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Premature Ejaculation: Past, Present, and Future Perspectives

Chairperson: Chris G. McMahon, MD; Faculty: Francesco Montorsi, MD; Mariano Sotomayor, MD; Ira D Sharlip, MD


Copyright 2005 the Postgraduate Institute for Medicine.

This CME activity "Premature Ejaculation: Past, Present, and Future Perspectives" was originally offered as a Webcast certified for CME.

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Release Date: March 8, 2005Valid for credit through March 8, 2006

Target Audience

This activity has been designed to meet the educational needs of urologists involved in the management of patients with premature ejaculation.

Goal

Learning Objectives

Upon completion of this activity, participants will be able to:
  1. Review the prevalence of premature ejaculation (PE).
  2. Explain theories of PE etiology.
  3. Discuss the barriers to diagnosis and treatment of PE.
  4. Describe current treatment options for PE.

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Physicians - up to 1.5 AMA PRA category 1 credit(s)

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Contents of This CME Activity

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    1. Premature Ejaculation: Past, Present, and Future Perspectives: Introduction
      by Chris G. McMahon, MD
      Introduction

    2. Prevalence of PE: A Global and Regional Perspective
      by Francesco Montorsi, MD
      Premature Ejaculation: Introduction and Definitions
      Prevalence of Premature Ejaculation by Region
      Other Factors Influencing Prevalence
      Etiologies and Comorbidities of Premature Ejaculation
      Summary

    3. Burden of PE: The Patient's Perspective
      by Mariano Sotomayor, MD
      Perceptions of Normal Sexual Function
      Control and Satisfaction: What Is Normal?
      Barriers to Patient Diagnosis and Treatment
      Burdens of Premature Ejaculation
      Other Issues Associated With Premature Ejaculation
      Summary

    4. Diagnosis and Treatment of PE: The Physician's Perspective
      by Ira D. Sharlip, MD
      Premature Ejaculation: Patient Screening and Evaluation
      Behavioral Therapy
      Topical Therapy
      Use of Phosphodiesterase Type 5 Inhibitors
      Use of Selective Serotonin Reuptake Inhibitors
      Summary





    Premature Ejaculation: Past, Present, and Future Perspectives

    Premature Ejaculation: Past, Present, and Future Perspectives: Introduction

    Chris G. McMahon, MD

    Introduction

    Slide
    Slide. Premature Ejaculation: Past, Present, and Future Perspectives: Introduction

    Understanding of premature ejaculation (PE) has evolved tremendously. The initial premise that PE had a psychogenic basis is slowly disappearing. Although clinical research has yet to clearly identify the specific causes or mechanisms underlying PE, we now accept that men with PE are not a homogenous group. Lifelong and acquired PE probably have different etiologies, and lifelong PE, the most common type of PE, most likely has a predominant biogenic basis.

    In parallel with this new understanding as to the mechanism of PE, a whole new approach in the way we treat and manage PE within the clinician's office has developed. Treatment with serotonergic drugs represents a novel and a refreshing approach to the treatment of PE and is a radical departure from the psychosexual model of treatment, which was previously regarded as the cornerstone of treatment. In many respects, it appears to adequately fill a treatment hiatus that is created by the nonacceptance by many patients of psychosexual counseling, the limitations of psychosexual counseling, and the lack of convincing longitudinal data to support the efficacy of psychosexual counseling. Drug treatment offers patients a likelihood of restoration of ejaculatory control and a heightened latency time within a few days and a favorable side effect profile, and as part of that, they achieve improvements in sexual desire and other domains of sexual function. This program will focus on the epidemiology of PE, the impact that PE has not only on the sufferer but also on his partner, and the office management of PE. Our scientific faculty comprises experts in sexual medicine from Europe, North America, and Central America.


    Prevalence of PE: A Global and Regional Perspective

    Francesco Montorsi, MD

    Premature Ejaculation: Introduction and Definitions

    Slide
    Slide 1. Prevalence of PE: A Global and Regional Perspective

    I am a urologist and although I spend much time removing prostates, I see many patients with rapid ejaculation, and I think that you share the same experience. This is the reason why so many people are interested in the field and are with us now.

