Dapoxetine in men with premature ejaculation and erectile dysfunction

Dapoxetine-N-oxide does not have any clinical efficacy, while desmethyldapoxetine and didesmethyldapoxetine have similar efficacy to dapoxetine, but as they comprise far smaller percentages of circulating dapoxetine species (less than 3%) their clinical effects are limited (80).

At 24 hours, plasma dapoxetine concentrations drop to 3.5% and 3.9% of peak concentrations for 30 and 60 mg doses, respectively (80).

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Rate of absorption of dapoxetine is slightly decreased by food as shown in Table 2. The initial half-life for 30 and 60 mg doses of dapoxetine is approximately 1.31 and 1.42 hours respectively and 18.7 and 21.9 hours for the terminal half-life, respectively (80). On account of its short half-life, the steady state plasma concentrations of dapoxetine are reached within four days compared to 1-22 months for fluoxetine (83,84). Dapoxetine is extensively metabolized in the liver by cytochrome P450 isoenzymes CYP3A4 and CYP2D6 and is excreted primarily in the urine (38,83). Dapoxetine has no inhibitory or inductive effects on cytochrome P450 enzymes (38). The pharmacokinetics of dapoxetine are unaffected by multiple dosing with minimal apparent accumulation (80).

In contrast, chronic use of paroxetine and sertraline has a 8- and 2-fold increases in plasma concentrations, respectively (85,86).

How long does dapoxetine make me last?

Dapoxetine (Priligy, Menarini, Italy) shares a similar mode of action with other SSRIs. Dapoxetine inhibits the serotonin reuptake transporter, with minimal inhibitory effects at the norepinephrine and dopamine reuptake transporters (41). The molecular weight of dapoxetine is 341.88 and is a water-soluble compound (38). The pKa is 8.6 and it is charged at a physiological pH of 5.87 (38). After administration, dapoxetine is rapidly absorbed (80). At 24 hours following the last dose on day 9, there is 5.5% and 6.6% of peak plasma dapoxetine concentrations left in the blood circulation for the 30 and 60 mg doses, respectively (80).

• Summary: a targeted on-demand treatment for premature ejaculation.
• Requires professional diagnosis and prescription for safe use.
• Most side effects are mild and manageable.
• Serious risks include serotonin syndrome and syncope.
• Improves ejaculatory control and sexual satisfaction.
• Part of a holistic management strategy.
• Patient education on expectations and safety is paramount.
• Regular medical follow-up ensures optimal and safe use.

Moreover, co-administration of PDE-5 inhibitors with dapoxetine has no effect on the pharmacokinetics of dapoxetine (81).

What if dapoxetine (Priligy) doesn't help?

However, as these methods require patient/partner commitment and practice to maintain viability, their efficacy decreases over time (45). Topical local anesthetics such as lidocaine and/or prilocaine are the oldest drugs used for PE treatment. These are available in cream, gel and aerosol formulations (46,47). These agents delay ejaculation in theory by reducing the sensitivity of the glans penis. The use of topical anesthetics is a relatively efficacious, user friendly, and inexpensive modality for PE treatment (48).

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However, they can cause penile glans numbness and condom use or prior washing off before sexual activity is required to prevent transference of the drug to the vaginal mucosa (14). Another potential medical treatment option for PE is the phosphodiesterase type 5 (PDE-5) inhibitors. PDE-5 inhibitors have traditionally been used to treat ED. Theoretically, a man trying to decrease his level of excitation to prevent PE may lead to ED, and conversely a man trying to excite himself to remedy his ED may experience PE. In theory, these are two sides of the same coin and may be superimposed upon each other (49). This favorable pharmacokinetic profile makes dapoxetine the drug of choice for on-demand treatment of PE. The long acting SSRIs, clomipramine, serotonin, fluoxetine and sertraline, inhibit increases in seminal vesicle pressure and the contractile responses induced by hypogastric nerve stimulation in the animal model of PE (87). However, dapoxetine appears to inhibit the ejaculatory reflex at a supraspinal level.

Psychological and Relationship Factors

With the exception of fluvoxamine, most SSRIs have been shown to clinically delay ejaculatory time (Table 1) (75). Daily use of SSRIs increases geometric mean IELT by 2.6 to 13.2 fold (75). Although daily administration of these drugs improves ejaculatory latency, chronic use of SSRIs also increases the likelihood of unwanted adverse events. Common adverse effects include fatigue, yawning, nausea, diarrhea and perspiration, which are usually mild and gradually improve within a few weeks (48). This class of drugs is also associated with unwanted sexual adverse events.

