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In the works: pharmacological treatment for premature ejaculation

MICHAEL G. WYLLIE

The ideal treatment for premature to be having sex on a daily basis (indeed, it ejaculation – the most common male sexual may be a relatively infrequent event), the ideal treatment for PE has often been dysfunction – would be an approved, described as one that can be taken or discreet and on-demand therapy that is administered ‘on-demand’. It is interesting, effective from the first dose and has no however, to note that surveys of the prescribing patterns of urologists indicate side-effects. The author takes a look at that similar proportions of urologists are what is available. prescribing on-demand dosing as daily dosing.2

remature ejaculation (PE) has been AETIOLOGY OF PE AND DRUG TARGETS Pdefined by the wise men and women of In contrast to ED, no organic disease the International Society for Sexual has been firmly associated with PE, Medicine (ISSM) as ‘a male sexual except perhaps some evidence that dysfunction characterised by ejaculation prostatitis, hyperthyroidism and penile which always or nearly always occurs prior hypersensitivity may play a role in the to or within about one minute of vaginal aetiology of PE in some men,3 with penetration; and inability to delay a possible familial genetic overlay.4 ejaculation on all or nearly all vaginal Many different pathways are involved penetrations; and negative personal (Figure 1)3 and the relative importance consequences, such as distress, bother, of these is incompletely understood. frustration and/or the avoidance of sexual A particular focus has been on intimacy’.1 (5-hydroxytryptamine, 5-HT), which appears to be a key mediator in the Premature ejaculation is a more common neurophysiology of ejaculation, with problem than erectile dysfunction (ED), at least three 5-HT subtypes although the prevalence data depend on (5-HT1A, 5-HT1B, and 5-HT2C) so far the definition used. In a study in the USA implicated. The final common path, of men aged 18–59 years, around 30 per however, is undoubtedly the afferent- cent of men reported that they ‘climaxed efferent reflex, which can be influenced too early’ compared to 10 per cent of men like any other by local anaesthetics. who reported that they ‘had trouble achieving or maintaining an erection’. This ASSESSMENT OF CLINICAL BENEFIT article gives a flavour of the differing Drug companies tend to present data in pharmacological options for treating PE. many different ways, which can make

‘ON-DEMAND’ VERSUS DAILY Dr M.G. Wyllie, PhD, PHARMACOTHERAPY Chief Scientific Officer, Given that PE is not a life-threatening Plethora Solutions, London condition and that most men are unlikely

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OT, oxytocin; 5-HT, 5-hydroxytryptamine; ACh, acetylcholine; NO, nitric oxide; BS, bulbospongiosus muscle.

Figure 1. Pathways involved in ejaculation3 interpretation and drug–drug comparison As PE is generally not life-threatening, studies using ‘on-demand’ dosing with problematic. A more reliable index of drug the regulators are insistent on wide have shown some degree performance can be an analysis of what therapeutic ratios, ie potential drugs of benefit. the regulatory authorities require for have to be squeaky clean. marketing authorisation. To circumvent some of the issues relating It is not anticipated that the endpoints used to the use of an in non- The efficacy of therapy in clinical trials is in clinical trials will have any real diagnostic depressed patients and the limitations of generally based on a change in intravaginal value in the work-up of patients with PE. clomipramine, other formulations of the ejaculatory latency time (IELT), which is drug have been evaluated. One such assessed by stopwatch measurement, ORAL THERAPIES example is VR776 (Vectura Group plc, sometimes coupled with a patient-reported Traditionally, as in most therapeutic areas, Chippenham, UK), a novel proprietary outcome, such as the index of PE. The latter patients with PE prefer oral to formulation of clomipramine delivered by is used to capture ‘bother’ or ‘distress’, other routes. oral inhalation via Vectura’s dry powder which may not be directly related to inhaler (Aspirair). Although having some ejaculation time. One potentially useful effect, VR776 has a high level of benchmark in evaluating clinical data is that Clomipramine is a respiratory side-effects, which suggest that the ISSM uses a cut-off point in their PE that inhibits the uptake of noradrenaline the drug may not reach the market. definition of ‘within about one minute’. It and 5-HT by adrenergic and 5-HT neurons. would appear that the regulatory authorities Daily dosing with 25mg or 50mg Selective serotonin reuptake inhibitors require to see at least a doubling of time as clomipramine can significantly increase The use of selective serotonin reuptake the index of an effective drug. IELT compared with placebo,5 and several inhibitors (SSRIs) in PE, like many

