Update on Treatments for Premature Ejaculation

W. J. G. Hellstrom

Disclosures

Int J Clin Pract. 2011;65(1):16-26. 

In This Article

Abstract and Introduction

Abstract

Current and upcoming treatment options for premature ejaculation (PE) are of global clinical interest. In 2008, the International Society for Sexual Medicine published an evidence-based definition for PE. While there are no US Food and Drug Administration-approved therapies for PE, the American Urological Association 2004 guidelines state the serotonergic antidepressants paroxetine, sertraline, fluoxetine and clomipramine and the topical lidocaine–prilocaine cream are effective treatment options. However, there are limitations associated with their use, which may be overcome by PE-specific therapies currently in development. Two agents that are in advanced stages of clinical development include: (i) dapoxetine, an on-demand short-acting selective serotonin reuptake inhibitor, and (ii) PSD502, a metered-dose aerosol containing lidocaine and prilocaine, also for on-demand treatment. Another on-demand agent in development is tramadol, a weak opioid that is currently approved for treating pain. Coupled with efficient diagnosis, it is hoped that these newer agents will improve the quality of life for patients who suffer from PE.

Introduction

Premature ejaculation (PE) is the most common male sexual disorder. Based on population studies conducted in the United States and the United Kingdom, the prevalence of PE is estimated to be between 5% and 30%.[1–8] This wide range is a result of the fact that until 2008, there was no universally accepted standard definition for PE. The most commonly used definition of PE was from the Diagnostic and Statistical Manual of Mental Disorders IV-TR,[9] and included a combination of intravaginal ejaculatory latency time (IELT), lack of ejaculatory control and personal distress; however, these criteria were based on expert opinion rather than clinical evidence, and have not been used in the majority of clinical trials. Thus, there was a large unmet need in the evaluation and diagnosis of patients with PE. This has recently been addressed with the development of the first evidence-based definition of PE by an Ad Hoc Committee of the International Society for Sexual Medicine in 2008. The committee proposed that lifelong PE (i.e., PE present since the onset of sexual maturity) be defined as a male sexual dysfunction characterised by ejaculation that always or nearly always occurs before or within approximately 1 min of vaginal penetration, 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.[10]

The exact aetiology of PE is unknown and is believed to include neurobiological and/or psychological components and/or penile hypersensitivity.[11,12] PE may be classified as lifelong or acquired.[12] Acquired PE is secondary to other conditions and has been associated with chronic prostatitis[13–15] and specific endocrinopathies, including diabetes mellitus and hyperthyroidism.[16–18] In these instances, PE is usually reversed when the underlying disorder is treated.

In this study, treatments in current use for PE as well as those that are in development are reviewed. The protocol used for the selection of articles was as follows: a general PubMed search was conducted for articles in English with 'PE' in any search field over the period from 2000 to 2009. After reviewing relevant articles (N = 430), pertinent references cited in the bibliographies were also obtained. In addition, guideline statements from the American Urological Association (AUA) and the Sexual Medicine Society of North America were reviewed for relevant citations.[19,20]

Treatment Options

While the development of the International Society of Sexual Medicine's definition for PE provides a significant advance in clinical diagnosis, there are still unmet needs in treatment. Currently, there is no US Food and Drug Administration (FDA) – approved treatment for PE. The ideal treatment for PE should meet the following criteria: on-demand treatment with quick onset of action so as not to interfere with sexual spontaneity, high rates of efficacy after early doses and minimal sexual and other adverse effects.[21]

Treatment Strategies Recommended by the AUA in 2004

The consensus of the AUA committee that drafted the guidelines for PE management was that although oral antidepressants and topical anaesthetic agents are not approved by the FDA for PE, they have been shown to delay ejaculation in men with PE and have a low side effect profile when used at the lower doses commonly used for the treatment of PE.[19] The treatments recommended by the AUA are as follows:

  • Serotonergic antidepressants, including the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, paroxetine and sertraline, and the tricyclic antidepressant clomipramine. (The antidepressants nefazodone, citalopram and fluvoxamine are not effective in treating PE.)

  • Topical lidocaine–prilocaine cream.

