In an effort to overcome the limitations of traditional definitions of PE, the ISSM has developed a definition of lifelong PE based on clinical evidence. Like other definitions of PE, the ISSM definition includes three components: 1 Time to ejaculation Inability to control ejaculation Negative impact on the man The definition was developed by an ad hoc committee of international experts in PE appointed by the ISSM. The committee evaluated the strengths and weaknesses of current definitions of PE, to critique the evidence in support of the constructs of ejaculatory latency, ejaculatory control, sexual satisfaction and personal/interpersonal distress, and to propose a new evidence-based definition of PE 1 References: McMahon CG, Althof SE, Waldinger MD et al. An evidence-based definition of lifelong premature ejaculation: report of the International Society for Sexual Medicine (ISSM) ad hoc committee for the definition of premature ejaculation. J Sex Med 2008;5:1590-1606. Waldinger MD. Towards evidence-based drug treatment research on premature ejaculation: a critical evaluation of methodology. Int J Impot Res 2003;15:309-313. PRIMED PRemature Ejaculation: Identify, Manage and Educate Presentation Slide Deck Version 2.0 (08 June 2010)
Despite the lack of knowledge or consensus regarding PE aetiology, most clinicians distinguish between lifelong (previously called primary) PE, which is continuously present from the first sexual encounter, and acquired (previously called secondary) PE, which occurs following years of normal sexual function 1 It is hypothesised that lifelong PE may have a biological component to its pathophysiology, possibly involving changes in central serotonin receptor sensitivity 1 Acquired PE also has a physiological component and may be the result of psychological stressors. It may also be ‘ situational ’ , i.e. confined to certain partners or circumstances. Onset of ED can also lead to acquired or compensatory PE 1 It may also be important to discuss PE with your male patients with hyperthyroidism. Carani et al (2005) 2 demonstrated that after thyroid hormone normalisation in patients with hyperthyroidism, PE prevalence fell from 50% to 15%. This suggests a direct involvement of thyroid hormones in the physiology of ejaculation Reference: Palmer NR, Stuckey BG. Premature ejaculation: a clinical update. Med J Aust 2008;188:662-666. Carani C, Isidori AM, Granata A et al. Multicenter study on the prevalence of sexual symptoms in male hypo- and hyperthyroid patients. J Clin Endocrinol Metab 2005;90:6472-6479. PRIMED PRemature Ejaculation: Identify, Manage and Educate Presentation Slide Deck Version 2.0 (08 June 2010)
There are striking regional differences in the perception of normal IELT. There is an almost twofold difference between the estimate of normal average IELT in the USA and Germany. On the whole women estimate shorter IELT values than men – except in Germany.
The PEPA study compared PE prevalence in the USA, Germany and Italy. While the lowest incidence of PE was found in Germany and the highest in Italy, these differences were not significant. As the prevalence of this condition is similar across both age and nationality (ethnicity), it can be difficult to identify patients who have PE – if they do not self present. References: Porst H, Montorsi F, Rosen RC et al. The Premature Ejaculation Prevalence and Attitudes (PEPA) survey: prevalence, comorbidities, and professional help-seeking. Eur Urology 2007;51:816-823. Janssen-Cilag Data On File 2009 PRIMED PRemature Ejaculation: Identify, Manage and Educate Presentation Slide Deck Version 2.0 (08 June 2010)
The consistent prevalence of PE contrasts with that of erectile dysfunction (ED) which increases with age (and is discussed later in this presentation).
The normal male sexual response is a sequential process, starting with sexual stimulation, penile tumescence and erection, and culminating in ejaculation—normally associated with orgasm—followed by detumescence. This can be expressed graphically as a cycle of four phases: excitement, plateau, orgasm (and associated ejaculation), and resolution.
In men with PE, the entire ejaculatory sequence is curtailed compared with the normal sequence. A very steep excitement phase with a normal erection, is followed by a shorter plateau and a rapid ejaculation and associated orgasm. Although these features are well established, the exact etiology of PE is unknown.
