Treatments for Premature Ejaculation: Progress Towards an Approved Therapy

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

JA Powell1 and MG Wyllie2

1Global Pharma Consulting Ltd, Sandwich, Kent, UK and 2Plethora Solutions Plc., London, UK

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. International Journal of Impotence Research (2009) 21, 107–115; doi:10.1038/ijir.2008.67; published online 15 January 2009

Keywords: premature ejaculation; pharmacotherapy; SSRI; topical treatment

Introduction States, Europe and Asia. PE was defined as ‘a male sexual dysfunction characterized by ejaculation In recent years both the definition and the manage- which always or nearly always occurs prior to or ment of premature ejaculation (PE) have changed within about one minute of vaginal penetration; and from the traditional authority-based to a more inability to delay ejaculation on all or nearly all evidence-based approach.1–3 A distinction between vaginal penetrations; and negative personal conse- primary (lifelong) or secondary (acquired) PE was quences, such as distress, bother, frustration and/or first established by Schapiro in 1943,4 and was the avoidance of sexual intimacy’.6,7 expanded by Waldinger5 to also include natural PE is thought to be a more common problem than variable PE and premature-like ejaculatory dysfunc- erectile dysfunction (ED), although as discussed tion. However, PE had never been formally defined above, prevalence data will depend on the definition as a clinical condition (at least not in a way used. In a study of men aged 18–59 conducted in the acceptable to the regulatory authorities) until the United States, around 30% of men reported that they publication by the International Society for Sexual ‘climaxed too early’ compared to 10% of men who Medicine (ISSM) in 2008 of a new contemporary reported that they ‘had trouble achieving or main- evidence-based definition for men experiencing taining an erection’.8 Although this number may not lifelong PE.6,7 This followed the deliberations with- represent the percentage of men with PE according to in a group representing specialist (urologist, androl- the most recent stringent guidelines, a sexual com- ogist, mental health clinicians, sexual counsellors) plaint with such a high prevalence together with an and primary care/family physicians from the United 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 Correspondence: Dr J Powell, Medical Communications, clinical trials for PE has been endorsed by some,9 Global Pharma Consulting Ltd, PO Box 189, Sandwich, Kent, CT13 3AB, UK. but has not been universally welcomed, as demon- E-mail: [email protected] strated by the recent publication of a controversial Received 24 September 2008; revised 17 November 2008; article regarding the selective serotonin reuptake 10 accepted 20 November 2008; published online 15 January inhibitor (SSRI) dapoxetine. However, the unusual 2009 number of detailed comments by leading workers in ‘Up and coming’ treatments for PE JA Powell and MG Wyllie 108 the field following the article gives a flavour of the Lack of spontaneity is one argument against the use differing, but clearly emotive views on the subject. of ‘on-demand’ treatments as opposed to daily oral Nonetheless (and side-stepping this ongoing de- therapy that is inherently less obtrusive and more bate for the present), a number of pharmaceutical conducive to spontaneity.16 However, one can draw products and devices are in various stages of parallels to the treatment of ED where lack of development for the treatment of PE, although the spontaneity with on-demand treatments has not been situation remains that, despite the clear unmet a stumbling block and in any case, is only one of medical need for an approved treatment, none has many factors that need to be weighed up by patient so far managed to reach the market. The main and physician when selecting a suitable therapy. reasons for this are the selection of an appropriate Publication of a recent survey of US urologists mechanistic approach and the apparent hardening ‘real-world’ practice patterns in treating PE20 in- of attitude of the regulatory authorities to the risk: dicates that most urologists are broadly following the benefit equation.11 Long-term safety studies are AUA guidelines for the treatment of PE.19 The most required, which may be prohibitively expensive commonly selected first-line therapy was on-demand and reduce the remaining patent life of the product. treatment with SSRIs, prescribed by 26% of urolo- Until very recently, the lack of evidence-based gists followed by daily dosing with SSRIs (22%). definition of PE and validated patient sexuality Topical anaesthetics were prescribed first line by questionnaires, known as patient-reported outcomes 11% of the urologists who responded and 14% as a (PROs), may also have hindered the ability of second-line option for patients who did not respond regulatory authorities to interpret and evaluate data to the initial therapy. It is interesting to note that as from clinical trials of pharmacological treatments for far as the prescribing patterns of this group of PE.12 This has been addressed with the recent urologists indicate, a similar proportion of urologists publication of a validated PE diagnostic tool, the are prescribing on-demand dosing to daily dosing. Premature Ejaculation Diagnostic Tool.13–15 Although the ISSM definition of PE and validated PROs are clearly steps in the right direction, it will Aetiology of PE and drug targets inevitably result in a need to re-evaluate the conclusions of previous studies in which the In contrast to ED, no organic disease has been firmly definitions of PE used for patient selection and associated with PE, except perhaps some evidence PROs are deemed to be potentially inadequate. that prostatitis, hyperthyroidism and penile hypersensitivity may have a function in the aetiology of PE in some men,21–23 although a more contemporary ‘On-demand’ versus daily pharmacother- theory is that PE is part of the normal biological variability of intra-ejaculatory latency time (IELT) in apy for PE men, with a possible familial genetic vulnerabil- ity.24,25 Serotonin (5-hydroxytryptamine, 5-HT), Given that PE is not a life-threatening condition and