Doi:10.1016/j.eururo.2007.08.005

e u r o p e a n u r o l o g y x x x ( 2 0 0 7 ) x x x – x x x a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n a l h o m e p a g e : w w w . e u r o p e a n u r o l o g y . c o m The Role of Phosphodiesterase Type 5 Inhibitorsin the Management of Premature Ejaculation:A Critical Analysis of Basic Science and Clinical Data Juza Chen Gal Keren-Paz, Yuval Bar-Yosef, Haim Matzkin Department of Urology, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel Objectives: To assess the usefulness of the phosphodiesterase type 5 inhibitors (PDE5-Is) in the treatment of premature ejaculation (PE) and to describe possible Methods: A MedLine search was performed for peer-reviewed articles on the roleof PDE5-Is in managing PE. No meta-analysis method was used.
Results: Five manuscripts that examined the efficacy of PDE5-Is in the treatmentof PE were retrieved. Three studies used sildenafil as monotherapy and two used it in combination with a serotonin selective reuptake inhibitor (SSRI). Three studies demonstrated a beneficial effect of sildenafil in the treatment of PE, as measured by intravaginal ejaculatory latency time (IELT) and by different ques- tionnaires assessing the patients’ subjective feelings of ejaculatory control, sexual satisfaction, and anxiety. One study showed the superiority of sildenafil compared to other modalities. Two studies showed that combination therapy of paroxetine and sildenafil was better than paroxetine alone. One study did not demonstrate a beneficial effect of sildenafil in prolonging IELT, but showed that sildenafil improved patients’ perception of ejaculatory control. Another study showed that topical anesthetics were better than sildenafil in the treatment ofPE but did not use IELT or a validated questionnaire to measure the efficacyof treatment. Several possible mechanisms could explain effectiveness of thePDE5-Is for treatment of PE: centrally, through the effect on the nitric oxide/cyclicguanosine monophosphate pathway; peripherally by causing relaxation ofsmooth muscle in the vas deferens, seminal vesicles, prostate, and urethraand inhibition of adrenergic transmission; or locally by inducing peripheralanalgesia. Another possibility might be prolongation of the duration of erection.
Conclusions: Encouraging evidence supports the role of PDE5-Is for treating PE.
Possible therapeutic mechanisms of action of PDE5-Is are multiple and complexand include central and peripheral effects. A large population, multicenter,randomized, double-blind, placebo-controlled study is needed to elucidate theefficacy of PDE5-Is in the treatment of PE.
# 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Corresponding author. Department of Urology, Tel-Aviv Sourasky Medical Center,6 Weitzmann str., Tel-Aviv 64239, Israel. Tel. +972 36973475; Fax: +972 36974822.
E-mail address: (J. Chen).
0302-2838/$ – see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. Please cite this article in press as: Chen J, et al., The Role of Phosphodiesterase Type 5 Inhibitors in the Management of PrematureEjaculation: A Critical Analysis of Basic Science and Clinical Data, Eur Urol (2007), e u r o p e a n u r o l o g y x x x ( 2 0 0 7 ) x x x – x x x nerves (S2–4) and involves pulsatile contractions ofthe bulbocavernosus and pelvic floor muscles together with relaxation of the external urinarysphincter.
Ejaculatory dysfunction, erectile dysfunction (ED), Ejaculation is a complex integration of actions and decreased libido are the major components of that occur in the central and peripheral nervous male sexual dysfunction. The introduction of oral systems. Structures in the central nervous system pharmacologic therapy for ED has focused much (CNS) that are involved in ejaculation include the attention on this pathology compared to others.
