in a Western European population of men with erectile dysfunction

Section Editor Michael G. Wyllie Panel of Advisors Ian Eardley, UK Jean Fourcroy, USA Sidney Glina, Brazil Julia Heiman, USA Chris McMahon, Australia Bob Millar, UK Alvaro Morales, Canada Michael Perelman, USA

OBJECTIVE

To evaluate, in a randomized, double‐blind, placebo‐controlled, multicentre trial, the safety and efficacy of on‐demand tadalafil (an oral phosphodiesterase type‐5 inhibitor approved in many countries for treating erectile dysfunction, ED) in a Western European population of men with mild‐to‐severe ED.

PATIENTS AND METHODS

Patients were randomized according to baseline severity of ED in a ratio of 3 : 1 to receive either tadalafil 20 mg or placebo for 12 weeks. Primary efficacy endpoints were mean changes from baseline to endpoint (12 weeks) in the erectile function (EF) domain of the International Index of Erectile Function (IIEF) and percentages of ‘Yes’ responses to Sexual Encounter Profile (SEP) diary Question 2 (‘Were you able to insert your penis into your partner's vagina?’) and Question 3 (‘Did your erection last long enough for you to have successful intercourse?’). Secondary endpoints included mean changes from baseline to endpoint in IIEF Intercourse Satisfaction and Overall Satisfaction domains, selected questions of the IIEF, and the percentage of ‘Yes’ responses to Global Assessment Questions (GAQ) at the last visit. Other analyses included the percentage of patients in each treatment group at endpoint with IIEF EF domain scores in the normal range (>26), the frequency of intercourse attempts and mean per‐patient intercourse success rate at various times after dosing.

RESULTS

The mean age of the patients was 53 years and 80% had a history of ED of ≥ 1 year. The mean baseline EF domain score was 13.5, with 40.5% of patients in the severe category. Tadalafil improved mean EF domain scores by 11.1, vs 0.4 for placebo (P < 0.001). In addition, 73.9% of sexual intercourse attempts were successful (SEP‐Q3) in tadalafil‐treated patients, compared with 29.9% in placebo‐treated patients during the period after baseline (P < 0.001). Tadalafil significantly improved the mean IIEF intercourse satisfaction (5.1, tadalafil; 1.1, placebo) and overall satisfaction domain scores (3.9, tadalafil; 0.5, placebo), P < 0.001. GAQs used to assess the overall effect of the treatment indicated that tadalafil was superior to placebo (P < 0.001) in improving erections (82.1%, tadalafil; 23.1%, placebo) and sexual activity (78.6% and 17.3%). The most common treatment‐emergent adverse events more frequent (>2%) with tadalafil than placebo were headache, dyspepsia, flushing, back pain, pain in limb and myalgia. These adverse events were mostly mild to moderate.

CONCLUSIONS

Tadalafil improved erectile function and was well tolerated when taken by men from Western Europe with mild‐to‐severe ED.

     

Treatment of premature ejaculation: new drugs and treatment strategies

This review discusses treatment options for men with premature ejaculation (PE), a common sexual dysfunction characterized by short ejaculatory latency, decreased sexual satisfaction, and distress. For a number of reasons, including embarrassment and the belief that PE is a normal part of aging, has no effective treatment, or will resolve itself, few men with PE seek treatment. Although several treatment options exist (eg, behavioral, cognitive, and sex therapy methods; desensitizing drugs; off-label use of antidepressants and/or phosphodiesterase type 5 inhibitors or α-blockers), the majority of men with PE generally are not satisfied with their results. New pharmacologic drugs, specifically for the treatment of PE, are undergoing evaluation in clinical trials. As an example, recent clinical research studies have revealed on-demand administration of one such drug, dapoxetine, which achieved significant improvements in ejaculatory latency, control over ejaculation, and satisfaction with sexual intercourse. In addition, partners of men who received dapoxetine likewise reported improved satisfaction with sexual intercourse. Future studies may reveal that integration of pharmacologic drugs with psychologic and/or behavioral therapy techniques may be the optimal approach to the management of PE. PE is a treatable condition, and new drugs in development may provide benefits over those available.     