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Decreased libido (41-64%), anorgasmia (31-53%), and impotence/erectile dysfunction (10-41%) have been observed following treatment with fluoxetine, paroxetine, fluvoxamine, sertraline, and citalopram (76,77). The sudden discontinuation of these medications or rapid dose reduction may lead to SSRI-withdrawal syndrome; a cluster of psychological and vegetative clinical symptoms occurring 3-4 days after drug withdrawal and lasting for longer than one week and sometimes accompanied by suicidal thoughts and actions (48,78). The ideal SSRI for treatment of PE should have rapid onset and clearance, good tolerability, fewer adverse effects, sildenafil dapoxetine tablets and be formulated for use as on-demand treatment (63). Dapoxetine is a short acting SSRI that fits the treatment requirements of PE by exhibiting these ideal parameters. In this review, we further examine the pharmacokinetics, animal and clinical studies and the adverse events associated with the use of dapoxetine for the treatment of PE. studied the effect of dapoxetine on pudendal motoneuron reflex discharges (PMRD) elicited by bilateral electrical stimulation of the dorsal nerve of the penis in the rat model (88). The results revealed that dapoxetine significantly increased PMRD latency and was more efficient than paroxetine in inhibiting PMRD (88). Microstimulation of the medullary reticular formation decreases the amplitude and increases the latency of PMRD (90). Intrathecal and intravenous injection of dapoxetine in rats with LPGi lesions did not alter either PMRD latency or amplitude, whereas rats with intact LPGi experienced significant increases in latency and decreases in amplitude of PMRD. Hence, dapoxetine was shown to inhibit the ejaculatory expulsion reflex by modulating activity at a supraspinal level and it is now established that LPGi is a requisite brain structure for this effect (91).

Counseling and Sex Therapy

PE is observed in about 1/3 of patients complaining of ED (50). The efficacy of PE treatment with PDE-5 inhibitors reveals conflicting results. Several authors report better IELT with PDE-5 inhibitors administration for PE (51-53). However, in one well designed, randomized, double blind, placebo-controlled study, IELT was not significantly improved in the sildenafil group compared to placebo (54). A systematic review of PDE-5 inhibitors used in this context failed to provide strong evidence to support a role for PDE-5 inhibitors in the treatment of men with lifelong PE who maintain normal erectile function (55,56).

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Despite these results, sildenafil reduces anxiety, increase confidence, and gives a perception of ejaculatory control (54). There is some evidence to support the efficacy and safety of off-label on-demand or daily dosing of PDE-5 inhibitors in the treatment of lifelong PE in men with normal erectile function (51-53). However, treatment of lifelong PE with PDE5-inhibitors in such situations is not recommended (level of evidence 4) and further evidence-based research is encouraged to understand these conflicting data (14). Tramadol hydrochloride is a synthetic opioid analgesic developed in the late 1970s (57). It is a centrally acting analgesic, which binds to both µ-opioid and gamma-aminobutyric acid (GABA) receptors. Clément’s behavioral study using Fos protein expression in the male rat as a marker of neuronal activity led to the identification of brain areas specifically involved in ejaculation (92).

Safety Screening: Why Medication Review Matters

Secondarily, it inhibits the reuptake of norepinephrine and serotonin (14,57). Systematic reviews and recent published data support the efficacy and safety of on-demand use of tramadol as an alternative treatment for PE (58-61). Meta-analysis reveals that tramadol increases IELT by three minutes (58). However, long-term clinical efficacy, safety issues, and the potential for addiction need to be clarified before tramadol can be routinely used in clinical practice for the treatment of PE (14,59). Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed medications for the treatment of a variety of mood disorders such as depression (62).

Lifelong PE

The use of SSRIs to treat PE is based on the observation that delayed ejaculation and anorgasmia are common side effects of this class of drugs (41,63). SSRIs, either alone at low doses or in combination with psychosexual counseling are widely accepted as first line treatments for lifelong PE (14). Men with acquired PE generally receive targeted therapy aimed at resolving the underlying etiology of their PE, either with or without the addition of SSRIs (10). SSRIs act to block the axonal reuptake of serotonin from the synaptic cleft of central serotonergic neurons by 5-HT transporters, which desensitize the 5-HT1A and 5-HT1B receptors (64). The delay in ejaculation can occur within a few days; however, chronic administration for at least 2-3 weeks is necessary to maximize the drugs therapeutic effects (10). In rapidly ejaculating rats, the density of Fos expressing cells in the hypothalamus, amygdala, and LPGi were significantly higher than in the normal and sluggish categories (92,93). These results demonstrate that acute oral dapoxetine significantly prolongs latency and decreases the number of ejaculations in the rapid ejaculation rat model of PE when compared to controls (vehicle) (92).

Fos expression levels in the hypothalamus, thalamus and amygdala were significantly lower in dapoxetine-treated rapid rats compared to vehicle-treated rapid rats (92). The rat model of PE clearly shows that dapoxetine significantly delays ejaculation by reducing neuronal activity in the excitatory thalamic and hypothalamic areas of the ejaculatory circuit.

Because of its rapid action and short half-life, the on-demand use of dapoxetine makes it a popular alternative for treating PE (94-97). Currently, dapoxetine is approved for the treatment of PE in over 50 countries.

• Dapoxetine's impact on libido is generally minimal, focusing on ejaculation control.
• Use of dapoxetine should be part of an overall sexual health plan.
• Adherence to prescribed doses maximizes benefits and minimizes risks.
• Side effects usually resolve within a few hours or days.
• Avoid driving or operating heavy machinery after taking dapoxetine if drowsiness occurs.
• Regular discussions with your healthcare provider improve treatment outcomes.