which has many functions throughout the body, that the majority of men are unlikely to be having including acting as a neurotransmitter in the central sex on a daily basis (indeed, it may be a relatively nervous system (CNS), appears to be a key mediator infrequent event), the ideal treatment for PE has 26,27 in the neurophysiology of ejaculation with at often (but not universally16) been described as one least three 5-HT receptor subtypes (5-HT1A,5-HT1B that can be taken or administered ‘on-demand’. and 5-HT )sofarimplicated.28 It has been postu- Short of invasive procedures such as augmentation 2C lated that primary PE might be mediated by dis- of the glans penis with hyaluronic gel to induce 17,18 turbances of 5-HT neurotransmission, 5-HT2C long-term penile hypoaesthesia, there is no receptor hyposensitivity and/or 5-HT receptor convincing evidence that any pharmacological treat- 1A hypersensitivity and, to a lesser extent, oxytocinergic ment to date offers a ‘cure’ for PE. The American 24,29 neurotransmission in the CNS. Opportunities for Urological Association (AUA 2004) guidelines on 19 therapeutic intervention related to 5-HT have re- the management of PE suggest that the risks and cently been thoroughly reviewed by Giuliano.30 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 Oral therapies who find a particular treatment that works for them might want to continue using that treatment for as Tricyclic antidepressants long as they remain sexually active. However, the Clomipramine is a tricyclic antidepressant (TCA) frequency of sexual activity is dependent on age and that inhibits the uptake of noradrenaline and 5-HT personal circumstances and a rational treatment by adrenergic and 5-HT neurons.31 Daily dosing regimen for PE therefore needs to offer a suitable with 25 or 50 mg clomipramine can significantly level of flexibility to adapt to changing lifestyles. increase IELT compared with placebo32–34 and

International Journal of Impotence Research ‘Up and coming’ treatments for PE JA Powell and MG Wyllie 109 several studies using ‘on-demand’ dosing with Although there is no doubt that daily SSRIs are clomipramine 25 mg 3–24 h before intercourse have highly effective in the treatment of PE, the accom- also shown a significant increase in IELT in men panying nuisance side effects (such dry mouth, with PE.35–37 In one study, clomipramine 25 mg headaches and dizziness), together with the risk of taken on-demand with a mean drug-intercourse the more serious consequences (including psychia- interval of 5.14 h resulted in an approximately tric and neurological as well as the potential for drug 4-fold increase in stopwatch-measured IELT (from interactions,43 overdose and problems related to a baseline of o1 min), compared to a 1.4-fold SSRI withdrawal44), may be considered to be less increase with on-demand paroxetine 20 mg.37 The acceptable in the treatment of PE than for the highest fold increase in IELT (6.2-fold) in the alleviation of depression. However, the AUA con- clomipramine group occurred between 3 and 4 h sensus panel stated (in 2004) that they considered after drug intake, although shorter intervals were not the level of adverse effects to be acceptable for the tested. However, as for their use in depression, the benefit derived in the patient with PE.19 The release utility of clomipramine, even with on-demand of an advisory notice from the US Food and Drug dosing, is limited by its side effects. Sleepiness, Administration (FDA) in May 2007 warning that yawning, dry mouth and nausea on the day of suicidal ideation and attempts have been associated dosing and the next day can be an annoying problem with the initiation of SSRI antidepressant medica- leading to treatment discontinuations.37 tions; especially in young adults aged 18–2445 VR776 (Vectura Group plc., Chippenham, UK) is a (chronic and on-demand dosing), is a strong argu- novel proprietary formulation of clomipramine ment in favour of a treatment regimen for PE with a delivered by oral inhalation through Vectura’s dry more favourable risk: benefit profile, at least in powder inhaler (Aspirair). In an abstract presented younger men. at the annual meeting of the European Society for The use of continuous versus on-demand admin- Sexual Medicine in 2007 (the only published data so istration of SSRIs for managing PE has recently been far), VR776 is reported to have a time to maximum reviewed by Guiliano and Hellstrom46 with the 38 plasma concentration (Tmax) of 1–2 min. VR776 conclusion that studies using conventional SSRI was reported to be ineffective in increasing IELT in antidepressants with as-needed dosing to date have men with PE (baseline IELT o2 min) at the 1 mg not been rigorous19,37,47,48 and that elevated 5-HT dose, but statistically superior to placebo at the 2 mg levels achieved with acute SSRI treatment might be dose (IELT 2.22 and 1.50 min for VR776 and placebo self-limiting because of activation of presynaptic respectively; P ¼ 0.0108), although the clinical 5-HT1A autoreceptors, ultimately limiting the significance of this difference in men selected on increased 5-HT release into the synapse. ‘Priming’ the basis of a baseline IELT of o2 min is debatable. by daily dosing with a low dose (10 mg) of The high level of respiratory side effects (cough paroxetine has been shown to enhance the effect of 70%, throat irritation 70% and respiratory tract a higher dose (20 mg) taken on-demand.49 irritation 35%) also suggests a need for reformula- Although most SSRIs used for the treatment of PE tion of the product. require chronic administration to maximise the therapeutic effect, newer short-active agents are being developed with the intention that they are SSRIs effective when used on-demand. In their recent Delayed ejaculation is a common side effect of the review, Guiliano and Hellstrom46 conjectured that it SSRI class of antidepressant drugs (such as parox- is possible that an on-demand administration of a etine, fluoxetine, sertraline and citalopram) when short-acting SSRI with a sufficiently rapid onset of used to treat depressed patients and this serendipi- action could provide an immediate increase in tous discovery has led to the use of SSRIs as a synaptic 5-HT levels, thus overwhelming synaptic treatment for PE. SSRIs