medial preoptic area (MPOA), nucleus paragiganto- Premature ejaculation (PE), however, is actually cellularis (nPGi), stria terminalis, amygdala, and more prevalent, involving up to 31% of men aged thalamus. Whereas the MPOA is involved in stimu- 18–59 and is considered to be the most common lation of emission and ejection, the nPGi has an among male sexual disorders. PE is more prevalent inhibitory influence. Descending serotonergic path- ways from the nPGi to the lumbosacral motor nuclei experience and frequency. The risk of PE does not inhibit ejaculation. The MPOA can inhibit the nPGi, vary significantly with age, and men with PE are at risk for suffering from psychological disturbances, Many neurotransmitters are involved in the control of ejaculation, including norepinephrine,serotonin, acetylcholine, oxytocin, g-aminobutyric acid (GABA), and nitric oxide (NO) . Serotonin(5-hydroxytryptamine [5-HT]) has an inhibitory There is no universally accepted definition of PE.
effect on ejaculation . The serotonin receptors The 4th edition of the Diagnostic and Statistical 5-HT1a and 5-HT2c were associated with ejaculation Manual of Mental Disorders (DSM-IV) defines PE as . 5-HT1a is a presynaptic autoreceptor that inhibits ‘‘persistent or recurrent onset of orgasm and serotonin secretion and thus may stimulate ejacula- ejaculation with minimal stimulation before, on, tion, whereas the 5-HT2c receptor is postsynaptic or shortly after penetration and before the person and its activation is related to inhibition of ejacula- wishes it,’’ which causes ‘‘marked distress or tion . NO has a central effect, mostly in the interpersonal difficulty’’ . This definition con- MPOA, in promoting penile erection, and it may sists of the four elements of PE: ejaculatory latency, control, distress, and sexual satisfaction.
Given the obscurity of ejaculation physiology, it DSM-IV divides PE into lifelong PE, which had been is not surprising that PE pathophysiology is equally present from the onset of sexual life, and acquired poorly understood. Historically, PE was considered PE, in which the dysfunction developed after a as being a problem with psychological causes, such period of normal sexual function. PE can be further as anxiety, early sexual experiences, sexual con- divided into global (regardless of partner or ditioning, and sexual technique . It was specu- situation) and situational (only with certain part- lated that anxiety activates sympathetic output ners or circumstances). Some authors suggested and thus leads to earlier emission and rapid defining PE as a syndrome, rather than a com- ejaculation Currently, a speculated neuro- plaint, comprising quantification of the ejaculation genic cause is either a hyposensitivity of 5-HT2c time, inability of ejaculatory control, and a receptors or a hypersensitivity of the 5-HT1a description of severity of PE in terms of psycho- receptors Other causes might be a hyperexci- logical distress . Still, the absence of an agreed- table ejaculatory reflex, resulting in faster emis- on definition causes wide variations in patient sion and ejection, prostatic pathologies such as inflammation or infection high fasting serumleptin levels hyperthyroidism and genetic Physiology of ejaculation and PE pathophysiology The physiology of ejaculation is still not clearly understood. Ejaculation involves three stages: emis-sion, ejection, and orgasm. Emission consists of PE can be treated with behavioral techniques, topical contractions of seminal vesicles (SVs) and prostate anesthetics, a-adrenergic receptor antagonists, tri- with expulsion of sperm and seminal fluid into the cyclic antidepressants, and selective serotonin posterior urethra and is mediated by sympathetic nerves (T10–L2). Ejection is mediated by somatic type 5 inhibitors (PDE5-Is), for example, sildenafil, Please cite this article in press as: Chen J, et al., The Role of Phosphodiesterase Type 5 Inhibitors in the Management of PrematureEjaculation: A Critical Analysis of Basic Science and Clinical Data, Eur Urol (2007), e u r o p e a n u r o l o g y x x x ( 2 0 0 7 ) x x x – x x x tadalafil, and vardenafil, inhibit PDE5 both centrallyand peripherally and lead to the accumulation ofintracellular (cGMP) . Although used successfully in the mana- gement of ED, novel applications include alleviating PE. In this review, we discuss the role of PDE5-Is in the treatment of PE and the possible mechanisms of We searched MedLine for peer-reviewed studies published from January 1, 1990 to February 28, 2007 on treatment with PDE5-Is for patients suffering from PE and on the pathophy- siologic explanation of the action of PDE5-Is on ejaculatory function. We used the key words ‘‘premature ejaculation,’’ ‘‘rapid ejaculation,’’ ‘‘sildenafil,’’ ‘‘tadalafil,’’ ‘‘vardenafil,’’ ‘‘PDE5-I,’’ and ‘‘medical treatment of PE.’’ The search wasrestricted to publications in the English literature, and letters to editor were excluded. The results of the individual studies are presented and discussed; no meta-analysis or integration Of 111 articles retrieved from the systematic search, we focused our analysis on the five that appeared in English, which examined the role of PDE5-Is in the management of patients with PE. These articles were selected for the quality of their methodology and the importance of the results pre-sented. We assessed each study protocol in terms of patient characteristics, definitions of PE used, the study’s primary and secondary end points, and its outcomes. We obtained additional information from data of European and Interna- tional Society for Sexual Medicine guidelines.
