Untitled

Medical therapy for premature ejaculation ! The Author(s), 2011.
Reprints and permissions:http://www.sagepub.co.uk/ Abstract: Premature ejaculation (PE) is a common male sexual dysfunction. Advances in PE research have been hampered owing to a nonstandardized definition of PE, until the definitionby the International Society of Sexual Medicine (ISSM) in 2009. Once the diagnosis of PE isestablished through a thorough history, a variety of medical therapies is available, includingtricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), centrally acting opi-ates, phosphodiesterase 5 inhibitors and topical desensitizing creams. Most of these treat-ments increase the intravaginal ejaculation latency time (IELT) and patient satisfaction scores,with the most convincing evidence for SSRIs and topical creams. Daily SSRIs such as parox-etine, although efficacious, do have a substantial and prolonged side effect profile. Dapoxetine,which is a on-demand SSRI, is the only licensed drug for the treatment of PE, increasing IELTby a factor of 2.5 to 3 with limited and tolerable side effects. In the near future, the topicalaerosol PSD502 is due to be licensed for the treatment of PE, increasing IELT by up to a factorof 6 but having minimal local and negligible systemic side effects.
Keywords: male sexual dysfunction, medical therapy, medical treatment, prematureejaculation arbitrary time of 1 minute from vaginal penetra- Premature ejaculation (PE) can be a debilitating tion to ejaculation was suggested by some male sexual impairment. A range of studies have [Marmor, 1976] while others defined the condi- suggested a prevalence of 4—39% [Laumann et al.
tion in terms of the number of penile thrusts 1999; Grenier and Byers, 1995; Spector and Carey, 1990; Nathan, 1986; Reading and West, ejaculation [Colpi et al. 1986]. Other authors 1984]. This wide range can be partly attributed added a more subjective element to the definition to variations in the way that PE is defined, but by defining PE as ejaculation that happens prior may also reflect differences between populations to when the male desires it [Hastings, 1963] or ejaculations which are satisfactory to the female Furthermore, because of the intimate nature of partner in less than 50% of sexual intercourses the problem, PE tends to be under-reported by [Masters and Johnson, 1970]. A consensus on a patients who do not typically seek medical help Several attempts have been made over the years Over the years, PE has been defined in various by a number of major societies (WHO, APA, ways. Some consider it controversial that PE is EAU, AUA, ISSM) dealing with male sexual dys- even considered to be a sexual dysfunction at all, function to reach a consensus on the definition of since all male upper mammalian species, includ- PE. Table 1 illustrates the various definitions ing primates ejaculate almost immediately on penetration of the vagina [Wainberg, 1984].
All of the above definitions acknowledge one or However, initial definitions of PE revolved around ejaculation which regularly occurs at oraround initial vaginal penetration [Marmor, 1976]. A quantitative element was subsequently added to the definition. For instance, the Table 1. Early definitions of premature ejaculation.
The World Health Organisation (WHO) (International An inability to delay ejaculation sufficiently to enjoy Classification of Diseases-ICD, 1994) [WHO, 1994] lovemaking, which manifests as either of the following: occurrence of ejaculation before or very soon afterthe beginning of intercourse (within 15 seconds of thebeginning of intercourse) occurrence of ejaculation in the absence of sufficienterection to make intercourse possible Exclusion criteria: PE is not the result of prolonged The American Psychiatric Association (APA) (The Persistent or recurrent ejaculation with minimal Diagnostic and Statistical Manual of Mental Disorders, sexual stimulation before, on or shortly after pene- Fourth Edition (DSM-IV), 2000) [APA, 2000] tration and before the person wishes it. The distur-bance causes marked distress or interpersonaldifficulty.
Exclusion: PE is not due exclusively to the direct effects of a substance (e.g. withdrawal from opioids) and fac-tors that affect duration of the excitement phase, suchas age, novelty of the sexual partner or situation, andrecent frequency of sexual activity.
The European Association of Urology (EAU) (Guidelines The inability to control ejaculation for a sufficient on Disorders of Ejaculation, 2001) [Colpi et al. 2001] length of time before vaginal penetration.
Exclusion: Impairment of fertility does not happen when The American Association of Urology (AUA) (Guidelines Ejaculation that occurs sooner than desired, either on the pharmacologic management of premature before or shortly after penetration, causing distress to ejaculation, 2004) [Montague et al. 2004] In 2009, the International Society of Sexual The impact of this new definition on the diagno- Medicine (ISSM) [Althof et al. 2009] produced sis and management of PE is awaited. In the its guidelines of the diagnosis and management of interim, the definition advocated by the authors PE. It postulated an evidence-based definition of PE and defined PE as a male sexual dysfunctioncharacterized by: Diagnosis and classificationPE can be divided into two distinct entities: . ejaculation which always or nearly always acquired and lifelong PE [Godpodinoff, 1989].
occurs prior to or within about 1 minute of Lifelong PE is a condition which has existed since the onset of sexual activity and is not reliant . inability to delay ejaculation on all or nearly on either the conditions or the environment under which sexual activity is taking place.
