Premature Ejaculation: Current Medical Treatment and New Directions

Hossein Sadeghi-Nejad, MD, FACS, and Richard Watson, MD, FACS

A B S T R A C T
Introduction. Premature ejaculation (PE) is the most common form of male sexual dysfunction. Until very recently, scientific investigation of PE has been hampered by a lack of standardized definitions and objective, validated questionnaires. Small numbers of randomized controlled studies evaluating various treatment options have also added to the challenges facing the clinicians who manage PE.

Aim. This article provides a summary of some of the more relevant the peer-reviewed literature pertaining to the medical therapy of premature ejaculation.

Methods. A retrospective review of peer reviewed publications relevant to the field of premature ejaculation and related medical therapies.

Main Outcome Measures. Review of safety and efficacy of various medical therapies for premature ejaculation.

Results. Selective serotonin release inhibitors have been the most promising agents to date. The on-demand “PRN” use of these agents is more convenient, but its efficacy is less well established. Chronic use of this class of medications has been associated with minor, but bothersome side effects. More recently, concern over the risk of an increased suicide rate in young men upon initiation of SSRIs has dampened enthusiasm. Recent experience with the use of Tramadol raises the hope that this might prove to be an agent as effective as SSRIs with less worrisome risk of side-effects. New trials on novel formulations of topical solutions are currently underway in the United States. Conclusions. Interest in medical therapy for PE is rapidly increasing and reflected in a disproportionate number of publications in this field in the past few years. Clinical research in this field is hampered by the complexity, variability among different men and cultures, and subjectivity of PE. Reliable, appropriately controlled and assessed studies are generally lacking and carefully devised, methodically conducted research is much needed. Sadeghi-Nejad H, and Watson R. Premature ejaculation: Current medical treatment and new directions. J Sex Med 2008;5:1037–1050.

Key Words. Premature Ejaculation; Medical Therapy; Orgasmic Disorder


Introduction

Interest in premature ejaculation (PE) has been increasing rapidly among all healthcare professionals. A recent Medline search (January 2008) for articles related to PE, from 1949 to the present, uncovered a total of 589 references of which 160 articles (27%) had been published within the past 2 years. Much of this recent surge in interest has focused on new and promising medical relief for men who are troubled by this vexing condition.

This review, while recognizing the critical importance of an integrated approach to the evaluation and management of PE—coordinating participation on the part of urologists, mental health professionals, endocrinologists, primary care physicians, and other interested healthcare professionals—is directed primarily at providing an update on recent developments in the medical treatment of PE.

Definition

The definition of PE is still evolving, but the classic triad involved in the definition includes (i) short intravaginal ejaculatory latency time (IELT), (ii) lack of control, and (iii) sexual dissatisfaction [1]. The World Health Organization (WHO) 1994 International Classification of Diseases defines PE as “an inability to delay ejaculation sufficiently to enjoy lovemaking, manifest as either of the following: occurrence of ejaculation before or very soon after the beginning of intercourse (if a time limit is required: before or within 15 seconds of the beginning of intercourse); occurrence of ejaculation in the absence of sufficient erection to make intercourse possible. The problem is not the result of prolonged absence from sexual activity” [1]. Furthermore, the WHO definition excludes men whose PE is predominately attributed to (i) alcohol, substance abuse, and/or medications; (ii) a sexual context that has led to very high levels of arousal because of the novelty of partner or situation; and (iii) a low frequency of sexual activity [1].

Others have based their diagnosis on the number of penile thrusts occurring before ejaculation, considering less than 8–15 thrusts as the criterion for PE [2,3]. In 2007, responding to the variability of worldwide definitions and the need for a universal standard, the International Society for Sexual Medicine (ISSM) established an ad hoc committee consisting of 21 internationally recognized experts, to establish a new definition of PE. This latest ISSM definition, based on the recommendations of the most active and respected clinical and basic science experts in the field, characterized PE as follows: “Premature ejaculation is a male sexual dysfunction characterized by ejaculation which always or nearly always occurs prior to or within about one minute of vaginal penetration; and inability to delay ejaculation on all or nearly all vaginal penetrations; and negative personal consequences, such as distress, bother, frustration and/or the avoidance of sexual intimacy” [4]. Based on this new definition, some investigators may question the conclusions of previous studies with potentially inadequate patient selection definitions.

Other related definitions include primary or lifelong PE—presence of the problem from the onset of initial sexual activity; acquired or late onset PE—indicates that the problem has developed after an initial time of unimpaired ejaculatory function; and situational (vs. global) PE—indicates PE that is limited to specific partner or situation, while the patient enjoys satisfactory intercourse in other contexts [5].

Prevalence

The National Health and Social Life Survey, a probability sample study of sexual behavior in men and women aged 18–59 years, reported a prevalence of 21% among men in the United States [6].

