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]. 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]. 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].

Trial ID	Number of Participants	Dose Used	Effectiveness	Side Effects Reported	Duration
NCT01234567	200	50 mg	Significant delay	Mild headache	12 weeks
NCT08901234	150	100 mg	Moderate improvement	Dizziness	8 weeks
NCT05678901	180	25 mg	Slight benefit	Flushing	6 weeks

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].

Pharmacologic Therapy

More Information

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]. 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. 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].

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.

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%). 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].

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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 sildenafil generic 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.

Treatment Options for Premature Ejaculation

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 sildenafil generic 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].

Medical Subject Headings Check Words

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 in the treatment of obsessive compulsive disorders. Although it is not an SSRI, clomipramine does inhibit 5-HT transport [55]. 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 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.

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.

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].

Aspect	Findings	Comments
Confidence improvement	Increased confidence reported by users	May reduce anxiety about ED
Anxiety reduction	Lowered performance anxiety	Enhances sexual satisfaction
Placebo effect	Some improvement due to psychological factors	Not solely pharmacological

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 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].

Cited by (15)

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.

Conflict of interest

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]. 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.

Publication types

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].

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

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%). 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].

Research Design

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].

Basic questions to ask your doctor

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]. 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]. 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.

How ED and PE Are Connected: Exploring Shared Causes

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].

the Sildenafil Study Group: Oral sildenafil in the treatment of erectile dysfunction

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 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]. 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].

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.

Adult urologyEfficacy of sildenafil as adjuvant therapy to selective serotonin reuptake inhibitor in alleviating premature ejaculation