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No job nameInternational Journal of Urology (2007) 14, 331–335
Original Article: Clinical Investigation
Can sildenaﬁl treat primary premature ejaculation? A prospective
Wei-Fu Wang,1 Yang Wang,1 Suks Minhas2 and David J Ralph2 1Department of Urology, People’s Hospital of Hainan Province, Haikou, China; and 2St Peter’s Center of Andrology, in Association with the Institute of Urology,UCL, London, UK Background:
Recently, sildenaﬁl has been demonstrated to be effective in treating premature ejaculation (PE). However, these studies ignored female factors and could not exclude the probability of drug interaction when combined with paroxetine. Therefore, the aim of this study was to
evaluate the efﬁcacy and safety of sildenaﬁl alone in the treatment of primary PE, taking female factors into consideration.
One hundred and eighty potent men with primary PE were randomly divided into three groups and followed up for 6 months. Group A were treated with 50 mg sildenaﬁl as needed , group B with 20 mg paroxetine daily and group C with squeeze technique daily. Intravaginal
ejaculatory latency time (IELT), PE grade, intercourse satisfactory score (ISS), frequency of intercourse, and adverse effects of drugs were
recorded before treatment, and 3 and 6 months after treatment.
Compared with pretreatment, the three groups had signiﬁcant differences in all the parameters after 3 or 6 months treatment, except the frequency of intercourse in Group C (all P = 0.00). However, there were no signiﬁcant differences between 3 and 6 months. Compared with
paroxetine and squeeze technique, after 3 or 6 months, sildenaﬁl had signiﬁcant differences in all the parameters (all P = 0.00). After 6 months,
1.7%, 18.3% and 36.7% patients in groups A, B and C, respectively, withdrew from the study and 86.7%, 60.0% and 45.0% patients, respectively,
wanted to be treated further with the original administration, and this was statistically signiﬁcant (both P = 0.00).
Sildenaﬁl is very effective and safe to treat PE, and has much higher efﬁcacy than paroxetine and squeeze technique.
premature ejaculation, paroxetine, sildenaﬁl, therapy.
demonstrated to effectively delay ejaculation. However, none of thesedrugs have been approved by the FDA as drugs for PE.9 Premature ejaculation (PE), also referred to as early or rapid ejacula- Sildenafil, a selective inhibitor of cyclic guanosine monophosphate tion, is currently defined as persistent or recurrent ejaculation with (cGMP)-specific phosphodiesterase type 5, as a first line oral therapy minimal sexual stimulation before, upon, or shortly after penetration for ED, has recently been reported to have efficacy on alleviating PE by and before the person wishes. It is associated with marked distress or a few studies.10,11 However, these studies employed a combination of interpersonal difficulty.1 With a prevalence of more than 21%,2 and paroxetine and sildenafil to treat PE. Therefore, it is difficult to exclude perhaps affecting as many as 75% of men at some point in their lives,3 a possibility of drug interactions. In addition, the authors only used PE is regarded as the most common male sexual disorder.2 It can im- male factors such as intravaginal ejaculatory latency time (IELT), PE pact on many aspects of a man’s life, including reducing self-esteem, grade, or international index of erectile function (IIEF) intercourse deteriorating relationships, and causing anxiety, embarrassment and satisfaction domain scores as the parameters to evaluate the effective- depressed feelings.4 Moreover, PE places a significant burden on the ness, but did not take into account the factors of the female sexual patient–partner relationship with evidence that there is a higher preva- partner, such intercourse satisfaction score (ISS).
lence of female sexual dysfunction associated with PE.5 About 30% of Therefore, employing IELT, PE grade, male ISS, female ISS, and the men with PE have co-occurring erectile dysfunction (ED), which typi- times of intercourse per week as major parameters, we conducted this cally results in early ejaculation without full erection.6 Recently, 522 prospective clinical study to evaluate the efficacy of sildenafil alone and patients with PE were investigated and 65.3% patients were found to compared it with 20 mg paroxetine daily or squeeze technique daily in To date, drugs to treat PE have been divided into two categories: oral drugs such as antidepressants, alpha-adrenoceptor blocking agents andChinese herbal medicines; and local remedies such as topical medicine, intracavernosal injection agents and local urethral drugs.8 Althoughsome of these drugs have some disturbing side-effects, daily use of Patients
them, particularly paroxetine, clomipramine and sertraline, have been From March 2001 to March 2004, 286 patients with primary PE whopresented to the urological outpatient clinic in People’s Hospital ofHainan Province were enrolled into this prospective clinical trial guided Correspondence: Wei-Fu Wang MD PhD, Department of Urology, People’s
by St Peter’s Center of Andrology. PE was defined as ejaculation before Hospital of Hainan Province, 19 Xiuhua Road , Xiuying District, Haikou City, vaginal penetration or within 2 min after vaginal penetration. All patients were heterosexual and had had one stable sexual partner for Received 9 February 2006; accepted 19 June 2006.