Serotonergic Antidepressants

Per AUA guidelines, the relative effectiveness of daily dosing vs. on-demand dosing of serotonergic antidepressants in the treatment of PE is inconclusive.[19] Based on the pharmacokinetics of the traditional serotonin reuptake inhibitors commonly used in the treatment of PE, chronic administration is needed to maximise therapeutic effect;[22] however, these agents have also been reported with on-demand protocols. While one study suggests that patients with PE preferred daily dosing to on-demand dosing,[23] there are many potential advantages to on-demand treatment. Chronic treatment with serotonergic antidepressants is associated with unwanted adverse events, including sexual side effects, as well as withdrawal symptoms upon abrupt discontinuation;[24] these would theoretically be reduced by on-demand use.

A review and meta-analysis of the use of drugs in PE between 1943 and 2003 was published in 2004.[25] The systematic review included data from all previous publications on drugs used for the treatment of PE (79 publications in a total of 3034 patients). The meta-analysis was conducted on data from all IELT-reporting trials between 1973 and 2003 that employed serotonergic antidepressants for the treatment of PE (43 SSRI and clomipramine studies – 35 studies on daily treatment and eight in on-demand treatment – for a total of 1514 patients). Notwithstanding major differences in design and drug dosage, daily treatment with paroxetine, sertraline, fluoxetine and clomipramine showed significantly greater percentage increases in IELT compared with placebo in all cases (Figure 1). The data from the eight studies in on-demand treatment were similar to those from the daily dosing studies. However, the small number of studies of on-demand treatment, the fact that the studies included in the meta-analysis greatly differed in methodology and were unbalanced for the antidepressants used, the baseline IELT values, design (double-blind vs. open) and assessment techniques (questionnaire vs. stopwatch) should be factored into any conclusions regarding on-demand dosing.

Figure 1.

Percentage increase in IELT for placebo vs. (A) daily (N = 35 studies) and (B) on-demand (N = 8 studies) treatment with serotonergic antidepressants. Error bars represent 95% confidence intervals. IELT, intravaginal ejaculatory latency time

While serotonergic drugs are extensively used for the treatment of PE, there are serious limitations associated with their use. Some of the side effects include unwanted sexual side effects, such as decreased libido, anorgasmia, impotence and erectile dysfunction;[26,27] there are a few case reports indicating that these sexual side effects may continue beyond cessation of SSRI treatment.[28,29] Other effects of treatment with serotonergic drugs include those on mood, such as reduced ability to cry, express feelings or care about the feelings of others;[30] and discontinuation syndrome (cluster of unpleasant physical and psychological symptoms, including dizziness, nausea or vomiting, fatigue, headache and unsteady gait on sudden termination of SSRI therapy).[24] Some general practitioners may be reluctant to prescribe SSRIs for PE to younger adult patients because of the finding that paediatric patients on antidepressants (including SSRIs) had about twice the rate of suicidal thoughts and behaviour compared with those in the placebo group, according to a meta-analysis of all available randomised trials.[31] In general, the side effects of SSRIs must be weighed against the value of these drugs in treating PE, especially in light of the existence of topical treatments that confer minimal systemic side effects.

Serotonergic Drugs in Development

Dapoxetine Dapoxetine is an SSRI designed for use as an oral on-demand therapy for PE. It has marketing authorisation in 10 countries (Finland, Sweden, Austria, Germany, Spain, Italy, Portugal, Mexico, South Korea and New Zealand). However, the US FDA issued a non-approval letter for dapoxetine in 2005 and despite the completion of several large clinical trials since then (Table 1), FDA approval is still awaited.

Dapoxetine 30 or 60 mg used 1–3 h before sexual intercourse has been tested extensively in large, multinational phase III trials and the safety and efficacy data are presented in Table 1.[32–38] The fold increase in mean geometric IELT with dapoxetine on-demand treatment was approximately three,[32,36,37] vs. an estimated ninefold increase with daily paroxetine, fivefold increase with daily clomipramine and fourfold increase with daily sertraline and fluoxetine,[25,39] This is in keeping with a hypothesis based on pharmacodynamic considerations that SSRIs with short half-lives, such as dapoxetine, are likely to have much lower ejaculation-delaying effects compared with traditional SSRIs.[40] Nonetheless, perceptions of satisfaction and control were significantly better with dapoxetine vs. placebo.[32,34–38] While discontinuation syndrome is considered to be more common with SSRIs that have shorter half-lives,[24] dapoxetine treatment was associated with a low incidence of discontinuation syndrome.[24,33] Although the safety profile of dapoxetine is encouraging, the effects of long-term exposure are as yet unknown.

