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‘Up and coming’ treatments for premature ejaculation: progress towards an approved therapy

Abstract

It is generally accepted that premature ejaculation (PE) is a more common problem than erectile dysfunction, although at present the options currently available for the treatment of PE are limited to behavioural psychotherapy and ‘off-label’ prescribing of pharmacological therapies. A sexual complaint with such a high prevalence together with an increasing understanding of the psychosocial consequences of PE has naturally stimulated the interest of the pharmaceutical industry and the first products designed specifically for the treatment of PE are either in late-stage clinical development or are already under regulatory review. Most of the new treatments for PE have been developed for ‘on-demand’ use, which may prove to offer the most favourable risk: benefit profile as well as the flexibility to adapt to differing frequencies of sexual activity. This paper reviews a number of emerging therapies in various stages of development that show potential for use in the treatment of PE.

Introduction

In recent years both the definition and the management of premature ejaculation (PE) have changed from the traditional authority-based to a more evidence-based approach.1, 2, 3 A distinction between primary (lifelong) or secondary (acquired) PE was first established by Schapiro in 1943,4 and was expanded by Waldinger5 to also include natural variable PE and premature-like ejaculatory dysfunction. However, PE had never been formally defined as a clinical condition (at least not in a way acceptable to the regulatory authorities) until the publication by the International Society for Sexual Medicine (ISSM) in 2008 of a new contemporary evidence-based definition for men experiencing lifelong PE.6, 7 This followed the deliberations within a group representing specialist (urologist, andrologist, mental health clinicians, sexual counsellors) and primary care/family physicians from the United States, Europe and Asia. PE was defined as ‘a male sexual dysfunction characterized by ejaculation which always or nearly always occurs prior to or within about one minute of vaginal penetration; and 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’.6, 7

PE is thought to be a more common problem than erectile dysfunction (ED), although as discussed above, prevalence data will depend on the definition used. In a study of men aged 18–59 conducted in the United States, around 30% of men reported that they ‘climaxed too early’ compared to 10% of men who reported that they ‘had trouble achieving or maintaining an erection’.8 Although this number may not represent the percentage of men with PE according to the most recent stringent guidelines, a sexual complaint with such a high prevalence together with an increasing understanding of the psychosocial consequences of PE has naturally stimulated the interest of the pharmaceutical industry. The involvement of pharmaceutical companies in the sponsorship of clinical trials for PE has been endorsed by some,9 but has not been universally welcomed, as demonstrated by the recent publication of a controversial article regarding the selective serotonin reuptake inhibitor (SSRI) dapoxetine.10 However, the unusual number of detailed comments by leading workers in the field following the article gives a flavour of the differing, but clearly emotive views on the subject.

Nonetheless (and side-stepping this ongoing debate for the present), a number of pharmaceutical products and devices are in various stages of development for the treatment of PE, although the situation remains that, despite the clear unmet medical need for an approved treatment, none has so far managed to reach the market. The main reasons for this are the selection of an appropriate mechanistic approach and the apparent hardening of attitude of the regulatory authorities to the risk: benefit equation.11 Long-term safety studies are required, which may be prohibitively expensive and reduce the remaining patent life of the product. Until very recently, the lack of evidence-based definition of PE and validated patient sexuality questionnaires, known as patient-reported outcomes (PROs), may also have hindered the ability of regulatory authorities to interpret and evaluate data from clinical trials of pharmacological treatments for PE.12 This has been addressed with the recent publication of a validated PE diagnostic tool, the Premature Ejaculation Diagnostic Tool.13, 14, 15 Although the ISSM definition of PE and validated PROs are clearly steps in the right direction, it will inevitably result in a need to re-evaluate the conclusions of previous studies in which the definitions of PE used for patient selection and PROs are deemed to be potentially inadequate.

