Managing Early Ejaculation: What Does the Future Hold?

Treatment Update

TREATMENT UPDATE Managing Early Ejaculation: What Does the Future Hold? Michael P. O’Leary, MD, MPH Division of Urology, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA Recent attention in the field of male sexual dysfunction has focused on erectile dysfunction. However, premature ejaculation (PE) is an extremely common condition that warrants clinical study and exploration of pharmacologic treatments. Until recently, PE was thought to be a behavioral problem for which the best remedy was a learned control technique. However, some drugs currently on the market, including sildenafil and the selective serotonin reuptake inhibitors, appear to have efficacy in the treatment of PE. More research is needed before FDA approval of such agents for this indication, but more and better options for men with PE are anticipated as attention to ejaculatory disorders grows and, hopefully, the associated stigma decreases. [Rev Urol. 2004;6(1):5-10] © 2004 MedReviews, LLC Key words: Premature ejaculation • Ejaculatory latency • Sildenafil • Selective serotonin reuptake inhibitors he field of sexual dysfunction continues to grow and, what began several decades ago with a focus on male erection, now encompasses female disorders as well. A recent literature search of the National Library of Medicine database yielded 15,506 entries for the term “male sexual dysfunction,” compared with 7939 for “female sexual dysfunction.” This increased awareness of and inter- T VOL. 6 NO. 1 2004 REVIEWS IN UROLOGY 5 Managing Early Ejaculation continued est in the field is not surprising, as the introduction of oral pharmacologic therapy for erectile dysfunction (ED) has brought this term into the twenty-first century popular lexicon (with thanks to former Senator Bob Dole and others). The prevalence of ED has been widely recognized since the landmark epidemiologic studies of McKinlay and colleagues in the early 1990s.1 But what about other disorders of male sexual function? In particular, sively to the direct effects of a substance (eg, withdrawal from opioids). The DSM-IV definition is intentionally broad, but recent studies give some indication of what should be considered normal versus early ejaculation. Rowland and colleagues4 compared ejaculatory response during coitus and masturbation in 26 men with PE with that in 13 agematched, sexually functional men. ning of stimulation (usually during vaginal penetration) until ejaculation is the measure most reported in PE studies.5 Other measures have also been reported, such as number of intravaginal thrusts.6 These measures are, at best, somewhat subjective and generally difficult to reproduce. A recently developed device attempts to solve this problem by applying continuous vibratory stimulation to the penis and measuring ejaculatory latency times.6 Epidemiology Mean ejaculatory latency during vaginal penetrative sex was 1.5 minutes in the PE group and 5.6 minutes in the control group. ejaculatory disorders and early or premature ejaculation (PE), although highly prevalent, have received little attention. The National Library of Medicine database contained only 290 entries for PE, yet community-based studies indicate that nearly one third of all men suffer with the condition.2 How is this disorder defined, what causes it, and how can we treat it? Definition and Prevalence There is no clear consensus on the definition of PE, although the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria are generally accepted3: 1. Persistent or recurrent ejaculation with minimal stimulation before or shortly after penetration and before the person wishes it. (The clinician must take into account the factors that affect duration of the excitement phase, such as age, novelty of the sex partner or situation, and recent frequency of sexual activity.) 2. The disturbance causes marked distress or interpersonal difficulty. 3. The condition is not due exclu- 6 VOL. 6 NO. 1 2004 REVIEWS IN UROLOGY Mean ejaculatory latency during vaginal penetrative sex was 1.5 minutes in the PE group and 5.6 minutes in the control group. Ejaculation during masturbation yielded different results, with men with PE having latency times similar to those of controls (approximately 4.5 minutes). Furthermore, the frequency of reported sexual activity (intercourse or masturbation) was similar in both groups. Thus, the long-held theory regarding the cause of PE—that it results from long intervals between attempts to ejaculate or fewer oppor- Recent studies from primary care settings place the prevalence of PE from 31% in the United States7 to as high as 66% in Germany.8 Lower estimates, ranging from 10% to 25%, have been reported from sexual dysfunction clinics.9 Despite the prevalence of PE, there is an obvious stigma associated with the condition and it is likely underreported. Physiology of Ejaculation The process of ejaculation is under both central and peripheral control. Efferent sympathetic nerves from the spinal segments T12 to L2 form the lumbar sympathetic ganglia. These encircle the aorta and coalesce in the midline to form the hypogastric Recent studies from primary care settings place the prevalence of PE from 31% in the United States to as high as 66% in Germany. tunities to