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Dapoxetine versus glans penis injection with hyaluronic acid gel in treatment of premature ejaculation

Dapoxetine versus glans penis injection with hyaluronic acid gel in treatment of premature... ARAB JOURNAL OF UROLOGY https://doi.org/10.1080/2090598X.2023.2245598 ORIGINAL ARTICLE Dapoxetine versus glans penis injection with hyaluronic acid gel in treatment of premature ejaculation a a a a b Ibrahim M. Ibrahim , Moustafa Mohamed , Mostafa Kamel , Lotfy Elbendary , Almaqtouf Mohamed and Mohamed S Elderey a b Faculty of Medicine, Department of Urology, Zagazig University, Sharkia, Egypt; Faculty of Medicine, Department of Urology, Zagazig University, benghazi, Libya ABSTRACT ARTICLE HISTORY Received 26 April 2023 Objective: to compare the results of using Dapoxetine and HA (hyaluronic acid) gel injection Accepted 2 August 2023 by Five puncture technique in the treatment of premature ejaculation (PE). Methods: 100 sexually active heterosexuals circumcised males with lifelong PE were included KEYWORDS in the study. Group A patients were treated with on-demand Dapoxetine, while group B was Hyaluronic Acid Gel; treated with HA gel glans penis injection using a five-puncture technique. Both groups were Dapoxetine; premature st rd th evaluated at 1 ,3 and 6 months post-treatment using IELT. ejaculation and glans penis Results: There were no significant differences between both groups regarding patient demo- injection graphic. Mean pretreatment IELT in groups A and B were 45.82 ± 7.44 and 46.18 ± 7.82 receptively. There was no significant difference between both groups. After treatment, both st rd th groups show significant ILET improvement during the 1 ,3 , and 6 months follow-up with a P value < 0.001. However, when comparing the improvement of ILET in group A (Dapoxetine) and group B (HA injection), there were high significance differences in favor of group B in the 1st,3rd, and 6th-month follow-up. Conclusion: Although both treatment modalities have improved IELT and premature ejacula- tion, but HA injection with five punctures technique was significantly better than oral Dapoxetine with self-limited side effects. Introduction recurrence rate of PE after stopping treatment and the systemic side effects create a need for seeking Premature ejaculation (PE) is reported as a common other treatment options [7]. male sexual problem and it affects nearly 20% of the Hyaluronic acid (HA) gel penile injection is sexually active male population [1,2]. Many definitions a promising treatment for PE. It lowers the level of were developed to define premature ejaculation. The stimulation of the penile skin receptors. Many studies definitions emphasize poor self-control, lack of satis- reported that HA penile injection increased the intra- faction, and short interval from penetration to ejacula- vaginal latency time (IELT) about four to five times and tion [3]. Lifelong PE is defined as ejaculation that this effect may continue for 5 years [8,9]. The most occurs between 30 and 60 seconds from penetrative reported side effects were transient discoloration and sexual intercourse nearly all times [4]. It is worth to swelling of the glans. Most of them resolved within 2 mention that many theories have been developed to weeks [9]. Also, HA injection allows spontaneous explain PE like psychological theory, hormonal, genetic relationship. and chronic prostatitis [1,2]. we aim in this study to compare the effectiveness 5- Hydroxytryptamine 1A (5-HT1A) hypersensitivity and safety of Hyaluronic acid gel injection versus and peripheral penile hypersensitivity are blamed to dapoxetine in treatment of premature ejaculation. have a role in lifelong PE [5]. Acquired PE occurs in men with previous normal sexual life [4]. Patient and methods Many drugs were used to treat PE like antidepres- sants and local anesthetics. Dapoxetine is the only This study is a comparative randomized controlled licensed short-acting selective serotonin reuptake inhi- clinical trial using Dapoxetine (group A) and HA (hya- bitor for treating PE. It prevents serotonin transporta- luronic acid) gel injection by Five puncture technique tion so it increases its level at the post-synaptic cleft [10] (group B) for PE treatment. Patients included in the and as a result it delays ejaculation [6]. But the study were sexually active heterosexual circumcised CONTACT Mohamed S Elderey mohamed.salah.urology@gmail.com Faculty of Medicine, Department of Urology, Zagazig University, Sharkia, Egypt © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent. 2 I. M. IBRAHIM ET AL. males with lifelong PE. PE diagnosis relied on the standards from the International Society for Sexual Medicine (ISSM), using IELT stopwatch testing. The baseline period was 4 weeks for assessment. All parti- cipants were required to have at least four sexual intercourses. Patients with chronic psychiatric, sys- temic disease, endocrine disorders, drug abuse, pros- tatitis, erectile dysfunction, acquired PE, and those who recently received treatment for PE were excluded. The sample size was 110, with 55 patients for each group. It was calculated using open Epi assuming that difference in IELT (3.2+_ 0.13 seconds) among the group injected with HA versus (2.4+_ 2.14 seconds) among the Dapoxetine group. However, 10 patients discontinued the study (5 in both groups during fol- low-up) (Figure 1). Patients were randomized accord- ing to the closed-envelope method. Group A patients were treated with Dapoxetine 60 mg tablet on demand given 3 hours before the sexual episode. Group B patients were treated by injection of 2 ml Figure 2. 