Efficacy and Safety of Botulinum Toxin Injection in the Management of Chronic Symptomatic Anal Fissure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Efficacy and Safety of Botulinum Toxin Injection in the Management of Chronic Symptomatic Anal Fissure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy and Safety of Botulinum Toxin Injection in the Management of Chronic Symptomatic Anal Fissure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials Kumarswamy Maradi Thippeswamy, Mei-yin Gruber, Heba Abdelaziz, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3889351/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Jan, 2025 Read the published version in Techniques in Coloproctology → Version 1 posted 9 You are reading this latest preprint version Abstract Background: Perianal fissure is one of the most painful anal conditions. Various management options are available, including topical nitrites, calcium channel blockers, botulinum toxin injection, and sphincterotomy. Aim: To assess the efficacy and safety of Botulinum Toxin A (BT) injection in the management of symptomatic chronic anal fissure by conducting a systematic review of literature and meta-analysis of published Randomised Controlled Trials (RCTs) Methodology: Systematic search conducted using Embase and Medline search platforms, extending from January 1974 to September 2020. The search identified 264 published papers, of which 35 RCTs were identified. Meta-analysis was performed on the collected data with a random effects model using the Freeman-Tukey arcsine transformed proportions. A p-value less than 0.05 was deemed significant. The I2 test was used to test for heterogeneity. Results: A total of 1532 patients were included. Upon pooling of the data, 1117 patients out of 1532 (72.7%) demonstrated healing of the fissure after the first injection with BT (P < 0.001, I2 = 86.6%). Subgroup analysis was done based on the follow-up period in months. 9 studies reported that a second BT injection was needed in patients who did not respond after the initial injection. 29 out of 38 patients (78.5%) showed a response to the second injection (p < 0.001, I2 = 50.6%). Complications were observed in 88 out of 1532 patients (4.02%) with p < 0.001, I2 = 60.2%. Conclusion: BT injection for chronic symptomatic anal fissures is effective and safe with minor temporary complications. There is evidence to support offering a repeat injection for recurrent/ persistent symptoms. Anal fissure Fissure-in-ano Botox Botulinuma Toxin A Perianal fissure Randomized controlled trial Botulinum Toxin meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 What does this paper add to the literature? This study presents a comprehensive review of all published RCTs involving Botulinum Toxin A (BT) injection as a treatment option for anal fissure. It concluded the overall efficacy and safety of BT injection for anal fissure management together with looking at BT re-injection justification and efficacy. Introduction The most common cause of severe anal pain in adults is anal fissures. There are various management options available for patients suffering from it. These options include topical nitrites, and calcium channel blockers as the conventional pharmacological treatment. Botulinum toxin injection can also be used and sphincterotomy is the most common surgical management option ( 1 ). Recamier first described it in 1829 and recommended stretching the anal sphincter to treat anal fissures ( 1 ). Peter Lord later popularized this procedure which is commonly known as Lord’s anal dilatation. The main pathology of chronic anal fissures is the spasm of internal anal sphincter ( 2 , 3 ). Therefore, the main goal of treatment of this condition is to reduce the internal sphincter hypertonia. ( 4 , 5 ) Lateral internal sphincterotomy is the most frequently performed surgical procedure for treating chronic anal fissures resulting in a healing rate of 90 to 95% ( 1 ). It works by reducing the sphincter hypertonia which is the main etiological factor in the development of chronic