PSD502 improves ejaculatory latency,control and sexual satisfaction when applied topically 5 min before intercourse in men with premature ejaculation: results of a phase III,multicentre, double‐blind,placebo‐controlled study

OBJECTIVES

To determine the effect of PSD502 applied topically 5 min before intercourse on the Index of Premature Ejaculation (IPE) and intravaginal ejaculatory latency time (IELT) of men with lifelong premature ejaculation (PE) defined according to the International Society of Sexual Medicine (ISSM) definition; secondary objectives were to evaluate the safety and tolerability of PSD502 in patients with PE, and their sexual partners.

PATIENTS AND METHODS

Men aged >18 years, in stable heterosexual, monogamous relationships, and with lifelong PE diagnosed according to both the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (text revision) criteria and the ISSM definition, consented (together with their partners) to enter the baseline period of the study. Patients who documented an IELT of ≤1 min with two or more of the first three sexual encounters during the 4‐week baseline period were randomized, in a 2:1 ratio, to receive double‐blind treatment with PSD502 (three actuations of spray each containing 7.5 mg lidocaine and 2.5 mg prilocaine applied 5 min before intercourse) or placebo for 3 months. Patients completed IPE and Premature Ejaculation Profile (PEP) questionnaires at entry and at monthly clinic visits, and recorded stopwatch‐timed IELT during each sexual encounter. Patients rated the quality of their orgasms on a 5‐point scale at baseline and at the end of the treatment period, and rated the study medication on a 4‐point scale. Safety was assessed by collecting adverse event data.

RESULTS

In all, 300 men with PE were randomized from 31 centres in Europe. The geometric mean (range) IELT over the 3‐month treatment period increased from a baseline of 0.6 min in both groups to 3.8 (0.3–57.8) and 1.1 (0–15.0) min in the PSD502 and placebo groups, respectively. Adjusting for treatment‐group imbalances, this represents a 6.3‐fold and 1.7‐fold increase in adjusted geometric means. There were significantly greater increases in the scores for the IPE domains of ejaculatory control and sexual satisfaction in the PSD502 group than in the placebo group, with a mean (sem ) 7.0 (0.59)‐point difference between treatments in change from baseline in the IPE domain for ejaculatory control and a 5.9 (0.57)‐ point difference in change from baseline in the IPE domain for sexual satisfaction (both P < 0.001). This was supported by improvements in all secondary endpoints. At the end of the treatment period 66% of patients rated PSD502 as ‘good’ or ‘excellent’. PSD502 was well tolerated and no systemic adverse events were reported. Localized treatment‐related adverse events were reported by 2.6% and 3.1% of patients and partners, respectively.

CONCLUSION

PSD502 applied topically 5 min before intercourse improved ejaculatory latency and significantly improved ejaculatory control and sexual satisfaction, factors relevant for acceptance of a PE treatment by both patient/physician and regulatory authorities. PSD502 was well tolerated by both patients and partners, with no systemic side‐effects and a low incidence of localized effects, and was rated favourably by most users. PSD502 therefore appears to offer significant advantages over other therapies in development for the treatment of PE.     

The effects of three phosphodiesterase type 5 inhibitors on ejaculation latency time in lifelong premature ejaculators: a double-blind laboratory setting study

Study Type – Therapy (RCT)
Level of Evidence 1b What’s known on the subject? and What does the study add? Several authors have reported their experience with PDE5 inhibitors alone or in combination with selective serotonin re‐uptake inhibitors for treating premature ejaculation. However, to our knowledge, this is the first laboratory design study to evaluate the effects of three PDE5 inhibitors throughout the ejaculation process in men with lifelong premature ejaculation. In this laboratory setting study PDE5 inhibitors seem to prolong ELT but the difference from placebo is significant only in vardenafil. The quality of penile rigidity is better with PDE5 inhibitors in the post‐ejaculatory period but the difference is significant only in sildenafil and vardenafil.

OBJECTIVE

? To evaluate the effects of three phosphodiesterase type 5 (PDE5) inhibitors on the ejaculation process in men with lifelong premature ejaculation using a double‐blind laboratory setting.

