What's known on the subject? and What does the study add?
It is now accepted that both biological and psychological factors are important in the aetiology of premature ejaculation (PE). Of particular interest is the correlation between ejaculatory latency and penile sensory thresholds. Men with PE appear to have a heightened sensory response to penile stimulation and also generally exhibit other abnormal reflex pathways within the ejaculatory process, suggesting a link between penile hypersensitivity and PE. Considering these sensory differences, drugs that selectively produce some degree of penile desensitization or act within the afferent-efferent reflex could delay ejaculatory latency without adversely affecting the sensation of ejaculation.
This review evaluates published clinical trial data for local anaesthetics used off-label in PE as well as novel topical agents in development. New analyses of the phase III data are presented for topical eutectic mixture for PE (TEMPE, also known as PSD502, Plethora Solutions Plc., London), a proprietary formulation of lidocaine and prilocaine in a metered-dose aerosol delivery system.
• To review the published clinical trial data for local anaesthetics used off-label in premature ejaculation (PE), as well as novel topical agents in development.
• To evaluate the safety and efficacy of topical eutectic mixture for PE (TEMPE) in subjects with PE and their sexual partners using all available phase III data.
• Topical treatments can be applied as needed and systemic side-effects are unlikely. However, existing off-label topical treatments for PE have several disadvantages: they can be messy, interfere with spontaneity, and could cause numbness in the man or his partner.
• Several novel topical agents are in development for the treatment of PE. TEMPE appears to be closest to approval.
• TEMPE, applied 5 min before sexual intercourse (539 subjects) resulted in an increase in the geometric mean intra-vaginal ejaculatory time (IELT) from a baseline of 0.58 min to 3.17 min during 3 months of double-blind treatment; a 3.3-fold delay in ejaculation compared with placebo (P < 0.001).
• IELT continued to increase further with continued use of TEMPE throughout the double-blind and open-label phases.
• Treatment with TEMPE also resulted in marked improvements in subjective measures, e.g. ejaculatory control, sexual satisfaction and distress, with little or no evidence of systemic side-effects and minimal desensitization of the genitalia in subjects or their sexual partners.
• The use of a topical agent could be an acceptable first-line option for PE, given the favourable risk/benefit ratio of these products.
• Topical aerosol application of TEMPE may provide safe, effective, on-demand treatment for PE.
topical eutectic mixture for premature ejaculation
EXISTING TREATMENT OPTIONS
Recommendations from the AUA  and the second International Consultation on Sexual Dysfunctions (ICSD)  recognise that premature ejaculation (PE) is a self-reported diagnosis and emphasise the importance of obtaining a comprehensive sexual history when making a diagnosis.
Treatment options for men with PE include behavioural therapy, conventional systemically active treatments, and topical therapies. Outside a small selection of countries in Europe, there are no pharmacological agents approved for use in PE, and apart from dapoxetine (PriligyTM), drugs have to be administered off-label.
The process of care algorithm for PE produced by the ICSD recommends pharmacotherapy with a selective serotonin reuptake inhibitor (SSRI) or topical anaesthetics as the first-line treatment in patients with lifelong PE and as second-line treatment in patients with acquired PE . In practice, pharmacotherapy is likely to be used first-line in both situations, due to limited access to skilled sex therapists and relationship counsellors. The use of a topical agent could be an acceptable first-line option, given the favourable risk/benefit ratio of these products. This is reflected in the treatment algorithm in Fig. 1, which is modified from the ICSD recommendations .
The rationale behind the use of SSRIs is based on side-effects in depressed patients who had normal sexual function. Delayed ejaculation is a common side-effect of many antidepressant drugs, particularly the serotoninergic antidepressant clomipramine  and the SSRIs fluoxetine, paroxetine, and sertraline [4–6]. These drugs increase the level of synaptic serotonin, presumably inhibiting the ejaculatory reflex, and thereby prolong intra-vaginal ejaculatory latency time (IELT). Doses of SSRIs are generally lower for PE than for depression. Despite this, the adverse-event profile including dry mouth, drowsiness, nausea, and reduced libido is similar . There is also the potential for development of a serious drug interaction that can lead to serotoninergic syndrome and suicidal ideation .
