Abstract
Premature ejaculation (PE) is the most common male sexual problem worldwide affecting 22–38% of men. It has a significant morbidity both on patients and their partners, causing distress, anxiety and relationship difficulties. The mainstay of treatment is a combined approach using behavioural therapies and non-licensed medication such as topical anaesthetic preparations, selective serotonin re-uptake inhibitors and phosphodiesterase-5 inhibitors. In recent years, there has been a greater emphasis placed on researching novel treatments and exploring the on-demand use of current preparations. This review provides an overview of current accepted treatments and emerging agents for the use in PE.
Keywords
INTRODUCTION
Premature ejaculation (PE) is recognized as the most common male sexual problem presenting in clinical practice. Its prevalence is estimated to be around 22–38%. 1–3 Despite its high prevalence, there is no Food and Drug Administration (FDA)-approved treatment and only recently has there been a focus on investigating and developing new therapeutic strategies for its management.
A new definition of lifelong PE was proposed by the International Society for Sexual Medicine in 2007, which states that lifelong PE is ‘… a male sexual dysfunction which is characterised by ejaculation which occurs or nearly always occurs prior to or within about a minute of vaginal penetration, and the 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’. 4 This is the first evidence-based definition and will hopefully aid ongoing research into the true prevalence of PE and the efficacy of new treatments.
Previous definitions of PE have been used in the past by researchers, none of which were evidence-based. The most commonly accepted of these definitions is from the The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), which defines PE as ‘persistent or recurrent ejaculation with minimal sexual stimulation, and before the subject wishes it’, which thereby results in ‘marked distress or interpersonal difficulty’. 5 This definition is subjective and does not provide any quantitative measure. In practice, however, most studies use intravaginal ejaculatory latency time (IELT) as an objective measurement by which to compare treatment efficacy and standardize clinical outcomes. IELT is the time measured from penetration to ejaculation during intercourse. This term was first introduced and defined by Waldinger et al.; 6 however, normal data were unavailable until a recent multinational study demonstrated that IELT was positively skewed, with a median IELT of 5.4 (range, 0.55–44.1) minutes. The 0.5 and 2.5 percentiles equated to an IELT of 0.9 and 1.3 minutes, respectively. It was therefore proposed that men with an IELT of <1 minute have ‘definite’ PE, while men with IELT of 1–1.5 minutes have ‘probable’ PE. 6
PE can be primary (lifelong), persisting from the first sexual encounter or secondary (acquired), occurring after a previously normal ejaculatory control. Its aetiology is thought to be multifactorial and associations with psychological, 7 environmental, endocrine 8 and neurobiological 9 factors have been made. Recently, there has been interest in investigating for a potential genetic link to PE. Waldinger et al. 10 showed that the likelihood of PE occurring in family members was significantly higher than the background prevalence rate within the population. This does not necessarily confirm the role of genetics as it could be argued that members of the same family would share a similar environment. In order to try to differentiate between these effects, a study involving 3946 male twins (monozygotic and dizygotic) and their siblings was carried out. 11 It confirmed a moderate (28%) genetic effect. Further research has been directed towards evaluating genotypes of the serotonin transporter gene (5-HTT) in those with PE. It is thought that a polymorphism of the gene is linked with lifelong PE 12–14 and may also be associated with treatment response to selective serotonin re-uptake inhibitors (SSRIs). 15 More investigation into this area is required.
With regards to treatment of PE, historically behavioural therapy was the mainstay of therapy. The first technique described was the ‘stop–start’ technique, in which stimulation would be stopped until the sensation of imminent ejaculation disappeared. 16 Stimulation would then be re-introduced and the cycle repeated as necessary. Other suggestions included Masters and Johnson's ‘squeeze’ technique. 17 Evidence for these therapies is inconclusive and many specialists feel they are unhelpful. While a comprehensive review of the literature is outside the scope of this article, a recent review of nine published studies was conducted by Melnik et al. 18 to determine the efficacy of psychological intervention in the management of PE. While three studies showed improved IELT with a combination of psychosexual therapy and pharmacotherapy, the evidence reviewed was limited by lack of randomization, unclear significance of outcomes and lack of convincing follow-up data. It was concluded that more large-scale randomized trials are required to assess the impact of psychological therapy alone and in combination with pharmacological interventions.
