Investigating Sildenafil as a Potential Treatment for PE

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%).

Author information

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].

About the Author

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].

Reasons and predictive factors for discontinuation of PDE-5 inhibitors despite successful intercourse in erectile dysfunction patients

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]. 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]. 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 is a tricyclic antidepressant used sildenafil pick up in the treatment of obsessive compulsive disorders.

• Sildenafil is a PDE5 inhibitor used mainly for erectile dysfunction.
• Some men use sildenafil to delay ejaculation temporarily.
• Sildenafil may improve confidence in sexual performance.
• It does not treat underlying causes of premature ejaculation.
• Sildenafil's effects can last up to 4-6 hours.
• Using sildenafil for PE is off-label and not medically approved.
• Combining sildenafil with other ED medications can be risky.
• Timing of sildenafil intake affects its effectiveness.
• Side effects include headaches, flushing, and nasal congestion.
• It may interact with nitrates, causing dangerous blood pressure drops.
• Always consult a doctor before using sildenafil for PE.

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. 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].

Can ED Medications Boost Confidence and Sexual Stamina?

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. 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.

Ejaculation Problems: Too Fast, Too Slow or Not at All

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]. 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, a centrally acting synthetic opioid analgesic, has shown promise as an sildenafil citrate 100mg tablets 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].

• PDE5 inhibitors may sometimes be prescribed for PE.
• Combining medications increases complexity and risk.
• Sensory training can help adapt to sexual stimuli.
• Managing stress is crucial in PE treatment.
• Adult men with PE should seek comprehensive evaluation.
• There is no one-size-fits-all solution for PE.
• Monitoring side effects ensures safe medication use.
• Sexual therapy can address performance anxiety.
• Proper medication timing improves efficacy.
• Lifestyle changes complement pharmacological treatment.
• Patient education empowers management of PE.

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.

Surgical Intervention

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]. 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].

Disorders of orgasm and ejaculation in men

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 is a tricyclic antidepressant used sildenafil pick up in the treatment of obsessive compulsive disorders. Although it is not an SSRI, clomipramine does inhibit 5-HT transport [55]. 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.

• Sildenafil's role in PE is still under research.
• Off-label use requires informed consent.
• Behavioral techniques are first-line in many cases.
• The impact of psychological health on PE should not be ignored.
• Educating patients on realistic expectations is important.
• Sometimes, medication just masks underlying issues.
• Regular sexual activity can decrease PE severity.
• Consulting a urologist is recommended for persistent PE.
• Combining medication with therapy often improves outcomes.
• Delaying ejaculation involves both physical and mental strategies.
• Support and understanding enhance treatment adherence.

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].

Rights and permissions

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.

Erectile dysfunction risk factors in non-insulin dependent diabetic Saudi patients

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. 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.

Research Design

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].

Other agents

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, a centrally acting synthetic opioid analgesic, has shown promise as an sildenafil citrate 100mg tablets 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]. 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].

Pharmacologic Therapy

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].

What Is the Role of Ejaculation Latency in the Diagnosis of Premature Ejaculation and Does the Ejaculation Latency Threshold Matter?

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%). Sildenafil was deemed “decidedly the most effective” and was recommended as a valid alternative to the use of SSRIs in the treatment of PE.