Is Botulinum Toxin-A the Breakthrough in Premature Ejaculation Treatment? Insights from a Meta-Analysis of Randomised Controlled Trials

Is Botulinum Toxin-A the Breakthrough in Premature Ejaculation Treatment? 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Insights from a Meta-Analysis of Randomised Controlled Trials Mohamed Mubarak, Qasim Isa, Vaibhav Modgil, Ian Pearce This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5331700/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Jan, 2025 Read the published version in International Journal of Impotence Research → Version 1 posted 10 You are reading this latest preprint version Abstract The ejaculatory reflex consists of emission and expulsion, with the latter involving rhythmic muscular contractions that propel seminal fluid. Botulinum toxin, through its inhibitory effects, has been hypothesized to improve premature ejaculation (PE). This study evaluates high-quality evidence on botulinum toxin-A injections into the bulbospongiosal muscle as a treatment for PE. We conducted a systematic review and meta-analysis of randomised-controlled trials following PRISMA guidelines. Outcomes included intravaginal ejaculatory latency time (IELT), Premature Ejaculation Profile (PEP) scores, and complications. Data were analysed using Microsoft Excel and R. ROB-2, Eggers test, and GRADE assessed risk of bias, publication bias, and certainty of evidence. Three randomised controlled trials were eligible, and covered data from 228 patients with 1:1 randomisation into intervention and control arms (100 units of BOTOX in 10mLs versus 10mLs of 0.9% NaCl). IELT & PEP scores demonstrated improvements at 1, 3, and 6 months, however, statistically significant was not achieved. Post-procedural complications were higher in the BOTOX group; however, all adverse effects were self-resolving. Given our findings, current high-quality evidence does not support using Botulinum Toxin-A in the management of premature ejaculation. Larger scale & standardised RCTs are recommended to conclusively outline its clinical benefits. Health sciences/Diseases Health sciences/Medical research Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction The male sexual response concludes with ejaculation, which comprises two distinct phases: emission and expulsion. [ 1 ] Emission involves the secretion of spermatozoa and seminal fluid into the prostatic urethra through the genital tract. Expulsion involves the propulsion of semen along the urethra via coordinated rhythmic contractions of the internal and external urethral sphincters, as well as the pelvic floor muscles, including the bulbospongiosus (BS) and ischiocavernosus (IC) muscles. These reflexes are orchestrated by the autonomic nervous system and involve a thorough interplay between these muscles to ensure antegrade flow. [ 1 ] Premature ejaculation (PE) is a male sexual disorder with a prevalence ranging from 3–30%. [ 1 – 2 ] This wide range reflects the lack of a universal definition, making it a challenging clinical entity to address. The International Society of Sexual Medicine (ISSM) outlined three domains: a) latency time, b) lack of control, and c) distress as key when defining PE. [ 1 – 2 ] Proven treatment modalities for PE range from conservative to minimally invasive approaches. Conservative management options include psychotherapy and behavioural therapy techniques, and adjuncts such as using multiple condoms and pelvic floor muscle exercises. [ 3 , 4 ] Medical management involves topical anaesthetic agents that increase IELT and, consequently, enhance sexual satisfaction. Agents such as prilocaine, lignocaine, and benzocaine creams and sprays are commonly used. Oral pharmacotherapy is mainly available in the form selective serotonin reuptake inhibitors (SSRIs), with current EAU guidelines recommending on-demand dapoxetine for both lifelong and acquired PE. [ 3 – 7 ] Other options, such as daily dosed or on-demand SSRIs, clomipramine, and tramadol, although recommended by the guidelines, are considered off-label indications. [ 3 – 7 ] Given the current understanding of the ejaculation reflex, Botulinum toxin-A was first hypothesized as a potential treatment for PE in 2010 by Serefoglu et al. [ 8 ]. They proposed that botulinum toxin-A’s selective inhibition of acetylcholine release at nerve endings, and subsequent inhibition of muscular contraction, could improve PE by inhibiting the rhythmic contraction of pelvic floor muscles during ejaculation. This hypothesis was further supported in 2014 with a pre-clinical animal study on 33 rats, showing that botulinum toxin-A injections of 0.5 and 1 unit in the BS improved IELT. [ 9 ] Ongun et al. conducted another pre-clinical animal study on 21 rats, yielding similar results and demonstrating decreased BS electromyography (EMG) activity in the botulinum toxin-A groups. [ 10 ] These pre-clinical studies paved the way for further research on the impact of botulinum toxin-A in human patients with PE. However, due to the niche nature of this topic, the availability of high-level evidence is limited, and accordingly that there is not enough substantial evidence to incorporate its use in the management PE. [ 3 , 7 ] Therefore, this review and meta-analysis aim to evaluate the evidence from all randomized controlled trials comparing the effects of botulinum toxin-A in patients with lifelong PE. Methods 2.1 Overview & Research Question A systematic review and meta-analysis of randomised controlled trials (RCT) was done tith the PRISMA guidelines being utilised as the working scaffold. [ 11 ] This review registered in PROSPERO (CRD42024564185). The research question was developed using the PICO framework. Our research question is to evaluate botulinum toxin’s efficacy in treating lifelong premature ejaculation in adults in comparison to placebo. The primary outcome of interest is intravaginal ejaculation latency time (IELT). The secondary outcome premature ejaculation profile (PEP) scores and documented adverse effect. Exclusions included patients with acquired PE, the use of medications concomitantly with botulinum toxin, and the use botulinum toxin for non-PE andrological or urological conditions. 2.2 Search Strategy & Study Selection We identified and searched six major databases (PubMed, Google Scholar, Scopus, Web of Science, Cochrane Library, WHO International Clinical Trials Registry Platform [ICTRP]). No restrictions were put on language, country, or publication date, and all relevant texts up to June 2024 was included in the initial screening process. Given the research question, all study designs except for randomised controlled trials were excluded. Eligible and retrieved texts were then uploaded to Covidence Software [ 12 ], and were screened, reviewed, and had data extracted from them by two independent reviewers (MM, QI). Discrepancies were settled through discussion, and where not possible through a third reviewer. Figure 1 demonstrates a PRISMA flowchart of our search. 2.3 Data Extraction The extracted baseline variables of interest included study name, year of publication, country, language, total sample size, number of patients assigned to intervention or control groups, dose of botulinum toxin, dose of placebo and follow up period. Additionally, the study’s outcomes were extracted as well and included IELT durations, PEP scores, and post-treatment adverse effects. Data was categorised based on critical time points: pre-intervention, 1-, 3-, and 6-months post-intervention. 