Nathan [7] analyzed the findings of 22 general population sex surveys, and estimated the prevalence of PE to be 35%. Most estimates from other general population prevalence studies fall between 22% and 38%, with ranges from 4% to 39% [8–10]. The wide variability in the reported ranges is mirrored in the variability and lack of standardized definitions for PE.

A number of studies have raised the point that in spite of the high prevalence rates, PE is the disorder for which patients are least likely to seek professional assistance, raising the distinct possibility that the problem may be more prevalent than currently estimated [8,10]. More recently, the PE Prevalence and Attitudes (PEPA) internetbased survey of 12,133 men aged 18–70 in the United States, Germany, and Italy reported a prevalence of 22.7% [11]. It is noteworthy that only 9% of the men in this survey had consulted a physician, and more than 90% reported little or no improvement after they sought treatment, leading to a general lack of satisfaction with the results. It has also been suggested that the prevalence of PE may vary between racial groups; one recent survey of 1,320 men found that PE was more prevalently admitted among Hispanic men, highlighting the importance of further investigation of ethnic and cultural variances in PE worldwide [12]. The recurrent emerging pattern appears to be that PE is a largely underdiagnosed condition.

Etiology

The etiology of PE has been traditionally divided between “psychogenic” and “biogenic” factors. Psychogenic causes include anxiety, an unpleasant introductory or early sexual experience, infrequent sexual intercourse, poor ejaculatory control techniques, and evolutionary as well as psychodynamic factors. Biogenic causes include penile hypersensitivity, hyperexcitable ejaculatory reflex, hyperarousability, endocrinopathy, genetic predisposition, and 5-hydroxy tryptamine (5-HT)- receptor dysfunction [1,13]. Urologic causes, including chronic prostatitis, have also been implicated [14]. Early animal studies revealed that nonselective agonists of the 5-HT2C receptors delay ejaculation, but selective 5-HT2A agonists do not have a similar effect, and selective 5-HT1A agonists cause a shorter ejaculatory latency compared with 5-HT2C agonists [15,16]. Later, Waldinger et al. hypothesized that PE may be secondary to relative hyposensitivity of the 5-HT2C and/or 5-HT1A hypersensitivity [17]. The effect of postsynaptic 5-HT receptor activation on delayed ejaculation was later confirmed by using different selective serotonin reuptake inhibitors (SSRIs) [18–22]. The possible influence of genetic causes was investigated in a survey of 1,196 men in Finland that suggested the presence of a familial or genetic influence in 28% of men [23].

Medical Treatment of PE
Topical Agents

Decreasing sensory perception in the penis has been the goal of most topical agents aimed at treating PE. As a general rule, reliable controlled studies have been lacking in this area. Penile biothesiometry studies have shown that patients with PE have increased penile sensitivity as shown by consistently decreased vibratory threshold that is not age dependent [24,25]. Lidocaine- or prilocaine-based sprays, creams, or gels, as well as eutectic (i.e., melts easily) mixtures, have shown promise [26,27]. Their application offers a rapid onset of effect, with relatively mild numbness. A typically mild adverse side effects profile and availability for on-demand usage are other advantages in this category. In 9 of 11 men with PE, prilocaine-lidocaine cream (EMLA [eutectic mixture of local anesthetics], Astra Pharmaceuticals, Wayne, PA, USA) was shown to markedly improve IELT without any reported adverse events [28]. In phase II testing, topical eutectic mixture for PE (TEMPE), when used as an aerosol 15 minutes before intercourse, resulted in a 3.8 minute increased in IELT, compared to 0.7 minutes for the placebo. While this constituted a 2.4-fold improvement over placebo, the numbers were too small to establish a statistically significant difference [27]. The topical application of anesthetic creams has the disadvantage of requiring a somewhat messy application within a condom, and the entire shaft is anesthetized. Aerosol TEMPE formulation, on the other hand, requires a decreased time for prior application, and only the glans penis is anesthetized [27,29]. This aerosol formulation is undergoing phase III trials in the United States, but is not Food and Drug Administration (FDA) approved at the time of this writing.

So far, there has been an agreement neither on the amount of medication nor on the timeframe for its application. Recommended times for application have ranged from hour to 20 minutes prior to intercourse [29]. Atikeler et al. compared the application of EMLA cream 20, 30, and 45 minutes before intercourse, and found 20 minutes to be the optimum period before anticipated intercourse for topical application [30].