. negative personal consequences, such as dis- Acquired PE develops in an individual who has tress, bother, frustration and/or the avoidance previously had normal ejaculatory control and This definition is regarded as the most robust to The cause of PE is usually not apparent. Some date owing to its evidence-based nature and has have characterized these cases as being psycho- largely replaced the previous definitions as the genic in origin, while others have postulated ‘bio- 2008]. This fundamental controversy about However, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) due has been reflected in the two differing approaches to be published in May 2013 [APA, 2013] may to therapy (i.e. behavioural or psychotherapy ver- offer an alternative take on the definition of PE.
sus pharmacological therapy). Those proposing a psychogenic basis in the absence of a definitive Classification of PE is still evolving as different physical cause suggest that PE may be associated classification models offer different clinical and research benefits [Cahangirov et al. 2011; Chanet al. 2011; Cle´ment et al. 2009; Waldinger and . novelty of partner or situation;. low frequency of sexual activity.
Biogenic PE is linked to an identifiable organic Clinical history plays an important part in the cause and the following conditions have been diagnosis of PE since it is by definition a self- reported diagnosis. However, clinical assessmentcan be challenging owing to the nature of the problem. Patients may be embarrassed and shy when relating details of their sexual experiences and exact details are not forthcoming. It may then be useful to involve the partner in the Once the condition is treated, the expectation is To elicit a diagnosis of PE, the three main com- Those who have proposed biogenic theories for ponents of PE (timing, control and satisfaction) the development of PE have suggested that one of should be specifically addressed. Once a diagno- the following may be the pathophysiological sis of PE is established, other related avenues that . the nature of the PE (lifelong or acquired); . the presence or absence of any associated . the impact of the PE on the relationship with . the impact of the PE on quality of life;. previous treatment (including over the coun- Waldinger and Schweitzer introduced the con- cept of PE as a syndrome, with patientsexperiencing Examination of the patient involves a general [Waldinger and Schweitzer, 2006]. The four examination as well as a more focused examina- tion of the genitalia outlining the scrotal contentsand the penis in detail. A digital rectal examina- . short IELT, with control;. short IELT, no control; tion to palpate the prostate gland is also recom- mended. Questionnaires such as the Index of Premature Ejaculation [Yuan et al. 2004] andthe [Symonds et al. 2007] also have a role is evaluat- include a category called ‘natural variable PE’ ing PE. It must be noted that the routine use of whereby the episodes of PE are not consistent questionnaires is not very useful, as they have a and can be situational. This group falls under tendency to confuse the picture, especially when the umbrella ‘short IELT and no control’. This ED occurs concurrently. ED specific question- may represent a variation of natural ejaculatory naires such as the IIEF and its shorter version, function. Another category that stems from IIEF-5, have been shown to further complicate this syndrome is the ‘Premature-like ejacula- the issue, especially in ED and PE trials tory function’ whereby the patients perceive IELTs fall in the normal range. This falls Laboratory and other physiological tests are rarely indicated. History and examination are • Time to ejaculation• Perceived degree of ejaculatory control• Degree of bother• Onset and duration• Psychosocial and relationship issues• Medical history • If PE secondary to ED, treat ED first Attempt withdrawal of drug therapy after 6-8 weeks Figure 1. Management of premature ejaculation. PE, premature ejaculation; ED, erectile dysfunction.
conclusive (after 3 years of follow up, 75% of Treatment of PE can be a real challenge for the men showed no lasting improvement) [Hawton clinician (Figure 1). This is primarily because et al. 1986]. One strategy, particularly for youn- the pathophysiology of PE is so poorly under- ger men suffering from PE, is precoitus mastur- stood. Over the years multiple treatment modal- bation which partially desensitizes the penis and ities have been tried, often with initial promise.
leads to a delay in ejaculation [Sadeghi-Nejad However, there are few studies on long-term effi- cacy and durability for most of the currentlyavailable treatment options. This article aims to Psychotherapy. Psychotherapy involves educat- provide an overview of the different treatment ing both the male patient and the female partner.
options available together with an assessment of This can happen in the context of marriage/rela- tionship counselling as well as psychosexual ther-apy [Hatzimouratidis et al. 2010]. Again short- term results have been promising although Psychological and behavioural therapy histori- cally have a significant role in the managementof PE.
