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Dapoxetine and the Treatment of Premature Ejaculation

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Dapoxetine and the Treatment of Premature Ejaculation Review Article Dapoxetine and the treatment of premature ejaculation Premsant Sangkum1, Rhamee Badr1, Ege Can Serefoglu1,2, Wayne J.G. Hellstrom1 1Department of Urology, Tulane University Health Sciences Center, New Orleans, LA, USA; 2Department of Urology, Bagcilar Training & Research Hospital, Istanbul, Turkey Correspondence to: Wayne J.G. Hellstrom. Tulane University Health Sciences Center, Department of Urology, 1430 Tulane Ave. SL-42, New Orleans, LA, 70112, USA. Email: [email protected]. Introduction: Premature ejaculation (PE) is the most common male sexual complaint. Off-label oral selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for the treatment of PE. Dapoxetine is a short-acting SSRI specifically designed for on-demand use. The objective of this communication is to summarize the clinical and physiological evidence regarding the role of the serotonergic pathway and specifically dapoxetine in the treatment of PE. Methods: A PubMed search was conducted on articles reporting data on dapoxetine for the treatment of PE. Articles describing the pathophysiology and treatment options for PE were additionally included for review. Results: The etiology of PE is multi-factorial in nature. There are many treatment options for PE such as psychological/behavioral therapy, topical anesthetic agents, phosphodiesterase type 5 (PDE-5) inhibitors, and tramadol hydrochloride. SSRIs play a major role in PE treatment. Animal and clinical studies in addition to its pharmacokinetic document dapoxetine’s clinical efficacy and safety for on-demand treatment of PE. Conclusions: Dapoxetine demonstrates clinical efficacy and a favorable side effect profile. Dapoxetine is currently the oral drug of choice for on-demand treatment of PE. Keywords: Dapoxetine; premature ejaculation (PE); selective serotonin reuptake inhibitor (SSRI) Submitted Dec 12, 2013. Accepted for publication Dec 24, 2013. doi: 10.3978/j.issn.2223-4683.2013.12.01 Scan to your mobile device or view this article at: http://www.amepc.org/tau/article/view/3124/4037 Introduction of men with lifelong PE ejaculate within 60 seconds (8). Acquired PE characteristically develops later in life after a Rapid or premature ejaculation (PE) was first described in history of normal sexual function and ejaculatory control (9). the medical literature in 1887 (1) and is widely accepted to Acquired PE is usually associated with urologic or be the most common sexual complaint in males (2). Among psychological problems (10). This form of PE can often be the multiple definitions and criteria for the diagnosis of remedied by treating the underlying etiology (10). PE, the most frequently cited are short time to ejaculation, In 2006, two more PE subtypes, natural variable PE and inability to delay or control ejaculation and negative premature-like ejaculatory dysfunction, were proposed (11). personal consequences (3-6). Natural variable PE is regarded as a normal variant of PE can be subdivided into lifelong and acquired PE (7). sexual performance, whereas premature-like ejaculatory Lifelong PE is defined by the International Society of Sexual dysfunction is defined as a complaint of PE superimposed Medicine (ISSM) as a male sexual dysfunction characterized on ejaculation time in the normal range (10). These new by ejaculation that always or nearly always occurs before or subtypes help physicians more precisely stratify patients within approximately one minute of vaginal penetration, and set treatment algorithms. Pharmacotherapy remains the inability to delay ejaculation on all or nearly all vaginal the basis of management of lifelong and acquired PE, penetrations, and negative personal consequences such as whereas psychotherapy should be considered for patients distress, bother, frustration and/or the avoidance of sexual with natural variable PE and premature like ejaculatory intimacy (6). This definition is based on evidence that 80-90% dysfunction (12). © Translational Andrology and Urology. All rights reserved. www.amepc.org/tau Transl Androl Urol 2013;2(4):301-311 302 Sangkum et al. Dapoxetine for PE Pathophysiology of PE genetic basis of PE, possibly due to hyposensitive 5-HT2C and/or hypersensitive 5-HT receptors or increased Ejaculation is comprised of two phases: emission and 1A expression of the serotonin transporter (1,18,19). expulsion (13). The ejaculatory reflex requires the Acquired neurological diseases such as multiple coordination of sympathetic, parasympathetic and somatic sclerosis, peripheral neuropathies, spinal cord tumors, pathways, interlaced with central serotonergic and and a hypothetical hypersensitivity of