    Slide
    Slide 2. Outline

    I would like to define what is normal in terms of ejaculation, what is abnormal; try to give you what we know about the definitions of premature ejaculation (PE); talk about the prevalence by region in the world (how many patients are there with this type of medical problem); talk about factors that may determine the regional variation in the prevalence of PE; talk about the relationship between PE, ethnicity, and age; talk a little bit about etiology of this medical condition; and talk about comorbidities.

    Slide
    Slide 3. What Is the Perceived Normal Time to Ejaculation?

    Here you see the differences in the perception of normal time to ejaculation within various countries, but this is the perception of the men; it's not really the truth!

    Slide
    Slide 4. Definitions of PE

    There are a number of definitions of PE out in the field, telling you that there is much that has to be done. You have to give your contributions, first of all as members of this society, to increase the knowledge that we have in this area. Premature ejaculation has been defined as an inability to delay ejaculation sufficiently to enjoy lovemaking, or as persistent or recurrent ejaculation with minimal stimulation before, on, or shortly after penetration and before the person wishes it. It is unclear to me how many patients within the Italian population, for example, really understand that having a rapid ejaculation may be a medical problem. So we will need to run many studies in this area.


    Prevalence of PE: A Global and Regional Perspective

    Francesco Montorsi, MD

    Prevalence of Premature Ejaculation by Region

    Slide
    Slide 5. Ejaculatory Disorders in Buenos Aires

    The problem is present also in Buenos Aires, Argentina -- 28% of the men have problems with some type of ejaculatory disorder, but specifically PE.

    Slide
    Slide 6. Global Study of Sexual Attitudes and Behaviors (GSSAB)

    There has been a study assessing in a large multicountry survey (29 countries) a very high number of women and men, evaluating their sexual attitudes.

    Slide
    Slide 7. Overall PE Prevalence by Region

    We have interesting data from this study. This is the overall prevalence of PE by region, and there is not much difference. The take-home message here is that one third of men have this type of medical condition, and I am pretty sure that with the effort of the scientific companies and pharmaceutical companies to study this type of medical condition, there will be more knowledge, and more patients will seek medical advice.

    Slide
    Slide 8. PE: Distribution of Frequencies

    In patients who have this type of problem, this is typically what we hear from patients in terms of frequency. They do not come to see us and tell us that the problem is there once a year; many times, they are desperate. This medical condition can create very important problems in the life of the couple.

    Slide
    Slide 9. Factors for Regional Variation

    There are factors for regional variation and here is a list of them. Probably there is a little truth in each of these points. The prevalence of circumcision, for example, is understandable; it may have a reason to be there. Also there are cultural issues and I think that each of you may recognize 1 of these bullets as more or less important in everyday practice.


    Prevalence of PE: A Global and Regional Perspective

    Francesco Montorsi, MD

    Other Factors Influencing Prevalence

    Slide
    Slide 10. PE Prevalence by Ethnicity in USA

    If you look at the prevalence of PE by ethnicity in the United States, according to 2 different studies, there may be a little bit of a difference between ethnic groups. But still, at least one third of men have this type of problem.

    Slide
    Slide 11. Prevalence of PE and ED With Age

    There is a difference between erectile dysfunction and PE with regards to age; we know that erectile dysfunction tends to increase in terms of overall prevalence with the increase of age. This is not the case with rapid ejaculation. Actually this is typical in young patients, so this type of medical condition appears to be very important, because we have to improve the life of young individuals to be married, for example.


    Prevalence of PE: A Global and Regional Perspective

    Francesco Montorsi, MD

    Etiologies and Comorbidities of Premature Ejaculation

    Slide
    Slide 12. Etiology: A Historical Perspective

    If we consider PE from an historical perspective, we have been talking about it for more than a century. At the end of the 1800s, there were already the first statements about PE and a number of theories associated with the pathophysiology and the treatment of PE.

    Slide
    Slide 13. Etiology: Psychological Theories

    There are a number of psychological theories that try to explain why PE is there. Being a urologist, I would tell you that certainly early sexual experience may play a role and anxiety may play a role; those are 2 factors that are typically there when I interview a patient who is complaining of this symptom. Clearly, I'm not in the position of being able to understand whether there are psychodynamic issues, and this is why the role of a psychosexologist is so important in this field.

