premature ejaculation
DESCRIPTION
李長茂沙巴談少人啟齒的早洩問題 PREMATURE EJACULATION Dr Clarence Lei Chang Moh MMA Sabah 3rd SABAH GP CONFERENCE Kota Kinabalu 15 May 2011TRANSCRIPT
PREMATURE EJACULATION:the less talked about sexual
conditionMMA Sabah
3rd SABAH GP CONFERENCEKota Kinabalu 15 May 2011
CHAIRMAN: Datuk Dr Jayaram MenonChief Physician, Queen Elizabeth Hospital, KK
by Dr Clarence Lei Chang Moh, FRCS UrolConsultant Urologistemail: [email protected]
48 yrs contractor, M, 6 +2 children, (real 12.5.11)
Ejaculation within <10 thrusts ( ? How many mins ?), less volume, trickle instead of projectile, slight pain ejaculation last month
Since 1st SI, better after few yrs (30min), deteriorated 2nd yr 2nd wife (youngest child 1 yr)
Nocturia 3 x DISTRESS, + partner “can’t climax, I need just 1 -
2 mins”; came with wife (spacing outside room) !
Real Case
TREATMENT: tried Levitra (“others not so good for improving erection”), im Nebido 3x stop start, (need coitus interruptus ? co-operate)Prior masturbation, prior sex foreplay, non penetrative (but ejaculates when he moves !) internet, ? Local anaesthetic, partner mouth bitter taste & numb? Medication, ? how ? safe
PREMATURE EJACULATION, PE
Persistent or recurrent ejaculation with minimal stimulation before, on, or shortly after penetration, and before the person wishes it.American Psychiatric Association’s Diagnostic and Statistical Manual
IV.
Evidence-based Evidence-based definition of lifelong PE: definition of lifelong PE: TThe International Society for Sexual he International Society for Sexual
MedicineMedicine
• PE is a male sexual dysfunction characterized by:
– Ejaculation which always or nearly always occurs prior to or within about one minute about one minute of vaginal penetration 90% IELT, intravaginal ejaculatory latency time); and
– Inability to delay Inability to delay ejaculation on all or nearly all vaginal penetrations; and
– Negative personal consequencesNegative personal consequences, such as distress, bother, frustration and/or the avoidance of sexual intimacy
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 PELifelong versus Acquired PE
1. Palmer & Stuckey, 2008.
Estimated IELT Reported by Men with “Normal” Ejaculation and by their Partners
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
Sotomayor M. J Sex Med 2 (Suppl 2): 110-114, 2005.
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
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
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/NZTaiwan Thailand Korea Hong Kong Malaysia Indonesia Philippines Total
Malaysia : 15% self-reported vs 29% objective assessment
.
Champion: koreans !!
23% 24%
20% 20%
31%29%
0%
5%
10%
15%
20%
25%
30%
35%
40%
Overall (US & EU)
USA Germany Italy Overall (AP)
Malaysia
Pre
vala
nce
(%)
Prevalence of PE is similar Prevalence of PE is similar across countriesacross 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 Prevalence of PE is Consistent Across Age GroupsAcross Age Groups
1.1. PEPA: Premature ejaculation perceptions and attitudes. Porst et al. (2007) Eur Urol 51:816–PEPA: Premature ejaculation perceptions and attitudes. Porst et al. (2007) Eur Urol 51:816–824 824
Normal Male Sexual ResponseNormal Male Sexual Response
TimeTime
Sexual interest/ Sexual interest/ stimulationstimulation
Penile Penile tumescencetumescence
High arousal / High arousal / penile erectionpenile erection
PlateauPlateau
OrgasmOrgasm Ejaculation Ejaculation accompanied accompanied by orgasmby orgasm
Penile Penile detumescencedetumescence
ResolutionResolution
Adapted from Adapted from Donatucci (2006) J Sex Med 3(suppl 4):303–Donatucci (2006) J Sex Med 3(suppl 4):303–308308
ExcitementExcitement
PenetrationPenetration
PE
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
Premature Ejaculation
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%
Current Treatment Options ?
