Dapoxetine “On-Demand” for Premature Ejaculation: What Guidelines Say, What’s New, and What Are the Real Risks?

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.

Can I get dapoxetine (Priligy) on the NHS?

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. Secondarily, it inhibits the reuptake of norepinephrine and serotonin (14,57).

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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). 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). Common adverse effects include fatigue, yawning, nausea, diarrhea and perspiration, which are usually mild and gradually improve within a few weeks (48).

• Differential diagnosis: rule out erectile dysfunction, hormonal issues.
• Physical exam is part of assessment but often normal in PE.
• Validated questionnaires (e.g., PEDT) aid in diagnosis and monitoring.
• Treatment goal: satisfactory sexual experience for both partners.
• Dapoxetine addresses the biological, not solely psychological, aspect.
• May reduce performance anxiety secondary to PE.
• Prescribing guidelines emphasize starting at lowest effective dose.
• Long-term data on intermittent use over years is limited.

This class of drugs is also associated with unwanted sexual adverse events. 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).

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Behavioral therapy is primarily comprised of the “stop and start” technique, established by Semans (39) and a variation/modification of this technique, the ‘squeeze’ technique, proposed by Masters and Johnson (40). The aim of these methodologies is to help a patient maintain his sexual excitement just below the threshold for triggering ejaculation, by either stopping sexual activity or squeezing the head of the penis until the urge to ejaculate subsides (41). Desensitization of the penis via masturbation before sexual intercourse is a practice used by younger men and has proved effective in prolonging the ejaculatory period (42). These psychological/behavioral practices can lead to short-term improvement with overall success rates of 50-60% (43,44). However, as these methods require patient/partner commitment and practice to maintain viability, their efficacy decreases over time (45).

Redefining a sexual medicine paradigm: subclinical premature ejaculation as a new taxonomic entity

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). 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). The ideal SSRI for treatment of PE should have rapid onset and clearance, good tolerability, fewer adverse effects, and be formulated for use as on-demand treatment (63).

• Combining dapoxetine with recreational drugs can be dangerous and is not recommended.
• Dapoxetine can improve quality of life in men with PE.
• Always consult a healthcare provider before starting or stopping medication.
• Maintain open communication with your partner about treatment options.
• Lifestyle adjustments, like reducing stress, can complement medication treatment.
• Regular health screenings are advised during dapoxetine therapy.

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.

• Dapoxetine helps improve sexual performance and decrease performance anxiety.
• It is a part of a broader treatment approach for premature ejaculation.
• Not recommended for men with a history of seizures or heart issues.
• Dapoxetine's effects may vary depending on individual health factors.
• Combining dapoxetine with other medications should only be done under supervision.
• Always follow dosage instructions to ensure safety and efficacy.

Dapoxetine (Priligy, Menarini, Italy) shares a similar mode of action with other SSRIs.

Types of Premature Ejaculation

SSRIs, either alone at low doses or in combination with psychosexual counseling are widely accepted dapoxetine over counter 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). With the exception of fluvoxamine, most SSRIs have been shown to clinically delay ejaculatory time (Table 1) (75). Dapoxetine inhibits the serotonin reuptake transporter, with minimal inhibitory effects at the norepinephrine and dopamine reuptake transporters (41).

What are the side effects of dapoxetine (Priligy)?

Possible pharmacological causes of PE include bupropion intake and withdrawal of opioid/SSRI drug use (21-23). Urological factors include a short frenula, with one study reporting 43% of its lifetime PE patients having short frenula and improvement with frenulectomy (24). Researchers have linked hyperthyroidism to PE (25-28). As many as 72% of untreated hyperthyroid men were found to have PE according to one study and the mean IELTs increased dramatically after treatment (28). Some studies have noted a strong association between chronic prostatitis and PE.

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Improvements in PE and IELTs following antimicrobial therapy were reported (29-32). PE is strongly associated with psychosocial factors such as immature techniques for controlling ejaculation, conditioning from early hurried sexual experiences, alexithymia, anxiety, social phobias, and distressed emotions (33-36). Conversely, men with psychosocial burden have often leads to PE, leading to the question of which came first and making it difficult to scientifically establish causality (20). There are multiple psychological/behavioral treatments for PE, which may be used as a single therapy for natural variable PE or premature-like ejaculatory dysfunction or in combination with pharmacologic therapy for other subtypes of PE (10,37). Psychotherapy and sexual education can reduce patient anxiety, increase communication between a man and his partner, give patients more confidence, and modify many maladaptive sexual scripts (10,14,38). The molecular weight of dapoxetine is 341.88 and is a water-soluble compound (38).

Privacy and Confidentiality in Sexual Health Care

Another potential dapoxetine 60 mg tablets 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). PE is observed in about 1/3 of patients complaining of ED (50).

Not recommended for primary or secondary care prescribing

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). Despite these results, sildenafil reduces anxiety, increase confidence, and gives a perception of ejaculatory control (54). The pKa is 8.6 and it is charged at a physiological pH of 5.87 (38).

• Dapoxetine can improve confidence and sexual satisfaction.
• It is contraindicated in men with severe heart or liver conditions.
• The optimal dose varies; typically, 30 mg or 60 mg based on tolerance.
• Do not take dapoxetine with other SSRIs or serotonin drugs without medical advice.
• The onset of action is usually within 1-3 hours after intake.
• Dapoxetine is rapidly absorbed and eliminated from the body.

After administration, dapoxetine is rapidly absorbed (80). 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).

Uses of Dapoxetine

5-HT1A receptors have been demonstrated to exert a pro-ejaculatory effect on male sexual behavior. These receptors act on serotonergic neuronal cell bodies as a means of down regulating the release of 5-HT into the synaptic cleft. Hence, microinjections and a systemic delivery of 8-hydroxy-2-(di-n-propyl-amino) tetralin hydrobromide (8-OH-DPAT), a selective agonist of 5-HT1A receptors, elicits a diminished ejaculatory latency time in rats. There is limited evidence on the function of 5-HT1B and 5-HT2C receptors on ejaculation; however, the studies conducted implicate inhibitory activity for 5-HT1B and 5-HT2C (16,17). Both 5-HT2C and 5-HT1B receptors are distributed within the hypothalamus and in the lumbosacral areas of the spinal cord, along with 5-HT1A receptors (18).

Lifelong PE

The etiology of PE is multi-factorial in nature. Clinical evidence is limited and contradictory for many purported mechanisms. PE has been associated with both inherited and non-inherited neurobiological etiologies, pharmacological factors, urological pathology, endocrine disorders, and psychological/psychosocial mechanisms. Inherited defects in serotonergic control have been proposed to underlie a genetic basis of PE, possibly due to hyposensitive 5-HT2C and/or hypersensitive 5-HT1A receptors or increased expression of the serotonin transporter (1,18,19). Acquired neurological diseases such as multiple sclerosis, peripheral neuropathies, spinal cord tumors, and a hypothetical hypersensitivity of the glans penis have been associated with PE; however, much of this evidence is limited and conflicting (20).