This introduces the issue of pharmacological management of PE and lists some of the historical and less rationally based therapies used before ending with the SSRIs. This provide a link to the next slide…
CNS control of ejaculation is mediated via spinal ejaculation centres including lumbar spinothalamic (LSt) cells. These cells integrate peripheral signals from the genital areas with excitatory and inhibitory control from supraspinal centres such as the nucleus paragigantocellularis (nPGi). The spinal ejaculation generators send co-ordinated outputs to the anatomic structures that allow ejaculation to occur. The ejaculation reflex consists of: Emission – the generation of semen by structures including the seminal vesicles and the prostate gland Expulsion – rhythmic muscular contractions involving the bulbocavernosus muscle controlled by the pudendal nerves The lumbar spinothalamic cells constitute the spinal ejaculation generator, which integrates the sensory inputs and outputs necessary to trigger ejaculation. The spinal ejaculation generator is discussed in more detail on the following two slides (which may be too technical for some audiences).
Central control of ejaculation involved many neurotransmitter systems including serotonin (5-HT), dopamine (DA), gamma-amino butyric acid (GABA) and norepinephrine (NE). Of these, 5-HT is a major player. Serotonin cell bodies are located in distinct clusters in the brainstem and send extensive projections throughout the brain and spinal cord. The actions of serotonin are mediated via one of the most extensive receptor systems known. Seven 5-HT receptor classes, encompassing some 14 different receptors, are currently recognized. These receptors and the serotonin transporter are widely distributed with particularly high density in the hypothalamus, brainstem and spinal cord.
This slide is intended, after dismissing the topical creams and PDE5 inhibitors, to introduce the SSRIs and to demonstrate that there is a rational pharmacological base for their use.
Looking at the central ejaculatory serotoninergic neuron we find further complexity of function. It has not been fully characterized but to date, 16 different 5-HT receptors each with varying expression and activity have been identified. Neural signalling is regulated by the 5-HT1A, 1B, and 1D and the 5-HT transporter re-uptake system. Each of these mechanisms is a negative feedback system which reduces synaptic cleft 5-HT and prevents over-stimulation of the postsynaptic receptors. Additionally, activation of 5 ‑HT1 a receptor is attenuated or blocked by activation of 5 ‑HT2 c. Waldinger has hypothesized PE is due to hypersensitivity of 5-HT1A receptors or hyposensitivity of 5-HT2C receptors with differing ejaculatory “set points” . The individual variability of the central 5-HT system may also account for the sexual side effect profiles of the widely prescribed SSRI class of drugs.
Marked increases in IELT values with dapoxetine were apparent irrespective of the method of reporting data. It has been argued that IELT values are not normally distributed but rather positively skewed and thus should be reported as medians or geometric means rather than arithmetic means (Waldinger, Lancet 2006; 368:1869). These data also show the magnitude of the effect of dapoxetine on IELT, providing a 2.5- and 3-fold increase compared with placebo (30 mg and 60 mg, respectively).
Dapoxetine use is well tolerated. Non-sexual side effects with dapoxetine were transient and characteristic of compounds with serotonergic effects. Some side effects (nausea, diarrhoea and dizziness) seemed dependent on dose Cardiovascular and central nervous system side effects were reported at a low incidence In the pooled analysis, the most commonly reported adverse events were nausea, headache, diarrhoea, and dizziness. Most of these events were mild and transient, and resulted in study discontinuation in only a few cases There were no deleterious effects on erectile function or libido and the incidence of serious AEs was low (≤1% across groups). References: McMahon et al. (2008) Presented at ESSM/ISSM Casey et al. (2008) Presented at EAU; Giuliano et al. (2008) Presented at EAU PRIMED PRemature Ejaculation: Identify, Manage and Educate Presentation Slide Deck Version 2.0 (08 June 2010)
This compares several SSRIs after 6 weeks of dosing. All are effective.
This slide illustrates the point. The effect of sertraline in this crossover design takes about 2 weeks at least to be effective. The effect is also slow to wash out.
