On-Demand Versus Daily Sildenafil for Premature Ejaculation

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. 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. 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]. 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].

Cited by (15)

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.

Treatment for PE

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.

What to expect from your doctor

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]. 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. 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]. 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 sildenafil oral strips shown that patients with PE have increased penile sensitivity as shown by consistently decreased vibratory threshold that is not age dependent [24,25].

• Premature ejaculation is classified as lifelong or acquired.
• Lifelong PE begins from the first sexual experience.
• Acquired PE develops after a period of normal function.
• Sensory sensitivity might influence PE severity.
• Partner communication can improve PE management.
• Pelvic floor exercises may help control ejaculation.
• Squeeze techniques can delay climax.
• Pharmacological options include SSRIs, dapoxetine.
• Biofeedback therapy is an emerging PE treatment.
• Erectile dysfunction and PE can coexist.
• Proper diagnosis ensures effective treatment.

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.

Cited by (115)

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. 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]. 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]. 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 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 sildenafil 130mg 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].

• Premature ejaculation affects about 30% of men.
• Psychological factors often contribute to PE.
• Behavioral therapies can help manage PE.
• Topical anesthetics are alternative treatments for PE.
• SSRI antidepressants are commonly prescribed for PE.
• Combining sildenafil with PE drugs requires care.
• Lifestyle changes like exercise may improve PE.
• Stress and anxiety can trigger premature ejaculation.
• Delay techniques include the stop-start method.
• Medical treatments should be personalized for each patient.
• Education about sexual response can reduce PE.

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].

References (14)

Penile biothesiometry studies have sildenafil oral strips 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].

Efficacy of sildenafil citrate in treatment of erectile dysfunction: effect of type 2 diabetes

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.

Male pelvic floor muscles

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]. 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]. 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].

• Early ejaculation is a normal variation for some men.
• Understanding personal sexual response helps manage PE.
• Sensory-enhancing devices may delay climax.
• Medications are not the only solution to PE.
• Regular exercise benefits erectile and ejaculatory health.
• Stress management techniques can improve PE outcomes.
• PE can be a sign of underlying medical issues.
• clinician-guided treatment yields better safety profiles.
• Support from partners encourages successful treatment.
• Combining therapy approaches often gives the best results.
• Healthy lifestyle choices support sexual function.

Kim and Seo compared the efficacy and safety of 4 weeks each of fluoxetine, sertraline, clomipramine, and placebo in treating PE in 36 men.

About this article

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].

Rapid ejaculation: a review of conceptual, etiological, and treatment issues

The recurrent emerging pattern appears to be that PE is a largely underdiagnosed condition. 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. 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].

New insights into erectile dysfunction: a practical approach

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]. 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. 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.

Other Therapy

Phenoxybenzamine, as well as more selective alpha blockers, such as terazosin and alfuzosin, were among the first agents utilized. 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 sildenafil 130mg 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.

Eur Urol

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].

J Urol

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. 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.