Dapoxetine (PriligyTM, Johnson & Johnson) is the first oral agent developed specifically for the management of PE . The drug has been approved in several European countries and a handful of countries elsewhere.
RATIONALE FOR THE USE OF LOCAL ANAESTHETICS
Although there are many theories on the aetiology of PE , it is now accepted that both biological and psychological factors are important. There is a strong correlation between ejaculatory latency and penile sensory thresholds [9,10], with men with PE having heightened sensory response to penile stimulation [9,11]. They also generally exhibit other abnormal reflex pathways within the ejaculatory process leading to the conclusion that there is a link between penile hypersensitivity and PE . Circumcision can have a desensitizing effect on the penile glans  and reduce the frequency of self-reported PE . On this basis, drugs that selectively produce some degree of penile desensitization or act within the afferent-efferent reflex could provide effective therapy for PE. Thus a reduction in the sensitivity of the glans penis with local anaesthetics could delay ejaculatory latency without adversely affecting the sensation of ejaculation .
STATUS OF LOCAL ANAESTHETIC TREATMENTS FOR PE
The lack of approved pharmacological therapy for PE has led to the use of over-the-counter remedies and the ‘off-label’ use of antidepressants and local anaesthetics. However, there are also novel desensitising agents specifically designed to treat PE in late stage clinical development.
Compared with oral treatments, topical treatments are appealing in that they can be applied on an ‘as needed’ basis and systemic side-effects are likely to be minimal. However, the application of a desensitising agent to the penis does have the potential for penile hypoesthesia and theoretically, as a result of trans-vaginal transfer, female genital hypoesthesia as side-effects.
In this era of evidence-based medicine, an important consideration is the availability of adequate supportive clinical data. The efficacy and adverse-events profiles for topical treatments are discussed below.
OVER-THE-COUNTER TOPICAL TREATMENTS
Lidocaine 9.6% spray, marketed as inter alia‘Stud 100’ or ‘Premjact’, has been available over the counter for over 25 years in some countries and, as their names suggest, are marketed as delaying ejaculation. The absence of reliable clinical trials data means that the validity of the claims cannot be assessed, although inclusion of the word ‘desensitising’ in the product descriptor may indicate the overall impact on the sexual experience.
Severance secret-cream (SS-cream; Cheil Jedan Corporation, Seoul, Korea) includes extracts from nine natural products, some of which have local anaesthetic properties. Several studies have been carried out in Korea, but the cream is not widely approved for use.
When applied to the glans penis the cream increased the latency and amplitude of somatosensory evoked potentials at the glans penis  and increased dose-dependently the penile vibratory threshold . In a multi-centre, double-blind study, SS-cream increased the mean stop-watch-measured IELT from a baseline of 1.4 min to 10.9 min and was 27-times more effective than placebo in increasing sexual satisfaction . However, one in five subjects reported mild localised irritation, including pain and burning, and 12% reported negative sexual side-effects such as delayed ejaculation, an-ejaculation, and erectile dysfunction . It is unlikely that this product will be approved outside Korea.
OFF-LABEL TOPICAL TREATMENTS
At normal temperature and pressure, lidocaine and prilocaine are solids. If mixed in equal quantities, however, they form a liquid, eutectic-like mixture. This can be formulated without the use of a solvent. Eutectic mixture of local anaesthetic (EMLA; AstraZeneca) is a local anaesthetic cream containing 2.5% each of lidocaine and prilocaine for topical application and was developed to anaesthetise intact skin. To be active fully the local anaesthetics must be in the un-ionized form.
