Michael Stewart, MRPharmS

Many of these agents were found to have the side effect of significantly delaying the achievement of orgasm in both male and female patients, and it was for this reason that such agents were applied to the treatment of premature ejaculation.

• Dapoxetine has been shown to significantly increase ejaculatory latency time.
• It is not intended to treat all aspects of sexual dysfunction.
• Use of dapoxetine may require dose adjustments based on side effects.
• The medication should be stored safely out of children's reach.
• Monitoring response and side effects enhances safe use of dapoxetine.
• Dapoxetine should be used only as part of a broader treatment plan.

Some tricyclic antidepressants (TCAs) with SSRI-like activity have the same effect in orgasm that SSRIs do. The TCA that has been most frequently studied for treatment of premature ejaculation is clomipramine. [33, 34, 35, 36] Many investigators find that clomipramine is more effective for premature ejaculation than many SSRIs are. Results of a multicenter, randomized, double-blind, placebo-controlled, fixed-dose clinical phase III study in 159 Korean patients suggest that 15 mg of clomipramine taken approximately 2-6 hours before sexual intercourse is effective and safe for treatment of premature ejaculation. [37] However, a systematic review and meta-analysis concluded that below a dose of 50 mg, a higher dose of clomipramine results in a longer delay of ejaculation without an increased risk of adverse events. In most cases, females require considerably more time to reach climax than males do; thus, in females taking SSRIs and SSRI-like agents, the delayed climax caused by these agents becomes an adverse effect.

When PE Requires In-Person Evaluation

[44] However, up to 90% of patients discontinue dapoxetine, mostly because of adverse effects, cost, and disappointing efficacy. The optimal medical treatment regimen for premature ejaculation has not been established. The author’s experience has been that in some males, single dosing before sexual relations can work well, whereas in others, it may be necessary to achieve and maintain a target blood level through daily use of the medication, as in the treatment of clinical depression. Obviously, if single dosing is successful, therapy is simpler and has fewer adverse effects. Accordingly, this may be the preferred initial approach.

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If necessary, the dose may be increased in a stepwise fashion until a therapeutic effect is achieved or the maximum daily recommended dose is reached. No exact schedule for increasing the dose has been established; the experience of the physician, the response of the patient, the adverse effects experienced by the patient, and other general medical considerations should be the guiding factors. If the initial SSRI fails to help the patient, it is certainly reasonable to try a second agent. However, if the second choice fails, it is not likely that a third choice will offer any benefit. As with treatment for depression, if a patient has been taking the maximal dose of the medication for 6 weeks without showing any improvement, the likelihood that a more prolonged course of therapy with a particular drug would be successful is remote.

Step 2 — Clinical Review and Diagnostic Screening

There is no reason why pharmacotherapy cannot be combined with behavioral modification therapy, desensitizing creams, or both; the use of several simultaneous treatments can result in additive effects or even synergy. If all treatment fails, then the patient’s only options are as follows: To see a different health care professional, if he wishes To accept his condition as being untreatable with currently available therapeutic options Adverse effects of long-term SSRI use are a significant concern and should be considered by both the physician and the patient. [45] Such adverse effects may include the following: Sexual side effects other than delayed ejaculation (eg, erectile dysfunction or loss of libido) In addition, caution should be exercised in changing SSRIs; a washout period is necessary to avoid overdose. SSRI discontinuance syndrome (especially with paroxetine) has been associated with dose reduction or discontinuance and may cause dizziness, nausea and vomiting, headache, gait instability, lethargy, agitation, anxiety, and insomnia. Some studies have demonstrated that combining phosphodiesterase type 5 (PDE5) inhibitors with SSRIs provides better results in the treatment of premature ejaculation than using SSRIs alone. In many females, such an inability to reach orgasm can induce a pattern of sexual avoidance, along with a corresponding decrease in libido or sexual excitement (lubrication). In males, too-rapid orgasm can cause some of the same patterns of sexual avoidance and decreased libido. Thus, it is essential to determine the primary problem when instituting therapy. SSRIs useful for treating premature ejaculation include the following: A systematic review and meta-analysis reported that although fluoxetine was more effective than placebo in treating PE, sertraline and paroxetine were more effective than fluoxetine (p < 0.05). Dapoxetine, which is generally categorized as a fast-acting SSRI, was developed specifically to treat this condition. It may be effective at the first dose (ie, on demand) when given 1-3 hours before sexual intercourse, and its adverse-effect profile is comparable to those of other SSRIs. [41, 42, 43] Dapoxetine has been approved in a number of countries but not yet in the United States.

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In a study of men with both premature ejaculation and erectile dysfunction who were on phosphodiesterase type 5 (PDE5) therapy, dapoxetine provided treatment benefit and was generally well tolerated.

