Instructional Course 4

Premature Ejaculation: Update onthe Management

Pharmacotherapy…Chris G McMahon MBBS FAChSHM

President ISSMAustralian Centre for Sexual Health

Relevant Disclosures …

Menarini Ixchelsis Plethora Solutions Pfizer Dong A ST

The following neurotransmitters areinvolved in the processing of emission and ejaculation: Serotonin (5-HT) Dopamine (DA) Oxytocin 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 in Control of Ejaculation

Pharmacological Treatment Over the past 20-30 years, the PE

treatment paradigm has expanded to include drug treatment

Level 1A evidence to support the efficacy & safety of off-label daily and on-demand SSRIs [1] Paroxetine, sertraline,

citalopram, fluoxetine Serotonergic tricyclic,

clomipramine Dapoxetine

Meta-analysis of all drug treatment studies has demonstrated that paroxetine exerts the strongest ejaculation delay (mean IELT fold increase of 8.8) [1,2]

1. ICSD Paris 20092. Waldinger, M.: Int J Imp Res: 1-13, 2004

The Criteria for the Ideal PE Drug is Controversial …

Daily dosing of SSRIs leads to superior increases in 5-HT neurotransmission due to several adaptive processes which may include 5-HT1A, 5-HT1B and 5-HT1D receptor desensitisation

Daily off-label dosing of SSRIs may be more effective than on-demand SRRIs but few direct head-to-head comparator studies have been conducted

Many men will prefer the convenience of “on-demand” medication

Dapoxetine

First compound specifically developed for the treatment of PE

Dapoxetine is a fast-acting, short half-life selective serotonin reuptake inhibitor (SSRI)

Level 1A evidence to support the efficacy and safety of on-demand dosing of dapoxetine (ICSD 2009)

• A 12/52, open-label, observational safety study

• Compare TEAEs in men taking DPX & men using other PE Rx incl. off-label SSRIs

• n=10,028 patients in 414 European sites

• n=6712 (67.6%) DPX 30–60 mg (group A)

• n=3316 (32.4%) other Rx incl.off-label SSRIs (group B)

• Endpoints• Treatment-emergent adverse

events (TEAEs)

• Data on concomitant therapy use

Vincenzo Mirone Urology. 2013 Sep;82(3):620-4

The PAUSE DPX Study

Oral drug No. (%)Clomipramine 98 (6.5)

Paroxetine 629 (41.5)Fluoxetine 27 (1.8)Sertraline 91 (6.0)

Other 680 (44.9)Total 1515

Other treatmentTopical drug 952 (32.5)

Condoms 432 (14.8)Behavioral counseling

1182 (40.4)

Other 362 (12.4)Total 2928

• The overall incidence of adverse events in patients treated with dapoxetine was lower in this study (12.0%) compared with phase 3 studies.

• TEAEs with DPX was lower than those treated with alternative care (oral drug) 12.0% vs 16.1%

• Most adverse events were mild to moderate and related to the gastrointestinal or nervous systems.

• Similarly, the proportion of patients who discontinued use due to adverse events (1.5%) was lower in this study than in the pooled phase 3 data (3.5% of dapoxetine 30 mg and 8.8% of dapoxetine 60 mg).

• No syncope with DPXVincenzo Mirone Urology. 2013 Sep;82(3):620-4

The PAUSE StudyTEAEs

Group A (DPX) Group B (non DX)

TotalOther drugs

Non-Oral

n 6,128 3,315 1,417 1,898

N with at least one AE, % 12.0% 8.9% 16.1% 3.5%

Nausea, % 3.1% 1.0% 2.3% 0.1%

Headache, % 2,6% 0.7% 1.3% 0.3%

Vertigo, % 1.0% 0.4% 0.9% 0%

Fatigue, % 0.4% 1.2% 2.8% 0%

Diarrhoea, % 0.6% 0.7% 1.6% 0.1%

• ~30% of men with ED have PE

• Evaluate efficacy and safety of dapoxetine 30 mg and 60 mg on demand (prn) in men with PE and ED who were being treated with PDE5 inhibitors (on-demand and daily)

• Randomized, double-blind, placebo controlled, parallel-group 18 week study

• N=495

• Treatment with a stable regimen of a PDE5 inhibitor >3 months before screening with IIEF EF ≥21

• Primary endpoint: Average IELT at week 12

The COUPLE Study

J Sex Med 2013;10:2312–2325

J Sex Med 2013;10:2312–2325

The COUPLE StudyResults: IELT

To assess both the acceptance and the discontinuation rates of DPX Single centre, 1-year prospective observational study n=120, lifelong PE and normal EF (IIEF EF >21) treated with DPX 30-60mg IELT was significantly and similarly improved compared to baseline in

patients who either continued or discontinued DPX

N. Mondaini et al. Urol 82:620-624, 2013

Reasons for treatment non-acceptance and discontinuation24 patients (20%)

decided not to start dapoxetine. Fear of using a “drug” (50%) was the main reason.

