Abstract
Premature ejaculation (PE) is a common male sexual dysfunction. Advances in PE research have been hampered owing to a nonstandardized definition of PE, until the definition by the International Society of Sexual Medicine (ISSM) in 2009. Once the diagnosis of PE is established through a thorough history, a variety of medical therapies is available, including tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), centrally acting opiates, phosphodiesterase 5 inhibitors and topical desensitizing creams. Most of these treatments increase the intravaginal ejaculation latency time (IELT) and patient satisfaction scores, with the most convincing evidence for SSRIs and topical creams. Daily SSRIs such as paroxetine, although efficacious, do have a substantial and prolonged side effect profile. Dapoxetine, which is a on-demand SSRI, is the only licensed drug for the treatment of PE, increasing IELT by a factor of 2.5 to 3 with limited and tolerable side effects. In the near future, the topical aerosol PSD502 is due to be licensed for the treatment of PE, increasing IELT by up to a factor of 6 but having minimal local and negligible systemic side effects.
Introduction
Premature ejaculation (PE) can be a debilitating male sexual impairment. A range of studies have suggested a prevalence of 4–39% [Laumann et al. 1999; Grenier and Byers, 1995; Spector and Carey, 1990; Nathan, 1986; Reading and West, 1984]. This wide range can be partly attributed to variations in the way that PE is defined, but may also reflect differences between populations and differences in the degree of bother. Furthermore, because of the intimate nature of the problem, PE tends to be under-reported by patients who do not typically seek medical help [Grenier and Byers, 1995].
Definition of premature ejaculation
Over the years, PE has been defined in various ways. Some consider it controversial that PE is even considered to be a sexual dysfunction at all, since all male upper mammalian species, including primates ejaculate almost immediately on penetration of the vagina [Wainberg, 1984].
However, initial definitions of PE revolved around ejaculation which regularly occurs at or around initial vaginal penetration [Marmor, 1976]. A quantitative element was subsequently added to the definition. For instance, the arbitrary time of 1 minute from vaginal penetration to ejaculation was suggested by some [Marmor, 1976] while others defined the condition in terms of the number of penile thrusts (at least 15) inside the vagina before ejaculation [Colpi et al. 1986]. Other authors added a more subjective element to the definition by defining PE as ejaculation that happens prior to when the male desires it [Hastings, 1963] or ejaculations which are satisfactory to the female partner in less than 50% of sexual intercourses [Masters and Johnson, 1970]. A consensus on a standardized definition for PE was clearly needed.
Early definitions of premature ejaculation.
PE, premature ejaculation.
All of the above definitions acknowledge one or more of the three core components to PE:
a short ejaculatory latency; a lack of control over ejaculation; a lack of sexual satisfaction.
In 2009, the International Society of Sexual Medicine (ISSM) [Althof et al. 2009] produced its guidelines of the diagnosis and management of PE. It postulated an evidence-based definition of PE and defined PE as a male sexual dysfunction characterized by:
ejaculation which always or nearly always occurs prior to or within about 1 minute of vaginal penetration; inability to delay ejaculation on all or nearly all vaginal penetrations; negative personal consequences, such as distress, bother, frustration and/or the avoidance of sexual encounters.
This definition is regarded as the most robust to date owing to its evidence-based nature and has largely replaced the previous definitions as the standard definition of PE.
However, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) due to be published in May 2013 [APA, 2013] may offer an alternative take on the definition of PE. The impact of this new definition on the diagnosis and management of PE is awaited. In the interim, the definition advocated by the authors is the ISSM's definition of PE.
Diagnosis and classification
PE can be divided into two distinct entities: acquired and lifelong PE [Godpodinoff, 1989]. Lifelong PE is a condition which has existed since the onset of sexual activity and is not reliant on either the conditions or the environment under which sexual activity is taking place. Acquired PE develops in an individual who has previously had normal ejaculatory control and can develop gradually or suddenly.