PREMATURE EJACULATION: the less talked about sexual condition <ul><li>MMA Sabah </li></ul><ul><li>3 rd SABAH GP CONFERENCE </li></ul><ul><li>Kota Kinabalu 15 May 2011 </li></ul><ul><li>CHAIRMAN: Datuk Dr Jayaram Menon </li></ul><ul><li>Chief Physician, Queen Elizabeth Hospital, KK </li></ul><ul><li>by Dr Clarence Lei Chang Moh, FRCS Urol </li></ul><ul><li>Consultant Urologist </li></ul><ul><li>email: firstname.lastname@example.org </li></ul><ul><li>kuchingurology.com </li></ul>
48 yrs contractor, M, 6 +2 children, (real 12.5.11) <ul><li>Ejaculation within <10 thrusts ( ? How many mins ?), less volume, trickle instead of projectile, slight pain ejaculation last month </li></ul><ul><li>Since 1 st SI, better after few yrs (30min), deteriorated 2 nd yr 2n d wife (youngest child 1 yr) </li></ul><ul><li>Nocturia 3 x </li></ul><ul><li>DISTRESS, + partner “ can’t climax, I need just 1 -2 mins ”; came with wife (spacing outside room) ! </li></ul>
Real Case <ul><li>TREATMENT: </li></ul><ul><li>tried Levitra ( “others not so good for improving erection”), im Nebido 3x </li></ul><ul><li>stop start, (need coitus interruptus ? co-operate) </li></ul><ul><li>Prior masturbation, prior sex </li></ul><ul><li>foreplay, non penetrative (but ejaculates when he moves !) </li></ul><ul><li>internet, ? Local anaesthetic, partner mouth bitter taste & numb </li></ul><ul><li>? Medication, ? how ? safe </li></ul>
PREMATURE EJACULATION, PE <ul><li>Persistent or recurrent ejaculation with minimal stimulation before, on, or shortly after penetration, and before the person wishes it. </li></ul><ul><li>American Psychiatric Association ’s Diagnostic and Statistical Manual IV. </li></ul>
Evidence-based definition of lifelong PE: T he International Society for Sexual Medicine <ul><li>PE is a male sexual dysfunction characterized by: </li></ul><ul><ul><li>Ejaculation which always or nearly always occurs prior to or within about one minute of vaginal penetration 90% IELT, intravaginal ejaculatory latency time); and </li></ul></ul><ul><ul><li>Inability to delay ejaculation on all or nearly all vaginal penetrations; and </li></ul></ul><ul><ul><li>Negative personal consequences , such as distress, bother, frustration and/or the avoidance of sexual intimacy </li></ul></ul>McMahon CG, Althof SE, Waldinger MD, et. al. An Evidence-Based Definition of Lifelong Premature Ejaculation: Report of the International Society for Sexual Medicine (ISSM) Ad Hoc Committee for the Definition of Premature Ejaculation. J Sex Med 2008;5:1590–1606
Lifelong versus Acquired PE 1. Palmer & Stuckey, 2008.
Estimated IELT Reported by Men with “ Normal ” Ejaculation and by their Partners Sotomayor M. J Sex Med 2 (Suppl 2): 110-114, 2005. Estimated IELT (minutes) Men Women USA 13.6 11.2 UK 9.9 8.5 France 9.3 8.4 Germany 6.9 7.4 Italy 9.6 8.6
A MultiNational Survey of IELT 500 couples >age 18 in Netherlands, UK, Spain, Turkey and US Not selected for ejaculatory status or co-morbidities IELT measured by stop-watch for 4 weeks ----------------------------------------------------------------------------------------------- RESULTS by Country (Median IELT in minutes) Netherlands UK Spain Turkey US ALL 5.1 7.6 5.8 3.7 7.0 5.4 ----------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------- Waldinger MD, Quinn P, Dilleen M et al. J Sex Med 2:492-7, 2005.
There is a confusion between PE & ED <ul><li>65% of Malaysian men believe PE and ED are very similar, and the same medication can treat both conditions which in fact they can ’t </li></ul>ISSM Sept 2010 Seoul, Janssen Cilag: Data on file
Up to 29% of Malaysian men suffer from PE at some point in their lives China Aust/NZ Taiwan Thailand Korea Hong Kong Malaysia Indonesia Philippines Total <ul><ul><ul><ul><li>Malaysia : 15% self-reported vs 29% objective assessment </li></ul></ul></ul></ul><ul><li>. </li></ul>Champion: koreans !!