PATIENTS AND METHODS

? Eighty men with lifelong premature ejaculation, 20 in each group, received placebo, vardenafil (10 mg), sildenafil (50 mg) or tadalafil (20 mg) in a double‐blind study design. Placebo or PDE5 inhibitor was ingested after at least 2 h fasting and non‐smoking. The subjects were placed in a silent room immediately and real‐time penile rigidity and tumescence was monitored. ? Subjects read some magazines or newspapers without any sexually stimulating material for 1.5 h. At the end of this period audiovisual sexual stimulation began with a video film and after the 8th minute the subject began vibratory stimulation to the frenular area. ? At the beginning of ejaculation the patient stopped stimulation. When the patient began and stopped stimulation, the light near the observer turned on and off and the observer calculated the ejaculation period with a chronometer. The elapsed time was the ejaculation latency time (ELT) in seconds. ? There was no interaction between subjects and observer during the test. The ELT, and the qualities of base and tip rigidities during ELT and after ejaculation were calculated.

RESULTS

? Median age of patients was 29 (range 22–39) years and median duration of premature ejaculation was 60 (range 7–180) months and there was no significant difference between groups. Median duration of vibratory stimulation (ELT) of subjects who received placebo was 48.5 s: 53.5 s for sildenafil, 70.0 s for tadalafil and 82.5 s for vardenafil. Compared with the placebo group, ELT was significantly longer only in subjects receiving vardenafil (P = 0.019). ? In the post‐ejaculatory refractory period, times to last recorded base rigidities were significantly longer than placebo in vardenafil and sildenafil groups with better erection quality (P < 0.01 for each).

CONCLUSIONS

? The PDE5 inhibitors seem to prolong ELT and the quality of penile rigidity is better with PDE5 inhibitors in post‐ejaculatory period. ? These findings suggest that PDE5 inhibitors might have some beneficial effects in men with lifelong premature ejaculation.     

Relationship between premature ejaculation and genetic polymorphisms of the dopamine transporter gene (SLC6A3)

What’s known on the subject? and What does the study add? The process of ejaculation is highly influenced by genetic and neurobiological factors. Central dopaminergic drugs facilitate ejaculation. Genetic variation in SLC6A3 may alter the expression of dopamine transporter gene (DAT). This study evaluated the associations between genetic polymorphisms of the DAT and PE. A statistically significant association was observed between the presence of 9‐repeat allele and 9/10 genotype and PE. The presence of 7‐repeat allele had protective effect against PE.

OBJECTIVE

? To investigate the possible relationships between premature ejaculation (PE) polymorphisms in the dopamine transporter (DAT) gene (SLC6A3, DAT1), which has a polymorphic 40 base pair (40 bp) variable number of tandem repeats (VNTR) sequence in the 3′‐untranslated region (3′ VNTR).

PATIENTS AND METHODS

? Cohorts of 270 Iranian men with PE and 266 age‐matched healthy Iranian subjects were genotyped for the DAT1‐VNTR polymorphism.

RESULTS

? The 10‐repeat allele frequencies were similar in the control (90.2%) and patient groups (88.5%) (P = 0.8). ? A statistically significant association was observed between the presence of the nine‐repeat allele and PE (chi‐squared test = 4.346, odds ratio [OR] = 2.46, 95% confidence interval [CI] = 1.57–3.15, P = 0.026). ? The frequencies of the 9/10 genotype were also significantly higher in the PE patients than in normal controls (chi‐squared test = 4.466, OR = 2.47, 95% CI = 1.52–3.21, P = 0.028). The presence of the seven‐repeat allele had a protective effect against PE (chi‐squared test = 2.324, OR = 0.62, 95% CI = 0.47–0.89, P = 0.034).

CONCLUSIONS

? The findings of the present study suggest that DAT1‐VNTR polymorphisms resulting in higher dopamine concentrations were associated with vulnerability to PE. ? Further studies are needed to replicate these results and to evaluate the role of inconsistency in the DAT genes and how this affects the development of PE.     