5 puncture technique Sakr a et al 2022(10). hyaluronic acid (HA; STYLAGE® IPN Like TECHNOLOGY, VIVACY Laboratories, Paris, France) in st rd th Both groups were evaluated at 1 ,3 and 6 the glans penis by 5 puncture technique [10]. months post-treatment using IELT. Topical local anaesthetic (Xylocaine Jelly 2%:lido- Statistical analysis: Data analysis was done using caine 20 mg (Aspen, Sweden) was applied 30 minutes IBM SPSS 23.0 for Windows (SPSS Inc., Chicago, IL, before injection using 30-gauge needle. The glans is USA) and NCSS 11 for Windows (NCSS LCC., divided by horizontal line into two halves with further Kaysville, UT, USA). Qualitative data is represented division of the distal one into two halves; right and left as number and percentage, and quantitative is con- using a vertical line. The proximal half is divided into tinuously represented by mean and standard devia- three parts using two vertical lines. Injection of 0.4 ml tion. The following tests were used to test of HA into the deep dermis of each part with a total differences for significance; difference, and associa- dose 2 ml (Figure 2) [10]. tion of qualitative variable by Chi-square test (X ). Differences between quantitative independent total number of groups by t-test or Mann-Whitney for non- paent (n:110) parametric data. Repeated measures ANOVA for comparison of multiple means. P value was set at < 0.05 for significant results &<0.001 for high sig- number of paent number of paent on oral nificant results. injected with HA dapoxene 60mg tablet (n:55) (n:55) Results total number of paent who total number of paent who Patients’ socio-demographic data completed one month of completed one month of follow up follow up In group A mean patients’ age and BMI were (40.73 (n:55) (n:55) ± 10.98) years and (25.44 ± 6.31) receptively. While in group B patient’s age and BMI were (42.31 ± 9.78) total number of paent total number of paent who who completed 3 months completed 3 months follow years and (25.3 ± 5.99). The mean wife age was follow up up 30.57 ± 6.78 years in group A and 32.41 ± 7.18 years (n:52) (n:52) in group B. Duration of marriage and frequency of intercourse in group A were 8.05 ± 5.12 years and total number of paent total number of paent 2.22 ± 0.93 receptively while in group B were 9.54 ± who completed 6 months who completed 6 month follow up follow up 5.1 years and 1.89 ± 0.92. There was no statistically (n:50) (n:50) significant difference among both studied groups regarding socio-demographic characters, both Figure 1. Total number of patient in each group. groups were matched (Table 1). ARAB JOURNAL OF UROLOGY 3 Table 1. Socio-demographic data. Group A Group B t-test P Age Mean± SD 40.73 ± 10.98 42.31 ± 9.78 0.79 0.43 Range 20–62 25–66 BMI Mean± SD 25.44 ± 6.31 25.3 ± 5.99 0.08 0.94 NS Range 16–36 15–36 Group A Group B MW\t-test* Mean SD Mean SD Wife age 30.57 ± 6.78 32.41 ± 7.18 1.38 0.17 (years) 20–47 20–47 NS Range Duration of marriage 8.05 ± 5.12 9.54 ± 5.1 1.58 0.14 (years) 7 (2–19 10 (1–22) NS Median (Range) Frequency of intercourse 2.22 0.93 1.89 0.92 1.99 0.05 (Per week) 2 (1–4) 2 (1–4) NS Median (Range) There was no statistical significant difference among both studied groups regarding socio-demographic characters, both groups were matched. Change in pre and post-treatment IELT Discussion Mean pretreatment IELT in groups A and B were 45.82 Premature ejaculation (PE) is considered a common ± 7.44 seconds and 46.18 ± 7.82 seconds receptively. sexual problem. Some studies reported a prevalence There was no significant difference between both between 2–23% [11]. Many theories were used to groups. After treatment, both groups show significant explain the etiology of PE like Chronic prostatitis and ILET improvement during the 1st,3rd, and 6th-month psychological causes such as anxiety. Also, genetic follow-up with a P value < 0.001. However, when com- causes and hormonal factors were suggested as paring the improvement of ILET in group a cause of PE [1,2]. A (Dapoxetine) and group B (HA injection), there Saleh R et al., 2021 in a systematic review study on were high significant differences in favor of group the treatment of PE stated that patients with PE B in the 1st,3rd, and 6th-month follow-up (Table 2) respond differently to various treatment options. So, (Figure 3). urologists need to be aware of different modalities which can fulfill the patients’ needs [12]. 