Behavioural therapy. The ‘stop—start’ strategy The quest to develop an effective tablet to aid (stopping coitus in situ and restarting after a and ultimately cure PE has been ongoing for delay) and its evolution to the ‘squeeze’ tech- many decades [Schapiro, 1943]. A number of nique (the physical application of pressure at drugs have shown some promise in treating PE the base of the head of the penis) have been with varying degrees of success. At the present time, only one drug (dapoxetine) is licensed (in However, while short-term benefits have been some countries only) for the treatment of PE.
reported (symptomatic benefit in 45—65%), the However, the other drugs described below can long-term results of treatment have not been also be used, as long as the patient is fully aware that they are not licensed for the treatment [Strassberg et al. 1999; Kim and Seo, 1998; Segraves et al. 1993], with reports of improvedsexual satisfaction both from patients and part- ners [Althof et al. 1995]. The use of clomipra-mine is limited by its associated side effects, mainly fatigue, dizziness, dry mouth and hypo- (Phenoxybenzamine, alfusozin, terazosin) and tension. During continuous dosing, the adverse monoamine oxidase inhibitor (Isocarboxazid, event profile of clomipramine in men with PE Phenelzine). Together with monoamine oxidase was reported to be significantly worse than with first oral medication used for the treatment ofPE.
SSRIs unlicensed (escitalopram, fluoxetine, flu- voxamine, paroxetine, sertraline). Serotonergic ited their use. These agents are not used for PE agents have been shown to be effective in the anymore [Beretta et al. 1986; Shilon et al.
1984; Aycock, 1949]. More selective alpha- blockers such as terazosin have shown some tor which leads to a delay of ejaculation [Lue and promise in treating PE in patients suffering Broderick, 2007; Waldinger et al. 1998]. The from concurrent lower urinary tract symptoms effect of SSRIs on the delay of ejaculation was first noted by Patterson when treating men with depression [Patterson, 1993]. Since then, studies A range of drugs are currently used by clinicians have shown that the effect of SSRIs to delay ejac- for the management of PE including antidepres- ulation can be seen within days of the start of sants, local anaesthetic agents and phosphodies- treatment with a plateauing of the effect within 4 weeks. In the variously reported studies theIELT is increased between twofold and eightfold Whether the medication is used regularly or on patients when choosing the most appropriate The use of fluoxetine to treat PE was first described in 1994 by Forster [Forster, 1994] on-demand drug offers the flexibility of using and Waldinger and colleagues conducted the the medication just prior to sexual intercourse, first randomized, controlled trial to evaluate the thereby reducing the risks of side effects associ- use of paroxetine in treating PE [Waldinger et al.
ated with the drug for the rest of the time. Data 1994]. Further work by the same research group so far suggest that generally speaking the benefit demonstrated efficacy of a number of SSRIs (flu- of on-demand dosing is inferior to the benefits oxetine, fluvoxamine, paroxetine and sertraline) seen with regular dosing. On the other hand, in the treatment of PE, although with varying daily dosage allows for a more spontaneous efficacy and side-effect profiles [Waldinger et al.
1998]. Fluoxetine, sertraline and paroxetine dosing results in greater exposure to the drug increased IELT significantly whereas there was and may be associated with more pronounced no statistical difference with fluvoxamine.
side effects. Waldinger and colleagues showedthat the majority of men (81%) preferred a Kim and Seo demonstrated that treatment with sertraline was nearly as effective and had a lower regimen [Waldinger et al. 2007]. Moreover, the incidence of side effects than clomipramine [Kim stigma associated with the daily use of an antide- and Seo, 1998]. Further studies (prospective pressant (i.e. selective serotonin reuptake inhibi- studies and randomized controlled trials) have tors [SSRI]) may be a complicating factor in the confirmed the efficacy of sertraline in the man- compliance of patients to the treatment.
agement of PE [Balbay et al. 1998; Biri et al.
1998; Mendels, 1995]. Duloxetine [Athanasios et al. 2007] and Escitalopram [Safarinejad, 2007] have also been shown to be effective in on-demand dosing of clomipramine increases treating PE. The efficacy and side-effects associ- ated with SSRIs are described later (see Table 5).
Adverse effects with SSRIs are usually minor and Dapoxetine is a drug specifically developed for include fatigue, yawning, mild nausea, loose the on-demand treatment of PE. It has been stools and perspiration. They usually present at extensively evaluated in five randomized, pla- the beginning of the treatment and they tend to cebo-controlled phase III clinical trials involving disappear within 2—3 weeks. There have been more than 6000 men with PE. This is the largest and most comprehensive clinical trial programme increased suicide risks with the use of SSRIs, to date for a drug therapy to treat PE. It is a short-acting SSRI designed to be taken only et al. 2004; Kim and Seo, 1998; Waldinger when needed and is taken 1—3 hours before et al. 1998]. Therefore, it is important that patients are adequately counselled about therisks involved with the use of these drugs.