learn control—should be seriously questioned. PE has also been described as either “global” or “situational” in reference to either a lifelong or an acquired problem. At some time in their lives, all men have probably experienced an episode of ejaculation before they desired it; thus, situational PE is likely an extremely common problem. The length of time from the begin- plexus just below the aortic bifurcation. They give rise to the hypogastric nerve, which terminates as postganglionic fibers at the bladder neck, seminal vesicles, vasa, and paraprostatic tissues. Acetylcholine acts as a neurotransmitter while sympathetic activity stimulates contraction at the bladder neck, seminal vesicles, and vasa. The ejaculatory reflex results from Managing Early Ejaculation somatic stimulation of the bulbocavernous and ischiocavernosus muscles and is controlled by the pudendal nerve. The central control of this process is not as well understood, but the locus ceruleus and the medial preoptic area have been identified as important cortical centers. Ejaculation generally occurs because of a reflex mechanism initially triggered by stimulation of the penis via pudendal sensory nerves, with communication to the spinal cord and the sensory cortex. The secondary reflex is completed after activation of the efferent somatic fibers to the ischiocavernosus and other perineal muscles. Why does this reflex occur in some men before they desire it? In the past, this was thought to be largely a behavioral problem. Recently, however, investigators have questioned whether the local penile response may be altered in men with PE. Xin and colleagues10 investigated penile sensory levels using biothesiometry in men with PE and compared them with normal levels. In men without PE, measurements of vibratory threshold increased with age, whereas, in men with PE, they were significantly decreased regardless of age (P < .001). In follow-up studies, the investiga- Table 1 Pharmacologic Therapy for Premature Ejaculation Study Agent Reported Benefit Goodman Abdel-Hamid et al22 Clomipramine Superior to placebo McMahon and Touma21 Abdel-Hamid et al22 Paroxetine Superior to placebo Kim and Paick20 Abdel-Hamid et al22 Sertraline Superior to placebo Phenoxybenzamine Minor benefit Cooper and Magnus Propranolol No efficacy Abdel-Hamid et al Sildenafil Superior to placebo 17 Beretta et al19 18 22 facilitates PE. This idea has been challenged by other investigators who have not been able to document penile hypersensitivity in men with PE and suggest that other somatic or cognitive factors are responsible.12 Evaluation Because PE and ED may coexist, it is important to clearly distinguish between these 2 common conditions in men presenting with sexual dysfunction. A detailed and complete sexual history should be obtained for all patients; the diagnosis of PE A detailed and complete sexual history should be obtained for all patients; the diagnosis of PE is largely made from self-report. tors further examined penile hypersensitivity by evaluating somatosensory evoked potential in men with PE and in controls.11 The mean latencies of dorsal nerve and glans penis somatosensory evoked potentials, respectively, were 1.51 and 6.80 milliseconds shorter in men with PE than in controls. The authors therefore concluded that men with PE have greater cortical representation of sensory stimuli from the penis, which and physiologic testing using standard techniques, such as Doppler ultrasonography or biothesiometry, is generally unrevealing. New devices that can stimulate patients to ejaculation may be useful in certain circumstances.6 is largely made from self-report. Patients should be questioned about frequency and duration of activity required for ejaculation, as well as whether the problem exists with certain types of sexual stimulation versus others (eg, masturbation, oral sexual activity, vaginal intercourse). Genital physical examination should also be performed, although few abnormalities associated with PE have been reported. Laboratory Treating PE As early as 1956, Semans13 described the pause technique for the treatment of PE. Masters and Johnson14 modified this to the pause/squeeze technique in 1970. Patients were advised to cease thrusting or any other penile stimulation at the point at which ejaculation seemed inevitable, forcibly squeeze the glans penis, and then resume activity.15 The rationale behind this process was to train the man to recognize the typical premonitory sensation immediately preceding ejaculation and, thus, lead to better control. As late as the early 1990s, this technique was still believed to be the most appropriate treatment choice for PE.16 Nevertheless, pharmacologic therapy was beginning to gain proponents. Pharmacologic Therapy Selective serotonin reuptake inhibitors (SSRIs) were the first class of phar- VOL. 6 NO. 1 2004 REVIEWS IN UROLOGY 7 Managing Early Ejaculation continued macologic agents widely used to treat PE (Table 1). In 1980, Goodman17 evaluated clomipramine for the treatment of PE and found it to be superior to placebo. Cooper and Magnus18 experimented with the ß-blocker propranolol in 1984, but results showed no improvement in men with PE. Beretta and colleagues19 evaluated phenoxybenzamine, a nonspecific -adrenergic antagonist, in 15 men with PE, occurred after 4 weeks of treatment and an additional 3-week drug-free washout period. At 4 weeks, mean ejaculatory latency was 3.2 minutes in the paroxetine group and 0.45 minutes in the placebo group (P < .001). No adverse events were reported. In the second study, men received paroxetine, 10 mg, or placebo daily for 3 weeks, followed by paroxetine, 20 mg, or placebo as needed 3 to 4 This study seems to indicate that better ejaculatory control is achieved with initial daily treatment followed by as-needed treatment thereafter. 