inhibit the reuptake of 5-HT feedback control mechanisms and producing a into the presynaptic cell as a result of blockade of 5- clinically meaningful effect in the absence of HT transporters, increasing levels of 5-HT within the continuous administration. Dapoxetine (Johnson & synaptic cleft.39 The use of SSRIs in the treatment of Johnson, Mountain View, CA, USA) is a short-acting PE has been the subject of a number of comprehen- SSRI in development for the on-demand treatment sive reviews19,28,40 and a meta-analysis,41 with the of PE. On-demand administration of dapoxetine 30 general conclusion that, with daily treatment, all the or 60 mg 3 h before intercourse resulted in up to 3.6- SSRIs produced an increase in IELT, with paroxetine fold increase in (natural mean) IELT in a group of exerting the strongest effect overall on time to men who met DSM-IV-TR criteria for PE, with an ejaculation (a geometric mean 8.8-fold increase).41 IELT at baseline of p2 min in X75% of episodes of Despite a lack of regulatory authority approval, the intercourse.50 Dapoxetine was also relatively well off-label use of SSRIs in the management of PE is tolerated compared to longer-acting SSRIs, although currently endorsed by the AUA guidelines19 as well nausea, diarrhoea, headache and dizziness were as the Second International Consultation on Sexual commonly reported adverse events.50 Despite these Dysfunctions.42 promising findings, the FDA issued a non-approvable

International Journal of Impotence Research ‘Up and coming’ treatments for PE JA Powell and MG Wyllie 110 letter for dapoxetine in 2005, although a European reported by patients receiving the daily combination marketing authorization application was recently treatment. This apparently effective SSRI/5-HT1A submitted and is still pending. receptor agonist combination may prove useful for Over the last few years, several other novel short- patients who do not respond to other therapies and acting SSRIs have reached pre-clinical and early certainly warrants further investigation. clinical development. These include UK-390957 (Pfizer Inc., New York, NY, USA) and BMS-505130 51 (Bristol-Myers Squibb, New York, NY, USA). Opioid receptor agonists However, Pfizer has withdrawn UK-390957 from Tramadol, a centrally acting agonist of m-opioid further clinical studies, and there appears to be no receptors, is a narcotic analgesic indicated for the further news of BMS-505130, possibly as a result of 52 management of moderate to severe pain. Its mode of problems with low oral bioavailability. Similarly, action in PE is not completely understood, however, VI-0134, an oral 5-HT4 agonist developed by Vivus in animal models it binds to opioid receptors and is Inc. (Mountain View, CA, USA), for on-demand use suggested to inhibit noradrenaline and serotonin in PE was reported in a 2003 press release to reuptake. Tramadol 25 or 50 mg has been shown to significantly increase the ejaculatory latency period 53 be effective in prolonging IELT when used on- in men with PE, although no data appear to have demand (1–2 h before anticipated intercourse) in been published, raising questions about the future of patients with PE,62,63 although interestingly, a recent this product too. Slightly more positively, Dong-A study showed that daily treatment with one 100-mg Pharmaceutical Company (Seoul, South Korea) sustained-release tablet for 4 weeks was no better at recently reported pre-clinical data for DA8031, prolonging IELT than placebo.64 Zertane (formerly a selective and potent SSRI that inhibited known as LI-301 and DM-7958; DMI Biosciences p-chloroamphetamine-induced ejaculation in rats 54 Greenwood Village, CO, USA) is a combination of an with a comparable efficacy to dapoxetine, which (unspecified) SSRI and a m-opioid receptor agonist. deserves further investigation. 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 5-HT1A receptor agonists evaluate the product. Moreover, serious concerns The time taken to desensitize 5-HT1A receptors is have been raised about the ethics of prescribing thought to be the reason for the delay of several opioid drugs with an associated risk of dependence weeks in the clinical improvement of depression 55 and abuse for the treatment of PE, particularly in with SSRIs. Co-prescribing of the b-adrenoreceptor younger men66 and considering the view of the FDA antagonist pindolol (which also antagonizes 5-HT1A in relation to a short-acting SSRI alone (dapoxetine), receptors) is thought to improve the onset of action a combination SSRI/opioid product is unlikely to be of SSRIs in terms of the relief of depressive 56,57 viewed favourably by the regulatory authorities. symptoms. 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 Phosphodiesterase-5 inhibitors the SSRI, thereby inducing strong immediate ejacu- On-demand oral phosphodiesterase-5 (PDE-5) inhibitors are a popular and effective treatment for ED, latory delay. Two 5-HT1A antagonists, WAY- 10063558,59 and Robalzotan (NAD-299)60 have been but there is no pharmacological rationale for their used in animal models of ejaculation and both drugs use in the treatment of PE. A review of 14 clinical delayed ejaculation acutely when administered trials of PDE-5 inhibitors in the treatment of PE together with an SSRI. Neither was effective when concluded that there is no convincing evidence to used alone confirming the hypothesis that the support their function in the treatment of men with lifelong PE and normal erectile function.67 However, 5-HT1A receptors are activated in response to extracellular serotonin levels after acute SSRI there is limited evidence to support a potential role administration. So far only the co-administration for PDE-5 inhibitors alone or combined with daily or on-demand SSRIs in the treatment of acquired PE in of daily pindolol 7.5 mg and paroxetine 20 mg in 19 men with PE that was refractory to treatment with men with comorbid ED. 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 Other potential drug targets for oral ther- from a baseline of 48 s).61 It remains to be seen apy whether the combination is effective when administered as needed and whether on-demand dosing can As ejaculation is a sympathetic spinal cord reflex, overcome the higher incidence of side effects sympatholytic agents such as a-1 adrenoreceptor (nausea, diarrhoea, dry mouth and headache) antagonists could theoretically be used in the