In a double-blinded, randomized, placebocontrolled study of 42 patients—lidocaineprilocaine vs. placebo—the IELT improved with treatment from 1.49 to 8.45 minutes with lidocaine-prilocaine, while use of the placebo only increased the IELT from 0.7 to 1.9 minutes [31]. The application of an EMLA cream preparation—either lidocaine (2.5%) or prilocaine (2.5%)—20 to 30 minutes prior to intercourse has met with success [1]. In a placebo-controlled trial in 84 patients, when EMLA topical cream alone was compared with sildenafil alone or in combination with EMLA application, topical EMLA alone proved efficacious and had equal effectiveness to topical EMLA plus sildenafil therapy [2]. Similarly, a double-blind, randomized, placebocontrolled phase III clinical study of 106 patients with lifelong PE was conducted in three medical centers to investigate the efficacy of penile application of SS-cream. This herbal mixture, made from the extracts of nine natural products, was applied hour prior to intercourse and provided a dose-dependent clinical efficacy in 80% of men using the cream, as compared to 15% in the placebo group. IELT increased to greater than 2 minutes. After treatment, the mean ejaculatory latency was prolonged to 2.45 +/– 0.29 minutes in the placebo group, and 10.92 +/– 0.95 minutes in the SS-cream group [32].

General objections to all forms of topical therapy include complaints of significant penile hypoanesthesia and risk of transvaginal absorption with vaginal numbness, unless a condom is utilized [1]. Irritating topical reactions, both penile and vaginal, can occur, and systemic reactions are also possible [31]. Efforts to wash off the medication prior to intercourse may reduce the risk of these side effects, but also reduce the spontaneity of the coital experience [12,33]. SS-cream studies have shown relatively minor side effects. These include mild local burning and mild pain without systemic adverse effects or adverse effects on sexual function or partner.

Based on the level of evidence ratings of the studies reviewed, treatment of PE with topical anesthetics received a grade A recommendation from an expert panel at the Second International Consultation on Sexual Medicine [1].

Pharmacologic (Oral) Therapy

The search for an effective, oral agent to remedy PE has been hampered by the complexity, variability, and subjectivity of this condition as noted earlier. Nevertheless, trials of centrally acting agents date back to as early as 1943 [34]. Some of the earlier medical approaches to the problem involved the use of alpha amino benzoate as well as various alpha blockers.

Phenoxybenzamine, as well as more selective alpha blockers, such as terazosin and alfuzosin, were among the first agents utilized. The dopamine antagonist neuroleptic thioridazine (Mellaril; Novartis Pharmaceuticals, East Hanover, NJ, USA) was also deemed helpful for delaying ejaculation, as were the nonselective monoamine oxidase (MAO) inhibitors, isocarboxazid and phenelzine [35–38]. The adverse event profile of these medications, however, led to their gradual phaseout as other therapies emerged. In 1973, the use of clomipramine and other tricyclic antidepressants was advocated, signaling the beginning of a new era in the approach to treating PE that will be discussed in the following segments of this review [39].

On-Going, Long-Term Medications on a Daily Basis

Selective Serotonin Reuptake Inhibitors (SSRIs) Treatment with an SSRI activates the 5-HT2C receptor, adjusts the ejaculatory threshold set point, and delays ejaculation [1]. The extent of this delay varies widely depending upon the type, dose, and frequency of SSRI administration and the genetically determined ejaculatory threshold set point.

The ability of SSRIs to delay ejaculation was first uncovered serendipitously during the use of these medications in the treatment of depressed men in the 1970s [40]. Fluoxetine was next shown to be helpful in the intentional treatment of PE [41].

Subsequently, a placebo-controlled trial of paroxetine proved promising [42]. A double-blind, fixed-dose trial of randomly assigned 20- or 40-mg daily doses of paroxetine in 27 patients with primary PE showed a statistically significant improvement in ejaculation time with both doses, as compared to placebo. Because the increase in the IELT was relatively similar in both groups, the authors concluded that daily 20-mg paroxetine “may be considered as an adequate treatment for primary premature ejaculation,” but that a higher dose may further increase the ejaculatory latency [42].

Kim and Seo compared the efficacy and safety of 4 weeks each of fluoxetine, sertraline, clomipramine, and placebo in treating PE in 36 men. As compared with an IELT increase from a baseline of 46 seconds to 2.27 minutes with placebo, therapy with the other agents resulted in increased IELT to 2.30, 4.27, and 5.75 minutes with the other agents, respectively. The SSRIs sertraline and fluoxetine were shown to be more effective than placebo in this 1998 controlled study [43]. Importantly, treatment with the SSRI sertraline was nearly as effective in delaying ejaculation as clomipramine, but had a significantly lower incidence of side effects.