There is evidence of its efficacy, its relatively Once patients have been started on SSRI treat- mundane side effect profile and its validity ment, it is essential to perform follow-up assess- as an on-demand medication [Feige et al. 2011; ments to not only evaluate the efficacy of the drug Hoy and Scott, 2010; Kaufman et al. 2009; but also to identify any side effects, especially McMahon et al. 2009; Giuliano et al. 2007].
regarding associated sexual dysfunction and sui- However, the durability of the effects of dapoxe- tine has not yet been demonstrated in prospec-tive, randomized trials since long-term follow upis not yet available [Safarinejad and Hosseini, Licensed SSRI (dapoxetine). Dapoxetine is the only licensed drug in the treatment of PE. Ithas been approved for treatment for the treat- Table 2 summarizes the double-blind, random- ment of PE in New Zealand, Sweden, Austria, ized, placebo-controlled parallel trials to date Finland, Germany, Spain, Italy and Portugal.
looking at the use of dapoxetine for the treatment National approvals and licenses in five other of PE [McMahon et al. 2011; Buvat et al. 2009; European countries are expected to follow.
Kaufman et al. 2009; Patrick et al. 2009; Pryor Dapoxetine is not approved for marketing in the et al. 2006]. A total of 6081 patients were Table 2. Treatment of premature ejaculation with dapoxetine (phase III clinical trials).
DizzinessSomnolenceHeadacheVomitingDiarrhoeaNasopharyngitis Statistically significant improvement in: Interpersonal difficulty related to ejaculation IELT, intravaginal ejaculation latency time; PRN, pro re nata.
Desensitizing agents (SS Cream, benzocaine, With this in mind there has been a move to prilocaine, lidocaine). The use of a local anaes- the use of aerosols which can be more discreet thetic to desensitize the penis prior to coitus and patient friendly [Dinsmore et al. 2007].
has been described since the middle part of the last century [Damrau, 1963]. A number caine—prilocaine spray for use in PE, labelled of these products are available as ‘over-the-coun- PSD 502 has been tested in two early stage ter’ medications and can be readily purchased online. They predominantly come in the form of creams although topical sprays are also Wyllie, 2009; Dinsmore et al. 2007; Henry and Morales, 2003]. The spray forms a clear,slightly oily, odourless solution that remains Xin and colleagues published data demonstrating that patients suffering from PE had an increased condom required. It is easily wiped off, if nec- vibratory threshold on the glans penis when it essary, before penetration and the anaesthetic penetrates the glans within 5 minutes although (SS-Cream — herbal cream). Moreover, the it is not capable of penetrating intact kerati- effect was dose related [Xin et al. 2000].
nised skin and will therefore not anaesthetize Thereafter, the same research group performed the shaft of the penis or the hands. Table 3 a randomized controlled trial demonstrating an shows the efficacy and side effect profiles of increase in IELT by eightfold when using the Desensitizing creams and sprays can cause side effects including hypoanaesthesia of the penile (EMLA cream) and aerosol sprays have been shaft and numbing of the vaginal vault of the partner, unless a condom is used [Lue and [Dinsmore et al. 2007; Henry and Morales, Broderick, 2007]. Irritating local and systemiceffects have also been reported, although they 2003; Berkovitch et al. 1995] and in randomized, are rare [Busato and Galindo, 2004; Atikeler controlled trials [Carson and Wyllie, 2010; Busato and Galindo, 2004]. The optimum timeof application of the EMLA cream has been shown to be 20 minutes prior to intercourse tadalafil). The role of PDE5 inhibitors (PDE5- and the optimum concentration 5% [Atikeler I) in the management of PE is controversial.
et al. 2002]. However, topical cream can be Although a prospective study showed an increase of IELT of a factor of 5.7 in patients using silden- condom to minimize the effect of the cream afil for the treatment of PE [Wang et al. 2007], there still is minimal evidence to propose the use Table 3. Treatment of PE with PSD 502 (randomized controlled trials).
Statistically significant improvement in: Statistically significant improvement in: IELT, intravaginal ejaculation latency time; PE, premature ejaculation; ED, erectile dysfunction.
Table 4. Randomized, controlled trials of PDE5-I.