2.4 Quality Assessment All eligible studies were randomised controlled trials, as such the ROB-2 scale was used to assess for quality and bias. [ 13 ] The assessment was carried out by two independent reviewers (MM, QI), and Discrepancies were settled through discussion, and where not possible through a third reviewer. The outcomes were then demonstrated in a bar chart and traffic light plot. A Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment was also carried out using GRADEpro software to evaluate the certainty of evidence. [ 14 – 15 ] 2.5 Data Synthesis & Analysis Basic data analysis including measures of central tendency was done using Microsoft Excel. As both IELT & PEP scores are considered continuous data, a meta-analysis of mean differences (MD) was done for continuous variables (IELT & PEP), and binary outcomes for adverse effects (AE). Meta-analyses was done using “metafor” package in R Studio. [ 16 – 17 ] We used a random effects model to accommodate for heterogeneity amongst studies. The outcomes were then showcased in forest plots demonstrating estimate effects and 95% confidence intervals. Heterogeneity studies were done using Higgin I 2 & Cochrane Q tests, whereas a sensitivity analysis was done using the leave-one-out analysis. Publication bias was assessed through visualisation of funnel plots and Eggers test. A P value of < 0.05 was considered statistically significant. A Results 3.1 Study Characteristics (Table 1) Overall, the total number of studies that met our eligibility criteria was five [ 18 – 23 ]. Only three where further included in the review and meta-analysis as one trial [ 18 ], did not have complete information with regards to the intervention provided and we were not able to retrieve any data after correspondence. Another trial was still ongoing, however preliminary results were neither available online nor on request. [ 19 ] The eligible trials included 228 patients, equally divided into intervention and control groups. The trials were published between 2018 and 2024, with two trials from Egypt published in English and one trial from China published in Chinese. All trials used 100 units of botulinum toxin-A diluted in 10mLs (10 units per mL) versus 10mLs of 0.9% NaCl. The injection techniques were described as part of the trial methodology. All trials followed up their patients up to 1 month, whereas only two extended follow up to 3 and 6 months. (Table 1). 3.2 IELT Duration Changes (Fig. 2 ) At one month follow up, improvements in IELT time were noted with a mean difference of 39.6 seconds between the groups (95% CI: 13.5–92.7, p = 0.14), however, this was not enough to achieve statistical significance. Likewise, non-statistically significant improvements of 11.5 seconds (95% CI: -16.8-39.9, p = 0.42), and 2.4 seconds (95% CI: -9.1-14.03, p = 0.68) seconds were noted, respectively, between the botulinum toxin and placebo groups at three and six month follow up. Overall, heterogeneity was significant across all three follow up periods. An Eggers test and visual inspection of a funnel plot demonstrated no publication bias (t = 6.57, df = 1, p > 0.05). The remaining two follow up periods did not have sufficient studies to assess for publication bias (k = 2). 3.3 PEP Scores (Fig. 3 ) Cumulative PEP score changes was documented in two trials (12–13). Score improvements were demonstrated between intervention and control groups at one, three, and six months. PEP scores improved by 1.54 (95% CI: -1.45, 4.63, p > 0.05), 1.08 (95% CI: -0.96, 3.13, p > 0.05) and 0.36 units (95% CI: -0.91, 1.63, p > 0.05), respectively. (table) However, none of the pooled mean differences achieved statistical significance. Heterogeneity tests demonstrated significant findings. Publication bias tests were not carried out due to the low number of included studies (k = 2). 3.4 Adverse Effects (Fig. 4 ) Overall, 11 patients (9.6%) developed adverse effects on the first follow up. 10 patients in the botulinum toxin groups were noted to have had voiding difficulties (n = 5), mild erectile dysfunction (n = 4), infection (n = 1), pain (n = 1) in comparison to 1 patient in the control group who developed voiding difficulties. The odds ratio (OR) of developing adverse effects is 5.89 (95% CI: 0.12–28.72, p < 0.05), with no significant heterogeneity noted (I 2 = 0%, Q = 0.53, p = 0.54) 3.5 Risk of Bias Assessment (Fig. 5 ) The three eligible demonstrated low risks of bias in all five domains of the Risk of Bias 2 (ROB-2) tool. A traffic light plot demonstrates the risks per domain and overall risk judgement. (Fig. 5 ) 3.6 GRADE Assessment & Recommendations (Table 2) The GRADE framework was used to evaluate for certainty of evidence for the main three outcomes of interest. IELT & PEP were assessed in seconds with a follow-up range of 1 to 6 months including 228 patients in 3 RCTs. The certainty of evidence for both outcomes was low due to inconsistency and a small total sample size. Adverse effects, on the other hand, included a similar participant cohort and was noted on the first month follow up. The quality of evidence was moderate as inconsistency was not detected, but the total sample size was still small. Discussion Lifelong PE is a challenging clinical entity with many treatment options available. However, despite significant progress in understanding and treating the disease, there is no universally recommended therapeutic agent yet. [ 3 – 7 ] This study aimed to evaluate the efficacy of botulinum toxin-A in treating lifelong PE in adults compared to placebo. The main outcomes of interest were intravaginal ejaculation latency time (IELT), the Premature Ejaculation Profile (PEP) as a surrogate for PE severity, and adverse effects (AE). The findings of this review and meta-analysis demonstrate that early evidence from three RCTs comparing botulinum toxin-A to placebo in the treatment of lifelong PE shows no clear benefit. While some trials report improvements in IELT and PEP scores over a six month follow up period, the overall pooled estimates indicate these changes are not statistically significant. Additionally, adverse effects were significantly higher in the intervention groups compared to the control groups. To date, no known review has compared botulinum toxin-A with placebo for the treatment of lifelong PE. In 2010, Serefoglu et al. first suggested using botulinum toxin-A within the context of PE, hypothesizing that its inhibitory effects would increase IELT by inhibiting rhythmic muscular contractions during the expulsion sub-phase [ 8 ]. They recommended a well-designed experimental study to demonstrate its therapeutic benefits and explore its adverse effects. Four years later, Serefoglu et al. conducted a pre-clinical animal trial involving 33 rats divided into three groups of 11, given a single injection of 1 unit, 0.5 units, or placebo in 0.1 mL of saline [ 9 ]. The results showed significant improvements in IELT in the botulinum toxin groups, and they noted that the treatment did not affect the rats' sexual behavior [ 9 ]. Ongun et al. then echoed these results with another pre-clinical trial using 1 and 5 units of botulinum toxin-A compared to placebo [ 10 ]. They added electromyographic measurements of the BS muscle to evaluate ejaculation parameters. Their findings echoed that of Serefoglu et al. [ 9 ]. Additionally, they found that rats receiving 5 units of botulinum toxin-A demonstrated lower BS EMG area under the curve values compared to the 1 unit and placebo groups. [ 10 ]. Clinical trials on patients did not start until 2017, with an RCT identified in our search by Allergan. [ 