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Home , Delayed ejaculation, Erectile dysfunction, Lidocaine, Mirtazapine, Premature ejaculation

From the Clinical Inquiries Family Physicians Inquiries Network

Michael G. Mercado, MD, Sandra L. Kimmer, MD, What’s the best drug treatment MPH, and John R. Holman, MD, MPH for premature ? Department of Family , Naval Hospital Camp Pendleton, Camp Pendleton, Calif Gerri Wanserski, MA Evidence-based answer Ebling Library, University —specifically There is no evidence that of Wisconsin-Madison , , , type 5 (PDE5) and —are best and have been inhibitors—such as (Viagra), shown to improve symptoms of premature (Levitra), and ejaculation (strength of recommendation (Cialis)—decrease instances of premature [SOR]: A, meta-analysis of randomized ejaculation in otherwise healthy men. controlled trials [RCTs]). The topical There is limited evidence, however, application of -lidocaine cream that PDE5 inhibitors reduce symptoms (trade name EMLA) improves intravaginal of for men with ejaculatory latency time (IELT), but penile concomitant numbness and loss of may occur (SOR: B, systematic review of RCTs of (SOR: B, based on several small RCTs). variable quality). fast track Clinical commentary SSRIs significantly Overcome any reluctance a thorough medical history, including to discuss premature ejaculation pertinent sexual history and physical delay ejaculation Family physicians should be comfortable examination, can often establish the compared with diagnosing and treating premature diagnosis of premature ejaculation. ejaculation because of their unique and Effective treatments can improve sexual long-term relationship with the patient. satisfaction and quality of life for both the But that’s not always the case. Premature men and their partners. ejaculation is underdiagnosed and Vincent Lo, MD undertreated because of a reluctance to San Joaquin Family Medicine Residency, discuss it, by both patient and physician. French Camp, Calif

z Evidence summary Studies in male rats have demon- Premature ejaculation is the most com- strated that with various mon male , but there 5-HT subtypes are involved in is no universally accepted definition or the ejaculatory process.2 Based on these validated screening instrument. The studies, it’s been suggested that lifelong pathophysiology and etiology remain premature ejaculation is a neurobiolog- incompletely understood.1 Based on ical phenomenon related to decreased surveys, prevalence rates for premature central neurotransmis-

ejaculation are approximately 20% to sion, 5-HT2c receptor hyposensitivity, or 1 3 30%. 5-HT1a receptor hypersensitivity.

192 vol 57, No 3 / March 2008 The Journal of Family Practice Antidepressants EMLA cream: “Improvement” delay ejaculation and “cure” seen The introduction of selective serotonin EMLA cream, a topical , has inhibitors (SSRIs) revolution- been evaluated as a treatment option ized the treatment of premature ejacula- for premature ejaculation. One double- tion.4 In 1994, the first study of SSRIs in blinded RCT7 (N=29) showed signifi- men with premature ejaculation demon- cant improvement in the IELT (mea- strated a delaying effect with paroxetine sured by stopwatch by the subject’s (Paxil).5 Since that time, SSRIs have been partner) from baseline compared with repeatedly investigated for their propensi- placebo (8.45 min vs 1.95 min; P<.001) ty to delay ejaculation. Certain SSRIs and at 2 months. the clomipramine Another RCT8 (N=84) compared (Anafranil) have become the agents of EMLA cream applied 15 minutes prior choice for the treatment of premature to intercourse, sildenafil 50 mg orally ejaculation.6 45 minutes prior to intercourse, EMLA A meta-analysis6 of 35 treatment cream plus sildenafil, and placebo. In the studies with serotonergic antidepressants sildenafil-plus-EMLA group, 32% of the from 1943 to 2003 shows that, despite patients reported “improvement” and major differences in design and drug 54% reported “cure,” which was defined dosing, clomipramine, fluoxetine (Pro- as ejaculation delayed until the patient zac), paroxetine, and sertraline (Zoloft) wished it. In the EMLA-only group, 27% significantly delay ejaculation compared of the patients reported “improvement” with placebo. The percentage increase and 50% reported “cure.” This was a in IELT was the primary outcome mea- statistically significant difference when sured. The rank order of efficacy was: compared with the placebo and sildena- 1) paroxetine (1492% IELT in- fil-only groups (number needed to treat crease; 95% confidence interval [CI], [NNT]=3). There was no significant dif- 918–2425) ference in reports of “improvement” or 2) sertraline (790% IELT increase; “cure” between the placebo and sildena- fast track 95% CI, 532–1173) fil-only groups. Topical prilocaine/ 3) clomipramine (512% IELT in- One small RCT9 (N=24) compared crease; 95% CI, 234–1122) placebo with the application of EMLA lidocaine cream 4) fluoxetine (295% IELT increase; cream 20, 30, and 45 minutes prior to (EMLA) improves 95% CI, 172–506).6 . Improvement was intravaginal Of the 35 studies used in the previ- seen in IELT in the 20- and 30-minute ejaculatory ous meta-analysis, 8 studies (N=263) group, but penile numbness and erection were prospective, double-blind, real-time loss increased in the 30- and 45-minute latency time stopwatch studies that were separately group. analyzed in a subsequent meta-analysis. These 8 studies evaluated clomipramine, PDE5 inhibitors: fluoxetine, paroxetine, sertraline, citalo- No convincing evidence pram (Celexa), (Luvox), A review10 of 14 clinical trials concluded mirtazapine (Remeron), and nefazo- that there is no convincing evidence for done (Serzone) against placebo. Par- PDE5 inhibitors in the treatment of men oxetine (783% IELT increase, 95% CI, with lifelong premature ejaculation and 499–1228), clomipramine (360% IELT normal erectile function. One RCT11 increase, 95% CI, 200–435), sertraline found no increase in IELT from baseline (313%, 95% CI, 161–608), and fluox- in men taking sildenafil when compared etine (295%, 95% CI, 200–435) exerted with placebo, although patients reported a significant delay in the IELT compared overall sexual satisfaction and confidence with placebo.6 based on a questionnaire. c o n TI n u e D