International Journal of Impotence Research ‘Up and coming’ treatments for PE JA Powell and MG Wyllie 111 treatment of PE68 and there has been some success known as TEMPE topical eutectic-like mixture for in ejaculatory delay with daily use of alfuzosin and premature ejaculation; Plethora Solutions plc., terazosin.69,70 However, as far as the authors are London, UK) appears to be in the latest stage of aware, the use of on-demand a-blockers has not been development. PSD502 is a proprietary metered dose evaluated. In man, plasma oxytocin levels rise aerosol that delivers a eutectic mixture of 7.5 mg during tumescence and at the point of ejaculation lidocaine and 2.5 mg prilocaine (dissolved in a non- are significantly higher than at baseline.71 Systemic chlorofluorocarbon propellant) per actuation.79 This administration of oxytocin has been shown to method of delivery enables a concentrated film of shorten the ejaculatory latency time and the post- local anaesthetics in their base form (uncharged) to ejaculation recovery interval in rats72,73 and a recent be deposited onto the glans penis. Because only the study elucidated the site of action of oxytocin base forms of local anaesthetics are able to penetrate receptors involved in the sexual response and skin or mucosa, the onset of action of the spray is ejaculation.74 Theoretically, oxytocin receptor an- more rapid than that seen with cream formulations tagonists could be used to prolong IELT, although to (which contain a mixture of base and ionized forms date there has been no report on their efficacy in the of local anaesthetics).79 Results from a phase II treatment of PE. 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, Po0.01) in the Topical therapies lidocaine-prilocaine spray group compared with placebo,80 with 12% of men reporting hypoaesthe- In terms of a treatment that can be used ‘as needed’ sia. Phase III trials with the lidocaine-prilocaine with the potential to avoid systemic toxicity, topical spray are ongoing. In theory, as the eutectic mixture treatments are a logical area for further develop- of lidocaine and prilocaine is absorbed by the poorly ment. There are indeed a number of new products in keratinised skin of the glans penis and is less likely the pipeline as well as the possibility of using to penetrate fully keratinised skin (that is on the existing products off-label. The logic behind all of shaft of the penis), sensation is more likely to be the topical treatments is to prolong ejaculatory retained.79 The spray offers other advantages over latency by reducing the sensitivity of the glans the cream, reflecting the fact that it has been penis with topical desensitizing agents. However, specifically designed as a treatment for PE: it is unless carefully designed, topical treatments can be easy to apply using the metered dose spray; the messy to use and the time to onset of action can product remains adherent to the delivery site with- mean spontaneity is compromised. Important differ- out mess; no condom is required as the product can entiating factors in potential treatments are whether be easily wiped off before intercourse.79 ejaculatory delay can be achieved without adversely Although the use of a eutectic mixture is one way effecting the sensation of ejaculation for the man of maximising skin/mucosa penetration, products and without transfer of the desensitizing agent to the containing other transdermal delivery systems are partner. Progress towards the development of topi- also in development. In 2006 promising results were cal treatments for PE based on this approach was presented by NexMed Inc. (East Windsor, NJ, USA) recently reviewed by Morales et al.75 for their topical cream (NM100061) containing the A variety of products with claims to delay local anaesthetic dyclonine with alprostadil, a pros- ejaculation are available over the Internet and from taglandin with vasodilatory effects together with adult shops, although no data have been published NexMed’s patented permeation enhancer known as on the efficacy (or indeed safety) of these products. NexACT.81 However, no news or publications have In terms of products for which clinical data are followed the initial brief abstract and the product no available, the current treatment options are creams longer appears in NexMed’s list of pipeline products. or sprays commonly used for topical anaesthesia of Recent non-approval by the FDA of NexMed’s Vitaros the skin and mucosa before minor skin procedures (formerly called Alprox-TD), a topical treatment for (for example lidocaine-prilocaine cream), which ED that also contains alprostadil and the same skin have been used off-label as a topical treatment for permeation enhancer, may well have also called into PE when applied to the penis and covered with a question the approvability of NM100061. Futura condom before intercourse.76 The optimum applica- Medical (Guildford, UK) is (according to the com- tion time for lidocaine-prilocaine before intercourse pany website82) developing a non-prescription topi- is considered to be 20 min77 and patients using the cal product (PET500) utilizing their proprietary skin cream have reported a 5.6-fold increase in IELT to delivery technology DermaSys and containing a 6.71±2.54 min and improved sexual satisfaction, ‘well-characterized mild topical anaesthetic com- although loss of sensation (hypoaesthesia) and pound’, targeting men who only suffer situational penile irritation were reported by around 17% of or occasional PE. men.78 Among the range of ‘herbal’ creams claiming to In terms of topical agents that have been designed delay ejaculation, SS-cream (Severance Secret- specifically for the treatment of PE, PSD502 (also Cream; Cheil Jedan Corporation, Korea) appears to