‘On-demand’ versus daily pharmacotherapy for PE

Given that PE is not a life-threatening condition and that the majority of men are unlikely to be having sex on a daily basis (indeed, it may be a relatively infrequent event), the ideal treatment for PE has often (but not universally16) been described as one that can be taken or administered ‘on-demand’. Short of invasive procedures such as augmentation of the glans penis with hyaluronic gel to induce long-term penile hypoaesthesia,17, 18 there is no convincing evidence that any pharmacological treatment to date offers a ‘cure’ for PE. The American Urological Association (AUA 2004) guidelines on the management of PE19 suggest that the risks and benefits of all therapeutic options should be presented to the patient (and partner) so that an educated treatment choice may be made by the patient in consultation with the physician. Patients who find a particular treatment that works for them might want to continue using that treatment for as long as they remain sexually active. However, the frequency of sexual activity is dependent on age and personal circumstances and a rational treatment regimen for PE therefore needs to offer a suitable level of flexibility to adapt to changing lifestyles. Lack of spontaneity is one argument against the use of ‘on-demand’ treatments as opposed to daily oral therapy that is inherently less obtrusive and more conducive to spontaneity.16 However, one can draw parallels to the treatment of ED where lack of spontaneity with on-demand treatments has not been a stumbling block and in any case, is only one of many factors that need to be weighed up by patient and physician when selecting a suitable therapy.

Publication of a recent survey of US urologists ‘real-world’ practice patterns in treating PE20 indicates that most urologists are broadly following the AUA guidelines for the treatment of PE.19 The most commonly selected first-line therapy was on-demand treatment with SSRIs, prescribed by 26% of urologists followed by daily dosing with SSRIs (22%). Topical anaesthetics were prescribed first line by 11% of the urologists who responded and 14% as a second-line option for patients who did not respond to the initial therapy. It is interesting to note that as far as the prescribing patterns of this group of urologists indicate, a similar proportion of urologists are prescribing on-demand dosing to daily dosing.

Aetiology of PE and drug targets

In contrast to ED, no organic disease has been firmly associated with PE, except perhaps some evidence that prostatitis, hyperthyroidism and penile hypersensitivity may have a function in the aetiology of PE in some men,21, 22, 23 although a more contemporary theory is that PE is part of the normal biological variability of intra-ejaculatory latency time (IELT) in men, with a possible familial genetic vulnerability.24, 25 Serotonin (5-hydroxytryptamine, 5-HT), which has many functions throughout the body, including acting as a neurotransmitter in the central nervous system (CNS), appears to be a key mediator in the neurophysiology of ejaculation26, 27 with at least three 5-HT receptor subtypes (5-HT1A, 5-HT1B and 5-HT2C) so far implicated.28 It has been postulated that primary PE might be mediated by disturbances of 5-HT neurotransmission, 5-HT2C receptor hyposensitivity and/or 5-HT1A receptor hypersensitivity and, to a lesser extent, oxytocinergic neurotransmission in the CNS.24, 29 Opportunities for therapeutic intervention related to 5-HT have recently been thoroughly reviewed by Giuliano.30

Oral therapies

Tricyclic antidepressants

Clomipramine is a tricyclic antidepressant (TCA) that inhibits the uptake of noradrenaline and 5-HT by adrenergic and 5-HT neurons.31 Daily dosing with 25 or 50 mg clomipramine can significantly increase IELT compared with placebo32, 33, 34 and several studies using ‘on-demand’ dosing with clomipramine 25 mg 3–24 h before intercourse have also shown a significant increase in IELT in men with PE.35, 36, 37 In one study, clomipramine 25 mg taken on-demand with a mean drug-intercourse interval of 5.14 h resulted in an approximately 4-fold increase in stopwatch-measured IELT (from a baseline of <1 min), compared to a 1.4-fold increase with on-demand paroxetine 20 mg.37 The highest fold increase in IELT (6.2-fold) in the clomipramine group occurred between 3 and 4 h after drug intake, although shorter intervals were not tested. However, as for their use in depression, the utility of clomipramine, even with on-demand dosing, is limited by its side effects. Sleepiness, yawning, dry mouth and nausea on the day of dosing and the next day can be an annoying problem leading to treatment discontinuations.37

