Journal Logo

Review article

Management of premature ejaculation

an update

McMahon, Chris G.

Author Information
doi: 10.1097/01.XHA.0000415235.79085.e6
  • Free

Abstract

Introduction

Ejaculatory dysfunction is one of the most common male sexual disorders. The spectrum of ejaculatory dysfunction extends from premature ejaculation (PE), through delayed ejaculation to a complete inability to ejaculate (known as anejaculation), and includes retrograde ejaculation.

The anatomy and physiology of the ejaculatory response

The ejaculatory reflex comprises sensory receptors and areas, afferent pathways, cerebral sensory areas, cerebral motor centers, spinal motor centers, and efferent pathways. Neurochemically, this reflex involves a complex interplay between central serotonergic and dopaminergic neurons, with the secondary involvement of cholinergic, adrenergic, oxytocinergic, and γ-aminobutyric acid (GABA) neurons.

On the basis of functional, central, and peripheral mediation, the ejaculatory process is typically subdivided into three phases: emission, ejection (or penile expulsion), and orgasm. Emission consists of contractions of seminal vesicles and the prostate, with the expulsion of sperm and seminal fluid into the posterior urethra, and is mediated by sympathetic nerves (T10–L2). Ejection is mediated by somatic nerves (S2–S4), and involves pulsatile contractions of the bulbocavernosus and pelvic floor muscles together with relaxation of the external urinary sphincter. Ejection also involves a sympathetic spinal cord reflex upon which there is limited voluntary control. The bladder neck closes to prevent retrograde flow; the bulbocavernosus, bulbospongiosus, and other pelvic floor muscles contract rhythmically and the external urinary sphincter relaxes. Intermittent contraction of the urethral sphincter prevents retrograde flow into the proximal urethra 1. Orgasm is the result of cerebral processing of pudendal nerve sensory stimuli resulting from increased pressure in the posterior urethra, sensory stimuli arising from the verumontanum, and contraction of the urethral bulb and accessory sexual organs.

Many neurotransmitters are involved in the control of ejaculation, including dopamine, norepinephrine, serotonin, acetylcholine, oxytocin, GABA, and nitric oxide 2. Of the many studies that have been carried out to examine the role of the brain in the development and mediation of sexual functioning, dopamine and serotonin have emerged as essential neurochemical factors. Whereas dopamine promotes seminal emission/ejaculation through D2 receptors, serotonin is inhibitory. Serotonergic neurons are widely distributed in the brain and the spinal cord and are predominantly found in the brainstem, raphe nuclei, and the reticular formation. Recently, multiple serotonin (5-HT) receptors have been characterized, for example 5-HT1a, 5-HT1b, 5-HT2a, 5-HT2b, etc. 3. The stimulation of the 5-HT2C receptor with 5-HT2C agonists results in a delay of ejaculation in male rats, whereas the stimulation of postsynaptic 5-HT1A receptors results in shortening of ejaculation latency 4, leading to the hypothesis that men with PE may have hyposensitivity of 5-HT2C and/or hypersensitivity of the 5-HT1A receptor 5,6.

Premature ejaculation

Definition of premature ejaculation

There are multiple definitions of PE (Table 1). The first contemporary multivariate evidence-based definition of lifelong premature ejaculation (L-PE) was developed in 2008 by a panel of international experts, convened by the International Society for Sexual Medicine (ISSM), who agreed that the diagnostic criteria necessary to define PE are as follows: time from penetration to ejaculation, inability to delay ejaculation, and negative personal consequences from PE. This panel defined L-PE as a male sexual dysfunction characterized by ‘…ejaculation which always or nearly always occurs prior to or within about one minute of vaginal penetration, the inability to delay ejaculation on all or nearly all vaginal penetrations, and the presence of negative personal consequences, such as distress, bother, frustration and/or the avoidance of sexual intimacy’ 7.

T1-1
Table 1:
Definitions of premature ejaculation

This definition is supported by evidence from several controlled clinical trials that suggest that 80–90% of men with L-PE ejaculate within 60 s and the remaining 10–20% ejaculate within 2 min (Fig. 1) 17,18. The evidence suggests that the multivariate evidence-based ISSM definition of L-PE provides the clinician a discriminating diagnostic tool. The intravaginal ejaculation latency time (IELT) cutoff of about 1 min captures the 90% of men with PE who actively seek treatment and ejaculate within 1 min and also provides the clinician with sufficient flexibility to diagnose PE in the 10% of men seeking treatment for PE who ejaculate within 1–2 min of penetration. If the ISSM definition is used, men who ejaculate in less than 1 min but report adequate control and no personal negative consequences related to their rapid ejaculation do not merit the diagnosis of PE. Similarly, men who have IELTs of 10 min but report poor control, dissatisfaction, and personal negative consequences also fail to meet the criteria for PE.

F1-1
Figure 1:
Intravaginal ejaculation latency time (IELT) measured with a stopwatch in 110 men with lifelong premature ejaculation, of whom 90% ejaculated within 1 min after vaginal penetration, including 80% within 30 s 17.

This definition should form the basis for the diagnosis of L-PE. It is limited to heterosexual men engaging in vaginal intercourse as there are few studies available on PE research in homosexual men or during other forms of sexual expression. The panel concluded that there is insufficient published evidence to propose an evidenced-based definition of acquired premature ejaculation (A-PE) 7. However, recent data suggest that men with A-PE have similar IELT and report similar levels of ejaculatory control and distress, also suggesting the possibility of a single unifying definition of PE 19. Preliminary recommendations of the American Psychiatric Association’s DSM-V committee suggest a definition that parallels the definition adopted recently by the ISSM 20.

Classifications of premature ejaculation

In 1943, Schapiro 21 proposed a distinction of PE into Types A and B. Men with Type B PE have always suffered from a very rapid ejaculation (or short latency), whereas in Type A, the rapid ejaculation develops later in life and is often associated with erectile dysfunction (ED). In 1989, these types were, respectively, referred to as L-PE (primary) and A-PE (secondary) 22. Over the years, other attempts have been made to identify various classifications of PE, including several that have been incorporated into PE definitions (e.g. global vs. situational). In 2006, Waldinger 23 proposed the existence of two additional PE subtypes: natural variable PE and premature-like ejaculatory dysfunction. Support for this new classification is gradually developing 24. In natural variable PE, the ejaculation time is never consistently rapid but merely coincidental and situational. This type of PE should be regarded as a normal variation in sexual performance, characterized by inconsistent and irregular early ejaculation, often with reduced ejaculatory control, and should be treated by reassuring and educating the patients that this pattern of ejaculatory response is normal 25.

Prevalence of premature ejaculation

There is a lack of reliable information on the prevalence of L-PE and A-PE in the general male population. PE has been estimated to occur in 4–39% of men in the general community 26–32, and is often reported as the most common self-reported male sexual disorder 33. There is, however, a substantial disparity between the incidence of PE in epidemiological studies that rely on either patient self-report of PE and/or inconsistent and poorly validated definitions of PE 31,34,35, and that suggested by community-based stopwatch studies of the IELT, the time interval between penetration and ejaculation 36. The latter shows that the distribution of the IELT is positively skewed, with a median IELT of 5.4 min (range, 0.55–44.1 min), decreases with age, and varies between countries, and supports the notion that IELTs of less than 1 min are statistically abnormal compared with men in the general western population (Fig. 2) 36.

F2-1
Figure 2:
Distribution of intravaginal ejaculatory latency time (IELT) values in a random cohort of 491 men with a median IELT of 5.4 min 36.

Prevalence data derived from patient self-report will be appreciably higher than prevalence estimates on the basis of clinician diagnosis utilizing the more conservative ISSM definition of PE. The following studies show the varying prevalence estimates ranging from 30% to 3%. Data from the Global Study of Sexual Attitudes and Behaviors (GSSAB), an international survey investigating the attitudes, behaviors, beliefs, and sexual satisfaction of 27 500 men and women aged 40–80 years, reported the global prevalence of PE (on the basis of participant self-report) to be approximately 30% across all age groups 37,38. Perception of ‘normal’ ejaculatory latency varied by country and differed when assessed either by the patient or their partner 39. A core limitation of the GSSAB survey stems from the fact that the youngest participants were aged 40 years, an age when the incidence of PE might be different from that in younger men 40. In contrast to the GSSAB study, the Premature Ejaculation Prevalence and Attitude Survey found the prevalence of PE among men aged 18–70 years to be 22.7% 32. The actual prevalence of PE is difficult to assess in clinical practice 33.

Etiology of premature ejaculation

Historically, attempts to explain the etiology of PE have included a diverse range of biological and psychological theories. Most of these proposed etiologies are not evidence based and are speculative at best. The determinants of PE are undoubtedly complex and multivariate, with the etiology of L-PE being different from that of A-PE. Our understanding of the neurochemical central control of ejaculation is at best rudimentary, although recent imaging and electrophysiological studies have identified increased and decreased neuronal activity in several brain areas during arousal and ejaculation 41.

Lifelong premature ejaculation

Waldinger 42 hypothesized that lifelong early ejaculation in humans may be explained by either a hyposensitivity of the 5-HT2C and/or a hypersensitivity of the 5-HT1A receptor. Recent studies have suggested that in some men, neurobiological and genetic variations could contribute toward the pathophysiology of L-PE, as defined by the ISSM criteria, and that the condition may be maintained and heightened by psychological/environmental factors 37–39.

Acquired premature ejaculation

A-PE is commonly because of sexual performance anxiety 43, psychological or relationship problems 43, ED 37, and occasionally prostatitis 44, hyperthyroidism 45, or during withdrawal/detoxification from prescribed 46 or recreational drugs 47. The acquired form of PE may be cured by medical and/or psychological treatment of the underlying cause 48.