A Novel Treatment of Premature Ejaculation

The investigation of the etiology and treatment of premature ejaculation (PE), a common and significant problem for men and their partners, has been limited by the lack of defined outcomes and differences in clinical trial designs. Currently, no medication has been approved for the treatment for PE worldwide. Recognition of serotonin as a key mediator in ejaculatory signaling has raised interest in the utility of pharmacologic intervention for treating PE. Selective serotonin reuptake inhibitors (SSRIs) have been used off-label for PE, with varied results. However, treatment with currently available SSRIs typically requires chronic dosing that increases drug accumulation and the attendant risk of adverse events. Dapoxetine is an SSRI with a short half-life (1.2 h), developed specifically for the treatment of men with PE. This agent has a unique pharmacokinetic profile characterized by rapid absorption and elimination. Dapoxetine is metabolized by multiple pathways, and no clinically relevant drug–drug interactions have been identified. Furthermore, dapoxetine pharmacokinetics do not appear to be affected by food, age, alcohol, or phosphodiesterase type 5 (PDE5) inhibitors to a relevant degree. In two placebo-controlled phase 3 trials involving >2600 men with PE, dapoxetine 60 mg given as needed over 12 wk significantly prolonged the stopwatch-assessed intravaginal ejaculatory latency time (IELT) from 0.91 min at baseline to 3.32 min (p < 0.0001), increased control over ejaculation, and increased sexual satisfaction for men and their partners compared with placebo (both p < 0.0001). These results suggest that dapoxetine may meet the medical need for on-demand therapy for PE.     

The effects of phosphodiesterase type 5 inhibitors on penile rigidity variables during a period with no sexual stimulation: a laboratory setting double‐blind study

Study Type – Therapy (RCT)
Level of Evidence 1b What’s known on the subject? and What does the study add? There is a positive effect of PDE5 inhibitors on several aspects of the men’s sex lives, chiefly erectile function, personal self‐esteem, and satisfaction from their sex lives. To our knowledge, our study is the first study to evaluate the effects of PDE5 inhibitors on erectile variables simultaneously in a laboratory setting. In the present study, significant penile rigidities were obtained with PDE5 inhibitors in a short period, with no sexual stimulation, in laboratory conditions. Our findings might support the use of PDE5 inhibitors in the men who need penile rehabilitation.

OBJECTIVE

To investigate the effects of phosphodiesterase type 5 (PDE5) inhibitors on erectile variables during a period with no sexual stimulation in a laboratory setting double‐blind study.

PATIENTS AND METHODS

In all, 80 men without erectile dysfunction (ED) but with lifelong premature ejaculation (PE) were included in the study. The men were divided equally in to four groups and received either placebo, vardenafil (10 mg), sildenafil (50 mg) or tadalafil (20 mg) in a double‐blind study design. The men attended the laboratory following 3 days of sexual abstinence and placebo or one of the PDE5 inhibitors was ingested after ≥2 h of fasting and non‐smoking. The men were then immediately placed in a silent room and real‐time penile rigidity and tumescence monitoring with Rigiscan Plus (Rigiscan Plus® System, Osbon Medical Systems, Augusta, GA, USA) began. The men read some magazines or newspapers that contained no sexually stimulating material for 1.5 h. There was no interaction between the men and observer during the test period. Times to first measured and total durations of base and tip rigidities, and also total and per minute rigidity were evaluated.

RESULTS

The recorded base and/or tip rigidity ratios were 40% (eight of 20), 71% (12/17), 47% (nine of 19) and 70% (14/20) in men who took placebo, sildenafil, tadalafil and vardenafil, respectively (P= 0.126). The ratio of men who could obtain ≥60% base and/or tip rigidities were 10% (two of 20), 41% (seven of 17), 26% (five of 19) and 55% (11/20) in placebo, sildenafil, tadalafil and vardenafil groups, respectively (P < 0.05). The median time to first measured base rigidity was 58.0, 21.5, 54.5 and 57 min with placebo, sildenafil, tadalafil and vardenafil, respectively (P= 0032). The median total duration of recorded base rigidity was 4.0, 27.5, 10.0 and 11.5 min in men who took placebo, sildenafil, tadalafil and vardenafil, respectively (P= 0.013). The median total base rigidity (area under the curve) was 72.8, 699.0, 360.5 and 553.0 with placebo, sildenafil, tadalafil and vardenafil, respectively (P= 0.016).

CONCLUSIONS

Significant penile rigidities were obtained with PDE5 inhibitors during the short test period, with no sexual stimulation, in laboratory conditions. This finding might support the use of PDE5 inhibitors in men who need penile rehabilitation.     

