Premature ejaculation (premature ejaculation) or rapid or early ejaculation is generally regarded as one of the most common male sexual problems, with an incidence of 20 – 30 %. Some have suggested a prevalence as high as 75 %, although the actual incidence of premature ejaculation depends on how premature ejaculation is defined.

Numerous definitions of premature ejaculation exist, but one of the most commonly accepted is that from the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), which defines premature ejaculation as ‘the persistent or recurrent onset of orgasm and ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the person wishes it ’. This definition is a subjective one and does not seek to quantify ejaculatory latency. In practice the intravaginal ejaculatory latency time (IELT), measured with a stopwatch, is commonly used as a way of quantifying premature ejaculation and treatment success, and also as a standardized way of comparing treatments in clinical research. Considerable variation exists as to where the threshold intravaginal ejaculatory latency time should be set to define premature ejaculation, although the consensus of opinion seems to be that men with premature ejaculation tend to have an intravaginal ejaculatory latency time of 1 – 2 minutes or less.

However, the impact that premature ejaculation has on quality of life is significant, with a similar qualitative impact on the sufferer as erectile dysfunction. Consequently, there is now general agreement that although intravaginal ejaculatory latency time comparisons are valuable, the evaluation of treatments in well-designed clinical trials should include measures of sexual satisfaction (by the man and his partner), and perception of control over ejaculation, in addition to IELT.

premature ejaculation is a self-diagnosed condition and most men with the condition do not seek treatment, for reasons of embarrassment, shame, or the belief that no effective treatment exists, but they may try self-help techniques or self-medication: In a large multi-country survey of more than 11,500 men in the USA, Italy, and Germany, fewer than 12 % of men who self-reported premature ejaculation had sought treatment. In a small survey involving in-depth interviews with 28 men with self-diagnosed premature ejaculation, 89 % had tried some form of treatment (including behavioral therapies, pharmaceutical agents, over-the-counter remedies, herbal remedies, creams, and condoms), regardless of whether or not they had consulted a healthcare professional. Such a high figure indicates that men experiencing premature ejaculation are highly motivated to seek a solution or treatment.

Considering that the frequency of sexual intercourse is highly variable, and spontaneity in sexual intercourse is usually an important factor, the ideal treatment for premature ejaculation would have the following characteristics; it would:

  • be discreet;
  • be an ‘on-demand’ therapy;
  • have rapid action;
  • be effective from the first dose;
  • have high efficacy on intravaginal ejaculatory latency time and patient-reported outcomes;
  • have a low incidence of side-effects; and
  • have no unwanted effect on the partner.

It has also been suggested that medication could be used to restore confidence together with behavioral treatment, where available, to help men to learn to overcome premature ejaculation on their own. premature ejaculation is of course not a life-threatening condition; therefore safety should be a primary consideration when deciding on a course of treatment.

 Current approaches to treatment

There are a range of treatment options for men with premature ejaculation, directed at different components of the complex mechanism of the ejaculatory process. These include behavioral therapy, systemic treatments, and topical therapies. However, there are currently no pharmacological agents approved for use in premature ejaculation, and all drugs have to be administered off-label.

Current recommendations from the American Urological Association (AUA) and the second International Consultation on Sexual Dysfunctions (ICSD) recognize that premature ejaculation is a self-reported diagnosis and emphasize the importance of obtaining a comprehensive sexual history when making a diagnosis; no laboratory or physiological tests are usually required. It is recommended that clinicians also determine if there is concomitant erectile dysfunction and, if present, it should be treated first. The management algorithm for premature ejaculation produced by the ICSD recommends pharmacotherapy with a selective serotonin reuptake inhibitor (SSRI) or topical anesthetics as the first-line treatment in patients with lifelong premature ejaculation and as second-line treatment in patients with acquired premature ejaculation. In reality, pharmacotherapy is likely to be used first-line in both cases, owing to the limited availability of skilled sex therapists and relationship counselors.

The choice between oral therapy with SSRIs (daily or as-needed), or the use of a topical agent is a decision to be made jointly by the patient or couple and the physician after the physician has ascertained their desires and expectations. If acceptable to the patient or couple, a trial of a topical agent could be a prudent first step, owing to the favorable risk – benefit ratio of these products. This is reflected in the treatment algorithm in Figure “Management algorithm for premature ejaculation”, which is modified from the ICSD recommendations.

Behavioral therapy

Behavioral therapies for premature ejaculation (such as the ‘stop – start’ and ‘squeeze ’ techniques) require a high level of commitment and the involvement of the man’s sexual partner. Although such therapies can be useful for some couples, they are rarely successful in the long term since most post-therapy benefits are lost within 3 years of treatment without regular follow-up therapies. In addition, the high cost and limited availability of sex therapists means that this approach is not always practical and indeed is not suitable for men without a steady and supportive sexual partner.