anal fissures ( 4 ). However, it may cause minor but permanent incontinence ( 6 ). Several therapeutic alternatives were proposed to reduce anal pressure leaving the sphincter ring intact to avoid incontinence ( 3 , 4 ). These therapeutic alternatives include CCB (diltiazem and nifedipine) and nitrites (nitroglycerin and nitrous oxide). Both of these classes of drugs act by relaxing the internal anal sphincter ( 2 ). There have been fewer reports of side effects with topical CCB or nitrites with the most common side effect being headache, however, their use is limited due to increased recurrence and lower efficacy than sphincterotomy and botulinum toxin ( 2 ). Botulinum toxin A (BT) injection in the internal sphincter muscle has become an acceptable alternative to internal anal sphincterotomy ( 6 ). It eliminates the spasm of the internal anal sphincter temporarily by blockage of neurotransmission without internal anal sphincter muscle disruption (chemical sphincterotomy) ( 7 ). Botulinum toxin has been preferred in some cases due to its higher efficacy despite being a minimally invasive procedure ( 8 ). Possible side effects of using botulinum toxin include a small amount of anal bleeding up to 24 hours following the procedure. Other side effects can include mild flu-like symptoms, body aches, or headaches. Moreover, some of the patients also reported an increase in passing gas ( 9 ). Despite years of research, there is still no common agreement on one single method for the treatment of anal fissures. Botulinum toxin and sphincterotomy are the two most efficacious methods to date. Sphincterotomy is routinely practiced, however, there has been increasing literature on the use of botulinum toxin for anal fissures. However, there have been contradicting views on its use and the literature has shown varying reports regarding its efficacy and safety. Aims Thus, this meta-analysis aims to assess the efficacy and safety of BT injection in the management of symptomatic chronic anal fissure through a systematic literature review and meta-analysis of published Randomised Controlled Trials (RCTs) Methodology Search Strategy and Study Selection: A systematic search was conducted using the Embase and Medline search platforms in December 2023. The search included all MeSH and entry terms related anal fissures and botulinum toxin. No time filters were applied. The search included all publications between January 1974 to September 2020. Two authors (K.M.T and M.G) identified 264 published papers from the initial search. All abstracts were reviewed to ensure the relevance of the paper, avoid duplication, and include only RCTs, thus narrowing the search down to 100 papers after primary screening. These papers were all reviewed fully and 35 articles were included in the meta-analysis. Any disagreements between the two authors were resolved by the help of a third author (H.A). PRISMA guidelines were followed and the literature screening process is summarised in Fig. 1 . The Inclusion Criteria of the studies were: 1- RCTs only included 2- English language studies 3- Studies where BT injection was the sole procedure 4- Studies with multiple arms where the data relevant to BT injection could be extracted separately. The exclusion criteria of the studies were: 1- Any publication that was not an RCT, non-relevant papers, and studies published in languages other than English 2- Studies in which BT injection was combined with another procedure 3- Studies with multiple arms where the data relevant to BT injection could not be extracted in isolation. Data Extraction and Quality Assessment: A data collection sheet on Microsoft Excel was created for comprehensive outcomes and variables. Microsoft Excel was chosen due to the author's familiarity with the software. The authors documented study details such as first author, publication year, sample size, the proportion of anal fissure healing after the first and second injection, and all reported complications. The analysis utilized Open Meta Analyst v5.26.14, and the quality of RCTs was