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.
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
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.
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.
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.
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.
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.
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
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.
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
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.
Waldinger MD . Lifelong premature ejaculation: from authority-based to evidence-based medicine. BJU Int 2004; 93: 201–207.
McMahon CG . Clinical trial methodology in premature ejaculation observational, interventional, and treatment preference studies—part I—defining and selecting the study population. J Sex Med 2008; 5: 1805–1816.
McMahon CG . Clinical trial methodology in premature ejaculation observational, interventional, and treatment preference studies—part II—study design, outcome measures, data analysis, and reporting. J Sex Med 2008; 5: 1817–1833.
Schapiro B . Premature ejaculation: a review of 1130 cases. J Urol 1943; 50: 374–379.
Waldinger MD . Premature ejaculation: definition and drug treatment. Drugs 2007; 67: 547–568.
McMahon CG, Althof S, Waldinger MD, Porst H, Dean J, Sharlip I et al. An evidence-based definition of lifelong premature ejaculation: report of the International Society for Sexual Medicine ad hoc Committee for the Definition of Premature Ejaculation. BJU Int 2008; 102: 338–350.
McMahon CG, Althof SE, Waldinger MD, Porst H, Dean J, Sharlip ID et al. An evidence-based definition of lifelong premature ejaculation: report of the International Society for Sexual Medicine (ISSM) ad hoc Committee for the Definition of Premature Ejaculation. J Sex Med 2008; 5: 1590–1606.
Laumann EO, Paik A, Rosen RC . Sexual dysfunction in the United States: prevalence and predictors. JAMA 1999; 281: 537–544.
Rowland D, Cooper S, Macias L . Pharmaceutical companies could serve their own interests by supporting research on the efficacy of psychotherapy on premature ejaculation. Int J Impot Res 2008; 20: 115–120.
Waldinger MD, Schweitzer DH . Premature ejaculation and pharmaceutical company-based medicine: the dapoxetine case. J Sex Med 2008; 5: 966–997.
Wyllie MG . Another year, another AUA. BJU Int 2006; 97: 1119–1120.
Althof SE, Symonds T . Patient reported outcomes used in the assessment of premature ejaculation. Urol Clin North Am 2007; 34: 581–589, vii.
Althof S, Rosen R, Symonds T, Mundayat R, May K, Abraham L . Development and validation of a new questionnaire to assess sexual satisfaction, control, and distress associated with premature ejaculation. J Sex Med 2006; 3: 465–475.
Symonds T, Perelman MA, Althof S, Giuliano F, Martin M, May K et al. Development and validation of a premature ejaculation diagnostic tool. Eur Urol 2007; 52: 565–573.
Symonds T, Perelman M, Althof S, Giuliano F, Martin M, Abraham L et al. Further evidence of the reliability and validity of the premature ejaculation diagnostic tool. Int J Impot Res 2007; 19: 521–525.
Waldinger MD, Zwinderman AH, Olivier B, Schweitzer DH . The majority of men with lifelong premature ejaculation prefer daily drug treatment: an observation study in a consecutive group of Dutch men. J Sex Med 2007; 4 (4 Part 1): 1028–1037.
Kim JJ, Kwak TI, Jeon BG, Cheon J, Moon DG . Effects of glans penis augmentation using hyaluronic acid gel for premature ejaculation. Int J Impot Res 2004; 16: 547–551.
Kwak TI, Jin MH, Kim JJ, Moon DG . Long-term effects of glans penis augmentation using injectable hyaluronic acid gel for premature ejaculation. Int J Impot Res 2008; 20: 425–428.
Montague DK, Jarow J, Broderick GA, Dmochowski RR, Heaton JP, Lue TF et al. AUA guideline on the pharmacologic management of premature ejaculation. J Urol 2004; 172: 290–294.
Shindel A, Nelson C, Brandes S . Urologist practice patterns in the management of premature ejaculation: a nationwide survey. J Sex Med 2008; 5: 199–205.
Carani C, Isidori AM, Granata A, Carosa E, Maggi M, Lenzi A et al. Multicenter study on the prevalence of sexual symptoms in male hypo- and hyperthyroid patients. J Clin Endocrinol Metab 2005; 90: 6472–6479.
Shamloul R, el-Nashaar A . Chronic prostatitis in premature ejaculation: a cohort study in 153 men. J Sex Med 2006; 3: 150–154.
Xin ZC, Chung WS, Choi YD, Seong DH, Choi YJ, Choi HK . Penile sensitivity in patients with primary premature ejaculation. J Urol 1996; 156: 979–981.
Waldinger MD . The neurobiological approach to premature ejaculation. J Urol 2002; 168: 2359–2367.
Waldinger MD, Rietschel M, Nothen MM, Hengeveld MW, Olivier B . Familial occurrence of primary premature ejaculation. Psychiatr Genet 1998; 8: 37–40.