4The treatment options for PE include on-demand Post-intervention complications and adverse effects Dapoxetine hydrochloride, and short-acting selective The adverse effects of oral Dapoxetine use were nau- serotonin reuptake inhibitor (SSRI). Also, other daily sea in six cases (12%), dizziness in six cases (12%), used antidepressants and on-demand topical anes- headache in five cases (10%), dry mouth in 4fourcases thetics were used [13]. (8), and diarrhea in three cases (6%) (Table 3). Regarding the improvement in IELT in this study, The complications with HA injection were pain at the pretreatment means IELT was 45.82 ± 7.44 and the site of injection in seven cases (14%), bullae forma- 46.18 ± 7.82 seconds in group A and group tion at the site of injection in four cases (8%), and B receptively without significant difference between ecchymosis in three cases (6%) (Table 3) both groups. The mean IELT after one month was All the previous complications resolved completely 154.6 and 291.4 seconds in group (A) and group (B), after 10 to 15 days from injection and were well toler- respectively. After 3 months, it was 149.1 seconds in ated by the patients. Table 2. Pretreatment and post treatment IELT. Group A Group B IELT Mean ± SD Mean ± SD t-test P Pre- 45.82 ± 7.44 46.18 ± 7.68 0.25 0.807NS NS After 1 month 154.6 ± 32.17 291.4 ± 9.74 30.1 <.001(HS) After 3 months 149.1 ± 2.12 244.7 ± 12.8 28.9 <.001(HS) After 6 months 137.8 ± 21.6 192.1 ± 9.32 16.3 <.001(HS) Significance test <0.001HS <0.001HS P value HS HS There was no significant difference between both groups regarding pretreatment IELT. After treatment both groups show significant ILET improvement during 1st,3rd and 6th month follow up with P value < 0.001. However when comparing improvement of ILET in group A (Dapoxetine) and group B (HA), there were high significance differences in favor of group B in 1st,3rd and 6th month follow up. 4 I. M. IBRAHIM ET AL. Group I Group II Aer 1 m. Aer 3 m. Aer 6 m. Figure 3. Difference in IELT among both studied groups post-treatment. Also, Abdallah H et al., 2012 showed a significant Table 3. Adverse effect of oral dapoxetine 60 mg tablet use in group a and complication of HA injection in group B post IELT increase in the 1st-month post-HA. However, it intervention. was still significantly better than baseline IELT. HA (Dapoxetine) Group A injection gave PE patients and their partners more complain Patients satisfaction than local anesthetics agents and condoms N % due to its prolonged effect without affecting the plea- Nausea 6 12 sure of the other partner [14]. Abdelazeem M et al., dizziness 6 12 Headache 5 10 2019 found that HA injection significantly improved Dry mouth 4 8 IELT within 6 months from 88.34 ± 3.14 to 192.5 ± 7.6 Diarrhea 3 6 seconds [11]. Group B (HA injection) While in patients treated by Dapoxetine, many ran- complain Patients domized controlled studies include more than six N % thousand patients with PE who studied the effect of Pain at site of injection 7 14 dapoxetine in the treatment of PE. Dapoxetine had Bullae formation at site of injection 4 8 Ecchymosis 3 6 shown significant improvement in baseline IELT from This table show the adverse effect with oral dapoxetine use were nausea (0.8 min) to (2.3 min) [15]. Also, many other studies had in six cases (12%), dizziness in six cases (12%), headache in five cases shown that Dapoxetine improves baseline IELT [13,16]. (10%),dry mouth in four cases (8), and diarrhea in three cases (6%). the complication with HA injection were pain at site of injection in seven Although Dapoxetine has favorable outcomes in the cases (14%), bullae formation at site of injection in four cases (8%), treatment of PE, the integrated analysis of clinical trials ecchymosis in three cases (6%), which resolved completely after 10 to 15 days post injection. using Dapoxetine had shown about 30% of patients included in the clinical trials had discontinued it. It was either lack of satisfaction with its results or personal issues [16]. It was reported that oral Dapoxetine sig- group (A), and 244.7 seconds in group (B). It was 137.8 nificantly improved baseline IELT up to three folds. seconds in group (A), and 192.1 seconds in group (B) However, by using Global Efficacy Question (GEQ), after 6 months. There was a significant difference only 29% of treated patients showed satisfaction with treatment results. This could be explained by that the between the follow-up periods within the group. The mean baseline IELT was 20 seconds. Even if it was post-treatment IELT was highly significantly improved improved by Dapoxetine by three folds, it was still for both groups. However, in comparing both groups, not satisfactory to the patient [17]. Many studies had group B with HA injection had significantly higher IELT reported that oral Dapoxetine use did not give satis- in comparison to group A