assessed using Cochrane’s Handbook for Systematic Reviews. A traffic plot was made to assess the bias in the studies using the RobVis 2.0 tool. Outcomes and Statistical Analysis: The primary outcome of efficacy was fissure healing (overall response) after the first BT injection. The secondary outcome of efficacy was the incidence of BT re-injection. The outcome of safety was all reported complications of BT injection. A meta-analysis of proportions was conducted for all outcomes. A binary random effects model was applied. The Freeman-Tukey double arcsine transformation was applied to stabilize variances of raw proportions. The transformed proportions were pooled using a random effects model with the DerSimonian Laird method. The pooled estimates were then back-transformed. Heterogeneity was assessed using the I2 statistics, with substantial heterogeneity being defined as I2 greater than 50%. Results After applying the inclusion and exclusion criteria, 35 RCTs were identified, and data was extracted and analyzed. There were 1532 patients (759 males and 773 females), aged 16–80. The quantity of BT injected varied from 20–100 IU when Botox® was used, 90–100 IU when Dysport® was used, 20–50 IU when Neuronox® was used and one study used Syposrt® 100 IU. All the above formulations are pharmacologically equivalent therefore, for this analysis, all the above have been treated as BT injections. There was variability in the aspects of the BT injection procedure as well. 32 studies reported injecting the BT into the Internal Anal Sphincter (IAS), 2 studies into the fissure edges and one study reported injection into the External Anal Sphincter (EAS). In 29 studies BT was injected into either side of the anal fissure, 4 studies reported injection at the 3 and 9 o’clock positions, 1 study injected into a single 9 o’clock position, and 1 study injected into 4 positions at 1, 5, 7, and 11 o’clock. The follow-up period in these studies varied from 2 to 60 months. Outcomes of Efficacy: Primary Outcome: The primary outcome measure of fissure healing (overall response) after the first BT injection is summarized in Table 1 . As can be seen, the healing rate ranged from 18.92–100%. 21 out of the 35 studies included reported statistically significant results whereas in 14 studies there was no statistically significant difference. Analysis using a random effect model showed that healing was observed in 1,117 patients out of 1532, with a proportion of 0.727, 95% CI = 0.673–0.781, p < 0.001, I2 = 86.6%. Substantial heterogeneity was noted (I2 = 86.6%) and a subgroup analysis was performed to combat heterogeneity. Studies were divided into 3 subgroups based on either a follow-up period of up to 6 months, 6 to 12 months, or more than 12 months. However, even after the subgroup analysis, the data showed significant heterogeneity. This data is depicted as a funnel plot (Fig. 2 ) and a Forest plot (Fig. 3). The funnel plot showed minimal publication bias. Table 1 Pooled analysis for overall response after first injection Study Total Positive cases Percent 95% CI z-value p-value 1 Nour H., et al.,2020 (10) 48 37 77.08 62.69 to 87.97 3.753 0.0001 2 Pilkington SA et al.,2018(11) 100 58 58 47.71 to 67.80 1.6 0.11 3 Iqbal Z.,et al.,2016 (12) 198 166 83.84 77.96 to 88.68 9.523 0.0001 4 Gandomkar H,et al.,2015(13) 49 37 75.51 61.13 to 86.66 3.571 0.0003 5 Ahmad M.S.,et al.,2014 (14) 50 40 80 66.28 to 89.97 4.243 0.0001 6 Asim M,et al.,2014 (15) 41 24 58.54 42.11 to 73.68 1.093 0.27 7 Berkel AE,et al.,2014 (16) 27 18 66.67 46.04 to 83.48 1.732 0.083 8 Karabulut Z., et al.,2012 (17) 20 18 90 68.30 to 98.77 3.578 0.0003 9 Valizadeh N,et al.,2012 (18) 25 12 48 27.8 to 68.7 -0.2 0.84 10 Samim M,et al.,2012 (19) 60 49 81.67 69.56 to 90.48 4.906 0.0001 11 Witte ME,. et al.,2010 (20) 21 19 90.48 69.62 to 98.83 1.147 0.25 12 Nasr M,et al.,2010 (21) 40 32 80 64.35 to 90.95 3.795 0.0001 13 Othman I. et al.,2010 (22) 40 35 87.5 73.2 to 95.81 4.743 0.0001 14 Mehrotra S. et al.,2009 (23) 30 28 93.33 77.93 to 99.18 4.747 0.0001 15 Abd Elhady HM,et al.,2009(24) 