Moderate increase in patient satisfaction IELT, intravaginal ejaculation latency time; PE, premature ejaculation.
of PDE5-I in treating PE. Table 4 gives a sum- on-demand medication, although the mechanism mary of the randomized, controlled trials for is poorly understood [Alghobary et al. 2010; Salem et al. 2008; Safarinejad and Hosseini,2006]. However, there is evidence that some Epidemiological studies have shown that a third cases of secondary PE are seen in men who are of men with ED suffer from PE [Corona et al.
withdrawing from opiate addiction. There may 2004]. This association between PE and ED therefore be a relation between central opioid may be explained by the fact that when a man suffers from ED, he makes a compensatory effortto achieve ejaculation before the loss of the erec- Table 5 gives a summary of the medication cur- tion, leading to PE. A possible carry on effect rently being used for the treatment of PE.
from this is when the man suffering from EDtries to overstimulate himself to achieve a rigid erection, whereby this overstimulation leads to Additional research is required to eventually PE [Jannini et al. 2005]. Therefore, by treating develop a product which is acceptable to the the ED with PDE5 inhibitors, the corresponding patient by being effective all of the time with min- associated PE improves. However, evidence that imal side effects and that is easy and discreet to this mechanism is actually occurring is not forth- use without compromising spontaneity during coming as yet. There are just two randomized sexual intercourse. Some of the possibilities are controlled trials evaluating a PDE5-I in the man- agement of PE [Aversa et al. 2009; McMahonet al. 2005].
. 9-hydroxycanthin-6-one (9-HC-6-one), a b- carboline alkaloid isolated from Eurycoma Although the evidences does not strongly support longifolia. In vitro, it has been noted that 9- the use of PDE5-I in primary PE, it may have a HC-6-one attenuated PE-induced contrac-tion by blocking calcium channels [Chiou role in treating PE in patients intolerant to dapoxetine, especially if the PE is associated . It has been noted that decreased levels of mag- nesium may give rise to vasoconstrictionfrom and decreased nitric oxide. This mechanism (tramadol). Safarinejad and Hosseini have pub- lished a randomized, controlled trial on the use of tramadol HCL to treat PE [Safarinejad andHosseini, 2006]. Various research groups have However, there is a long way to go before these shown tramadol to have some efficacy in treating products can be marketed. Moreover, reproduc- PE [Alghobary et al. 2010], especially as an ible in vitro and in vivo studies are required and Table 5. Efficacy and side effects of drugs used in the management of PE.
IELT, intravaginal ejaculation latency time; PE, premature ejaculation; ED, erectile dysfunction; SSRI, selective serotonin reuptake inhibitor; PRN,pro re nata.
the formulation of a standardized definition of PE is possibly the first building block towards This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement The authors declare no conflicts of interest in PE is a common condition affecting around one in five men. It can be a cause of significant per-sonal distress which may in turn affect the rela- tionship of the man with his partner. While many Alghobary, M.M.D., El-Bayoumy, Y.M.D., Mostafa, men with PE do not seek medical attention, when Y.M.D., Mahmoud, E.-H.M.M.D. and Amr, M.M.D.
they do, SSRIs, desensitizing creams and to a (2010) Evaluation of tramadol on demand vs. daily lesser extent PDE5-I have been used in the treat- paroxetine as a long-term treatment of lifelong pre-mature ejaculation. J Sexual Med 7: 2860—2867.
ment. All of these medications are sold off-labelfor the treatment of PE except for the recently Althof, S., Abdo, C., Dean, J., Hackett, G., McCabe, licensed dapoxetine (PriligyTM) which provides M., McMahon, C. et al. (2009) International Societyfor Sexual Medicine’s guidelines for the diagnosis and an effective, on-demand treatment regimen with treatment of premature ejaculation. http://www.issm.
relatively minimal side effects. PSD 502 is cur- info/v4/. Accessed on 23 September 2011.
rently in the development phase and with the Althof, S., Levine, S., Corty, E., Risen, C., Stern, E.
conclusion of phase III trials, may soon be and Kurit, D. (1995) A double-blind crossover trial of licensed as a topical aerosolised spray for the clomipramine for rapid ejaculation in 15 couples.
APA. (2000) Diagnostic and Statistical Manual of ejaculation: results of a phase III, double-blind, pla- Mental Disorders. Washington, DC: American cebo-controlled study. J Sex Med 7: 3179—3189.
Chan, J.S.W., Snoeren, E.M.S., Cuppen, E., APA (2013) Diagnostic and Statistical Manual of Mental Waldinger, M.D., Olivier, B. and Oosting, R.S. (2011) Disorders Development, 5th edition (DSM-5). Available The serotonin transporter plays an important role in at: http://www.dsm5.org/proposedrevision/pages/ male sexual behavior: a study in serotonin transporter proposedrevision.aspx?rid¼174# (Accessed knockout rats. J Sexual Med 8: 97—108.
Athanasios, Z., Polyanthi, P. and George, K. (2007) Hydroxycanthin-6-one induces penile erection and The efficacy of duloxetine in the treatment of prema- delays ejaculation. J Sexual Med DOI: 10.1111/ ture ejaculation. Int Urol Nephrol 39: 115—118.