24 patients (20%) decided not to start dapoxetine. Fear of using a “drug” (50%) was the main reason.

Comparison of efficacy of on-demand dapoxetine (30 and 60 mg) and daily paroxetine (20 mg) usage in treating PE.

n=150 with PE (lifelong and acquired, IELT < 1min) Open label, 3 parallel arm OD DPX 30 mg, OD DPX 60mg, PAR 20mg

daily for 4/52 Endpoint-study end stopwatch IELT

Simsek A et al. Asian Journal of Andrology (2014) 16, 725–727

2.2 fold2.2 Fold 2.7 Fold 2.2 Fold

Simsek A et al. Asian Journal of Andrology (2014) 16, 725–727

Jeon HJ, Kim HS, Lee CH, et al. Urology. 2011;77: 1006 e17-21.

Kang KK , Sung JH, Kim SH, Lee S.Int J Urol. 2014 Mar;21(3):325-9.

DA-8031 Potent SSRI (Dong-A ST, Korea) Oral & intravenous DA-8031

significantly inhibited ejaculation in PCA-mediated ejaculation rat model

Dose-dependent increase in ejaculation latency time with statistical significance at 30 and 100 mg/kg dosage levels compared with the vehicle (P < 0.05)

PK studies showed blood concentration peaked at 0.38 ± 0.14 h after oral administration, and then rapidly declined with a half-life of 1.79 ± 0.32 h.

DA-8031 is a potential therapeutic agent in the treatment of PE

1. Jeon HJ, Kim HS, Lee CH, et al. Urology. 2011;77: 1006 e17-21.2. Kang KK , Sung JH, Kim SH, Lee S.Int J Urol. 2014 Mar;21(3):325-9.

Tramadol The efficacy of on-demand tramadol in the treatment of

premature ejaculation was recently reported [1-6] Tramadol is an oral centrally acting opioid analgesic

indicated for the treatment of moderate to severe pain Readily absorbed with T1/2 of 5-7h For analgesic purposes, 50-100 mg tramadol is

administrated 3-4 times a day Tramadol’s mode of action is unclear

Binds to µ-opioid receptors Weak serotonin, GABA and norepinephrine re-uptake

inhibitor

1. Safarinejad MR, Hosseini SY. J Clin Psychopharmacol 2006; 26(1):27-312. Salem EA, Wilson SK, Bissada NK et al. J Sex Med 20073. Kaynar M, Kilic O, Yurdakul T. Urology. 2012 Jan;79(1):145-9 4. Xiong GG, Wu FH, Chen SH, Yao WL Zhonghua Nan Ke Xue. 2011 Jun;17(6):538-41. 5. Alghobary M, El-Bayoumy Y, Mostafa Y, Mahmoud el-HM, Amr M. J Sex Med. 2010 Aug;7(8):2860-7 6. Bar-Or D, Salottolo KM, Orlando A, Winkler JV. Eur Urol. 2011 Aug 30. [Epub ahead of print]

TramadolAuthor/s n Design

IELT Fold IncreasePlacebo Other Tramadol

Safarinejad MR et al.[1] 57 Single Blind PBO - - 12.7 (50mg)

Salem EA et al.[2] 60Lifelong PE

Single Blind PBO1.4

-6.3 (25mg)

Kaynar M et al.[3] 60Lifelong PE

Single Blind, Cross Over PBO

--

Xiong GG et al.[4] 72 Open Label vs. CBT - 47.2% (CBT) 72.3% (50mg)

Alghobary M et al. [5] 35 Open Label, Cross Over vs PAR 20 daily - 11 (PAR20 Daily) 7

Bar-Or D et al. [6] 604 Lifelong PEDouble Blind PBO 1.6 - 2.4 (62mg ODT)

2.5 (89mg ODT)

Eassa B et al, [7] 300 Open Label - -4.7 (25mg)8.4 (50mg)

12.2 (100mg)

Khan et al [8] 60Lifelong PE

Double Blind PBO1.6

3.4 (Daily)4.0 (Daily + OD)