18 ] Although neither the results nor the botulinum toxin-A doses were formally published, a statement in the AUA guidelines for disorders of ejaculation indicated that the trial was discontinued at phase II due to lack of efficacy based on interim results. [ 7 ] One year later, Li et al. published the first RCT involving 70 patients who were followed up for one month. [ 20 ] Their primary outcome was IELT, and secondary outcomes included PEP, Partner’s Sexual Satisfaction Score (PSSS), Male Sexual Health Questionnaire – Ejaculatory Disorders (MHSQ-EjD), Hospital Anxiety & Depression Scale (HADS), and adverse effects (AEs). Li et al. noted significant improvements in IELT, PEP, and partner sexual satisfaction scores at the 4-week follow-up. Conversely, there were no significant changes in MHSQ-EjD or HADS scores. Six adverse events were noted a few days post-procedure in the intervention group, with all resolving spontaneously within three weeks and none requiring further treatment. Although the results were promising, the follow-up duration was limited to one month, restricting a formal assessment of the long-term benefits of botulinum toxin-A, especially given the chronic nature of the condition. Additionally, the description of PEP scores was based on averages of each question, which made using PEP in further meta-analysis challenging and not feasible for comparison with the other eligible trials. In 2024, both Almekaty and Shaher et al. [ 21 – 22 ] published RCTs conducted in Egypt. Almekaty et al.'s trial included 60 patients, divided equally, and followed up for six months. The outcomes of interest included IELT, PEP, and PSSS. Their findings contradicted those of Li et al., as Almekaty et al. found that 100 units of botulinum toxin-A injected into the BS muscle had no significant effect on IELT, PEP, or PSSS. The results consistently demonstrated comparable outcomes between the intervention and control groups with no statistical significance. In discussing their results, they hypothesized that the potential difference in outcomes could be attributed to the injection technique; Li et al. injected botulinum toxin-A at five points along the BS, whereas Almekaty et al. used an ultrasound-guided single injection with a fanning technique. Additionally, they used a non-validated Arabic version of the PEP questionnaire, which could have introduced bias. [ 21 ] Shaher et al. published a similar trial one month later involving 90 patients, followed up over six months. [ 22 ] The outcomes of interest in this trial were IELT, PEP, PEDT, changes in erectile function, and adverse effects. Although Shaher et al.'s methodology was not as well-defined as the previous trials, they described a similar injection technique to Almekaty et al., using a single ultrasound-guided injection distributed across most muscle fibers. Further clarification is needed on whether the botulinum toxin-A was delivered via a fanning motion or longitudinally into the muscle. Shaher et al.'s outcomes echoed those of the 2018 RCT, with significant improvements in IELT, PEP, and other parameters. They reported an efficacy rate of 44.7% at one month (vs. 47.06% in Li et al.), with a lower efficacy at six months follow-up. [ 20 ] They also noted a similar incidence of adverse effects (4 vs. 6 in the intervention groups). During our search, another RCT was identified using the WHO ICTRP database in Iran involving 30 patients. At the time of writing, this project had been ongoing for six months, but we were unable to obtain any preliminary evidence to include in this review and meta-analysis. [ 19 ] Strengths & Limitations There are several limitations that could have influenced the outcomes of this study. Firstly, there was heterogeneity in determining the optimal sample size. Li et al. did not specify the methodology through which their sample size and study power was determined. Almekaty used a post-hoc analysis. Shaher et al. calculated an optimal sample size of 90 a priori using gpowersoft software and based their sample size on Serefoglu et al.’s outcomes. To address this and given that more data is available, larger-scale trials are advocated to produce robust results that can better outline the impact of botulinum toxin-A on PE. Secondly, the follow-up durations were not matched and were relatively short. Although this can be justified given what we know about the pharmacokinetics of botulinum toxin-A and axonal regeneration, [ 23 ] additional information on long-term effects would be beneficial in understanding the maximal duration of effect and adverse effect profile over the long term. Moreover, there was noticeable heterogeneity in trial methodologies, particularly regarding the injection technique, which was a prominent issue used to explain differences in outcomes. The three trials described two different techniques, with Shaher et al. [ 22 ] not clearly describing their injection technique. This issue was identified and commented on by Wang & Pan in May 2024 [ 24 ]. A standardized drug delivery technique or trials with intervention arms using different techniques would help clarify if this contributed to the non-significant findings of our study. Lastly, Li et al.'s study was published in Mandarin. [ 20 ] Although experienced independent translators were used to translate the text into English, elements of language bias could have been introduced. Conclusion Theoretically, botulinum toxin-A delays ejaculation by inhibiting rhythmic muscular contractions of the pelvic floor muscles. However, our findings from early randomized placebo-controlled trials suggest that it has yet to show any statistically significant benefit. As such, its role in managing PE remains unclear, echoing the recommendations from guideline panels based on pre-clinical trials. [ 3 , 7 ] We believe that further trials with larger sample sizes, a standardized botulinum toxin-A delivery technique, and validated surrogate parameters are required to clearly outline its role, adverse effect profile, and longevity of effect. Declarations Funding: Nil Ethical Approval: Not Applicable Conflict of Interest: Nil Author Contribution Statement: MM: Study Conception & Design, Data Collection & Analysis, Manuscript Writing & Editing QI: Study Conception & Design, Data Collection, Manuscript Writing VB: Supervision, Manuscript Writing & Editing, Approval of Final Version IP: Supervision, Manuscript Writing & Editing, Approval of Final Version References Pereira-Lourenço M, Vieira e Brito D, Pereira BJ. Premature Ejaculation – From Physiology to Treatment. Journal of Family & Reproductive Health. 2019; Parnham A, Serefoglu EC. Classification and definition of premature ejaculation. Translational Andrology and Urology [Internet]. 2016 Aug 1 [cited 2022 Jan 15];5(4):416–23. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5001991/ Althof SE, McMahon CG, Waldinger MD, Serefoglu EC, Shindel AW, Adaikan PG, et al. An Update of the International Society of Sexual Medicine’s Guidelines for the Diagnosis and Treatment of Premature Ejaculation (PE). Sexual Medicine [Internet]. 2014;2(2):60–90. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184677/ Salonia A, Bettocchi C, Boeri L, Capogrosso P, Carvalho J, Cilesiz NC, et al. European Association of Urology Guidelines on Sexual and Reproductive Health—2021 Update: Male Sexual Dysfunction. European Urology. 2021;80(3). Chung E, Gilbert B, Perera M, Roberts MJ. Premature ejaculation: A clinical review for the general physician. Australian family physician. 