Add-on fesoterodine for residual storage symptoms suggestive of overactive bladder in men receiving α-blocker treatment for lower urinary tract symptoms

Study Type – Therapy (RCT) Level of Evidence 1b What's known on the subject? and What does the study add? Male lower urinary tract symptoms are often attributed to bladder outlet obstruction secondary to benign prostatic hyperplasia and treated with drugs targeting the prostate. However, many men with storage lower urinary tract symptoms may not respond adequately to these agents. Antimuscarinics, with or without an α‐blocker, may be effective for the treatment of the storage symptoms of overactive bladder in some men. Flexible‐dose fesoterodine as an add‐on treatment significantly improved urinary frequency and symptom bother, but not urgency episodes (primary endpoint), versus add‐on placebo and was well tolerated in men with persistent overactive bladder symptoms despite receiving α‐blocker.

OBJECTIVE

• ? To evaluate flexible‐dose fesoterodine vs placebo in men with persistent overactive bladder (OAB) symptoms despite receiving α‐blocker treatment

SUBJECTS AND METHODS

• ? This was a double‐blind, 12‐week, flexible‐dose trial.
• ? Men with persistent storage symptoms (≥8 micturitions and ≥3 urgency episodes per 24 h) after receiving an α‐blocker for ≥6 weeks were randomized to add‐on fesoterodine 4 mg or placebo, with optional dose escalation to 8 mg at week 4 and reduction back to 4 mg at week 8 (or matching placebo adjustments).
• ? Subjects completed 3‐day diaries, International Prostate Symptom Score (IPSS), Overactive Bladder Questionnaire (OAB‐q), Patient Perception of Bladder Condition (PPBC), and Urgency Perception Scale (UPS) at baseline and weeks 4 and 12.

RESULTS

• ? A total of 943 men were randomized and received at least one dose of study treatment (fesoterodine, n= 471; placebo, n= 472).
• ? Among these, 251 (53%) in the fesoterodine group and 300 (64%) in the placebo group requested dose escalation at week 4 and 35 (7%) and 15 (3%) requested dose reduction at week 8. Changes from baseline to week 12 in urgency episodes (primary endpoint) in the fesoterodine (?3.2) and placebo (?2.9) groups were not significantly different (P= 0.196), but improvements in micturitions (P= 0.009) and OAB‐q symptom bother score (P= 0.007) were significantly greater with fesoterodine.
• ? At week 4, significantly greater improvements in micturitions (P= 0.006), severe urgency episodes (P= 0.006), IPSS storage score (P= 0.022), OAB‐q symptom bother score (P= 0.004), and OAB‐q health‐related quality of life (P= 0.041), but not urgency episodes (P= 0.062), were observed with add‐on fesoterodine.
• ? Dry mouth (fesoterodine, 21%; placebo, 6%) and constipation (fesoterodine, 6%; placebo, 2%) were the most common adverse events. Dysuria and urinary retention were reported by 3% and 2% of subjects, respectively, in the fesoterodine add‐on group vs 1% and <1% of subjects, respectively in the placebo add‐on group. One subject in each group had acute urinary retention requiring catheterization.

CONCLUSIONS

• ? Flexible‐dose fesoterodine was well tolerated as an add‐on treatment in men with persistent storage symptoms.
• ? Changes in urgency episodes at week 12 (primary endpoint) and many secondary endpoints were not significantly different between fesoterodine and placebo add‐on treatment; however, improvements in frequency and symptom bother were significantly greater with fesoterodine.
• ? These data suggest that there remains a limited understanding of the optimal evaluation and treatment of men with LUTS.

     

Dapoxetine and the treatment of premature ejaculation

Background

Premature ejaculation (PE) is the most common male sexual complaint. Off-label oral selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for the treatment of PE. Dapoxetine is a short-acting SSRI specifically designed for on-demand use. The objective of this communication is to summarize the clinical and physiological evidence regarding the role of the serotonergic pathway and specifically dapoxetine in the treatment of PE.

Methods

A PubMed search was conducted on articles reporting data on dapoxetine for the treatment of PE. Articles describing the pathophysiology and treatment options for PE were additionally included for review.