    Slide
    Slide 14. Etiology: Organic Theories

    At the same time, we have organic theories and we must not forget them: penile hypersensitivity; ejaculatory reflex, which is too often there; some type of genetic predisposition; and some type of abnormality in the sensitivities to the serotonin receptors. I think there are some patients who have all 4 things put together. Because they are so difficult to treat and do not respond to any drug or any type of behavioral therapy, we really need to put all our efforts into finding the best way to address their needs.

    Slide
    Slide 15. Possible Psychological Risk Factors and Physiological Co-morbidities

    Clearly, there are some psychological risk factors and physiological comorbidities including sexual inexperience, infrequent sexual intercourse, relationship problems (another take-home message would be to try to see the sexual partner of the patient to deal with this problem), fear/anxiety, and poor understanding of sexual responses -- this is something which is key. In my country, for example, sexual education is not part of the education given to the young student in high school, and this is very bad; we should increase the exposure of students to this type of knowledge. So we also have many things to do in the field of education.

    Physiologically, there is poor/fair health and erectile dysfunction, which is a comorbidity, although patients who have erectile dysfunction and at the same time are complaining of PE have 2 different things. They are a different subset of patient compared with the young guy who does have a brilliant erection but still is coming too quickly. Diabetes may be there, and clearly we live in an age when opiate drug abuse is frequently there.


    Prevalence of PE: A Global and Regional Perspective

    Francesco Montorsi, MD

    Summary

    Slide
    Slide 16. Summary

    In summary, my take-home messages would be that normal ejaculatory latency varies widely among the different regions of the world. There are various definitions of rapid ejaculation, but most refer to a lack of an ejaculatory latency, control, and sexual satisfaction, and these 3 items are telling you why it will be more and more important to find the best way, hopefully with a drug, to treat this type of patient. Thirty percent of men are suffering with this medical condition. We must make them understand that this is first of all a medical condition that needs to be treated, if they wish; that it does have an impact that is important in the life of the couple; and that the etiology is multifactorial, but probably a neurobiological basis is there; it's not only psychological. I strongly support this statement. And comorbidities and risk factors may include poor health, anxiety, and erectile dysfunction.


    Burden of PE: The Patient's Perspective

    Mariano Sotomayor, MD

    Perceptions of Normal Sexual Function

    Slide
    Slide 1. Burden of PE: The Patient's Perspective

    My task is to discuss the burden of premature ejaculation (PE) from the patient's perspective.

    Slide
    Slide 2. Outline

    I will discuss some perceptions of what constitutes a normal sexual function, what the barriers for patient diagnosis are, and finally how PE is seen by patients and partners.

    Slide
    Slide 3. What Is Normal Ejaculation and What Is PE?

    As you already heard, there are many definitions of PE, but no one is perfect. But most of them take into account 3 major criteria: there should be a shortened intravaginal ejaculatory latency time (IELT), reduced control over ejaculation, and decreased satisfaction with intercourse. Nonetheless, few men or their partners know what is a normal time of ejaculation, or what is a normal sexual function in these terms. Some studies have tried to define normal ejaculatory function in order to provide comparators for PE.

    Slide
    Slide 4. "Normal" Men vs Their Female Partners' Assessment of Their IELT

    These data have been shown before by Dr. Montorsi, but I want to point out that the estimated IELT varies widely in different countries of the world. For example, in Germany, the normal estimated IELT is about half the normal perceived in the United States. Another thing that needs to be pointed out is that female partners almost always consider this time less than that considered to be normal by men.


    Burden of PE: The Patient's Perspective

    Mariano Sotomayor, MD

    Control and Satisfaction: What Is Normal?

    Slide
    Slide 5. Perceptions of Sexual Functioning Among the General Male Population

    This study was done to determine what is normal vs what is PE in ratings of control and satisfaction. They used an Internet survey using a research panel; this research panel is a national population-based sample of men, and it is formed by approximately 40,000 families. This was a 3-part survey; in the first one, they addressed issues about general health; in the second one, they addressed issues about normal or general sexual functioning; and in the third one, they addressed some questions about self-identified PE. Patients were male, older than 20 years of age; they had to be sexually active during the past 6 months; and they had to have a stable relationship with a single partner.

    Slide
    Slide 6. Categorization of Results

    They had a very good response rate; about three fourths of this research panel answered the first question but only 1158 met all the selection criteria. The first question they were asked was if they ejaculated before they wished. And based on that, the global prevalence of PE among this population is around 30%. The second question they were asked was if there was an impact in their quality of sexual relationships. If they answered none or little, they were categorized as possible PE, and if they answered that there was somewhat or very much of an impact, they were categorized as probable PE. And this is the population I will show you next.