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good drug discoveries, started with short-active agents are being developed to Opioid receptor clinical observation rather than rational optimise on-demand benefit. Dapoxetine , a centrally acting of drug design. Delayed ejaculation is a (Johnson & Johnson, Mountain View, µ-opioid receptors, is a narcotic analgesic common side-effect of the SSRI class of California, USA) is a short-acting SSRI in indicated for the management of moderate antidepressant drugs (such as , development for the on-demand treatment to severe pain. Its mode of action in PE is , and ) when of PE.8 On-demand administration of not completely understood; however, in used to treat depressed patients, and this dapoxetine three hours before intercourse animal models it binds to opioid receptors serendipitous discovery has led to the use resulted in an up to four-fold increase in and is suggested to inhibit noradrenaline of SSRIs as a treatment for PE. IELT. Dapoxetine was also relatively well and serotonin reuptake. tolerated compared to longer-acting SSRIs, SSRIs inhibit the reuptake of 5-HT into the although nausea, diarrhoea, headache and Tramadol 25 or 50mg has been shown to presynaptic cell as a result of blockade of dizziness were commonly reported adverse be effective in prolonging IELT when used 5-HT transporters, increasing levels of 5-HT events. In spite of these promising findings, on-demand (one to two hours before within the synaptic cleft. The use of SSRIs the Food and Drug Administration issued a anticipated intercourse) in patients with in the treatment of PE has been the subject non-approvable letter for dapoxetine in PE, although interestingly, a recent study of a number of comprehensive reviews 2005, although a European marketing showed that daily treatment with one and a meta-analysis,6 with the general authorisation has been obtained. 100mg sustained-release tablet for four conclusion that, with daily treatment, all weeks was no better at prolonging IELT the SSRIs produced an increase in IELT. Several other novel short-acting SSRIs than placebo.9 have reached preclinical and early clinical In spite of a lack of regulatory authority development. These include UK-390,957 Phosphodiesterase-5 inhibitors approval, the off-label use of SSRIs in the (Pfizer Inc., New York, USA) and BMS- On-demand oral phosphodiesterase-5 management of PE is currently endorsed 505130 (Bristol-Myers Squibb, New York, (PDE-5) inhibitors are a popular and by the American Urological Association USA). However, Pfizer has withdrawn effective treatment for ED, but there is guidelines as well as the Second International UK-390,957 from further clinical studies, no pharmacological rationale for their Consultation on Sexual Dysfunctions. and there appears to be no further news use in the treatment of PE. A review of of BMS-505130, possibly as a result of 14 clinical trials of PDE-5 inhibitors in the Although daily SSRIs are highly effective problems with low oral bioavailability. treatment of PE concluded that there is no in the treatment of PE, there are Similarly, VI-0134, an oral 5-HT4 agonist convincing evidence to support their role accompanying nuisance side-effects (such developed by Vivus Inc. (Mountain View, in the treatment of men with lifelong PE as dry mouth, headaches and dizziness) and California, USA) for on-demand use in PE and normal erectile function.10 However, the risk of more serious consequences also appears to have been abandoned. there is limited evidence to support a (including psychiatric and neurological as potential role for PDE-5 inhibitors alone or well as the potential for drug interactions 5-HT1A receptor antagonists combined with daily or on-demand SSRIs and problems related to SSRI withdrawal The time taken to desensitise 5-HT1A in the treatment of acquired PE in men and the potential for suicidal ideation). receptors is thought to be the reason for with comorbid ED. These may be important considerations the delay of several weeks in the clinical when SSRIs are used outside our normal improvement of depression with SSRIs. Other potential drug targets for oral comfort zone in the treatment of depression, 5-HT1A antagonists have therefore been therapy ie for the management of PE. investigated as potential treatments for As ejaculation is a sympathetic spinal PE on the basis that they could mimic cord reflex (see Figure 1), The use of continuous versus on-demand the desensitisation of the receptor and agents such as alpha-1 adrenoreceptor administration of SSRIs for managing PE speed up the onset of action of the SSRI, antagonists could theoretically be used in has recently been reviewed by Giuliano thereby inducing strong immediate the treatment of PE, and there has been 7 and Hellstrom, with the conclusion ejaculatory delay. Two 5-HT1A antagonists, some success in ejaculatory delay with that studies using conventional SSRI WAY-100635 and robalzotan (NAD-299), daily use of alfuzosin and terazosin. Plasma antidepressants with as-needed dosing have been used in animal models of oxytocin levels rise during tumescence and to date have not been rigorous. ejaculation and both drugs delayed are significantly higher at the point of ejaculation acutely when administered ejaculation than at baseline. Systemic To get round the actual or perceived issues together with an SSRI. Neither was administration of oxytocin has been shown of long-term use of ‘off-label’ SSRIs, effective when used alone. to shorten the ejaculatory latency time and