Premature ejaculation and sexual performance anxiety, psychological, or relationship problems

Psychological theories include the effect of early experience and sexual conditioning, anxiety, sexual technique, the frequency of sexual activity, and psychodynamic explanations 40,41. Anxiety has been reported to be a cause of PE by multiple authors and is entrenched in the folklore of sexual medicine as the most likely cause of PE despite scant empirical research evidence to support any causal role 45,46. Several authors have suggested that anxiety activates the sympathetic nervous system and reduces the ejaculatory threshold as a result of an earlier emission phase of ejaculation 42. Hypoactive sexual desire may lead to PE, because of an unconscious desire to abbreviate unwanted penetration 40. Similarly, diminished sexual desire can be a consequence of chronic and frustrating PE 7. Female sexual dysfunctions (such as anorgasmia, hypoactive sexual desire, sexual aversion, sexual arousal disorders, and sexual pain disorders, such as vaginismus 49) may also be related to A-PE.

Premature ejaculation and comorbid erectile dysfunction

Recent data show that as many as half of men with ED also experience PE 32,37,50. Men with ED may either require higher levels of stimulation to achieve an erection or intentionally ‘rush’ intercourse to prevent early detumescence of a partial erection, resulting in ejaculation with a brief latency 16. This may be compounded by the presence of high levels of performance anxiety related to their ED, which serves to only worsen their prematurity. However, caution should be exercised in the diagnosis of comorbid ED in men with PE as 33.3% of potent men with PE confuse the ability to maintain erections before ejaculation and following ejaculation, record contradictory response/s to some/all questions of the SHIM especially Q3 and Q4, and receive a false-positive SHIM diagnosis of ED 51.

Premature ejaculation and prostate disease

Acute and chronic lower urogenital infection, prostatodynia, or chronic pelvic pain syndrome is associated with ED, PE, and painful ejaculation 37,52. Several studies have reported PE as the main sexual disorder symptom in men with chronic prostatitis or chronic pelvic pain syndrome, with a prevalence of 26–77% 37.

Premature ejaculation and hyperthyroidism

The majority of patients with thyroid hormone disorders experience sexual dysfunction. Studies suggest a significant correlation between PE and suppressed thyroid-stimulating hormone values in a selected population of andrological and sexological patients. The prevalence of PE in men with hyperthyroidism decreased from 50% to 15% after treatment with normalization of the thyroid hormone 37,52,53. Although occult thyroid disease has been reported in the elderly hospitalized population, it is uncommon in the population who present for the treatment of PE, and routine thyroid-stimulating hormone screening is not indicated unless clinically indicated 54.

Prostatic inflammation and chronic bacterial prostatitis have been reported as common findings in men with both L-PE and A-PE 37,53,55,56. The exact pathophysiology of the link between chronic prostatitis, ED, and PE is unknown. It has been hypothesized that prostatic inflammation may result in altered sensation and modulation of the ejaculatory reflex, but evidence is lacking 52,55,57. It has been reported that antibiotic treatment of microbiologically confirmed bacterial prostatitis in men with A-PE resulted in a 2.6-fold increase in IELT and improved ejaculatory control in 83.9% of men 52.

Evaluation of men with a complaint of premature ejaculation

Medical history

Men presenting with self-reported PE should be evaluated by an assessment of the full medical/sexual history, a focused physical examination, inventory assessment of erectile function, and any investigations suggested by these findings. Inclusion of the partner in the management process is important but not mandatory for treatment success. Some patients may not understand why the clinician wishes to include the partner and some partners may be reluctant to join the patient in treatment. However, if partners are not involved in treatment, they may be resistant to changing the sexual interaction 58. A cooperative partner can enhance the man’s self-confidence, skills, self-esteem, sense of masculinity, and more generally help the man develop ejaculatory control 55. This is, in turn, likely to lead to an improvement in the couple’s sexual relationship as well as the broader aspects of their relationship. There are no controlled studies on the impact of involving partners in the treatment of PE. However, a review of treatment studies for ED has shown the important role of including a focus on interpersonal factors in treatment success 57.

Patients expect clinicians to enquire about their sexual health 56. Often, patients are too embarrassed and shy, and they are uncertain whether sexual complaints can be discussed in the health care professional’s office 59. Enquiry into sexual health requires patients’ permission to discuss their sexual concerns and also screens for associated health risks (e.g. cardiovascular risk and ED). Table 2 lists the recommended and optional questions that patients with a complaint of PE should be asked 60,61. The recommended questions establish the diagnosis and direct treatment considerations and the optional questions gather details for initiating treatment. Finally, the committee recommends that the health care professionals carry out an assessment of medical and psychosocial history.

T2-1
Table 2:
Recommended and optional questions to establish the diagnosis of premature ejaculation and direct treatment 60

Diagnosis of premature ejaculation

The ISSM definition of L-PE should form the basis for the diagnosis of L-PE. Although there is no evidenced-based definition of A-PE, its dimensions closely parallel those of L-PE, suggesting that that the ISSM definition of L-PE may serve as a surrogate definition of A-PE 19. However, the patient’s report of a substantial difference between premorbid and current IELT should also be considered in the diagnosis of A-PE in men with an IELT greater than 2 min.

A significant population of men with self-reported PE fail to fulfill the criteria of the ISSM definition of L-PE. This parallels the substantial disparity between the self-reported incidence of PE in epidemiological studies 31 and that suggested by community-based normative stopwatch IELT studies 36. This population has recently been categorized as suffering from either natural variable PE or a premature-like ejaculatory dysfunction 23,61. Men with premature-like ejaculatory dysfunction complain of PE but have a normal ejaculatory latency typically of 2–6 min, but on some occasions, as long as 25 min. It is characterized by a preoccupation with a subjective but false perception of PE, with an ejaculation latency time within the normal range but often with reduced ejaculatory control.

Determination of intravaginal ejaculation latency time

Self-estimation of ejaculatory latency by the patient and the partner should be used to determine IELT in clinical practice. Stopwatch measures of IELT are widely used in clinical trials and observational studies of PE, but have not been recommended for use in routine clinical management of PE. Despite the potential advantage of objective measurement, stopwatch measures have the disadvantage of being intrusive and potentially disruptive of sexual pleasure or spontaneity. More recently, studies have indicated that patient or partner self-reports of ejaculatory latency correlate relatively well with objective stopwatch latency and might be useful as a proxy measure of IELT 62–65. As patient self-report is the determining factor in treatment seeking and satisfaction, it is recommended that self-estimation of ejaculatory latency by the patient and the partner are accepted as the method for determining IELT in clinical practice.

Patient-reported outcome measures

Standardized assessment measures such as validated questionnaires and patient-reported outcome (PRO) measures can be used as an adjunct to a full medical/sexual history and self-estimation of ejaculatory latency in the evaluation of men presenting with self-reported PE. These measures are all relatively new and were developed primarily for use as research tools. Some have shown good psychometric properties and are potentially valuable adjuncts for clinical screening and assessment.

Several PE measures have been described in the literature 66–72, although only a small number have undergone extensive psychometric testing and validation. Five validated questionnaires have been developed and published to date. Currently, there are two questionnaires that have extensive databases and fulfill most of the criteria for test development and validation: the Premature Ejaculation Profile (PEP) and the Index of Premature Ejaculation (IPE) 66,68. A third brief diagnostic measure, the Premature Ejaculation Diagnostic Tool, has also been developed, which has a modest database, and is available for clinical use 70. Two other measures, the Arabic and Chinese PE questionnaires, have minimal validation or clinical trial data available and are not recommended for clinical use.

Premature Ejaculation Profile

A four-item, self-report measure of PE has been developed by Patrick et al.68. The PEP includes single-item constructs of (a) perceived control over ejaculation; (b) satisfaction with sexual intercourse; (c) personal distress related to ejaculation; (d) interpersonal difficulty related to ejaculation; and (e) an index or total score. Each of the four individual items is assessed on a five-point scale, which are averaged to yield an index PE score. The measure has been used in observational studies and clinical trials of PE 34. It has also been recommended for clinical use to evaluate the subjective components of the disorder. Validation studies have been performed in comparison with stopwatch measures of intravaginal latency and other PRO measures of sexual function and distress 34,68. The scale has adequate test–retest reliability (total scale=0.80) and moderate to strong correlations with stopwatch-measured IELT. A major limitation of the scale is the lack of validated cutoff scores, which makes it less suitable for use as a diagnostic or a clinical screening tool. On the positive side, it is very brief and easy to administer and may be valuable for use in a clinical setting as a measure of treatment responsiveness.

Index of Premature Ejaculation

The IPE was developed by Althof et al.66. It is a 10-item self-administered questionnaire designed to evaluate sexual satisfaction, control, and distress in men with PE. It was developed using four stages: item pool development, initial psychometric analyses, patient interviews, and final psychometric analyses. The IPE contains three factor analytically derived domains: control, sexual satisfaction, and distress. All three domains have shown adequate internal consistency and reliability, as well as known group validity in comparing men with and without PE. Convergent validity against IELT was also strong for all three domains [control (r=0.75); sexual satisfaction (r=0.60); and distress (r=0.68)].

The IPE also has the advantage of being relatively brief and easy to administer, although the measure is not as brief as the PEP above. It also assesses clinically relevant domains and has adequate known group validity data. However, similar to the PEP, it lacks norms and diagnostic cutoffs, and has limited value as a diagnostic or a screening measure for PE.