Five manuscripts were found concerning the use of PDE5-I in PE (Two were placebo-controlled studies None fulfilled the criteria of a level 1 study (double-blind, placebo-controlled, random- ized study). Four articles were comparative, using reports assessed therapy with sildenafil as mono- In a prospective, randomized, double-blind cross- over study, Abdel-Hamid et al assessed the efficacy of as-needed clomipramine, sertraline, paroxetine, or sildenafil and the pause-squeeze technique in 31 men with lifelong PE without ED PE was defined as patient self-reported intravaginal ejaculation latency time (IELT) < 2 min and lack or little control over ejaculation. Sildenafil (50 mg) was given 3–5 h before intercourse. IELT was measured by the patient using a stopwatch, and the patient answered a questionnaire and received a sexual satisfaction score and an anxiety score. Although all regimens Please cite this article in press as: Chen J, et al., The Role of Phosphodiesterase Type 5 Inhibitors in the Management of PrematureEjaculation: A Critical Analysis of Basic Science and Clinical Data, Eur Urol (2007), e u r o p e a n u r o l o g y x x x ( 2 0 0 7 ) x x x – x x x showed prolongation of IELT, the effect of sildenafil in 75% of intercourse attempts. IELT, which was was significantly greater (from 1 to 15 min, effective measured using a stopwatch, was prolonged in in 90% of patients) and was correlated to improve- patients who were taking sildenafil, but the differ- ment in the sexual satisfaction score and the anxiety ence was not statistically significant. The patients score. The relation between IELT and the ques- were asked to answer the Index of Premature tionnaires was not evaluated. The effect of sildenafil Ejaculation (IPE) questionnaire. There was no sig- remained during the washout period in 29% of nificant difference in the overall IPE score, but patients. The incidence of side effects was similar patients who were taking sildenafil had significantly among groups and included headache, flushing, and higher scores on questions assessing ejaculatory nasal congestion in 18% of the patients who received control and confidence as well as overall sexual satisfaction. Sildenafil also significantly shortened the refractory time after orgasm. The correlation sildenafil and paroxetine to paroxetine alone in between IELT and the IPE questionnaire was not the treatment of 80 potent men with nonorganic PE as defined by an IELT of <1 min. Eighteen of them Atan et al compared the efficacy of sildenafil had secondary PE. Forty men received 10 mg alone, sildenafil with topical EMLA cream, topical paroxetine daily for 21 d and then 20 mg as needed EMLA cream alone, and placebo in 84 potent patients for 6 mo, whereas the other 40 men received the with lifelong and acquired PE. PE was defined same, only with the addition of as-needed 50 mg according to the DSM-IV definition, and improve- sildenafil 1 h before intercourse. IELT, which was ment was determined solely on the basis of patients’ measured using a stopwatch, was significantly statement after eight attempts at intercourse. IELT longer after 6 mo for the patients who received was not measured. Twenty patients received pla- sildenafil (from a mean of 0.33 min to 5.3 min vs.
cebo for 2 mo, 20 patients received 50 mg sildenafil 4.2 min in patients who received paroxetine alone, 45 min before intercourse, 22 patients received p < 0.05). There were also improvements in inter- sildenafil and topical EMLA cream before inter- course frequency and in sexual satisfaction, as course, and 22 patients received EMLA cream alone.