2007 The Japanese Urological Association All the patients underwent a detailed medical and sexual history Intercourse satisfaction score
inquiry, physical examination (including Meares–Stamey test toexclude genital tract infection), and psychological profile. PE grade, Referring to PE grade, patients and their sexual partners evaluated their IELT, IIEF-5, ISS and frequency of intercourse were recorded. Their ISS by answering the question: ‘How often did you feel satisfaction sexual partners were also requested to record their ISS. For the pur- about intercourse in the past 3 months?’. The answers were graded on poses of the study, only potent patients (IIEF-5 >21) with primary PE a scale of 0–8: 0 = almost never, 2 = sometimes, 4 = about half the time, 6 = most of the time, and 8 = almost always.
Study exclusion criteria were: secondary PE; erectile dysfunction (ED); low libido; major psychiatric or psychological illnesses including Frequency of intercourse
depression; alcohol, drugs or substances abuse; organic diseasescausing limitation in using selective serotonin reuptake inhibitors or The frequency of intercourse was the number of instances of vaginal sildenafil; and use of other treatments for PE within the previous intercourse per week. Men whose frequency of intercourse in the past 3 months. Secondary PE was identified in 65 of 286 patients (25.4%), 3 months reached 0.5 or more were enrolled in the study.
who were excluded from analysis. Of these 65 patients, 56 (86.2%) hadchronic prostatitis. A further 41 patients (14.3%) who had accompany- Study protocol
ing ED were also excluded from this study, although they were consid-ered for inclusion in another parallel study that was being performed to Patients in Group A received 50 mg sildenafil as needed an hour before evaluate sildenafil in alleviating PE with and without ED.
intended intercourse according to the standard administration instruc- Thus, 180 potent men with primary PE were enrolled in the study.
tions (not less than one time per week). Patients in Group B received The men were randomly divided into three treatment groups: Group A 20 mg paroxetine daily. Patients and their sexual partners in Group C were treated with sildenafil as needed , Group B with paroxetine daily were asked to use the classical squeeze technique daily. Patients and and Group C with squeeze technique daily. Each group had 60 patients.
their sexual partners in Group C were shown how to employ thesqueeze technique by the same specialist.
All groups were followed up for 6 months. Patients and/or their Intravaginal ejaculatory latency time
sexual partners were required to record their IELT, PE grade, ISS andfrequency of intercourse, and adverse effects of drugs before treatment, Intravaginal ejaculatory latency time (IELT) is defined as the time that intercourse lasts from initiation of vaginal penetration to ejaculation.12It was measured by the female sexual partner using a stopwatch andexpressed in minutes. All the stopwatches were calibrated and provided Statistical analysis
by the same company. If ejaculation occurred before or during penis One way ANOVA test was used to compare data on the clinical details, penetration into the vagina, it was defined as 0 minute. Men whose IELT, PE grade, ISS and the frequency of intercourse in the three mean IELT in the past 3 months was <2 min were enrolled in the study.
groups. Student’s t-test was employed to compare data on PE grade, ISSand the frequency of intercourse between 3 and 6 month follow up. Thechi-squared test was used to compare data on the adverse effect of Premature ejaculation grade
sildenafil and paroxetine, and the rates of withdraw and willing to betreated further with original administration in the three groups.
According to the Center for Marital and Sexual Health questionnaire P < 0.05 was defined as statistically significant.
that dealt with PE,13 patients graded their ejaculatory dysfunction byanswering the question: ‘How often did you ejaculate rapidly beforevaginal penetration or within 2 min after vaginal penetration in the past 3 months?’. The answers were graded on a scale of 0–8: 0 = almostnever, 2 = sometimes, 4 = about half the time, 6 = most of the time, and Table 1 shows the clinical details of the three groups, including the age 8 = almost always. Men who graded their mean PE as 4 or greater in the and age range of patients and their partners, and the duration of PE.
past 3 months were enrolled in the study.