Premature Ejaculation Diagnostic Tool

The previous two measures (PEP, IPE) are available for use as treatment change or outcome measures of PE treatment. The Premature Ejaculation Diagnostic Tool, in contrast, was developed specifically for use as a screening questionnaire 69,70,72. This questionnaire is a brief, five-item measure used to screen men for the potential presence of PE on the basis of the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision criteria of lack of control, frequency, minimal stimulation, distress, and interpersonal difficulty.

Depending on the specific need, the PEP and IPE are currently the preferred questionnaire measures for assessing PE, particularly when monitoring responsiveness to treatment. Overall, these measures may serve as useful adjuncts, but should not substitute for assessment of a detailed sexual history by a qualified clinician.

Assessment of erectile function

The presence of comorbid ED should be evaluated using a validated instrument such as the International Index of Erectile Function (IIEF) or the IIEF-5 (SHIM). Normal erectile function should be defined as an IIEF EF Domain ≥26 or IIEF-5>21 73,74. Recent data have shown that as many as half of men with ED also experience PE 33,48,49. In the European Premature Ejaculation Study (PEPA), ED was present in 31.9% of men with PE compared with 11.8% of non-PE men 32. In the GSSAB, the odds ratio for ED in men with PE ranged from 6.0 in Europe to as high as 11.9 in South America 37. Consistent with this, ED is more prevalent in men with A-PE than L-PE 75. PE is also more common with increasing severity of ED after adjustment for age 76–78. Men with ED may either require higher levels of stimulation to achieve an erection or intentionally ‘rush’ intercourse to prevent early detumescence of a partial erection, resulting in ejaculation with a brief latency 16. This may be compounded by the presence of high levels of performance anxiety related to their ED, which serves to only worsen their prematurity. However, caution should be exercised in the diagnosis of comorbid ED in men with PE as 33.3% of potent men with PE confuse the ability to maintain erections before ejaculation and following ejaculation, record contradictory response/s to some/all questions of the SHIM, especially Q3 and Q4, and receive a false-positive SHIM diagnosis of ED 51.

Physical examination

The current literature suggests that the diagnosis of L-PE is made purely on the basis of the medical history as there are no predictive physical findings or confirmatory investigations 79. As the differentiation of L-PE and A-PE may be difficult in either young men or men with none or few previous sexual partners and/or limited sexual experience, a physical examination is highly desirable and represents an opportunity for screening for cardiovascular or sex-specific diseases. However, in men with A-PE, a physical examination is mandatory to identify the etiology of the PE and to alleviate its possible cause 80. The presence of ED should be evaluated either by assessment of medical history or with the use of a validated instrument. Laboratory or imaging investigations are occasionally required on the basis of the patient’s medical history. A digital prostate examination, routine in an andrological setting for all men older than 40 years of age, is useful in the identification of possible evidence of prostatic inflammation or infection 81. Figure 3 shows a flow chart for the management of PE 37.

F3-1
Figure 3:
Management algorithm for PE 37. IELT, intravaginal ejaculatory latency time; PE, premature ejaculation; PRO, patient-reported outcome.

Treatment of premature ejaculation

There are multiple psychosexual and pharmacological treatments for PE. Men with L-PE are best managed with PE pharmacotherapy alone or in combination with graded levels of patient and couple psychotherapy. Men with A-PE should receive etiology-specific treatment, for example psychosexual counseling or ED pharmacotherapy, alone or in combination with PE pharmacotherapy. Men with natural variable PE or PE-like ejaculatory dysfunction should be primarily treated with psychosexual education and graded patient and couple psychotherapy.

Psychosexual therapy

All men seeking treatment for PE should receive basic psychosexual education or coaching 82–85. This may include providing information on the prevalence of PE, and the IELT in the general population, to dispel myths about PE, information on enjoyable sexual activities to extend the man and his partner’s sexual repertoire, as well as strategies to address avoidance of sexual activity or unwillingness to discuss sex with his partner. These educational strategies are designed to provide the man with the confidence to try the medical intervention, reduce performance anxiety, and modify his maladaptive sexual scripts.

Graded levels of patient and couple counseling, guidance and/or relationship therapy, either alone or ideally in combination with PE pharmacotherapy, should be offered as a treatment option for most men with PE. PE places a significant psychological burden on men, their partners, the male/partner relationship, and their overall relationship 85–87. Men with PE show other negative effects, including a general negative affect associated with sexual situations, and more intense feelings of embarrassment/guilt, worry/tension, and fear of failure 88,89. Sufferers indicate decreased self-confidence, increased distress and interpersonal difficulty, and mental preoccupation with their condition 34,43. As partner satisfaction may play a greater role in PE than ED, it is not surprising that relationship dysfunction is reported as the second most common negative effect of PE 43,86. Not only is PE associated with marital discord 87, but the insecurity of men with PE about satisfying the partner may also be an obstacle to initiating and maintaining new relationships 86,88.

Until recently, treatment options have been limited to behavioral and psychological procedures. Psychological factors such as anxiety and negative affect have frequently been associated with sexual dysfunctions such as PE 89,90 and treatment addressing such issues has represented a logical approach. Psychological-behavioral strategies for treating PE have been at least moderately successful in alleviating the dysfunction in the short term 91–95.

Psychological interventions are designed to achieve more than just an increase in the IELT. Targeted factors focus on the man, his partner, and their relationship. Psychotherapy and behavioral interventions help improve ejaculatory control by helping men/couples to: (a) learn techniques to control and/or delay ejaculation, (b) gain confidence in their sexual performance, (c) lessen performance anxiety, (d) modify rigid sexual repertoires, (e) overcome barriers to intimacy, (f) resolve interpersonal issues that precipitate and maintain the dysfunction, (g) increase communication 96,97, and (h) come to terms with the feelings/thoughts that interfere with sexual function.

Present-day psychotherapy for PE most often represents an integration of behavioral (e.g. the well-known start–stop and pause–squeeze methods) and cognitive approaches within a short-term psychotherapy model 98–107. The guiding principles of treatment are to learn to control ejaculation while understanding the meaning of the symptom and the context in which it occurs.

Although the new and often more expedient pharmacological therapies are overshadowing traditional psychological-behavioral methods in the treatment of PE, the psychological-behavioral approach remains an attractive option for several reasons. The treatment is specific to the problem, is neither harmful nor painful, is less dependent on the man’s medical history, produces minimal or no adverse side effects, and encourages open communication about sexuality in the couple, which is likely to lead to a more satisfying sexual relationship 108,109. Once the techniques have been learned and incorporated into intercourse, PE men continue to have access to strategies that help them control their ejaculation. At the same time, there are drawbacks to the psychological-behavioral approach: it is time consuming, often requires substantial resources of both time and money, lacks immediacy, requires the partner’s cooperation, and has mixed (and less well documented) efficacy 99,100. Furthermore, data to support long-term efficacy are lacking 110,111.

A combination of a medical and a psychological approach may be especially useful in men with A-PE, where there is a clear psychosocial precipitant, or L-PE, where the individual or the couple’s responses to PE are likely to interfere with the medical treatment and with the ultimate success of therapy. Similarly, in men with PE and comorbid ED, combination therapy may also aid management of the psychosocial aspects of these sexual dysfunctions. Once the man’s self-confidence and sense of control have improved, it may then be possible to reduce or discontinue the medical intervention 18.

Pharmacotherapy

On-demand dapoxetine, off-label daily dosing of paroxetine, sertraline, citalopram, fluoxetine, or clomipramine, and off-label on-demand dosing of clomipramine and/or off-label on-demand topical anesthetics, either alone or in combination with psychosexual counseling, are regarded as first-line treatments for L-PE.

In 1943, Schapiro 21 described the use of a topical anesthetic ointment to delay ejaculation. The use of anesthetics to reduce the sensitivity of the glans penis is probably the oldest known form of treating PE. In 1973, the first report of successful ejaculation delay by clomipramine was published 112. However, in the 1970s and the 1980s, drug treatment of PE was not used extensively. The introduction of the serotonergic tricyclic clomipramine and the selective serotonin reuptake inhibitors (SSRIs) paroxetine, sertraline, fluoxetine, and citalopram has revolutionized the approach to and treatment of PE. These drugs block axonal reuptake of serotonin from the synaptic cleft of central and peripheral serotonergic neurons by 5-HT transporters, resulting in enhanced 5-HT neurotransmission and stimulation of postsynaptic membrane 5-HT2C receptors. Although the methodology of the initial drug treatment studies was poor, later double-blind and placebo-controlled studies confirmed the ejaculation-delaying effect of clomipramine and SSRIs.

Daily treatment with off-label selective serotonin reuptake inhibitors

Daily treatment with paroxetine 10–40 mg, clomipramine 12.5–50 mg, sertraline 50–200 mg, fluoxetine 20–40 mg, and citalopram 20–40 mg is usually effective in delaying ejaculation (Fig. 4) 98–100,113–115. A meta-analysis of published data suggests that paroxetine induces the strongest ejaculation delay, increasing IELT approximately 8.8-fold over the baseline 114. However, the use of these drugs is limited by the lack of approval from the Food and Drug Administration (FDA) and European Medicines Agency (EMEA), and therefore by the need to be prescribed ‘off-label’ 116.

F4-1
Figure 4:
Selective serotonin reuptake inhibitors produce ejaculatory delay within 5–10 days 113.

