Premature Ejaculation: a Clinical Review for the General Physician

Home , Delayed ejaculation, Erectile dysfunction, Premature ejaculation

CLINICAL

Premature ejaculation: A clinical review for the general physician

Eric Chung, Brent Gilbert, Marlon Perera, Matthew J Roberts

Background remature ejaculation is one of the ejaculatory latency time (IELT). The most common sexual dysfunctions, IELT is defined as the time from vaginal Premature ejaculation is one of the most P affecting up to 21–31% of the penetration to ejaculation. Lifelong common sexual dysfunctions in men. Australian adult male population, premature ejaculation is characterised Recent epidemiological studies suggest irrespective of their age, marital status or by an IELT of <1 minutes since first its prevalence in Australia may range ethnicity.1–5 This sexual condition is likely intercourse, whereas IELT of <3 minutes from 21–31%. to be under-reported and under-treated at any point in a man’s life is considered 12 Objective because of the patients’ perceived shame to be acquired premature ejaculation. and low self-esteem. This is in addition to Premature ejaculation can be further This article will discuss the current many physicians feeling uncomfortable divided into authority-based subtypes definition of premature ejaculation from or uncertain about the management ‘variable’ and ‘subjective’ (Table 1), a urological perspective. It will provide of premature ejaculation.6,7 The impact which describe individuals experiencing an understanding of the pathogenesis of premature ejaculation is mostly felt significant distress and dissatisfaction of premature ejaculation, as well as psychologically and in interpersonal with ejaculation.12 assessment and management options. relationships.8 Men with premature ejaculation often experience significant Pathophysiology and Discussion psychological distress, avoid physical and associations Premature ejaculation can have a emotional intimacy, and become victims Psychological components often significant adverse effect on the quality of false medical advertisings and unproven contribute to acquired premature of life for the patient and his sexual medical management.8 –11 ejaculation. However, it is likely partner’s. It can potentially lead to The aim of this article is to provide that a complex interplay between psychological distress, diminished self- general practitioners (GPs) with an neurophysiological factors predominantly esteem, anxiety, erectile dysfunction, overview to assess and manage patients influence premature ejaculation. In reduced libido and poor interpersonal with premature ejaculation and other particular, genetic predisposition for relationships. Most men feel reluctant associated sexual dysfunction. impairment of inhibitory serotonergic to discuss premature ejaculation with pathways that regulate ejaculation, their general practitioner despite its Definition and classification modulated by 5-HT2c , 5-HT1a, 5-HT1b psychological, emotional and relational Premature ejaculation is defined as the receptors and synaptic serotonin effects. Effective, evidence-based inability to control or delay ejaculation, transporters has been reported for treatment options are available and which results in dissatisfaction or distress lifelong premature ejaculation.13,14 Other physicians should feel confident when for the patient. Recently, the International conditions, such as chronic prostatitis and exploring ways to improve the quality of Society of Sexual Medicine (ISSM) hyperthyroidism, may also be associated life for men with sexual dysfunction. classified premature ejaculation as lifelong with acquired premature ejaculation.15,16 or acquired, and proposed inclusion of an Erectile dysfunction and premature objective, quantifiable time to ejaculation, ejaculation frequently co-exist,5,17 as men which is referred to as the intravaginal with erectile dysfunction might try to