International Journal of Impotence Research ‘Up and coming’ treatments for PE JA Powell and MG Wyllie 112 be the only one that has been subject to clinical Surgery trials. It is made from extracts of natural products, Neurotomy of the dorsal nerves of the penis is some of which have local anaesthetic and vasodila- reported to be effective in the treatment of PE.89 tory properties and is applied to the glans penis 1 h However, the procedure is invasive, irreversible and before intercourse and washed off immediately remains experimental as it has not been properly before coitus.83 Despite promising results in clinical evaluated in published clinical trials and does not trials where it significantly prolonged ejaculatory have wide support in the medical community. latency in 89% of patients,83 SS-cream is unaccep- table to some patients due to its unpleasant odour and colour and it is unlikely to gain approval Devices outside of Korea. Despite anecdotal reports, there is no convincing clinical evidence that mechanical devices are useful Intracavernosal injection in the treatment of PE. In a recent study, the use of a constriction ring (such as those used with vacuum On-demand intracavernosal injection (ICI) with therapy devices) over a period of 4 weeks failed to 90 some of the agents used in the treatment of ED (for have any effect on IELT. Some success has been example alprostadil or the papaverine–phentola- reported with a densensitizing penile band, which is mine combination known as ‘bimix’), typically not used during intercourse, but rather during prolongs an erection beyond the point of ejacula- masturbation to produce an habituation effect. The tion, allowing intercourse to continue. ICI can long-term success of this strategy is unknown and, therefore be used as a strategy to allow men with as it requires a period of dedicated use, is not an 91 PE to maintain their erections, as opposed to effective on-demand therapy for PE. 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 Phytotherapy greater level of patient (if not partner) satisfaction in The list of natural/herbal products shown in men with PE. Given that alprostadil and ICIs preliminary pre-clinical or clinical trials to have an containing papaverine have been associated with inhibitory effect on ejaculatory function is growing. intracorporeal pain, priapism and fibrosis, it is This includes the constituents of SS-cream (as unlikely to be a popular choice for the on-demand mentioned above), hyperforin (a concentrated ex- treatment of PE. tract 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 Non-pharmacological therapy (Camellia sinensis).94 Of course natural does not equal safe, and although drinking a cup of tea before Behavioural techniques and psychological therapy intercourse in the belief that it might delay ejacula- There is nothing new about the use of psychological tion may be acceptable to a PE sufferer, in terms of therapy in the treatment of PE, indeed, variations of bringing new pharmaceutical products to market, the stop-squeeze and stop-pause technique as there is no reason to suspect that the view taken by introduced by Masters and Johnson85 and Kaplan,86 the regulatory authorities of extracts from plants (or respectively, have been in use for decades. However, animal venom, cf SS-cream) is likely to be any less the contemporary approach to psychological ther- stringent than for a conventional small molecule. apy is evidence based and integrates the best The lack of patent protection and the anticipated available research with clinical expertise in the unfavourable return on investment means that context of patient characteristics, culture and pre- phytotherapy is unlikely to be the basis of licensed ferences.87 It has been argued that a combination products to treat PE in the near future. treatment integrating pharmaceuticals and sex therapy would provide an optimized approach to treatment,88 although the question of which psy- Summary and conclusions chotherapies are most effectively combined with pharmacotherapy remains unanswered. Rowland In the absence of a ‘cure’ for PE, one must look et al. (2008) raises the point that pharmaceutical towards long-term pharmacological treatment either companies could best serve their own interests by with or without behavioural or psychological supporting research on the treatment of PE through therapy. As appears to be the case with all other cognitive behavioural therapy (CBT) and/or com- issues surrounding PE, there are differences of bined pharmacotherapy/CBT as combination thera- opinion as to the attributes of an ideal treatment pies are likely to be more effective in the long-term for PE. However, for those who do not engage in treatment of PE than pharmacological interventions sexual activity on a daily basis, it is our opinion that applied alone.9 the ideal pharmacotherapy for PE would be an

International Journal of Impotence Research ‘Up and coming’ treatments for PE JA Powell and MG Wyllie 113 approved, discreet and on-demand therapy that is premature ejaculation: report of the International Society for effective from the first dose, has proven efficacy in Sexual Medicine (ISSM) ad hoc Committee for the Definition terms of IELT and PROs, and a low incidence of side of Premature Ejaculation. J Sex Med 2008; 5: 1590–1606. 8 Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the effects and with no unwanted effects on the partner. United States: prevalence and predictors. JAMA 1999; 281: A number of novel pharmacological and non- 537–544. pharmacological therapies are emerging that show 9 Rowland D, Cooper S, Macias L. Pharmaceutical companies promising results for the future treatment of this could serve their own interests by supporting research on the efficacy of psychotherapy on premature ejaculation. Int J problem, although others appear to have fallen by Impot Res 2008; 20: 115–120. the wayside. 10 Waldinger MD, Schweitzer DH. Premature ejaculation and As all existing therapies for PE are used ‘off-label’ pharmaceutical company-based medicine: the dapoxetine and demand appears to be growing, there is an case. J Sex Med 2008; 5: 966–997. unmet need for an effective, licensed treatment. 