Giuliano F, Clement P . Physiology of ejaculation: emphasis on serotonergic control. Eur Urol 2005; 48: 408–417.
Giuliano FA, Rampin O, Benoit G, Jardin A . Neural control of penile erection. Urol Clin North Am 1995; 22: 747–766.
Giuliano F, Clement P . Serotonin and premature ejaculation: from physiology to patient management. Eur Urol 2006; 50: 454–466.
Waldinger MD, Berendsen HH, Blok BF, Olivier B, Holstege G . Premature ejaculation and serotonergic antidepressants-induced delayed ejaculation: the involvement of the serotonergic system. Behav Brain Res 1998; 92: 111–118.
Giuliano F . 5-Hydroxytryptamine in premature ejaculation: opportunities for therapeutic intervention. Trends Neurosci 2007; 30: 79–84.
Gur E, Lerer B, Newman ME . Chronic clomipramine and triiodothyronine increase serotonin levels in rat frontal cortex in vivo: relationship to serotonin autoreceptor activity. J Pharmacol Exp Ther 1999; 288: 81–87.
Kim SC, Seo KK . Efficacy and safety of fluoxetine, sertraline and clomipramine in patients with premature ejaculation: a double-blind, placebo controlled study. J Urol 1998; 159: 425–427.
Althof SE, Levine SB, Corty EW, Risen CB, Stern EB, Kurit DM . A double-blind crossover trial of clomipramine for rapid ejaculation in 15 couples. J Clin Psychiatry 1995; 56: 402–407.
Segraves RT, Saran A, Segraves K, Maguire E . Clomipramine versus placebo in the treatment of premature ejaculation: a pilot study. J Sex Marital Ther 1993; 19: 198–200.
Haensel SM, Rowland DL, Kallan KT . Clomipramine and sexual function in men with premature ejaculation and controls. J Urol 1996; 156: 1310–1315.
Strassberg DS, de Gouveia Brazao CA, Rowland DL, Tan P, Slob AK . Clomipramine in the treatment of rapid (premature) ejaculation. J Sex Marital Ther 1999; 25: 89–101.
Waldinger MD, Zwinderman AH, Olivier B . On-demand treatment of premature ejaculation with clomipramine and paroxetine: a randomized, double-blind fixed-dose study with stopwatch assessment. Eur Urol 2004; 46: 510–515; discussion 516.
Leaker B . Abstract P-05-048: a double blind, placebo-controlled, randomised crossover study to investigate the effect of inhaled doses of VR776 on intravaginal ejaculatory latency in patients with premature ejaculation. J Sex Med 2008; 5 (Suppl 2): 60.
Ahlenius S, Larsson K, Svensson L . Further evidence for an inhibitory role of central 5-HT in male rat sexual behavior. Psychopharmacology (Berl) 1980; 68: 217–220.
Wang WF, Chang L, Minhas S, Ralph DJ . Selective serotonin reuptake inhibitors in the treatment of premature ejaculation. Chin Med J (Engl) 2007; 120: 1000–1006.
Waldinger MD, Zwinderman AH, Schweitzer DH, Olivier B . Relevance of methodological design for the interpretation of efficacy of drug treatment of premature ejaculation: a systematic review and meta-analysis. Int J Impot Res 2004; 16: 369–381.
Lue TF, Giuliano F, Montorsi F, Rosen RC, Andersson KE, Althof S et al. Summary of the recommendations on sexual dysfunctions in men. J Sex Med 2004; 1: 6–23.
Lane R, Baldwin D . Selective serotonin reuptake inhibitor-induced serotonin syndrome: review. J Clin Psychopharmacol 1997; 17: 208–221.
Tamam L, Ozpoyraz N . Selective serotonin reuptake inhibitor discontinuation syndrome: a review. Adv Ther 2002; 19: 17–26.
FDA. FDA proposes new warnings about suicidal thinking, behavior in young adults who take antidepressant medications. FDA News 2007.
Giuliano F, Hellstrom WJ . The pharmacological treatment of premature ejaculation. BJU Int 2008; 102: 668–675.
McMahon CG . Treatment of premature ejaculation with sertraline hydrochloride: a single-blind placebo controlled crossover study. J Urol 1998; 159: 1935–1938.
McMahon CG, Touma K . Treatment of premature ejaculation with paroxetine hydrochloride. Int J Impot Res 1999; 11: 241–245; discussion 246.
McMahon CG, Touma K . Treatment of premature ejaculation with paroxetine hydrochloride as needed: 2 single-blind placebo controlled crossover studies. J Urol 1999; 161: 1826–1830.
