Lidocaine Cream in Primary Premature Ejaculation

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ORIGINAL ARTICLE A reassessment of penile sensory pathways and effects of prilocaine–lidocaine cream in primary premature ejaculation

J-D Xia1, L-H Zhou2, Y-F Han1, Y Chen1,2, R Wang3 and Y-T Dai1,2

To assess the penile sensory pathway abnormalities of the patients with primary premature ejaculation (PPE) and effects of prilocaine–lidocaine (PLA) cream, we enrolled 82 PPE patients and 34 normal potent male volunteers. Somatosensory evoked potentials of dorsal nerve (DNSEP) and glans penis (GPSEP) were performed in each subject. In addition, among the 82 patients, 60 were selected and randomly divided into PLA and placebo subgroups, each with 30 patients. Cream was applied evenly on the glans penis for 10 min and washed off just before DNSEP and GPSEP were repeatedly measured. Mean latencies of DNSEP and GPSPE were both remarkably shorter in the patients than those in the normal potent men (Po0.001, both). Compared with the control group, the mean amplitudes of GPSEP were significantly greater in the patient group (Po0.001), but not considerably on the amplitudes of DNSEP (P ¼ 0.229). After cream application, the latencies and amplitudes of both DNSEP and GPSEP were significantly prolonged and reduced, respectively, in the PLA cream subgroup (Po0.001, all). These results showed that hyperexcitable ejaculatory reflex neurological factor was linked to PPE, because of hypersensitivity of the penile, accelerated conduction and cortical amplification of the genital stimuli. The PLA cream could delay sensory latency and decrease glans penile hyperexcitability, which may be the mechanism for PPE treatment.

International Journal of Impotence Research (2014) 26, 186–190; doi:10.1038/ijir.2014.5; published online 27 February 2014 Keywords: local application; premature ejaculation; prilocaine-lidocaine; somatosensory evoked potentials

INTRODUCTION stimuli7 and did not show correlation between penile sensitivity 8 Premature ejaculation (PE) is the most common male sexual and ejaculation latency time. Interestingly, with quantitative 9 dysfunction and affects 20–30% of the world’s male population.1 sensory testing analysis, Salonia et al. reported that the PPE There are several definitions of PE crafted by various professional patients had hyposensitivity, instead of hypersensitivity, profile. organizations or individuals. In 2008, the International Society of In the present study, we used somatosensory evoked potential Sexual Medicine developed the first contemporary multivariate (SEP) tests to reassess whether the PPE patients had penile evidence-based definition of the primary premature ejaculation sensory pathway abnormalities. (PPE): a male sexual dysfunction characterized by ejaculation that To date, there are no pharmacological agents approved for 10 always or nearly always occurs before or within about 1 min of use in PE, apart from dapoxetine in some European countries. vaginal penetration, and the inability to delay ejaculation on all or On the other hand, topical local anesthetics such as lidocaine and/ nearly all vaginal penetrations, and negative personal conse- or prilocaine, in the form of a cream, gel or spray, are moderately 11 quences, such as distress, bother, frustration and/or the avoidance effective in delaying ejaculation, although they were not of sexual intimacy.2 approved for the treatment of PE. To further evaluate the Clinically, PE is usually classified as either primary or acquired mechanism of local anesthetics in treating PPE, we conducted a depending on the time of onset of the problem in one’s life.3 randomized placebo-controlled study to observe the effects of Historically, it was thought that PE was caused by psycho- prilocaine–lidocaine (PLA) cream on latencies and amplitudes of logical and conditioning factors, such as unsolved unconscious SEPs in the patients with PPE. conflicts, interpersonal problems, inappropriate conditioning by early experiences or too low frequency of sex.4 Recently, opioid substance withdrawal, prostatic inflammation and hyper- MATERIALS AND METHODS thyroidism are considered to be the causes of acquired PE in Subjects some patients.5 On the other hand, studies have indicated that From October 2011 to January 2013, 82 patients with PPE attending to the somatic disorders and/or neurobiological imbalances constitute Department of Andrology of our hospital, and 34 voluntary, normal, the organic basis of PPE.5 It is considered that penile hyper- potent, adult men were enrolled in this study. Each subject had a stable sensitivity may be one of the pathologic mechanisms of PPE. The heterosexual partner for over 1 year. All the subjects signed informed consent, and the local ethics committee approved our investigations. results of a case–control study suggested that PPE patients had 6 PPE was determined based on the definition established by the hypersensitivity and hyperexcitability of the glans penis. How- International Society of Sexual Medicine,2 which is characterized by the ever, other investigations did not find either a faster conduction chronic inability to exert voluntary control over the ejaculatory reflex since or a greater cortical representation of the genital area sensory the beginning of sexual life, with the stopwatch intravaginal ejaculation