The cause of PE is usually not apparent. Some have characterized these cases as being psychogenic in origin, while others have postulated ‘biogenic’ causes [Sadeghi-Nejad and Watson, 2008]. This fundamental controversy about whether PE is behavioural or biomedical has been reflected in the two differing approaches to therapy (i.e. behavioural or psychotherapy versus pharmacological therapy). Those proposing a psychogenic basis in the absence of a definitive physical cause suggest that PE may be associated with situations such as:
anxiety; novelty of partner or situation; low frequency of sexual activity.
Biogenic PE is linked to an identifiable organic cause and the following conditions have been identified as possible causes:
substance abuse (e.g. alcohol); endocrinopathy (e.g. hyperthyroidism); chronic prostatitis; opiate withdrawal.
Once the condition is treated, the expectation is for PE to cease.
Those who have proposed biogenic theories for the development of PE have suggested that one of the following may be the pathophysiological mechanism:
penile hypersensitivity; hyperexcitable ejaculatory reflex; hyperarousability; genetic predisposition; 5-hydroxy tryptamine (5-HT)-receptor dysfunction.
Waldinger and Schweitzer introduced the concept of PE as a syndrome, with patients experiencing a continuum of symptoms [Waldinger and Schweitzer, 2006]. The four main interweaving sets of symptoms are:
short IELT, with control; short IELT, no control; normal IELT, no control; normal IELT, with control.
This spectrum of symptoms can therefore include a category called ‘natural variable PE’ whereby the episodes of PE are not consistent and can be situational. This group falls under the umbrella ‘short IELT and no control’. This may represent a variation of natural ejaculatory function. Another category that stems from this syndrome is the ‘Premature-like ejaculatory function’ whereby the patients perceive that they are experiencing PE while the IELTs fall in the normal range. This falls under the umbrella ‘normal IELT and no control’.
Classification of PE is still evolving as different classification models offer different clinical and research benefits [Cahangirov et al. 2011; Chan et al. 2011; Clément et al. 2009; Waldinger and Olivier, 2005; Pattij et al. 1995].
Clinical assessment
Clinical history plays an important part in the diagnosis of PE since it is by definition a self-reported diagnosis. However, clinical assessment can be challenging owing to the nature of the problem. Patients may be embarrassed and shy when relating details of their sexual experiences and exact details are not forthcoming. It may then be useful to involve the partner in the consultation.
To elicit a diagnosis of PE, the three main components of PE (timing, control and satisfaction) should be specifically addressed. Once a diagnosis of PE is established, other related avenues that should be explored are:
the nature of the PE (lifelong or acquired); the presence or absence of any associated erectile dysfunction (ED); the impact of the PE on the relationship with his partner; the impact of the PE on quality of life; previous treatment (including over the counter medication) and response to that treatment.
Examination of the patient involves a general examination as well as a more focused examination of the genitalia outlining the scrotal contents and the penis in detail. A digital rectal examination to palpate the prostate gland is also recommended. Questionnaires such as the Index of Premature Ejaculation [Yuan et al. 2004] and the Premature Ejaculation Diagnostic Tool [Symonds et al. 2007] also have a role is evaluating PE. It must be noted that the routine use of questionnaires is not very useful, as they have a tendency to confuse the picture, especially when ED occurs concurrently. ED specific questionnaires such as the IIEF and its shorter version, IIEF-5, have been shown to further complicate the issue, especially in ED and PE trials [Ramanathan et al. 2007].
Laboratory and other physiological tests are rarely indicated. History and examination are sufficient to reach a diagnosis.
Treatment
Treatment of PE can be a real challenge for the clinician (Figure 1). This is primarily because the pathophysiology of PE is so poorly understood. Over the years multiple treatment modalities have been tried, often with initial promise. However, there are few studies on long-term efficacy and durability for most of the currently available treatment options. This article aims to provide an overview of the different treatment options available together with an assessment of the supporting evidence.
Nonmedical therapy
Psychological and behavioural therapy historically have a significant role in the management of PE.
Behavioural therapy
The ‘stop–start’ strategy (stopping coitus in situ and restarting after a delay) and its evolution to the ‘squeeze’ technique (the physical application of pressure at the base of the head of the penis) have been reported since the 1950s [Semans, 1956]. However, while short-term benefits have been reported (symptomatic benefit in 45–65%), the long-term results of treatment have not been conclusive (after 3 years of follow up, 75% of men showed no lasting improvement) [Hawton et al. 1986]. One strategy, particularly for younger men suffering from PE, is precoitus masturbation which partially desensitizes the penis and leads to a delay in ejaculation [Sadeghi-Nejad and Watson, 2008].