ejaculate early, before loss of erection.1 7, 1 8 It is also important to explore the neurological, lower limb and genital Thus, detection of comorbid erectile perceived degree of ejaculatory control, examinations are recommended. Although dysfunction is crucial in guiding therapeutic estimated IELT (precise timing is not examination has a low diagnostic yield, it implementation.19 necessary), previous attempts to correct facilitates important reassurance for the premature ejaculation, and the impact patient that he is anatomically normal. Assessment of premature on interpersonal relationships and quality There are no specific investigations to ejaculation of life. Various screening questionnaires confirm or exclude premature ejaculation. Patients with premature ejaculation may such as the Premature Ejaculation Any additional investigations should present to general practice because Diagnostic Tool (PEDT), when combined investigate suspicion of contributory of personal or partner-initiated reports with clinical assessment, are accurate factors identified during history and of erectile or sexual dysfunction, and in diagnosing premature ejaculation if examination. relationship difficulties. However, when the it is unclear.20–22 It is particularly crucial physician is unsure of the context of the to ascertain whether the diagnosis is Management of premature presenting complaint, or uncertain about lifelong or acquired, and be aware that ejaculation what to ask, an open-ended question, such erectile dysfunction may exacerbate the Ideally, discussions about management as ‘How are things at home?’, may evoke presentation. Simply inquiring about the should involve the patient and his regular disclosure of relevant symptoms. A full loss of an erection before ejaculation can sexual partner. Treatment choice requires evaluation of the patient’s medical, sexual, help to distinguish erectile dysfunction consideration of symptom severity, psychological, social and drug history, from premature ejaculation. reversible causes, psychosocial impact, along with his partner’s sexual history, is Physical examination of patients side effects and patient preferences.23 necessary to identify any factors that may who experience premature ejaculation In clinical practice, management is be potentially reversible. is often unremarkable. Full abdominal, complex and requires a combination

Table 1. Summary of the four classifications of premature ejaculation

Lifelong (primary) Acquired (secondary) Variable Subjective

IELT criteria <1 minute4 <3 minutes4 Short or normal Normal or prolonged

Symptoms Ejaculation occurs too New onset of premature PE is inconsistent Subjective, self- early in nearly every ejaculation, usually the and occurs irregularly perception of rapid sexual encounter result of an identifiable and not the result of ejaculation despite source and patient has (psycho)pathology normal ejaculation experienced normal time ejaculations in the past

Onset Early, usually from first Can occur at any time in Can occur at any time Can occur at any time sexual encounter a man’s life in a man’s life in a man’s life

Prevalence Low Low High High

Quality of Ejaculation remains Ability to delay Ability to delay Ability to delay ejaculation rapid throughout ejaculation may be ejaculation may be ejaculation may be control lifetime with no ability diminished or lacking diminished or lacking diminished or lacking to control ejaculation

Aetiology • Genetic • Urological (erectile Normal variance of Psychological • Neurobiological dysfunction, prostatitis) sexual performance preoccupation with • Hormonal imagined rapid (hyperthyroidism) ejaculation • Psychological • Relationship problems

Treatment • Pharmacotherapy • Medical management • Reassurance • Psychotherapy • Psychotherapy +/– • Pharmacotherapy • Education • Reassurance • Psychotherapy • Behavioural therapy • Education • Education

IELT, intravaginal ejaculatory latency time

738 REPRINTED FROM AFP VOL.44, NO.10, OCTOBER 2015 © The Royal Australian College of General practitioners 2015 PREMATURE EJACULATION CLINICAL

of pharmacological, psychological and constraints, costs and requirement for related to sexual dysfunctional, or in behavioural treatments (Figure 1). strong compliance from couples. combination with pharmacotherapy.12,27 Inconsistent, randomised evidence Conservative management evaluating psychological therapy suggests Behavioural therapy options its efficacy decreases over time24 and is Various behavioural changes have been inferior to pharmacotherapy.25 However, suggested in the literature. For example, Psychological therapy psychological therapy may be a suitable precoital masturbation is widely thought Initially, psychological therapy was the first-line treatment for patients with to improve IELT, but there is a lack of mainstay of treatment for premature subjective premature ejaculation, or when data to support this practice. Alternative ejaculation. It is used less in current a clear psychological aetiology is present.26 behavioural therapy modalities attempt clinical practice because of time This can also be used to manage distress to attenuate the sensory responses of

Patient/partner history –– Establish presenting complaint –– Estimate intravaginal ejaculatory time Variable PE Treatment –– Perceived degree of ejaculatory control -- Reassurance –– Degree of patient/partner distress -- Education –– Onset and duration of PE PE unlikely - Psychotherapy –– Psychosocial history - –– Medical history -- Behavioural therapy –– Physical examination Subjective PE -- Follow-up