Ejaculation delay usually occurs within 5–10 days of starting treatment, but the complete therapeutic effect may require 2–3 weeks of treatment and is usually sustained with long-term use (Fig. 4) 18. Although tachyphylaxis is uncommon, some patients report a reduced response after 6–12 months of treatment. Men treated with PE pharmacotherapy should be informed about the potential adverse effects and the risk of withdrawal syndrome, advised to increase the frequency of intercourse, and reviewed after 4–6 weeks of treatment and thereafter as determined by the physician.

The adverse effects of daily SSRIs are usually minor, start in the first week of treatment, gradually disappear within 2–3 weeks, and include fatigue, yawning, mild nausea, diarrhea, or perspiration. Hypoactive desire and ED are infrequently reported and appear to have a lower incidence in nondepressed PE men compared with depressed men treated with SSRIs 23. This effect may be related to the protective action of increased oxytocin release in men with L-PE 5.

Neurocognitive adverse effects include significant agitation and hypomania in a small number of patients, and treatment with SSRIs should be avoided in men with a history of bipolar depression 107. Systematic analysis of randomized-controlled studies indicates no statistical evidence of an increased risk of suicide with SSRIs in adults 110,111. However, an FDA meta-analysis of all pediatric randomized clinical trials of antidepressants suggested a small increase in the risk of suicidal ideation or suicide attempts in youth 111. This effect is quite variable across SSRIs and it is not clear whether this variance is a measurement error or represents a real difference between medications. Furthermore, systematic questionnaire data, epidemiological and autopsy studies, recent cohort surveys, and the negligible number of suicides that occur in youth taking antidepressants at the time of death do not support the hypothesis that SSRIs induce suicidal acts and suicide, raising concerns over ascertainment artifacts in the adverse event report method 110. However, it would seem prudent to not prescribe SSRIs to young men aged 18 years or younger, and to men with a depressive disorder, particularly when associated with suicidal thoughts. Patients should be advised to avoid sudden cessation or rapid dose reduction of SSRIs, which may be associated with an SSRI Withdrawal Syndrome, characterized by dizziness, headache, nausea, vomiting, and diarrhea and occasionally agitation, impaired concentration, vivid dreams, depersonalization, irritability, and suicidal ideation 117,118.

Platelet serotonin release plays an important role in hemostasis 101 and SSRIs, especially with the concurrent use of aspirin and nonsteroidal anti-inflammatory drugs, and may be associated with an increased risk of upper gastrointestinal bleeding 119,120. Priapism is a rare adverse effect of SSRIs and requires urgent medical treatment 121–123. Long-term SSRI use may be associated with weight gain and an increased risk of type-2 diabetes mellitus 102. In a significant proportion of men with normal semen parameters, paroxetine has been reported to induce abnormal sperm DNA fragmentation, without a measurable effect on semen parameters. The fertility potential of a substantial number of men on paroxetine may be adversely affected by these changes in sperm DNA integrity 103.

On-demand treatment with off-label selective serotonin reuptake inhibitors

The administration of clomipramine, paroxetine, sertraline, and fluoxetine 4–6 h before intercourse is modestly efficacious and well tolerated, but is associated with substantially less ejaculatory delay than daily treatment 104–107. Following acute on-demand administration of an SSRI, increased synaptic 5-HT levels are downregulated by presynaptic 5-HT1A and 5-HT1B/1D autoreceptors to prevent overstimulation of postsynaptic 5-HT2C receptors. However, during chronic daily administration of SSRI, a series of synaptic adaptive processes, which may include presynaptic 5-HT1A and 5-HT1B/1D receptor desensitization, markedly enhances synaptic 5-HT levels, resulting in superior fold increases in IELT compared with on-demand administration 124. On-demand treatment may be combined with either an initial trial of daily treatment or a concomitant low-dose daily treatment 104–106.

On-demand treatment with dapoxetine

Dapoxetine is the first compound specifically developed for the treatment of PE. Dapoxetine is a potent SSRI (pKi=8 nmol/l), structurally similar to fluoxetine, with a pharmacokinetic profile suggesting a role as an on-demand treatment modality for PE 125. Dapoxetine has a Tmax of 1.4–2.0 h and a terminal half-life of 19 h, with a rapid decrease in plasma levels to about 5% of Cmax at 24 h, ensuring rapid absorption and achievement of peak plasma concentration with minimal accumulation 126. Both plasma concentration and area under the curve are dose dependent up to 100 mg, and are unaffected by repeated daily dosing, food, or alcohol 127–129. Food and ethanol do not exert a clinically significant effect on dapoxetine pharmacokinetics 130. No drug–drug interactions associated with dapoxetine, including phosphodiesterase inhibitor drugs, have been reported 131.

Dapoxetine is extensively metabolized in the liver by multiple isozymes to multiple metabolites, including desmethyldapoxetine, didesmethyldapoxetine, and dapoxetine-N-oxide, which are eliminated primarily in the urine 126,132. Although didesmethyldapoxetine is equipotent to the parent dapoxetine, its substantially lower plasma concentration, compared with dapoxetine, limits its pharmacological activity and it exerts little clinical effect, except when dapoxetine is coadministered with CYP3A4 or CYP2D6 inhibitors. Coadministration of dapoxetine and potent CYP3A4 such as ketoconazole is contraindicated. Caution should be exercised in the coadministration of dapoxetine and moderate CYP3A4 inhibitors and potent CYP2D6 inhibitors such as fluoxetine.

The results of two phase 2 and five phase 3 trials have been published (Table 3) 139–144. The five randomized, placebo-controlled, phase 3 clinical trials included 6 081 men, mean age 40.6 years (range, 18–82 years), from 32 countries. An analysis of pooled phase 3 data confirmed that dapoxetine 30 and 60 mg increased IELT and improved PROs of control, ejaculation-related distress, interpersonal distress, and sexual satisfaction, compared with placebo. Efficacy results were similar among each of the individual trials and for a pooled analysis, indicating that dapoxetine is consistently more efficacious than placebo irrespective of an individual’s demographic characteristics.

T3-1
Table 3:
Results of dapoxetine phase 2 and 3 studies 133–138

Across trials, dapoxetine 30 and 60 mg were well tolerated, with a low incidence of severe adverse effects 139–144. The most frequently reported adverse effects were nausea, diarrhea, headache, dizziness, insomnia, somnolence, fatigue, and nasopharyngitis. Unlike other SSRIs used to treat depression, which have been associated with high incidences of sexual dysfunction in depressed patients 145,146, dapoxetine was associated with low rates of sexual dysfunction in men with PE. Finally, dapoxetine had no effect on mood, and was not associated with anxiety, akathisia, suicidality, or withdrawal syndrome 144.

The criteria for the ideal PE drug remain controversial. However, many men may prefer the convenience of ‘on-demand’ dosing of dapoxetine compared with daily dosing. Men who infrequently engage in sexual intercourse may prefer on-demand treatment, whereas men in established relationships may prefer the convenience of daily medication. Well-designed preference trials will provide additional detailed insights into the role of on-demand dosing.

The assertion that on-demand drug treatment of PE is preferable to daily dosing parallels the rationale for the treatment of ED, but is in contrast to the results of the only PE drug preference study 147. The methodology of this trial was not ideal as it involved comparison of preference for daily paroxetine, on-demand clomipramine or a topical anesthetic only on the basis of participant information/questionnaires and not on the actual use of the drug/s. Well-designed preference trials will provide additional detailed insights into the role of on-demand dosing.

Off-label topical anesthetics

The use of topical local anesthetics such as lidocaine and/or prilocaine as a cream, gel, or spray is well established and is moderately effective in retarding ejaculation. A recent study has reported that a metered-dose aerosol spray containing a eutectic mixture of lidocaine and prilocaine (TEMPE, Plethora, UK) produced a 2.4-fold increase in baseline IELT and significant improvements in ejaculatory control and both patient and partner sexual quality of life 148,149. The use of topical anesthetics may be associated with significant penile hypoanesthesia and possible transvaginal absorption, resulting in vaginal numbness and resultant female anorgasmia unless a condom is used 150–152.

Daily treatment with off-label 1-adrenoceptor antagonists

Ejaculation is a sympathetic spinal cord reflex that could theoretically be delayed by α1-adrenergic blockers. Several researchers have reported their experience with the selective α1-adrenergic blockers, alfuzosin and terazosin, in the treatment of PE. Both drugs have been approved only for the treatment of lower urinary tract symptoms in men with obstructive benign prostatic hyperplasia. In a double-blind placebo-controlled study, Cavallini 153 reported that both alfuzosin (6 mg/day) and terazosin (5 mg/day) were effective in delaying ejaculation in approximately 50% of the cases. Similarly, Basar et al. 154 reported that terazosin was effective in 67% of men. However, both studies were limited by the use of subjective study endpoints of patient impression of change and sexual satisfaction, and they did not evaluate actual ejaculatory latency. Additional controlled studies are required to determine the role of α1-blockers in the treatment of PE.

On-demand treatment with off-label tramadol

Tramadol is a centrally acting synthetic opioid analgesic with an unclear mode of action that is believed to include binding of parent and M1 metabolite to μ-opioid receptors and weak inhibition of reuptake of GABA, norepinephrine, and serotonin 155. The efficacy of on-demand tramadol in the treatment of PE has been reported recently (Table 4) 117–119,156. Most studies are poorly designed open-label trials with a wide range of efficacy. The only double-blind, well-designed study showed a superiority to placebo but a mediocre fold increase in IELT of 2.49, consistent with the weak SSRI activity of tramadol 119. The unclear safety profile and the potential for addiction discourage the use of tramadol in PE clinical practice.

T4-1
Table 4:
Results of tramadol studies 11–15

Intracavernous injection of off-label vasoactive drugs

Intracavernous self-injection treatment of PE has been reported but is currently without any evidence-based support for efficacy or safety 120.

