Oral Medications Used for Premature Ejaculation

Side effects from clomipramine include dry mouth, fatigue, nausea, and dizziness [54].

• Dapoxetine has a rapid onset, typically within 1-3 hours.
• Topical anesthetics should be applied in small amounts to avoid overdose.
• SSRI side effects may include sleep disturbances or gastrointestinal upset.
• Tramadol can cause dizziness, dry mouth, and nausea as side effects.
• Behavioral techniques teach men to recognize early signs of ejaculation.
• Pelvic floor training can enhance ejaculatory control.
• Counseling sessions help address performance anxiety and stress.
• Medications should be used as prescribed to minimize risks.
• Some men respond better to combination therapies.
• Abstaining from excessive masturbation may help in some cases.
• Lifestyle changes and psychological support are important adjuncts.
• Any medication or supplement should be discussed with a healthcare professional.

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].

• Topical anesthetic creams temporarily desensitize the penis to delay ejaculation.
• SSRI medications like paroxetine are prescribed off-label for premature ejaculation.
• Dapoxetine is a short-acting SSRI specifically approved for PE treatment.
• Tramadol, an opioid, can help delay ejaculation but carries dependency risks.
• Topical sprays offer quick, localized numbing effects to control ejaculation timing.
• PDE5 inhibitors like sildenafil may improve performance in men with PE and ED.
• Behavioral therapies include the stop-start and squeeze techniques to extend duration.
• Kegel exercises strengthen pelvic muscles, potentially delaying ejaculation.
• Counseling and sex therapy can address psychological causes of PE.
• Combining medication with behavioral techniques enhances treatment effectiveness.
• Herbal supplements lack robust clinical evidence but are used by some for PE.
• Consultation with a healthcare provider is essential to tailor appropriate therapy.

At higher doses (75 mg for more than 3 months), clomipramine may have an adverse effect on sperm function [76].

Expected duration

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].

Treatment Options For Premature Ejaculation

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” vigora 200 mg of PE.

Stop-start technique

The other five patients in the study continued to use ICIs after the completion of the study. 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]. Not only clomipramine, but also SSRIs, by blocking calcium channel mechanisms, may impede both sperm motility and vasal/ epididymal contractility [77].

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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]. 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]. The association of erectile dysfunction (ED) with rapid ejaculation has been reported in vardenafil premature ejaculation 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.

Warning: Watch out for unreliable pills

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]. 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].

Fluoxetine (Prozac)

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.

Medication Options to Reduce Sensitivity and Improve Control

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]. 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.

Side Effect	Medication Type	Incidence Rate	Severity Level	Management Strategies	Notes
Nausea	SSRIs, topical anesthetics	10-15%	Mild to Moderate	Dose adjustment, timing	Usually transient
Dizziness	SSRIs, topical anesthetics	8-12%	Mild	Standing slowly, hydration	Common with beginning treatment
Headache	SSRIs, topical anesthetics	5-10%	Mild	Analgesics, time to adjust	Typically diminishes over time
Reduced Sensation	Topical anesthetics	10-20%	Mild	Reduced dose, application timing	Can affect partner satisfaction

Nevertheless, the value of PDE5 inhibitors in the treatment of PE alone has vardenafil 5 mg not been established.

• Dapoxetine is taken as needed, usually 1-3 hours before sex for rapid action.
• Topical anesthetics should be used sparingly to avoid numbness of partner.
• SSRIs may cause side effects like nausea, dizziness, or decreased libido.
• Tramadol carries potential for abuse and should only be used under medical supervision.
• Daily use of certain medications may be recommended for persistent PE.
• Psychological counseling helps address performance anxiety contributing to PE.
• Pelvic floor exercises improve control and delay ejaculation naturally.
• Partner involvement in therapy can improve treatment adherence.
• Discontinuing medication abruptly may cause withdrawal symptoms or rebound.
• For some men, combining therapy with lifestyle changes yields better results.
• Over-the-counter remedies should be approached cautiously and discussed with a doctor.
• Research continues into new pharmacological and non-pharmacological treatments.

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]. 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.

What is Premature 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].

• Dapoxetine is specifically designed for on-demand use in PE.
• Topical anesthetics require minimal use to avoid excessive numbness.
• SSRIs impact neurotransmitters involved in ejaculation control.
• Tramadol's side effects limit its routine use for PE.
• Non-drug approaches include psychological counseling and exercises.
• Pelvic strengthening exercises aid in delay of ejaculation.
• Partner education enhances understanding and support.
• Managing stress and anxiety can significantly improve PE.
• Some therapies combine medication with sex therapy sessions.
• Medical evaluation is essential before initiating treatment.
• Lifestyle factors like smoking can influence sexual performance.
• Patient adherence to treatment plans improves outcomes.

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” vigora 200 mg of PE. The other five patients in the study continued to use ICIs after the completion of the study. 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].

What are the symptoms of premature ejaculation?

The association of erectile dysfunction (ED) with rapid ejaculation has been reported in vardenafil premature ejaculation 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].

The pause-squeeze technique

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.

Pelvic floor exercises

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 vardenafil 5 mg 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]. 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]. 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]. 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.

Cited sources

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].

Vardenafil (Levitra®) for PE

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].

Symptoms of Premature Ejaculation

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]. 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].