VR776 (Vectura Group plc., Chippenham, UK) is a novel proprietary formulation of clomipramine delivered by oral inhalation through Vectura's dry powder inhaler (Aspirair). In an abstract presented at the annual meeting of the European Society for Sexual Medicine in 2007 (the only published data so far), VR776 is reported to have a time to maximum plasma concentration (Tmax) of 1–2 min.38 VR776 was reported to be ineffective in increasing IELT in men with PE (baseline IELT <2 min) at the 1 mg dose, but statistically superior to placebo at the 2 mg dose (IELT 2.22 and 1.50 min for VR776 and placebo respectively; P=0.0108), although the clinical significance of this difference in men selected on the basis of a baseline IELT of <2 min is debatable. The high level of respiratory side effects (cough 70%, throat irritation 70% and respiratory tract irritation 35%) also suggests a need for reformulation of the product.

SSRIs

Delayed ejaculation is a common side effect of the SSRI class of antidepressant drugs (such as paroxetine, fluoxetine, sertraline and citalopram) when used to treat depressed patients and this serendipitous discovery has led to the use of SSRIs as a treatment for PE. SSRIs inhibit the reuptake of 5-HT into the presynaptic cell as a result of blockade of 5-HT transporters, increasing levels of 5-HT within the synaptic cleft.39 The use of SSRIs in the treatment of PE has been the subject of a number of comprehensive reviews19, 28, 40 and a meta-analysis,41 with the general conclusion that, with daily treatment, all the SSRIs produced an increase in IELT, with paroxetine exerting the strongest effect overall on time to ejaculation (a geometric mean 8.8-fold increase).41 Despite a lack of regulatory authority approval, the off-label use of SSRIs in the management of PE is currently endorsed by the AUA guidelines19 as well as the Second International Consultation on Sexual Dysfunctions.42

Although there is no doubt that daily SSRIs are highly effective in the treatment of PE, the accompanying nuisance side effects (such dry mouth, headaches and dizziness), together with the risk of the more serious consequences (including psychiatric and neurological as well as the potential for drug interactions,43 overdose and problems related to SSRI withdrawal44), may be considered to be less acceptable in the treatment of PE than for the alleviation of depression. However, the AUA consensus panel stated (in 2004) that they considered the level of adverse effects to be acceptable for the benefit derived in the patient with PE.19 The release of an advisory notice from the US Food and Drug Administration (FDA) in May 2007 warning that suicidal ideation and attempts have been associated with the initiation of SSRI antidepressant medications; especially in young adults aged 18–2445 (chronic and on-demand dosing), is a strong argument in favour of a treatment regimen for PE with a more favourable risk: benefit profile, at least in younger men.

The use of continuous versus on-demand administration of SSRIs for managing PE has recently been reviewed by Guiliano and Hellstrom46 with the conclusion that studies using conventional SSRI antidepressants with as-needed dosing to date have not been rigorous19, 37, 47, 48 and that elevated 5-HT levels achieved with acute SSRI treatment might be self-limiting because of activation of presynaptic 5-HT1A autoreceptors, ultimately limiting the increased 5-HT release into the synapse. ‘Priming’ by daily dosing with a low dose (10 mg) of paroxetine has been shown to enhance the effect of a higher dose (20 mg) taken on-demand.49

Although most SSRIs used for the treatment of PE require chronic administration to maximise the therapeutic effect, newer short-active agents are being developed with the intention that they are effective when used on-demand. In their recent review, Guiliano and Hellstrom46 conjectured that it is possible that an on-demand administration of a short-acting SSRI with a sufficiently rapid onset of action could provide an immediate increase in synaptic 5-HT levels, thus overwhelming synaptic feedback control mechanisms and producing a clinically meaningful effect in the absence of continuous administration. Dapoxetine (Johnson & Johnson, Mountain View, CA, USA) is a short-acting SSRI in development for the on-demand treatment of PE. On-demand administration of dapoxetine 30 or 60 mg 3 h before intercourse resulted in up to 3.6-fold increase in (natural mean) IELT in a group of men who met DSM-IV-TR criteria for PE, with an IELT at baseline of 2 min in 75% of episodes of intercourse.50 Dapoxetine was also relatively well tolerated compared to longer-acting SSRIs, although nausea, diarrhoea, headache and dizziness were commonly reported adverse events.50 Despite these promising findings, the FDA issued a non-approvable letter for dapoxetine in 2005, although a European marketing authorization application was recently submitted and is still pending.