In a pilot study evaluating EMLA for PE  11 subjects applied the cream to the whole glans and shaft of the penis 30 min before intercourse (covered with a condom, which could be removed before intercourse and the cream wiped off if desired). Nine of the 11 subjects rated their performance as ‘excellent’ or ‘better’ and all 11 partners were satisfied with the treatment results . A further placebo-controlled trial determined that the optimal application time was 20 min . All subjects using EMLA with an application time of 45 min had penile numbness and loss of erection.
In a larger double-blind, placebo-controlled trial , subjects applied a thin layer of cream to the glans penis. The cream was then covered with a condom for 10–20 min before intercourse and response was assessed 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. In all, 11 of 16 subjects who responded reported ‘great’ or ‘excellent’ sexual satisfaction. Loss of penile sensation, retarded ejaculation, and penile irritation were a problem for five men, and one female partner reported substantially decreased vaginal sensitivity.
Overall, it can be concluded that EMLA has some degree of efficacy in PE but due to hypoaesthesia has low benefit risk. It is inconvenient, messy and slow-acting, and it is not approved for this indication. However, it represented a starting point for the development of novel formulations which would be devoid of compliance limiting systemic side effects.
NOVEL TOPICAL AGENTS IN DEVELOPMENT
Closest to approval by the regulators is topical eutectic mixture for PE (TEMPE [also known as PSD502], Plethora Solutions Plc, London). This is a proprietary formulation of lidocaine and prilocaine in a metered-dose aerosol-delivery system specifically designed for use in PE; the system delivers 7.5 mg lidocaine base plus 2.5 mg prilocaine base per actuation, with three actuations being a standard dose. 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, odourless solution that remains adherent to the application site. It is easily wiped off with a damp wipe, so no condom is required .
The metered-dose spray-delivery system allows the desensitising agents, importantly in the optimal un-ionized form, to be deposited in a dose-controlled, concentrated film on the glans penis, which can then penetrate the glans within 5–10 min . The eutectic mixture is slower to penetrate intact keratinized skin and as such is not likely to anaesthetise the shaft of the penis or the hands .
In the first open label study , 11 subjects recorded stopwatch-timed IELTs at baseline and on five subsequent encounters when using the spray 15 min before intercourse. The average IELT increased from 1.4 to 11.35 min (P= 0.008), representing an average eight-fold increase. In addition, 8 of 11 subjects and 7 of 11 partners rated their sexual satisfaction as ‘better’ or ‘much better’. In a phase 2, placebo-controlled trial , 54 subjects using the prilocaine-lidocaine spray increased their IELT from a baseline of 1.0 min to 4.9 min. The treatment was also well tolerated, with only three (12%) reporting hypoaesthesia (penile numbness) and one 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 reporting a mild burning sensation during intercourse each time her partner used the spray; again, this did not result in discontinuation.
Two double-blind placebo controlled multi-centre phase III clinical trials have been completed [23,24]. Over 530 subjects, all meeting the International Society for Sexual Medicine (ISSM) definition of lifelong PE , have been evaluated using IELT and the domains of two questionnaires, the Index of Premature Ejaculation (IPE) and the Premature Ejaculation Profile (PEP). The data from the individual studies have been published separately [23,24], and new analyses of the phase III data, are summarised below.
In the phase III studies, TEMPE was applied 5 min before sexual intercourse. In the combined analysis the geometric mean IELT increased from a baseline of 0.58 min to 3.17 min during the 3 months of the double-blind treatment phase, in the TEMPE group and from 0.56 min to 0.94 min in the placebo group. Analysis of covariance of the log-transformed values revealed that ejaculation was delayed 5.6-fold from baseline values in the TEMPE group and 1.7-fold from baseline in the placebo group. When IELT values of TEMPE-treated subjects were compared with those of the placebo-treated subjects, a 3.3-fold (95% CI: 2.78, 4.01) delay in ejaculation that was statistically (P < 0.001) and clinically significant was observed.