Pharmacological Treatment of PE, previous
• Topical (local) anesthetics eg Emla, Gambir Swak,
• PDE5 inhibitors• Tricyclic antidepressant (clomipramine)• Selective Serotonin Reuptake Inhibitors
(SSRI’s)• Tramadol
Topical PE Therapy ?
• Desensitizing creams use lidocaine (Emla) or lidocaine with prilocaine applied 20-30 minutes prior to sexual activity
– Lessen penile sensitivity during foreplay and intercourse
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 1The mechanism of ejaculation
2005 BJU International 95, 1181-1186
ejaculate
Neurophysiology of EjaculationNeurophysiology of Ejaculation
Motor supply to bulbospongiosus muscle
Motor supply to bulbospongiosus muscle
Pudendal nervePudendal nerve
Sensory inputs from genital areas
Sensory inputs from genital areas
Supraspinal Centres
Spinothalamiccells L3-L4:Coordination of spinal nuclei
Spinothalamiccells L3-L4:Coordination of spinal nuclei
Hypogastric Plexus ~ T12-L1:Emission
Hypogastric Plexus ~ T12-L1:Emission
Spinal Reflex S1-S3: Expulsion
Spinal Reflex S1-S3: Expulsion
afferent
efferent
Giuliano & Clement (2005) Ann Rev Sex Res 16:190–216
Higher brain CentresHigher brain Centres
Excitatory & inhibitory control
Excitatory & inhibitory control
Sympathetic supply to:Epididymis, Vas deferensSeminal VesiclesProstate
Sympathetic supply to:Epididymis, Vas deferensSeminal VesiclesProstate
Pons:
nPGi: Nucleus paragigantocellularis
Pons:
nPGi: Nucleus paragigantocellularis
Dorsal nerve of penisDorsal nerve of penis
The following neurotransmitters areinvolved in the processing of emission
and ejaculation: Serotonin (5-HT) Dopamine (DA) Gamma-aminobutyric acid (GABA) Noradrenaline Serotonin is considered to
be the key inhibitory neurotransmitter involved in the processing of ejaculation• There are multiple serotonin
receptors in the hypothalamus, brainstem and the spinal cord
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
Neurotransmitters Involved Neurotransmitters Involved in Control of Ejaculation in Control of Ejaculation
• Nucleus ParaGiganto- cellularis (nPGi) and other centers have projections to the lumbosacral spinal cord which are thought to exert tonic inhibition of ejaculation
Central Serotonin and PE
Tonic descending serotonergic inhibition of ejaculation from NPGi
nPGi (brainstem)MPOA (hypothalamus)PVN (hypothalamus)
Sympathetic controlof ejaculation in the lumbosacral cord
Ejaculation reflex mediated by the L-S cord
Lifelong PE: NOT psychogenicORGANIC CAUSE OF
PREMATURE EJACULATION 1
• Serotonin in the CNS inhibits the ejaculation reflex
• With low CNS serotonin, ejaculation is not inhibited, setting the ejaculatory threshold at a lower point
• PE seems to have a neurologic basis in some men
1 Waldinger MD, Schweitzer DH and Olivier B. J Sex Med 2:121-131, 2005
Indirect Evidence for a Genetic Explanation of PE
• (1) Dutch study in men with lifelong PE with IELT < 1 minute showed an increased familial occurrence of lifelong
PE in first degree male relatives1
• (2) Finnish male twin questionnaire study showed a moderate genetic
influence on PE2
• (3) Animal studies showed a subgroup of persistent rapidly ejaculating
Wistar rats3-5
1. Waldinger M, et al. Psychiatr Genet 1998;8:37-402. Jern P, et al. J Sex Med 2007;4:1739-493. Pattij T, et al Curr Pharm Des 2005;11:4069-774. Waldinger M, et al. World J Urol 2005;23:115-85. Pattij T, et al. Eur J Neurosci 2005;22:724-34
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 hrT ½ initial = 1.5 hr
Single dose and multiple dose pharmacokinetics are similar 1
No interaction when used with food2, alcohol3 or PDE5 inhibitors4
1 Dresser M, et al. Clin Pharmacol Therap 32:2004. Abstract Pl-1132 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.