Over the last few years, several other novel short-acting SSRIs have reached pre-clinical and early clinical development. These include UK-390957 (Pfizer Inc., New York, NY, USA) and BMS-505130 (Bristol-Myers Squibb, New York, NY, USA).51 However, Pfizer has withdrawn UK-390957 from further clinical studies, and there appears to be no further news of BMS-505130, possibly as a result of problems with low oral bioavailability.52 Similarly, VI-0134, an oral 5-HT4 agonist developed by Vivus Inc. (Mountain View, CA, USA), for on-demand use in PE was reported in a 2003 press release to significantly increase the ejaculatory latency period in men with PE,53 although no data appear to have been published, raising questions about the future of this product too. Slightly more positively, Dong-A Pharmaceutical Company (Seoul, South Korea) recently reported pre-clinical data for DA8031, a selective and potent SSRI that inhibited p-chloroamphetamine-induced ejaculation in rats with a comparable efficacy to dapoxetine,54 which deserves further investigation.

5-HT1A receptor agonists

The time taken to desensitize 5-HT1A receptors is thought to be the reason for the delay of several weeks in the clinical improvement of depression with SSRIs.55 Co-prescribing of the β-adrenoreceptor antagonist pindolol (which also antagonizes 5-HT1A receptors) is thought to improve the onset of action of SSRIs in terms of the relief of depressive symptoms.56, 57 5-HT1A antagonists have therefore been investigated as potential treatments for PE on the basis that they could mimic the desensitization of the receptor and speed up the onset of action of the SSRI, thereby inducing strong immediate ejaculatory delay. Two 5-HT1A antagonists, WAY-10063558, 59 and Robalzotan (NAD-299)60 have been used in animal models of ejaculation and both drugs delayed ejaculation acutely when administered together with an SSRI. Neither was effective when used alone confirming the hypothesis that the 5-HT1A receptors are activated in response to extracellular serotonin levels after acute SSRI administration. So far only the co-administration of daily pindolol 7.5 mg and paroxetine 20 mg in men with PE that was refractory to treatment with paroxetine alone has been evaluated, demonstrating the effectiveness of the daily SSRI/5-HT1A blocker combination (a 3.9-fold increase in IELT to 188 s from a baseline of 48 s).61 It remains to be seen whether the combination is effective when administered as needed and whether on-demand dosing can overcome the higher incidence of side effects (nausea, diarrhoea, dry mouth and headache) reported by patients receiving the daily combination treatment. This apparently effective SSRI/5-HT1A receptor agonist combination may prove useful for patients who do not respond to other therapies and certainly warrants further investigation.

Opioid receptor agonists

Tramadol, a centrally acting agonist of μ-opioid receptors, is a narcotic analgesic indicated for the management of moderate to severe pain. Its mode of action in PE is not completely understood, however, in animal models it binds to opioid receptors and is suggested to inhibit noradrenaline and serotonin reuptake. Tramadol 25 or 50 mg has been shown to be effective in prolonging IELT when used on-demand (1–2 h before anticipated intercourse) in patients with PE,62, 63 although interestingly, a recent study showed that daily treatment with one 100-mg sustained-release tablet for 4 weeks was no better at prolonging IELT than placebo.64 Zertane (formerly known as LI-301 and DM-7958; DMI Biosciences Greenwood Village, CO, USA) is a combination of an (unspecified) SSRI and a μ-opioid receptor agonist. It is reported to be in phase III clinical trials, and believed to be developed for ‘as-needed’ use.65 However, as far as the authors are aware, no results have ever been released, so it is impossible to evaluate the product. Moreover, serious concerns have been raised about the ethics of prescribing opioid drugs with an associated risk of dependence and abuse for the treatment of PE, particularly in younger men66 and considering the view of the FDA in relation to a short-acting SSRI alone (dapoxetine), a combination SSRI/opioid product is unlikely to be viewed favourably by the regulatory authorities.