Systemic therapy

The AUA currently recommends three drug treatment strategies to treat premature ejaculation:

  1. Daily treatment with serotonergic antidepressants
  2. As-needed treatment with serotonergic antidepressants
  3. Anesthetic topical treatment.

Delayed ejaculation is a common side-effect of many psychotropic or antidepressant drugs, in particular of the serotonergic tricyclic antidepressant clompiramine and the SSRIs fluoxetine, paroxetine, and sertraline. These drugs, which are primarily indicated for the treatment of depression, can increase the level of serotonin in the brain, inhibiting the ejaculatory reflex center, and they can prolong intravaginal ejaculatory latency time for several minutes.

Dosing levels of SSRIs are generally lower for premature ejaculation than for depression, and various dosing regimens have been tested (including continuous, daily, or situational). Despite this the adverse-event profile appears to be similar; adverse events include dry mouth, drowsiness, nausea, and reduced libido. There is also the potential for development of a serious drug interaction that can lead to serotoninergic syndrome, which manifests itself as headache, nausea, sweating, and dizziness in mild cases and as hyperthermia, rigidity, and delirium in severe cases. Many physicians may consider the side-effects hard to justify for the treatment of premature ejaculation, in which the primary outcome is patient satisfaction, although the AUA has suggested that the level of adverse events is acceptable for the benefit derived by the patient with premature ejaculation, and the type and rate of occurrence of side-effects also appears to be acceptable to most patients.

Dapoxetine, a novel SSRI, is the first oral agent specifically developed for the management of premature ejaculation and it has been shown to be effective, well tolerated, and suitable for on-demand use. Further research with this drug continues despite the US Food and Drug Administration’s non-approval of dapoxetine for the treatment of premature ejaculation in 2005.

Rationale for the use of topical treatment

There are a variety of theories concerning the etiology of premature ejaculation. Historically, premature ejaculation was considered a learned behavior and, as a result, behavioral therapy was the standard treatment. However, it is now generally accepted that both biological and psychological factors are important in the etiology of premature ejaculation. Men with premature ejaculation appear to have a heightened sensory response to penile stimulation, with a vibration threshold significantly lower than that of normal men. They also generally exhibit other abnormal autonomic reflex pathways for the ejaculatory process, including shorter bulbocavernous latency time, and higher bulbocavernous evoked potentials. Considering these sensory differences in men with premature ejaculation, agents that selectively produce some degree of penile desensitization or act within the afferent – efferent reflex should be effective therapy for premature ejaculation. Thus, reducing the sensitivity of the glans penis with topical desensitizing agents (such as local anesthetics) should delay ejaculatory latency without adversely affecting the sensation of ejaculation.

Current status of topical treatments

As described above there is currently no approved pharmacological therapy for premature ejaculation and this has led to the use of over-the-counter remedies and the ‘off-label’ use of local anesthetics. However, there are also novel desensitizing agents specifically designed to treat premature ejaculation in development.

Compared with orally delivered treatments for premature ejaculation, topical treatments are appealing in that they can be applied on an as-needed basis and because systemic side-effects are likely to be minimal. However, the application of a desensitizing agent to the penis does have the potential for some degree of penile hypoesthesia and theoretically, transvaginal contamination and female genital hypoesthesia as side-effects.

An important consideration for physician and patient, in this era of evidence-based medicine, is whether there is adequate supportive clinical data for the use of these off-label and novel topical agents. The efficacy and adverse-events profiles for topical treatments, where available, are discussed in the following sections, and comparative data are presented in Table “Comparative efficacy and adverse event data for clinical trials of topical treatments for premature ejaculation”.

Over-the-counter topical treatments

Lidocaine spray

Lidocaine 9.6% spray, marketed as ‘Studd 100’ or ‘Premjact’, has been available over the counter for over 25 years in some countries and, as their names suggest, these are marketed as products for delaying ejaculation. However the absence of reliable data from clinical trials means that the validity of the claims by the manufacturers cannot be assessed.

Severance secret-cream

Severance secret-cream (SS-cream; Cheil Jedan Corporation, Seoul, Korea), developed at the Yong-Dong Severance Hospital in Korea is made with extracts from nine natural products. Some of these products have local anesthetic as well as vasoac-tive properties. Several studies using SS-cream on men with premature ejaculation have been carried out in Korea, but the cream is not approved for use in Europe or the USA and is not legally available outside Korea.