11 Wyllie MG. Another year, another AUA. BJU Int 2006; 97: 1119–1120. With the recent publication of the ISSM definition 12 Althof SE, Symonds T. Patient reported outcomes used in the of PE and the development of validated PE diag- assessment of premature ejaculation. Urol Clin North Am nostic tools, the scene is now set for the regulatory 2007; 34: 581–589, vii. approval of the first products for the treatment of PE. 13 Althof S, Rosen R, Symonds T, Mundayat R, May K, Abraham L. Development and validation of a new questionnaire to The emerging oral agents reviewed may have a assess sexual satisfaction, control, and distress associated difficult hurdle to cross to gain regulatory approval with premature ejaculation. J Sex Med 2006; 3: 465–475. in terms of the risk: benefit ratio, particularly the 14 Symonds T, Perelman MA, Althof S, Giuliano F, Martin M, combination therapies for which there are addi- May K et al. Development and validation of a premature tional issues to consider such as cost and drug ejaculation diagnostic tool. Eur Urol 2007; 52: 565–573. 15 Symonds T, Perelman M, Althof S, Giuliano F, Martin M, interactions. As most of the emerging oral therapies Abraham L et al. Further evidence of the reliability and are modified antidepressants, the regulatory autho- validity of the premature ejaculation diagnostic tool. Int J rities will, at the very least, want to see long-term Impot Res 2007; 19: 521–525. safety data (for example suicide risk and addiction 16 Waldinger MD, Zwinderman AH, Olivier B, Schweitzer DH. The majority of men with lifelong premature ejaculation potential). Currently available topical agents are prefer daily drug treatment: an observation study in a effective and have a more favourable risk: benefit consecutive group of Dutch men. J Sex Med 2007; 4 profile, but have issues to do with application and (4 Part 1): 1028–1037. spontaneity. These have been largely overcome in 17 Kim JJ, Kwak TI, Jeon BG, Cheon J, Moon DG. Effects of glans the novel topical spray formulation of lidocaine- penis augmentation using hyaluronic acid gel for premature ejaculation. Int J Impot Res 2004; 16: 547–551. prilocaine, which shows promise as an on-demand 18 Kwak TI, Jin MH, Kim JJ, Moon DG. Long-term effects of glans therapy with proven efficacy and a low incidence of penis augmentation using injectable hyaluronic acid gel for side effects. premature ejaculation. Int J Impot Res 2008; 20: 425–428. 19 Montague DK, Jarow J, Broderick GA, Dmochowski RR, Heaton JP, Lue TF et al. AUA guideline on the pharmacologic Conflict of interest management of premature ejaculation. J Urol 2004; 172: MG Wyllie is a Board Member of Plethora Solutions 290–294. 20 Shindel A, Nelson C, Brandes S. Urologist practice patterns in and JA Powell is a contractor to Plethora Solutions. the management of premature ejaculation: a nationwide survey. J Sex Med 2008; 5: 199–205. 21 Carani C, Isidori AM, Granata A, Carosa E, Maggi M, Lenzi A et al. Multicenter study on the prevalence of sexual symptoms References in male hypo- and hyperthyroid patients. J Clin Endocrinol Metab 2005; 90: 6472–6479. 1 Waldinger MD. Lifelong premature ejaculation: from author- 22 Shamloul R, el-Nashaar A. Chronic prostatitis in premature ity-based to evidence-based medicine. BJU Int 2004; 93: ejaculation: a cohort study in 153 men. J Sex Med 2006; 3: 201–207. 150–154. 2 McMahon CG. Clinical trial methodology in premature 23 Xin ZC, Chung WS, Choi YD, Seong DH, Choi YJ, Choi HK. ejaculation observational, interventional, and treatment pre- Penile sensitivity in patients with primary premature ejacula- ference studies—part I—defining and selecting the study tion. J Urol 1996; 156: 979–981. population. J Sex Med 2008; 5: 1805–1816. 24 Waldinger MD. The neurobiological approach to premature 3 McMahon CG. Clinical trial methodology in premature ejaculation. J Urol 2002; 168: 2359–2367. ejaculation observational, interventional, and treatment pre- 25 Waldinger MD, Rietschel M, Nothen MM, Hengeveld MW, ference studies—part II—study design, outcome measures, Olivier B. Familial occurrence of primary premature ejacula- data analysis, and reporting. J Sex Med 2008; 5: 1817–1833. tion. Psychiatr Genet 1998; 8: 37–40. 4 Schapiro B. Premature ejaculation: a review of 1130 cases. 26 Giuliano F, Clement P. Physiology of ejaculation: emphasis on J Urol 1943; 50: 374–379. serotonergic control. Eur Urol 2005; 48: 408–417. 5 Waldinger MD. Premature ejaculation: definition and drug 27 Giuliano FA, Rampin O, Benoit G, Jardin A. Neural control of treatment. Drugs 2007; 67: 547–568. penile erection. Urol Clin North Am 1995; 22: 747–766. 6 McMahon CG, Althof S, Waldinger MD, Porst H, Dean J, 28 Giuliano F, Clement P. Serotonin and premature ejaculation: Sharlip I et al. An evidence-based definition of lifelong from physiology to patient management. Eur Urol 2006; 50: premature ejaculation: report of the International Society for 454–466. Sexual Medicine ad hoc Committee for the Definition of 29 Waldinger MD, Berendsen HH, Blok BF, Olivier B, Holstege G. Premature Ejaculation. BJU Int 2008; 102: 338–350. Premature ejaculation and serotonergic antidepressants-in- 7 McMahon CG, Althof SE, Waldinger MD, Porst H, Dean J, duced delayed ejaculation: the involvement of the serotoner- Sharlip ID et al. An evidence-based definition of lifelong gic system. Behav Brain Res 1998; 92: 111–118.

International Journal of Impotence Research ‘Up and coming’ treatments for PE JA Powell and MG Wyllie 114 30 Giuliano F. 5-Hydroxytryptamine in premature ejaculation: 51 Taber MT, Wright RN, Molski TF, Clarke WJ, Brassil PJ, opportunities for therapeutic intervention. Trends Neurosci Denhart DJ et al. Neurochemical, pharmacokinetic, and 2007; 30: 79–84. behavioral effects of the novel selective serotonin reuptake 31 Gur E, Lerer B, Newman ME. Chronic clomipramine and inhibitor BMS-505130. Pharmacol Biochem Behav 2005; 80: triiodothyronine increase serotonin levels in rat frontal cortex 521–528. in vivo: relationship to serotonin autoreceptor activity. 52 Mathias N, Moench P, Heran C, Wall D, Smith R. Alternate J Pharmacol Exp Ther 1999; 288: 81–87. routes of administration of a selective serotonin reuptake 32 Kim SC, Seo KK. Efficacy and safety of fluoxetine, sertraline inhibitor in rabbits and evaluation of different dosage forms. and clomipramine in patients with premature ejaculation: a The APPS Journal 2006; 8(S2): Abstract 1563. double-blind, placebo controlled study. J Urol 1998; 159: 53 VIVUS Inc.. VIVUS Reports Data from Premature Ejaculation 425–427. Proof-of-Concept Trial. Business Wire. Press release, 2003 [cited 33 Althof SE, Levine SB, Corty EW, Risen CB, Stern EB, Kurit 2008 August]; Available from: http://ir.vivus.com/phoenix. DM. A double-blind crossover trial of clomipramine for rapid zhtml?c=79161&p=irol-newsArticle&ID=427244&highlight=. ejaculation in 15 couples. J Clin Psychiatry 1995; 56: 402–407. 