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the post-ejaculation recovery interval in aerosol that delivers a eutectic mixture of Other transdermal delivery systems rats, and a recent study elucidated the site 7.5mg lidocaine and 2.5mg prilocaine While the use of a eutectic mixture is one of action of oxytocin receptors involved in (dissolved in a non-chlorofluorocarbon way of maximising skin/mucosa the sexual response and ejaculation. propellant) per actuation.13 penetration, products containing other Theoretically, oxytocin receptor antagonists transdermal delivery systems are also in could be used to prolong IELT, although to This method of delivery enables a development. Promising results were date there has been no report on their concentrated film of local anaesthetics in presented by NexMed Inc. (East Windsor, efficacy in the treatment of PE. their base form (uncharged) to be New Jersey, USA) for their topical cream deposited onto the glans penis. As only the (NM100061) containing the local TOPICAL THERAPIES base forms of local anaesthetics are able to anaesthetic dyclonine with alprostadil, a Treatments that can be used ‘as needed’, penetrate skin or mucosa, the onset of prostaglandin with vasodilatory effects with the potential to avoid systemic action of the spray is more rapid than that together with NexMed’s patented toxicity, are a logical area for further seen with cream formulations (which permeation enhancer known as NexACT. development. Topical treatments can be contain a mixture of base and ionised However, the product no longer appears in messy to use and the time to onset of forms of local anaesthetics; Figure 2). NexMed’s list of pipeline products. action can mean that spontaneity is compromised. Important differentiating Results from phase 2/3 placebo-controlled Futura Medical (Guildford, UK) is (according factors in patient acceptability are whether studies have shown a four- to six-fold to the company website) developing a or not ejaculatory delay can be achieved increase in geometric IELT (from baseline in non-prescription topical product (PET500) without adversely affecting the sensation the lidocaine-prilocaine spray group utilising their proprietary skin delivery of ejaculation for the man and without compared with placebo),13,14 with only 3–5 technology DermaSys and containing a transfer of the desensitising agent to the per cent of men reporting hypoaesthesia. ‘well characterised mild topical anaesthetic partner. Progress on this approach has In theory, as the eutectic mixture of compound’, targeting men who suffer only been reviewed by Morales et al.11 lidocaine and prilocaine is absorbed by the situational or occasional PE. poorly keratinised skin of the glans penis Anaesthetic creams and sprays and is less likely to penetrate fully Natural products The treatment options are creams or sprays keratinised skin on the shaft of the penis, Among the range of ‘herbal’ creams commonly used for topical anaesthesia of sensation is more likely to be retained. claiming to delay ejaculation, SS-Cream the skin and mucosa before minor skin procedures (eg lidocaine-prilocaine cream). These have been used off-label as a topical treatment for PE when applied to the penis and covered with a condom before intercourse. The optimum application time for lidocaine-prilocaine is considered to be 20 minutes before intercourse. Patients using the cream have reported a 5.6-fold increase in IELT to 6.7±2.5 minutes and improved sexual satisfaction, although loss of sensation (hypoaesthesia) and penile irritation were reported by around 17 per cent of men.12

A topical agent that has been designed specifically for the treatment of PE (Topical Eutectic-like Mixture for Premature Ejaculation, TEMPE/PSD502; Plethora Figure 2. Mode of action of topical local anaesthetics (LA).11 Aerosol sprays contain purely Solutions plc, London, UK; Shionogi base (uncharged) forms of local anaesthetics, while creams contain a mixture of base and ionised forms. Only the uncharged base forms are able to penetrate skin or mucous Pharma Inc., New Jersey, USA) appears to membranes. Local anaesthetics produce localised reversible inhibition of nerve conduction by be in the latest stage of development. reducing the permeability of the neuronal membranes to sodium ions, the movement of which PSD502 is a proprietary metered-dose is necessary for the transmission of nerve impulses