40 19 47.5 31.51 to 63.87 -0.32 0.75 16 Festen S, et al.,2009 (25) 37 7 18.92 7.96 to 35.16 -3.78 0.0002 17 Algaithy ZK. et al.,2008 (26) 50 43 86 73.26 to 94.18 5.091 0.0001 18 Brisinda G;et al.,2007 (27) 50 46 92 80.77 to 97.78 5.94 0.0001 19 Jones OM,et al.,2006 (28) 30 23 76.67 57.72 to 90.07 2.921 0.003 20 Fruehauf H,et al.,2006 (29) 25 16 64 42.52 to 82.03 1.4 0.16 21 De Nardi P,et al.,2006 (30) 30 11 36.67 19.93 to 56.14 -1.46 0.14 22 Massoud BW,et al.,2005 (31) 25 20 80 59.3 to 93.15 3 0.003 23 Arroyo Sebastian A,et al.,2005 (32) 100 48 48 37.90 to 58.22 -0.4 0.69 24 Iswariah H,et al.,2005 (33) 17 8 47.06 22.98 to 72.19 -0.24 0.81 25 Brisinda G; et al.,2004 (34) 100 93 93 86.11 to 97.14 8.6 0.0001 26 Roka S.,et al.,2004 (35) 21 18 85.71 63.66 to 96.95 3.273 0.001 27 Siproudhis L,et al.,2003 (36) 20 10 50 27.2 to 72.80 0 0.99 28 Mentes BB, et al.,2003 (37) 61 46 75.41 62.71 to 85.54 3.969 0.0001 29 Madalinski MH,et al.,2002 (38) 96 96 100 96.23 to 100 9.798 0.0001 30 Wollina U, et al.,2002 (39) 10 8 80 44.39 to 97.48 1.897 0.057 31 Colak T,et al.,2002 (40) 34 24 70.59 52.52 to 84.90 2.401 0.016 32 Lysy J,et al.,2001 (41) 30 19 63.33 43.86 to 80.07 1.461 0.14 33 Maria G,et al.,2000 (42) 50 37 74 59.66 to 85.37 3.394 0.0006 34 Brisinda G, et al.,1999 (43) 25 24 96 79.65 to 99.9 4.6 0.0001 35 Maria G,et al.,1998 (44) 15 11 73.33 44.90 to 92.21 1.807 0.07 Overall effect: 1532 1117 72.7% 67.3 to 78.1 19.53 < 0.001 Secondary Outcome: The secondary outcome of efficacy was the response to repeat BT injection in patients who did not respond to the initial injection. 8 out of the 35 studies reported that a second BT injection was administered to patients who did not respond after the first injection. As shown in Table 2 , the pooled analysis showed that the response after repeated injection was achieved in 29 out of 38 patients, (proportion = 0.785, 95% CI = 0.626 to 0.945, p < 0.001, I2 = 50.97%). A moderate level of heterogeneity was observed and this was dealt with by making sub-groups based on the periods of follow-up. The studies were divided into three subgroups i.e. studies with follow-up periods of up to 6 months, up to 12 months, and more than 12 months. This decreased the heterogeneity significantly. Moreover, it was also seen that most of the studies that involved the outcome of repeated injections had a follow-up of more than 12 months. Statistical methodology as described above showed an overall efficacy of 73.19% after the second injection achieving statistical significance (P < 0.0001). No funnel plot was made because the number of studies included was less than 10 and the forest plot is depicted in Fig. 4 . Table 2 Meta-analysis for response after repeated injection Study Total Positive cases Proportion 95% CI z-value p-value Pilkington SA,et al.,2018 (11) 12 5 0.417 15.17 to 72.33 -0.57 0.56 Karabulut Z., et al.,2012(17) 2 2 100 15.81 to 100 1.414 0.157 Othman I. et al.,2010 (22) 3 3 100 29.24 to 100 1.732 0.08 Brisinda G, et al.,2007 (27) 4 4 100 39.76 to 100 2 0.045 Iswariah H,et al.,2005 (33) 1 1 100 2.50 to 100 1 0.317 Mentes BB,et al.,2003 (37) 10 10 100 69.15 to 100 3.162 0.001 Maria G, et al.,1998 (44) 4 2 50 6.76 to 93.24 0 0.99 Mehrotra S. et al.,2009 (23) 2 2 0.945 15.81 to 100 1.414 0.157 Overall effect 38 29 0.785 0.626 to 0.945 9.674 < 0.001 The outcome of Safety: Safety was assessed by the number of reported complications in the patients. Table 3 shows the different complications reported in the patients in the included studies. Table 3 Summary of reported complications Complication Number of patients Percentage % Incontinence to flatus 78 (4.8%), 70 4.8% Incontinence to faeces 10 (0.6%) 10 0.6% Anal haematoma 17 (1%), 17 1% Thrombosed Haemorrhoids 4 (0.2%) 4 0.2% Flu-like symptoms 5 (0.3%) 5 0.3% Epididymitis 2 (0.12%), 2 0.12% Protrusion of hemorrhoids 2(0.12%) 2 0.12% Perianal itching 2(0.12%) 2 0.12% Fistula in ano 3 (0.18%). 