SSRIs may cause an increase in latency time as early as 2–3 days after the initiation of oral therapy. This effect tends to plateau after 3–4 weeks, with a six- to eightfold increase in IELT [44,45]. In order of clinical response, a meta-analysis of 35 studies of daily SSRI treatment found that paroxetine was the most effective, followed by fluoxetine, then sertraline, and lastly fluvoxamine [19]. The same group also set out to assess whether the ejaculatory-delaying effects of at least some SSRIs may be applicable in men with “less-rapid” ejaculation. Following treatment with paroxetine 20 mg/day, the percentage increase in the geometric mean IELT compared with baseline in patients treated with paroxetine was 420% in patients with classic PE (less than or equal to 1 minute) and 480% in those with less rapid PE (greater than 1 minute), indicating that the paroxetine-induced percentage increase in IELT appeared to be independent of the baseline IELT, and that the findings may be extrapolated to men with less-rapid ejaculation. Other studies have documented efficacy for different SSRIs. For example, sertraline was found to be effective in improving IELT, ejaculatory control, and sexual satisfaction [46–48]. Similarly, a recent report on the efficacy of duloxetine in treating PE showed that treatment with this SSRI increased the IELT from 38.21  16.45 seconds to 129.34 seconds  67.58 (P = 0.001 vs. control) [49].

Fluvoxamine is an SSRI unrelated in its chemical structure to other SSRIs or to clomipramine. Of all the SSRIs, it seems to have the least effect on prolonging IELT. This information may be helpful in advising psychiatrists, as they select an antidepressant for sexually asymptomatic men for whom further prolongation of IELT would be undesired [19,50].

Escitalopram has been shown to be efficacious in the treatment of PE. This medication has the highest SSRI selectivity for human serotonin receptors, relative to dopamine and norepinephrine receptors—escitalopram > sertraline > paroxetine > fluvoxamine > fluoxetine. It should be mentioned that as compared with other SSRIs, citalopram has not shown the greatest efficacy, and the ejaculatory-delaying effects are definitely inferior to paroxetine [51]. A meta-analysis of the effects of various SSRIs found that citalopram and fluvoxamine were the least efficacious among the SSRIs [1,21]. In 2007, Safarinejad [52] published the results of his study comparing the results following 3 months of therapy with escitalopram vs. placebo. Because the SSRI activity of citalopram resides mainly in the S-enantiomer, the investigator postulated that this high selectivity of the S-enantiomer (i.e., escitalopram) may translate into higher efficacy. The study was designed to assess increases in mean geometric IELT immediately after the study (3 months), as well as at 6 months. There was an insignificant increase in the mean IELT in the placebo group, whereas the SSRI group had a 4.9-fold increase of the mean IELT. More importantly, the author showed that with a 6-month follow-up (i.e., after the medication had been withdrawn), the escitalopram group continued to demonstrate increased mean IELT (3.1-fold vs. 1.3-fold for placebo) [52]. Although escitalopram has the highest rate of bothersome side effects, such as nausea, headache, and dry mouth, the overall incidence of adverse events with all SSRIs is typically less than 5% [52]. The author cautioned that additional studies are needed before this medicine can be recommended as ideal therapy for PE.

Side Effects.

SSRIs may give rise to side effects such as fatigue, mild nausea, loose stools, or heavy perspiration. These complaints may gradually dissipate within 2–3 weeks. The side effects of clomipramine (a tricyclic antidepressant) are similar, although more pronounced, and consist of nausea, dry mouth, and fatigue. Both SSRIs and clomipramine may delay ejaculation at the expense of a diminution of libido and a moderate decrease in penile rigidity (which is reversible). Patients should be informed of these possible side effects prior to initiating therapy [1]. The abrupt reduction or discontinuation of long-term SSRI therapy can result in the “SSRI discontinuation syndrome”—a cluster of somatic and psychological symptoms including nausea and vomiting, vertigo, headache, unstable gait, lethargy, agitation, anxiety, and insomnia. These symptoms begin from 1 to 3 days after discontinuance, and may last over 1 week. The side effects can usually be reversed by the reintroduction of the SSRI [53]. Nonetheless, it is recommended that with the exception of fluoxetine, SSRIs should not be withdrawn acutely but gradually over 3–4 weeks [1]. It is also recommended that patients on SSRIs over an extended period of time undergo intermittent “wash-out periods” in order to avoid excessive levels of accumulation after multiple doses [53].

Overdose of SSRIs or (more commonly) drug– drug interactions between SSRIs and other agents that enhance the central nervous system 5-HT activity can lead to the “serotonin syndrome”—a cluster of severe, persistent symptoms including myoclonus, hyperreflexia, sweating, shivering, discoordination, and mental status changes [53]. Patients receiving long-term SSRI therapy for PE must be made aware of potential drug–drug interactions between SSRIs and other concurrent medications, and schedule their doses accordingly [53]. In men with lifelong PE,cessation of treatment results in reestablishment of the original set point within 5–7 days [1].

table 1 table 2 On-Demand Intervention (on a “Prn” Basis)

Encouraging as the success of the chronic administration of SSRIs has been in the treatment of PE, side effects, such as dry mouth, headaches, and dizziness, have presented a problem [54]. Men are understandably reluctant to accept continuous, long-term headaches, dry mouth, and dizziness on a daily basis, as the price for improving IELT on significantly less frequent occasions [12,33,55,56]. In an attempt to minimize these side effects and better target the patient’s needs in a cost-effective manner, on-demand use of SSRI has been advocated [54].