    Slide
    Slide 7. Control Over Ejaculation

    In this histogram, there are very wide differences between probable PE and normal patients in terms of control. Those patients with probable PE believed their control is much lower than the normal population.

    Slide
    Slide 8. Fair to Very Poor Control Over Ejaculation: Male vs Female Ratings

    These data come from a multicountry study performed by Johnson & Johnson. Again, they asked about control, and patients who believed that their control was fair to very poor -- around 30% in all the countries that were evaluated.

    Slide
    Slide 9. Satisfaction With Intercourse

    Coming back to the study of probable PE, this is satisfaction. There are not wide differences, but still, there are differences between those with probable PE and normal patients, and those with probable PE tend to be less satisfied than normal people.


    Burden of PE: The Patient's Perspective

    Mariano Sotomayor, MD

    Barriers to Patient Diagnosis and Treatment

    Slide
    Slide 10. Barriers to Diagnosis and Treatment

    What are the barriers to diagnosis and treatment? These patients feel stigmatized; they are embarrassed to discuss this condition with someone strange. They believe that the problem will go away if they wait; they believe also that the problem is psychological. There is the perception that there is no available medical treatment or any behavioral technique that is useful for the treatment of this condition. And finally, the healthcare providers don't do a routine screening of sexual dysfunction.

    Slide
    Slide 11. Self-help Approaches to PE

    What do patients do before they come to us? They use many strategies: for example, they use condoms to reduce sensitivity; they masturbate before engaging in sexual activity; they try to have nonerotic thoughts while having sex; and finally they use harder and faster thrusting to satisfy their partner. The problem is that these strategies may exacerbate PE by deliberately ignoring the sexual sensations that are needed to establish control.


    Burden of PE: The Patient's Perspective

    Mariano Sotomayor, MD

    Burdens of Premature Ejaculation

    Slide
    Slide 12. The Emotional Burden of PE

    What's the burden on the patient's side? Self-esteem is lower in these patients; they feel inferior to others. They feel deflated. There is anxiety, maybe as a reason or as a consequence of the problem. They feel depressed, and particularly in Latin America it has been shown that PE is a risk factor for depression. Finally, these patients feel embarrassed; they are ashamed of not satisfying their partners.

    Slide
    Slide 13. The Burden of PE on the Relationship

    What happens with the relationship? There is a strain on these relationships; men tend to mistrust their partners. They believe that they can cheat on them with other partners, because they are not having sexual satisfaction. On the women's side, they perceive these men as selfish. Men who suffer from PE have difficulties initiating and maintaining relationships; there is dissatisfaction with the sexual relationship; and there are studies that have shown that there can be a higher incidence of associated female sexual dysfunctions.


    Burden of PE: The Patient's Perspective

    Mariano Sotomayor, MD

    Other Issues Associated With Premature Ejaculation

    Slide
    Slide 14. Association of PE With Female Sexual Disorders

    To show you that, these data come from Abdos' study in Brazil, and this was a prevalence study. The global prevalence of PE in Brazil is around 30%. But there are clear differences in different states; it can be as low as 10.8% and as high as almost 30%. And the important thing, an interesting thing, is that the rates of anorgasmia are also higher in those states where PE is higher.

    Slide
    Slide 15. How Is PE Seen by Patients and Partners?

    How is this condition seen by patients and partners? Most of them believe this is a psychological condition, as has been stated before, and physicians see it more as a neurobiological condition. As I said before, many women believe this is a selfish behavior; erectile dysfunction (ED), in general, generates more sympathy than PE. Patients try to compensate for PE by using manual stimulation or using sexual toys. From the sexological point of view, it might be that it's not the individual who is dysfunctional, but the couple is responsible for the problem. Premature ejaculation is often confused with other sexual dysfunctions, particularly ED. In general, it's not associated with other pathology and is generally seen as a quality-of-life issue.

    Slide
    Slide 16. Association of Divorce With PE Status

    These data come from the Laumann study; this was a worldwide study and he tried to find risk factors for different sexual dysfunctions. On the PE side, he found that recent divorce was associated very heavily with PE, mainly in some areas of the world such as Latin America.