Off-label daily dosing of α1-adrenoceptor antagonists, tramadol, and penile injection therapy are not currently recommended for the treatment of PE.

Phosphodiesterase type-5 inhibitors

Off-label on-demand or daily dosing of PDE-5 inhibitors is not recommended for the treatment of L-PE in men with normal erectile function. ED pharmacotherapy alone or in combination with PE pharmacotherapy is recommended for the treatment of L-PE or A-PE in men with comorbid ED. Phosphodiesterase type-5 isoenzyme (PDE-5) inhibitors, sildenafil, tadalafil, and vardenafil, are effective treatments for ED. Several authors have reported experiences with PDE-5 inhibitors alone or in combination with SSRIs as a treatment for PE 121–123,127–129,133,134,158–168. The putative role of PDE-5 inhibitors as a treatment for PE is speculative and based only on the role of the nitric oxide/cGMP transduction system as a central and peripheral mediator of inhibitory nonadrenergic, noncholinergic nitrergic neurotransmission in the urogenital system 135. Although systematic reviews of studies on the PDE-5i drug treatment of PE have failed to provide robust empirical evidence to support a role of PDE-5i in the treatment of PE, with the exception of men with PE and comorbid ED 136,137, recent well-designed studies do support a potential role for these agents, suggesting a need for further evidence-based research 168.

Surgery

Selective dorsal nerve neurotomy or hyaluronic acid gel glans penis augmentation is not recommended for the treatment of PE. Surgery may be associated with permanent loss of sexual function and is contraindicated in the management of PE. Several authors have reported the use of surgically induced penile hypoanesthesia through selective dorsal nerve neurotomy or hyaluronic acid gel glans penis augmentation in the treatment of L-PE refractory to behavioral and/or pharmacological treatment 138,145,146. The role of surgery in the management of PE remains unclear until the results of further studies have been reported.

Assessment of treatment outcome

Clinical Global Impression of Change (CGIC) measures have high utility in clinical practice. Response to treatment is best assessed with the use of a simple, brief, and validated question known as the CGIC. It asks patients, ‘Compared to before starting treatment, would you describe your premature ejaculation problem as: much worse, worse, slightly worse, no change, slightly better, better, or much better?’. The CGIC allows patients to evaluate their treatment response overall by self-interpretation of changes in ejaculatory latency, control, negative psychological consequences, sexual satisfaction, and partner response. Higher CGIC ratings are correlated with greater improvement in latency, control, and satisfaction, and with greater reduction in distress and interpersonal difficulty. The CGIC can provide clinicians in practice with a valid and brief outcome assessment of their patient’s condition 169.

There is currently no published literature that identifies a meaningful and clinically significant threshold response to intervention. Statistical superiority to baseline or placebo outcome measures does not always imply a clinically significant response. The threshold response to intervention can be identified by either a threshold IELT fold increase or a composite PRO responder definition. The point at which the IELT fold increase achieved by intervention is associated with a significant reduction in personal distress probably represents a measure of intervention success. These data are currently not available but the author’s anecdotal impression, derived from the treatment of patients, suggests that a 3–4-fold increase in IELT represents the threshold of intervention success, with higher fold increases indicating improving intervention success. On the basis of a post-hoc path analysis of IELT and PRO data from the US observational trial, a composite PRO responder definition of at least two-category increase in control and a one-category decrease in personal distress from baseline (0–5 categorical scale) was developed and used as an efficacy outcome measure in a Phase III Asia Pacific dapoxetine trial 34,150–152.

Conclusion

Recent epidemiological and observational research has provided new insights into PE and the associated negative psychosocial effects of this dysfunction. Recent normative data suggest that 80–90% of treatment-seeking men with L-PE will ejaculate within 1 min and form the basis of the ISSM definition of L-PE. Although there is insufficient empirical evidence to clearly identify the etiology of PE, there is limited evidence to suggest that men with PE may have a genetic predisposition toward rapid ejaculation, high levels of sexual anxiety, and comorbid ED.

The use of dapoxetine and off-label SSRIs, clomipramine, and topical anesthetics has drawn new attention to this common and often ignored sexual problem. PE pharmacotherapy fails to directly completely address causal psychological or relationship factors, and data are either lacking or scarce on the efficacy of combined psychosexual counseling and pharmacological treatment, and the maintenance of improved ejaculatory control after drug withdrawal.

Acknowledgements

Conflicts of interest

Chris G. McMahon is an investigator, member of an advisory board and speaker’s panel for Janssen-Cilag and Bayer Schering.

