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: clarencelei@gmail.comkuchingurology.com

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 !