2015 Oct. Sansone A, Aversa A, Corona G, Fisher AD, Isidori AM, La Vignera S, et al. Management of premature ejaculation: a clinical guideline from the Italian Society of Andrology and Sexual Medicine (SIAMS). Journal of Endocrinological Investigation. 2020;44(5):1103–18. Shindel AW, Althof SE, Carrier S, Chou R, McMahon CG, Mulhall JP, et al. Disorders of Ejaculation: An AUA/SMSNA Guideline. The Journal of Urology [Internet]. 2022;207(3):504–12. Available from: https://pubmed.ncbi.nlm.nih.gov/34961344/ Serefoglu EC, Silay MS. Botulinum toxin-A injection may be beneficial in the treatment of life-long premature ejaculation. Medical Hypotheses. 2010;74(1):83–4. Serefoglu EC, Hawley WR, Lasker GF, Grissom EM, Mandava SH, Sikka SC, et al. Effect of Botulinum-A Toxin Injection into Bulbospongiosus Muscle on Ejaculation Latency in Male Rats. The Journal of Sexual Medicine. 2014;11(7):1657–63. Ongün Ş, Acar S, Koca P, Uzut M, Esen AA, Durmus N, et al. Can Botulinum-A Toxin Be Used to Delay Ejaculation: Results of an Ejaculation Model in Male Rats. The Journal of Sexual Medicine. 2019;16(9):1338–43. Tetzlaff J, Page M, Moher D. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Value in Health. 2020;23(10):S312–3. Covidence - Better systematic review management [Internet]. Covidence. 2023. Available from: https://www.covidence.org Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ [Internet]. 2019;366(1):l4898. Available from: https://www.bmj.com/content/366/bmj.l4898 Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction—GRADE evidence profiles and summary of findings tables. Journal of Clinical Epidemiology. 2011;64(4):383–94. GRADEpro [Internet]. Gradepro.org. 2024 [cited 2024 Oct 18]. Available from: https://gradepro.org Balduzzi S, Rücker G, Schwarzer G. How to perform a meta-analysis with R: a practical tutorial. Evidence Based Mental Health. 2019;22(4):153–60. Viechtbauer W. Conducting Meta-Analyses in R with the metafor package. Journal of Statistical Software. 2010;36(3). NCT01917006: A safety and efficacy study of onabotulinumtoxinA in premature ejaculation. ClinicalTrials.gov [Internet]. clinicaltrials.gov. Available from: https://clinicaltrials.gov/study/NCT01917006#study-overview IRCT20190624043991N23: The effectiveness of botulinum A injection in the treatment of premature ejaculation patients. ICTRP Search Portal [Internet]. Who.int. 2024. Available from: https://trialsearch.who.int/Trial2.aspx?TrialID=IRCT20190624043991N23 . Li ZT, Li YF, Zhang Y, Luo Y, Zhu T, Li K, et al. [Injection of botulinum-A toxin into bulbospongiosus muscle for primary premature ejaculation: A preliminary clinical study]. PubMed. 2018;24(8):713–8. Khaled Almekaty, Ghaith A, Ragab M, Rashed A, Ayman Hagras, Ayman Ghoneem, et al. Effect of bulbospongiosus muscle injection with botulinum-A toxin for treatment of lifelong premature ejaculation; a randomized controlled trial. International Journal of Impotence Research. 2024; Hussein Shaher, Noah K, Abdelzaher M, Kandil W, Ahmed IS, Nouh IS. Is bulbospongiosus muscle botox injection safe and effective in treating lifelong premature ejaculation? Randomized controlled study. World Journal of Urology. 2024;42(1). Sulaiman W, Gordon T. Neurobiology of peripheral nerve injury, regeneration, and functional recovery: from bench top research to bedside application. PubMed. 2013;13(1):100–8. Wang Y, Pan Y. Letter to the editor for the article “Is bulbospongiosus muscle botox injection safe and effective in treating lifelong premature ejaculation? Randomized controlled study.” World Journal of Urology. 2024;42(1). Tables Table 1 and 2 are available in the Supplementary Files section. Additional Declarations There is NO conflict of interest to disclose. Supplementary Files Table2GRADEAssessment.pdf Table 2 Table1BaselineCharacteristics.pdf Table 1 Cite Share Download PDF Status: Published Journal Publication published 27 Jan, 2025 Read the published version in International Journal of Impotence Research → Version 1 posted Editorial decision: revise 21 Nov, 2024 Review # 2 received at journal 17 Nov, 2024 Reviewer # 2 agreed at journal 07 Nov, 2024 Review # 1 received at journal 07 Nov, 2024 Reviewer # 1 agreed at journal 04 Nov, 2024 Reviewers invited by journal 01 Nov, 2024 Submission checks completed at journal 01 Nov, 2024 First submitted to journal 31 Oct, 2024 Unknown event 28 Oct, 2024 Editor assigned by journal 25 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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2","display":"","copyAsset":false,"role":"figure","size":202500,"visible":true,"origin":"","legend":"\u003cp\u003eIELT Changes\u003c/p\u003e","description":"","filename":"Figure2IELTChanges.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5331700/v1/60d064de66a57db68ccca680.jpg"},{"id":70041589,"identity":"2ed0e80b-d016-4dca-b964-1a8424edfafc","added_by":"auto","created_at":"2024-11-27 18:09:42","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":272142,"visible":true,"origin":"","legend":"\u003cp\u003ePEP Scores\u003c/p\u003e","description":"","filename":"Figure3PEPChanges.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5331700/v1/b004bfe21ff57da65707d1f3.jpg"},{"id":70041588,"identity":"6053e1ef-d6a8-4fb5-9b23-5bf4ba66a4dd","added_by":"auto","created_at":"2024-11-27 18:09:41","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":121991,"visible":true,"origin":"","legend":"\u003cp\u003eAdverse Effects\u003c/p\u003e","description":"","filename":"Figure4AE.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5331700/v1/c80813f6ad9ee61737108c23.jpg"},{"id":70040871,"identity":"525a28ff-66dc-4579-b720-32caf431d6db","added_by":"auto","created_at":"2024-11-27 18:01:42","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1363280,"visible":true,"origin":"","legend":"\u003cp\u003eTraffic Light Plot Demonstrating Risk of Bias Assessment\u003c/p\u003e","description":"","filename":"Figure5ROB2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5331700/v1/c1ffaca1c509a4f9d04e222b.jpg"},{"id":74905708,"identity":"20bf0125-172e-42d2-b2d6-321c5c5f4ebb","added_by":"auto","created_at":"2025-01-28 08:09:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2693917,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5331700/v1/cc1696e9-3c02-4d15-8b53-6027b7d0b8e8.pdf"},{"id":70040868,"identity":"8bf174fa-2905-40be-8189-b05faa68e5ac","added_by":"auto","created_at":"2024-11-27 18:01:42","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":42241,"visible":true,"origin":"","legend":"Table 2","description":"","filename":"Table2GRADEAssessment.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5331700/v1/132228fb5928bb831807ac22.pdf"},{"id":70040865,"identity":"2ec36b2d-0961-452b-8f7f-3bcde742537e","added_by":"auto","created_at":"2024-11-27 18:01:41","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":32531,"visible":true,"origin":"","legend":"Table 1","description":"","filename":"Table1BaselineCharacteristics.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5331700/v1/2a2898293a87f38126fc80cd.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Is Botulinum Toxin-A the Breakthrough in Premature Ejaculation Treatment? Insights from a Meta-Analysis of Randomised Controlled Trials","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe male sexual response concludes with ejaculation, which comprises two distinct phases: emission and expulsion. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] Emission involves the secretion of spermatozoa and seminal fluid into the prostatic urethra through the genital tract. Expulsion involves the propulsion of semen along the urethra via coordinated rhythmic contractions of the internal and external urethral sphincters, as well as the pelvic floor muscles, including the bulbospongiosus (BS) and ischiocavernosus (IC) muscles. These reflexes are orchestrated by the autonomic nervous system and involve a thorough interplay between these muscles to ensure antegrade flow. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/p\u003e \u003cp\u003ePremature ejaculation (PE) is a male sexual disorder with a prevalence ranging from 3\u0026ndash;30%. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] This wide range reflects the lack of a universal definition, making it a challenging clinical entity to address. The International Society of Sexual Medicine (ISSM) outlined three domains: a) latency time, b) lack of control, and c) distress as key when defining PE. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] Proven treatment modalities for PE range from conservative to minimally invasive approaches. Conservative management options include psychotherapy and behavioural therapy techniques, and adjuncts such as using multiple condoms and pelvic floor muscle exercises. [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] Medical management involves topical anaesthetic agents that increase IELT and, consequently, enhance sexual satisfaction. Agents such as prilocaine, lignocaine, and benzocaine creams and sprays are commonly used. Oral pharmacotherapy is mainly available in the form selective serotonin reuptake inhibitors (SSRIs), with current EAU guidelines recommending on-demand dapoxetine for both lifelong and acquired PE. [\u003cspan additionalcitationids=\"CR4 CR5 CR6\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] Other options, such as daily dosed or on-demand SSRIs, clomipramine, and tramadol, although recommended by the guidelines, are considered off-label indications. [\u003cspan additionalcitationids=\"CR4 CR5 CR6\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eGiven the current understanding of the ejaculation reflex, Botulinum toxin-A was first hypothesized as a potential treatment for PE in 2010 by Serefoglu et al. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. They proposed that botulinum toxin-A\u0026rsquo;s selective inhibition of acetylcholine release at nerve endings, and subsequent inhibition of muscular contraction, could improve PE by inhibiting the rhythmic contraction of pelvic floor muscles during ejaculation. This hypothesis was further supported in 2014 with a pre-clinical animal study on 33 rats, showing that botulinum toxin-A injections of 0.5 and 1 unit in the BS improved IELT. [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] Ongun et al. conducted another pre-clinical animal study on 21 rats, yielding similar results and demonstrating decreased BS electromyography (EMG) activity in the botulinum toxin-A groups. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThese pre-clinical studies paved the way for further research on the impact of botulinum toxin-A in human patients with PE. However, due to the niche nature of this topic, the availability of high-level evidence is limited, and accordingly that there is not enough substantial evidence to incorporate its use in the management PE. [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] Therefore, this review and meta-analysis aim to evaluate the evidence from all randomized controlled trials comparing the effects of botulinum toxin-A in patients with lifelong PE.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Overview \u0026amp; Research Question\u003c/h2\u003e \u003cp\u003e A systematic review and meta-analysis of randomised controlled trials (RCT) was done tith the PRISMA guidelines being utilised as the working scaffold. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] This review registered in PROSPERO (CRD42024564185). The research question was developed using the PICO framework. Our research question is to evaluate botulinum toxin\u0026rsquo;s efficacy in treating lifelong premature ejaculation in adults in comparison to placebo. The primary outcome of interest is intravaginal ejaculation latency time (IELT). The secondary outcome premature ejaculation profile (PEP) scores and documented adverse effect. Exclusions included patients with acquired PE, the use of medications concomitantly with botulinum toxin, and the use botulinum toxin for non-PE andrological or urological conditions.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003e2.2 Search Strategy \u0026 Study Selection\u003c/h3\u003e\n\u003cp\u003eWe identified and searched six major databases (PubMed, Google Scholar, Scopus, Web of Science, Cochrane Library, WHO International Clinical Trials Registry Platform [ICTRP]). No restrictions were put on language, country, or publication date, and all relevant texts up to June 2024 was included in the initial screening process. Given the research question, all study designs except for randomised controlled trials were excluded. Eligible and retrieved texts were then uploaded to Covidence Software [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], and were screened, reviewed, and had data extracted from them by two independent reviewers (MM, QI). Discrepancies were settled through discussion, and where not possible through a third reviewer. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e demonstrates a PRISMA flowchart of our search.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003e2.3 Data Extraction\u003c/h3\u003e\n\u003cp\u003eThe extracted baseline variables of interest included study name, year of publication, country, language, total sample size, number of patients assigned to intervention or control groups, dose of botulinum toxin, dose of placebo and follow up period. Additionally, the study\u0026rsquo;s outcomes were extracted as well and included IELT durations, PEP scores, and post-treatment adverse effects. Data was categorised based on critical time points: pre-intervention, 1-, 3-, and 6-months post-intervention.\u003c/p\u003e\n\u003ch3\u003e2.4 Quality Assessment\u003c/h3\u003e\n\u003cp\u003eAll eligible studies were randomised controlled trials, as such the ROB-2 scale was used to assess for quality and bias. [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] The assessment was carried out by two independent reviewers (MM, QI), and Discrepancies were settled through discussion, and where not possible through a third reviewer. The outcomes were then demonstrated in a bar chart and traffic light plot. A Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment was also carried out using GRADEpro software to evaluate the certainty of evidence. [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e\n\u003ch3\u003e2.5 Data Synthesis \u0026 Analysis\u003c/h3\u003e\n\u003cp\u003eBasic data analysis including measures of central tendency was done using Microsoft Excel. As both IELT \u0026amp; PEP scores are considered continuous data, a meta-analysis of mean differences (MD) was done for continuous variables (IELT \u0026amp; PEP), and binary outcomes for adverse effects (AE). Meta-analyses was done using \u0026ldquo;metafor\u0026rdquo; package in R Studio. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] We used a random effects model to accommodate for heterogeneity amongst studies. The outcomes were then showcased in forest plots demonstrating estimate effects and 95% confidence intervals. Heterogeneity studies were done using Higgin I\u003csup\u003e2\u003c/sup\u003e \u0026amp; Cochrane Q tests, whereas a sensitivity analysis was done using the leave-one-out analysis. Publication bias was assessed through visualisation of funnel plots and Eggers test. A P value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant. A\u003c/p\u003e "},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003e3.1 Study Characteristics (Table\u0026nbsp;1)\u003c/h2\u003e \u003cp\u003eOverall, the total number of studies that met our eligibility criteria was five [\u003cspan additionalcitationids=\"CR19 CR20 CR21 CR22\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Only three where further included in the review and meta-analysis as one trial [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], did not have complete information with regards to the intervention provided and we were not able to retrieve any data after correspondence. Another trial was still ongoing, however preliminary results were neither available online nor on request. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] The eligible trials included 228 patients, equally divided into intervention and control groups. The trials were published between 2018 and 2024, with two trials from Egypt published in English and one trial from China published in Chinese. All trials used 100 units of botulinum toxin-A diluted in 10mLs (10 units per mL) versus 10mLs of 0.9% NaCl. The injection techniques were described as part of the trial methodology. All trials followed up their patients up to 1 month, whereas only two extended follow up to 3 and 6 months. (Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e3.2 IELT Duration Changes\u003c/span\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAt one month follow up, improvements in IELT time were noted with a mean difference of 39.6 seconds between the groups (95% CI: 13.5\u0026ndash;92.7, p\u0026thinsp;=\u0026thinsp;0.14), however, this was not enough to achieve statistical significance. Likewise, non-statistically significant improvements of 11.5 seconds (95% CI: -16.8-39.9, p\u0026thinsp;=\u0026thinsp;0.42), and 2.4 seconds (95% CI: -9.1-14.03, p\u0026thinsp;=\u0026thinsp;0.68) seconds were noted, respectively, between the botulinum toxin and placebo groups at three and six month follow up.\u003c/p\u003e \u003cp\u003eOverall, heterogeneity was significant across all three follow up periods. An Eggers test and visual inspection of a funnel plot demonstrated no publication bias (t\u0026thinsp;=\u0026thinsp;6.57, df\u0026thinsp;=\u0026thinsp;1, p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). The remaining two follow up periods did not have sufficient studies to assess for publication bias (k\u0026thinsp;=\u0026thinsp;2).\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e3.3 PEP Scores\u003c/span\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eCumulative PEP score changes was documented in two trials (12\u0026ndash;13). Score improvements were demonstrated between intervention and control groups at one, three, and six months. PEP scores improved by 1.54 (95% CI: -1.45, 4.63, p\u0026thinsp;\u0026gt;\u0026thinsp;0.05), 1.08 (95% CI: -0.96, 3.13, p\u0026thinsp;\u0026gt;\u0026thinsp;0.05) and 0.36 units (95% CI: -0.91, 1.63, p\u0026thinsp;\u0026gt;\u0026thinsp;0.05), respectively. (table) However, none of the pooled mean differences achieved statistical significance. Heterogeneity tests demonstrated significant findings. Publication bias tests were not carried out due to the low number of included studies (k\u0026thinsp;=\u0026thinsp;2).\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e3.4 Adverse Effects\u003c/span\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOverall, 11 patients (9.6%) developed adverse effects on the first follow up. 10 patients in the botulinum toxin groups were noted to have had voiding difficulties (n\u0026thinsp;=\u0026thinsp;5), mild erectile dysfunction (n\u0026thinsp;=\u0026thinsp;4), infection (n\u0026thinsp;=\u0026thinsp;1), pain (n\u0026thinsp;=\u0026thinsp;1) in comparison to 1 patient in the control group who developed voiding difficulties. The odds ratio (OR) of developing adverse effects is 5.89 (95% CI: 0.12\u0026ndash;28.72, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), with no significant heterogeneity noted (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%, Q\u0026thinsp;=\u0026thinsp;0.53, p\u0026thinsp;=\u0026thinsp;0.54)\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e3.5 Risk of Bias Assessment\u003c/span\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe three eligible demonstrated low risks of bias in all five domains of the Risk of Bias 2 (ROB-2) tool. A traffic light plot demonstrates the risks per domain and overall risk judgement. (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e3.6 GRADE Assessment \u0026amp; Recommendations\u003c/span\u003e (Table\u0026nbsp;2)\u003c/p\u003e \u003cp\u003eThe GRADE framework was used to evaluate for certainty of evidence for the main three outcomes of interest. IELT \u0026amp; PEP were assessed in seconds with a follow-up range of 1 to 6 months including 228 patients in 3 RCTs. The certainty of evidence for both outcomes was low due to inconsistency and a small total sample size. Adverse effects, on the other hand, included a similar participant cohort and was noted on the first month follow up. The quality of evidence was moderate as inconsistency was not detected, but the total sample size was still small.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eLifelong PE is a challenging clinical entity with many treatment options available. However, despite significant progress in understanding and treating the disease, there is no universally recommended therapeutic agent yet. [\u003cspan additionalcitationids=\"CR4 CR5 CR6\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] This study aimed to evaluate the efficacy of botulinum toxin-A in treating lifelong PE in adults compared to placebo. The main outcomes of interest were intravaginal ejaculation latency time (IELT), the Premature Ejaculation Profile (PEP) as a surrogate for PE severity, and adverse effects (AE). The findings of this review and meta-analysis demonstrate that early evidence from three RCTs comparing botulinum toxin-A to placebo in the treatment of lifelong PE shows no clear benefit. While some trials report improvements in IELT and PEP scores over a six month follow up period, the overall pooled estimates indicate these changes are not statistically significant. Additionally, adverse effects were significantly higher in the intervention groups compared to the control groups.\u003c/p\u003e \u003cp\u003eTo date, no known review has compared botulinum toxin-A with placebo for the treatment of lifelong PE. In 2010, Serefoglu et al. first suggested using botulinum toxin-A within the context of PE, hypothesizing that its inhibitory effects would increase IELT by inhibiting rhythmic muscular contractions during the expulsion sub-phase [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. They recommended a well-designed experimental study to demonstrate its therapeutic benefits and explore its adverse effects. Four years later, Serefoglu et al. conducted a pre-clinical animal trial involving 33 rats divided into three groups of 11, given a single injection of 1 unit, 0.5 units, or placebo in 0.1 mL of saline [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The results showed significant improvements in IELT in the botulinum toxin groups, and they noted that the treatment did not affect the rats' sexual behavior [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Ongun et al. then echoed these results with another pre-clinical trial using 1 and 5 units of botulinum toxin-A compared to placebo [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. They added electromyographic measurements of the BS muscle to evaluate ejaculation parameters. Their findings echoed that of Serefoglu et al. [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Additionally, they found that rats receiving 5 units of botulinum toxin-A demonstrated lower BS EMG area under the curve values compared to the 1 unit and placebo groups. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eClinical trials on patients did not start until 2017, with an RCT identified in our search by Allergan. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] Although neither the results nor the botulinum toxin-A doses were formally published, a statement in the AUA guidelines for disorders of ejaculation indicated that the trial was discontinued at phase II due to lack of efficacy based on interim results. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] One year later, Li et al. published the first RCT involving 70 patients who were followed up for one month. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] Their primary outcome was IELT, and secondary outcomes included PEP, Partner\u0026rsquo;s Sexual Satisfaction Score (PSSS), Male Sexual Health Questionnaire \u0026ndash; Ejaculatory Disorders (MHSQ-EjD), Hospital Anxiety \u0026amp; Depression Scale (HADS), and adverse effects (AEs). Li et al. noted significant improvements in IELT, PEP, and partner sexual satisfaction scores at the 4-week follow-up. Conversely, there were no significant changes in MHSQ-EjD or HADS scores. Six adverse events were noted a few days post-procedure in the intervention group, with all resolving spontaneously within three weeks and none requiring further treatment. Although the results were promising, the follow-up duration was limited to one month, restricting a formal assessment of the long-term benefits of botulinum toxin-A, especially given the chronic nature of the condition. Additionally, the description of PEP scores was based on averages of each question, which made using PEP in further meta-analysis challenging and not feasible for comparison with the other eligible trials.\u003c/p\u003e \u003cp\u003eIn 2024, both Almekaty and Shaher et al. [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] published RCTs conducted in Egypt. Almekaty et al.'s trial included 60 patients, divided equally, and followed up for six months. The outcomes of interest included IELT, PEP, and PSSS. Their findings contradicted those of Li et al., as Almekaty et al. found that 100 units of botulinum toxin-A injected into the BS muscle had no significant effect on IELT, PEP, or PSSS. The results consistently demonstrated comparable outcomes between the intervention and control groups with no statistical significance. In discussing their results, they hypothesized that the potential difference in outcomes could be attributed to the injection technique; Li et al. injected botulinum toxin-A at five points along the BS, whereas Almekaty et al. used an ultrasound-guided single injection with a fanning technique. Additionally, they used a non-validated Arabic version of the PEP questionnaire, which could have introduced bias. [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eShaher et al. published a similar trial one month later involving 90 patients, followed up over six months. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] The outcomes of interest in this trial were IELT, PEP, PEDT, changes in erectile function, and adverse effects. Although Shaher et al.'s methodology was not as well-defined as the previous trials, they described a similar injection technique to Almekaty et al., using a single ultrasound-guided injection distributed across most muscle fibers. Further clarification is needed on whether the botulinum toxin-A was delivered via a fanning motion or longitudinally into the muscle. Shaher et al.'s outcomes echoed those of the 2018 RCT, with significant improvements in IELT, PEP, and other parameters. They reported an efficacy rate of 44.7% at one month (vs. 47.06% in Li et al.), with a lower efficacy at six months follow-up. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] They also noted a similar incidence of adverse effects (4 vs. 6 in the intervention groups). During our search, another RCT was identified using the WHO ICTRP database in Iran involving 30 patients. At the time of writing, this project had been ongoing for six months, but we were unable to obtain any preliminary evidence to include in this review and meta-analysis. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStrengths \u0026amp; Limitations\u003c/h2\u003e \u003cp\u003eThere are several limitations that could have influenced the outcomes of this study. Firstly, there was heterogeneity in determining the optimal sample size. Li et al. did not specify the methodology through which their sample size and study power was determined. Almekaty used a post-hoc analysis. Shaher et al. calculated an optimal sample size of 90 a priori using gpowersoft software and based their sample size on Serefoglu et al.\u0026rsquo;s outcomes. To address this and given that more data is available, larger-scale trials are advocated to produce robust results that can better outline the impact of botulinum toxin-A on PE. Secondly, the follow-up durations were not matched and were relatively short. Although this can be justified given what we know about the pharmacokinetics of botulinum toxin-A and axonal regeneration, [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] additional information on long-term effects would be beneficial in understanding the maximal duration of effect and adverse effect profile over the long term. Moreover, there was noticeable heterogeneity in trial methodologies, particularly regarding the injection technique, which was a prominent issue used to explain differences in outcomes. The three trials described two different techniques, with Shaher et al. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] not clearly describing their injection technique. This issue was identified and commented on by Wang \u0026amp; Pan in May 2024 [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. A standardized drug delivery technique or trials with intervention arms using different techniques would help clarify if this contributed to the non-significant findings of our study. Lastly, Li et al.'s study was published in Mandarin. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] Although experienced independent translators were used to translate the text into English, elements of language bias could have been introduced.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eTheoretically, botulinum toxin-A delays ejaculation by inhibiting rhythmic muscular contractions of the pelvic floor muscles. However, our findings from early randomized placebo-controlled trials suggest that it has yet to show any statistically significant benefit. As such, its role in managing PE remains unclear, echoing the recommendations from guideline panels based on pre-clinical trials. [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] We believe that further trials with larger sample sizes, a standardized botulinum toxin-A delivery technique, and validated surrogate parameters are required to clearly outline its role, adverse effect profile, and longevity of effect.