References

1. Yeates WPryor JP, Lipschultz L. Ejaculatory disturbances. Andrology. 1987 London Butterworths:183
2. McMahon CG, Abdo C, Incrocci L, Perelman M, Rowland D, Waldinger M, Xin ZC. Disorders of orgasm and ejaculation in men. J Sex Med. 2004;1:58–65
3. Peroutka SJ, Snyder SH. Multiple serotonin receptors: differential binding of [3H]5-hydroxytryptamine, [3H]lysergic acid diethylamide and [3H]spiroperidol. Mol Pharmacol. 1979;16:687–699
4. Ahlenius SLK, Svensson L, Hjorth S, Carlsson A, Lindberg P, Wikström H, et al. Effects of a new type of 5-HT receptor agonist on male rat sexual behavior. Pharmacol Biochem Behav. 1981;15:785–792
5. Waldinger MD. The neurobiological approach to premature ejaculation. J Urol. 2002;168:2359–2367
6. Waldinger MD, Olivier B. Animal models of premature and retarded ejaculation. World J Urol. 2005;23:115–118
7. McMahon CG, Althof SE, Waldinger MD, Porst H, Dean J, Sharlip ID, et al. An evidence-based definition of lifelong premature ejaculation: report of the International Society for Sexual Medicine (ISSM) ad hoc committee for the definition of premature ejaculation. J Sex Med. 2008;5:1590–1606
8. Diagnostic and statistical manual of mental disorders, DSM-IV-TR. 20004th ed. Revised. Washington DC American Psychiatric Association
9. International classification of diseases and related health problems. 199410th ed. Geneva World Health Organization
    10. Hatzimouratidis K, Amar E, Eardley I, Giuliano F, Hatzichristou D, Montorsi F, et al. Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. Eur Urol. 2010;57:804–814
      11. McMahon CG, Abdo C, Incrocci I, Perelman M, Rowland D, Stuckey B, et al.Lue TF, Basson R, Rosen R, Giuliano F, Khoury S, Montorsi F Disorders of orgasm and ejaculation in men. Sexual medicine: sexual dysfunctions in men and women (2nd International Consultation on Sexual Dysfunctions-Paris). 2004 Paris France Health Publications:409–468
        12. Montague DK, Jarow J, Broderick GA. AUA guideline on the pharmacologic management of premature ejaculation. J Urol. 2004;172:290–294
          13. Metz M, McCarthy B Coping with premature ejaculation: how to overcome PE, please your partner and have great sex. 2003 Oakland, CA New Harbinber Publications
            14. Masters WH, Johnson VE Human sexual inadequacy. 1970 Boston Little Brown
              15. Waldinger MD, Zwinderman AH, Olivier B, Schweitzer DH. Proposal for a definition of lifelong premature ejaculation based on epidemiological stopwatch data. J Sex Med. 2005;2:498–507
                16. Jannini EA, Lombardo F, Lenzi A. Correlation between ejaculatory and erectile dysfunction. Int J Androl. 2005;28(Suppl 2):40–45
                17. Waldinger M, Hengeveld M, Zwinderman A, Olivier B. An empirical operationalization of DSM-IV diagnostic criteria for premature ejaculation. Int J Psychiatry Clin Pract. 1998;2:287–293
                18. McMahon CG. Long term results of treatment of premature ejaculation with selective serotonin re-uptake inhibitors. Int J Impot Res. 2002;14:S19
                19. Porst H, McMahon CG, Althof SE, Sharlip I, Bull S, Aquilina JW, et al. Baseline characteristics and treatment outcomes for men with acquired or lifelong premature ejaculation with mild or no erectile dysfunction: integrated analyses of two phase 3 dapoxetine trials. J Sex Med. 2010;7:2231–2242
                20. Segraves RT. Considerations for an evidence-based definition of premature ejaculation in the DSM-V. J Sex Med. 2010;7:672–679
                21. Schapiro B. Premature ejaculation, a review of 1130 cases. J Urol. 1943;50:374–379
                22. Godpodinoff ML. Premature ejaculation: clinical subgroups and etiology. J Sex Marital Ther. 1989;15:130–134
                23. Waldinger MD. Premature ejaculation: definition and drug treatment. Drugs. 2007;67:547–568
                24. Serefoglu EC, Cimen HI, Atmaca AF, Balbay MD. The distribution of patients who seek treatment for the complaint of ejaculating prematurely according to the four premature ejaculation syndromes. J Sex Med. 2009;7:810–815
                25. Waldinger MD, Schweitzer DH. Changing paradigms from a historical DSM-III and DSM-IV view toward an evidence-based definition of premature ejaculation. Part II – proposals for DSM-V and ICD-11. J Sex Med. 2006;3:693–705
                26. Reading A, Wiest W. An analysis of self-reported sexual behavior in a sample of normal males. Arch Sex Behav. 1984;13:69–83
                27. Nathan SG. The epidemiology of the DSM-III psychosexual dysfunctions. J Sex Marital Ther. 1986;12:267–281
                28. Spector KR, Boyle M. The prevalence and perceived aetiology of male sexual problems in a non-clinical sample. Br J Med Psychol. 1986;59:351–358
                29. Spector IP, Carey M. Incidence and prevalence of the sexual dysfunctions: a critical review of the empirical literature. Arch Sex Behav. 1990;19:389
                30. Grenier G, Byers ES. The relationships among ejaculatory control, ejaculatory latency, and attempts to prolong heterosexual intercourse. Arch Sex Behav. 1997;26:27–47
                31. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA. 1999;281:537–544
                32. Porst H, Montorsi F, Rosen RC, Gaynor L, Grupe S, Alexander J. The Premature Ejaculation Prevalence and Attitudes (PEPA) survey: prevalence, comorbidities, and professional help-seeking. Eur Urol. 2007;51:816–823
                33. Jannini EA, Lenzi A. Epidemiology of premature ejaculation. Curr Opin Urol. 2005;15:399–403
                34. Patrick DL, Althof SE, Pryor JL, Rosen R, Rowland DL, Ho KF, et al. Premature ejaculation: an observational study of men and their partners. J Sex Med. 2005;2:358–367
                35. Giuliano F, Patrick DL, Porst H, La Pera G, Kokoszka A, Merchant S, et al. Premature ejaculation: results from a five-country European observational study. Eur Urol. 2008;53:1048–1057
                36. Waldinger MD, Quinn P, Dilleen M, Mundayat R, Schweitzer DH, Boolell M. A Multinational population survey of intravaginal ejaculation latency time. J Sex Med. 2005;2:492–497
                37. Laumann EO, Nicolosi A, Glasser DB, Paik A, Gingell C, Moreira E, Wang T. Sexual problems among women and men aged 40-80 y: prevalence and correlates identified in the Global Study of Sexual Attitudes and Behaviors. Int J Impot Res. 2005;17:39–57
                38. Nicolosi A, Laumann E, Glaser D, Moreira E, Paik A, Gingell C. Global Study of Sexual Attitudes and Behaviors investigator’s group. Sexual behavior and sexual dysfunctions after age 40: the global study of sexual attitudes and behaviors. Urology. 2004;64:991–997
                39. Montorsi F. Prevalence of premature ejaculation: a global and regional perspective. J Sex Med. 2005;2(Suppl 2):96–102
                40. Jannini E, Lenzi A. Epidemiology of premature ejaculation. Curr Opin Urol. 2005;15:399–403
                41. Hyun JS, Kam SC, Kwon OY. Changes of cerebral current source by audiovisual erotic stimuli in premature ejaculation patients. J Sex Med. 2008;5:1474–1481
                42. Waldinger M. The neurobiological approach to premature ejaculation. J Urol. 1998;168:2359–2367
                43. Hartmann U, Schedlowski M, Kruger TH. Cognitive and partner-related factors in rapid ejaculation: differences between dysfunctional and functional men. World J Urol. 2005;10:10
                44. Screponi E, Carosa E, Di Stasi SM, Pepe M, Carruba G, Jannini EA. Prevalence of chronic prostatitis in men with premature ejaculation. Urology. 2001;58:198–202
                45. Carani C, Isidori AM, Granata A, Carosa E, Maggi M, Lenzi A, Jannini EA. Multicenter study on the prevalence of sexual symptoms in male hypo- and hyperthyroid patients. J Clin Endocrinol Metab. 2005;90:6472–6479
                46. Adson DE, Kotlyar M. Premature ejaculation associated with citalopram withdrawal. Ann Pharmacother. 2003;37:1804–1806
                47. Peugh J, Belenko S. Alcohol, drugs and sexual function: a review. J Psychoactive Drugs. 2001;33:223–232
                48. Waldinger MD, Schweitzer DH. The use of old and recent DSM definitions of premature ejaculation in observational studies: a contribution to the present debate for a new classification of PE in the DSM-V. J Sex Med. 2008;5:1079–1087
                49. Dogan S, Dogan M. The frequency of sexual dysfunctions in male partners of women with vaginismus in a Turkish sample. Int J Impot Res. 2008;20:218–221
                50. Fasolo CB, Mirone V, Gentile V, Parazzini F, Ricci E. Premature ejaculation: prevalence and associated conditions in a sample of 12,558 men attending the andrology prevention week 2001-A Study of the Italian Society of Andrology (SIA). J Sex Med. 2005;2:376–382
                51. McMahon CG. Screening for erectile dysfunction in men with lifelong premature ejaculation – Is the Sexual Health Inventory for Men (SHIM) reliable? J Sex Med. 2009;6:567–573
                52. El-Nashaar A, Shamloul R. Antibiotic treatment can delay ejaculation in patients with premature ejaculation and chronic bacterial prostatitis. J Sex Med. 2007;4:491–496
                53. Waldinger MD, Zwinderman AH, Olivier B, Schweitzer DH. Thyroid-stimulating hormone assessments in a Dutch cohort of 620 Men with lifelong premature ejaculation without erectile dysfunction. J Sex Med. 2005;2:865–870
                54. Atkinson RL, Dahms WT, Fisher DA, Nichols AL. Occult thyroid disease in an elderly hospitalized population. J Gerontol. 1978;33:372–376
                55. Perelman MA. Sex coaching for physicians: combination treatment for patient and partner. Int J Impot Res. 2003;15(Suppl 5):S67–S74
                56. Schein M, Zyzanski SJ, Levine S, Medalie JH, Dickman RL, Alemagno SA. The frequency of sexual problems among family practice patients. Fam Pract Res J. 1988;7:122–134
                57. Mohr D, Bentler L. Erectile dysfunction: a review of diagnostic and treatment procedures. Clin Psychol Rev. 1990;10:123–150
                58. Donahey K, Miller S. Applying a common factors perspective to sex therapy. J Sex Educat Ther. 2000;25:221–230
                59. Humphrey S, Nazareth I. GP’s view on their management of sexual dysfunction. Fam Pract. 2001;18:516–518
                60. Althof SE, Abdo CH, Dean J, Hackett G, McCabe M, McMahon CG, et al. International Society for Sexual Medicine’s guidelines for the diagnosis and treatment of premature ejaculation. J Sex Med. 2010;7:2947–2969