treated by Dapoxetine in all factory results in patients with severe PE who ejaculate periods of follow up at 1st,3rd, and 6th month fol- rapidly within seconds [18,19] low up. In our study, the complications with HA injection in Regarding the improvement of IELT post-HA injec- our study were pain at the site of injection in seven tion, it was in agreement with Sakr A et al., 2022. They cases (14%), bullae formation at the site of injection in had shown significant improvement in IELT during four cases (8%), and ecchymosis in three cases (6%). one year of follow-up. Despite there being a drop in However, all these complications were self-limited IELT in the 3rd, 6th, and 12th months than the 1st within 2 weeks and patients were satisfied. One of month of treatment, IELT was still significantly higher the strength points added to the HA injection group than pre-injection IELT [10]. is the possibility of a spontaneous relationship. This ARAB JOURNAL OF UROLOGY 5 was in agreement with Abdallah H et al., 2012 who had Moustafa Mohamed: Manuscript writing and Data analysis. Mostafa Kamel: Data collection. shown that the complications of HA injection were Lotfy Elbendary: Data analysis mild pain and bullae formation at the site of injection Almaqtouf Mohamed: Protocol development and Data [14]. Abdelazeem M et al., 2019 mentioned that HA analysis injection had no adverse effects on over 20 patients S Elderey Mohamed: Protocol development, Data collection, included in the study [11]. Many other studies had and Manuscript writing. revealed that the side effects of HA injection were mild and self-limited like ecchymosis and injection- References site discomfort. This could be explained by the nature of HA as it is a polysaccharide that is naturally found in [1] Serefoglu EC, Yaman O, Cayan S, et al. Prevalence of the complaint of ejaculating prematurely and the four the intercellular matrix of human dermal layers so, it premature ejaculation syndromes: results from the doesn’t cause a foreign body reaction [20,21]. Turkish society of andrology sexual health survey. In the current study, the adverse effect of oral J Sex Med. 2011;8(2):540–548. doi: 10.1111/j.1743- Dapoxetine use was nausea in six cases (12%), dizzi- 6109.2010.02095.x ness in six cases (12%), headache in five cases (10%), [2] Saitz TR, Serefoglu EC. The epidemiology of premature dry mouth in five cases (8), and diarrhea in three cases ejaculation. Transl Androl Urol. 2016;5(4):409. doi: 10. 21037/tau.2016.05.11 (6%). Although five patients in this group dropped out [3] Serefoglu EC, McMahon CG, Waldinger MD, et al. An during 1st follow-up visit and this may be explained by evidence‐based unified definition of lifelong and intolerable side effects. Minestrone V., et al 2014 acquired premature ejaculation: Report of the second showed that Dapoxetine use had side effects like nau- international society for sexual medicine ad hoc com- sea (17.3%), dizziness (9.4%), headache (7.9%), diarrhea mittee for the definition of premature ejaculation. J Sex Med. 2014;11(6):1423–1441. doi: 10.1111/jsm.12524 (5.9%), somnolence (3.9%), fatigue (3.9%), insomnia [4] Shindel AW, Althof SE, Carrier S, et al. Disorders of (3.8%) and nasopharyngitis (3.1%). Side effects were ejaculation: an AUA/SMSNA guideline. J Urol. more in patients aged 65 years or older [22]. Alghobary 2022;207(3):504–512. doi: 10.1097/JU. M ., et al 2020 reported that Dapoxetine had many side effects like nausea (20%), headache (14.5%), dizziness [5] Guo L, Liu Y, Wang X, et al. Significance of penile (10.9%), diarrhea (10.9%), and insomnia (7.3%) [17]. hypersensitivity in premature ejaculation. Sci Rep. 2017;7(1):1–6. doi: 10.1038/s41598-017-09155-8 Our limitations in this study were the need for larger [6] McMahon CG. Dapoxetine: a new option in the med- sample size and longer follow up time. Also, to assess ical management of premature ejaculation. Ther Adv the long-term quality of life and patient satisfaction. Urol. 2012;4(5):233–251. doi: 10.1177/ [7] McMahon CG, Jannini E, Waldinger M, et al. Standard Conclusions operating procedures in the disorders of orgasm and ejaculation. J Sex Med. 2013;10(1):204–229. doi: 10. Although both treatment modalities have improved 1111/j.1743-6109.2012.02824.x IELT and premature ejaculation HA injection with five [8] Kwak T, Jin M, Kim J, et al. Long-term effects of glans punctures technique was significantly better than oral penis augmentation using injectable hyaluronic acid Dapoxetine with lower self-limited side effects. gel for premature ejaculation. Int J Impot Res. 2008;20 (4):425–428. doi: 10.1038/ijir.2008.26 [9] Kosseifi F, Chebbi A, Raad N, et al. Glans penis aug- Disclosure statement mentation using hyaluronic acid for the treatment of premature ejaculation: a narrative review. Transl No potential conflict of interest was reported by the Androl Urol. 2020;9(6):2814. doi: 10.21037/tau-20-1026 author(s). [10] Sakr A, Elgalaly H, Seleem MM, et al. Outcome of hyaluronic acid gel injection in glans penis for treat- ment of lifelong premature ejaculation: A pilot study. Funding Arab J Urol. 2022;21(1):1–5. doi: 10.1080/2090598X. 2022.2100580 The author(s) reported there is no funding associated with [11] Abdelazeem M, Esawy A. Hyaluronic acid in the treat- the work featured in this article. ment of premature ejaculation by glans augmentation. Hum Androl. 