    Slide
    Slide 17. Association of Education Level and PE Status

    From the same study, he found that education matters. If people are less educated, the prevalence of PE is also higher, and this is most important in Latin America and in the Middle East.


    Burden of PE: The Patient's Perspective

    Mariano Sotomayor, MD

    Summary

    Slide
    Slide 18. Summary

    Summarizing my presentation, a perceived control over ejaculation is low or absent in men with PE, and is an important source of distress that can impact other areas of life. Mutual sexual satisfaction is a major concern of individuals and partners, and is a source of relationship stress. The effects of this condition are not confined to the sufferer; it can affect the partner of the sufferer. Still, we have significant patient barriers to seeking treatment for PE. Healthcare providers have an important role in helping these patients to overcome these barriers.


    Diagnosis and Treatment of PE: The Physician's Perspective

    Ira D. Sharlip, MD

    Premature Ejaculation: Patient Screening and Evaluation

    Slide
    Slide 1. Diagnosis and Treatment of PE: The Physician's Perspective

    Premature ejaculation (PE) is an exciting new area to add to our interest in sexual medicine.

    Slide
    Slide 2. Outline

    I'll be covering some information about the medical and psychosocial history related to PE; treatment approaches, including behavioral approaches and pharmacotherapy; some information about central 5-hydroxytryptamine (5-HT) function and its relationship to PE; information about current treatment with selective serotonin reuptake inhibitors (SSRIs); and some ideas about what the ideal treatment profile would be for the perfect drug to treat PE.

    Slide
    Slide 3. Screening for PE

    Let's start with some ideas about the evaluation of patients with PE. One question is: who should be doing this? Should it be the primary care physician or should it be the urologist, a psychologist, a psychiatrist, or any other specialty? I think the answer to this is that wherever the patient presents with the complaint is the appropriate person to start with screening. Should the approach be proactive or passive? What we mean by proactive is: should physicians, particularly primary care physicians, be asking patients whether they have PE or should we wait for patients to make the complaint? I don't think that there's an answer to that question. I do think as new treatment options become available, more and more patients will come forward for treatment. I see many parallels between where we are now with PE and where we were 10 or 15 or maybe 20 years ago with regard to the evaluation and treatment of erectile dysfunction (ED). And I think urologists and people in psychosexual medicine are used to treating and used to the idea of dealing with problems in sexual medicine.

    It's important for us to be able to differentiate between ED and PE. Many patients are mistaken when they come with a presentation of ED when the problem actually is PE. Then there's the controversy over drug therapy vs behavioral therapy. It's also important to understand that there are links between sexual function, overall health, and quality of life. This is particularly true with regard to PE because we recognize that PE can have a major impact on the sufferer of this condition and his partner.

    Slide
    Slide 4. Medical and Psychosocial History

    The medical and psychosocial history is critically important in identifying patients who have this problem, and there are 3 distinct areas that we need to sort out when we take the history of the patient with PE. We need to understand the degree of patient distress that this problem produces and, equally important, we need to understand the degree of distress this condition places on the patient's partner. So distress is one element that we must pay attention to. Another element is the patient's perceived degree of ejaculatory control. Does the patient think that he's able to hold himself back, or does he get to a point where he just loses control? It's important for us to sort those 2 things out. We also should be asking patients for an estimate of their intravaginal ejaculatory latency time (IELT). The answers may not be terribly accurate and the patient's female partner may not agree with the answer, but it's important to ask this question and understand what the patient's perception is of this problem. Understanding the onset and the duration of PE will help us separate primary from secondary PE.

    The psychosocial history is very important, particularly if there's a history of childhood physical or sexual abuse. And the medical history is equally important, not only for general reasons but also because we know that there are some medical conditions that have been reported to be risk factors for PE, such as prostatitis and opiate drug abuse. Primary among these questions is whether the PE is a problem in itself or whether it is secondary to ED. If it's secondary to ED, the ED should be treated first; often that will resolve the problem.


    Diagnosis and Treatment of PE: The Physician's Perspective

    Ira D. Sharlip, MD

    Behavioral Therapy

    Slide
    Slide 5. Current Treatment Approaches

    Current treatment approaches to PE can be divided into 2 categories: behavioral and pharmacotherapeutic. The behavioral therapies are focused on the stop/start technique and squeeze techniques; the pharmacotherapeutic approaches can be divided into topical agents, phosphodiesterase type 5 (PDE5) inhibitors, and SSRIs. Let's look at these different options.