SS-cream is applied to the glans penis 1 hour before intercourse and washed off immediately prior to coitus. Both the latency and amplitude of somatosensory evoked potentials measured at the glans penis were increased over baseline after the application of SS-cream, which has also been shown to increase the penile vibratory threshold at the glans penis in a dose-dependent fashion. Xin et al. reported significantly prolonged ejaculatory latency in 89.2 % of patients treated with SS-cream. Adverse effects were noted in 5.9 % of patients; these included mild local irritation (local burning or pain) and delayed ejaculation.

The prologation of intravaginal ejaculatory latency time has been shown to be dose-dependent, with an optimal dose of 0.2g cream. In a multi-center, double-blind study involving 106 patients, the use of 0.2g of SS-cream was reported to increase the mean stopwatch-measured intravaginal ejaculatory latency time from a baseline of 1.37 minutes to 10.92 minutes, compared with 2.45 minutes with placebo (p <0.001) and was 27 times more effective than placebo in increasing sexual satisfaction (p <0.001). However, almost 19 % of episodes of use were associated with mild localized irritation, including pain and burning, and 12 patients reported negative sexual side-effects such as delayed ejaculation, anejaculation, and erectile dysfunction.

Despite these promising results, SS-cream has an unpleasant smell and color, which makes it unacceptable to many patients. A reformulation has resulted in ‘renewed SS-cream ’ (RSSC) which is a new topical agent composed of the two main components of the original SS-Cream; Korean ginseng and Bufonis venenum in a hydrobase and enhancer without smell or color. So far, only the results of animal studies have been published. The authors claim that RSSC delays the latencies of the spinal somatosensory evoked potentials in rabbits more effectively than the original SS-cream. However, the ingredient Bufonis venenum, has been shown to produce contact dermatitis and the likelihood of this cream gaining regulatory approval outside of Korea appears to be remote.

Off-label topical treatments

Lidocaine – prilocaine cream

Separately, lidocaine and prilocaine are crystalline solids. When mixed together in equal quantities by weight, however, they form a liquid eutectic mixture that can be formulated into preparations without the use of a non-aqueous solvent. This allows higher concentrations of anesthetic to be formulated into the preparation and maintained during application. EMLA ® (Eutectic Mixture of Local Anaesthetic; AstraZeneca) is a local anesthetic cream containing 2.5 % each of lidocaine and prilocaine for topical application. Developed to anesthetize intact skin, it is available as an over-the-counter product in some countries.

The first pilot study evaluating lidocaine – prilocaine cream for the treatment of premature ejaculation included 11 subjects. The cream (2.5g) was applied to the whole glans and shaft of the penis 30 minutes prior to intercourse and covered with a condom, which could be removed prior to intercourse (and the cream wiped off) if desired. Nine of the 11 patients rated their performance as ‘excellent ’ or ‘better ’ and all 11 partners were satisfied with the treatment results.

In order to determine the optimal time that the anesthetic cream should be on the penis prior to intercourse, Atikeler et al. carried out a placebo-controlled trial with 10 patients in each treatment group, varying the application time from 20 – 45 minutes, with a condom. In the 20- and 30-minute application groups the intravaginal ejaculatory latency time increased compared with placebo, but all men in the 45-minute group suffered from penile numbness and loss of erection. The optimal application time was considered to be 20 minutes.

The largest double-blind, placebo-controlled clinical trial of lidocaine – prilocaine cream to date involved 42 patients; 21 in each group. Patients were asked to apply a thin layer of cream to the glans penis, extending the coverage for up to 2cm on the penile shaft. They were then asked to cover the cream with a condom for 10 – 20 minutes before intercourse and to use this treatment each time they had intercourse over 30 – 60 days. The treatment resulted in a 5.6-fold increase in IELT. However, only 29 of the initial 42 participants completed the study. Of the patients completing the study, 11 out of the 16 who responded reported ‘great’ or ‘excellent’ sexual satisfaction. Loss of penile sensation, retarded ejaculation, and penile irritation were a problem for 5 men, and 1 female partner reported decreased vaginal sensitivity.

It can be concluded that lidocaine – prilocaine cream has some degree of efficacy in the treatment of premature ejaculation but is inconvenient, messy, and slow-acting, and it is not approved for this indication. It also has problems associated with hypoesthesia.