Other Serotonergic Drugs Escitalopram, which is the S-enantiomer of citalopram, has been investigated as daily therapy in two studies (n = 100 and n = 276) and was found to improve IELT vs. placebo and to a similar extent as fluoxetine and paroxetine.[41,42] Surprisingly, one of the studies found that at the 6-month follow up after a 12-week treatment period, patients in the escitalopram group still had a significantly longer IELT (3.1-fold from baseline) compared with patients in the placebo group (1.3-fold from baseline; p = 0.001).[42] Additional studies are warranted to confirm the utility of escitalopram in the treatment of PE.

Locally Acting Topical Therapy

Locally acting topical therapies address the penile hypersensitivity aspect of the ejaculatory reflex.[43] The advantages of local therapies are that they can be applied as needed and any systemic effects are minimised. Limitations include inconvenience of use, messiness and interference with spontaneity (as the agents have to be applied and wiped off at specific times before sexual contact), possibility of penile hypoesthesia, and transvaginal contamination that may lead to genital hypoesthesia in the partner.[11]

Lidocaine–prilocaine Cream

As described in the AUA 2004 guideline document, the 2.5% lidocaine–2.5% prilocaine cream is effective in treating PE when applied 20–30 min before intercourse.[19] While topical local anaesthetics have traditionally been used to induce anaesthesia of the mucous membranes, providing anaesthesia to intact skin has been problematic, as penetrating the epidermis requires high water content and a high concentration of the base form of the anaesthetic. The high water content of 2.5% lidocaine–2.5% prilocaine cream enables it to penetrate the intact skin of the penis.[44]

In a small randomised study (N = 40), patients were treated with various protocols using the 2.5% lidocaine–2.5% prilocaine cream (n = 30) and compared with placebo (n = 10). All patients reported an IELT of < 1 min before treatment. Patients (n = 10) exposed to the cream for 20 min had a mean IELT of 6.71 ± 2.54 min (p < 0.05 vs. baseline) and reported no adverse events. In four of 10 patients exposed to the cream for 30 min, the mean IELT was 8.70 ± 1.70 min (p < 0.05 vs. baseline). However, six of 10 patients reported loss of erection because of hypoesthesia. All patients exposed to the cream for 45 min (n = 10) reported penile hypoesthesia and loss of erection. In this group, there was no significant change in IELT vs. baseline. It is not clear how the IELT was measured in this trial.[44]

In another small placebo-controlled study, a significant improvement in IELT was reported in PE patients who were treated with a cream containing 25 mg each of lidocaine and prilocaine (N = 42 and completed by 29 patients). The mean IELT (standard deviation) was 1.49 (0.9) minutes at baseline and 8.45 (0.9) minutes post-treatment compared with 1.67 (0.7) minutes at baseline and 1.95 (0.12) minutes post-treatment for placebo (n = 18). Adverse events were reported in five (17%) patients in the treatment group: two cases of decreased penile sensitivity and retarded ejaculation (> 30 min), one case of decreased vaginal sensitivity despite removing the cream with water before sexual intercourse and two cases of penile irritation.[45]

Topical Therapies in Development

PSD502 PSD502, also known as Topical Eutectic Mixture for Premature Ejaculation, is a metered-dose aerosol containing the anaesthetics lidocaine (7.5 mg) and prilocaine (2.5 mg) in a hydrofluoroalkane propellant, which acts as a solvent. Deployment from the container vaporises the propellant and forces the concentrated anaesthetics into a slightly oily, eutectic-like combination [i.e., in a liquid state at temperatures below the melting points of the individual components; Figure 2.[11] The oily texture enhances adherence to the penile surface and is easily washed off with water.[11,46]

Figure 2.