Pryor JL, Althof SE, Steidle C, Rosen RC, Hellstrom WJ, Shabsigh R et al. Efficacy and tolerability of dapoxetine in treatment of premature ejaculation: an integrated analysis of two double-blind, randomised controlled trials. Lancet 2006; 368: 929–937.
Taber MT, Wright RN, Molski TF, Clarke WJ, Brassil PJ, Denhart DJ et al. Neurochemical, pharmacokinetic, and behavioral effects of the novel selective serotonin reuptake inhibitor BMS-505130. Pharmacol Biochem Behav 2005; 80: 521–528.
Mathias N, Moench P, Heran C, Wall D, Smith R . Alternate routes of administration of a selective serotonin reuptake inhibitor in rabbits and evaluation of different dosage forms. The APPS Journal 2006; 8 (S2): Abstract 1563.
VIVUS Inc.. VIVUS Reports Data from Premature Ejaculation Proof-of-Concept Trial. Business Wire. Press release, 2003 [cited 2008 August]; Available from: http://ir.vivus.com/phoenix.zhtml?c=79161&p=irol-newsArticle&ID=427244&highlight=.
Abn B, Kang KK, Lee YG, Choi SM, Kim DS, Yoo M . Abstract P-05-046: DA8031, a selective and potent serotonin transporter inhibitor, inhibits p-chloramphetamine-induced ejaculation in rats. J Sex Med 2008; 5 (Suppl 2): 59.
Celada P, Puig M, Amargos-Bosch M, Adell A, Artigas F . The therapeutic role of 5-HT1A and 5-HT2A receptors in depression. J Psychiatry Neurosci 2004; 29: 252–265.
Artigas F, Romero L, de Montigny C, Blier P . Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists. Trends Neurosci 1996; 19: 378–383.
Ballesteros J, Callado LF . Effectiveness of pindolol plus serotonin uptake inhibitors in depression: a meta-analysis of early and late outcomes from randomised controlled trials. J Affect Disord 2004; 79: 137–147.
Looney C, Thor KB, Ricca D, Marson L . Differential effects of simultaneous or sequential administration of paroxetine and WAY-100,635 on ejaculatory behavior. Pharmacol Biochem Behav 2005; 82: 427–433.
de Jong TR, Pattij T, Veening JG, Dederen PJ, Waldinger MD, Cools AR et al. Citalopram combined with WAY 100635 inhibits ejaculation and ejaculation-related Fos immunoreactivity. Eur J Pharmacol 2005; 509: 49–59.
Williamson I, Turner L, Woods K, Wayman C, Van Der Graaf P . The 5-HT1A receptor antagonist robalzotan enhances SSRI-induced ejaculation delay in the rat. Br J Pharmacol 2003; 138 (Suppl 1): PO32.
Safarinejad MR . Once-daily high-dose pindolol for paroxetine-refractory premature ejaculation: a double-blind, placebo-controlled and randomized study. J Clin Psychopharmacol 2008; 28: 39–44.
Safarinejad MR, Hosseini SY . Safety and efficacy of tramadol in the treatment of premature ejaculation: a double-blind, placebo-controlled, fixed-dose, randomized study. J Clin Psychopharmacol 2006; 26: 27–31.
Salem EA, Wilson SK, Bissada NK, Delk JR, Hellstrom WJ, Cleves MA . Tramadol HCL has promise in on-demand use to treat premature ejaculation. J Sex Med 2008; 5: 188–193.
Mohammadi-Jazi A, Nori Mahdavi K, Salehi S . POS-01.88: study of efficacy and safety of oral tramadol in the treatment of premature ejaculation. Urology 2007; 70 (3 Suppl): 217.
DMI Biosciences Inc.. Clinical products: web page http://www.dmibio.com/index.php?option=com_content&task=view&id=26&Itemid=53. Access date: August 2008.
Palmer NR . Tramadol for premature ejaculation. J Sex Med 2008; [e-pub ahead of print] DOI: 10.1111/j.1743-6109.2008.00916.x.
McMahon CG, McMahon CN, Leow LJ, Winestock CG . Efficacy of type-5 phosphodiesterase inhibitors in the drug treatment of premature ejaculation: a systematic review. BJU Int 2006; 98: 259–272.
Hsieh JT, Liu SP, Hsieh CH, Cheng JT . An in vivo evaluation of the therapeutic potential of sympatholytic agents on premature ejaculation. BJU Int 1999; 84: 503–506.
Cavallini G . Alpha-1 blockade pharmacotherapy in primitive psychogenic premature ejaculation resistant to psychotherapy. Eur Urol 1995; 28: 126–130.
Basar MM, Yilmaz E, Ferhat M, Basar H, Batislam E . Terazosin in the treatment of premature ejaculation: a short-term follow-up. Int Urol Nephrol 2005; 37: 773–777.