1Department of Andrology, Nanjing Drum Tower Hospital, Nanjing Medical University, Nanjing, China; 2Department of Andrology, The Affiliated Drum Tower Hospital of Nanjing University, School of Medicine, Nanjing, China and 3Department of Urology, University of Texas Medical School at Houston and M.D. Anderson Cancer Center, Houston, TX, USA. Correspondence: Dr Y-T Dai, Department of Andrology, Nanjing Drum Tower Hospital, Nanjing Medical University, Nanjing 210008, China. E-mail: [email protected] Received 27 April 2013; revised 9 December 2013; accepted 9 January 2014; published online 27 February 2014 Penile sensory pathways and effects of PLA in PPE J-d Xia et al 187 latency time (IELT) of fewer than 1 min. IELT was measured for the 4-week RESULTS baseline period during which all patients were asked to have sexual Subject characteristics intercourse at least four times. The normal potent men who presented satisfactory sexual intercourse and good control over ejaculation with the The median IELT of the 82 PPE patients was 38.9 s (27 of them average-estimated IELT more than 3 min were classified as the control within 30 s). Their PE symptoms lasted for 1–25 years, median 4.6 group. Neither normal subjects nor the patients had erectile dysfunction, years. Compared with the control group, the average CIPE-5 score genitourinary tract infection, systemic (diabetes, alcoholism, hyper- of the PPE group was significantly lower, indicating that the sexual tension, hyper- or hypo-thyroidism and others) or neurological disorders function of patients was highly worse than that of the normal and obvious psychological problems requiring psychiatric support or controls on ejaculation. However, there was no statistical continuous drug use that might alter sexual activities. Physical difference in marital status, age, height, body weight and IIEF-5 examinations, including the genitalia, were normal. To assist the score in both groups (Table 1). In addition, there was no diagnosis for the enrollment of PPE patients, we used The Chinese Index statistically significant difference in age, height, weight, CIPE-5 of PE, with five questions (CIPE-5) and International Index of Erectile Function-5 (IIEF-5).12,13 and IIEF-5 scores between the PLA and placebo cream application subgroups.

