Premature Ejaculation: Update on the Management

Instructional Course 4

Pharmacotherapy…

Chris G McMahon MBBS FAChSHM President ISSM Australian Centre for Sexual Health Relevant Disclosures …

 Menarini

 Ixchelsis

 Plethora Solutions

 Pfizer

 Dong A ST Neurotransmitters Involved in Control of Ejaculation

The following neurotransmitters are involved 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 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 1. ICSD Paris 2009 8.8) [1,2] 2. 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)



The PAUSE DPX Study

• A 12/52, open-label, observational safety Oral drug No. (%) study Clomipramine 98 (6.5) • Compare TEAEs in men taking DPX & men Paroxetine 629 (41.5) using other PE Rx incl. off-label SSRIs Fluoxetine 27 (1.8) •n=10,028 patients in 414 European sites Sertraline 91 (6.0) • n=6712 (67.6%) DPX 30–60 mg (group A) Other 680 (44.9) • n=3316 (32.4%) other Rx incl.off- Total 1515 label SSRIs (group B) Other treatment • Endpoints Topical drug 952 (32.5) • Treatment-emergent adverse Condoms 432 (14.8) events (TEAEs) Behavioral 1182 (40.4) • Data on concomitant therapy use counseling Other 362 (12.4) Total 2928

Vincenzo Mirone Urology. 2013 Sep;82(3):620-4 The PAUSE Study TEAEs • 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% Group A (DPX) Group B (non DX) • Most adverse events were mild to Other Total Non-Oral moderate and related to the drugs gastrointestinal or nervous systems. n 6,128 3,315 1,417 1,898 N with at least • Similarly, the proportion of patients 12.0% 8.9% 16.1% 3.5% who discontinued use due to adverse one AE, % events (1.5%) was lower in this study Nausea, % 3.1% 1.0% 2.3% 0.1% than in the pooled phase 3 data (3.5% Headache, % 2,6% 0.7% 1.3% 0.3% of dapoxetine 30 mg and 8.8% of Vertigo, % 1.0% 0.4% 0.9% 0% dapoxetine 60 mg). Fatigue, % 0.4% 1.2% 2.8% 0% • No syncope with DPX Diarrhoea, % 0.6% 0.7% 1.6% 0.1% Vincenzo Mirone Urology. 2013 Sep;82(3):620-4 The COUPLE Study

• ~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

J Sex Med 2013;10:2312–2325 The COUPLE Study Results: IELT

J Sex Med 2013;10:2312–2325  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

Reasons for treatment non-acceptance and discontinuation 24 patients (20%) decided not to start dapoxetine. Fear of using a “drug” (50%) was the main reason.

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

2.22.2 Fold fold  2.7 Fold  2.2 Fold 

Simsek A et al. Asian Journal of Andrology (2014) 16, 725–727 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 1/2  Readily absorbed with T 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):27-31 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 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] Tramadol

IELT Fold Increase Author/s n Design Placebo Other Tramadol Safarinejad MR et al.[1] 57 Single Blind PBO - - 12.7 (50mg) Lifelong PE - Salem EA et al.[2] 60 1.4 6.3 (25mg) Single Blind PBO Lifelong PE - Kaynar M et al.[3] 60 Single Blind, Cross - Over PBO Xiong GG et al.[4] 72 Open Label vs. CBT - 47.2% (CBT) 72.3% (50mg) Open Label, Cross Alghobary M et al. [5] 35 - 11 (PAR20 Daily) 7 Over vs PAR 20 daily Lifelong PE - 2.4 (62mg ODT) Bar-Or D et al. [6] 604 1.6 Double Blind PBO 2.5 (89mg ODT)

4.7 (25mg) Eassa B et al, [7] 300 Open Label - - 8.4 (50mg) 12.2 (100mg)

Lifelong PE 3.4 (Daily) Khan et al [8] 60 1.6 Double Blind PBO 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)

 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

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

site, placebo controlled Tramadol study of tramadol

 n=60 3.4 Fold   Placebo versus tramadol 100 mg daily 4.0 Fold  for 4 weeks and then Placebo on-demand for 4 weeks

more 1.6 Fold  1.6 Fold  “On-Demand” Topical Anesthetics

®  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

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-controlled study. 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 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. 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 Silodosin 8.0 Fold 

Tamsulosin 3.9 Fold  Alfuzosin

3.4 Fold 

Terazosin 3.9 Fold  Doxazosin 3.7 Fold   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 P=0.013*

900 P=0.04*

800

700 p=0.53

600

500 (sec.)

400 Time 668 300 590,2

453,8 200 402,3 361,6 302,8 100

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