3 0.18% The data showed that there was a wide variation in the reported complication rate ranging from 0% to 27% as depicted in Table 4. Upon pooling the data, complications were reported in 88 out of 1532, with a proportion of 0.042, 95% CI= 0.028 – 0.055, p<0.001, and I2=60.27%. The results showed significant heterogeneity and thus a subgroup analysis was performed with the studies divided into 3 subgroups based on the period of follow-up. These subgroups were studies with a follow-up period of up to 6 months, 6 to 12 months, or more than 12 months. This significantly decreased the heterogeneity especially in the subgroups with 6 and 12 months follow-up. There was still significant heterogeneity in the group with more than 12 months follow-up period and it can be attributed to the wide range (from 18 to 60 months) of follow-up periods pooled in that subgroup. The funnel and forest plots are shown in Figures 5 and 6 respectively. The funnel plot showed minimal publication bias. Table 4 Pooled analysis for all reported complications Study Total Complications Percent 95% CI z-value p-value 1 Nour H., et al.,2020 (10) 48 8 16.67 7.48 to 30.22 4.62 0.0001 2 Pilkington SA et al.,2018(11) 100 3 3 0.62 to 8.52 -9.4 0.0001 3 Iqbal Z.,et al.,2016 (12) 198 0 0 0.00 to 1.85 -14.07 0.0001 4 Gandomkar H,et al.,2015(13) 49 2 4.08 0.5 to 13.98 -6.429 0.0001 5 Ahmad M.S.,et al.,2014(14) 41 3 7.32 1.54 to 19.93 -5.466 0.0001 6 Asim M,et al.,2014 (15) 27 3 11.11 2.35 to 29.16 -4.041 0.0001 7 Berkel AE,et al.,2014 (16) 50 3 6 1.26 to 16.55 -6.223 0.0001 8 Karabulut Z., et al.,2012 (17) 20 1 5 0.13 to 24.87 -4.025 0.0001 9 Valizadeh N,et al.,2012 (18) 25 3 12 2.55 to 31.22 -3.8 0.0001 10 Samim M,et al.,2012 (19) 60 3 5 1.04 to 13.92 -6.971 0.0001 11 Witte ME,. et al.,2010 (20) 40 4 10 2.79 to 23.66 -5.06 0.0001 12 Nasr M,et al.,2010 (21) 40 0 0 0.00 to 8.81 -6.325 0.0001 13 Othman I. et al.,2010 (22) 21 2 9.52 1.18 to 30.38 -3.71 0.0002 14 Mehrotra S. et al.,2009 (23) 30 1 3.33 0.08 to 17.22 -5.112 0.0001 15 Abd Elhady HM,et al.,2009(24) 40 3 7.5 1.57 to 20.39 -5.376 0.0001 16 Festen S, et al.,2009 (25) 37 1 2.7 0.07 to 14.16 -5.754 0.0001 17 Algaithy ZK. et al.,2008 (26) 50 10 20 10.03 to 33.7 -4.243 0.0001 18 Brisinda G;et al.,2007 (27) 50 3 6 1.26 to 16.55 -6.223 0.0001 19 Jones OM,et al.,2006 (28) 25 1 4 0.10 to 20.35 -4.6 0.0001 20 Fruehauf H,et al.,2006 (29) 30 6 20 7.71 to 38.57 -3.286 0.001 21 De Nardi P,et al.,2006 (30) 30 0 0 0.00 to 11.57 -5.477 0.0001 22 Massoud BW,et al.,2005 (31) 25 0 0 0.00 to 13.72 -5 0.0001 23 Arroyo Sebastian A,et al.,2005 (32) 17 2 11.77 1.46 to 36.44 -3.153 0.001 24 Iswariah H,et al.,2005 (33) 100 11 11 5.62 to 18.83 -7.8 0.0001 25 Brisinda G; et al.,2004 (34) 21 2 9.52 1.18 to 30.38 -3.71 0.0002 26 Roka S.,et al.,2004 (35) 100 19 19 11.84 to 28.1 -6.2 0.0001 27 Siproudhis L,et al.,2003 (36) 61 0 0 0.00 to 5.87 -7.81 0.0001 28 Mentes BB, et al.,2003 (37) 20 0 0 0.00 to 16.84 -4.472 0.0001 29 Madalinski MH,et al.,2002 (38) 10 1 10 0.25 to 44.50 -2.53 0.011 30 Wollina U, et al.,2002 (39) 34 0 0 0.00 to 10.28 -5.831 0.0001 31 Colak T,et al.,2002 (40) 96 26 27.08 18.52 to 37.11 -4.491 0.0001 32 Lysy J,et al.,2001 (41) 30 0 0 0.00 to 11.57 -5.477 0.0001 33 Maria G,et al.,2000 (42) 50 0 0 0.00 to 7.11 -7.071 0.0001 34 Brisinda G, et al.,1999 (43) 25 0 0 0.00 to 13.72 -5 0.0001 35 Maria G,et al.,1998 (44) 15 0 0 0.00 to 21.80 -3.873 0.0001 Risk of Bias: The risk of bias was assessed using the Cochrane’s handbook for systemic reviews and a traffic plot was created using the Robvis visualisation tool. The traffic plot is shown in Fig. 7 . It assesses the risk of bias in RCTs on 5 domains i.e. selection (D1), performance (D2), detection (D3), attrition (D4), and reporting (D5). The assessment showed a high risk of bias in the studies Pilkington et al ( 11 ), Berkel et al ( 16 ), Valizadeh et al ( 18 ), Abd el Hady et al ( 24 ), Festen et al ( 25 ), Jones OM et al ( 28 ), De Nardi et al ( 30 ), Brisinda G et al ( 34 ), Roka S et al ( 35 ), Siproudhis et al ( 36 ), Madalinski et al ( 38 ), and Brisinda G et al ( 43 ). This can account for the high amounts of heterogeneity present in the results as well. Discussion This study presents a comprehensive