Wyllie MG, Powell JA.
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.
Dinsmore WW, Wyllie MG.
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.
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
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.
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.
Carson C, Wyllie M.
PSD502 is a novel aerosolized, lidocaine-prilocaine, spray being developed for the treatment of lifelong premature ejaculation. The clinical profile of PSD502 is described in one of two double-blind, placebo-controlled, phase III studies.
To determine the effect of PSD502 on the Index of Premature Ejaculation (IPE) and intravaginal ejaculatory latency (IELT) of men with lifelong PE.
Men with lifelong PE who documented an IELT ≤ 1 minute with two or more of the first three sexual encounters during a 4-week baseline period were randomized to receive double-blind treatment with PSD502 or placebo for 3 months. Patients completed IPE and Premature Ejaculation Profile questionnaires at entry and monthly visits, and recorded stop-watch timed IELT during each encounter. Safety was assessed by collecting adverse event data and standard safety measures.
Stopwatch timed IELT recordings and a patient-reported outcome questionnaire the IPE were used in this study to determine the effect of PSD502 applied topically 5 minutes before intercourse.
Two hundred fifty-six men with PE were randomized from 38 centers in the U.S., Canada, and Poland. The geometric mean IELT over the 3-month treatment period increased from a baseline of 0.56 minute and 0.53 minute in the PSD502 and placebo group respectively to 2.60 and 0.80 minute. There were significantly greater increases in the scores for the IPE domains of ejaculatory control, sexual satisfaction and distress in the PSD502 group than in the placebo group, with a mean 5.0 point difference between treatments in change from baseline in the IPE domain for ejaculatory control, 4.6 point difference in change from baseline in the IPE domain for sexual satisfaction, and a 2.5 point difference in change from baseline in the IPE domain for distress. This was supported by improvements in all secondary endpoints.
In this study, PSD502 applied topically to the glans penis 5 minutes before intercourse showed significantly improved ejaculatory latency, ejaculatory control, sexual satisfaction and distress and was shown to be well tolerated by patients and partners.
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.
Dinsmore WW1, Hackett G, Goldmeier D, Waldinger M, Dean J, Wright P, Callander M, Wylie K, Novak C, Keywood C, Heath P, Wyllie M.
To evaluate, in a phase II study, the efficacy and safety of a topical eutectic mixture for premature ejaculation (TEMPE), a metered-dose aerosol spray containing a eutectic mixture of lidocaine and prilocaine, as a treatment for PE.
Men with PE (Diagnostic and Statistical Manual-IV definition) aged 18-75 years were randomized into a double-blind, placebo-controlled study in the UK and the Netherlands. Efficacy variables included the mean change in intravaginal ejaculatory latency time (IELT) from baseline and the proportion of patients who achieved an IELT of > or = 4, > or = 3 or > or = 2 min on two occasions, and the effect of TEMPE on the index of ejaculatory control (IEC) and sexual quality-of-life (SQoL) scores of patients and their partners. Safety and adverse event data were also collected. Fifty-four patients were randomized and received study treatment.
The observed mean change in IELT from baseline to the end of the treatment period was 3.8 min in the TEMPE group and 0.7 min in the placebo group, and when adjusted for baseline and centre was 2.4 times higher in the TEMPE than the placebo group (P < 0.01). The efficacy of TEMPE in increasing IELT was further supported by positive trends in the other efficacy endpoints. The proportion of men who had an IELT time > or = 2, > or = 3 or > or = 4 min on two occasions after treatment was 11/20 (55%), 8/20 (40%) and 5/25 (20%) in the TEMPE group, and 8/23 (35%), 3/23 (13%) and 3/23 (13%) in the placebo group, respectively, although these differences were not statistically significant. Improvements in IEC and SQoL (male and female) scores also showed trends towards greater efficacy for TEMPE than placebo. In all, 35 of 42 (83%) patients considered the spray easy to use. Mild to moderate local numbness occurred in three (12%) of the TEMPE-treated patients but did not lead to discontinuation.