Over the last decade, there has been a greater emphasis on pharmacological treatment. The most commonly accepted treatment options include topical anaesthetic agents, antidepressants, phosphodiesterase-5 (PDE-5) inhibitors and alpha-blockers. These medications are used ‘off-label’ in the management of PE, in that their use for this purpose has not been approved by the regulatory bodies in America or Europe. This article will address the current treatment options available for use in PE and the evidence supporting their use.
TOPICAL AGENTS
The use of topical anaesthetic creams was first described in 1943 by Schapiro. 19 The hypothesis being that reducing penile sensitivity would result in prolongation of sexual intercourse without adversely affecting the sensation of ejaculation. 20 There are a number of creams and gels widely available and used in the treatment of PE. The use of topical treatment is appealing in that they can be applied on a ‘when required’ basis and as a result there are minimal systemic side-effects. However, they may lead to penile hypoaesthesia and reduced sensation in the female partner due to contamination.
Lidocaine–prilocaine cream
A mixture of prilocaine and lidocaine (EMLA) has been commonly used in the first-line management of PE. It may be applied thinly to the glans and distal shaft of the penis and subsequently covered by a condom. The optimum time for application was studied by Atikeler et al. 21 in a single-blind, placebo-controlled, randomized trial involving 40 patients. This showed a reasonable prolongation of IELT when the cream was applied 20 minutes prior to intercourse. More prolonged application resulted in numbness and loss of erection; indeed, this occurred in all patients applying the cream for 45 minutes. A further double-blind trial reported the efficacy of EMLA cream with a 5.6-fold increase in IELT from 1.49 to 8.45 minutes following application 10–20 minutes prior to penetration. 22 Reported side-effects included loss of sensation, retarded ejaculation, penile irritation and decreased vaginal sensitivity in the partner. Partner transfer of cream and the ‘messy’ nature of the cream are significant problems.
Topical eutectic mixture for premature ejaculation
Topical eutectic mixture for PE (TEMPE) is a metered dose aerosol spray delivering 7.5 mg lidocaine and 2.5 mg prilocaine per spray as a topical eutectic mixture. It is in phase III clinical trials and license application is expected. With this delivery a single ion layer of anaesthetic is delivered to the glans in a rapidly drying formulation. It is thought that improved tissue penetration will result in a faster onset of effect. A phase II prospective double-blind, placebo-controlled study involving 54 patients showed that with the application of TEMPE 15 minutes prior to intercourse, the increase in IELT from baseline was 2.4 times higher than with placebo. 23 The spray was reported to be easy to use by 83% of participants. Mild or moderate side-effects were reported in only four (15%) men treated with TEMPE; three of these related to reduced penile sensation and one to erectile dysfunction. Following on from these encouraging results, a recent phase III, double-blinded, placebo-controlled study of 300 patients in 31 countries aimed to determine the effect of TEMPE on Index of PE (IPE) and IELT with secondary objectives to determine its safety and tolerability. 24 Three self-administered actuations of spray were applied 5 minutes before sexual intercourse (delivering total dose of 22.5 mg lidocaine/7.5 mg prilocaine). Results indicate a 6.3-fold increase in IELT from baseline when compared with a 1.7-fold increase with placebo, with IELT increasing to 3.8 minutes. Besides this objective outcome measure, there were significant increases in the IPE scores from baseline by a mean of 7.0 and 5.9 points for ejaculatory control and sexual satisfaction, respectively. At the end of the three-month treatment period, 66% of patients rated the formulation as ‘good’ or ‘excellent’. It was well tolerated with no systemic adverse side-effects. Mild local side-effects were reported by only 2.6% of patients and 3.1% of partners.
Severance secret cream
Severance secret (SS) cream, manufactured in Korea, is an agent containing the extracts of nine herbal products that have both anaesthetic and vasoactive properties. It is applied to the glans penis one hour before intercourse and washed off immediately prior to penetration. Its use has been studied in Korea and it has not received licensing in Europe or USA. An open-label pilot study by Xin et al. 25 reported significantly prolonged mean ejaculatory latency in 89.2% of patients using SS cream. The response appears to be dose dependent, with the optimum dose being 0.2 g of cream. 26 A double-blind, randomized, placebo-controlled phase III study of 106 patients showed the mean ejaculatory latency was prolonged from 1.37 minutes at baseline to 10.92 minutes with SS cream compared with 2.45 minutes with placebo. 27 The patient satisfaction was deemed effective in 89.12% and 19.81% for SS and placebo, respectively. Of the patients, 18.5% reported mild local irritation following application; however, there were no systemic side-effects.