DapoxetineDapoxetine• Dapoxetine is the first compound specifically
developed for the treatment of PE, 30-60mg, 1-3 hrs before, on demand, short acting
Approved in several EU countries, Mexico, Korea, New Zealand ,Malaysia (1.8.2010) with anticipated approval in other countries
• Level 1A evidence to support the efficacy and safety of on-demand dosing of dapoxetine [1]
11. ICSD Paris 2009. ICSD Paris 200911. ICSD Paris 2009. ICSD Paris 2009
Dapoxetine PharmacokineticsDapoxetine Pharmacokinetics• 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
• Minimal accumulation with plasma concentration rapidly declining to about 5% of Cmax at 24 hours.
• Dose-dependent pharmacokinetics with plasma concentrations and area under the curve (AUC) which are unaffected by multiple dosing
Dapoxetine Phase III StudiesSummary
Study number
Description Subjects enrolled
Sites
012 & 013 12 week phase III trials of dapoxetine in men with moderate to severe premature ejaculation
(completed 2004)
2614
121 sites in USA
014 9 month open label extension of studies 012 & 013
(completed 2005)
1774
121 sites in USA
3001 24 week phase III trial of dapoxetine in men with moderate to severe premature ejaculation
(completed 2007)
1162
143 sites in Europe, South Mexico, America, Canada,
Israel and South Africa
3002 Withdrawal effects of chronic daily and as-needed dosing with dapoxetine in the treatment of PE
(completed 2005)
1238
91 sites in USA and Canada
3003 12 week phase III trial of dapoxetine in men with moderate to severe premature ejaculation
(completed 2007)
1349
52 sites in Asia and Australia
© J & J Pharmaceutical Services LLC, 2007
0.5
0.8
0.30.50.5
0.30.5
0.3
0.9*
1.4*1.2*
1.8*
0
0.5
1
1.5
2
2.5
3
Baseline <1min Endpoint <1min Baseline <0.5min Endpoint <0.5min
Mea
n IE
LT (M
in)
Placebo Dapoxetine 30 mg Dapoxetine 60 mg
0.5
0.8
0.30.50.5
0.30.5
0.3
0.9*
1.4*1.2*
1.8*
0
0.5
1
1.5
2
2.5
3
Baseline <1min Endpoint <1min Baseline <0.5min Endpoint <0.5min
Mea
n IE
LT (M
in)
Placebo Dapoxetine 30 mg Dapoxetine 60 mg
Pooled IELT values at endpoint for baseline IELT Pooled IELT values at endpoint for baseline IELT ≤1min & ≤1min & ≤0.5min≤0.5min † †
Dapoxetine IELT for ≤1min & Dapoxetine IELT for ≤1min & ≤0.5min≤0.5min
McMahon et al. (2008) Presented at McMahon et al. (2008) Presented at ESSM/ISSMESSM/ISSM
* Fold-increase=geometric endpoint/geometric baseline, not model based. Values are * Fold-increase=geometric endpoint/geometric baseline, not model based. Values are unadjusted.unadjusted.
††Week 12 (012, 013, 3001, 3003) or last observation carried forwardWeek 12 (012, 013, 3001, 3003) or last observation carried forward
Fold Increase=4.3Fold Increase=4.3
Fold Increase=3.4Fold Increase=3.4
Fold Increase=2.7Fold Increase=2.7 Fold Increase=3.4Fold Increase=3.4
IELT≤Imin IELT≤0.5min
Dapoxetine Mean IELT Results Over Time (3x, NOT 3 hours)
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Baseline First Dose Week 4 Week 8 Week 12(LPOCF)
Week 24(LPOCF) 3001
IELT
(m
inu
tes)
Placebo Dapoxetine 30 mg Dapoxetine 60 mg
*P<0.001 vs. placebo ANCOVA
** **
* **
*
Pooled study data: C-2002-012, C-2002-013, PRE-3001, PRE-3003
**
Pooled Studies
1. McMahon et al., 2008 2. Casey et al., 2008 3. Giuliano et al., 2008
Dapoxetine: Dapoxetine: Most adverse events mild to Most adverse events mild to moderate in severity and moderate in severity and occurred within occurred within
first 4 weeks of treatmentfirst 4 weeks of treatment
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 EventsPhase III Data - Pooled
Subjects Reporting Adverse Event
0
5
10
15
20
25
30
35
Per
cent
of
subj
ects
PBO Dpx 30 mg Dpx 60 mg
Discontinuation due to Nausea: 0.1% placebo, 0.9% 30 mg, 3.0% 60 mgPooled data: C-2002-012, C-2002-013, PRE-3001, PRE-3002, PRE-3003
48 yrs architect,
• ? Give Priligy ?