Psychotherapy
Psychotherapy involves educating both the male patient and the female partner. This can happen in the context of marriage/relationship counselling as well as psychosexual therapy [Hatzimouratidis et al. 2010]. Again short-term results have been promising although long-term benefits are unproven.
Medical therapy
The quest to develop an effective tablet to aid and ultimately cure PE has been ongoing for many decades [Schapiro, 1943]. A number of drugs have shown some promise in treating PE with varying degrees of success. At the present time, only one drug (dapoxetine) is licensed (in some countries only) for the treatment of PE. However, the other drugs described below can also be used, as long as the patient is fully aware that they are not licensed for the treatment of PE.
Historical agents
Alpha-adrenergic blocking agent (Phenoxybenzamine, alfusozin, terazosin) and monoamine oxidase inhibitor (Isocarboxazid, Phenelzine)
Together with monoamine oxidase (MAO) inhibitors, alpha-blockers were the first oral medication used for the treatment of PE. However, the side effects associated with the nonselective alpha-blockers limited their use. These agents are not used for PE anymore [Beretta et al. 1986; Shilon et al. 1984; Aycock, 1949]. More selective alpha-blockers such as terazosin have shown some promise in treating PE in patients suffering from concurrent lower urinary tract symptoms [Başar et al. 2005].
More recent agents
A range of drugs are currently used by clinicians for the management of PE including antidepressants, local anaesthetic agents and phosphodiesterase type 5 inhibitors.
Whether the medication is used regularly or on demand is an important consideration for patients when choosing the most appropriate drug for the treatment of their PE. An on-demand drug offers the flexibility of using the medication just prior to sexual intercourse, thereby reducing the risks of side effects associated with the drug for the rest of the time. Data so far suggest that generally speaking the benefit of on-demand dosing is inferior to the benefits seen with regular dosing. On the other hand, daily dosage allows for a more spontaneous sexual experience. Set against this, regular dosing results in greater exposure to the drug and may be associated with more pronounced side effects. Waldinger and colleagues showed that the majority of men (81%) preferred a daily regimen as opposed to an on-demand regimen [Waldinger et al. 2007]. Moreover, the stigma associated with the daily use of an antidepressant (i.e. selective serotonin reuptake inhibitors [SSRI]) may be a complicating factor in the compliance of patients to the treatment.
Tricyclic antidepressants (clomipramine)
There is evidence that continuous and on-demand dosing of clomipramine increases the IELT in patients suffering from PE [Strassberg et al. 1999; Kim and Seo, 1998; Segraves et al. 1993], with reports of improved sexual satisfaction both from patients and partners [Althof et al. 1995]. The use of clomipramine is limited by its associated side effects, mainly fatigue, dizziness, dry mouth and hypotension. During continuous dosing, the adverse event profile of clomipramine in men with PE was reported to be significantly worse than with SSRI treatment [Kim and Seo, 1998].
SSRIs unlicensed (escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline)
Serotonergic agents have been shown to be effective in the management of PE. The mechanism probably revolves around activation of the 5-HT2C receptor which leads to a delay of ejaculation [Lue and Broderick, 2007; Waldinger et al. 1998]. The effect of SSRIs on the delay of ejaculation was first noted by Patterson when treating men with depression [Patterson, 1993]. Since then, studies have shown that the effect of SSRIs to delay ejaculation can be seen within days of the start of treatment with a plateauing of the effect within 4 weeks. In the variously reported studies the IELT is increased between twofold and eightfold with the use of SSRI.
The use of fluoxetine to treat PE was first described in 1994 by Forster [Forster, 1994] and Waldinger and colleagues conducted the first randomized, controlled trial to evaluate the use of paroxetine in treating PE [Waldinger et al. 1994]. Further work by the same research group demonstrated efficacy of a number of SSRIs (fluoxetine, fluvoxamine, paroxetine and sertraline) in the treatment of PE, although with varying efficacy and side-effect profiles [Waldinger et al. 1998]. Fluoxetine, sertraline and paroxetine increased IELT significantly whereas there was no statistical difference with fluvoxamine.