2019;9(1):1–5. doi: 10. 21608/ha.2019.10587.1039 ORCID [12] Saleh R, Majzoub A, Abu El-Hamd M. An update on the treatment of premature ejaculation: A systematic Mohamed S Elderey http://orcid.org/0000-0001-5570- review. Arab J Urol. 2021;19(3):281–302. doi: 10.1080/ 2090598X.2021.1943273 [13] Buvat J, Tesfaye F, Rothman M, et al. Dapoxetine for the treatment of premature ejaculation: results from Authors contributions a randomized, double-blind, placebo-controlled phase Ibrahim M. Ibrahim: Protocol development and Manuscript 3 trial in 22 countries. Eur Urol. 2009;55(4):957–968. writing. doi: 10.1016/j.eururo.2009.01.025 6 I. M. IBRAHIM ET AL. [14] Abdallah H, Abdelnasser T, Hosny H, et al. dapoxetine case. J Sex Med. 2008;5(4):966–997. doi: Treatment of premature ejaculation by glans penis 10.1111/j.1743-6109.2008.00633.x augmentation using hyaluronic acid gel: a pilot [19] Jian Z, Wei X, Ye D, et al. Pharmacotherapy of study. Andrologia. 2012;44:650–653. doi: 10.1111/j. premature ejaculation: a systematic review and 1439-0272.2011.01244.x network meta-analysis. Int Urol Nephrol. 2018;50 [15] Sangkum P, Badr R, Serefoglu EC, et al. Dapoxetine and (11):1939–1948. doi: 10.1007/s11255-018-1984-9 the treatment of premature ejaculation. Transl Androl [20] Littara A, Palmieri B, Rottigni V, et al. A clinical study to assess the effectiveness of a hyaluronic acid-based pro- Urol. 2013;2(4):301. doi: 10.3978/j.issn.2223-4683.2013. 12.01 cedure for treatment of premature ejaculation. [16] McMahon CG, Althof SE, Kaufman JM, et al. Efficacy and Int J Impot Res. 2013;25(3):117–120. doi: 10.1038/ijir. safety of dapoxetine for the treatment of premature 2013.13 ejaculation: integrated analysis of results from five [21] Alahwany A, Ragab MW, Zaghloul A, et al. Hyaluronic acid injection in glans penis for treatment of prema- phase 3 trials. J Sex Med. 2011;8(2):524–539. doi: 10. 1111/j.1743-6109.2010.02097.x ture ejaculation: a randomized controlled cross-over [17] Alghobary M, Gaballah M, El‐Kamel MF, et al. Oral study. Int J Impot Res. 2019;31(5):348–355. doi: 10. dapoxetine versus topical lidocaine as on‐demand 1038/s41443-018-0104-9 treatment for lifelong premature ejaculation: [22] Mirone V, Arcaniolo D, Rivas D, et al. Results from A randomised controlled trial. Andrologia. 2020;52(5): a prospective observational study of men with prema- ture ejaculation treated with dapoxetine or alternative e13558. doi: 10.1111/and.13558 [18] Waldinger MD, Schweitzer DH. Premature ejaculation care: the PAUSE study. Eur Urol. 2014;65(4):733–739. and pharmaceutical company-based medicine: the doi: 10.1016/j.eururo.2013.08.018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Arab Journal of Urology Taylor & Francis

Dapoxetine versus glans penis injection with hyaluronic acid gel in treatment of premature ejaculation

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ARAB JOURNAL OF UROLOGY https://doi.org/10.1080/2090598X.2023.2245598 ORIGINAL ARTICLE Dapoxetine versus glans penis injection with hyaluronic acid gel in treatment of premature ejaculation a a a a b Ibrahim M. Ibrahim , Moustafa Mohamed , Mostafa Kamel , Lotfy Elbendary , Almaqtouf Mohamed and Mohamed S Elderey a b Faculty of Medicine, Department of Urology, Zagazig University, Sharkia, Egypt; Faculty of Medicine, Department of Urology, Zagazig University, benghazi, Libya ABSTRACT ARTICLE HISTORY Received 26 April 2023 Objective: to compare the results of using Dapoxetine and HA (hyaluronic acid) gel injection Accepted 2 August 2023 by Five puncture technique in the treatment of premature ejaculation (PE). Methods: 100 sexually active heterosexuals circumcised males with lifelong PE were included KEYWORDS in the study. Group A patients were treated with on-demand Dapoxetine, while group B was Hyaluronic Acid Gel; treated with HA gel glans penis injection using a five-puncture technique. Both groups were Dapoxetine; premature st rd th evaluated at 1 ,3 and 6 months post-treatment using IELT. ejaculation and glans penis Results: There were no significant differences between both groups regarding patient demo- injection graphic. Mean pretreatment IELT in groups A and B were 45.82 ± 7.44 and 46.18 ± 7.82 receptively. There was no significant difference between both groups. After treatment, both st rd th groups show significant ILET improvement during the 1 ,3 , and 6 months follow-up with a P value < 0.001. However, when comparing the improvement of ILET in group A (Dapoxetine) and group B (HA injection), there were high significance differences in favor of group B in the 