There is only modest laboratory-based support for the on-demand use of SSRI. While the acute administration of SSRI leads to an abrupt lowering of 5-HT release into the synapse, it only effects a mild increase in the postsynaptic neurotransmission and stimulation of 5-HT receptors there [57–59]. Nevertheless, laboratory assessments have documented a marked increase in 5-HT in both the cerebrospinal and the extravascular fluid following a single dose of SSRI [60–62]. Examination of the time course of central and peripheral neurochemical effects of sertraline (SER) in nonhuman primates showed that the 5-HT level achieved after one oral dose of sertraline was comparable to that measured throughout a 28-day course [63].

Waldinger et al. investigated the degree of ejaculation delay induced by on-demand treatment with 20-mg paroxetine and 25-mg clomipramine in a randomized, double-blind, fixed-dose, ondemand study in 30 men with lifelong PE with an IELT of less than 1 minute. The authors found that whereas on-demand treatment with 25-mg clomipramine led to a clinically relevant ejaculation delay, this was not the case with 20-mg paroxetine. Interestingly, when this same SSRI was taken daily for 6 weeks, the IELT increased significantly by 146 seconds [64].

Dapoxetine, an SSRI structurally related to fluoxetine, is the first SSRI developed with a short half-life, convenient for the on-demand treatment of PE [65]. Oral dapoxetine achieves peak plasma concentrations within hour, and is effectively eliminated within 24 hours. Other SSRIs may require 6–8 hours to reach peak plasma concentrations, and up to 4 weeks to achieve a steady-state [65]. Dapoxetine seems to have a physiological benefit, superior to paroxetine, in reducing the expulsion reflex of ejaculation [66]. While not yet FDA approved for use in the treatment of PE, the efficacy and tolerability of dapoxetine have been assessed in an integrated analysis of two, double-blind, randomized, controlled trials [67]. When taken 3 hours prior to intercourse, dapoxetine increased the IELT from 0.92 to 2.78 minutes with the 30-mg dose, and from 0.91 to 3.32 minutes with the 60-mg dose, while with placebo, the IELT only improved from 0.9 to 1.75 minutes. Dapoxetine increased the IELT 3.0– 3.7 times over baseline [67]. Nausea was the most frequently noted side effect reported in up to 20.1% of patients on the higher (60 mg) dose of dapoxetine; other commonly observed side effects in the 30- and 60-mg doses, respectively, were diarrhea (3.9%, 6.8%), headache (5.9%, 6.8%), and dizziness (3.0%, 6.2%).

Two-Phase Therapy

A two-phase or hybrid strategy has been proposed, augmenting long-term SSRIs at a low dose, with higher doses prior to intercourse, on an on-demand basis [1,53]. McMahon and Touma evaluated the efficacy of paroxetine on-demand for the treatment of PE. The authors found that the ejaculatory control achieved with paroxetine as needed is significantly better when the patients were initially treated with a daily dose of the medication and later changed to an on-demand regimen [68]. Their findings were later corroborated in a study by Salonia et al who reported that paroxetine, when initially prescribed on a longterm basis, then later switched to an on-demand basis, proved safe and effective in prolonging the IELT (from 0.33 +/– 0.04 to 4.2 +/– 0.03), and 75% of the men reported an improved satisfaction with their sexual activity [69].

SSRI and Suicide Risk

Enthusiasm for treatment of PE with SSRI has recently been dampened by the release of the FDA advisory in May 2007, which warned that suicidal ideation and attempts have been associated with the initiation of these antidepressant medications, especially in young adults aged 18–24 [70]. The risk of suicide seems to be highest during the first 1 or 2 months of therapy. While a report at the 2007 American Urological Association (AUA) annual convention found that there was no associated “suicidality,” when the SSRI dapoxetine was used in the treatment of PE, the FDA advisory indicates that there is as yet insufficient evidence to exculpate any single medication from this risk. At a minimum, the circumspect clinician would carefully follow the patients for any signs of depression or suicidal ideation; it is also wise to document that the patient has been fully informed that there may be an increased risk of suicidal tendency, and also that SSRIs are not FDA approved for the treatment of PE [70–72].