    Slide
    Slide 6. Behavioral Therapy of PE

    Behavioral therapy was originally popular in the past and still is because of the lack of a consistent and effective biologically based treatment. The squeeze technique was first developed by Semans in 1956, but was popularized by Masters and Johnson in 1970. This technique involves withdrawal during intercourse, and prior to the moment of ejaculatory inevitability, the female partner is instructed to give a very sharp and hard squeeze to the glans penis to abort the ejaculation. My experience with this is that it's a totally unpractical approach, and I think most of you would agree. The stop/start technique was originally popularized by Helen Singer Kaplan in 1983. She recommended pausing during sexual stimulation prior to impending ejaculation to allow the patient to acclimate to the sensation and eventually to condition himself to increased control.

    These techniques may heighten the man's awareness of his sexual sensation; they decrease the emphasis on coitus as the activity during sex, and they may succeed partly for those reasons.

    Slide
    Slide 7. Drawbacks of Behavioral Therapies

    There are drawbacks of the behavioral techniques. They work best in a stable relationship, because they require the assistance of the partner and they are burdensome on both the patient and the partner. They can be time-consuming and costly, particularly because of the potential cost of the psychotherapy and instruction that goes along with them. They take time to become effective, so they generally are not effective immediately after initiation. And there is mixed efficacy; some data show that about half of patients have some response, but the response often declines with time and the problem is likely to relapse.


    Diagnosis and Treatment of PE: The Physician's Perspective

    Ira D. Sharlip, MD

    Topical Therapy

    Slide
    Slide 8. Topical Treatment of PE

    Let's look at the biological treatments, starting with topical treatment of PE. Local anesthetics have been used such as lidocaine or prilocaine cream, gel, or spray. These anesthetics diminish the sensitivity of the glans penis and they can be effective in delaying the point of ejaculation. There's a Korean product called SS cream (Severance Secret cream), which many of us are familiar with, made from extracts of 9 herbs; some of them have local anesthetic properties. They are applied to the glans penis about 1 hour prior to coitus and washed off immediately prior to intercourse.

    Slide
    Slide 9. Drawbacks of Topical Treatments

    There are problems, of course, with topical therapies. They can produce significant penile hypoesthesia and work too well and interfere with the patient's achieving an orgasm. There can be transvaginal absorption of the drugs, producing vaginal numbness, even female anorgasmia. These problems can be prevented with condom use. There's also the problem of local irritation, burning pain from the topical application of these products. So they can help, but they're not ideal.


    Diagnosis and Treatment of PE: The Physician's Perspective

    Ira D. Sharlip, MD

    Use of Phosphodiesterase Type 5 Inhibitors

    Slide
    Slide 10. PDE5 Inhibitors

    Phosphodiesterase type 5 inhibitors have been tried for the treatment of PE. What we don't really know is whether sildenafil or any other PDE5 inhibitor really increases IELT. We think that they work by reducing performance anxiety, allowing the patient not to have to rush to the point of ejaculation and orgasm before he loses his transient erection if he has ED. Several papers show that PDE5 inhibitors can be used as adequate adjuvant therapy in combination with SSRIs, but there are problems with the studies of PDE5 inhibitors because they've been tested mostly in uncontrolled protocols, using open-label studies. The IELT estimates are by patient recall and the patient groups are self-diagnosed with PE. So the subject of the use of PDE5 inhibitors is invested with a lot of uncertainty.


    Diagnosis and Treatment of PE: The Physician's Perspective

    Ira D. Sharlip, MD

    Use of Selective Serotonin Reuptake Inhibitors

    Slide
    Slide 11. Central 5-HT Function and PE

    This brings us to the subject of the use of SSRIs for the treatment of PE. The idea came forth because in the clinical trials many years ago with antidepressants in this category, one of the adverse events that patients complained of was delayed or absent ejaculation. We now understand some of the neurophysiology and neuropharmacology behind this effect. In the brain stem, in the medial pre-optic area, is located the paraventricular nucleus. This is an area that is active in integration of sexual responses in the human male. In this area, there is the nucleus paragigantocellularis (nPGI), and we, in urology, are going to get used to the idea of saying nPGI and understanding what it means. The most important thing is that the nPGI seems to exert tonic inhibition to ejaculation on the lumbosacral cord. So the tonic inhibition coming from projections from the nPGI down to the lumbosacral cord is the reason that men don't go around in a state of blissful orgasm constantly. Therefore, the nPGI and the 5-HT systems located in the nPGI may be the targets for therapy for PE. And as I go through this, I want to emphasize that 5-HT is serotonin; those 2 words, 5-HT and serotonin, are interchangeable.