1st,3rd, and 6th-month follow-up. Conclusion: Although both treatment modalities have improved IELT and premature ejacula- tion, but HA injection with five punctures technique was significantly better than oral Dapoxetine with self-limited side effects. Introduction recurrence rate of PE after stopping treatment and the systemic side effects create a need for seeking Premature ejaculation (PE) is reported as a common other treatment options [7]. male sexual problem and it affects nearly 20% of the Hyaluronic acid (HA) gel penile injection is sexually active male population [1,2]. Many definitions a promising treatment for PE. It lowers the level of were developed to define premature ejaculation. The stimulation of the penile skin receptors. Many studies definitions emphasize poor self-control, lack of satis- reported that HA penile injection increased the intra- faction, and short interval from penetration to ejacula- vaginal latency time (IELT) about four to five times and tion [3]. Lifelong PE is defined as ejaculation that this effect may continue for 5 years [8,9]. The most occurs between 30 and 60 seconds from penetrative reported side effects were transient discoloration and sexual intercourse nearly all times [4]. It is worth to swelling of the glans. Most of them resolved within 2 mention that many theories have been developed to weeks [9]. Also, HA injection allows spontaneous explain PE like psychological theory, hormonal, genetic relationship. and chronic prostatitis [1,2]. we aim in this study to compare the effectiveness 5- Hydroxytryptamine 1A (5-HT1A) hypersensitivity and safety of Hyaluronic acid gel injection versus and peripheral penile hypersensitivity are blamed to dapoxetine in treatment of premature ejaculation. have a role in lifelong PE [5]. Acquired PE occurs in men with previous normal sexual life [4]. Patient and methods Many drugs were used to treat PE like antidepres- sants and local anesthetics. Dapoxetine is the only This study is a comparative randomized controlled licensed short-acting selective serotonin reuptake inhi- clinical trial using Dapoxetine (group A) and HA (hya- bitor for treating PE. It prevents serotonin transporta- luronic acid) gel injection by Five puncture technique tion so it increases its level at the post-synaptic cleft [10] (group B) for PE treatment. Patients included in the and as a result it delays ejaculation [6]. But the study were sexually active heterosexual circumcised CONTACT Mohamed S Elderey mohamed.salah.urology@gmail.com Faculty of Medicine, Department of Urology, Zagazig University, Sharkia, Egypt © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent. 2 I. M. IBRAHIM ET AL. males with lifelong PE. PE diagnosis relied on the standards from the International Society for Sexual Medicine (ISSM), using IELT stopwatch testing. The baseline period was 4 weeks for assessment. All parti- cipants were required to have at least four sexual intercourses. Patients with chronic psychiatric, sys- temic disease, endocrine disorders, drug abuse, pros- tatitis, erectile dysfunction, acquired PE, and those who recently received treatment for PE were excluded. The sample size was 110, with 55 patients for each group. It was calculated using open Epi assuming that difference in IELT (3.2+_ 0.13 seconds) among the group injected with HA versus (2.4+_ 2.14 seconds) among the Dapoxetine group. However, 10 patients discontinued the study (5 in both groups during fol- low-up) (Figure 1). Patients were randomized accord- ing to the closed-envelope method. Group A patients were treated with Dapoxetine 60 mg tablet on demand given 3 hours before the sexual episode. Group B patients were treated by injection of 2 ml Figure 2. 5 puncture technique Sakr a et al 2022(10). hyaluronic acid (HA; STYLAGE® IPN Like TECHNOLOGY, VIVACY Laboratories, Paris, France) in st rd th Both groups were evaluated at 1 ,3 and 6 the glans penis by 5 puncture technique [10]. months post-treatment using IELT. Topical local anaesthetic (Xylocaine Jelly 2%:lido- Statistical analysis: Data analysis was done using caine 20 mg (Aspen, Sweden) was applied 30 minutes IBM SPSS 23.0 for Windows (SPSS Inc., Chicago, IL, before injection using 30-gauge needle. The glans is USA) and NCSS 11 for Windows (NCSS LCC., divided by horizontal line into two halves with further Kaysville, UT, USA). Qualitative data is represented division of the distal one into two halves; right and left as number and percentage, and quantitative is con- using a vertical line. The proximal half is divided into tinuously represented by mean and standard devia- three parts using two vertical lines. Injection of 0.4 ml tion. The following tests were used to test of HA into the deep dermis of each part with a total differences for significance; difference, and associa- dose 2 ml (Figure 2) [10]. tion of qualitative variable by Chi-square test (X ). Differences between quantitative independent total number of groups by t-test or Mann-Whitney