Clomipramine

Clomipramine is a tricyclic antidepressant used in the treatment of obsessive compulsive disorders. Although it is not an SSRI, clomipramine does inhibit 5-HT transport [55]. A 25-mg dose has effected delay in ejaculation, when taken as a onetime treatment 5 hours before intercourse by men with lifelong PE [1]. It has been shown to be effective in a placebo-controlled, double-blind trial, with a dose-dependent response rate. Efficacy was established, using a 10-mg dose, but the IELT increased by 249% over controls when a 25-mg dose was used, and 517% with a 50-mg dose [73,74].

Clomipramine has been studied both as a chronic-care and as an on-demand medication. Rowland et al. have recommended a two-tiered approach, initially using a single dose of up to 25 mg, taken from 4 to 24 hours prior to intercourse. If on-demand treatment proved unsatisfactory, a daily, long-term dose of 10–30 mg was instated [75]. Treatment with clomipramine, when compared with SSRIs and placebo, over a 4-week period, produced a sexual satisfaction rate that was significantly higher. Unfortunately, the side effect rate was higher as well. The authors concluded that, while clomipramine was the most efficacious for the treatment of PE, sertraline was nearly as effective and had a lower incidence of side effects [43]. Other studies have similarly shown that sertraline and fluoxetine are comparable to clomipramine in their effect on delaying ejaculation with a lower incidence of side effects [17,19,50].

Side effects from clomipramine include dry mouth, fatigue, nausea, and dizziness [54]. These side effects seem to abate over time, but stopping the medication is also associated with a loss of efficacy [73,74]. Tricyclic antidepressants seem to share with the SSRIs the risk of increased suicide, when initiated in men under age 24 [70]. At higher doses (75 mg for more than 3 months), clomipramine may have an adverse effect on sperm function [76]. Not only clomipramine, but also SSRIs, by blocking calcium channel mechanisms, may impede both sperm motility and vasal/ epididymal contractility [77]. While none of these agents have been proven to impair male fertility, this potential consequence of long-term, highdose usage should be kept in mind when selecting PE therapy for men who may be contemplating fatherhood in the future.

Tramadol

Tramadol, a centrally acting synthetic opioid analgesic, has shown promise as an effective on-demand agent that avoids many of the risks associated with SSRIs. Although the ejaculatorydelaying mechanism of tramadol has not been fully understood, it is hypothesized that this may be related to tramadol’s effect on inhibition of reuptake of norepinephrine and serotonin [78].

In 2006, Safarinejad and Hosseini published the results of their evaluation of the safety and efficacy of this serotonergic drug in delaying ejaculation. A double-blinded, placebo-controlled, fixed-dose study demonstrated a 13-fold increase in IELT with the on-demand use of 50 mg of Tramadol [79]. Among the 57 patients who completed the study, the mean IELT after tramadol and placebo increased from a baseline of 19 and 21 seconds to 243 and 34 seconds, respectively. Although more adverse events were noted when the patients were on tramadol, the authors did not report any study withdrawals because of medication-related adverse events. More recently, in a single-blind, placebocontrolled, crossover, stop-watch study, these findings were confirmed using the 25-mg dose in 60 patients with lifelong PE [78]. The overall mean increase in IELT was from 0.79 to 6.20, as opposed to a minimal 0.84 in the crossed over placebo treatment arm (P = <0.0001). Mild side effects were experienced in eight patients (13.3%), consisting of mild dyspepsia and somnolence [78].

Phosphodiesterase Type 5 (PDE5) Inhibitors

The association of erectile dysfunction (ED) with rapid ejaculation has been reported in important epidemiological studies, and PE may be seen in up to a third of patients with ED [80,81]. It is generally accepted that the association between PE and ED may be rooted in a compensatory mechanism where a man with PE develops ED simply as a result of the anxiety associated with the condition, and conversely, a patient suffering from ED may ejaculate early in the course of his erection before the failure-to-maintain phase of the erection sets in. An alternative, but related, view held by other investigators suggests that PE and ED share a vicious circle, where the level of excitation is instinctively reduced by a man with PE trying to control his ejaculation (thus leading to ED), and conversely, a man suffering from ED will try to increase his excitation to achieve an erection, thus leading to a rapid ejaculation [82].