Results

The etiology of PE is multi-factorial in nature. There are many treatment options for PE such as psychological/behavioral therapy, topical anesthetic agents, phosphodiesterase type 5 (PDE-5) inhibitors, and tramadol hydrochloride. SSRIs play a major role in PE treatment. Animal and clinical studies in addition to its pharmacokinetic document dapoxetine’s clinical efficacy and safety for on-demand treatment of PE.

Conclusions

Dapoxetine demonstrates clinical efficacy and a favorable side effect profile. Dapoxetine is currently the oral drug of choice for on-demand treatment of PE.     

Correlates to the clinical diagnosis of premature ejaculation: results from a large observational study of men and their partners

PURPOSE: A recent observational study characterized intravaginal ejaculatory latency time and single item patient reported outcome measures in a large population of males with and without premature ejaculation, as well as their female partners. In the current analysis we assessed the relative influence of those measures in identifying premature ejaculation as diagnosed by the clinician. MATERIALS AND METHODS: Data were from a 4-week, multicenter, observational study of men with (207) and without (1,380) premature ejaculation (diagnosed using The Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision criteria), as well as their female partners. Estimated and measured intravaginal ejaculatory latency time, age, and responses to single item (control over ejaculation, personal distress, satisfaction with sexual intercourse and interpersonal difficulty) and multiple item (male and female Golombok-Rust Inventory of Sexual Satisfaction, male Self-Esteem and Relationship questionnaire, and Short Form 36) measures were evaluated with stepwise logistic regression analysis. RESULTS: Self-estimated and stopwatch measured intravaginal ejaculatory latency time were interchangeable, correctly assigning premature ejaculation status with 80% sensitivity and 80% specificity, increasing to 80% sensitivity and 96% specificity when combined with single item patient reported outcomes. Subject reported control over ejaculation and personal distress most strongly indicated premature ejaculation status. Partner personal distress was more influential in determining premature ejaculation status than estimated or measured intravaginal ejaculatory latency time, and single item measures were more influential than multiple item measures. Age was not influential in assigning premature ejaculation status. CONCLUSIONS: Neither self-estimated nor stopwatch measured intravaginal ejaculatory latency time alone was optimal for assigning premature ejaculation status. Subject and partner responses to single item measures, particularly control over ejaculation and personal distress, were important. Results suggest that a combination of estimated intravaginal ejaculatory latency time and the 4 single item patient reported outcome measures can adequately identify premature ejaculation status.     

The link between penile hypersensitivity and premature ejaculation

Study Type – Aetiology (case control)
Level of Evidence 3b What’s known on the subject? and What does the study add? Very little is known about the aetiology of premature ejaculation. This analysis shows that many PE patients have a heightened penile sensitivity. This information could result in the design and development of new drugs.

OBJECTIVES

To investigate the correlation between penile hypersensitivity and premature ejaculation (PE), as defined by the criteria identified by the International Society of Sexual Medicine (ISSM). Penile hypersensitivity as a cause of PE is based on historical clinical neurophysiological data and clinical efficacy of the topical desensitizing agent PSD502 in the treatment of PE. PSD502 is a eutectic‐like mixture of two local anaesthetics, lidocaine and prilocaine, whose primary action is to reduce neuronal conduction in sensory afferents.

METHODS

Historical neurophysiological data was reviewed, together with data from the recent PSD502 clinical trials, including the first published double‐blind clinical trial data evaluating a topical desensitizing agent in a population of men with PE, as per the new ISSM definition. The clinical profile of PSD502, based on its local anaesthetic properties, is used as a surrogate index of the role of sensory afferents in the ejaculatory reflex.

RESULTS

The published data does not support unequivocally penile hypersensitivity as the cause of PE. Interpretation of the data is hampered by the variability of the populations described as having PE across studies. Data from the PSD502 clinical trials clearly shows that PSD502 increases ejaculatory latency, and improves control and sexual satisfaction when applied topically to men with PE 5 min before intercourse, enabling subjects to delay ejaculation up to six times longer than those who used a placebo.

CONCLUSION

The clinical profile of PSD502 lends credibility to the penile hypersensitivity hypothesis for PE. The predominant action of local anaesthetics is to reduce neuronal firing in sensory afferents; the clinical profile of PSD502, which shows improvement of ejaculatory function in the absence of a generalized reduction in penile sensitivity, can most readily be explained based on an underlying hypersensitivity in patients with PE.