In the TEMPE-treated subjects the IELT increased markedly on the first measurement after initiation of treatment (month 1). Not only was this effect maintained, but IELT continued to increase further throughout the double-blind phase (Fig. 2) [23,24]. In contrast, after a small rise during the first month, the IELT scores of placebo-treated subjects remained fairly constant.
Subjects had the option to participate in an open-label phase of either 5  or 9 months  duration at the end of the double-blind phase. The positive changes in IELT seen during the double-blind phase in TEMPE-treated subjects were maintained and indeed augmented during the open-label phase and there was a marked improvement in IELT in subjects converting from placebo to TEMPE (Fig. 3) [23,24].
The changes in IELT were mirrored in all domains of the IPE (Fig. 4) and PEP for subjects, and in the PEP domains for partners [23,24].
There was little or no evidence of systemic side-effects and only minimal desensitisation of the genitalia in either subject or partner, which as evidenced by IPE and PEP scores did not detract from sexual satisfaction (Table 1) [23,24].
Table 1. Local treatment-related adverse events (AEs) reported by subjects (358) and their sexual partners using TEMPE 30 mg (applied 5 min before intercourse) for 3 months double-blind treatment: combined data from two Phase III clinical trials [23,24]
Subject (n= 358)
Partner (n= 358)
A subject with multiple occurrences of an AE under one treatment is counted only once in the AE category for that treatment. A subject with multiple AEs within a primary system organ class is counted only once in the total row.
There was no evidence of tachyphylaxis and indeed with time, as sexual confidence presumably improved, the treatment became even more effective. This is consistent with the belief of many sexual medicine specialists that the patho-physiology of PE has both neurobiogenic and psychogenic elements [26,27]. It seems plausible that as treatment with TEMPE prolongs IELT through activity on the neurobiogenic factors, the subject becomes more confident in his ability to control ejaculation, and this has a positive effect on the psychogenic factors, resulting in further improvement in the symptoms and signs of PE.
Compared with systemic treatments for PE, topical local anaesthetic treatments do offer certain advantages: they can be applied as needed and systemic side-effects are unlikely. However, they do have several potential drawbacks: they can be messy, they can interfere with spontaneity, and they could cause numbness in the man or his partner. Dependent on formulation, they may also require a period of time between application and maximum effect and need either to be used with a condom or to be washed or wiped off before intercourse, which could have an effect on spontaneity and may decrease arousal. The local anaesthetic cream formulations require application 5–20 min before intercourse whereas the aerosol preparation (TEMPE) can be applied 5 min before. It is easy to administer, remaining adherent to the glans penis after application and is less likely to penetrate intact keratinized skin or cause anaesthesia of the shaft of the penis [10,20].
The evaluation and comparison of clinical trials in PE was problematic until an evidence-based definition of PE was developed . A critical review of the methodology of studies in PE has revealed the scale of the differences and the resultant difficulties in comparing results from these studies . Recommendations for standards for clinical trials in PE [2,28,29] include the use of a precise PE definition (e.g. ejaculation that occurs ≤1 min after vaginal penetration in >90% of intercourses); a randomised, double-blind, prospective design; the use of validated outcome measures (e.g. IELT); the use of a stopwatch at each coitus, both during baseline and during drug treatment and ‘validated’ subject and partner reported outcomes. It would appear that the phase III studies on TEMPE were conducted to these exacting standards [23,24]. Under these conditions TEMPE has a favourable benefit-risk profile and gave a consistent durable improvement.
In conclusion, topical aerosol application of TEMPE may provide a safe and effective, on-demand treatment option for men with PE.
CONFLICT OF INTEREST
Michael G. Wyllie is a Board Member of Plethora Solutions and Julia A. Powell is a contractor to Plethora Solutions. Funding for this publication was provided by Plethora Solutions Holdings Plc.