1. Safarinejad MR, Hosseini SY. J Clin Psychopharmacol 2006; 26(1):27-31 2. Salem EA, Wilson SK, Bissada NK et al. J Sex Med 2007 3. Kaynar M, Kilic O, Yurdakul T. Urology. 2012 Jan;79(1):145-9 3. Xiong GG, Wu FH, Chen SH, Yao WL Zhonghua Nan Ke Xue. 2011 Jun;17(6):538-41. 4. Alghobary M, El-Bayoumy Y, Mostafa Y, Mahmoud el-HM, Amr M. J Sex Med. 2010 Aug;7(8):2860-7 5. Bar-Or D, Salottolo KM, Orlando A, Winkler JV. Eur Urol. 2011 Aug 30. [Epub ahead of print] 6. Eassa BI Asian Journal of Andrology (2013) 15, 138–142

Tramadol ODT (Zertane®) Intravaginal Ejaculation Latency Times (IELTs)

1. Bar-Or D, Salottolo KM, Orlando A, Winkler JV. Eur Urol. 2011 Aug 30. [Epub ahead of print]

Integrated analysis of two 12-wk double-blind, placebo-controlled phase 3 trials RCT

Lifelong PE (18–65 yr of age) n=604, lifelong PE - DSM IV TR

& IELT<120s Endpoints …

Fold increase in median IELT mean change in all four PEP

measures

A prospective, single site, placebo controlled study of tramadol

n=60 Placebo versus

tramadol 100 mg daily for 4 weeks and then on-demand for 4 weeks more

Placebo

Tramadol

1.6 Fold

3.4 Fold

4.0 Fold

1.6 Fold

Lidocaine, lidocaine/prilocaine (EMLA), TEMPE® spray, Promescent® Spray

Few controlled studies Moderately effective in delaying ejaculation [1-3] Potential risk of penile hypo-anaesthesia, transvaginal

absorption, resulting in vaginal numbness and resultant female anorgasmia

Level 1A evidence to support the efficacy and safety of on-demand topical anaesthetics in the treatment of PE

“On-Demand” Topical Anesthetics

1. Berkovitch M, Keresteci AG, Koren G. Efficacy of prilocaine-lidocaine cream in the treatment of premature ejaculation. J Urol 1995; 154(4):1360-1.

2. Xin ZC, Choi YD, Lee SH, Choi HK. Efficacy of a topical agent SS-cream in the treatment of premature ejaculation: preliminary clinical studies. Yonsei Med J 1997; 38(2):91-5.

3. Busato W, Galindo CC. Topical anaesthetic use for treating premature ejaculation: a double-blind, randomized, placebo-controlledstudy. BJU Int 2004; 93(7):1018-21.

PSD502 - TEMPE®

Metered-dose spray of lidocaine and prilocaine for topical treatment of PE (Plethora Solutions Ltd, London, UK)

The physiochemical characteristics of the eutectic mixture and the spray delivery have been designed to optimize tissue penetration so that the onset of effect should be more rapid than that obtained with a cream

Also the spray only penetrates, and hence anaesthetises, the mucosa of the glans penis (and not the keratinized skin of the shaft)

Dinsmore, W.W., G. Hackett, D. Goldmeier, M. Waldinger, J. Dean, P. Wright, et al., Topical eutectic mixture for premature ejaculation (TEMPE): a novel aerosol-delivery form of lidocaine-prilocaine for treating premature ejaculation. BJU Int, 2007. 99(2): p. 369-75.

PSD502 - TEMPE®

Improved Ejaculatory Latency, Control and Sexual Satisfaction When PSD502 is Applied Topically in Men with Premature Ejaculation

Carson C et al. JSM Volume 7, Issue 9, pages 3179-3189

Modafinil was first identified as a wake promoting agent and is used for the treatment of narcolepsy. MOA involves induction of changes in brain activation

Exact mechanisms for its stimulatory effects are still to be determined Catecholamine and indolamine pathways, including dopamine and

serotonin, are probably involved Male sexual behavior in the rat was examined after acute oral

administration of d-modafinil in copulation studies with receptive females Results d-modafinil (30 mg/kg and 100 mg/kg) produced a significant delay

in ejaculation, accompanied by an increase in the number of intromissions without any change in the mount or intromission latency

Greatest delay in ejaculation was observed in animals with shorter baseline ejaculatory latencies.

Marson L, Yu G, Farber NM. JSM 2010;7: 70-8.

Marson L, Yu G, Farber NM.JSM 2010;7: 70-8.