There was no significant improvement in PE of Erectile Function (IIEF) questionnaire. Side between sildenafil alone and placebo. Only the effects were more frequent in the group that groups that received EMLA cream with or without received the combination therapy, with 20% sildenafil showed significant improvement in PE.
complaining of headache and 15% of flushing.
Only the patients who received sildenafil experi- Nevertheless, 90% of the patients were willing to enced side effects, which included headaches (26%) Chen et al examined the efficacy of sildenafil We found no peer-reviewed publications on the as adjuvant therapy with paroxetine in potent role of tadalafil or vardenafil in the treatment of PE, patients with primary PE. Patients who reported other than abstracts presented at international that PE occurred in >50% of intercourse attempts and had a self-reported IELT < 3 min (measuredqualitatively using a questionnaire) were enrolled.
All 138 patients received psychological and beha- vioral counseling in addition to topical lidocainetreatment. Patients who remained dissatisfied after Possible mechanisms of actions of PDE5-Is in PE 3 mo were then treated with paroxetine daily for 30 dand then on an as-needed basis. After an additional The physiology of ejaculation and the pathophy- 3 mo, 25–100 mg sildenafil was added 1 h before siology of PE are still not fully understood. Like- intercourse to dissatisfied patients. Of the 58 wise, the mechanisms of action of PDE5-Is in the patients who received adjuvant sildenafil, 56 were treatment of PE still need to be elucidated. Never- satisfied (97%) compared to 42% who were satisfied with paroxetine alone and 28% who were satisfied explain their effects in PE, as has been demon- strated in animal and human studies. PDE5-Is may In a randomized, 8-wk, double-blind, placebo- exert their influence both centrally and periph- controlled multicenter study, McMahon et al erally. We will describe the presence and affects of assessed the efficacy of 50–100 mg as-needed the NO/cGMP pathway, the presence of PDE, and sildenafil in 157 potent men with lifelong PE, defined the possible actions of PDE5-Is in each nervous according to DSM-IV criteria and with IELT < 2 min Please cite this article in press as: Chen J, et al., The Role of Phosphodiesterase Type 5 Inhibitors in the Management of PrematureEjaculation: A Critical Analysis of Basic Science and Clinical Data, Eur Urol (2007), e u r o p e a n u r o l o g y x x x ( 2 0 0 7 ) x x x – x x x strip preparations and adrenergic transmission The NO/cGMP pathway seems to play a role in sexual behavior via a central effect, as nitric oxide synthase Medina et al described a mechanism that is inde- (NOS) and guanylate cyclase are present and active pendent of the NO/cGMP pathway. They demon- in areas of the CNS that are responsible for sex strated that sildenafil also has a direct inhibitory drive and sexual behavior Some authors have effect on smooth muscle of human VD by activation demonstrated that NO donors increase cGMP in the of pre-junctional large conductance Ca2+-activated hypothalamus, and infusion of NO donors to the extracellular environment in the MPOA of rat’s braininduces erection and copulatory behavior NO 4.1.2.2. Induction of peripheral analgesia. One presumed decreases central sympathetic output to the pe- cause of PE is penile hypersensitivity, leading to the riphery via a cGMP-dependent mechanism or suggested treatment modality of topical anesthetics.