review of all published RCTs involving BT injection as a treatment option for anal fissure. A recent systematic review conducted by Poland et al. ( 45 ) included a total of 775 patients of which the Botox injection arm included 132 patients. The study compared the outcomes of different modalities of treatment of anal fissure. At 8 weeks, healing rates were 95.13% in those treated with sphincterotomy, 66.7% in the botulinum toxin group, 63.8% in the nitrate group, 52.3% for topical diltiazem and 50% for topical minoxidil. There was a risk of permanent incontinence with sphincterotomy (2.3%). In our meta-analysis, the success following a single BT injection was pooled to be 72.7% and thus, the Botox arm results of this systematic review are similar to our results. The risk of permanent incontinence with sphincterotomy emphasizes the need for a ladder approach in the management of anal fissures starting with the least invasive options of topical applications first, then BT injections, and reserving the operative solutions for the last. The heterogeneity in the groups for the outcome of efficacy (overall response after the first BT injection) can be attributed to the different follow-up periods of the study. The studies had a follow-up period ranging from 2 months in Colak et al ( 40 ) to 60 months in Abd El Hady et al ( 24 ). Subgroups were made to combat the heterogeneity however they did not provide satisfactory results. Another possible reason for heterogeneity could be the different doses used in each study. The dose of BT injection used ranged from 20 IU to 100 IU. Such differences in studies can impact significant heterogeneity in the results. Festen et al ( 25 ) used a dose of 20 mg and reported results in only 14 out of 37 patients, whereas Othman et al ( 22 ) used 80 mg and showed a response in 35 out of 40 patients. However, subgroup analysis by stratifying data based on follow-up yielded better results than stratifying on doses (especially for the outcome of safety). Moreover, some of the studies had a high risk of bias as well and thus, they can also contribute to the heterogeneity. Overall, the pooled analysis showed that BT injection is an efficacious method for treatment of chronic anal fissures. Pilkington et al. ( 11 ) reported an RCT conducted to compare unilateral with bilateral BT injections. In the group who failed to have a resolution of their symptoms after the first injection, twelve patients had repeat BT injections administered in the same manner as their initial randomization: 5 in the bilateral injection group and 7 in the unilateral group. The healing rate after repeat BT was 2/5 (40%) in the bilateral group and 3/7 (43%) in the unilateral group, overall 5/12 (41.6%). This evidence seems to suggest that the site of injection or whether the injection was unilateral or bilateral appears to have very little impact on the effectiveness of this treatment. However, other studies such as Othman et al ( 22 ) and Brisinda G ( 27 ) showed a 100% success rate in patients having repeat injections. The meta-analysis presented here included 38 patients who had a repeat BT injection reported through 5 different studies with an overall healing of 78.5%. This result lies between that reported by Pilkington et al and Othman et al/Brisinda et al. A possible explanation for this could be the period of follow-up. Amongst the included studies, only Pilkington ( 11 ) had a significantly decreased efficacy of repeat BT injection This could be attributed to the type of BT injection used. Other studies such as Othman et al ( 22 ) used Botox, but Pilkington ( 11 ) used Dysport or Syposrt. The data seems to suggest that a repeat injection may be beneficial before proceeding with surgical alternatives. There is some variability in the perception and reporting of complications following BT injection. Madaliński et al., ( 38 ) presented their experience of complications after BT in 105 chronic anal fissure patients in 2002. They reported incontinence to flatus 5%, incontinence to feces 2.8%, anal hematoma 