There were no significant differences among the three groups.
Baseline characteristics of patients with premature ejaculation (PE) according to treatment group 2007 The Japanese Urological Association Sildenafil for primary premature ejaculation IELT, PE grade, ISS of patients and their sexual partners, and the frequency of intercourse at baseline, 3 and 6 months follow up IELT, intravaginal ejaculatory latency time; ISS, intercourse satisfaction score; PE, premature ejaculation. Group A, 50 mg sildenaﬁl as needed; Group B, 20 mgparoxetine daily; Group C, squeeze technique daily.
Values shown as mean Ϯ SD.
Table 2 shows the mean IELT, PE grade, ISS of patients, ISS of their After 6 months follow-up, one (1.67%), 11 (18.33%) and 22 sexual partners, and the frequency of intercourse at baseline, and at 3 (36.67%) patients in groups A, B and C, respectively, withdrew from and 6 months follow up in the three groups. Before treatment, there was the study because of no efficacy or adverse effects, and there was a no significant difference among the three groups in all the parameters.
significant difference among the three groups (P = 0.00). After After 3 or 6 months treatment, there were significant differences among 6 months study, 52 (86.67%), 26 (60.00%) and 16 (45.00%) patients in the three groups in all the parameters (all P = 0.00). Compared with groups A, B and C, respectively, hoped to be treated further with the pretreatment, all the groups after 3 or 6 months follow-up had signifi- original administration, and there was a significant difference among cant differences in all parameters (all P = 0.00), except the frequency of intercourse. All the groups had no statistical differences between3 months and 6 months follow-up. In the term of efficacy, the descend- Discussion
ing trend was sildenafil > paroxetine > squeeze technique, and sildenafilwas much better than paroxetine and squeeze technique (all P = 0.00).
To date, PE has not had a universally agreed definition. Many defini- In general, sildenafil and paroxetine were well tolerated. Anejacula- tions are partial, subjective and non-specific. An ideal definition should tion occurred in one patient in group A and one patient in group B, who consist of IELT, the ability to control ejaculation, the extent of male withdrew from study after 1 months and 3 months, respectively. Table 3 sexual satisfaction, the extent of female sexual satisfaction, the fre- shows the adverse effects of the two drugs. Typical light or mild quency of female sexual partner reaching orgasm and the extent of headache, nausea, nasal congestion and flushing were reported when psychological and pathological factors.14 So, according to the ideal using sildenafil. Light dizziness, headache, nausea, fatigue and consti- criteria to define PE14 and the report for defining PE for experimental pation occurred when using paroxetine. Most adverse effects disap- and clinical investigations,15 IELT, PE grade, ISS of patients, ISS of their sexual partners, and the frequency of intercourse were employed 2007 The Japanese Urological Association Adverse effects of sildenaﬁl and paroxetine in our study to describe PE. Our intention was that this definition could explained:20 inhibiting the contractile response of the vas deferens, be clearer and widely accepted. The acceptability and reasonability of seminal vesicle, prostate and urethra; inducing a state of peripheral these selected parameters to assess PE have been supported recently by analgesia; augmenting the total duration of erection; and lessening the the Chinese Index of Premature Ejaculation (CIPE).16 central sympathetic output. Furthermore, there is evidence from knock- In many reports, IELT was used to describe PE, but PE was defined out mice to explain the efficacy of sildenafil in the treatment of PE.
as ejaculation within 1 or more than 1 minute of vaginal intromission, Mice lacking the eNOS (nitric oxide synthase) gene developed a con- and did not include ejaculation before vaginal intromission. We think dition similar to PE; however, mice lacking heme oxygenase-2 (HO-2) this is incomplete, because this condition is most common among developed a condition similar to delayed ejaculation. Some evidence young adults and men who lack sexual experience. In addition, we indicates that carbon monoxide (CO) generated by HO-2 could bind defined PE as IELT within 2 min of vaginal penetration, because the and inactivate NOS.20 In addition, sildenafil has been reported to normal average IELT of Chinese men was 2–6 min.8 Moreover, an increase confidence, the perception of ejaculatory control, and overall updated proposal for PE definition and diagnosis provided after the sexual satisfaction, and decrease the postorgasmic refractory time to second consultation on sexual dysfunctions6 also defined that ejacula- achieve a second erection after ejaculation in men with PE.21,22 To date, tory latency of 2 min or less may qualify a man for the diagnosis.