Methods Comparison of SEPs latencies and amplitudes between the control An electromyograph and evoked potential equipment (Keypoint 4, Alpine and PPE groups BioMed ApS, Copenhagen, Denmark) was used to measure SEPs. SEPs M-shaped SEPs (DNSEP and GPSEP) were obtainable in both the consisted of dorsal nerve (DNSEP) and glans penis (GPSEP), with electrical normal subjects and the PPE patients. The typical GPSEP wave- stimuli on different places. DNSEP was performed as follows: the anode forms of the PPE patients and the controls are shown in Figure 1. ring was put on the subcoronal region and the cathode was placed on the shaft 2 cm proximal to the anode. The duration of stimuli was 1.0 ms and The Kolmogorov–Smirnov test showed that the latencies of SEPs the frequency was 3 s À 1. First, we detected the penile shaft sensory were normally distributed, but the amplitudes were abnormally threshold value, which was determined by gradually increasing from 0 mA distributed. The mean latencies of DNSEP and GPSEP were until the subject sensed tiny synchronous prickle stimulation. Subse- 39.33±4.62 ms and 41.48±3.53 ms, respectively, in the PPE quently, it was decreased step by step until the subject just could not feel group; and 43.24±2.15 ms and 44.57±1.78 ms in the control the stimulation. The decreasing intensity was considered as the critical group, respectively . Mean latencies of both DNSEP and GPSEP value. The same procedure was repeated 3 times, and all the critical values were significantly shorter in the PPE group than those in the were recorded and averaged to estimate the sensory threshold of the control group (Po0.001, both). In the two groups, the mean penile shaft. Following the determination of penile shaft sensory threshold, latencies of DNSEP were statistically shorter than those of GPSEP electrical stimuli were delivered to the penile shaft via ring electrodes with an intensity of three times that of the threshold value. In order to examine (Po0.001, 0.001, respectively). The median (interquartile range) whether there were differences in the cerebral response to the same values of DNSEP and GPSEP amplitudes were 1.32 (0.97–1.87) and intensity stimuli, we conducted GPSEP with a pair of round surface 1.87 (1.40–2.51) mV, respectively, in the PPE patients; and 1.22 electrodes placed at the glans penis and set the stimuli intensity at 10.0 mA (0.87–1.62) and 1.32 (1.01–1.64) mV, respectively, in the control (at this level, the subjects perceived no pain) in each subject. subjects. The amplitudes of GPSEP were considerably greater in Recording electrodes consisted of two needles. According to the the PPE group than those in the control group (P 0.001); 14 o international 10–20 electrode placement protocol, the active recording however, no statistically significant difference was found in the electrode was placed on the scalp 2 cm behind the Cz electroencephalo- amplitudes of DNSEP (P ¼ 0.229). In both the groups, the graphic recording site, and the reference electrode on the forehead in the amplitudes of GPSEP were larger than those of DNSEP, which midline (Fpz). The right arm was used for grounding. Responses were was notably obvious in the PPE group (P 0.001). recorded on the skin with an impedance of o5kO. Both tests were o performed twice and each time 200 cortical potentials were averaged. In all the subjects, there were positive correlations between When there were significant differences between the two tests, the test latencies of DNSEP and GPSEP (r ¼ 0.600, Po0.001, Figure 2a). was repeated three or four times to evaluate test-to-test variability. Results Besides, the amplitudes of DNSEP and GPSEP also had a good were recorded in latencies and amplitudes of SEPs. The latency was correlation (r ¼ 0.391, Po0.001, Figure 2b). Because the ampli- measured at the time of the stimulus to the first cerebral response (the tudes of various evoked potential components are affected by level of the first positive peak). The amplitude was measured from the first stimulation and recording parameters as well as by biological positive peak to the first negative peak points of the tracing. Of the 82 patients, 60 were randomly grouped into PLA cream (lidocaine 2.5% and prilocaine 2.5%, Beijing Ziguang Pharmaceutical, Beijing, China) and placebo subgroups, respectively. The randomization sequence was generated by a statistician (LHZ). Patients were 1:1 randomized into Table 1. Characteristics of the patients with primary premature one of the two study subgroups (each with 30 patients), using the SAS ejaculation and controls statistical software (Version 9, SAS, Buckinghamshire, UK). The placebo only contained the cream base with the same color. The patients did not know Characteristic Patients Controls P which substance was being applied. Two grams of cream was applied evenly on the glans penis including the corona for a 10 min duration and Population (N)8234 washed off just before DNSEP and GPSEP were repeatedly measured. Marital status, n (%) Married 63 (76.8%) 26 (76.5%) 0.967 Statistical analysis Single 19 (23.2%) 8 (23.5%) The Kolmogorov–Smirnov was applied to test normal distribution. Age (years) 31.0±6.8 30.9±6.8 0.959 Continuous variables normally distributed were expressed as mean±s.d. Height (cm) 171.5±5.2 172.4±5.5 0.444 and compared using independent t-test between two groups; quantitative Body weight (kg) 69.5±9.6 72.2±10.2 0.186 data abnormally distributed were presented as median (interquartile Stopwatch IELT Estimated IELT range) and compared using nonparametric test. w2-test or Fisher’s exact IELT o30 s (27 men) 43 min (34 men) test was for categorical variables. Pearson correlation was estimated for 30 s-1 min (55 men) two continuous variables. In addition, within each group the data were IIEF-5 (score) 24.4±0.19 24.2±0.20 0.548 compared with values before and after application using a paired Student’s CIPE-5 (score) 9.0±0.25 21.0±0.23 o0.001 t-test. The deviation, 41.96 s.d. away from the mean of controls, was Abbreviations: CIPE-5, Chinese Index Of Premature Ejaculation with five regarded as abnormal. All the statistical analysis was performed using SPSS questions; IELT, intravaginal ejaculation latency time; IIEF-5, International V16.0 (SPSS, Chicago, IL, USA). A two-sided P 0.05 was considered o Index of Erectile Function of five items. statistically significant.

& 2014 Macmillan Publishers Limited International Journal of Impotence Research (2014), 186 – 190 Penile sensory pathways and effects of PLA in PPE J-d Xia et al 188

Figure 1. The results of somatosensory evoked potential of glans penis (GPSEP). (a) GPSEP recording of the normal potent man. (b) GPSEP recording of the patient with primary premature ejaculation.

of SEPs in PPE patients. The overall results suggested that 31 of 82 patients with PPE (37.8%) had shorter latencies of DNSEP, 34 patients (41.5%) had shorter latencies of GPSEP and 47 patients (57.3%) had shorter latencies of DNSEP or GPSEP, compared with the normal reference values of the control group.