Phosphodiesterase-5 inhibitors

On-demand oral phosphodiesterase-5 (PDE-5) inhibitors are a popular and effective treatment for ED, but there is no pharmacological rationale for their use in the treatment of PE. A review of 14 clinical trials of PDE-5 inhibitors in the treatment of PE concluded that there is no convincing evidence to support their function in the treatment of men with lifelong PE and normal erectile function.67 However, there is limited evidence to support a potential role for PDE-5 inhibitors alone or combined with daily or on-demand SSRIs in the treatment of acquired PE in men with comorbid ED.19

Other potential drug targets for oral therapy

As ejaculation is a sympathetic spinal cord reflex, sympatholytic agents such as α-1 adrenoreceptor antagonists could theoretically be used in the treatment of PE68 and there has been some success in ejaculatory delay with daily use of alfuzosin and terazosin.69, 70 However, as far as the authors are aware, the use of on-demand α-blockers has not been evaluated. In man, plasma oxytocin levels rise during tumescence and at the point of ejaculation are significantly higher than at baseline.71 Systemic administration of oxytocin has been shown to shorten the ejaculatory latency time and the post-ejaculation recovery interval in rats72, 73 and a recent study elucidated the site of action of oxytocin receptors involved in the sexual response and ejaculation.74 Theoretically, oxytocin receptor antagonists could be used to prolong IELT, although to date there has been no report on their efficacy in the treatment of PE.

Topical therapies

In terms of a treatment that can be used ‘as needed’ with the potential to avoid systemic toxicity, topical treatments are a logical area for further development. There are indeed a number of new products in the pipeline as well as the possibility of using existing products off-label. The logic behind all of the topical treatments is to prolong ejaculatory latency by reducing the sensitivity of the glans penis with topical desensitizing agents. However, unless carefully designed, topical treatments can be messy to use and the time to onset of action can mean spontaneity is compromised. Important differentiating factors in potential treatments are whether ejaculatory delay can be achieved without adversely effecting the sensation of ejaculation for the man and without transfer of the desensitizing agent to the partner. Progress towards the development of topical treatments for PE based on this approach was recently reviewed by Morales et al.75

A variety of products with claims to delay ejaculation are available over the Internet and from adult shops, although no data have been published on the efficacy (or indeed safety) of these products. In terms of products for which clinical data are available, the current treatment options are creams or sprays commonly used for topical anaesthesia of the skin and mucosa before minor skin procedures (for example lidocaine-prilocaine cream), which have been used off-label as a topical treatment for PE when applied to the penis and covered with a condom before intercourse.76 The optimum application time for lidocaine-prilocaine before intercourse is considered to be 20 min77 and patients using the cream have reported a 5.6-fold increase in IELT to 6.71±2.54 min and improved sexual satisfaction, although loss of sensation (hypoaesthesia) and penile irritation were reported by around 17% of men.78