Kim and Seo demonstrated that treatment with sertraline was nearly as effective and had a lower incidence of side effects than clomipramine [Kim and Seo, 1998]. Further studies (prospective studies and randomized controlled trials) have confirmed the efficacy of sertraline in the management of PE [Balbay et al. 1998; Biri et al. 1998; Mendels, 1995]. Duloxetine [Athanasios et al. 2007] and Escitalopram [Safarinejad, 2007] have also been shown to be effective in treating PE. The efficacy and side-effects associated with SSRIs are described later (see Table 5).
Adverse effects with SSRIs are usually minor and include fatigue, yawning, mild nausea, loose stools and perspiration. They usually present at the beginning of the treatment and they tend to disappear within 2–3 weeks. There have been reports of decreased libido, mild ED and increased suicide risks with the use of SSRIs, especially long-term paroxetine [McMahon et al. 2004; Kim and Seo, 1998; Waldinger et al. 1998]. Therefore, it is important that patients are adequately counselled about the risks involved with the use of these drugs. Once patients have been started on SSRI treatment, it is essential to perform follow-up assessments to not only evaluate the efficacy of the drug but also to identify any side effects, especially regarding associated sexual dysfunction and suicide risks.
Licensed SSRI (dapoxetine)
Dapoxetine is the only licensed drug in the treatment of PE. It has been approved for treatment for the treatment of PE in New Zealand, Sweden, Austria, Finland, Germany, Spain, Italy and Portugal. National approvals and licenses in five other European countries are expected to follow. Dapoxetine is not approved for marketing in the United States.
Dapoxetine is a drug specifically developed for the on-demand treatment of PE. It has been extensively evaluated in five randomized, placebo-controlled phase III clinical trials involving more than 6000 men with PE. This is the largest and most comprehensive clinical trial programme to date for a drug therapy to treat PE. It is a short-acting SSRI designed to be taken only when needed and is taken 1–3 hours before sexual intercourse is anticipated.
There is evidence of its efficacy, its relatively mundane side effect profile and its validity as an on-demand medication [Feige et al. 2011; Hoy and Scott, 2010; Kaufman et al. 2009; McMahon et al. 2009; Giuliano et al. 2007]. However, the durability of the effects of dapoxetine has not yet been demonstrated in prospective, randomized trials since long-term follow up is not yet available [Safarinejad and Hosseini, 2006].
Treatment of premature ejaculation with dapoxetine (phase III clinical trials).
IELT, intravaginal ejaculation latency time; PRN, pro re nata.
Desensitizing agents (SS Cream, benzocaine, prilocaine, lidocaine)
The use of a local anaesthetic to desensitize the penis prior to coitus has been described since the middle part of the last century [Damrau, 1963]. A number of these products are available as ‘over-the-counter’ medications and can be readily purchased online. They predominantly come in the form of creams although topical sprays are also available.
Xin and colleagues published data demonstrating that patients suffering from PE had an increased vibratory threshold on the glans penis when it was smeared with desensitizing cream (SS-Cream – herbal cream). Moreover, the effect was dose related [Xin et al. 2000]. Thereafter, the same research group performed a randomized controlled trial demonstrating an increase in IELT by eightfold when using the cream [Choi et al. 2000].
The efficacy of prilocaine–lidocaine cream (EMLA cream) and aerosol sprays have been demonstrated in prospective cohort studies [Dinsmore et al. 2007; Henry and Morales, 2003; Berkovitch et al. 1995] and in randomized, controlled trials [Carson and Wyllie, 2010; Busato and Galindo, 2004]. The optimum time of application of the EMLA cream has been shown to be 20 minutes prior to intercourse and the optimum concentration 5% [Atikeler et al. 2002]. However, topical cream can be messy to apply and requires the use of a condom to minimize the effect of the cream upon vaginal sensation.