Mechanism of action of the PSD502 spray. PSD502 aerosol contains purely base (uncharged) forms of local anaesthetics vs. creams that contain a mixture of base and ionised forms. Only uncharged base forms are able to penetrate skin or mucous membranes. LA produce localised reversible inhibition of nerve conduction by reducing permeability of neuronal membranes to sodium ions, the movement of which is necessary for transmission of nerve impulses (11). LA, local anaesthetics; Na+, sodium ion Reproduced from Ref. (11), with permission from John Wiley & Sons

PSD502 has been examined in a pilot study (N = 14),[47] a placebo-controlled phase II study (N = 55),[48] and in two large, placebo-controlled phase III trials.[49,50] The results are presented in Table 2.[47–50]

The advantages of PSD502 lie in its dose-controlled delivery system and rapid onset of effect. Data from phase III trials indicate that PSD502 is efficacious within 5 min of application and so the problems of interference with spontaneity typically associated with on-demand therapies may not be associated with PSD502 use.[49,50] Furthermore, the local anaesthetics in the PSD502 spray only minimally penetrate intact, fully keratinised skin. Thus, full sensation is maintained in the shaft of the penis.[11,46,48] Circumcision increases keratinisation of the glans penis but the sensitive areas of the frenulum and urethral meatus remain unkeratinised, thus PSD502 should, theoretically, be effective in circumcised patients as well.[46] This hypothesis was recently tested in a retrospective analysis, which confirmed that while the IELT improvement in men with PE who are circumcised was 24% less than in uncircumcised men, it was still statistically and clinically significant compared with placebo.[51] Unlike aqueous creams, condoms are not required for use with PSD502 so long as the penis is cleaned with a moist cloth prior to intercourse.[47–49] Patients reported that the spray was easy to use.[48]

SS-cream The SS-cream is formulated from the extracts of nine natural products, some of which have local anaesthetic as well as vasoactive properties.[11] SS-cream is applied to the glans penis 1 h prior to and washed off before intercourse. In one clinical trial, the optimum dose was established to be 0.2 g.[52] In one report of SS-cream use in a placebo-controlled trial, there was a significant improvement in mean stopwatch-measured IELT compared with placebo (baseline 1.37 ± 0.12 min, and post-treatment 2.45 ± 0.29 min vs. 10.92 ± 0.95 min in the placebo vs. SS-cream groups respectively).[53] Side effects were mild and included mild local burning and pain (19%).

However, after publication of the aforementioned paper in 2000, no further data have been reported. According to a recent review article, because of its unpleasant odour, the original SS-cream was unlikely to be of interest outside of South Korea.[22] A revised formulation has been tested in rabbits and appears to have similar efficacy as the original formulation;[54] however, it appears that neither form of SS-cream is currently available in Korea.

Other Drugs in Development

Tramadol Tramadol is a centrally acting synthetic on-demand analgesic agent that combines μ-opioid receptor activation and reuptake inhibition of serotonin and noradrenalin;[39] the exact mechanism by which it delays ejaculation is not delineated.[55,56] Tramadol has been used off-label and empirically since 2000 for the treatment of PE because of its acceptable safety profile and because patients taking tramadol for analgesia reported delayed ejaculation or anejaculation.[55] As a result of its short half-life, tramadol can be used in an on-demand dosing protocol.[57]

Data from two small clinical trials of tramadol for PE indicated that the drug produced significant improvements in IELT vs. placebo [Table 3].[55,58] A large phase III trials is in progress in Europe (ClinicalTrials.gov identifier: NCT00983151 and NCT00983736) and other trials are anticipated.

As tramadol is an opioid, albeit with a weak μ-opioid activity, there are concerns about its abuse and dependence.[59] Long-term studies are needed to determine the verifiable risk of opioid addiction.

PDE-5 Inhibitors A publication in 2006 reviewed all reports on the use of phosphodiesterase type 5 (PDE-5) inhibitors for PE that were published between 2001 and 2006.[60] In all, 14 studies that reported on sildenafil, vardenafil and tadalafil were analysed. The authors concluded that while PDE-5 inhibitors may have a role as monotherapy or in combination with SSRIs in the treatment of acquired PE with comorbid erectile dysfunction, they were not effective in the treatment of men with lifelong PE and normal erectile function.

Drugs in Preclinical Development

It has been observed that desensitisation of the 5-HT1A receptor during chronic administration of SSRIs [e.g., combination of WAY-100635 with paroxetine[61] and citalopram[62] and combination of robalzotan (NAD-299) with fluoxetine and citalopram][63] induces prolonged delay in ejaculation in the rat. This novel concept has the potential for development of new agents to treat PE.[39]

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....