PE likely

PE secondary to ED or Yes Manage the primary cause medical condition

No Treatment Follow-up -- Behavioural/psychotherapy Acquired PE May attemptPersistent graduated headache? withdrawal of -- SSRI pharmacotherapy pharmacotherapy after 6–8 weeks -- Combination therapy

Treatment Follow-up -- SSRI pharmacotherapy May attempt graduated withdrawal of Lifelong PE -- Behavioural/psychotherapy pharmacotherapy after 6–8 weeks, but will -- Combination therapy often require lifelong pharmacotherapy

Figure 1. Premature ejaculation management algorithm4 Reproduced with permission from Althof SE, Abdo CH, Dean J, et al. International Society for Sexual Medicine’s guidelines for the diagnosis and treatment of premature ejaculation. J Sex Med 2010;7:2947–69.

ejaculation by interrupting heightened The therapeutic efficacy of SSRIs for 30 minutes before sexual intercourse. arousal. These include the ‘stop- premature ejaculation is well supported Published studies found dapoxetine to be start’ (ceased genital stimulation until by the literature.36 Daily SSRI use may equally effective in men with lifelong and heightened arousal sensation subsides)28 improve ejaculation delay after a few days; acquired premature ejaculation. It was and ‘squeeze’ (where the glans prepuce maximal delay is usually achieved after 1–2 also found to be well tolerated in men is squeezed at heightened arousal)29 weeks. Paroxetine is the most effective with premature ejaculation and comorbid techniques. These techniques are often SSRI. However, paroxetine is not suitable erectile dysfunction treated with considered intrusive, mechanical and for on-demand use because it has a slow phosphodiesterase-5 type drugs.36,40 disruptive of the normal spontaneity of onset of action (5 hours) and long half-life coitus, and of little benefit when used (1–3 days), and daily dosing is required to Phosphodiesterase-5 inhibitors alone. Other behavioural techniques maintain efficacy.12 Daily SSRI dosing is The precise beneficial mechanism include the use of multiple condoms and more effective than on-demand treatment of phosphodiesterase-5 inhibitors for pelvic floor exercises. These techniques and is often favoured by patients because premature ejaculation is unclear and its may improve premature ejaculation when spontaneity of sex is maintained; however, use as monotherapy is controversial.41,42 combined with pharmacotherapy, but compliance issues can occur with long- It does not affect IELT but may improve further efficacy studies are required.30 term use. premature ejaculation in patients Doses of SSRI for premature ejaculation with comorbid erectile dysfunction Complementary and alternative are significantly less than those used by providing a perception of greater therapy for depression, but have a similar side control over ejaculation.41 In this There is limited evidence supporting the effect profile. Common side effects are population, guidelines suggest treating use of acupuncture for the treatment fatigue, nausea, diarrhoea, dry mouth erectile dysfunction and assessing the of premature ejaculation.31 However, and decreased libido.37 There are also response on premature ejaculation 12 complementary and alternative medicine anecdotal accounts of infertility.38 symptomatology. is not a recommended form of treatment Serotonin syndrome may also pose a risk Tramadol for premature ejaculation.32 if the patient is on concomitant treatment with drugs that elevate serotonin levels.37 Tramadol is an effective, on-demand Medical management Despite evidence supporting the use treatment for premature ejaculation, of clomipramine and traditional SSRIs (eg although the mechanism of action is Topical anaesthetic agents paroxetine, sertraline and fluoxetine) for unknown. Doses of 25–62 mg were Anaesthetic aerosols and creams the treatment of premature ejaculation, well tolerated, compared with placebo, containing lignocaine, lignocaine/ they are not licenced for treatment of and were found to significantly increase prilocaine or herbal-derived anaesthetic this condition. As such, use of these IELT, heighten sexual satisfaction and agents can increase IELT and sexual agents for premature ejaculation would improve ejaculatory control.43,44 These satisfaction. These agents are often be off-label and incur costs to the results were more pronounced in patients recommended as treatments for patient, as they are not subsidised by the with severe premature ejaculation premature ejaculation.12,33–35 They are Pharmaceutical Benefits Scheme (PBS) for (baseline IELT <1 minute). Tramadol has applied to the glans penis well ahead of this indication.24 a number of drug interactions and should sexual intercourse and should be used In 2010, the Therapeutic Goods be used with caution in combination in conjunction with condoms to avoid Administration (TGA) approved dapoxetine with SSRIs because of the risk of numbness in the partner’s genitals. for the use in premature ejaculation serotonin syndrome. It should only be in Australia. However, this remains considered for monotherapy use in men Serotonergic antidepressants unsubsidised by the PBS. Dapoxetine is with refractory premature ejaculation.12 Serotonin inhibits ejaculation and its a newly developed SSRI that is rapidly Ongoing studies are required to evaluate effects are potentiated by tricyclic absorbed (1–3 hours) and provides drug interactions, opioid dependence antidepressants (TCAs) and selective fast-acting treatment of premature issues and the underlining mechanism of serotonin reuptake inhibitors (SSRIs). ejaculation.39 Similarly to other SSRIs, action.43 TCAs are effective, but infrequently dapoxetine should be used with caution used because they have prominent side in patients with cardiac, hepatic or renal Surgical management effects, including nausea, dry mouth, impairment. Dapoxetine has been shown Circumcision and surgical management erectile dysfunction, hot flushes and to increase IELT by 2.5–3 minutes with options for premature ejaculation are cardiotoxicity. Clomipramine is the only minimal adverse effects.36,40 Patients currently under investigation and not TCA in routine use.12,35 should take 30 mg of dapoxetine at least recommended. Experimental surgical