Prevalence of PE is similar across countries 1. Porst et al, 2007. 2. Janssen-Cilag Data On File 2009 PEPA (Premature Ejaculation Perceptions and Attitudes) Study * Men classified as having PE if low / absent control over ejaculation that is viewed as a problem by men or/ their partners ** Men classified as having PE or Probable PE by PEDT diagnosis ** ** * * * *
Prevalence of PE is Consistent Across Age Groups <ul><li>PEPA: Premature ejaculation perceptions and attitudes. Porst et al. (2007) Eur Urol 51:816–824 </li></ul>
Normal Male Sexual Response Time Sexual interest/ stimulation Penile tumescence High arousal / penile erection Plateau Orgasm Ejaculation accompanied by orgasm Penile detumescence Resolution Adapted from Donatucci (2006) J Sex Med 3(suppl 4):303–308 Excitement Penetration
Premature Ejaculation Time Rapid ejaculation and associated orgasm with normal erection Normal response Adapted from Donatucci (2006) J Sex Med 3(suppl 4):303–308 Short plateau phase Steep excitement phase with normal erection PE
What percentage of men with PE might want treatment? Authors Percent Rowland et al ( JSexMed 1:225, 2004) 50% Carson et al ( JUrol 169 Suppl 2003) 24% Brock et al ( JUrol 177 Suppl 2007) 38%
Topical PE Therapy ? <ul><li>Desensitizing creams use lidocaine (Emla) or lidocaine with prilocaine applied 20-30 minutes prior to sexual activity </li></ul><ul><ul><li>Lessen penile sensitivity during foreplay and intercourse </li></ul></ul>
New topical penile spray using a combination of lidocaine and prilocaine to treat PE DB PC phase 2 study of 43 men with PE Drug Placebo Number of men 20 23 Baseline IELT (min) 1.0 0.9 Follow-up (min) 4.9 1.6 Dinsmore WW et al. BJU International 99:369-375, 2007 (Feb)
Efficacy of Sildenafil for Premature Ejaculation and Post-Ejaculatory Refractory Time Double-blind placebo-controlled study 157 men with PE ages 18-65 (mean 43 yrs) Compared flexible-dose sildenafil (50-100 mg) to placebo Results: No signficant difference between sildenafil and placebo in IELT Sildenafil-treated men had greater ejaculatory control and sexual satisfaction scores Sildenafil-treated men had decreased post-ejaculatory refractory time McMahon CG, Stuckey BGA, Andersen M, et al. J Sex Med 2: 368-375, 2005
FIG 1 The mechanism of ejaculation 2005 BJU International 95, 1181-1186 ejaculate
Neurophysiology of Ejaculation Motor supply to bulbospongiosus muscle Pudendal nerve Sensory inputs from genital areas Supraspinal Centres Spinothalamic cells L3-L4: Coordination of spinal nuclei Hypogastric Plexus ~ T12-L1: Emission Spinal Reflex S1-S3: Expulsion afferent efferent Giuliano & Clement (2005) Ann Rev Sex Res 16:190–216 Higher brain Centres Excitatory & inhibitory control Sympathetic supply to: Epididymis, Vas deferens Seminal Vesicles Prostate Pons: nPGi: Nucleus paragigantocellularis Dorsal nerve of penis
<ul><li>The following neurotransmitters are involved in the processing of emission and ejaculation: </li></ul><ul><ul><li>Serotonin (5-HT) </li></ul></ul><ul><ul><li>Dopamine (DA) </li></ul></ul><ul><ul><li>Gamma-aminobutyric acid (GABA) </li></ul></ul><ul><ul><li>Noradrenaline </li></ul></ul><ul><ul><li>Serotonin is considered to be the key inhibitory neurotransmitter involved in the processing of ejaculation </li></ul></ul><ul><ul><ul><li>There are multiple serotonin receptors in the hypothalamus, brainstem and the spinal cord </li></ul></ul></ul>Neurotransmitters Involved in Control of Ejaculation McMahon et al, Disorders of orgasm and ejaculation in men. In Sexual Medicine: Sexual dysfunctions in men and women. 2nd International Consultation on Sexual Dysfunctions, Paris, 2004