54 Abn B, Kang KK, Lee YG, Choi SM, Kim DS, Yoo M. Abstract 34 Segraves RT, Saran A, Segraves K, Maguire E. Clomipramine P-05-046: DA8031, a selective and potent serotonin transpor- versus placebo in the treatment of premature ejaculation: a ter inhibitor, inhibits p-chloramphetamine-induced ejacula- pilot study. J Sex Marital Ther 1993; 19: 198–200. tion in rats. J Sex Med 2008; 5(Suppl 2): 59. 35 Haensel SM, Rowland DL, Kallan KT. Clomipramine and 55 Celada P, Puig M, Amargos-Bosch M, Adell A, Artigas F. The sexual function in men with premature ejaculation and therapeutic role of 5-HT1A and 5-HT2A receptors in depres- controls. J Urol 1996; 156: 1310–1315. sion. J Psychiatry Neurosci 2004; 29: 252–265. 36 Strassberg DS, de Gouveia Brazao CA, Rowland DL, Tan P, 56 Artigas F, Romero L, de Montigny C, Blier P. Acceleration Slob AK. Clomipramine in the treatment of rapid (premature) of the effect of selected antidepressant drugs in major ejaculation. J Sex Marital Ther 1999; 25: 89–101. depression by 5-HT1A antagonists. Trends Neurosci 1996; 37 Waldinger MD, Zwinderman AH, Olivier B. On-demand 19: 378–383. treatment of premature ejaculation with clomipramine 57 Ballesteros J, Callado LF. Effectiveness of pindolol plus and paroxetine: a randomized, double-blind fixed-dose study serotonin uptake inhibitors in depression: a meta-analysis of with stopwatch assessment. Eur Urol 2004; 46: 510–515; early and late outcomes from randomised controlled trials. discussion 516. J Affect Disord 2004; 79: 137–147. 38 Leaker B. Abstract P-05-048: a double blind, placebo-con- 58 Looney C, Thor KB, Ricca D, Marson L. Differential effects of trolled, randomised crossover study to investigate the effect simultaneous or sequential administration of paroxetine and of inhaled doses of VR776 on intravaginal ejaculatory latency WAY-100,635 on ejaculatory behavior. Pharmacol Biochem in patients with premature ejaculation. J Sex Med 2008; Behav 2005; 82: 427–433. 5(Suppl 2): 60. 59 de Jong TR, Pattij T, Veening JG, Dederen PJ, Waldinger MD, 39 Ahlenius S, Larsson K, Svensson L. Further evidence for an Cools AR et al. Citalopram combined with WAY 100635 inhibitory role of central 5-HT in male rat sexual behavior. inhibits ejaculation and ejaculation-related Fos immunoreac- Psychopharmacology (Berl) 1980; 68: 217–220. tivity. Eur J Pharmacol 2005; 509: 49–59. 40 Wang WF, Chang L, Minhas S, Ralph DJ. Selective serotonin 60 Williamson I, Turner L, Woods K, Wayman C, Van Der Graaf P. reuptake inhibitors in the treatment of premature ejaculation. The 5-HT1A receptor antagonist robalzotan enhances SSRI- Chin Med J (Engl) 2007; 120: 1000–1006. induced ejaculation delay in the rat. Br J Pharmacol 2003; 41 Waldinger MD, Zwinderman AH, Schweitzer DH, Olivier B. 138(Suppl 1): PO32. Relevance of methodological design for the interpretation of 61 Safarinejad MR. Once-daily high-dose pindolol for paroxe- efficacy of drug treatment of premature ejaculation: a tine-refractory premature ejaculation: a double-blind, placebo- systematic review and meta-analysis. Int J Impot Res 2004; controlled and randomized study. J Clin Psychopharmacol 16: 369–381. 2008; 28: 39–44. 42 Lue TF, Giuliano F, Montorsi F, Rosen RC, Andersson KE, 62 Safarinejad MR, Hosseini SY. Safety and efficacy of tramadol Althof S et al. Summary of the recommendations on sexual in the treatment of premature ejaculation: a double-blind, dysfunctions in men. J Sex Med 2004; 1: 6–23. placebo-controlled, fixed-dose, randomized study. J Clin 43 Lane R, Baldwin D. Selective serotonin reuptake inhibitor- Psychopharmacol 2006; 26: 27–31. induced serotonin syndrome: review. J Clin Psychopharmacol 63 Salem EA, Wilson SK, Bissada NK, Delk JR, Hellstrom WJ, 1997; 17: 208–221. Cleves MA. Tramadol HCL has promise in on-demand use to 44 Tamam L, Ozpoyraz N. Selective serotonin reuptake inhibitor treat premature ejaculation. J Sex Med 2008; 5: 188–193. discontinuation syndrome: a review. Adv Ther 2002; 19: 64 Mohammadi-Jazi A, Nori Mahdavi K, Salehi S. POS-01.88: 17–26. study of efficacy and safety of oral tramadol in the treatment of 45 FDA. FDA proposes new warnings about suicidal thinking, premature ejaculation. Urology 2007; 70(3 Suppl): 217. behavior in young adults who take antidepressant medica- 65 DMI Biosciences Inc.. Clinical products: web page http:// tions. FDA News 2007. www.dmibio.com/index.php?option ¼ com_content&task ¼ 46 Giuliano F, Hellstrom WJ. The pharmacological treatment of view&id ¼ 26&Itemid ¼ 53 . Access date: August 2008. premature ejaculation. BJU Int 2008; 102: 668–675. 66 Palmer NR. Tramadol for premature ejaculation. J Sex Med 47 McMahon CG. Treatment of premature ejaculation with 2008; [e-pub ahead of print] DOI: 10.1111/j.1743-6109.2008. sertraline hydrochloride: a single-blind placebo controlled 00916.x. crossover study. J Urol 1998; 159: 1935–1938. 67 McMahon CG, McMahon CN, Leow LJ, Winestock CG. 48 McMahon CG, Touma K. Treatment of premature ejaculation Efficacy of type-5 phosphodiesterase inhibitors in the drug with paroxetine hydrochloride. Int J Impot Res 1999; 11: treatment of premature ejaculation: a systematic review. BJU 241–245; discussion 246. Int 2006; 98: 259–272. 49 McMahon CG, Touma K. Treatment of premature ejaculation 68 Hsieh JT, Liu SP, Hsieh CH, Cheng JT. An in vivo evaluation of with paroxetine hydrochloride as needed: 2 single- the therapeutic potential of sympatholytic agents on prema- blind placebo controlled crossover studies. J Urol 1999; 161: ture ejaculation. BJU Int 1999; 84: 503–506. 1826–1830. 69 Cavallini G. Alpha-1 blockade pharmacotherapy in primitive 50 Pryor JL, Althof SE, Steidle C, Rosen RC, Hellstrom WJ, psychogenic premature ejaculation resistant to psychotherapy. Shabsigh R et al. Efficacy and tolerability of dapoxetine in Eur Urol 1995; 28: 126–130. treatment of premature ejaculation: an integrated analysis of 70 Basar MM, Yilmaz E, Ferhat M, Basar H, Batislam E. Terazosin two double-blind, randomised controlled trials. Lancet 2006; in the treatment of premature ejaculation: a short-term follow- 368: 929–937. up. Int Urol Nephrol 2005; 37: 773–777.