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Inqu However, a study by Li et al treat- 3. Waldinger MD, Berendsen HH, Blok BF, Olivier B, ed 45 men with premature ejaculation Holstege G. Premature ejaculation and serotoner-

al gic antidepressants-induced :

c and comorbid erectile dysfunction with the involvement of the serotonergic system. Behav sildenafil. Eighty-nine percent reported Brain Res 1998; 92:111–118. improved erectile function, and 60% re- 4. Waldinger MD, Olivier B. Utility of selective sero-

Clini tonin reuptake inhibitors in premature ejaculation. ported decreased severity of premature Curr Opin Investig Drugs 2004; 5:743–747. ejaculation. 5. Waldinger MD, Hengeveld MW, Zwinderman AH. Paroxetine treatment of premature ejaculation: Recommendations from others a double-blind, randomized, placebo-controlled study. Am J 1994; 151:1377–1379. The American Urological Association13 6. Waldinger MD, Zwinderman AH, Schweitzer DH, recommends antidepressants as first-line Olivier B. Relevance of methodological design for systemic for premature ejacula- the interpretation of efficacy of drug treatment of premature ejaculation: a systematic review and tion, specifically the SSRIs fluoxetine, meta-analysis. Int J Impot Res 2004; 16:369–381. paroxetine, sertraline, and the tricyclic 7. Busato W, Galindo CC. Topical anaesthetic use clomipramine. Topical EMLA cream is for treating premature ejaculation: a double-blind, also recommended, but the reduction of randomized, placebo-controlled study. BJU Int 2004; 93:1018–1021. penile sensation may limit the accept- 8. atan A, Basar MM, Tuncel A, Ferhat M, Agras K, ability of this treatment option. Tekdogan U. Comparison of efficacy of sildenafil- The British Association for Sexual only, sildenafil plus topical EMLA cream, and topi- Health and HIV Special Interest Group cal EMLA-cream-only in treatment of premature ejaculation. 2006; 67:388–391. for Sexual Dysfunction14 also recom- 9. atikeler MK, Gecit I, Senol FA. Optimum usage of mends SSRIs and clomipramine as they prilocaine-lidocaine cream in premature ejacula- have the strongest evidence for their tion. Andrologia 2002; 34:356–359. efficacy. The group emphasizes the im- 10. McMahon CG, McMahon CN, Leow LJ, Winestock CG. Efficacy of type-5 phosphodiesterase inhibi- portance of combining behavioral and tors in the drug treatment of premature ejaculation: pharmacologic as the manage- a systematic review. BJU Int 2006; 98:259–272. ment approach should be tailored to the 11. McMahon CG, Stuckey BG, Andersen M, et al. Ef- ficacy of sildenafil citrate (Viagra) in men with pre- individual patient. n fast track mature ejaculation. J Sex Med 2005; 2:368–375. Acknowledgments 12. li X, Zhang SX, Cheng HM, Zhang WD. Clinical There is no good study of sildenafil in the treatment of premature The views expressed in this article are those of the au- ejaculation complicated by erectile dysfunction [in thors and do not necessarily reflect the official policy or Chinese]. Zhonghua Nan Ke Xue 2003; 9:266–269. evidence that position of the Department of the Navy, Department of Defense, nor the US Government. 13. Montague DK, Jarow J, Broderick GA, et al; AUA PDE5 inhibitors Erectile Dysfunction Guideline Update Panel. AUA treat premature References guideline on the pharmacologic management of premature ejaculation. J Urol 2004; 172:290–294. 1. althof SE. Prevalence, characteristics and implica- ejaculation tions of premature ejaculation/rapid ejaculation. 14. richardson D, Goldmeier D, Green J, Lamba H, effectively J Urol 2006; 175(3 pt 1):842–848. Harris JR; BASHH Special Interest Group for Sex- 2. ahlenius S, Larsson K, Svensson L, et al. Effects ual Dysfunction. Recommendations for the man- of a new type of 5-HT receptor on male rat agement of premature ejaculation: BASHH Special sexual behavior. Pharmacol Biochem Behav 1981; Interest Group for Sexual Dysfunction. Int J STD 15:785–792. AIDS 2006; 17:1–6.

194 vol 57, No 3 / March 2008 The Journal of Family Practice