In terms of topical agents that have been designed specifically for the treatment of PE, PSD502 (also known as TEMPE topical eutectic-like mixture for premature ejaculation; Plethora Solutions plc., London, UK) appears to be in the latest stage of development. PSD502 is a proprietary metered dose aerosol that delivers a eutectic mixture of 7.5 mg lidocaine and 2.5 mg prilocaine (dissolved in a non-chlorofluorocarbon propellant) per actuation.79 This method of delivery enables a concentrated film of local anaesthetics in their base form (uncharged) to be deposited onto the glans penis. Because only the base forms of local anaesthetics are able to penetrate skin or mucosa, the onset of action of the spray is more rapid than that seen with cream formulations (which contain a mixture of base and ionized forms of local anaesthetics).79 Results from a phase II placebo-controlled study have shown a 2.4-fold increase in geometric IELT (from baseline (s.d.) of 1.0 (1.2) min to 4.9 (4.9) min, P<0.01) in the lidocaine-prilocaine spray group compared with placebo,80 with 12% of men reporting hypoaesthesia. Phase III trials with the lidocaine-prilocaine spray are ongoing. In theory, as the eutectic mixture of lidocaine and prilocaine is absorbed by the poorly keratinised skin of the glans penis and is less likely to penetrate fully keratinised skin (that is on the shaft of the penis), sensation is more likely to be retained.79 The spray offers other advantages over the cream, reflecting the fact that it has been specifically designed as a treatment for PE: it is easy to apply using the metered dose spray; the product remains adherent to the delivery site without mess; no condom is required as the product can be easily wiped off before intercourse.79

Although the use of a eutectic mixture is one way of maximising skin/mucosa penetration, products containing other transdermal delivery systems are also in development. In 2006 promising results were presented by NexMed Inc. (East Windsor, NJ, USA) for their topical cream (NM100061) containing the local anaesthetic dyclonine with alprostadil, a prostaglandin with vasodilatory effects together with NexMed's patented permeation enhancer known as NexACT.81 However, no news or publications have followed the initial brief abstract and the product no longer appears in NexMed's list of pipeline products. Recent non-approval by the FDA of NexMed's Vitaros (formerly called Alprox-TD), a topical treatment for ED that also contains alprostadil and the same skin permeation enhancer, may well have also called into question the approvability of NM100061. Futura Medical (Guildford, UK) is (according to the company website82) developing a non-prescription topical product (PET500) utilizing their proprietary skin delivery technology DermaSys and containing a ‘well-characterized mild topical anaesthetic compound’, targeting men who only suffer situational or occasional PE.

Among the range of ‘herbal’ creams claiming to delay ejaculation, SS-cream (Severance Secret-Cream; Cheil Jedan Corporation, Korea) appears to be the only one that has been subject to clinical trials. It is made from extracts of natural products, some of which have local anaesthetic and vasodilatory properties and is applied to the glans penis 1 h before intercourse and washed off immediately before coitus.83 Despite promising results in clinical trials where it significantly prolonged ejaculatory latency in 89% of patients,83 SS-cream is unacceptable to some patients due to its unpleasant odour and colour and it is unlikely to gain approval outside of Korea.

Intracavernosal injection

On-demand intracavernosal injection (ICI) with some of the agents used in the treatment of ED (for example alprostadil or the papaverine–phentolamine combination known as ‘bimix’), typically prolongs an erection beyond the point of ejaculation, allowing intercourse to continue. ICI can therefore be used as a strategy to allow men with PE to maintain their erections, as opposed to increasing IELT.84 Although not yet evaluated, it is likely that therapies that extend the IELT as opposed to the duration of erection alone would provide a greater level of patient (if not partner) satisfaction in men with PE. Given that alprostadil and ICIs containing papaverine have been associated with intracorporeal pain, priapism and fibrosis, it is unlikely to be a popular choice for the on-demand treatment of PE.

Non-pharmacological therapy

Behavioural techniques and psychological therapy

There is nothing new about the use of psychological therapy in the treatment of PE, indeed, variations of the stop-squeeze and stop-pause technique as introduced by Masters and Johnson85 and Kaplan,86 respectively, have been in use for decades. However, the contemporary approach to psychological therapy is evidence based and integrates the best available research with clinical expertise in the context of patient characteristics, culture and preferences.87 It has been argued that a combination treatment integrating pharmaceuticals and sex therapy would provide an optimized approach to treatment,88 although the question of which psychotherapies are most effectively combined with pharmacotherapy remains unanswered. Rowland et al. (2008) raises the point that pharmaceutical companies could best serve their own interests by supporting research on the treatment of PE through cognitive behavioural therapy (CBT) and/or combined pharmacotherapy/CBT as combination therapies are likely to be more effective in the long-term treatment of PE than pharmacological interventions applied alone.9

Surgery

Neurotomy of the dorsal nerves of the penis is reported to be effective in the treatment of PE.89 However, the procedure is invasive, irreversible and remains experimental as it has not been properly evaluated in published clinical trials and does not have wide support in the medical community.