                61. McMahon CG, Althof SE, Waldinger MD, Porst H, Dean J, Sharlip ID, et al.Lue T, Basson R, Rosen R Disorders of orgasm and ejaculation in men. Sexual medicine: sexual dysfunctions in men and women (2nd International Consultation on Sexual Dysfunctions). 2004 Paris Health Publications:409–468
                62. Althof SE. Evidence based assessment of rapid ejaculation. Int J Impot Res. 1998;10(Suppl 2):S74–S76 discussion S7-S9
                63. Pryor JL, Broderick GA, Ho KF, Jamieson C, Gagnon D. Comparison of estimated versus measured intravaginal ejaculatory latency time in men with and without premature ejaculation. J Sex Med. 2005;3:54
                64. Rosen R, McMahon C, Niederberger C, Broderick G, Jamieson C, Gagnon DD. Correlates to the clinical diagnosis of premature ejaculation: results from a large observational study of men and their partners. J Urol. 2007;177:1059–1064
                65. McMahon C. Clinical trial methodology in premature ejaculation observational, interventional and treatment preference studies-Part 1 – Defining and selecting the study population. J Sex Med. 2008;6:1805–1816
                66. Althof S, Rosen R, Symonds T, Mundayat R, May K, Abraham L. Development and validation of a new questionnaire to assess sexual satisfaction, control and distress associated with premature ejaculation. J Sex Med. 2006;3:465–475
                67. Arafa M, Shamloul R. Development and validation of the Arabic Index of Premature Ejaculation (AIPE). J Sex Med. 2007;4:1750–1756
                68. Patrick DL, Giuliano F, Ho KF, Gagnon DD, McNulty P, Rothman M. The Premature Ejaculation Profile: validation of self-reported outcome measures for research and practice. BJU Int. 2008;103:358–367
                69. Symonds T, Perelman M, Althof S, Giuliano F, Martin M, Abraham L, et al. Further evidence of the reliability and validity of the Premature Ejaculation Diagnostic Tool. Int J Impot Res. 2007;19:521–525
                70. Symonds T, Perelman M, Althof S, Giuliano F, Martin M, May K, et al. Development and validation of a Premature Ejaculation Diagnostic Tool. Eur Urol. 2007;52:565–573
                71. Yuan Y, Xin ZC, Jiang J, Guo Y, Liu W, Tian L, Zhu J. Sexual function of premature ejaculation patients assayed with the Chinese Index of Premature Ejaculation. Asian J Androl. 2004;6:121–126
                72. Serefoglu E, Cimen H, Ozdemir A, Symonds T, Berktas M, Balbay M. Turkish validation of the premature ejaculation diagnostic tool and its association with intravaginal ejaculatory latency time. Int J Impot Res. 2009;21:139–144
                73. Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology. 1997;49:822–830
                74. Cappelleri JC, Siegel RL, Glasser DB, Osterloh IH, Rosen RC. Relationship between patient self-assessment of erectile dysfunction and the sexual health inventory for men. Clin Ther. 2001;23:1707–1719
                75. Basile Fasolo C, Mirone V, Gentile V, Parazzini F, Ricci E. Premature ejaculation: prevalence and associated conditions in a sample of 12,558 men attending the andrology prevention week 2001 – a study of the Italian Society of Andrology (SIA). J Sex Med. 2005;2:376–382
                76. Corona G, Petrone L, Mannucci E, Jannini EA, Mansani R, Magini A, et al. Psycho-biological correlates of rapid ejaculation in patients attending an andrologic unit for sexual dysfunctions. Eur Urol. 2004;46:615–622
                77. El-Sakka AI. Association of risk factors and medical comorbidities with male sexual dysfunctions. J Sex Med. 2006;4:1691–1700
                78. El-Sakka AI. Severity of erectile dysfunction at presentation: effect of premature ejaculation and low desire. Urology. 2008;71:94–98
                79. McMahon CG. The etiology and management of premature ejaculation. Nat Clin Pract Urol. 2005;2:426–433
                80. Jannini EA, Lenzi A, Wagner GSchill WB, Comhaire FH, Hargreave TB. Behavioural Therapy and Counselling. Andrology for the Clinician. 2006 Berlin Springer:598–607
                81. Jannini EA, Carosa E, Pepe M, Lombardo F, Lenzi A. Update of pathophysiology of premature ejaculation: the bases for new pharmacological treatments. EAU-EBU Updates. 2006;4:141–149
                82. Althof S. Sex therapy in the age of pharmacotherapy. Annu Rev Sex Res. 2006:116–132
                83. Althof SLeiblum S. Treatment of rapid ejaculation: psychotherapy, pharmacotherapy, and combined therapy. Principles and practice of sex therapy. 20074th ed. New York Guilford Press
                84. Perelman M. Sex coaching for physicians: combination treatment for patient and partner. Int J Impot Res. 2003;15:S67–S74
                85. Perelman M. A new combination treatment for premature ejaculation. A sex therapist’s perspective. J Sex Med. 2006;3:1004–1012
                86. Symonds T, Roblin D, Hart K, Althof S. How does premature ejaculation impact a man’s life? J Sex Marital Ther. 2003;29:361–370
                87. Rust J, Golombok S, Collier J. Marital problems and sexual dysfunction: how are they related? Br J Psychiatry. 1988;152:629–631
                88. Sotomayor M. The burden of premature ejaculation: the patient’s perspective. J Sex Med. 2005;2(Suppl 2):110–114
                89. Kaplan HS PE: how to overcome premature ejaculation. 1989 New York Brunner/Mazel
                90. Kaplan H The evaluation of sexual disorders: the urologic evaluation of ejaculatory disorders. 1983 New York Brunner/Mazel
                91. Levine SLevine S. Helping men to control ejaculation. Sexual life: a clinician’s guide. 1992 New York Plenum Press:90–106
                92. De Carufel F, Trudel G. Effects of a new functional-sexological treatment for premature ejaculation. J Sex Marital Ther. 2006;32:97–114
                93. Golden JS, Price S, Heinrich AG, Lobitz WC. Group vs. couple treatment of sexual dysfunctions. Arch Sex Behav. 1978;7:593–602
                94. Hawton K, Catalan J, Martin P, Fagg J. Long-term outcome of sex therapy. Behav Res Ther. 1986;24:665–675
                95. De Amicis LA, Goldberg DC, LoPiccolo J, Friedman J, Davies L. Three-year follow-up of couples evaluated for sexual dysfunction. J Sex Marital Ther. 1984;10:215–228
                96. Althof SE, Wieder M. Psychotherapy for erectile dysfunction: now more relevant than ever. Endocrine. 2004;23:131–134
                97. Althof SLevine S, Risen C, Althof S. Therapeutic weaving: the integration of treatment techniques. Handbook of clinical sexuality for mental health professionals. 2003 New York Bruner-Routledge:359–376
                98. Atmaca M, Kuloglu M, Tezcan E, Semercioz A. The efficacy of citalopram in the treatment of premature ejaculation: a placebo-controlled study. Int J Impot Res. 2002;14:502–505
                99. Waldinger MD, Hengeveld MW, Zwinderman AH. Paroxetine treatment of premature ejaculation: a double-blind, randomized, placebo-controlled study. Am J Psychiatry. 1994;151:1377–1379
                100. Goodman RE. An assessment of clomipramine (Anafranil) in the treatment of premature ejaculation. J Int Med Res. 1980;8:53–59
                101. Li N, Wallen NH, Ladjevardi M, Hjemdahl P. Effects of serotonin on platelet activation in whole blood. Blood Coagul Fibrinolysis. 1997;8:517–523
                102. Fava M, Judge R, Hoog SL, Nilsson ME, Koke SC. Fluoxetine versus sertraline and paroxetine in major depressive disorder: changes in weight with long-term treatment. J Clin Psychiatry. 2000;61:863–867
                103. Tanrikut C, Feldman AS, Altemus M, Paduch DA, Schlegel PN. Adverse effect of paroxetine on sperm. Fertil Steril. 2010;94:1021–1026
                104. McMahon CG, Touma K. Treatment of premature ejaculation with paroxetine hydrochloride as needed: 2 single-blind placebo controlled crossover studies. J Urol. 1999;161:1826–1830
                105. Strassberg DS, de Gouveia Brazao CA, Rowland DL, Tan P, Slob AK. Clomipramine in the treatment of rapid (premature) ejaculation. J Sex Marital Ther. 1999;25:89–101
                106. Kim SW, Paick JS. Short-term analysis of the effects of as needed use of sertraline at 5 PM for the treatment of premature ejaculation. Urology. 1999;54:544–547
                107. Waldinger MD, Zwinderman AH, Olivier B. On-demand treatment of premature ejaculation with clomipramine and paroxetine: a randomized, double-blind fixed-dose study with stopwatch assessment. Eur Urol. 2004;46:510–515
                108. Verhulst J, Heiman JLieblum S, Rosen R. A systems perspective on sexual desire. Sexual desire disorders. 1988 New York Guilford:243–267
                109. Wincze JP, Carey MP Sexual dysfunction: a guide for assessment and treatment. 1991 New York Guilford
                110. Mann JJ, Emslie G, Baldessarini RJ, Beardslee W, Fawcett JA, Goodwin FK, et al. ACNP Task Force report on SSRIs and suicidal behavior in youth. Neuropsychopharmacology. 2006;31:473–492
                111. Khan A, Khan S, Kolts R, Brown WA. Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports. Am J Psychiatry. 2003;160:790–792
                112. Eaton H. Clomipramine in the treatment of premature ejaculation. J Int Med Res. 1973;1:432–434
                113. McMahon CG. Treatment of premature ejaculation with sertraline hydrochloride: a single-blind placebo controlled crossover study. J Urol. 1998;159:1935–1938
                114. Waldinger M. Towards evidenced based drug treatment research on premature ejaculation: a critical evaluation of methodology. Int J Impot Res. 2003;15:309–313
                115. Kara H, Aydin S, Yucel M, Agargun MY, Odabas O, Yilmaz Y. The efficacy of fluoxetine in the treatment of premature ejaculation: a double-blind placebo controlled study. J Urol. 1996;156:1631–1632
                116. Waldinger MD. Drug treatment of premature ejaculation: pharmacodynamic and pharmacokinetic paradigms. Drug Discov Today Ther Strateg. 2005;2:37–40
                117. Kaynar M, Kilic O, Yurdakul T. On-demand tramadol hydrochloride use in premature ejaculation treatment. Urology. 2011;79:145–149
                118. Xiong GG, Wu FH, Chen SH, Yao WL. Safety and efficacy of tramadol hydrochloride with behavioral modification in the treatment of premature ejaculation. Zhonghua Nan Ke Xue. 2011;17:538–541
                119. Bar-Or D, Salottolo KM, Orlando A, Winkler JV. A randomized double-blind, placebo-controlled multicenter study to evaluate the efficacy and safety of two doses of the tramadol orally disintegrating tablet for the treatment of premature ejaculation within less than 2 minutes. Eur Urol. 2011;61:736–743
                120. Fein RL. Intracavernous medication for treatment of premature ejaculation. Urology. 1990;35:301–303