48 yrs architect,
• EHS & TMT: DRE, normal (BS, LFT, RFT, cholesterol, testosterone)
• Urine normal • US normal urinary tract, & prostate• Uroflow: 21 ml/sec (wants to show wife !)• Re-assure, Stress Mx, Exercise• Priligy 30 mg, 3 + 3 (kiv 60mg)
Summary (1)• PE is a common male sexual dysfunction.
Both psychological and physiological causesCan be either lifelong or acquiredMay cause serious psychological problems for patients
and/ or their partners
• Be proactive about initiating PE conversation. High prevalence across age, nationality, ethnicityPoor treatment seeking rates
• Diagnosis should be multidimensional and should assess
Short time to ejaculation
Inability to control ejaculation
Negative personal consequences+ +
Summary (2)
• Manage patient expectations and involve partners (if possible) Patient’s needs and preferences Set treatment goal
• Pharmacotherapy is the basis of treatment in lifelong PE All are off-label indications and not amenable to on-demand dosing Dapoxetine is the first short-acting SSRI approved for on-demand, oral
treatment of PE Dapoxetine is shown to improve all components of PE – time, control
and satisfaction with sexual intercourse
Summary (3)
Patient presents with suspected PE• Establish PE diagnosis using ISSM definition
• Perform a sexual, medical and psychological history and physical examination
NO
Patient preference
Adapted from 1. McMahon et al, 2004. 2. Hatzimouratidis K et al, 2010 3. Althof et. al, 2010
PE management algorithm
Thank you !
(Damai Lagoon KUCHING)
Premature Ejaculation 1
Questions• ?
Medical Therapy Options for Treatment of PE - AUA Guidelines
Oral Therapies Trade Names Recommended Dose
Nonselective serotonin reuptake inhibitor
Clomipramine Anafranil® 25 to 50 mg/day or25 mg 4 - 24 hr pre-intercourse
Selective serotonin reuptake inhibitors
Fluoxetine Prozac®, Sarafem® 5 to 20 mg/day
Paroxetine Paxil® 10, 20, 40 mg/day or20 mg 3 to 4 hr pre-intercourse
Sertraline Zoloft® 25 to 200 mg/day or50 mg 4 to 8 hr pre-intercourse
Topical Therapies Trade Name Dose
Lidocaine/prilocaine cream EMLA® Cream Lidocaine 2.5%, prilocaine 2.5% 20 to 30 minutes pre-intercourse
Effectiveness of SSRIs
But successes limited by: Chronic dosing Antidepressant stigma Side effects
Waldinger MD, Hengeveld MW, Zwinderman AH, et al. J Clin Psychopharmacol 18:274‑81, 1998
PlaceboFluvoxamine(100 mg/day)
Fluoxetine(20 mg/day)
Paroxetine(20 mg/day)
Sertraline(50 mg/day)
IELT
(se
con
ds)
0
50
100
150
200
250
300
350
400
450
500
Baseline 6 weeks
Slow onset of effect of SSRIs in PE
0
1
2
3
4
0 1 2 3 4 5 6 7 8 9 10 11
Sertraline thenplaceboPlacebo thensertraline
sertraline washout placebo
IE
LT (
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 2
Questions• ?
Premature Ejaculation Profile(PEP)
1.Over the past month, was your satisfaction with sexual intercourse
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 Partners1.Over the past month, was your satisfaction with sexual intercourse
2. Over the past month, was your partner’s control over ejaculation during sexual intercourse
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?
END
Come again !