<ul><li>Nucleus ParaGiganto- cellularis (nPGi) and other centers have projections to the lumbosacral spinal cord which are thought to exert tonic inhibition of ejaculation </li></ul>Central Serotonin and PE Tonic descending serotonergic inhibition of ejaculation from NPGi nPGi (brainstem) MPOA (hypothalamus) PVN (hypothalamus) Sympathetic control of ejaculation in the lumbosacral cord Ejaculation reflex mediated by the L-S cord
Lifelong PE: NOT psychogenic ORGANIC CAUSE OF PREMATURE EJACULATION 1 <ul><li>Serotonin in the CNS inhibits the ejaculation reflex </li></ul><ul><li>With l ow CNS serotonin, ejaculation is not inhibited, setting the ejaculatory threshold at a lower point </li></ul><ul><li>PE seems to have a neurologic basis in some men </li></ul>1 Waldinger MD, Schweitzer DH and Olivier B. J Sex Med 2:121-131, 2005
Indirect Evidence for a Genetic Explanation of PE <ul><li>(1) Dutch study in men with lifelong PE with IELT < 1 minute showed </li></ul><ul><li>an increased familial occurrence of lifelong </li></ul><ul><li> PE in first degree male relatives 1 </li></ul><ul><li>(2) Finnish male twin questionnaire study showed a moderate genetic </li></ul><ul><li>influence on PE 2 </li></ul><ul><li>(3) Animal studies showed a subgroup of persistent rapidly ejaculating </li></ul><ul><li>Wistar rats 3-5 </li></ul><ul><li>1. Waldinger M, et al. Psychiatr Genet 1998;8:37-40 </li></ul><ul><li>2. Jern P, et al. J Sex Med 2007;4:1739-49 </li></ul><ul><li>3. Pattij T, et al Curr Pharm Des 2005;11:4069-77 </li></ul><ul><li>4. Waldinger M, et al. World J Urol 2005;23:115-8 </li></ul><ul><li>5. Pattij T, et al. Eur J Neurosci 2005;22:724-34 </li></ul>
Dapoxetine (Priligy) A highly potent inhibitor of serotonin reuptake transporter Following oral administration, it is rapidly absorbed After reaching T max, serum concentration declines rapidly At 60 mg dose: 1 T max = 1.2 hr T ½ initial = 1.5 hr Single dose and multiple dose pharmacokinetics are similar 1 No interaction when used with food 2 , alcohol 3 or PDE5 inhibitors 4 1 Dresser M, et al. Clin Pharmacol Therap 32:2004. Abstract Pl-113 2 Dresser M, et al. J Sex Med 3 (Suppl 1):25, 2005. Abstract 37. 3 Modi N, et al. J Urol 173 (Suppl):239, 2005. Abstract 879. 4 Dresser M, et al. J Urol 173 (Suppl):201, 2005. Abstract 739.
Dapoxetine <ul><li>Dapoxetine is the first compound specifically developed for the treatment of PE, 30-60mg , 1-3 hrs before, on demand, short acting </li></ul><ul><li>Approved in several EU countries, Mexico, Korea, New Zealand ,Malaysia (1.8.2010) with anticipated approval in other countries </li></ul><ul><li>Level 1A evidence to support the efficacy and safety of on-demand dosing of dapoxetine  </li></ul>1 . ICSD Paris 2009
Dapoxetine Pharmacokinetics <ul><li>Dapoxetine undergoes rapid absorption (Tmax of 1.0 hours), rapidly achieves peak plasma concentration (Cmax) and has a mean half-life after a single dose is 1.3 hours </li></ul><ul><li>Minimal accumulation with plasma concentration rapidly declining to about 5% of Cmax at 24 hours. </li></ul><ul><li>Dose-dependent pharmacokinetics with plasma concentrations and area under the curve (AUC) which are unaffected by multiple dosing </li></ul>
Dapoxetine IELT for ≤1min & ≤0.5min Pooled IELT values at endpoint for baseline IELT ≤1min & ≤0.5min † McMahon et al. (2008) Presented at ESSM/ISSM IELT≤Imin IELT≤0.5min * Fold-increase=geometric endpoint/geometric baseline, not model based. Values are unadjusted. † Week 12 (012, 013, 3001, 3003) or last observation carried forward Fold Increase=4.3 Fold Increase=3.4 Fold Increase=2.7 Fold Increase=3.4
Dapoxetine Mean IELT Results Over Time (3x, NOT 3 hours) *P<0.001 vs. placebo ANCOVA * * * * * * * * Pooled study data: C-2002-012, C-2002-013, PRE-3001, PRE-3003 * * Pooled Studies
Dapoxetine: Most adverse events mild to moderate in severity and occurred within first 4 weeks of treatment 1. McMahon et al., 2008 2. Casey et al., 2008 3. Giuliano et al., 2008 SSRI Class Effects are not evident: No deleterious effects on mood and anxiety symptoms, suicidal ideation or withdrawal syndrome, erectile function or libido