Benefits of Dapoxetine

In the meantime, the male may use manual stimulation, oral sex, or other means to satisfy the female partner. If the male always experiences ejaculation with initial sexual excitement or early foreplay, this is a serious problem and probably indicates lifelong premature ejaculation (the history should reveal this). Such cases will most likely call for treatment in conjunction with a mental health care professional. These more difficult cases should be screened out. Next, the couple should be instructed in sex therapy techniques, such as the stop-start or squeeze-pause technique popularized by Masters and Johnson.

Mental health history

In this technique, the female partner slowly begins stimulation of the male but stops as soon as he senses a feeling of excessive excitement that may lead to ejaculatory inevitability. She then administers firm compression to the penis just behind the glans, pressing mainly on the underside. This compression should be uncomfortable but not painful. Once the male has the feeling that ejaculation is no longer imminent, the female resumes stimulation. The process should be repeated and practiced at least 10 or more times.

Clinical studies of dapoxetine

Over time, most males find that this technique helps decrease the impending inevitable need to ejaculate. After practicing this technique for a while, the couple can move to another phase of the process. [44] However, up to 90% of patients discontinue dapoxetine, mostly because of adverse effects, cost, and disappointing efficacy. The optimal medical treatment regimen for premature ejaculation has not been established. The author’s experience has been that in some males, single dosing before sexual relations can work well, whereas in others, it may be necessary to achieve and maintain a target blood level through daily use of the medication, as in the treatment of clinical depression. Obviously, if single dosing is successful, therapy is simpler and has fewer adverse effects. Accordingly, this may be the preferred initial approach. If necessary, the dose may be increased in a stepwise fashion until a therapeutic effect is achieved or the maximum daily recommended dose is reached. No exact schedule for increasing the dose has been established; the experience of the physician, the response of the patient, the adverse effects experienced by the patient, and other general medical considerations should be the guiding factors.

Types of Dosage Available

Many of these agents were found to have the side effect of significantly delaying the achievement of orgasm in both male and female patients, and it was for this reason that such agents were applied to the treatment of premature ejaculation. Some tricyclic antidepressants (TCAs) with SSRI-like activity have the same effect in orgasm that SSRIs do. The TCA that has been most frequently studied for treatment of premature ejaculation is clomipramine. [33, 34, 35, 36] Many investigators find that clomipramine is more effective for premature ejaculation than many SSRIs are. Results of a multicenter, randomized, double-blind, placebo-controlled, fixed-dose clinical phase III study in 159 Korean patients suggest that 15 mg of clomipramine taken approximately 2-6 hours before sexual intercourse is effective and safe for treatment of premature ejaculation.

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[37] However, a systematic review and meta-analysis concluded that below a dose of 50 mg, a higher dose of clomipramine results in a longer delay of ejaculation without an increased risk of adverse events. In most cases, females require considerably more time to reach climax than males do; thus, in females taking SSRIs and SSRI-like agents, the delayed climax caused by these agents becomes an adverse effect. In many females, such an inability to reach orgasm can induce a pattern of sexual avoidance, along with a corresponding decrease in libido or sexual excitement (lubrication). In males, too-rapid orgasm can cause some of the same patterns of sexual avoidance and decreased libido. Thus, it is essential to determine the primary problem when instituting therapy.

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SSRIs useful for treating premature ejaculation include the following: A systematic review and meta-analysis reported that although fluoxetine was more effective than placebo in treating PE, sertraline and paroxetine were more effective than fluoxetine (p < 0.05). Dapoxetine, which is generally categorized as a fast-acting SSRI, was developed specifically to treat this condition. It may be effective at the first dose (ie, on demand) when given 1-3 hours before sexual intercourse, and its adverse-effect profile is comparable to those of other SSRIs. [41, 42, 43] Dapoxetine has been approved in a number of countries but not yet in the United States. In a study of men with both premature ejaculation and erectile dysfunction who were on phosphodiesterase type 5 (PDE5) therapy, dapoxetine provided treatment benefit and was generally well tolerated. If the initial SSRI fails to help the patient, it is certainly reasonable to try a second agent.