Effects of PLA and placebo cream on SEPs The latencies and amplitudes of DNSEP and GPSEP of both groups before and after applying cream are presented in Table 2. There were no statistically significant differences in the mean latencies or amplitudes of DNSEP and GPSEP between the PLA and placebo subgroups before application. After applying cream on the glans penis including the corona for 10 min duration, compared with the pre-application values, significant prolonga- tion of the latencies of DNSEP and GPSEP were achieved for those patients following the use of PLA cream (Po0.001, both). The increment of the mean latencies of DNSEP and GPSEP were 2.55 and 2.70 ms, respectively. Furthermore, the amplitudes of DNSEP and GPSEP reduced significantly after application in the PLA cream subgroup (Po0.001, both). On the other hand, the latencies or amplitudes of either DNSEP or GPSEP did not remarkably change after application in the placebo subgroup (P ¼ 0.523, 0.967, 0.829, 0.902, respectively).

DISCUSSION PE is characterized as a shortened ejaculatory latency time, poor control over ejaculation, low satisfaction with sexual intercourse and distress regarding the condition.16 Recently, based on controlled clinical and epidemiological stopwatch studies, Waldinger et al.17 proposed the existence of four PE subtypes, Figure 2. Correlations of DNSEP and GPSEP. (a) A significant positive which included two other PE symptoms: nature variable PE correlation was found between latencies of DNSEP and that of and premature-like ejaculatory dysfunction. The causes of PE are GPSEP (r ¼ 0.600, Po0.001). (b) There was significant positive complex and multivariate, each type with its own etiology, correlation between DNSEP and GPSEP amplitudes (r ¼ 0.391, therefore we only estimated the patients with PPE. Po0.001). DNSEP, somatosensory evoked potential of dorsal nerve; In our study, DNSEP and GPSEP had a high positive correlation GPSEP, somatosensory evoked potential of glans penis. on latencies and amplitudes. DNSEP is an electroencephalographic response after sending stimuli at the somatic sensory area of penile dorsal nerve, while GPSEP is a modification of DNSEP by sending factors, which vary widely in the normal population and are stimuli at the glans penis. The latency of GPSEP was delayed considered to be of much less diagnostic importance than latency compared with DNSEP, which is in part caused by the longer measurement,15 we only assessed the abnormality of the latencies conduction distance. When comparing the amplitudes of DNSEP

International Journal of Impotence Research (2014), 186 – 190 & 2014 Macmillan Publishers Limited Penile sensory pathways and effects of PLA in PPE J-d Xia et al 189 Table 2. Outcome measures in both groups before and after application

Outcome measure Placebo (n ¼ 30) PLA (n ¼ 30)