                121. Abdel-Hamid IA, El Naggar EA, El Gilany AH. Assessment of as needed use of pharmacotherapy and the pause-squeeze technique in premature ejaculation. Int J Impot Res. 2001;13:41–45
                122. Chia S. Management of premature ejaculation – a comparison of treatment outcome in patients with and without erectile dysfunction. Int J Androl. 2002;25:301–305
                123. Salonia A, Maga T, Colombo R, Scattoni V, Briganti A, Cestari A, et al. A prospective study comparing paroxetine alone versus paroxetine plus sildenafil in patients with premature ejaculation. J Urol. 2002;168:2486–2489
                124. Waldinger MD, Berendsen HH, Blok BF, Olivier B, Holstege G. Premature ejaculation and serotonergic antidepressants-induced delayed ejaculation: the involvement of the serotonergic system. Behav Brain Res. 1998;92:111–118
                125. Sorbera LA, Castaner J, Castaner RM. Dapoxetine hydrochloride. Drugs Future. 2004;29:1201–1205
                126. Dresser MJ, Lindert K, Lin D. Pharmacokinetics of single and multiple escalating doses of dapoxetine in healthy volunteers (abstract). Clin Pharmacol Ther. 2004;75:113 P1
                127. Sommer F, Klotz T, Mathers MJ. Treatment of premature ejaculation: a comparative vardenafil and SSRI crossover study (abstract). J Urol. 2005;173:202 741
                128. Mattos RM, Lucon AM. Tadalafil and slow-release fluoxetine in premature ejaculation – a prospective study (abstract). J Urol. 2005;173:239 880
                129. Atan A, Basar MM, Tuncel A, Ferhat M, Agras K, Tekdogan U. Comparison of efficacy of sildenafil-only, sildenafil plus topical EMLA cream, and topical EMLA-cream-only in treatment of premature ejaculation. Urology. 2006;67:388–391
                130. Dresser MJ, Kang D, Staehr P, Gidwani S, Guo C, Mulhall JP, Modi NB. Pharmacokinetics of dapoxetine, a new treatment for premature ejaculation: impact of age and effects of a high-fat meal. J Clin Pharmacol. 2006;46:1023–1029
                131. Dresser MJ, Desai D, Gidwani S, Seftel AD, Modi NB. Dapoxetine, a novel treatment for premature ejaculation, does not have pharmacokinetic interactions with phosphodiesterase-5 inhibitors. Int J Impot Res. 2006;18:104–110
                132. Modi NB, Dresser MJ, Simon M, Lin D, Desai D, Gupta S. Single- and multiple-dose pharmacokinetics of dapoxetine hydrochloride, a novel agent for the treatment of premature ejaculation. J Clin Pharmacol. 2006;46:301–309
                133. Mathers MJ, Klotz T, Roth S, Lummen G, Sommer F. Safety and efficacy of vardenafil versus sertraline in the treatment of premature ejaculation: a randomised, prospective and crossover study. Andrologia. 2009;41:169–175
                134. Jannini EA, McMahon C, Chen J, Aversa A, Perelman M. The controversial role of phosphodiesterase type 5 inhibitors in the treatment of premature ejaculation. J Sex Med. 2011;8:2135–2143
                135. Mamas MA, Reynard JM, Brading AF. Nitric oxide and the lower urinary tract: current concepts, future prospects. Urology. 2003;61:1079–1085
                136. McMahon CG, McMahon CN, Leow LJ, Winestock CG. Efficacy of type-5 phosphodiesterase inhibitors in the drug treatment of premature ejaculation: a systematic review. BJU Int. 2006;98:259–272
                137. Asimakopoulos AD, Miano R, Agro EF, Vespasiani G, Spera E. Does current scientific and clinical evidence support the use of phosphodiesterase type 5 inhibitors for the treatment of premature ejaculation? A systematic review and meta-analysis. J Sex Med. 2012
                138. Kim JJ, Kwak TI, Jeon BG, Cheon J, Moon DG. Effects of glans penis augmentation using hyaluronic acid gel for premature ejaculation. Int J Impot Res. 2004;16:547–551
                139. Hellstrom WJ, Althof S, Gittelman M, Streidle C, Ho KF, Kell S, Nilson-Beijber A. Dapoxetine for the treatment of men with premature ejaculation (PE): dose-finding analysis (abstract). J Urol. 2005;173:238 877
                140. Hellstrom WJ, Gittelman M, Althof S. Dapoxetine HCl for the treatment of premature ejaculation: a Phase II, randomised, double-blind, placebo controlled study (abstract). J Sex Med. 2004;1(Suppl 1):59, 97
                141. Pryor JL, Althof SE, Steidle C, Rosen RC, Hellstrom WJ, Shabsigh R, et al. Efficacy and tolerability of dapoxetine in treatment of premature ejaculation: an integrated analysis of two double-blind, randomised controlled trials. Lancet. 2006;368:929–937
                142. Buvat J, Tesfaye F, Rothman M, Rivas DA, Giuliano F. Dapoxetine for the treatment of premature ejaculation: results from a randomized, double-blind, placebo-controlled phase 3 trial in 22 countries. Eur Urol. 2009;55:957–967
                143. Kaufman JM, Rosen RC, Mudumbi RV, Tesfaye F, Hashmonay R, Rivas D. Treatment benefit of dapoxetine for premature ejaculation: results from a placebo-controlled phase III trial. BJU Int. 2009;103:651–658
                144. McMahon C, Kim SW, Park NC, Chang CP, Rivas D, Tesfaye F, et al. Treatment of premature ejaculation in the Asia-Pacific region: results from a phase III double-blind, parallel-group study of dapoxetine. J Sex Med. 2010;7:256–268
                145. Shi WG, Wang XJ, Liang XQ, Liu ZQ, Huang MJ, Li SQ, et al. Selective resection of the branches of the two dorsal penile nerves for primary premature ejaculation. Zhonghua Nan Ke Xue. 2008;14:436–438
                146. Kwak TI, Jin MH, Kim JJ, Moon DG. Long-term effects of glans penis augmentation using injectable hyaluronic acid gel for premature ejaculation. Int J Impot Res. 2008;20:425–428
                147. Waldinger MD, Zwinderman AH, Olivier B, Schweitzer DH. The majority of men with lifelong premature ejaculation prefer daily drug treatment: an observation study in a consecutive group of Dutch men. J Sex Med. 2007;4:1028–1037
                148. Dinsmore WW, Hackett G, Goldmeier D, Waldinger M, Dean J, Wright P, et al. Topical eutectic mixture for premature ejaculation (TEMPE): a novel aerosol-delivery form of lidocaine-prilocaine for treating premature ejaculation. BJU Int. 2006;99:369–375
                149. Henry R, Morales A, Wyllie MG. TEMPE: topical eutectic-like mixture for premature ejaculation. Expert Opin Drug Deliv. 2008;5:251–261
                150. Patrick DL, Rowland D, Rothman M. Interrelationships among measures of premature ejaculation: the central role of perceived control. J Sex Med. 2007;4:780–788
                151. McMahon CG, Park NC, Zhao Y, Rothman M, Rivas D Treatment of premature ejaculation in the Asia-Pacific Region: results from a Phase III double-blind, parallel-group study of dapoxetine. 2007 Jeju, Korea Asia Pacific Society for Sexual Medicine (APSSM)
                152. Shabsigh R, Patrick DL, Rowland DL, Bull SA, Tesfaye F, Rothman M. Perceived control over ejaculation is central to treatment benefit in men with premature ejaculation: results from phase III trials with dapoxetine. BJU Int. 2008;102:824–828
                153. Cavallini G. Alpha-1 blockade pharmacotherapy in primitive psychogenic premature ejaculation resistant to psychotherapy. Eur Urol. 1995;28:126–130
                154. Basar MM, Yilmaz E, Ferhat M, Basar H, Batislam E. Terazosin in the treatment of premature ejaculation: a short-term follow-up. Int Urol Nephrol. 2005;37:773–777
                155. Frink MC, Hennies HH, Englberger W, Haurand M, Wilffert B. Influence of tramadol on neurotransmitter systems of the rat brain. Arzneimittelforschung. 1996;46:1029–1036
                156. Salem EA, Wilson SK, Bissada NK, Delk JR, Hellstrom WJ, Cleves MA. Tramadol HCL has promise in on-demand use to treat premature ejaculation. J Sex Med. 2008;5:188–193
                157. Alghobary M, El-Bayoumy Y, Mostafa Y, Mahmoud EH, Amr M. Evaluation of tramadol on demand vs. daily paroxetine as a long-term treatment of lifelong premature ejaculation. J Sex Med. 2010;7:2860–2867
                  158. Erenpreiss J, Zalkalns J. Premature ejaculation: comparison of patroxetine alone, paroxetine plus local lidocaine and paroxetine plus sildenafil (abstract). Int J Impot Res. 2002;14:S33 PS-7-4
                  159. Linn R, Ginesin Y, Hardak S, Mertyk S. Treatment of sildenfil as part of the treatment in premature ejaculation (abstract). Int J Impot Res. 2002;14:S39 P-168
                  160. Chen J, Mabjeesh NJ, Matzkin H, Greenstein A. Efficacy of sildenafil as adjuvant therapy to selective serotonin reuptake inhibitor in alleviating premature ejaculation. Urology. 2003;61:197–200
                  161. Li X, Zhang SX, Cheng HM, Zhang WD. Clinical study of sildenafil in the treatment of premature ejaculation complicated by erectile dysfunction. Zhonghua Nan Ke Xue. 2003;9:266–269
                  162. Lozano AF. Premature ejaculation: pharmacological treatment three years after (abstract). Int J Impot Res. 2003;15:S11 MP-2-6
                  163. Tang W, Ma L, Zhao L, Liu Y, Chen Z. Clinical efficacy of Viagra with behavior therapy against premature ejaculation. Zhonghua Nan Ke Xue. 2004;10:366–367 70
                  164. Zhang XS, Wang YX, Huang XY, Leng J, Li Z, Han YF. Comparison between sildenafil plus sertraline and sertraline alone in the treatment of premature ejaculation. Zhonghua Nan Ke Xue. 2005;11:520–522 5
                  165. McMahon CG, Stuckey B, Andersen ML. Efficacy of viagra: sildenafil citrate in men with premature ejaculation. J Sex Med. 2005;2:368–375
                  166. Sun XZ, Deng CH, Dai YP. A clinical study of sertralin and vardenafil in the treatment of premature ejaculation complicated by erectile dysfunction. Zhonghua Nan Ke Xue. 2007;13:610–612
                  167. Mattos RM, Marmo Lucon A, Srougi M. Tadalafil and fluoxetine in premature ejaculation: prospective, randomized, double-blind, placebo-controlled study. Urol Int. 2008;80:162–165
                  168. Aversa A, Pili M, Francomano D, Bruzziches R, Spera E, La Pera G, Spera G. Effects of vardenafil administration on intravaginal ejaculatory latency time in men with lifelong premature ejaculation. Int J Impot Res. 2009;21:221–227
                  169. Althof SE, Brock GB, Rosen RC, Rowland DL, Aquilina JW, Rothman M, et al. Validity of the patient-reported Clinical Global Impression of Change as a measure of treatment response in men with premature ejaculation. J Sex Med. 2010;7:2243–2252
                  Keywords:

                  dapoxetine; phosphodiesterase inhibitors; premature ejaculation; psychotherapy; selective serotonin reuptake inhibitors; topical anesthetics; tramadol; treatment

                  © 2012 Human Andrology