for non- paent (n:110) parametric data. Repeated measures ANOVA for comparison of multiple means. P value was set at < 0.05 for significant results &<0.001 for high sig- number of paent number of paent on oral nificant results. injected with HA dapoxene 60mg tablet (n:55) (n:55) Results total number of paent who total number of paent who Patients’ socio-demographic data completed one month of completed one month of follow up follow up In group A mean patients’ age and BMI were (40.73 (n:55) (n:55) ± 10.98) years and (25.44 ± 6.31) receptively. While in group B patient’s age and BMI were (42.31 ± 9.78) total number of paent total number of paent who who completed 3 months completed 3 months follow years and (25.3 ± 5.99). The mean wife age was follow up up 30.57 ± 6.78 years in group A and 32.41 ± 7.18 years (n:52) (n:52) in group B. Duration of marriage and frequency of intercourse in group A were 8.05 ± 5.12 years and total number of paent total number of paent 2.22 ± 0.93 receptively while in group B were 9.54 ± who completed 6 months who completed 6 month follow up follow up 5.1 years and 1.89 ± 0.92. There was no statistically (n:50) (n:50) significant difference among both studied groups regarding socio-demographic characters, both Figure 1. Total number of patient in each group. groups were matched (Table 1). ARAB JOURNAL OF UROLOGY 3 Table 1. Socio-demographic data. Group A Group B t-test P Age Mean± SD 40.73 ± 10.98 42.31 ± 9.78 0.79 0.43 Range 20–62 25–66 BMI Mean± SD 25.44 ± 6.31 25.3 ± 5.99 0.08 0.94 NS Range 16–36 15–36 Group A Group B MW\t-test* Mean SD Mean SD Wife age 30.57 ± 6.78 32.41 ± 7.18 1.38 0.17 (years) 20–47 20–47 NS Range Duration of marriage 8.05 ± 5.12 9.54 ± 5.1 1.58 0.14 (years) 7 (2–19 10 (1–22) NS Median (Range) Frequency of intercourse 2.22 0.93 1.89 0.92 1.99 0.05 (Per week) 2 (1–4) 2 (1–4) NS Median (Range) There was no statistical significant difference among both studied groups regarding socio-demographic characters, both groups were matched. Change in pre and post-treatment IELT Discussion Mean pretreatment IELT in groups A and B were 45.82 Premature ejaculation (PE) is considered a common ± 7.44 seconds and 46.18 ± 7.82 seconds receptively. sexual problem. Some studies reported a prevalence There was no significant difference between both between 2–23% [11]. Many theories were used to groups. After treatment, both groups show significant explain the etiology of PE like Chronic prostatitis and ILET improvement during the 1st,3rd, and 6th-month psychological causes such as anxiety. Also, genetic follow-up with a P value < 0.001. However, when com- causes and hormonal factors were suggested as paring the improvement of ILET in group a cause of PE [1,2]. A (Dapoxetine) and group B (HA injection), there Saleh R et al., 2021 in a systematic review study on were high significant differences in favor of group the treatment of PE stated that patients with PE B in the 1st,3rd, and 6th-month follow-up (Table 2) respond differently to various treatment options. So, (Figure 3). urologists need to be aware of different modalities which can fulfill the patients’ needs [12]. 4The treatment options for PE include on-demand Post-intervention complications and adverse effects Dapoxetine hydrochloride, and short-acting selective The adverse effects of oral Dapoxetine use were nau- serotonin reuptake inhibitor (SSRI). Also, other daily sea in six cases (12%), dizziness in six cases (12%), used antidepressants and on-demand topical anes- headache in five cases (10%), dry mouth in 4fourcases thetics were used [13]. (8), and diarrhea in three cases (6%) (Table 3). Regarding the improvement in IELT in this study, The complications with HA injection were pain at the pretreatment means IELT was 45.82 ± 7.44 and the site of injection in seven cases (14%), bullae forma- 46.18 ± 7.82 seconds in group A and group tion at the site of injection in four cases (8%), and B receptively without significant difference between ecchymosis in three cases (6%) (Table 3) both groups. The mean IELT after one month was All the previous complications resolved completely 154.6 and 291.4 seconds in group (A) and group (B), after 10 to 15 days from injection and were well toler- respectively. After 3 months, it was 149.1 seconds in ated by the patients. Table 2. Pretreatment and post treatment IELT. Group A Group B IELT Mean ± SD Mean ± SD t-test P Pre- 45.82 ± 7.44 46.18 ± 7.68 0.25 0.807NS NS After 1 month 154.6 ± 32.17 291.4 ± 9.74 30.1 <.001(HS) After 3 months 149.1 ± 2.12 244.7 ± 12.8 28.9 <.001(HS) After 6 months 137.8 ± 21.6 192.1 ± 9.32 16.3 <.001(HS) Significance test <0.001HS <0.001HS P value HS HS There was no significant difference between both groups regarding pretreatment IELT. After treatment both groups show significant ILET improvement during 1st,3rd and 6th month follow up with P value < 0.001. However when comparing improvement of ILET in group A (Dapoxetine) and group B (HA), there were high significance