Daily Alpha 1-Adrenoceptor Blockers

Ejaculation is a sympathetic spinal cord reflex which could theoretically be delayed by α1-adrenoceptor blockers

Several authors have reported their experience with the selective α1-blockers, alfuzosin and terazosin, in the treatment of PE 1,2

Current data is confusing and conflicting as both studies were limited by the use of subjective study endpoints of patient impression of change and sexual satisfaction and not objective endpoints such as IELT 1,2

1. Cavallini G. Alpha-1 blockade pharmacotherapy in primitive psychogenic premature ejaculation resistant to psychotherapy. Eur Urol 1995; 28(2):126-30

2. Basar MM, Yilmaz E, Ferhat M, Basar H, Batislam E. Terazosin in the Treatment of Premature Ejaculation: A Short-term Follow-up. Int Urol Nephrol 2005; 37(4):773-77

Sato, Y., et al., Silodosin and its potential for treating premature ejaculation: a preliminary report. Int J Urol, 2012. 19(3): p. 268-72.

3 fold

Sato, Y., et al., Silodosin and its potential for treating premature ejaculation: a preliminary report. Int J Urol, 2012. 19(3): p. 268-72.

The aim of this study was to compare the efficiency, and safety of alpha blocker drugs in the treatment of patients with premature ejaculation (PE). Additionally we investigated the quality of life (QoL) in patients with PE who were treated with alpha blocker drugs.

n=108 Open label parallel arm comparison of silodosin 4mg,

tamsulosin 0.4mg, alfuzosin 10mg, terazosin 5mg, doxazosin 4mg

Endpoints- Study-end IELT, PEP and QoL index

3.4 Fold

8.0 Fold

3.9 Fold

3.9 Fold

3.7 Fold

Silodosin

Tamsulosin

Alfuzosin

Terazosin

Doxazosin

Long-Evans rats (33 males) ~2 weeks to adapt to the light–dark cycle Treatment

Placebo: Saline injection (0.1 ml) Low Dose: Botulinum toxin-A (0.5 U in 0.1 ml) High Dose: Botulinum toxin-A (1 U in 0.1 ml)

Bulbospongiosus Muscle

The Effects of Btx-A Injection on Male Rat Ejaculatory Behavior

402,3453,8

361,6

590,2

302,8

668

0

100

200

300

400

500

600

700

800

900

Pre‐Inj Post‐Inj Pre‐Inj Post‐Inj Pre‐Inj Post‐Inj

Time (sec.)

p=0.53

P=0.04*

P=0.013*

PLACEBO LOW-DOSE HIGH-DOSE* Paired-sample T-test

Oxytocin and Sexual Response The role of oxytocin as a regulator of erection and ejaculatory latency is

only partially understood. Preclinical and clinical data indicate that OT may play a unifying role in

establishing ejaculatory latency through central and peripheral mechanisms [1,2].

Systemic administration of oxytocin reduces latency time to ejaculation and also increases the number of sperm per ejaculate in rabbits [3].

Additionally, the ejaculatory delay observed with SSRIs may be mediated through alterations in central oxytocin release [4,5], and the ejaculatory inhibition was reversed by oxytocin [5].

Oxytocin release increases modestly during sexual arousal, followed by a marked increase at ejaculation in humans, bulls, rams, and rabbits [6,7]. 1. Filippi S, Vignozzi L et al. J Endocrinol Invest 2003;26(3 suppl):82–6.2. de Jong TR, Veening JG, Olivier B,Waldinger MD. J Sex Med 2007;4:14–28.3. Stoneham MD, Everitt BJ, Hansen S, Lightman SL, Todd K. J Endocrinol 1985;107:97–106.4. Ivell R, Balvers M, Rust W, Bathgate R, Einspanier A. Adv Exp Med Biol 1997;424:253–64.5. Cantor JM, Binik YM, Pfaus JG. Psychopharmacology (Berl) 1999;144:355–62.6. Carmichael MS, Humbert R et al. J Clin Endocrinol Metab 1987;64:27–31.7. Murphy MR, Seckl JR, Burton S, Checkley SA, Lightman J Clin Endocrinol Metab 1987;65:738–41.

Double-blind, randomized, parallel-group, placebo-controlled, stopwatch-monitored, phase 2, multicenter study

n = 77, 18–55 years of age, with lifelong PE defined as per ISSM definition of lifelong PE and normal EF (IIEF EF ≥ 22)

Placebo, epelsiban 50 mg, or 150 mg, taken 1 hour before sexual activity.

Main Outcome Measures. Stopwatch IELT recordings Modified version of the IPE PRO

Conclusions …

The neurochemical control of ejaculation is complex and incompletely understood

Multiple neurotransmitters/neuromodulators and receptors are involved at multiple levels of the nervous system

The manipulation of several new pharmacological targets can potentially delay ejaculation

Continued basic research will further identify those mechanisms which control ejaculation and serve to identify new therapeutic targets and treatment for PE

Thank You