SS cream has been reformulated in an attempt to diminish the unpleasant odour and colour.
Dyclonine/alprostadil cream
A cream combining 0.4% alprostadil and 0.5% dyclonine (a local anaesthetic commonly used in dentistry) is currently being developed as a potential agent for use in PE. The only available report (abstract only) is a pilot study involving 30 patients, which showed a synergistic effect when the cream containing both alprostadil and dyclonine was compared with one containing the individual components alone. 28 Mild to moderate local side-effects were reported in 17.5% of subjects. More studies are needed to further evaluate this product.
ORAL MEDICATION
The majority of commonly used oral treatments for PE are antidepressants, specifically SSRIs and clomipramine, a tricyclic antidepressant. Recently, there has been research into the use of tramadol and also PDE-5 inhibitors, given that many patients also have coexisting problems with erectile dysfunction.
Selective serotonin re-uptake inhibitors
Although not approved by the FDA, SSRIs are commonly used in the treatment of PE and are recommended as part of first-line treatment by American Urological Association. 29 By large depression study observations were made of delayed ejaculation as a side-effect when SSRIs were used. The incidence of delayed ejaculation ranged from 50% to 64%, depending on which agent was used. 30 Paroxetine had the greatest association with retarded ejaculation.
There are four SSRIs that have consistently been shown to be effective, namely paroxetine, sertraline, fluoxetine and citalopram. A meta-analysis by Waldinger et al. 31 of 35 studies involving serotonergic antidepressants showed that despite markedly different designs and doses, paroxetine, sertraline, fluoxetine and clomipramine significantly delay ejaculation. The primary outcome measured was percentage increase in IELT, and was 1492%, 790%, 512% and 295% for paroxetine, sertraline, clomipramine and fluoxetine, respectively. However, only eight of the 35 studies were prospective, double-blind, realtime studies with stopwatch assessment at baseline and each intercourse. These studies were analysed separately and the rank order of SSRIs established as paroxetine, sertraline and fluoxetine in terms of efficacy.
The main concern with using daily SSRI's relates to undesirable side-effects. These include anticholinergic effects, cognitive impairment and other sexual side-effects such as erectile dysfunction and reduced libido. A further concern arises with dose amendment or cessation as this has been associated with ‘SSRI discontinuation syndrome’ in which a cluster of psychological and somatic symptoms emerge, including dizziness, headache, agitation and insomnia. 32 This is more common with paroxetine. 33 These symptoms tend to occur 1–3 days following discontinuation and last for greater than one week. 32 They subside on re-introduction of the SSRI.
With this in mind, it was postulated that the use of on-demand dosing with a short-acting SSRI may be just as efficacious but more convenient and with fewer side-effects. 34
Dapoxetine is a novel potent short-acting SSRI and is the first agent specifically developed for the treatment of PE. It reaches peak plasma concentration approximately one hour after dosing, is readily absorbed and undergoes rapid elimination in 1.4 hours. 35 These pharmacokinetic characteristics make it a suitable candidate for on-demand treatment.
There has been extensive investigative research into the efficacy and tolerability of dapoxetine in the last few years. There are five reported phase III, randomized, double-blind, placebo-controlled trials, with more than 6000 participants demonstrating the efficacy and safety of dapoxetine. 36–39 Pryor et al. 36 showed a significantly prolonged IELT using 30 and 60 mg doses of dapoxetine compared with placebo. The common side-effects with dapoxetine 30 and 60 mg, respectively, were nausea (8.7%, 20.1%), diarrhoea (3.9%, 6.8%), headache (5.9%, 6.8%) and dizziness (3%, 6.2%).
Similar findings were noted in a multicentre study conducted over 22 countries involving 1162 men who satisfied the DSM-IV criteria for PE for greater than six months. 38 The mean IELT increased from 0.9 minutes at baseline in all groups to 1.9, 3.1 and 3.5 minutes with placebo and dapoxetine, 30 and 60 mg, respectively. Patient reported outcome measures included the PE Profile, which was completed by the patient and their partner. Improvements from baseline in control and satisfaction were significantly greater with dapoxetine than placebo. Distress and interpersonal difficulty were also significantly reduced with dapoxetine by the end of the study. Adverse effects were comparable to those previously reported and tended to appear early in treatment and were usually dose dependent. The resultant discontinuation rate was 1.3% with placebo, 3.9% with dapoxetine 30 mg and 8.2% with dapoxetine 60 mg.