the mechanisms by which sildenafil treats PE are not clear, and well- In many studies, IELT, PE grade and frequency of intercourse were designed clinical and experimental trials are needed to elucidate them.
used to evaluate PE, but ISS of patients and their sexual partners were Sildenafil, as the first oral drug approved by FDA to treat ED, has not. Unlike in animals, one of the main aims of intercourse in humans, been used in millions of patients with ED around the world for nearly besides reproduction, is to make men and their sexual partners happy, 8 years. All the reports demonstrate that sildenafil is very safe with satisfactory and comfortable and let both men and their sexual partners some tolerable adverse effects using the dose 50 mg as needed , such as enjoy the happiness caused by orgasm. Therefore, ISS of patients and light or mild headache, nausea, nasal congestion and flushing, and their sexual partners were taken into consideration in our study.
these adverse effects will disappear with time. Sildenafil has similar In order to avoid the possibility that there was interaction of sildena- adverse effects in the treatment of PE as it does in the treatment of ED.
fil and paroxetine, we designed the study using sildenafil alone, and In order to gain more scientific and exact data, we conducted a compared it with paroxetine and squeeze technique, as well as pretreat- perspective randomized clinical trial. Certainly, owing to the limits of ment, to confirm the efficacy of sildenafil in the treatment of PE.
clinical patients and funds, there are some shortcomings in the design Paroxetine daily has been regarded as the most effective drugs to treat such as not employing perspective randomized , placebo-controlled , PE so far.17,18 We also confirmed that paroxetine was much more effec- double-blinded clinical trial methods. However, this study can present tive when compared with baseline and squeeze technique. The squeeze clues for manufacturer-sponsored double-blinded , placebo-controlled , technique has previously been thought to be a classically effective multicenter trials to further research the potential value of sildenafil in method , but it has recently been confirmed that it has little effect on the treatment of PE. In addition, some study should be carried out to PE,18 which also is supported by our study, although the squeeze tech- testify the efficacy of the other phosphodiesterase 5 inhibitors (PDE5- nique prolonged IELT significantly when compared with pretreatment.
Is) such as vardenafil and tadalafil in the treatment of PE. Recently, the Our results showed that compared with paroxetine, squeeze potential usefulness of vardenafil and tadalafil were presented at the 7th technique or pretreatment, sildenafil led to statistically significant Congress of the European Society for Sexual Medicine and 2005 improvement in all measured parameters. Our results are supported by American Urological Association meeting, respectively.23,24 Interest- Abdel-Hamid ,19 who demonstrated that sildenafil alone could prolong ingly, updated data suggest that PDE5-Is should be employed in hypo- IELT significantly. Moreover, compared with paroxetine and squeeze orgasmic forms, in old age or when PE is associated with ED, and technique, the dropout rate of sildenafil was significantly lower, and the therapeutic association with psychosexual therapy techniques might percentage of hoping to be treated further with original administration improve the efficacy, particularly in the long term, while selective was statistically significantly higher. All these results demonstrated that serotonin reuptake inhibitors should be used in young patients with sildenafil was superior to paroxetine and squeeze technique in the treatment of PE. In this study all the patients only had PE alone, not In summary, sildenafil can significantly increase IELT, ISS of accompanied by ED. In the other parallel study, we also confirmed that patients and their sexual partners and the frequency of intercourse, sildenafil could alleviate PE accompanied by ED and improve erectile and decrease PE grade with light or mild adverse effects. It is a very function simultaneously. So, sildenafil is a promising agent to treat PE; effective, promising and safe drug to treat PE. To determine whether in addition, it could be a case of ‘two birds with one stone’ if patients selective PDE5-Is will have a place in the treatment of PE, a manufacturer-sponsored , double-blinded , placebo-controlled , and With the increased understanding of the pathway of nitric oxide multicenter trial with a large number of patients should be (NO)-cGMP, the possible mechanisms of sildenafil to treat PE could be 2007 The Japanese Urological Association Sildenafil for primary premature ejaculation References
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2007 The Japanese Urological Association
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