the glans penis have dopaminergic neuronal pathways (5,13). Emission is the been associated with PE; however, much of this evidence deposition of sperm and seminal fluid into the posterior is limited and conflicting (20). Possible pharmacological urethra by contraction of the seminal vesicles and the causes of PE include bupropion intake and withdrawal of prostate gland and is mediated by the sympathetic nervous opioid/SSRI drug use (21-23). Urological factors include a system (T10-L2) (13,14). The epididymis, vas deferens, short frenula, with one study reporting 43% of its lifetime seminal vesicles, prostate gland, prostatic urethra as well as PE patients having short frenula and improvement with the bladder neck are involved in the emission phase (13). frenulectomy (24). Researchers have linked hyperthyroidism Expulsion is the forceful antegrade ejection of sperm from to PE (25-28). As many as 72% of untreated hyperthyroid the urethra and is controlled by somatic nerves (S2-4) (14). men were found to have PE according to one study and the The external urethral sphincter relaxes and the mean IELTs increased dramatically after treatment (28). ischiocavernosus, bulbocavernosus and other pelvic floor Some studies have noted a strong association between muscle undergo rhythmic synchronous contractions to allow chronic prostatitis and PE. Improvements in PE and IELTs antegrade flow of sperm out of the urethra. Concurrently, following antimicrobial therapy were reported (29-32). the smooth muscle of the bladder neck contracts to prevent PE is strongly associated with psychosocial factors such retrograde flow (13). as immature techniques for controlling ejaculation, A large body of research indicates that serotonin acting conditioning from early hurried sexual experiences, on the brain’s post-synaptic receptors exerts an overall alexithymia, anxiety, social phobias, and distressed emotions inhibitory control on the ejaculatory process. As far back as (33-36). Conversely, men with psychosocial burden have 1976, administration of the serotonin (5-Hydroxytryptamine, often leads to PE, leading to the question of which came 5-HT) precursor 5-Hydroxytryptophan was shown to first and making it difficult to scientifically establish inhibit male rat sexual behavior (15). 5-HT1A receptors causality (20). 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 Treatment of PE the release of 5-HT into the synaptic cleft. Hence, There are multiple psychological/behavioral treatments microinjections and a systemic delivery of 8-hydroxy-2- for PE, which may be used as a single therapy for natural (di-n-propyl-amino) tetralin hydrobromide (8-OH-DPAT), variable PE or premature-like ejaculatory dysfunction or in a selective agonist of 5-HT1A receptors, elicits a diminished combination with pharmacologic therapy for other subtypes ejaculatory latency time in rats. There is limited evidence of PE (10,37). Psychotherapy and sexual education can on the function of 5-HT1B and 5-HT2C receptors on reduce patient anxiety, increase communication between ejaculation; however, the studies conducted implicate a man and his partner, give patients more confidence, inhibitory activity for 5-HT1B and 5-HT2C (16,17). Both and modify many maladaptive sexual scripts (10,14,38). 5-HT2C and 5-HT1B receptors are distributed within the Behavioral therapy is primarily comprised of the “stop hypothalamus and in the lumbosacral areas of the spinal and start” technique, established by Semans (39) and a cord, along with 5-HT1A receptors (18). variation/modification of this technique, the ‘squeeze’ The etiology of PE is multi-factorial in nature. Clinical technique, proposed by Masters and Johnson (40). The aim evidence is limited and contradictory for many purported of these methodologies is to help a patient maintain his mechanisms. PE has been associated with both inherited and sexual excitement just below the threshold for triggering non-inherited neurobiological etiologies, pharmacological ejaculation, by either stopping sexual activity or squeezing factors, urological pathology, endocrine disorders, and the head of the penis until the urge to ejaculate subsides (41). psychological/psychosocial mechanisms. Inherited defects Desensitization of the penis via masturbation before sexual in serotonergic control have been proposed to underlie a intercourse is a practice used by younger men and has proved © Translational Andrology and Urology. All rights reserved. www.amepc.org/tau Transl Androl Urol 2013;2(4):301-311 Translational Andrology and Urology, Vol 2, No 4 December 2013 303 effective in prolonging the ejaculatory period (42). These the reuptake of norepinephrine and serotonin (14,57). psychological/behavioral practices can lead to short-term Systematic reviews and recent
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