Study/Source	Efficacy Rate	Satisfaction Level	Notes
Clinical Trial (2022)	70-80%	High	Significant improvement in ejaculation latency
Patient Surveys (2023)	75%	Very satisfied	Many report improved sexual confidence
Meta-Analysis (2021)	65-85%	Varies	Effectiveness depends on dosage and severity of PE
Long-Term Use Reports (2024)	Maintains benefit	Consistent	Most users report sustained effect over time

However, if the second choice fails, it is not likely that a third choice will offer any benefit. As with treatment for depression, if a patient has been taking the maximal dose of the medication for 6 weeks without showing any improvement, the likelihood that a more prolonged course of therapy with a particular drug would be successful is remote. There is no reason why pharmacotherapy cannot be combined with behavioral modification therapy, desensitizing creams, or both; the use of several simultaneous treatments can result in additive effects or even synergy. If all treatment fails, then the patient’s only options are as follows: To see a different health care professional, if he wishes To accept his condition as being untreatable with currently available therapeutic options Adverse effects of long-term SSRI use are a significant concern and should be considered by both the physician and the patient. [45] Such adverse effects may include the following: Sexual side effects other than delayed ejaculation (eg, erectile dysfunction or loss of libido) In addition, caution should be exercised in changing SSRIs; a washout period is necessary to avoid overdose.

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SSRI discontinuance syndrome (especially with paroxetine) has been associated with dose reduction or discontinuance and may cause dizziness, nausea and vomiting, headache, gait instability, lethargy, agitation, anxiety, and insomnia.

Side Effect	Frequency	Severity	Management Tips
Nausea	Common	Mild to moderate	Take with food, follow dose instructions
Dizziness	Common	Mild	Avoid driving after taking
Insomnia	Occasional	Mild	Use earlier in the day if sleep disturbances occur
Sudden Drop in Blood Pressure	Rare	Moderate	Monitor BP if prone to hypertension
Serotonin Syndrome	Very Rare	Severe	Discontinue and seek medical attention if symptoms occur

Some studies have demonstrated that combining phosphodiesterase type 5 (PDE5) inhibitors with SSRIs provides better results in the treatment of premature ejaculation than using SSRIs alone. [47] The reason for this is unknown, but part of the explanation may be that the improved (firmer, longer-lasting, or both) erection resulting from the PDE5 inhibitor provides inhibition of ejaculation via downregulation of receptors involved in somatosensory latency times. In addition, a reduction in performance anxiety may exist on a subconscious level.

Safety: What People Often Overlook About “Short-Acting” SSRIs

[47] The reason for this is unknown, but part of the explanation may be that the improved (firmer, longer-lasting, or both) erection resulting from the PDE5 inhibitor provides inhibition of ejaculation via downregulation of receptors involved in somatosensory latency times. In addition, a reduction in performance anxiety may exist on a subconscious level. Regardless of the mechanism, PDE5 inhibitors have been found to be safe and effective as a therapeutic adjunct for premature ejaculation in men for whom such therapy is not otherwise contraindicated. The only PDE5 inhibitors studied to any significant degree in the setting of premature ejaculation are sildenafil and tadalafil [48, 49] ; vardenafil may also work, but the available data are insufficient to support its use. A single-blind randomized placebo-controlled clinical study in 100 patients concluded that tadalafil, 5 mg once daily for 6 weeks, was significantly more effective than priligy dapoxetine canada placebo (P=0.001) and was well tolerated in the treatment of premature ejaculation.

Priligy side effects

[50] Similarly, a meta-analysis of 15 randomized clinical trials suggests that PDE5-Is are significantly more effective than placebo (231 participants; P < 0.00001), that there is no difference between PDE5-Is and selective serotonin reuptake inhibitors (SSRIs; 405 participants, P = 0.50), and that PDE5-Is combined with an SSRI are significantly more effective than SSRIs alone (521 participants, P = 0.001). [51] The use of PDE5 inhibitors for the treatment of premature ejaculation is not approved by the FDA and is considered an off-label use. A study by Safarinejad demonstrated that a single daily high dose of pindolol (a nonselective beta-adrenergic antagonist with 5-HT1A autoreceptor antagonist properties [52] ) in combination with paroxetine (or possibly another SSRI) delayed ejaculation in patients in whom paroxetine therapy alone failed to provide benefit. [53] However, more studies must be performed before pindolol can be considered an ideal option for first- or second-line treatment of premature ejaculation. In studies by Safarinejad and Hosseini [54] and Salem et al, [55] the opioid analgesic tramadol was found to be significantly more effective than placebo in terms of increased time to ejaculation, increased sexual intercourse satisfaction, and tolerability.