In contrast to long-acting SSRI's, the incidence of undesirable sexual side-effects appears low. In one study, sexual dysfunction (including erectile dysfunction and reduced libido) was reported in 1.9% of those receiving placebo compared with 4.5% of those receiving dapoxetine 30 mg and 5.4% of those receiving dapoxetine 60 mg. 36 Furthermore, in the nine-month open-label extension of this trial during which all 1774 participants received 60 mg, sexual side-effects were reported by 2.6% of subjects. 40
The potential for SSRI discontinuation syndrome following abrupt withdrawal was evaluated within two randomized controlled phase III trials and appears to be lower with dapoxetine than long-acting SSRI agents. 41
No drug–drug interactions have been reported with dapoxetine. Its pharmacokinetics was not altered significantly by ethanol 42 and studies with PDE-5 inhibitors showed no interaction with tadalafil 20 mg or sildenafil 100 mg. 43 Conversely, dapoxetine did not alter the pharmacokinetics of tadalafil or sildenafil.
An observational study to determine how men with lifelong PE would feel about taking serotonergic antidepressants, either on a daily basis or on demand, was carried out by Waldinger et al. 44 The results showed 81% would prefer daily treatment, 16% on-demand treatment and 3% topical anaesthetic cream only. Those preferring daily treatment did not change their mind after receiving further information regarding efficacy and safety; however, 53% of those initially favouring on-demand treatment changed their preference to daily dosing. The most commonly stated reason for preferring daily treatment was so as not to disrupt the spontaneity of sex.
Daily dosing may be the preferred option for many in the short term; however, the impact of taking daily treatment may be greater than initially anticipated. There has been one recent study evaluating the acceptance and discontinuation rate from daily paroxetine. 45 A total of 93 patients were recruited and given a prescription for paroxetine 10 mg daily for 21 days, then 20 mg as required for three months. Thereafter the patients could stay with the on-demand treatment or opt to return to 10 mg daily for another three months. They were evaluated at three and six months using a global assessment questionnaire. Thirty percent of patients decided not to commence treatment at all, the main reason being ‘fear’ of commencing an antidepressant. Thirty-one percent who commenced treatment discontinued it prior to the end of the study. The reason cited in 75% was the effects were below their expectations, while 15% reported a loss of interest in sex. Of the 39% continuing treatment, 78% of these preferred daily paroxetine, while 22% favoured as required treatment.
In a recent article, Waldinger and Schweitzer 46 controversially raised concerns regarding some clinical trials studying the use of dapoxetine for PE that have received pharmaceutical funding. The role of the pharmaceutical-sponsored clinical trials across all fields of medicine has often been open to debate. In this instance, firmer evidence supporting the use of dapoxetine as an on-demand treatment compared with daily dosing SSRI is needed, but evidence thus far does seem to suggest a potential role for dapoxetine in the management of PE.
To date (October 2009), dapoxetine use has been approved in several European countries including Finland, Sweden, Germany, Portugal and Austria. There is also another short-acting SSRI, BMS-505130, which has been shown to be potent; however, to date only preclinical trials have been carried out.
Tramadol
Tramadol is licensed as a centrally acting analgesic, is now generic, and has a proven safety record. There are at present only two publications on the use of tramadol in the treatment of PE. Safarinejad and Hosseini 47 published a double-blind, placebo-controlled, fixed-dose, randomized study using an on-demand dose of 50 mg tramadol. A 12.7-fold increase in IELT was demonstrated when compared with placebo. Adverse events were reported in 28.1% of participants in the treatment arm compared with 15.6% in the placebo arm and included nausea, vomiting and dizziness. A second study by Salem et al. 48 was a single-blind, placebo-controlled, crossover, prospective study over two years to investigate the on-demand dose of 25 mg tramadol. There was a 6.3-fold increase in IELT from the baseline of 1.17 minutes with tramadol compared with a 1.7-fold increase with placebo. Ninety-eight percent who received tramadol reported a significant increase in their control over ejaculation and significantly improved satisfaction. Tramadol was generally well tolerated at this dose with no serious adverse effects. Of these, 13.3% reported mild side-effects such as mild dyspepsia and somnolence. Although both these studies show improved IELT with the use of on-demand tramadol, there is a suggestion that the effect may be dose dependent. Further studies to evaluate its efficacy at a range of doses are required.