Devices

Despite anecdotal reports, there is no convincing clinical evidence that mechanical devices are useful in the treatment of PE. In a recent study, the use of a constriction ring (such as those used with vacuum therapy devices) over a period of 4 weeks failed to have any effect on IELT.90 Some success has been reported with a densensitizing penile band, which is not used during intercourse, but rather during masturbation to produce an habituation effect. The long-term success of this strategy is unknown and, as it requires a period of dedicated use, is not an effective on-demand therapy for PE.91

Phytotherapy

The list of natural/herbal products shown in preliminary pre-clinical or clinical trials to have an inhibitory effect on ejaculatory function is growing. This includes the constituents of SS-cream (as mentioned above), hyperforin (a concentrated extract of Hypericum perforatum found in the herbal preparation St John's Wort),92 Uighur medicine gu-jing-mai-si-ha tablet (GJMSHT)93 and even black tea (Camellia sinensis).94 Of course natural does not equal safe, and although drinking a cup of tea before intercourse in the belief that it might delay ejaculation may be acceptable to a PE sufferer, in terms of bringing new pharmaceutical products to market, there is no reason to suspect that the view taken by the regulatory authorities of extracts from plants (or animal venom, cf SS-cream) is likely to be any less stringent than for a conventional small molecule. The lack of patent protection and the anticipated unfavourable return on investment means that phytotherapy is unlikely to be the basis of licensed products to treat PE in the near future.

Summary and conclusions

In the absence of a ‘cure’ for PE, one must look towards long-term pharmacological treatment either with or without behavioural or psychological therapy. As appears to be the case with all other issues surrounding PE, there are differences of opinion as to the attributes of an ideal treatment for PE. However, for those who do not engage in sexual activity on a daily basis, it is our opinion that the ideal pharmacotherapy for PE would be an approved, discreet and on-demand therapy that is effective from the first dose, has proven efficacy in terms of IELT and PROs, and a low incidence of side effects and with no unwanted effects on the partner. A number of novel pharmacological and non-pharmacological therapies are emerging that show promising results for the future treatment of this problem, although others appear to have fallen by the wayside.

As all existing therapies for PE are used ‘off-label’ and demand appears to be growing, there is an unmet need for an effective, licensed treatment. With the recent publication of the ISSM definition of PE and the development of validated PE diagnostic tools, the scene is now set for the regulatory approval of the first products for the treatment of PE. The emerging oral agents reviewed may have a difficult hurdle to cross to gain regulatory approval in terms of the risk: benefit ratio, particularly the combination therapies for which there are additional issues to consider such as cost and drug interactions. As most of the emerging oral therapies are modified antidepressants, the regulatory authorities will, at the very least, want to see long-term safety data (for example suicide risk and addiction potential). Currently available topical agents are effective and have a more favourable risk: benefit profile, but have issues to do with application and spontaneity. These have been largely overcome in the novel topical spray formulation of lidocaine-prilocaine, which shows promise as an on-demand therapy with proven efficacy and a low incidence of side effects.

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Correspondence to J A Powell.

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MG Wyllie is a Board Member of Plethora Solutions and JA Powell is a contractor to Plethora Solutions.

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Powell, J., Wyllie, M. ‘Up and coming’ treatments for premature ejaculation: progress towards an approved therapy. Int J Impot Res 21, 107–115 (2009). https://doi.org/10.1038/ijir.2008.67

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Keywords

  • premature ejaculation
  • pharmacotherapy
  • SSRI
  • topical treatment

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