Dapoxetine - Most Common Adverse Events Phase III Data - Pooled Discontinuation due to Nausea: 0.1% placebo, 0.9% 30 mg, 3.0% 60 mg Pooled data: C-2002-012, C-2002-013, PRE-3001, PRE-3002, PRE-3003
48 yrs architect, <ul><li>? Give Priligy ? </li></ul>
48 yrs architect, <ul><li>EHS & TMT: DRE, normal (BS, LFT, RFT, cholesterol, testosterone) </li></ul><ul><li>Urine normal </li></ul><ul><li>US normal urinary tract, & prostate </li></ul><ul><li>Uroflow: 21 ml/sec (wants to show wife !) </li></ul><ul><li>Re-assure, Stress Mx, Exercise </li></ul><ul><li>Priligy 30 mg, 3 + 3 (kiv 60mg) </li></ul>
Summary (1) <ul><li>PE is a common male sexual dysfunction. </li></ul><ul><ul><li>Both psychological and physiological causes </li></ul></ul><ul><ul><li>Can be either lifelong or acquired </li></ul></ul><ul><ul><li>May cause serious psychological problems for patients and/ or their partners </li></ul></ul><ul><li>Be proactive about initiating PE conversation. </li></ul><ul><ul><li>High prevalence across age, nationality, ethnicity </li></ul></ul><ul><ul><li>Poor treatment seeking rates </li></ul></ul><ul><li>Diagnosis should be multidimensional and should assess </li></ul>Short time to ejaculation Inability to control ejaculation Negative personal consequences + +
Summary (2) <ul><li>Manage patient expectations and involve partners (if possible) </li></ul><ul><ul><li>Patient ’s needs and preferences </li></ul></ul><ul><ul><li>Set treatment goal </li></ul></ul><ul><li>Pharmacotherapy is the basis of treatment in lifelong PE </li></ul><ul><ul><li>All are off-label indications and not amenable to on-demand dosing </li></ul></ul><ul><ul><li>Dapoxetine is the first short-acting SSRI approved for on-demand, oral treatment of PE </li></ul></ul><ul><ul><li>Dapoxetine is shown to improve all components of PE – time, control and satisfaction with sexual intercourse </li></ul></ul>
Summary (3) <ul><li>Patient presents with suspected PE </li></ul><ul><li>Establish PE diagnosis using ISSM definition </li></ul><ul><li>Perform a sexual, medical and psychological history and physical examination </li></ul>NO Adapted from 1. McMahon et al, 2004. 2. Hatzimouratidis K et al, 2010 3. Althof et. al, 2010 PE management algorithm Patient preference
Slow onset of effect of SSRIs in PE sertraline washout placebo IELT (min) Weeks McMahon CG. J Urol 159:1935-8, 1998
Evaluating the Patient on Dapoxetine Evaluating patient responses - Does the patient want to continue on treatment? - somewhat worse, the same, somewhat better or much better? What is a successful treatment? - A 3-fold increase in IELT is considered clinically significant and adequate for patient satisfaction Managing nausea and somnolence - Antacid - Timing of sexual activity
Premature Ejaculation Profile (PEP) <ul><li>1.Over the past month, was your satisfaction with sexual intercourse </li></ul>2.Over the past month, was your control over ejaculation during sexual intercourse 3.Over the past month, how distressed were you by how fast you ejaculated during sexual intercourse? 4.Over the past month, to what extent did how fast you ejaculated during sexual intercourse cause difficulty in your relationship with your partner?
PEP for Partners <ul><li>1.Over the past month, was your satisfaction with sexual intercourse </li></ul><ul><li>2. Over the past month, was your partner ’s control over ejaculation during sexual intercourse </li></ul>3. Over the past month, how distressed were you by how fast your partner ejaculated during sexual intercourse? 4. Over the past month, to what extent did how fast your partner ejaculated during sexual intercourse cause difficulty in your relationship with your partner?