740 REPRINTED FROM AFP VOL.44, NO.10, OCTOBER 2015 © The Royal Australian College of General practitioners 2015 PREMATURE EJACULATION CLINICAL

Table 2. Summary of current medical agents for premature ejaculation

Recommended Half-life IELT fold Agent dose (hours) increase Adverse effects Additional notes

Dapoxetine 30–60 mg, 1.5 2.5–3 Nausea, diarrhoea, • TGA approved, not (SSRI) – short 1–3 hours before headache, currently on PBS acting intercourse somnolence, dizziness • No significant drug–drug interactions • Effective treatment for both acquired and lifelong PE

Paroxetine 10–40 mg/day 21 11.6 Insomnia, anxiety, (SSRI) and nausea, loss of libido, 20 mg, 3–4 hours ED, anhidrosis prior to intercourse • Off-label prescriptions Fluoxetine 20–40 mg/day 36 5 Insomnia, anxiety, • Used for lifelong and (SSRI) nausea, loss of libido, acquired PE ED, anhidrosis • Therapeutic effect achieved in 2–3 weeks Sertraline 50–200 mg/day 26 5 Insomnia, anxiety, • May hinder sperm motility (SSRI) and nausea, loss of libido, • May induce mania in 50 mg, 4–8 ED, anhidrosis bipolar patients hours prior to • On-demand use not as intercourse effective without daily regimen Clomipramine 12.5–50 mg/day 19–37 6 Nausea, dry mouth, (TCA) and ED, hot flushes, 25 mg, 4–24 arrhythmias hours prior to intercourse

Tramadol 25–50 mg, 3–5 5–7 4–7.3 Nausea, dizziness, • Possible opioid addiction hours prior to insomnia, dyspepsia, • TCAs and SSRIs are intercourse seizures contraindicated with Tramadol use • Multiple drug interactions- only indicated as monotherapy in refractory PE

Phosphodiester- 25–100 mg, 3–6 Monotherapy Headache, flushing, • Used for concomitant ED ase-5 inhibitors 30–50 minutes has no effect dyspepsia and PE prior to on IELT • Improved efficacy when intercourse combined with SSRI therapy • Not established monotherapy for PE

Prilocaine- 2.5 g, applied 1–2 4–6 ED, loss of sensation • Condom use encouraged lignocaine topical 20–30 minutes in penis and partner’s • Used with SSRIs cream/aerosols prior to vagina, skin irritation • Off-label prescription intercourse