Novel topical agents in development

Dyclonine – alprostadil cream

Dyclonine, a local anesthetic used most commonly in dentistry, has been combined in a cream formulation with alprostadil (prostaglandin E-1), a vasodilator used in erectile dysfunction (ED), and the combination is under development (NexMed, USA) as a topical treatment for premature ejaculation. So far only one pilot study has been published (in abstract form) in which creams containing dyclonine alone, alprostadil alone, or a dyclonine – alprostadil combination with two different drug concentrations were compared in a double-blind, crossover trial. This pilot study involved 30 patients who applied the cream 5 – 20 minutes before intercourse. A significant synergistic effect was observed with the cream containing 0.5 % dyclonine and 0.4 % alpros-tadil in comparison with the treatment with creams containing 1 % dyclonine alone or 0.4 % alprostadil alone (p<0.05) (see Table 63.1). Baseline intravaginal ejaculatory latency times are unfortunately not reported, but the mean intravaginal ejaculatory latency time post-dosing were 2.34 minutes and 4.08 minutes in the placebo and dyclonine – alprostadil combination groups, respectively (p <0.05). Adverse events were experienced by 17.5 % of men and are described as local and mild to moderate in nature, with an average duration of 18.2 minutes. Details of the adverse events and also whether or not any of the patients ’ partners experienced adverse events are also not provided. The most frequently reported adverse events in patients using alprostadil cream to treat erectile dysfunction are application site-related, such as penile burning, genital pain, and genital erythema, mostly resolving within 2 hours. The results of further studies using this cream are awaited with interest.

Prilocaine – lidocaine spray

TEMPE (Topical Eutectic Mixture for Premature Ejaculation, Plethora Solutions Ltd.) is a proprietary formulation of lido-caine and prilocaine in a metered dose aerosol delivery system specifically designed for use in premature ejaculation; the system delivers 7.5mg lidocaine base plus 2.5mg prilocaine base per actuation. The mixture is alcohol-free so there is little risk of stinging on application, and although it is oil-free, the mixture forms a clear, slightly oily, odorless solution that remains adherent to the application site. It can easily be wiped off if necessary with a damp cloth, so no condom is required.

The metered dose spray delivery system allows the desensitizing agents to be deposited in a dose-controlled, concentrated film on the glans penis, and they can then penetrate the glans within 5 – 10 minutes. The eutectic mixture is slower to penetrate intact keratinized skin and as such is not likely to anesthetize the shaft of the penis or the hands.

In the first open-label pilot study, 11 patients recorded stopwatch-timed intravaginal ejaculatory latency times at baseline and on five subsequent encounters when using the spray 15 minutes before intercourse. The average intravaginal ejaculatory latency time increased from 1 minute 24 seconds to 11 minutes 21 seconds (p = 0.008), representing an average eight-fold increase. In addition, 8 out of 11 patients and 7 out of 11 partners rated their sexual satisfaction as ‘better ’ or ‘much better’.

In a recently published phase 2, placebo-controlled trial, 54 patients using the prilocaine – lidocaine spray were able to prolong their intravaginal ejaculatory latency time from a baseline of 1.0 minute to 4.9 minutes. The treatment was also well tolerated, with only three patients (12 %) experiencing hypoesthesia (numbness of the penis) and a fourth patient experiencing loss of erection; none of the adverse events resulted in treatment discontinuation. The spray was also well tolerated by the female partners, with only one partner experiencing a mild burning sensation during intercourse each time her partner used the spray; again, this did not result in discontinuation.

Topical agents for the treatment of premature ejaculation: Discussion

Compared with systemic treatments for premature ejaculation, topical treatments do offer certain advantages: they can be applied when needed, and systemic side effects are unlikely. However, they do have a number of potential drawbacks: they can be messy, they can interfere with spontaneity, and they can cause numbness in the man or his partner. Dependent on formulation, they also require a period of time between application and maximum effect and need either to be used with a condom or be washed or wiped off before intercourse, which will have an effect on spontaneity and may decrease arousal. The cream formulations (lidocaine – prilocaine, dyclonine – alprostadil, and EMLA®) require a 5 – 20-minute application and the potential use of a condom, whereas the spray formulation (lidocine – prilocaine) has 5 – 15-minute application time and is easy to administer, remaining adherent to the glans penis after application and being less likely to penetrate intact keratinized skin causing anesthesia of the shaft of the penis.

However, the evaluation and comparison of the outcomes of clinical trials for premature ejaculation agents remains difficult whilst considerable debate over the definition of premature ejaculation continues. A critical review of the methodology of studies in premature ejaculation has revealed the scale of the differences and the resultant difficulties in comparing results from these studies. It is therefore important to exercise a degree of caution when comparing headline results. Recommendations for standards for clinical trials in premature ejaculation include the use of a precise definition of premature ejaculation (e.g. ejaculation that occurs within 1 minute after vaginal penetration in more than 90 % of intercourses); a randomized, double-blind, prospective design; the use of validated outcome measures (such as IELT); and the use of a stopwatch at each coitus, both during baseline and during drug treatment. Use of such stringent parameters in all future trials would enable meaningful meta-analyses to be carried out.

In conclusion, the treatments options for men with premature ejaculation are limited until a safe, efficacious, practical and preferably as-needed agent with a suitable risk – benefit profile is approved.

 

Selections from the book: “Textbook of Erectile Dysfunction”, 2009

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