Treatment of PE with PSD 502 (randomized controlled trials).
IELT, intravaginal ejaculation latency time; PE, premature ejaculation; ED, erectile dysfunction.
Desensitizing creams and sprays can cause side effects including hypoanaesthesia of the penile shaft and numbing of the vaginal vault of the partner, unless a condom is used [Lue and Broderick, 2007]. Irritating local and systemic effects have also been reported, although they are rare [Busato and Galindo, 2004; Atikeler et al. 2002].
PDE5 inhibitors (sildenafil, vardenafil, tadalafil)
Randomized, controlled trials of PDE5-I.
IELT, intravaginal ejaculation latency time; PE, premature ejaculation.
Efficacy and side effects of drugs used in the management of PE.
IELT, intravaginal ejaculation latency time; PE, premature ejaculation; ED, erectile dysfunction; SSRI, selective serotonin reuptake inhibitor; PRN, pro re nata.
Epidemiological studies have shown that a third of men with ED suffer from PE [Corona et al. 2004]. This association between PE and ED may be explained by the fact that when a man suffers from ED, he makes a compensatory effort to achieve ejaculation before the loss of the erection, leading to PE. A possible carry on effect from this is when the man suffering from ED tries to overstimulate himself to achieve a rigid erection, whereby this overstimulation leads to PE [Jannini et al. 2005]. Therefore, by treating the ED with PDE5 inhibitors, the corresponding associated PE improves. However, evidence that this mechanism is actually occurring is not forthcoming as yet. There are just two randomized controlled trials evaluating a PDE5-I in the management of PE [Aversa et al. 2009; McMahon et al. 2005].
Although the evidences does not strongly support the use of PDE5-I in primary PE, it may have a role in treating PE in patients intolerant to dapoxetine, especially if the PE is associated with ED.
Centrally acting opioid analgesic (tramadol)
Safarinejad and Hosseini have published a randomized, controlled trial on the use of tramadol HCL to treat PE [Safarinejad and Hosseini, 2006]. Various research groups have shown tramadol to have some efficacy in treating PE [Alghobary et al. 2010], especially as an on-demand medication, although the mechanism is poorly understood [Alghobary et al. 2010; Salem et al. 2008; Safarinejad and Hosseini, 2006]. However, there is evidence that some cases of secondary PE are seen in men who are withdrawing from opiate addiction. There may therefore be a relation between central opioid receptors and ejaculatory control.
Table 5 gives a summary of the medication currently being used for the treatment of PE.
Future possibilities
Additional research is required to eventually develop a product which is acceptable to the patient by being effective all of the time with minimal side effects and that is easy and discreet to use without compromising spontaneity during sexual intercourse. Some of the possibilities are as follows:
9-hydroxycanthin-6-one (9-HC-6-one), a β-carboline alkaloid isolated from Eurycoma longifolia. In vitro, it has been noted that 9-HC-6-one attenuated PE-induced contraction by blocking calcium channels [Chiou and Wu, 2011]. It has been noted that decreased levels of magnesium may give rise to vasoconstriction from an increased thromboxane level, increased endothelial intracellular Ca2+, and decreased nitric oxide. This mechanism has been attributed to PE [Mohammadreza et al. 2009].
However, there is a long way to go before these products can be marketed. Moreover, reproducible in vitro and in vivo studies are required and the formulation of a standardized definition of PE is possibly the first building block towards standardization of PE research.
Conclusion
PE is a common condition affecting around one in five men. It can be a cause of significant personal distress which may in turn affect the relationship of the man with his partner. While many men with PE do not seek medical attention, when they do, SSRIs, desensitizing creams and to a lesser extent PDE5-I have been used in the treatment. All of these medications are sold off-label for the treatment of PE except for the recently licensed dapoxetine (PriligyTM) which provides an effective, on-demand treatment regimen with relatively minimal side effects. PSD 502 is currently in the development phase and with the conclusion of phase III trials, may soon be licensed as a topical aerosolised spray for the treatment of PE.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Management of premature ejaculation. PE, premature ejaculation; ED, erectile dysfunction.
Conflict of interest statement
The authors declare no conflicts of interest in preparing this article.