differences in favor of group B in 1st,3rd and 6th month follow up. 4 I. M. IBRAHIM ET AL. Group I Group II Aer 1 m. Aer 3 m. Aer 6 m. Figure 3. Difference in IELT among both studied groups post-treatment. Also, Abdallah H et al., 2012 showed a significant Table 3. Adverse effect of oral dapoxetine 60 mg tablet use in group a and complication of HA injection in group B post IELT increase in the 1st-month post-HA. However, it intervention. was still significantly better than baseline IELT. HA (Dapoxetine) Group A injection gave PE patients and their partners more complain Patients satisfaction than local anesthetics agents and condoms N % due to its prolonged effect without affecting the plea- Nausea 6 12 sure of the other partner [14]. Abdelazeem M et al., dizziness 6 12 Headache 5 10 2019 found that HA injection significantly improved Dry mouth 4 8 IELT within 6 months from 88.34 ± 3.14 to 192.5 ± 7.6 Diarrhea 3 6 seconds [11]. Group B (HA injection) While in patients treated by Dapoxetine, many ran- complain Patients domized controlled studies include more than six N % thousand patients with PE who studied the effect of Pain at site of injection 7 14 dapoxetine in the treatment of PE. Dapoxetine had Bullae formation at site of injection 4 8 Ecchymosis 3 6 shown significant improvement in baseline IELT from This table show the adverse effect with oral dapoxetine use were nausea (0.8 min) to (2.3 min) [15]. Also, many other studies had in six cases (12%), dizziness in six cases (12%), headache in five cases shown that Dapoxetine improves baseline IELT [13,16]. (10%),dry mouth in four cases (8), and diarrhea in three cases (6%). the complication with HA injection were pain at site of injection in seven Although Dapoxetine has favorable outcomes in the cases (14%), bullae formation at site of injection in four cases (8%), treatment of PE, the integrated analysis of clinical trials ecchymosis in three cases (6%), which resolved completely after 10 to 15 days post injection. using Dapoxetine had shown about 30% of patients included in the clinical trials had discontinued it. It was either lack of satisfaction with its results or personal issues [16]. It was reported that oral Dapoxetine sig- group (A), and 244.7 seconds in group (B). It was 137.8 nificantly improved baseline IELT up to three folds. seconds in group (A), and 192.1 seconds in group (B) However, by using Global Efficacy Question (GEQ), after 6 months. There was a significant difference only 29% of treated patients showed satisfaction with treatment results. This could be explained by that the between the follow-up periods within the group. The mean baseline IELT was 20 seconds. Even if it was post-treatment IELT was highly significantly improved improved by Dapoxetine by three folds, it was still for both groups. However, in comparing both groups, not satisfactory to the patient [17]. Many studies had group B with HA injection had significantly higher IELT reported that oral Dapoxetine use did not give satis- in comparison to group A treated by Dapoxetine in all factory results in patients with severe PE who ejaculate periods of follow up at 1st,3rd, and 6th month fol- rapidly within seconds [18,19] low up. In our study, the complications with HA injection in Regarding the improvement of IELT post-HA injec- our study were pain at the site of injection in seven tion, it was in agreement with Sakr A et al., 2022. They cases (14%), bullae formation at the site of injection in had shown significant improvement in IELT during four cases (8%), and ecchymosis in three cases (6%). one year of follow-up. Despite there being a drop in However, all these complications were self-limited IELT in the 3rd, 6th, and 12th months than the 1st within 2 weeks and patients were satisfied. One of month of treatment, IELT was still significantly higher the strength points added to the HA injection group than pre-injection IELT [10]. is the possibility of a spontaneous relationship. This ARAB JOURNAL OF UROLOGY 5 was in agreement with Abdallah H et al., 2012 who had Moustafa Mohamed: Manuscript writing and Data analysis. Mostafa Kamel: Data collection. shown that the complications of HA injection were Lotfy Elbendary: Data analysis mild pain and bullae formation at the site of injection Almaqtouf Mohamed: Protocol development and Data [14]. Abdelazeem M et al., 2019 mentioned that HA analysis injection had no adverse effects on over 20 patients S Elderey Mohamed: Protocol development, Data collection, included in the study [11]. Many other studies had and Manuscript writing. revealed that the side effects of HA injection were mild and self-limited like ecchymosis and injection- References site discomfort. 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Journal

Arab Journal of UrologyTaylor & Francis

Published: Aug 9, 2023

Keywords: Hyaluronic Acid Gel; Dapoxetine; premature ejaculation and glans penis injection

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