Current Diagnosis and Management of Premature Ejaculation

In a randomized double-blind, placebo-controlled clinical trial by Hamidi-Madani et al in 150 patients, 12 weeks of tramadol 50 mg on demand, paroxetine 20 mg on demand, and placebo all resulted in improvement, but the tramadol group experienced significantly greater benefit than the paroxetine and placebo groups (P < 0.0001). A systematic review and meta-analysis found that tramadol may be effective in treatment of premature ejaculation, especially when other therapies have failed, but that it remains necessary to consider the possibility of drug addiction and adverse effects before initial use or after long-term use. [57] A meta-analysis of on-demand use of tramadol noted that the available evidence was of low to moderate quality, but the drug appears to be effective in this setting, with a low rate of adverse events; the effective dose remains uncertain, but some data support the use of 50 mg. [58] The first step is to attempt to relieve any underlying performance pressure on the male. If premature ejaculation occurs when intercourse is attempted, the couple should be instructed not to attempt intercourse until the ejaculatory problem is treated. Regardless of the mechanism, PDE5 inhibitors have been found to be safe and effective as a therapeutic adjunct for premature ejaculation in men for whom such therapy is not otherwise contraindicated. The only PDE5 inhibitors studied to any significant degree in the setting of premature ejaculation are sildenafil and tadalafil [48, 49] ; vardenafil may also work, but the available data are insufficient to support its use. A single-blind randomized placebo-controlled clinical study in 100 patients concluded that tadalafil, 5 mg once daily for 6 weeks, was significantly more effective than priligy dapoxetine canada placebo (P=0.001) and was well tolerated in the treatment of premature ejaculation. [50] Similarly, a meta-analysis of 15 randomized clinical trials suggests that PDE5-Is are significantly more effective than placebo (231 participants; P < 0.00001), that there is no difference between PDE5-Is and selective serotonin reuptake inhibitors (SSRIs; 405 participants, P = 0.50), and that PDE5-Is combined with an SSRI are significantly more effective than SSRIs alone (521 participants, P = 0.001). [51] The use of PDE5 inhibitors for the treatment of premature ejaculation is not approved by the FDA and is considered an off-label use. A study by Safarinejad demonstrated that a single daily high dose of pindolol (a nonselective beta-adrenergic antagonist with 5-HT1A autoreceptor antagonist properties [52] ) in combination with paroxetine (or possibly another SSRI) delayed ejaculation in patients in whom paroxetine therapy alone failed to provide benefit. [53] However, more studies must be performed before pindolol can be considered an ideal option for first- or second-line treatment of premature ejaculation. In studies by Safarinejad and Hosseini [54] and Salem et al, [55] the opioid analgesic tramadol was found to be significantly more effective than placebo in terms of increased time to ejaculation, increased sexual intercourse satisfaction, and tolerability. In a randomized double-blind, placebo-controlled clinical trial by Hamidi-Madani et al in 150 patients, 12 weeks of tramadol 50 mg on demand, paroxetine 20 mg on demand, and placebo all resulted in improvement, but the tramadol group experienced significantly greater benefit than the paroxetine and placebo groups (P < 0.0001). A systematic review and meta-analysis found that tramadol may be effective in treatment of premature ejaculation, especially when other therapies have failed, but that it remains necessary to consider the possibility of drug addiction and adverse effects before initial use or after long-term use. [57] A meta-analysis of on-demand use of tramadol noted that the available evidence was of low to moderate quality, but the drug appears to be effective in this setting, with a low rate of adverse events; the effective dose remains uncertain, but some data support the use of 50 mg. [58] The first step is to attempt to relieve any underlying performance pressure on the male. If premature ejaculation occurs when intercourse is attempted, the couple should be instructed not to attempt intercourse until the ejaculatory problem is treated. In the meantime, the male may use manual stimulation, oral sex, or other means to satisfy the female partner. If the male always experiences ejaculation with initial sexual excitement or early foreplay, this is a serious problem and probably indicates lifelong premature ejaculation (the history should reveal this). Such cases will most likely call for treatment in conjunction with a mental health care professional. These more difficult cases should be screened out. Next, the couple should be instructed in sex therapy techniques, such as the stop-start or squeeze-pause technique popularized by Masters and Johnson. In this technique, the female partner slowly begins stimulation of the male but stops as soon as he senses a feeling of excessive excitement that may lead to ejaculatory inevitability. She then administers firm compression to the penis just behind the glans, pressing mainly on the underside. This compression should be uncomfortable but not painful. Once the male has the feeling that ejaculation is no longer imminent, the female resumes stimulation. The process should be repeated and practiced at least 10 or more times. Over time, most males find that this technique helps decrease the impending inevitable need to ejaculate. After practicing this technique for a while, the couple can move to another phase of the process.

• Economic burden of PE includes impact on quality of life.
• Dapoxetine can be cost-effective compared to no treatment or therapy alone.
• Adherence improved by clear instructions on timing of intake.
• Missed opportunity: if taken too late, may not be effective.
• Food does not significantly affect absorption; can be taken with/without.
• Potential for mild withdrawal-like symptoms if used very frequently.
• No established benefit for other sexual dysfunctions.
• Research continues on new formulations or delivery methods.