Atikeler, M., Gecit, I. and Senol, F. (2002) Optimum Choi, H.K., Jung, G.W., Moon, K.H., Xin, Z.C., usage of prilocaine-lidocaine cream in premature Choi, Y.D., Lee, W.H. et al. (2000) Clinical study of ejaculation. Andologia 34: 356—359.
SS-cream in patients with lifelong premature ejacula-tion1 1 SS-cream was developed originally by Drs. H.
Aversa, A., Pili, M., Francomano, D., Bruzziches, R., K. Choi and Z. C. Xin in Korea. The drug was sup- Spera, E., La Pera, G. et al. (2009) Effects of vardenafil ported and sponsored by the research fund of Cheil administration on intravaginal ejaculatory latency time Jedang Co. in Seoul, Korea. All authors have financial in men with lifelong premature ejaculation. Int J Impot interests and other relationships with SS-cream.
Aycock, L. (1949) The medical management of pre- Cle´ment, P., Pozzato, C., Heidbreder, C., Alexandre, L., Giuliano, F. and Melotto, S. (2009) Delay of Balbay, M., Yildiz, M., S¸alvarci, A., O Ejaculation Induced by SB-277011, a selective dopa- ¨ zbek, E. (1998) Treatment of premature ejaculation mine D3 receptor antagonist, in the rat. J Sexual Med with sertralin. Int Urol Nephrol 30: 81—83.
Bas¸ar, M., Ylmaz, E., Ferhat, M., Bas¸ar, H. and Colpi, G.M., Fanciullacci, F., Beretta, G., Negri, L.
Batislam, E. (2005) Terazosin in the treatment of and Zanollo, A. (1986) Evoked sacral potentials in premature ejaculation: a short-term follow-up. Int Urol subjects with true premature ejaculation. Andrologia Beretta, G., Chelo, E., Fanciullacci, F. and Zanollo, A.
Colpi, G. M., Hargreave, T.B., Papp, G. K., Pomerol, (1986) Effect of an alpha-blocking agent (phenoxy- J. M. and Weidner, W. (2001) Guidelines on disorders benzamine) in the management of premature ejacula- of ejaculation. European Association of Urology.
Available at: http://www.uroweb.org/fileadmin/user_upload/Guidelines/2001_Disorders_of_ Berkovitch, M., Keresteci, A. and Koren, G. (1995) Efficacy of prilocaine-lidocaine cream in the treatmentof premature ejaculation. J Urol 154: 1360—1361.
Corona, G., Petrone, L., Mannucci, E., Jannini, E.A.,Mansani, R., Magini, A. et al. (2004) Psycho-biologi- Biri, H., Isen, K., Sinik, Z., Onaran, M., Ku cal correlates of rapid ejaculation in patients attending and Bozkirli, I. (1998) Sertraline in the treatment of an andrologic unit for sexual dysfunctions. Eur Urol premature ejaculation: A double-blind placebo con- trolled study. Int Urol Nephrol 30: 611—615.
Damrau, F. (1963) Premature ejaculation: Use Busato, W. and Galindo, C.C. (2004) Topical anaes- of ethyl aminobenzoate to prolong coitus. J Urol thetic use for treating premature ejaculation: a double- blind, randomized, placebo-controlled study. BJU Int93: 1018—1021.
Dinsmore, W.W., Hackett, G., Goldmeier, D.,Waldinger, M., Dean, J., Wright, P. et al. (2007) Buvat, J., Tesfaye, F., Rothman, M., Rivas, D.A. and Giuliano, F. (2009) Dapoxetine for the treatment of ejaculation (TEMPE): a novel aerosol-delivery premature ejaculation: results from a randomized, form of lidocaine-prilocaine for treating premature double-blind, placebo-controlled phase 3 trial in 22 Dinsmore, W.W. and Wyllie, M.G. (2009) PSD502 Cahangirov, A., Cihan, A., Murat, N., Demir, O., improves ejaculatory latency, control and sexual satis- Aslan, G., Gidener, S. et al. (2011) Investigation of the faction when applied topically 5 min before intercourse neural target level of hyperthyroidism in premature in men with premature ejaculation: results of a phase ejaculation in a rat model of pharmacologically III, multicentre, double-blind, placebo-controlled induced ejaculation. J Sexual Med 8: 90—96.
Carson, C. and Wyllie, M. (2010) Improved ejacula- Feige, A.M., Pinsky, M.R. and Hellstrom, W.J. (2011) tory latency, control and sexual satisfaction when Dapoxetine for Premature Ejaculation. Clin Pharmacol PSD502 is applied topically in men with premature Forster, P. (1994) Fluoxetine for premature ejacula- Masters, W. and Johnson, V. (1970) Himan Sexual Inadequacy. Boston, MA: Little, Brown & Co.