    The way the serotonin mechanism works in the nPGI is very complex and not well understood. There are about 16 different receptors for 5-HT in this area of the brain and there are also 5-HT transporters that are active in this area. But mechanisms of action on the 5-HT1A and 5-HT2C receptors seem to be the most active and most promising points of attack, pharmacologically, as well as activity on the 5-HT transporters.

    Slide
    Slide 12. Proposed Action of Chronic SSRIs on Central 5-HT Transmission

    How might this work? What is the theory about why SSRIs can be effective and are effective in delaying ejaculation? With chronic SSRI treatment, there is blockade of the serotonin transport receptors. This increases extracellular 5-HT and in the process of increasing the extracellular 5-HT, there is desensitization of the 5-HT1A autoreceptors, which normally act as a brake on the 5-HT system. Chronic treatment with SSRIs then results in increased synaptic release of serotonin, strong serotonin neurotransmission, and the result of that is increased inhibition of the lumbosacral cord by the nPGI. This is currently the best explanation that we have for the effect of chronic SSRI treatment resulting in delay of ejaculation in men who have PE. So this constitutes a pharmacologic and physiologic explanation for the mechanisms of action of SSRI treatment.

    Slide
    Slide 13. Use of SRIs in PE

    What's the evidence that SSRIs are effective for the treatment of PE? In this slide, we're using the term "SRIs" (serotonin reuptake inhibitors) not "SSRIs." The reason for this is that clomipramine, which was the first drug to be used for this treatment, is not an SSRI. It is actually a tricyclic antidepressant that acts as an SRI, but not an SSRI. It was first tried in 1973 and it was moderately effective, but it has a high incidence of adverse effects. Subsequently, SSRIs were developed and 5 of them -- citalopram, paroxetine, sertraline, fluoxetine, and fluvoxamine -- were introduced for depression in the 1980s. Delayed ejaculation was recognized as a side effect of these drugs in the treatment of men with depression, and the first trials of SSRIs for the treatment of PE were conducted in 1995, starting with sertraline. The effects were measured mainly on IELT, but not other patient-related measures such as control, satisfaction, or the bothersomeness of PE. Most of these studies have used chronic, rather than prn (as needed) dosing.

    Slide
    Slide 14. Onset of Effect of SSRIs

    Here is a report on the use of sertraline in a double-blind, crossover study. Let's look first at the patients who were treated with sertraline. At baseline, their IELT was less than a half of a minute. Over a period of about 1 to 2 weeks after initiation of therapy, the IELT increased to the range of 3 minutes. After termination of treatment with sertraline in the washout period, the curve comes back down in another 1 to 2 weeks and eventually, after about 4 weeks, to baseline. If we look at the patients who were started on placebo, they had a minor placebo response rate; there was a little bit of increase in the IELT, no further increase during the washout period, but when they were converted from placebo to sertraline, the graph mirrors the effects that we saw with the initial group of patients who were treated with sertraline. So what we see here is that with sertraline treatment, the IELT changes from about half a minute to about 3 minutes, and it's seen in both arms of the study.

    Slide
    Slide 15. Effectiveness of SSRIs

    Here are some data comparing the effectiveness of all 4 of the SSRIs -- fluvoxamine, fluoxetine, paroxetine, and sertraline -- compared with placebo. At baseline, the IELT is about 20 seconds; a small placebo response rate is seen. All 4 of these drugs produce a response rate that is statistically significant, but the greatest of them is with paroxetine, in which the IELT increased from about 30 seconds to over 450 seconds. For that reason, my personal practice is to begin treatment with paroxetine.

    Slide
    Slide 16. Drawbacks of Existing SSRIs

    There are drawbacks, however, of these existing SSRIs. They work better in chronic dosing, although they can work adequately in prn dosing. They have a slow onset of action, a slow clearance with a risk of accumulation because of a relatively long half-life, and they can induce various adverse effects, including nausea, drowsiness, cognitive impairment, sexual side effects, and other problems.