Topical treatment with TEMPE produced a statistically and clinically significant increase in IELT compared with placebo, and resulted in positive trends in ejaculatory control and SQoL. TEMPE was considered easy to use and was well tolerated. The data support the conduct of further large-scale studies to establish the utility of TEMPE as a first-line treatment for PE.
TEMPE: Topical Eutectic-Like Mixture for Premature Ejaculation.
Henry R, Morales A, Wyllie MG.
Premature ejaculation (also known as rapid or early ejaculation) is the most common form of sexual dysfunction experienced by men, but there is presently an unmet need for a licensed pharmaceutical product that can be used on demand and that is effective from the first dose.
TEMPE (Topical Eutectic-Like Mixture for Premature Ejaculation; Plethora Solutions Plc.) is a proprietary metered-dose aerosol containing a combination of the well-known local anaesthetics lidocaine and prilocaine in a novel formulation. The authors evaluate here the progress that has been made towards the reformulation of these local anaesthetic agents into a unique eutectic-like formulation for use as a desensitising agent in the treatment of premature ejaculation, as well as examining other potential uses for the spray, such as pain relief at skin-graft donor sites.
Both lidocaine and prilocaine are soluble in the hydrofluoroalkane (HFA-134a) propellant, providing a unique formulation in which the pressurised liquid propellant is used as the solvent. Deployment of the metered-dose chamber vaporises the propellant, spraying lidocaine and prilocaine, now forced into a eutectic-like combination that remains in liquid form at temperatures well below their individual melting points, onto the target surface. The site is thus easily covered in a controlled dose of pure local anaesthetic in base form, providing ideal circumstances for optimised absorption through non- or poorly-keratinised skin, mucus membranes and wound surfaces.
TEMPE has been developed for use in premature ejaculation and preliminary results show promising improvements in intravaginal ejaculatory latency, as well as patient-reported outcomes.
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.
A review of the current status of topical treatments for premature ejaculation.
Morales A, Barada J, Wyllie MG.
We examine the progress that has been made towards the development of topical treatments for premature ejaculation (PE). Although generally regarded as one of the most common male sexual problems, the lack of approved pharmacological agents for PE means that treatment options are limited to behavioural therapy, where available, and the use of drugs ‘off-label’. There are various theories on the aetiology of PE, but it seems likely that both biological and psychological factors are important. One theory, that men with PE might have a heightened sensory response to penile stimulation, provides the rationale for using topical therapy; reducing the sensitivity of the glans penis with topical desensitizing agents (e.g. local anaesthetics) might improve ejaculatory latency without adversely affecting the sensation of ejaculation. Off-label topical treatments are now relatively widely used, despite limited supportive efficacy data. There are also new topical treatments in various stages of development, designed specifically for use in PE. Treatments reviewed include TEMPE spray, containing a eutectic mixture of the topical anaesthetics lidocaine and prilocaine, and several creams, including one containing natural products (SS-cream), and preliminary results from another containing the local anaesthetic dylonine, with alprostadil (prostaglandin E1). Despite wide variations in the methods of clinical trials, it is possible to conclude that all placebo-controlled studies of topical treatments have reported a significant increase in intravaginal ejaculatory latency time compared to baseline and placebo. Topical treatments for PE are appealing in that they can be applied as needed and only minimal systemic effects are likely. However, without well-controlled drug delivery there is the theoretical possibility of penile hypoaesthesia and/or transvaginal contamination. Unlike the cream formulations, the TEMPE spray has a well-controlled delivery system, making it easy to administer locally, and it appears to be well tolerated in early clinical trials. It appears that topical treatments might be able to satisfy many of the requirements of an ideal treatment for PE, and certainly have the potential for use as a first-line treatment.
Wyllie MG, Hellstrom WJ.
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.
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.
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.
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.