Giuliano, F., Bernabe, J., Gengo, P., Alexandre, L. and McMahon, C., Althof, S., Kaufman, J., Buvat, J., Clement, P. (2007) Effect of acute dapoxetine Aquilina, J., Rivas, D. et al. (2009) Efficacy and safety administration on the pudendal motoneuron reflex in of dapoxetine for premature ejaculation: integrated anesthetized rats: comparison with paroxetine. J Urol analysis of 5 phase 3 trials: PD-068. J Sexual Med Godpodinoff, M. (1989) Premature ejaculation: clini- McMahon, C., Kim, S.W., Park, N.C., Chang, C.-p., cal subgroups and etiology. J Sex Marital Ther Rivas, D., Tesfaye, F. et al. (2011) Treatment of pre- mature ejaculation in the Asia-Pacific region: resultsfrom a phase III double-blind, parallel-group study of Grenier, G. and Byers, E. (1995) Rapid ejaculation: A dapoxetine. J Sexual Med 7: 256—268.
review of conceptual, etiological, and treatment issues.
Arch Sex Behav 24: 447—472.
McMahon, C.G., Abdo, C., Incrocci, L., Perelman,M., Rowland, D., Waldinger, M. et al. (2004) Hastings, D. (1963) Impotence and Frigidity. Boston, Disorders of orgasm and ejaculation in men. J Sexual Hatzimouratidis, K., Amar, E., Eardley, I., McMahon, C.G., Stuckey, B.G.A., Andersen, M., Giuliano, F.H.D., Montorsi, F. et al. (2010) Purvis, K., Koppiker, N., Haughie, S. et al. (2005) Guidelines on male sexual dysfunction: Erectile Efficacy of sildenafil citrate (Viagra) in men with pre- dysfunction and premature ejaculation. Eur Urol, mature ejaculation. J Sexual Med 2: 368—375.
Mendels, J. (1995) Sertraline for premature ejacula- Hawton, K., Catalan, J., Martin, P. and Fagg, J. (1986) Long-term outcome of sex therapy. Behav Res Therapy24: 665—675.
Mohammadreza, N., Mehdi, A. and Mohammad, H.
(2009) Seminal plasma magnesium and premature Henry, R. and Morales, A. (2003) Topical lidocaine- ejaculation: a case-control study. Urol J 2: 102—105.
prilocaine spray for the treatment of premature ejacu-lation: a proof of concept study. Int J Impot Res Montague, D.K., Jarow, J., Broderick, G.A., Dmochowski, R.R., Heaton, J.P., Lue, T.F. et al.
(2004) Premature Ejaculation: Guideline on the Hoy, S.M. and Scott, L.J. (2010) Dapoxetine: in pre- pharmacologic management of premature ejaculation.
mature ejaculation. Drugs 70: 1433—1443.
Jannini, E.A., Lombardo, F. and Lenzi, A. (2005)Correlation between ejaculatory and erectile dysfunc- Nathan, S. (1986) The epidemiology of the DSM-III psychosexual dysfunctions. J Sex Marital Ther12: 267—281.
Kaufman, J.M., Rosen, R.C., Mudumbi, R.V.,Tesfaye, F., Hashmonay, R. and Rivas, D. (2009) Patrick, D.L., Giuliano, F., Ho, K.F., Gagnon, D.D., Treatment benefit of dapoxetine for premature ejacu- McNulty, P. and Rothman, M. (2009) The Premature lation: results from a placebo-controlled phase III trial.
Ejaculation Profile: validation of self-reported outcome measures for research and practice. BJU Int103: 358—364.
Kim, S.C. and Seo, K.K. (1998) Efficacy andsafety of fluoxetine, sertraline and clomipra- Patterson, W. (1993) Fluoxetine induced sexual dys- mine in patients with premature ejaculation: a function (letter). Clin Psychiatry 54: 71.
double-blind, placebo controlled study. J Urol Pattij, T., Olivier, B. and Waldinger, M.D. (1995) Animal models of ejaculatory behavior. Curr Pharm Laumann, E., Paik, A. and Rosen, R. (1999) Sexual dysfunction in the United States: Prevalence and pre- Pryor, J.L., Althof, S.E., Steidle, C., Rosen, R.C., Hellstrom, W.J.G., Shabsigh, R. et al. (2006) Efficacy Lue, T. and Broderick, G. (2007) Evaluation and tolerability of dapoxetine in treatment of prema- and nonsurgical management of erectile dysfunc- ture ejaculation: an integrated analysis of two double- tion and premature ejaculation, In: Walsh, P., blind, randomised controlled trials. Lancet Retik, A., Vaughan, E., Wein, A., Kavoussi, L., Novick, A. et al. (eds). Campbell-Walsh Urology, Ramanathan, R., Mulhall, J., Rao, S., Leung, R., Vol. 1, Philadelphia, PA: Saunders-Elsevier, Martinez Salamanca, J.I., Mandhani, A. et al. (2007) Predictive correlation between the International Index Marmor, J. (1976) Impotence and ejaculatory distur- of Erectile Function (IIEF) and Sexual Health bances, In: Sadock, B., Kaplan, H. and Freedman, A.