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(Severance Secret-Cream; Cheil Jedan KEY POINTS Corporation, Korea) appears to be the only one that has been subject to clinical trials. It • There is now a consensus definition for premature ejaculation is made from extracts of natural products, some of which have local anaesthetic and • Premature ejaculation is the most common male sexual dysfunction vasodilatory properties and is applied to the • Penile hypersensitivity and genetics may be important glans penis one hour before intercourse • Regulatory authorities are insistent on an excellent therapeutic ratio in what and washed off immediately before coitus. they sometimes see as a ‘lifestyle’ disorder In spite of promising results in clinical trials, where it significantly prolonged ejaculatory • There is no good evidence that ‘off-label’ selective serotonin reuptake latency in 89 per cent of patients, SS-cream inhibitors are effective ‘on-demand’. However, their chronic ‘off-label’ use is unacceptable to some patients as a result represents the mainstay of current therapy of its unpleasant odour and colour, and it is • Dapoxetine, although approved, does not appear to be widely used; cost could unlikely to gain approval outside of Korea. be an issue BEHAVIOURAL TECHNIQUES AND • The evidence supporting the use of phosphodiesterase-5 inhibitors in the PSYCHOLOGICAL THERAPY treatment of premature ejaculation is somewhat limited Ironically, based not so much on evidence- • Available topical treatments have limitations in terms of patient acceptability; based support but history, behavioural there is no approved topical agent but there is some degree of ‘off-label’ use techniques and psychological therapy are of desensitising creams the only approved therapies in the USA. There is nothing new about the use of • PSD502, if approved, may have an optimal clinical profile in terms of psychological therapy in the treatment of therapeutic ratio and patient acceptance PE; indeed, variations of the stop-squeeze and stop-pause technique, as introduced by Masters and Johnson and Kaplan, sales in the EU may have curbed the risk–benefit profile, but may have deficits respectively, have been in use for decades. enthusiasm of the pharmaceutical industry. because of ease of application and It has been argued that a combination spontaneity. These may have been largely treatment integrating pharmaceuticals and Apart from dapoxetine (in the EU), as all overcome in PSD502, the novel topical sex therapy would provide an optimised therapies for PE are used ‘off-label’ and spray formulation of lidocaine-prilocaine, approach to treatment, although the demand appears to be growing, there is which shows promise as an on-demand question of which psychotherapies an unmet need for an effective, licensed therapy with proven efficacy and a low are most effectively combined with treatment. With the recent publication incidence of systemic side-effects. pharmacotherapy remains unanswered. of the ISSM definition of PE and the development of validated PE diagnostic Declaration of interests SUMMARY AND CONCLUSIONS tools, the scene is now set for wider Michael Wyllie is a Board Member of In the absence of a ‘cure’ for PE, one must regulatory approval of more products Plethora Solutions. look towards long-term pharmacological for the treatment of PE. treatment either with or without REFERENCES behavioural or psychological therapy. For Any of the novel oral agents described 1 McMahon CG, Althof S, Waldinger MD, et al. those who do not engage in sexual activity above may have a difficult hurdle to cross An evidence-based definition of lifelong on a daily basis, the ideal pharmacotherapy to gain regulatory approval in terms of premature ejaculation: report of the for PE would be an approved, discreet and the risk–benefit ratio, particularly the International Society for Sexual Medicine Ad on-demand therapy that is effective from combination therapies, for which there are Hoc Committee for the Definition of Premature the first dose, has proven efficacy, a low additional issues to consider such as cost Ejaculation. BJU Int 2008;102:338–50. incidence of side-effects and with no and drug interactions. As a minimum, 2 Montague DK, Jarow J, Broderick GA, et al. unwanted effects on the partner. Within regulatory authorities will want to see AUA guideline on the pharmacologic the past decade, a number of novel long-term safety data, such as suicidal management of premature ejaculation. pharmacological therapies were emerging ideation risk and addiction potential. J Urol 2004;172:290–4. for the treatment of this problem, but the Topical agents, used ‘off-label’, are demise of dapoxetine in the USA and poor effective and have a more favourable Continued on page 29

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