ED, erectile dysfunction; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressants; TGA, Therapeutic Goods Administration; PBS, Pharmaceutical Benefits Scheme

therapies, such as dorsal penile nerve • Currently, no premature ejaculation 13. Jern P, Santtila P, Witting K, et al. Premature and cryoablation, and neuromodulation and therapies are subsidised by the PBS. delayed ejaculation: Genetic and environmental effects in a population-based sample of Finnish hyaluronic acid gel glans augmentation for twins. J Sex Med 2007;4:1739–49. Authors refractory lifelong premature ejaculation 14. Janssen PK, Bakker SC, Rethelyi J, et al. Eric Chung MBBS, FRACS, Consultant Urological 45–47 Serotonin transporter promoter region (5-HTTLPR) have been reported to improve IELT. Surgeon, University of Queensland, Princess polymorphism is associated with the intravaginal Botulinum toxin injections into ejaculatory Alexandra Hospital, Brisbane QLD; and ejaculation latency time in Dutch men with AndroUrology Centre, Brisbane QLD. ericchg@ muscles are currently being explored to lifelong premature ejaculation. J Sex Med hotmail.com 2009;6:276–84. 48 prevent premature ejaculation. Brent Gilbert MBBS, Urology Resident Medical 15. Maggi M, Buvat J, Corona G, Guay A, Torres LO. Officer, Mackay Base Hospital, Mackay QLD Hormonal causes of male sexual dysfunctions Follow-up and referral Marlon Perera MBBS, Urology Registrar, Mackay and their management (hyperprolactinemia, Base Hospital, Mackay QLD thyroid disorders, GH disorders, and DHEA). J Sex Follow-up is an essential part of premature Matthew J Roberts MBBS, PhD, Urology Registrar, Med 2013;10:661–77. ejaculation management. It facilitates Mackay Base Hospital, Mackay QLD, and The 16. Liang CZ, Zhang XJ, Hao ZY, Shi HQ, Wang KX. Prevalence of sexual dysfunction in Chinese men treatment optimisation, emphasis on key University of Queensland, School of Medicine, Brisbane QLD with chronic prostatitis. BJU Int 2004;93:568–70. features of premature ejaculation and Competing interests: Eric Chung has previously 17. Jannini EA, Lombardo F, Lenzi A. Correlation enables additional information gathering.49 been paid for consultancy and/or lectures by Lilly, between ejaculatory and erectile dysfunction. Int GSK and Astellas. J Androl 2005;28 Suppl 2:40–45. In complex or refractory cases, specialist 18. Rowland D, McMahon CG, Abdo C, et al. Provenance and peer review: Not commissioned, Disorders of orgasm and ejaculation in men. assistance may be sought from a sexual externally peer reviewed. health physician or urologist. Input from J Sex Med 2010;7:1668–86. 19. McMahon CG. Screening for erectile dysfunction sex therapists or psychiatrists may also be References in men with lifelong premature ejaculation – Is the beneficial. 1. Althof SE. Prevalence, characteristics and Sexual Health Inventory for Men (SHIM) reliable? implications of premature ejaculation/rapid J Sex Med 2009;6:567–73. Conclusion ejaculation. J Urol 2006;175:842–48. 20. Althof S, Rosen R, Symonds T, Mundayat R, May 2. McMahon CG, Lee G, Park JK, Adaikan PG. K, Abraham L. Development and validation of a Premature ejaculation is the most Premature ejaculation and erectile dysfunction new questionnaire to assess sexual satisfaction, prevalence and attitudes in the Asia-Pacific region. control, and distress associated with premature common cause of male sexual J Sex Med 2012;9:454–65. ejaculation. J Sex Med 2006;3:465–75. dysfunction. Most patients who 3. Porst H, Montorsi F, Rosen RC, Gaynor L, Grupe S, 21. Symonds T, Perelman M, Althof S, et al. Further experience premature ejaculation are Alexander J. The Premature Ejaculation Prevalence evidence of the reliability and validity of the and Attitudes (PEPA) survey: Prevalence, premature ejaculation diagnostic tool. Int J Impot likely to require multi-modal management comorbidities, and professional help-seeking. Eur Res 2007;19:521–25. strategies involving pharmacological, Urol 2007;51:816–23. 