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eNil\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval:\u003c/strong\u003e Not Applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest:\u0026nbsp;\u003c/strong\u003eNil\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution Statement:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMM: Study Conception \u0026amp; Design, Data Collection \u0026amp; Analysis, Manuscript Writing \u0026amp; Editing\u003c/p\u003e\n\u003cp\u003eQI: \u0026nbsp;Study Conception \u0026amp; Design, Data Collection, Manuscript Writing\u003c/p\u003e\n\u003cp\u003eVB: Supervision, Manuscript Writing \u0026amp; Editing, Approval of Final Version\u003c/p\u003e\n\u003cp\u003eIP: Supervision, Manuscript Writing \u0026amp; Editing, Approval of Final Version\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePereira-Louren\u0026ccedil;o M, Vieira e Brito D, Pereira BJ. 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Can Botulinum-A Toxin Be Used to Delay Ejaculation: Results of an Ejaculation Model in Male Rats. The Journal of Sexual Medicine. 2019;16(9):1338\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTetzlaff J, Page M, Moher D. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Value in Health. 2020;23(10):S312\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCovidence - Better systematic review management [Internet]. Covidence. 2023. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.covidence.org\u003c/span\u003e\u003cspan address=\"https://www.covidence.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. 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Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://trialsearch.who.int/Trial2.aspx?TrialID=IRCT20190624043991N23\u003c/span\u003e\u003cspan address=\"https://trialsearch.who.int/Trial2.aspx?TrialID=IRCT20190624043991N23\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi ZT, Li YF, Zhang Y, Luo Y, Zhu T, Li K, et al. [Injection of botulinum-A toxin into bulbospongiosus muscle for primary premature ejaculation: A preliminary clinical study]. PubMed. 2018;24(8):713\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhaled Almekaty, Ghaith A, Ragab M, Rashed A, Ayman Hagras, Ayman Ghoneem, et al. Effect of bulbospongiosus muscle injection with botulinum-A toxin for treatment of lifelong premature ejaculation; a randomized controlled trial. International Journal of Impotence Research. 2024;\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHussein Shaher, Noah K, Abdelzaher M, Kandil W, Ahmed IS, Nouh IS. Is bulbospongiosus muscle botox injection safe and effective in treating lifelong premature ejaculation? Randomized controlled study. World Journal of Urology. 2024;42(1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSulaiman W, Gordon T. Neurobiology of peripheral nerve injury, regeneration, and functional recovery: from bench top research to bedside application. PubMed. 2013;13(1):100\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Y, Pan Y. Letter to the editor for the article \u0026ldquo;Is bulbospongiosus muscle botox injection safe and effective in treating lifelong premature ejaculation? Randomized controlled study.\u0026rdquo; World Journal of Urology. 2024;42(1).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-impotence-research","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"ijir","sideBox":"Learn more about [International Journal of Impotence Research](http://www.nature.com/ijir/)","snPcode":"41443","submissionUrl":"https://mts-ijir.nature.com/cgi-bin/main.plex","title":"International Journal of Impotence Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5331700/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5331700/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe ejaculatory reflex consists of emission and expulsion, with the latter involving rhythmic muscular contractions that propel seminal fluid. Botulinum toxin, through its inhibitory effects, has been hypothesized to improve premature ejaculation (PE). This study evaluates high-quality evidence on botulinum toxin-A injections into the bulbospongiosal muscle as a treatment for PE. We conducted a systematic review and meta-analysis of randomised-controlled trials following PRISMA guidelines. Outcomes included intravaginal ejaculatory latency time (IELT), Premature Ejaculation Profile (PEP) scores, and complications. Data were analysed using Microsoft Excel and R. ROB-2, Eggers test, and GRADE assessed risk of bias, publication bias, and certainty of evidence. Three randomised controlled trials were eligible, and covered data from 228 patients with 1:1 randomisation into intervention and control arms (100 units of BOTOX in 10mLs versus 10mLs of 0.9% NaCl). IELT \u0026amp; PEP scores demonstrated improvements at 1, 3, and 6 months, however, statistically significant was not achieved. Post-procedural complications were higher in the BOTOX group; however, all adverse effects were self-resolving. Given our findings, current high-quality evidence does not support using Botulinum Toxin-A in the management of premature ejaculation. Larger scale \u0026amp; standardised RCTs are recommended to conclusively outline its clinical benefits.\u003c/p\u003e","manuscriptTitle":"Is Botulinum Toxin-A the Breakthrough in Premature Ejaculation Treatment? Insights from a Meta-Analysis of Randomised Controlled Trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-27 18:01:37","doi":"10.21203/rs.3.rs-5331700/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-11-21T11:18:12+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-11-18T03:44:56+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-11-08T01:08:35+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-11-07T09:10:14+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-11-04T17:02:07+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-11-01T16:02:22+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-11-01T10:28:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Impotence Research","date":"2024-10-31T21:16:17+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2024-10-28T15:20:46+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-25T10:34:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-impotence-research","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"ijir","sideBox":"Learn more about [International Journal of Impotence Research](http://www.nature.com/ijir/)","snPcode":"41443","submissionUrl":"https://mts-ijir.nature.com/cgi-bin/main.plex","title":"International Journal of Impotence Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"76e93124-bd4a-4a04-bb54-adfbb569d395","owner":[],"postedDate":"November 27th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":39713469,"name":"Health sciences/Diseases"},{"id":39713470,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2025-01-28T08:09:00+00:00","versionOfRecord":{"articleIdentity":"rs-5331700","link":"https://doi.org/10.1038/s41443-025-01022-9","journal":{"identity":"international-journal-of-impotence-research","isVorOnly":false,"title":"International Journal of Impotence Research"},"publishedOn":"2025-01-27 05:00:00","publishedOnDateReadable":"January 27th, 2025"},"versionCreatedAt":"2024-11-27 18:01:37","video":"","vorDoi":"10.1038/s41443-025-01022-9","vorDoiUrl":"https://doi.org/10.1038/s41443-025-01022-9","workflowStages":[]},"version":"v1","identity":"rs-5331700","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5331700","identity":"rs-5331700","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}