    Slide
    Slide 17. Ideal PE Treatment Profile

    What would be the profile of an ideal drug for the treatment of PE, an ideal SSRI? It would be a drug that could be used orally, discretely, in a single dose; it would be effective from the first dose (no loading dose would be needed); it would be available and used on an on-demand or prn dosing profile, not requiring chronic administration; it would have a rapid onset of action to fit the time period that the patient recognizes from the beginning of sexual interest until intercourse occurs; and there would be a low incidence of adverse effects. We are yet to hear of a drug that fits these characteristics, but there are several compounds that are being developed.


    Diagnosis and Treatment of PE: The Physician's Perspective

    Ira D. Sharlip, MD

    Summary

    Slide
    Slide 18. Summary

    In summary, diagnostic criteria are variable and not well understood for PE. Behavioral therapies are effective, but cumbersome. Topical agents and various pharmacological agents have been used but their efficacy rates are not good. Selective serotonin reuptake inhibitors have been shown to have the best efficacy, but their pharmacologic characteristics make them less than ideal. And the ideal profile for a PE drug would be an on-demand oral treatment with a rapid onset of action, rapid elimination, and a low incidence of side effects.


    Flash Section

    Flash Section

    1. Premature Ejaculation: Past, Present, and Future Perspectives: Introduction
      by Chris G. McMahon, MD
      Introduction

    2. Prevalence of PE: A Global and Regional Perspective
      by Francesco Montorsi, MD
      Premature Ejaculation: Introduction and Definitions
      Prevalence of Premature Ejaculation by Region
      Other Factors Influencing Prevalence
      Etiologies and Comorbidities of Premature Ejaculation
      Summary

    3. Burden of PE: The Patient's Perspective
      by Mariano Sotomayor, MD
      Perceptions of Normal Sexual Function
      Control and Satisfaction: What Is Normal?
      Barriers to Patient Diagnosis and Treatment
      Burdens of Premature Ejaculation
      Other Issues Associated With Premature Ejaculation
      Summary

    4. Diagnosis and Treatment of PE: The Physician's Perspective
      by Ira D. Sharlip, MD
      Premature Ejaculation: Patient Screening and Evaluation
      Behavioral Therapy
      Topical Therapy
      Use of Phosphodiesterase Type 5 Inhibitors
      Use of Selective Serotonin Reuptake Inhibitors
      Summary




    Authors and Disclosures

    Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient's conditions and possible contraindications on dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

    Postgraduate Institute for Medicine has a conflict of interest policy that requires course faculty to disclose any real or apparent commercial financial affiliations related to the content of their presentations/materials. It is not assumed that these financial interests or affiliations will have an adverse impact on faculty presentations; they are simply noted here to fully inform participants.

    This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by FDA. The Postgraduate Institute for Medicine (PIM), Medscape and Ortho-McNeil do not recommend the use of any agent outside of the labeled indications.

    The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of PIM, Medscape and Ortho-McNeil. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings.

    Author

    Chris G. McMahon, MD

    Director, Australian Centre for Sexual Health, St Leonards, Australia

    Disclosure: Consultant: Johnson & Johnson Pharmaceuticals; Speakers' Bureau: Johnson & Johnson Pharmaceuticals.

    Francesco Montorsi, MD

    Associate Professor of Urology, Universita Vita-Salute San Raffaele, Milan, Italy

    Disclosure: Dr. Montorsi disclosed having no financial interest/relationships with commercial entities related to his presentation materials.

    Ira D. Sharlip, MD

    Assistant Clinical Professor of Urology, University of California San Francisco; Secretary General, International Society for Sexual and Impotence Research, San Francisco, CA, United States of America

    Disclosure: Consultant: Bayer Pharmaceuticals, Eli Lilly & Company, GlaxoSmithKline, Icos, Ortho-McNeil, Pfizer, Inc.; Speakers' Bureau: Bayer Pharmaceuticals, Eli Lilly & Company, GlaxoSmithKline, Icos, Pfizer, Inc.

    Mariano Sotomayor de Zavaleta, MD

    Professor of Urology, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico

    Disclosure: Dr. Sotomayor disclosed having no financial interest/relationships with commercial entities related to his presentation materials.

     

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