22. Kam SC, Han DH, Lee SW. The diagnostic value of the premature ejaculation diagnostic tool and behavioural and psychological 4. Althof SE, Abdo CH, Dean J, et al. International Society for Sexual Medicine’s guidelines for the its association with intravaginal ejaculatory latency components. Patients should be diagnosis and treatment of premature ejaculation. time. J Sex Med 2011;8:865–71. monitored closely to ensure treatment and J Sex Med 2010;7:2947–69. 23. Porst H. An overview of pharmacotherapy in 5. Laumann EO, Paik A, Rosen RC. Sexual premature ejaculation. J Sex Med 2011;8 Suppl sexual satisfaction. dysfunction in the United States: Prevalence and 4:335–41. predictors. JAMA 1999;281:537–44. 24. Melnik T, Althof S, Atallah AN, Puga ME, Glina S, Key points 6. Moreira ED Jr, Brock G, Glasser DB, et al. Help- Riera R. Psychosocial interventions for premature seeking behaviour for sexual problems: The global ejaculation. Cochrane Database Syst Rev • Premature ejaculation is the most study of sexual attitudes and behaviors. Int J Clin 2011:CD008195. common cause of sexual dysfunction, Pract 2005;59:6–16. 25. Steggall MJ, Fowler CG, Pryce A. Combination especially in the younger age group. 7. Aschka C, Himmel W, Ittner E, Kochen MM. Sexual therapy for premature ejaculation: Results of a problems of male patients in family practice. J Fam small scale study. Sex Relation Ther 2008;23: • It is estimated that premature Pract 2001;50:773–78. 365–76. ejaculation affects up to 31% of 8. Symonds T, Roblin D, Hart K, Althof S. How does 26. Waldinger MD. Recent advances in the classification, neurobiology and treatment of Australian males. premature ejaculation impact a man s life? J Sex Marital Ther 2003;29:361–70. premature ejaculation. Adv Psychosom Med • Premature ejaculation causes 9. Althof S. The psychology of premature ejaculation: 2008;29:50–69. significant psychological, emotional and Therapies and consequences. J Sex Med 2006;3 27. De Amicis LA, Goldberg DC, LoPiccolo J, Suppl 4:324–31. Friedman J, Davies L. Clinical follow-up of couples interpersonal distress for the patient 10. Rosen RC, Althof S. Impact of premature treated for sexual dysfunction. Arch Sex Behavior and his partner. ejaculation: The psychological, quality of life, and 1985;14:467–89. • Premature ejaculation can be lifelong sexual relationship consequences. J Sex Med 28. Semans JH. Premature ejaculation: A new 2008;5:1296–307. approach. South Med J 1956;49:353–58. (primary) or acquired (secondary), and 11. Rowland D, Perelman M, Althof S, et al. Self- 29. Masters WJV. Human sexual inadequacy. Boston: this distinction guides management. reported premature ejaculation and aspects of Little Brown, 1970. • Management of premature ejaculation sexual functioning and satisfaction. J Sex Med 30. Hartmann UH. Words of wisdom. Re: Effects 2004;1:225–32. of a new functional-sexological treatment for should involve the patient and his 12. Althof SE, McMahon CG, Waldinger MD, et al. premature ejaculation. Eur Urol 2007;52:1259–61. partner, and is likely to require a multi- An update of the International Society of Sexual 31. Sunay D, Sunay M, Aydogmus Y, et al. Medicine’s Guidelines for the Diagnosis and Acupuncture versus paroxetine for the treatment modal approach with pharmacological, Treatment of Premature Ejaculation (PE). J Sex of premature ejaculation: A randomized, placebo- behavioural and psychological therapies. Med 2014;2:60–90. controlled clinical trial. Eur Urol 2011;59:765–71.