Inventory for Men (SHIM): implications for calculat- (eds). Sexual Experience. Baltimore, MD: The ing a derived SHIM for clinical use. J Sexual Med Williams & Wilkins Co, pp. 407—410.
Reading, A. and West, W. (1984) An analysis of self- Wainberg, J. (1984) Essai d’interpretation ontogene- reported sexual behavior in a sample of normal males.
tique de l’ejaculation prematuree, In: Buvat, J. and Jouaunnet, P. (eds). L’ejaculation et ses perturbances,Simep: Lyon-Villeurbanne, pp. 112—116.
Sadeghi-Nejad, H. and Watson, R. (2008) Continuingmedical education: premature ejaculation: current Waldinger, M., Hengeveld, M., Zwinderman, A. and medical treatment and new directions (CME). J Sexual Olivier, B. (1998) Effect of SSRI antidepressants on ejaculation: a double-blind, randomized, placebo-controlled study with fluoxetine, fluvoxamine, parox- Safarinejad, M.R.M.D. (2007) Safety and efficacy of etine, and sertraline. J Clin Psychopharmacol escitalopram in the treatment of premature ejaculation: a double-blind, placebo-controlled, fixed-dose, ran-domized study. J Clin Psychopharmacol 27: 444—450.
Wainberg, J. (1984) Essai d’interpretation ontogene-tique de l’ejaculation prematuree., In: Buvat, J. and Safarinejad, M.R.M.D. and Hosseini, S.Y.M.D.
Jouaunnet, P., (eds), L’ejaculation et ses perturbances.
(2006) Safety and efficacy of tramadol in the treatment Lyon-Villeurbanne: Simep, pp. 112—116.
of premature ejaculation: a double-blind, placebo-controlled, fixed-dose, randomized study. J Clin Waldinger, M.D. and Olivier, B. (2005) Animal models of premature and retarded ejaculation. World JUrol 23: 115—118.
Salem, E.A., Wilson, S.K., Bissada, N.K., Delk, J.R.,Hellstrom, W.J. and Cleves, M.A. (2008) ORIGINAL Waldinger, M.D. and Schweitzer, D.H. (2006) Changing paradigms from a historical DSM-III Tramadol HCL has promise in on-demand use to treat premature ejaculation. J Sexual Med 5: 188—193.
definition of premature ejaculation. PartII—Proposals for DSM-V and ICD-11. J Sexual Med Schapiro, B. (1943) Premature ejaculation: A review of Waldinger, M.D., Zwinderman, A.H., Olivier, B. and Segraves, R., Saran, A., Segraves, K. and Maguire, E.
Schweitzer, D.H. (2007) The majority of men (1993) Clomipramine versus placebo in the treatment with lifelong premature ejaculation prefer daily of premature ejaculation: a pilot study. J Sex Marital drug treatment: an observation study in a consecutive group of Dutch men. J Sexual Med Semans, J. (1956) Premature ejaculation: a new Wang, W.-F., Wang, Y., Minhas, S. and Ralph, D.J.
Shilon, M., Paz, G. and Homonnai, Z. (1984) The use (2007) Can sildenafil treat primary premature ejacu- of phenoxybenzamine treatment in premature ejacu- lation? A prospective clinical study. Int J Urol Spector, I. and Carey, M. (1990) Incidence and prevalence of the sexual dysfunctions: A critical review International classification of diseases and related of the empirical literature. Arch Sex Behav health problems. Geneva: World Health Organization.
Xin, Z.C., Choi, Y.D., Lee, W.H., Choi, Y.J., Yang, Strassberg, D., Brazao, C.d.G., Rowland, D., Tan, P.
W.J., Choi, H.K. et al. (2000) Penile vibratory thresh- and Slob, A. (1999) Clomipramine in the treatment of old changes with various doses of SS-cream in patients rapid (premature) ejaculation. J Sex Marital Ther with primary premature ejaculation. Yonsei Med J Yuan, Y.M., Xin, Z.C., Jiang, H., Guo, Y.J., Liu, W.J., Symonds, T., Perelman, M.A., Althof, S., Giuliano, F., Martin, M., May, K. et al. (2007) Development and Tian, L. et al. (2004) Sexual function of premature validation of a premature ejaculation diagnostic tool.
ejaculation patients assayed with Chinese Index of Premature Ejaculation. Asian J Androl 6: 121—126.

Source: http://www.entrepatients.net/sites/default/files/pathologies/ejac-precoce-pubmed-2.pdf