In cases of PE associated with ED, treatment of ED by using PDE5 inhibitors may have a salutary effect on ejaculatory dysfunction [83]. Mancina and colleagues have demonstrated the expression of PDE5 in all the muscular layers of human and rabbit vas deferens [84]. Based on their findings documenting the presence of this enzyme in the ejaculatory tract, the authors postulated a potential direct effect of PDE5 inhibitors in mediating ejaculatory function. Experiments with knockout mice suggest that endothelial nitric oxide synthase (eNOS) gene deletion may adversely affect ejaculatory as well as erectile function. Kriegsfeld and colleagues set out to study the effects of eNOS on sexual function, and discovered that male mice missing the gene for eNOS exhibited significant abnormalities in ejaculatory function. More specifically, the data from their animal study suggest that ejaculatory function may be inhibited by nitric oxide from eNOS in nongenetically altered mice, and that this effect is most likely achieved by decreasing sympathetic nervous system activity to prevent PE [85]. The authors hypothesized that administration of medications peripherally that can selectively increase eNOS may be effective in treating PE with minimal central nervous system adverse events.

Patients with lifelong PE, as opposed to those with acquired or late-onset PE, are reported to have a 50% rate of concomitant ED. Nevertheless, the value of PDE5 inhibitors in the treatment of PE alone has not been established. A crossover study of 31 potent men with lifelong PE found sildenafil treatment to be associated with a significantly higher IELT and higher sexual satisfaction score than any other therapy including the use of any one of a variety of SSRIs and the use of the squeezepause method [1,86]. Sildenafil was deemed “decidedly the most effective” and was recommended as a valid alternative to the use of SSRIs in the treatment of PE. Conversely, the presence of concomitant PE did not impair patient satisfaction with their improved erections, when men were treated with PDE5 inhibitors for their ED [87].

A recent review found that of five studies, three have concluded that the use of PDE5 inhibitors was helpful, even superior, in treating PE, while two placebo-controlled studies found no such improvement [88]. The single study, which used objective, double-blinded, placebo-controlled measures, found no improvement in PE following PDE5 inhibitors in men who did not also have associated ED [83]. In a placebo-controlled trial in 84 patients, sildenafil proved ineffective, either alone or in combination with topical therapy, in the treatment of acquired PE [2].

PDE5 inhibitors may exert a secondary benefit for patients with PE when they (i) allow for a sustained penile erection, even after ejaculation; (ii) facilitate a second intercourse after the initial ejaculation, which is often less prone to PE; and/or (iii) help the patient to overcome performance anxiety, which often exacerbates PE [83,89]. However, it is deemed unlikely that PDE5 inhibitors have a significant role in the treatment of PE—with the exception of men with acquired PE secondary to ED [1].

Intracavernosal Injection (ICI) Therapy

The use of ICI for “treatment” of PE is not supported by a large body of peer-reviewed literature, and is infrequently used in clinical practice. However, ICI has been used as a strategy in certain cases to allow men with PE to maintain their erections and continue satisfactory sexual intercourse despite rapid ejaculation. In 1990, Fein reported on a small group (N = 8) of patients with PE who used vasoactive intracavernosal pharmacotherapy (mixture of phentolamine mesylate [1.0 mg/mL] and papaverine hydrochloride [30 mg/mL]) to address their PE [90]. When exploited as a temporary intervention, these artificially induced erections provided patients with confidence and encouragement, while they were awaiting results from more conventional therapies. With dosages ranging from 0.10 to 0.40 mL, the author reported that all eight patients responded successfully to this approach, while three were apparently “cured” of PE. The other five patients in the study continued to use ICIs after the completion of the study.

Combination Therapy—Oral

An open-label study involving 80 potent men found that the combined use of sildenafil and paroxetine proved more efficacious than either treatment alone [69]. In treating 138 men with a progressive armamentarium of treatments, Chen et al. obtained best results when the use of sildenafil was combined with SSRIs and behavioral counseling. Sildenafil in combination with paroxetine was effective in97%of patients, compared to an improvement for only 47% using paroxetine alone [91].

Combination Therapy—Oral/Topical

An alternate approach combines the use of oral agents with the concomitant application of topical solutions. For example, oral fluoxetine, when reinforced by the topical application of lidocaine ointment, effected a “cure” or an improvement in 83.3% of men, compared with 72% of those treated with fluoxetine alone [92].

Combination Therapy—Oral/Psychotherapy,

Combining a psychotherapeutic with a pharmaceutical approach can provide either a stepwise or concurrent integration of psychological and medical interventions [93]. Several investigators have documented the added value of combining psychotherapy with pharmacotherapy in the treatment of ED, utilizing care models that should transfer readily to the integrated multidisciplinary management of PE [33]. Sildenafil has proven helpful as an adjunctive measure in support of a program of SSRI therapy, when combined with psychosexual counseling [91].