PDE5 inhibitors
PDE-5 inhibitors, which are licensed for the treatment of erectile dysfunction, have been evaluated in PE. Despite their success in treating ED, there is limited data supporting their use for PE only. A double-blind prospective study comparing the effectiveness of sildenafil with the squeeze technique and on-demand SSRI in 31 men showed prolongation of IELT with all therapies, but this was significantly greater with sildenafil. 49 These findings correlated with an improvement in self-reported sexual satisfaction. The side-effect profile included flushing, headache and nasal congestion in those receiving the PDE-5 inhibitor.
Another study compared the use of sildenafil and paroxetine to paroxetine alone in 80 men. 50 All participants received an induction dose of 10 mg paroxetine daily for 21 days followed by 20 mg as needed for six months. Half of these (40 men) also were given as needed sildenafil 50 mg to be taken one hour prior to sexual intercourse. Stopwatch measured IELT increased significantly from a mean of 0.33 to 5.3 minutes with combination therapy versus 4.2 minutes with paroxetine alone.
The only randomized, placebo-controlled, double-blind multicentre study evaluating the efficacy of sildenafil showed a 2.6-fold increase in IELT; however, this was not significantly different from placebo. 51 It did however demonstrate an improvement in ejaculatory control, confidence and overall sexual satisfaction as assessed by patient questionnaires.
A systematic review of 14 clinical trials assessing the efficacy of PDE-5 inhibitors, on-demand SSRIs and therapy with both agents combined, concluded that the broad range of IELT changes reflects inconsistencies in the study designs and therefore makes findings difficult to interpret. 52
Clomipramine
Clomipramine was the first antidepressant drug used in the management of PE. A number of studies have reported the efficacy of low-dose daily clomipramine over placebo in delaying ejaculation. 53–55 A double-blind randomized controlled study by Kim et al. 56 compared the efficacy and safety of clomipramine, sertraline and fluoxetine. The baseline IELT of 46 seconds was found to increase 7.5-fold (to 5.75 minutes) with clompramine and 5.6-fold (to 4.27 minutes) with sertraline, while fluoxetine was comparable to placebo. Although clomipramine resulted in greater patient satisfaction rate, the incidence of side-effects was significantly higher than with the SSRI's. A subsequent meta-analysis by Waldinger et al. 31 showed that daily dosing of clomipramine increased IELT 4.6-fold; however, this was not significantly different from sertraline and fluoxetine. On this basis, the likelihood of increased side-effects outweighs any potential treatment benefit of the tricyclic antidepressant over an SSRI.
The use of on-demand clomipramine at a dose of 25 mg was evaluated in a head to head study with paroxetine 20 mg. 57 The mean time for taking both drugs prior to coitus was around 5 hours. The results revealed a 4.05- and 1.41-fold increase in IELT for clomipramine and paroxetine, respectively. Mild side-effects, including nausea, were reported for both drugs on the day of sexual intercourse and the next day.
Alpha-1 adrenoceptor antagonist
It has been hypothesized that alpha-blockers may be helpful in treating PE as a result of their effect on the peripheral sympathetic nervous system. Limited data on their use is available, although one double-blind, placebo-controlled, crossover study compared the use of two alpha-blockers, terazocine and alphuzocine, with placebo in 91 patients who did not respond to psychotherapy. 58 Alpha-blockers were shown to be significantly more effective than placebo, and reassuringly there was no significant difference in reported side-effects. A second study supported the use of terazocine in men with PE, especially in those with concurrent lower urinary tract symptoms. 59
CONCLUSION
PE is a common sexual problem among men. Until now, problems with definition along with the lack of studies meeting evidence-based criteria have hindered progress on developing and evaluating new therapies. The mainstay of treatment at present is topical anaesthetic agents or SSRIs. There are however several promising developments, including the potential licensing of TEMPE and the short-acting SSRI, dapoxetine. With the emphasis on more research into this area, hopefully the evidence base for a range of treatments, both topical and oral, will grow. This will prove valuable in an era where patient choice and acceptability are paramount.