8 of whom reported improvement in the condition. Some study patients reported a “dry ejaculation,” which most likely represented retrograde ejaculation. -Blockers are known to cause bladder neck relaxation and also affect seminal emission and, potentially, vasal smooth muscle contraction. No other -blockers, however, have been reported to be useful in treating ejaculatory disturbances. Sertraline, another SSRI, has also been proposed as a treatment of PE. Kim and Paick20 reported increased ejaculatory latency times, from 23 ± 19 seconds before treatment to 5.9 ± 4.2 minutes after use of sertraline, 50 mg daily. Similar results were achieved with sertraline, 50 mg or 100 mg, used on an as-needed basis. Peak plasma levels are achieved at 4 to 8 hours; thus, the authors recommend taking the drug in the early evening when intercourse or sexual activity is anticipated.20 McMahon and Touma21 reported results of 2 single-blind, placebocontrolled, crossover studies of the SSRI paroxetine. Mean pretreatment ejaculatory latency time was less than 30 seconds in both studies. In the first study, patients received paroxetine, 20 mg, or placebo 3 to 4 hours before intercourse. Crossover 8 VOL. 6 NO. 1 2004 REVIEWS IN UROLOGY hours before anticipated sexual activity. Mean ejaculatory latency time was 4.3 minutes in the daily-paroxetine phase and 5.8 minutes in the as-needed phase, compared with 0.9 minutes and 0.6 minutes in the daily and asneeded placebo phases, respectively (P < .001). Adverse events, including anejaculation, anorexia, decreased libido, and gastrointestinal upset, were reported in 17% of patients. This study seems to indicate that better ejaculatory control is achieved with initial daily treatment followed by as-needed treatment thereafter. Recently, Abdel-Hamid and colleagues22 compared clomipramine, sertraline, paroxetine, sildenafil, and the pause/squeeze technique for the other treatments in prolonging ejaculatory latency time; clomipramine, sertraline, and paroxetine were all superior to the pause/squeeze technique. The reason for sildenafil’s superiority is unclear but may be explained by central effects involving increased cyclic guanosine monophosphate activity. Many clinicians currently recommend a combination of sildenafil and an SSRI, particularly for patients who complain of both PE and ED. Topical Agents Choi and colleagues23 recently reported on an agent that is applied to the ventral penile area and has previously been shown to increase penile vibratory threshold and prolong ejaculatory latency, as well as reduce the amplitude of penile somatosensory evoked potentials.24 This topical agent, called SS cream, is a mixture of Ginseng Redix Alba, Angelicae Gigantic Radix, Cistanchis Herba, Zanthoxylli Fructs, Torlidis Semen, Asiasari Radix, Caryophylli Flos, Cinnamoni Cortex, and Bufonis Veneum. A randomized, double-blind, placebo-controlled trial was conducted in 106 men with lifelong PE. Subjects were instructed to apply the cream to the glans and frenular area of the penis 1 hour before intercourse. Mean ejaculatory latency time was pro- Many clinicians currently recommend a combination of sildenafil and an SSRI, particularly for patients who complain of both PE and ED. treatment of PE in a prospective, randomized, double-blind crossover study (not placebo-controlled). Thirtyone men with PE were randomized to receive 4 weeks of treatment with one of the 5 treatment modalities. At the end of the study, all subjects noted significant improvement from baseline. Sildenafil was superior to all longed from 1.37 ± 0.12 minutes to 10.92 ± 0.95 minutes in the treatment group versus 2.45 ± 0.29 minutes in the placebo group. Mild local burning was reported in 18% of treatment subjects; no adverse partner effects were observed. SS cream, which was developed in Korea, is not commercially available in the United States. Managing Early Ejaculation Topical lidocaine and prilocaine cream (EMLA cream, lidocaine 2.5% and prilocaine 2.5%, AstraZeneca Pharmaceuticals) has been anecdotally reported to have some efficacy in the treatment of PE. This agent should probably be used in conjunction with a condom. Herbal Agents Numerous over-the-counter agents are advertised for the treatment of PE. These range from oral remedies to creams and other topical Although the precise definition of the disorder is unclear, with most studies pointing to an ejaculatory latency time of less than 1 to 2 minutes, the condition is bothersome enough to most men and/or their partners to consider treatment. The phosphodiesterase-5 inhibitor sildenafil and the SSRIs sertraline, clomipramine, and paroxetine appear to have potentially promising therapeutic roles. It should be emphasized that none of these drugs has been approved by the FDA for the treat- 3. 