Carmichael MS, Humbert R, Dixen J, Palmisano G, Greenleaf W, Davidson JM . Plasma oxytocin increases in the human sexual response. J Clin Endocrinol Metab 1987; 64: 27–31.
Arletti R, Bazzani C, Castelli M, Bertolini A . Oxytocin improves male copulatory performance in rats. Horm Behav 1985; 19: 14–20.
Arletti R, Benelli A, Bertolini A . Sexual behavior of aging male rats is stimulated by oxytocin. Eur J Pharmacol 1990; 179: 377–381.
Clement P, Peeters M, Bernabe J, Denys P, Alexandre L, Giuliano F . Brain oxytocin receptors mediate ejaculation elicited by 7-hydroxy-2-(di-N-propylamino) tetralin (7-OH-DPAT) in anaesthetized rats. Br J Pharmacol 2008; 154: 1150–1159.
Morales A, Barada J, Wyllie MG . A review of the current status of topical treatments for premature ejaculation. BJU Int 2007; 100: 493–501.
Berkovitch M, Keresteci AG, Koren G . Efficacy of prilocaine-lidocaine cream in the treatment of premature ejaculation. J Urol 1995; 154: 1360–1361.
Atikeler MK, Gecit I, Senol FA . Optimum usage of prilocaine-lidocaine cream in premature ejaculation. Andrologia 2002; 34: 356–359.
Busato W, Galindo CC . Topical anaesthetic use for treating premature ejaculation: a double-blind, randomized, placebo-controlled study. BJU Int 2004; 93: 1018–1021.
Henry R, Morales A, Wyllie MG . TEMPE: topical eutectic-like mixture for premature ejaculation. Expert Opin Drug Deliv 2008; 5: 251–261.
Dinsmore WW, Hackett G, Goldmeier D, Waldinger M, Dean J, Wright P et al. Topical eutectic mixture for premature ejaculation (TEMPE): a novel aerosol-delivery form of lidocaine-prilocaine for treating premature ejaculation. BJU Int 2007; 99: 369–375.
Gittleman MC, Mo J, Lu M . Synergistic effect of meatal application of dyclonine/alprostadil cream for the treatment of early ejaculation (EE) in a double-blind and crossover study. Proceedings of the 8th Congress of the European Society for Sexual Medicine, Copenhagen, Denmark. J Sex Med 2006; 3 (Suppl 3): 176.
Futura Medical. Product description: PET500, [cited 2008 August]; Available from: http://www.futuramedical.co.uk/content/products/pet_500.asp.
Xin ZC, Choi YD, Lee SH, Choi HK . Efficacy of a topical agent SS-cream in the treatment of premature ejaculation: preliminary clinical studies. Yonsei Med J 1997; 38: 91–95.
Fein RL . Intracavernous medication for treatment of premature ejaculation. Urology 1990; 35: 301–303.
Masters WH, Johnson VE . Human Sexual Inadequacy. Bantam, 1980: Toronto; London, 1970, x, 463pp.
Kaplan HS . The New Sex Therapy: Active Treatment of Sexual Dysfunctions. Brunner/Mazel: Levittown, PA; [Great Britain], 1974, xvi, 544pp.
American Psychological Association. Policy Statement on Evidence-Based Practice in Psychology 2005, [cited 2008 August]; Available from: http://www2.apa.org/practice/ebpstatement.pdf.
Perelman MA . A new combination treatment for premature ejaculation: a sex therapist's perspective. J Sex Med 2006; 3: 1004–1012.
Fischer Santos BO, deDues Vieira LA, Fischer R . Neurotomy: a new technique for the treatment of premature ejaculation. Int J Impotence Res 2001; 13 (Suppl 1): 11.
Hosseini SR, Khazaeli MH, Atharikia D . Role of postcircumcision mucosal cuff length in lifelong premature ejaculation: a pilot study. J Sex Med 2008; 5: 206–209.
Wise JME, Watson JP . A new treatment for premature ejaculation: case series for a desensitizing band. Sex Relationship Ther 2000; 15: 345–350.
Thomas CA, Tyagi S, Yoshimura N, Chancellor MB, Tyagi P . Effect of hyperforin-enriched extract on pro-ejaculatory effect of 8-hydroxy-2-(di-N-propylamino)tetralin in anesthetized rats. Urology 2007; 70: 813–816.
Song GH, Halmurat U, Geng JC, Feng LC, Yilihamujiang S, Ma C et al. Clinical study on the treatment of premature ejaculation by Uighur medicine gu-jing-mai-si-ha tablet. Chin J Integr Med 2007; 13: 185–189.
Ratnasooriya WD, Fernando TS . Effect of black tea brew of Camellia sinensis on sexual competence of male rats. J Ethnopharmacol 2008; 118: 373–377.
Conflict of interest
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
- premature ejaculation
- topical treatment
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