International Journal of Impotence Research ‘Up and coming’ treatments for PE JA Powell and MG Wyllie 115 71 Carmichael MS, Humbert R, Dixen J, Palmisano G, Greenleaf 82 Futura Medical. Product description: PET500, [cited 2008 W, Davidson JM. Plasma oxytocin increases in the human August]; Available from: http://www.futuramedical.co.uk/ sexual response. J Clin Endocrinol Metab 1987; 64: 27–31. content/products/pet_500.asp. 72 Arletti R, Bazzani C, Castelli M, Bertolini A. Oxytocin 83 Xin ZC, Choi YD, Lee SH, Choi HK. Efficacy of a topical agent improves male copulatory performance in rats. Horm Behav SS-cream in the treatment of premature ejaculation: prelimin- 1985; 19: 14–20. ary clinical studies. Yonsei Med J 1997; 38: 91–95. 73 Arletti R, Benelli A, Bertolini A. Sexual behavior of aging male 84 Fein RL. Intracavernous medication for treatment of prema- rats is stimulated by oxytocin. Eur J Pharmacol 1990; 179: ture ejaculation. Urology 1990; 35: 301–303. 377–381. 85 Masters WH, Johnson VE. Human Sexual Inadequacy. Ban- 74 Clement P, Peeters M, Bernabe J, Denys P, Alexandre L, tam, 1980: Toronto; London, 1970, x, 463pp. Giuliano F. Brain oxytocin receptors mediate ejaculation 86 Kaplan HS. The New Sex Therapy: Active Treatment of Sexual elicited by 7-hydroxy-2-(di-N-propylamino) tetralin (7-OH- Dysfunctions. Brunner/Mazel: Levittown, PA; [Great Britain], DPAT) in anaesthetized rats. Br J Pharmacol 2008; 154: 1974, xvi, 544pp. 1150–1159. 87 American Psychological Association. Policy Statement 75 Morales A, Barada J, Wyllie MG. A review of the current status on Evidence-Based Practice in Psychology 2005, [cited 2008 of topical treatments for premature ejaculation. BJU Int 2007; August]; Available from: http://www2.apa.org/practice/ 100: 493–501. ebpstatement.pdf. 76 Berkovitch M, Keresteci AG, Koren G. Efficacy of prilocaine- 88 Perelman MA. A new combination treatment for premature lidocaine cream in the treatment of premature ejaculation. ejaculation: a sex therapist’s perspective. J Sex Med 2006; 3: J Urol 1995; 154: 1360–1361. 1004–1012. 77 Atikeler MK, Gecit I, Senol FA. Optimum usage of prilocaine- 89 Fischer Santos BO, deDues Vieira LA, Fischer R. Neurotomy: a lidocaine cream in premature ejaculation. Andrologia 2002; new technique for the treatment of premature ejaculation. Int J 34: 356–359. Impotence Res 2001; 13(Suppl 1): 11. 78 Busato W, Galindo CC. Topical anaesthetic use for treating 90 Hosseini SR, Khazaeli MH, Atharikia D. Role of postcircumci- premature ejaculation: a double-blind, randomized, placebo- sion mucosal cuff length in lifelong premature ejaculation: a controlled study. BJU Int 2004; 93: 1018–1021. pilot study. J Sex Med 2008; 5: 206–209. 79 Henry R, Morales A, Wyllie MG. TEMPE: topical eutectic-like 91 Wise JME, Watson JP. A new treatment for premature mixture for premature ejaculation. Expert Opin Drug Deliv ejaculation: case series for a desensitizing band. Sex Relation- 2008; 5: 251–261. ship Ther 2000; 15: 345–350. 80 Dinsmore WW, Hackett G, Goldmeier D, Waldinger M, Dean J, 92 Thomas CA, Tyagi S, Yoshimura N, Chancellor MB, Tyagi P. Wright P et al. Topical eutectic mixture for premature Effect of hyperforin-enriched extract on pro-ejaculatory effect ejaculation (TEMPE): a novel aerosol-delivery form of lido- of 8-hydroxy-2-(di-N-propylamino)tetralin in anesthetized caine-prilocaine for treating premature ejaculation. BJU Int rats. Urology 2007; 70: 813–816. 2007; 99: 369–375. 93 Song GH, Halmurat U, Geng JC, Feng LC, Yilihamujiang S, Ma 81 Gittleman MC, Mo J, Lu M. Synergistic effect of meatal C et al. Clinical study on the treatment of premature application of dyclonine/alprostadil cream for the treatment of ejaculation by Uighur medicine gu-jing-mai-si-ha tablet. Chin early ejaculation (EE) in a double-blind and crossover study. J Integr Med 2007; 13: 185–189. Proceedings of the 8th Congress of the European Society for 94 Ratnasooriya WD, Fernando TS. Effect of black tea brew of Sexual Medicine, Copenhagen, Denmark. J Sex Med 2006; Camellia sinensis on sexual competence of male rats. 3(Suppl 3): 176. J Ethnopharmacol 2008; 118: 373–377.

International Journal of Impotence Research