Research Issues

Advance in the understanding of PE has been hobbled by a categorical lack of solid studies on which to base clinical decision making. As a case in point, an attempt at performing a meta-analysis of all studies, which evaluate the potential for PDE5 inhibitors in the treatment of PE, found that only 2 of 14 studies assessed the patient’s reaction to his problem (“bother score”), and none took into consideration the partner’s distress. Only 1 of the 14 studies met the criteria for an evidence-based, double-blinded, placebo-controlled investigation, using validated outcome assessment tools and including objective physiological measurements [83]. The artificiality involved in studying PE under conditions necessary for objective, physiological measurement conflicts with attempts to understand, evaluate, and treat PE in its natural setting. Findings derived from studies of stopwatch timed, methodically recorded intercourse do not necessarily correlate well with performance under more spontaneous, private, and intimate circumstances. On the brighter side, a most welcome addition to the field is the recent development and validation of a “user-friendly” questionnaire in 2007 to capture the multidimensional nature of PE and lend objectivity to diagnosing this entity [94].

New Directions

A permanent cure for PE remains a distant goal. In the interim, ideal medical treatment for PE would entail the development of a medication that is effective on a rapid-acting, “on-demand” basis, without impairing the spontaneity and intimacy of the relationship. Sexual side effects (e.g., diminished libido and ED), as well as generalized side effects (e.g., nausea, insomnia, and headache), would be avoided.

Novel topical therapies in the form of aerosol (i.e., TEMPE, Plethora Solutions; London, UK) and short-acting SSRI compounds that target the serotonergic system are currently undergoing clinical trials in the United States. Alza/Johnson & Johnson is soliciting an FDA approval for dapoxetine. Pfizer and Bristol-Myers Squibb also have patented agents under development [56]. Although specific data about these compounds are not available at the time of this writing, the Pfizer medication (UK 390957, Pfizer Inc., New York,NY, USA) has been described as a rapid-acting serotonin modulator, i.e., a short-acting SSRI [95]. The Bristol-Myers Squibb drug, BMS-505130, is a potent and selective SSRI with a short half-life with potential advantages in the treatment ofPEbecause of the relatively rapid fall in plasma concentrations [96]. Should these effective, short-acting, “ondemand” agents receive FDA and European Medicines Agency (EMEA) approval for this indication, they could dramatically alter the treatment landscape [12]. Enlivened interest on the part of the pharmaceutical industry would channel a significant increase in funding into this area, which is much in need of improved investigation, awareness promotion, and effective treatment. Despite these promising leads, it is evident that the recent FDA warning about SSRIs has resulted in a flurry of interest in alternative forms of therapy.

Immunohistochemical studies have demonstrated local synthesis of oxytocin and its synthesis-associated protein, neurophysin I, in the epithelial cells of the epididymis [97]. Thus, competing against the SSRI approach, the use of oxytocin compounds as potential therapeutic agents for PE is under investigation [56]. Intervention at other points in the pathophysiologic pathway and topical therapy is also undergoing further testing and improvement [56]. Dietary deficiencies, such as low magnesium intake, may prove to play a limited role [98].

Conclusion

Interest in medical therapy for PE is surging. New oral agents are now providing important relief for men afflicted with this condition. On the other hand, no agent provides a cure in lifelong PE, and no medical therapy has as yet received FDA and EMEA approval for use in the treatment of this condition [12]. Studies to date have been relatively few and often limited with respect to the number of patients enrolled and/or the study design [26]. Nevertheless, based on the level of evidence rating of those studies reviewed, both SSRIs and clomipramine have received a grade A recommendation from an expert panel at the Second International Consultation on Sexual Medicine [1].

Clinical research in this field is hampered by the complexity, variability, and subjectivity of this complaint. The placebo effect is high and reliable, appropriately controlled studies are in the minority. Carefully devised, methodically conducted research is much needed.

SSRIs have been the most promising agents to date. The on-demand “prn” use of these agents is more convenient, but its efficacy is less well established. Minor but nettlesome side effects have long been a disincentive to chronic use of these medications. More recently, concern over the risk of an increased suicide rate in young men upon initiation of SSRIs has dampened enthusiasm. Recent experience with the use of tramadol raises the hope that this might prove to be an agent as effective as SSRIs with less worrisome risk of side effects.

The recognition of the high prevalence of PE and its significant impact on quality of life will hopefully translate into novel therapies that offer high efficacy and a favorable adverse effect profile for all forms of PE. Until then, it is wise to remember that no oral medication in isolation will entirely replace the need for compassionate patient counseling, coordinating treatment of the genital function aspects of PE with the management of the often highly charged psychosocial and partnership issues attendant to this condition.

Corresponding Author: Hossein Sadeghi-Nejad, MD, FACS, UMDNJ New Jersey Medical School—Surgery, Division of Urology, 185 South Orange Ave., MSB G 536, Newark, NJ 07103-2714, USA. Tel: (973) 972- 4488; Fax: (973) 395-7197

Conflict of Interest: Dr. Sadeghi-Nejad is a speaker for Pfizer, and is an investigator in a clinical trial sponsored by Plethora Solutions.

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