4. 5. 6. 7. All men are likely to experience PE at some point in their lives. 8. products. A recent Internet search revealed products such as “Indian God Lotion,” “Quang’s Solution,” “Stud 100,” and “Iron Wood.” Because none of these agents is regulated by the FDA, their contents, as well as their efficacy, are unknown. ment of PE. However, given the prevalence of this condition and the potentially large market for agents to treat it, these and other similar products are likely to be approved for this indication at some time in the future. Conclusion References Of the 3 major forms of male sexual dysfunction—ED, PE, and decreased libido—PE is probably the most common. All men are likely to experience PE at some point in their lives. 1. 2. Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychological correlates: results of the Massachusetts Male Aging Study. J Urol. 1994;151:54-61. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predic- 9. 10. 11. 12. 13. tors. JAMA. 1999;281:537-555. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. Arlington, Va: American Psychiatric Press; 1994. Rowland DL, Strassberg DS, de Gouveia Brazao CA, Slob AK. Ejaculatory latency and control in men with premature ejaculation: an analysis across sexual activities using multiple sources of information. J Psychosom Res. 2000;48:69-77. Rowland DL, Cooper SE, Schneider M. Defining premature ejaculation for experimental and clinical investigators. Arch Sex Behav. 2001; 30:235-253. O’Leary M, Wylie M. Assessing ejaculatory latency in normals and in men with early ejaculation: use of a new automated device [abstract]. J Urol. 2001;165:1105A. Read S, King M, Watson J. Sexual dysfunction in primary medical care: prevalence, characteristics and detection by the general practitioner. J Public Health Med. 1997;19:387-391. Aschka C, Himmel W, Ittner E, Kochen M. Sexual problems of male patients in family practice. J Fam Pract. 2001;50:773-778. Goldmeier D, Keane FE, Carter P, et al. Prevalence of sexual dysfunction in heterosexual patients attending a central London genitourinary medicine clinic. Int J STD AIDS. 1997;8:303-306. Xin ZC, Chung WS, Choi YD, et al. Penile sensitivity in patients with primary premature ejaculation. J Urol. 1996;156:979-981. Xin ZC, Choi YD, Rha KH, Choi HK. Somatosensory evoked potentials in patients with primary premature ejaculation. J Urol. 1997; 158:451-455. Rowland DL, Haensel SM, Blom JH, Slob AK. Penile sensitivity in men with premature ejaculation and erectile dysfunction. J Sex Marital Ther. 1993;19:189-197. Semans JH. Premature ejaculation: a new Main Points • Although there is no clear consensus on the definition of premature ejaculation (PE), it is generally accepted that PE consists of persistent or recurrent ejaculation with minimal stimulation before or shortly after penetration and before the person wishes it, which causes marked distress or interpersonal difficulty and is not due exclusively to the direct effects of a substance. • A biothesiometry study by Xin and colleagues concluded that men with PE have greater cortical representation of sensory stimuli from the penis; however, other studies have failed to document penile hypersensitivity and, therefore, other somatic or cognitive factors may be responsible. • Because self-report is often more revealing than physical findings or standard laboratory and physiologic testing, a thorough sexual history is the most important tool in establishing the diagnosis of PE. • Although not yet FDA-approved for this indication, sildenafil, a topical treatment called SS cream, and some of the selective serotonin reuptake inhibitors (sertraline, clomipramine, and paroxetine) have been shown to be promising potential therapies for PE (and perhaps more effective than previous remedies, such as the “pause/squeeze” technique). VOL. 6 NO. 1 2004 REVIEWS IN UROLOGY 9 Managing Early Ejaculation continued 18. approach. South Med J. 1956;49:353-358. Masters WH, Johnson VE. Human Sexual Response. Boston: Little Brown; 1970. Westheimer RK. Encyclopedia of Sex. New York: Continuum; 2002. St Lawrence JS, Madakasira S. Evaluation and treatment: a critical review. Int J Psychiatry Med. 1992;22:77-97. Goodman RE. An assessment of clomipramine (Anafranil) in the treatment of premature ejaculation. J Int Med Res. 1980;8(suppl 3):53-59. Cooper AJ, Magnus RV. A clinical trial of the 10 VOL. 6 NO. 1 2004 14. 15. 16. 17. REVIEWS IN UROLOGY 19. 20. 21. beta blocker propranolol in premature ejaculation. J Psychosom Res. 1984;28:331-336. Beretta G, Chelo E, Fanciullacci F, Zanollo A. Effect of an alpha-blocker agent (phenoxybenzamine) in the management of premature ejaculation. Acta Eur Fertil. 1986;17:43-45. 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. McMahon CG, Touma K. Treatment of premature ejaculation with paroxetine hydrochloride as 22. 23. 24. needed: 2 single-blind placebo controlled crossover studies. J Urol. 1990;161:1826-1830. 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. Choi HK, Jung GW, Moon KH, et al. Clinical study of SS-cream in patients with lifelong premature ejaculation. Urology. 2000;55:257-261. Xin ZC, Seong DH, Choi HK. A double blind clinical trial of SS cream on premature ejaculation [abstract]. Int J Impot Res. 1994;6(suppl):D73.