through interactions with other neurotransmitters Sildenafil may mimic this effect given that activa- . Specifically, a decrease of sympathetic tone by tion of the NO/cGMP signaling pathway by sildenafil NO activity in the MPOA is related to inhibition of was shown to induce a state of peripheral anti- ejaculation . PDE5 has been demonstrated in the nociception Another explanation for peripheral CNS and PDE5-Is can cross the blood–brain analgesia could be mechanical. PDE5-Is cause barrier into the brain Administration of silde- cavernosal congestion by maximal dilatation of nafil intrathecally in rats increases NO and cGMP in blood vessels supplying the corpus cavernosum, the MPOA . Moreover, incubation of rat hippo- leading to an increase in intracavernosal volume campal slices with vardenafil results in an increase and, therefore, to increased pressure on nerve receptors, thus causing hypoesthesia of the glanspenis and prolongation of ejaculatory latency time.
This theory, however, is highly controversial 4.1.2.1. Relaxation of smooth muscle in the VD, SVs, prostate,and urethra. Because the NO/cGMP and NO/cyclic 4.1.2.3. Prolongation of the duration of erection. To date, adenosine monophosphate (cAMP) signaling path- many studies have demonstrated the effect of ways are involved in relaxation of corporal smooth different PDE5-Is in prolonging the duration of muscles, they could also affect smooth muscle in erection, as part of the rationale of this treatment the VD, SVs, prostate, and urethra. Many lines of modality in ED. Some works have correlated the evidence support the presence and activity of the duration of erection with the ejaculation latency time NO/cGMP and NO/cAMP signaling pathways in the in such a manner that the longer the duration VD, smooth muscles, prostate, and urethra. Nitrer- of erection, the more prolonged the ejaculatory gic innervation and NO synthase activity have latency time Therefore, PDE5-Is might have a been detected in human VD, SVs, prostate, urethra, beneficial effect on PE by improving the duration of agents have been shown to inhibit seminal emissionsin rats , whereas NO inhibitors decrease the latency to emission in rats and reduce thecontractile response of guinea pig VD and human Overall effectiveness of using PDE5-Is for treating PE SVs . Moreover, one study on knockout mice Of the five studies we reviewed, three found PDE5-Is demonstrated that mice homozygous for a deletion in to be helpful in the treatment of PE, whereas two did the gene for endothelial NOS (eNOS) have shorter not. Three reports assessed the efficacy of sildenafil latency times with much less stimulation than wild- as monotherapy . One found that sildenafil type mice . Elevation of intracellular cGMP and was superior to other treatment modalities, such cAMP leads to relaxation of smooth muscle in rat and as clomipramine, sertraline, paroxetine, and the pause-squeeze technique in terms of IELT and activity has been demonstrated in the VD, SVs, sexual satisfaction The other two studies, prostate, and skeletal muscles and sildenafil which were placebo-controlled, found no significant has been shown to cause selective potentiation of advantage to treatment with sildenafil in PE. One nitrergic transmission in urogenital smooth muscle study did not demonstrate any difference between sildenafil and placebo in terms of improvement in Another way in which PDE5-Is can prolong latency stopwatch-measured IELT but did show significant is by inhibiting adrenergic transmission. PDE5-I was changes in ejaculatory control, confidence, and able to reverse adrenergic tension in human prostatic overall sexual satisfaction in favor of sildenafil as Please cite this article in press as: Chen J, et al., The Role of Phosphodiesterase Type 5 Inhibitors in the Management of PrematureEjaculation: A Critical Analysis of Basic Science and Clinical Data, Eur Urol (2007), e u r o p e a n u r o l o g y x x x ( 2 0 0 7 ) x x x – x x x assessed by the IPE questionnaire The other study did not show any advantage of sildenafil over and in one study based on the patients’ estima- placebo but rather that topical anesthetics were better in treating patients with PE; IELT, however, Although the measurement of IELT by a stopwatch was not measured and the noted improvement is the most accepted tool because it is considered to was based only on the patients’ responses toward be ‘‘objective,’’ many authors find this modality to be treatment and not according to any validated controversial, first, due to the inconvenience of the use of a stopwatch during intercourse, second, Two studies assessed PDE5-Is as part of a because it may decrease the quality of the sexual combination therapy with SSRI Both of them intercourse, and third, because it may not be showed that sildenafil with paroxetine is superior to acceptable to all patients or their sexual partners.