Before Tx After Tx Before Tx After Tx

Latency (ms)a DNSEP 38.69±3.55 39.13±2.75 38.44±4.73 40.99±4.33c GPSEP 40.78±2.45 40.79±2.34 40.17±4.03 42.87±2.34c Amplitude (mV)b DNSEP 1.50 (0.93–1.87) 1.51 (0.94–1.79) 1.49 (1.17–1.87) 1.10 (0.77–1.50)c GPSEP 1.66 (1.41–2.21) 1.68 (1.46–2.15) 2.11 (1.52–2.49) 1.35 (1.04–1.98)c Abbreviations: DNSEP, somatosensory evoked potential of dorsal nerve; GPSEP, somatosensory evoked potential of glans penis; PLA, lidocaine 2.5% and prilocaine 2.5% cream; Tx, apply cream on the glans penis including the corona for 10 min duration. aThe values are expressed as mean±s.d. bThe values are presented in median (interquartile range). cPo0.001, compared with the results of before and after application. and GPSEP, we also found that the amplitude from the glans penis reuptake inhibitors, alpha blockers and phosphodiesterase-5 was higher than that from the penile shaft. This may contribute to inhibitors with variable rates of success.20 Regarding pharmaco- the glans penis with a predominance of free nerve endings, logic therapy, the main treatments at present are the topical numerous genital-end bulbs and rarely Pacinian and Ruffinian anesthetics and selective serotonin reuptake inhibitors. It is corpuscles, which is different from typical glabrous skin.18 speculated that selective serotonin reuptake inhibitors enhance Ejaculation is a spinal reflex, controlled by three interacting the inhibitory effects of the serotonergic neurons in the brain- levels of nervous system, including the modulator influence stem, which mediate the ejaculation threshold through serotonin originating from the supraspinal level, interaction at the spinal neurotransmission and 5-HT receptors.21 According to this cord level and sensory input determining the amplitude of sacral ejaculation threshold hypothesis, it appears that selective reflex. Allard et al.19 proposed that the amount of peripheral serotonin-reuptake inhibitors are more appropriate for PPE stimulation required to trigger ejaculation depended on both the patients with a low threshold set point. At the same time, the descending input from supraspinal centers and the intrinsic local anesthetics or selective resection of the dorsal nerve could capacitance of the spinal ejaculation center. Our results indicated produce some degree of glans penile desensitization or act within that the latencies of DNSEP and GPSEP were both significantly the afferent–efferent reflex in the same mechanism, on which they shortened in the patient group than those in the control group, could delay the ejaculatory latency.22,23 However, it was reported and the amplitudes of GPSEP were considerably larger in the PPE that the obvious clinical efficacy of the anesthetics and selective group. Most of our findings are consistent with Xin et al.’s study.6 resection of the dorsal nerve was 65.9 and 72.9%, respectively.24,25 However, we did not find the latencies of GPSEP reversely shorter This might be owing to the fact that only the PE patients than those of DNSEP in the patients as they described. They exhibiting hyperexcitable ejaculatory reflex neurological sensory hypothesized that the glans penis sensory stimuli in patients with pathways are suitable to undergo local anesthetics or selective PPE could be conducted by a pathway different from the dorsal resection of the dorsal nerve treatment, which need further nerve, which has not been demonstrated. Neither did we find the studies to unravel this important and intriguing question. amplitudes of DNSEP considerably greater in the patient group Therefore, DNSEP associated with GPSEP could provide objective than those in the control group. This might be due to the fact that neurophysiologic information for the complete afferent pathway the specificity of GPSEP was better than DNSEP, especially for PPE involved in the penis, pelvis, spinal cord and brain. With the results patients. In another study, using the same electrophysiologic of DNSEP and GPSEP tests, clinicians can choose the appropriate approach, Perretti et al.7 did not confirm either a faster conduction treatment for the PPE patients with penile sensory pathway or a greater cortical representation of the sensory stimuli from the abnormalities. genital area in PPE patients. What is worth noting isthat the cutoff Finally, although our groups were age-, height- and weight- of IELT for diagnosing PPE in their study was 3 min, which is comparable, there are some biases and deficiencies. Most approximately the same in the voluntary normal potent men certainly, electrical stimuli may not be considered physiological. recruited for our study; in addition, the size of their sample is very Electrical stimulation results in nonspecific activation of the nerve small—14 PPE patients and 12 normal voluntary subjects, and fibers, which supply to the penis. However, the advantage of only 3 patients underwent GPSEP tests. According to our study, electrical stimulation is that it has a rapid on/off, thus producing although about 60% of the patients with PPE exhibited better quality evoked potentials than that of mechanical stimula- hyperexcitation of penis, there were still 40% of the patients tion. Another deficiency is that in this present study we did not who had normal sensory pathways. Therefore, there should be follow up the clinical efficacy of the PLA cream in PPE treatment, other factors involved in the pathological mechanisms of PPE. observing changes on IELT. Nevertheless, the aim of this study is From these results, we could conclude that the hyperexcitable to assess the penile afferent neuronal function and the mechan- ejaculatory reflex neurological factor was linked to PPE, but only ism of PLA cream in PPE treatment rather than the topical accounting for a proportion of the PPE patients. From another anesthetics in treating PPE. point of view, PPE is a multifactorial disease, which needs to be further explored for more important mechanisms. Additionally, we also explored the effects of PLA cream on the SEPs. The latencies CONCLUSIONS and amplitudes of DNSEP and GPSEP were both delayed and The hyperexcitable ejaculatory reflex neurological factor was reduced remarkably after application in the active group; while no linked to PPE, because of hypersensitivity of the glans, accelerated significant change was seen in the placebo group, indicating that conduction and cortical amplification of the genital stimuli. the parameters of SEPs were stable. However, this mechanism could only account for about 60% of PPE has been treated with various modalities, including sex patients with PPE. The PLA cream could produce some degree of therapy, topical anesthetics, oral drug use of selective serotonin glans penile desensitization or act within the afferent–efferent

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International Journal of Impotence Research (2014), 186 – 190 & 2014 Macmillan Publishers Limited