742 REPRINTED FROM AFP VOL.44, NO.10, OCTOBER 2015 © The Royal Australian College of General practitioners 2015 PREMATURE EJACULATION CLINICAL

32. Ho CC, Singam P, Hong GE, Zainuddin ZM. 39. Pryor JL, Althof SE, Steidle C, et al. Efficacy premature ejaculation: A double-blind, placebo- Male sexual dysfunction in Asia. Asian J Androl and tolerability of dapoxetine in treatment of controlled, fixed-dose, randomized study. J Clin 2011;13:537–42. premature ejaculation: An integrated analysis of Psychopharmacol 2006;26:27–31. 33. Atan A, Basar MM, Tuncel A, Ferhat M, Agras K, two double-blind, randomised controlled trials. 45. Kwak TI, Jin MH, Kim JJ, Moon DG. Long-term Tekdogan U. Comparison of efficacy of sildenafil- Lancet 2006;368:929–37. effects of glans penis augmentation using only, sildenafil plus topical EMLA cream, and 40. Porst H, McMahon CG, Althof SE, et al. Baseline injectable hyaluronic acid gel for premature topical EMLA-cream-only in treatment of characteristics and treatment outcomes for men ejaculation. Int J Impot Res 2008;20:425–28. premature ejaculation. Urol 2006;67:388–91. with acquired or lifelong premature ejaculation 46. Abdallah H, Abdelnasser T, Hosny H, Selim O, 34. Busato W, Galindo CC. Topical anaesthetic use with mild or no erectile dysfunction: Integrated Al-Ahwany A, Shamloul R. Treatment of premature for treating premature ejaculation: A double- analyses of two phase 3 dapoxetine trials. J Sex ejaculation by glans penis augmentation using blind, randomized, placebo-controlled study. BJU Med 2010;7:2231–42. hyaluronic acid gel: A pilot study. Andrologia 2012;44 Suppl 1:650–53. Int 2004;93:1018–21. 41. McMahon CG, McMahon CN, Leow 35. Hatzimouratidis K, Amar E, Eardley I, et al. LJ, Winestock CG. Efficacy of type-5 47. Namavar MR, Robati B. Removal of foreskin Guidelines on male sexual dysfunction: Erectile phosphodiesterase inhibitors in the drug remnants in circumcised adults for treatment of dysfunction and premature ejaculation. Eur Urol treatment of premature ejaculation: A systematic premature ejaculation. Urol Ann 2011;3:87–92. 2010;57:804–14. review. BJU Int 2006;98:259–72. 48. Serefoglu EC, Silay MS. Botulinum toxin-A injection 36. McMahon CG, Althof SE, Kaufman JM, et 42. Aversa A, Pili M, Francomano D, et al. Effects may be beneficial in the treatment of life-long al. Efficacy and safety of dapoxetine for the of vardenafil administration on intravaginal premature ejaculation. Med Hypoth 2010;74:83–84. treatment of premature ejaculation: Integrated ejaculatory latency time in men with lifelong 49. Moncada I. The importance of follow-up in patients analysis of results from five phase 3 trials. J Sex premature ejaculation. Int J Impot Res with premature ejaculation. The J Sex Med 2011;8 Med 2011;8:524–39. 2009;21:221–27. Suppl 4:353–59. 37. Montague DK, Jarow J, Broderick GA, et al. AUA 43. Salem EA, Wilson SK, Bissada NK, Delk JR, guideline on the pharmacologic management of Hellstrom WJ, Cleves MA. Tramadol HCL has premature ejaculation. J Urol 2004;172:290–94. promise in on-demand use to treat premature 38. Tanrikut C, Feldman AS, Altemus M, Paduch DA, ejaculation. J Sex Med 2008;5:188–93. Schlegel PN. Adverse effect of paroxetine on 44. Safarinejad MR, Hosseini SY. Safety and sperm. Fert Ster 2010;94:1021–26. efficacy of tramadol in the treatment of