paroxetine alone in the treatment of PE. Salonia et al We believe that the IELT as estimated by the patient demonstrated improvements in stopwatch-mea- and his partner is comparable to stopwatch-mea- sured IELT, sexual satisfaction, and frequency of intercourse with sildenafil and paroxetine . Chenet al showed that the combination of sildenafil and Overall effectiveness instruments and general paroxetine was efficient in 97% of patients so treated compared to 42% of patients treated with paroxetine Different types of questionnaires have been used to assess the patients’ sense of improvement. Twostudies used questionnaires developed originally for ED patients. Abdel-Hamid et al used an The European and International Society for Sexual Arabic questionnaire to assess anxiety and the Medicine guidelines state that the inclusion criteria first nine items of the sexual satisfaction ques- for studies on management of PE must ensure that tionnaire designed originally for ED patients participants have PE and no other sexual dysfunc- to assess sexual satisfaction. Salonia et al used tion, such as ED, and that the IELT measurement as a the IIEF questionnaire and a general efficacy ques- specific entry criterion is not a necessity The tion. The other two studies used novel instruments: definition of PE, as reflected by the inclusion criteria, Chen et al used a modification of a question from was varied among the studies we reviewed. All but the Center for Marital and Sexual Health (CMASH) one defined PE using IELT, either measured by Ejaculatory Function questionnaire on PE, and stopwatch or self-reported. Two studies defined PE McMahon et al used the IPE and a general efficacy as IELT < 2 min , one study defined PE as IELT question. In another PE study we used the Index < 3 min , whereas another defined it as IELT of Ejaculatory Control (IEC) 10-item questionnaire, < 1 min . Two studies used the DSM-IV criteria which was validated and designed to assess the for defining PE, one in addition to a measured IELT patient’s feeling of control, sexual satisfaction, and , whereas the other one based its definition solely on the DSM-IV . Two more investigations, Given that PE may be psychogenic, at least in part, which used IELT as a criterion, used also a question and possibly related to anxiety while part of its definition are feelings of lack of ejaculatory control, variation in criteria is not surprising in light of the bother, and distress, there is considerable room for a lack of a widely accepted definition of PE, but placebo effect in all studies on the management of it seems reasonable to include patients with IELT PE. For this reason, any well-constructed study < 2 min together with a subjective feeling of lack of aimed at assessing the effect of PDE5-Is on PE must be placebo-controlled. In our recent randomized,double-blind, placebo-controlled, crossover study, we compared sildenafil with placebo in 61 potent The European and International Society for Sexual men with PE We showed that patients receiving Medicine guidelines state that outcome measures sildenafil had prolonged IELT compared with those should include IELT, ejaculatory control, and who received placebo, as measured by a specially sexual satisfaction . Only one study did not designed visual scale Ejaculatory Latency Time use IELT as an end point, but rather patients’ self- Questionnaire (ELTQ). Significant improvements were also observed in the IEC score for patients improvement All the other studies used IELT who received sildenafil. The number of patients and different questionnaires to assess the patients’ responding positively to the global assessment subjective feeling of improvement. IELT in three question (‘‘Did you have better control over your Please cite this article in press as: Chen J, et al., The Role of Phosphodiesterase Type 5 Inhibitors in the Management of PrematureEjaculation: A Critical Analysis of Basic Science and Clinical Data, Eur Urol (2007), e u r o p e a n u r o l o g y x x x ( 2 0 0 7 ) x x x – x x x ejaculation?’’) while on sildenafil was significantly [3] American Psychiatric Association. Diagnostic criteria higher than those on placebo ( p < 0.01).
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