2.8% thrombosed hemorrhoids 1.1% flu-like symptoms 1.7% epididymitis 0.5%, and protrusion of hemorrhoids 0.5%. This is almost certainly due to reporting bias as most of these side effects are only temporary and require little active intervention. Our meta-analysis has shown complications in only 88 out of 1532 (4.2%) of the patients and it is a lower incidence than some of the studies. Studies with 6 and 12-month follow-up periods showed a lower incidence of complications (2.1% and 2.5% respectively), however, studies with a follow-up period of more than 12 months showed a higher rate (8.9%) and heterogeneity amongst complications. Thus, it is logical to conclude that with increased time, there is an increased time of developing complications. This is further solidified by the results of studies like Al Gaithy et al ( 26 ) and Roka et al ( 35 ) with complications occurring in 20% and 19% of patients respectively and follow-up times of 24 months. This coupled with the increased rate of repeat injection in studies with longer follow-up periods ( 22 , 27 , 33 , 44 ) reinforces the fact that even though BT injection is a suitable first-line, minimally invasive treatment option, it should be augmented with repeat injection after sufficient time. However, for a definite and permanent solution, other treatment options might be considered. Moreover, recently, the efficacy of BT injection is superior to nifedipine with lignocaine and anal dilation as well, thus further reinforcing its use for the treatment of chronic anal fissures ( 47 ). However, every article is bound by some limitations. A meta-analysis is only as good as the studies included in it and some of the studies included in this analysis showed a high risk of bias and were not as robust. This affects the results and has resulted in significant heterogeneity, especially in the primary outcome of efficacy. Moreover, broad inclusion criteria which included all drug types of BT injection can affect the results. Lastly, this meta-analysis also suffers from a low publication bias in the outcome of efficacy. Conclusion BT injection for chronic anal fissures is an effective, safe, and less invasive treatment option for chronic anal fissures, and offering a repeat injection for recurrent/ persistent symptoms after the first injection can lead to very good results. Declarations Acknowledgements: The authors would like to acknowledge the authors of the original studies and their participants. Funding: No external funding was provided for this article. Conflicts of Interest: The authors have no conflicts of interest to disclose. Ethical Statement: Since this is a review article, no ethical approval is required. Data availability Statement: Data is provided within the supplementary information files. Author Contribution: K.M.T: Data collection, Data analysis and manuscript preparation M.G: Data Collection H.A: Statistical analysis of data M.A.D: Project supervision, review of results, and manuscript preparation. References Kodner IJ, Fry RD, Fleshman JW, Birnbaum EH, Read TE. Colon, Rectum, and Anus. In: Schwartz Seymour I, et al., editors. Principles of Surgery. 7th ed. Mac Grow-Hill: 1999. pp. 1265–1382. PMID: 17604520 Cook TA, Brading AF, Mortensen NJ. The pharmacology of the internal anal sphincter and new treatments of anorectal disorders. Aliment Pharmacol Ther. 2001;15:887–898. DOI: 10.1046/j.1365-2036.2001.00995. Beck DE, Timmcke AE. Pruritus ani and fissure-in-ano. In: Beck DE, editor. Handbook of Colorectal Surgery. 2nd ed. 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Medical Journal Armed Forces India. 65 (3) (pp 213-215), 2009. DOI: 10.1016/S0377-1237(09)80005-1 Abd Elhady HM; Othman IH; Hablus MA; Ismail TA; Aboryia MH; Selim MF. Long-term prospective randomized clinical and manometric comparison between surgical and chemical sphincterotomy for treatment of chronic anal fissure. South African Journal of Surgery. 47(4):112-4, 2009 Nov. PMID: 20141067 Festen S; Gisbertz SS; van Schaagen F; Gerhards MF. Blinded randomized clinical trial of botulinum toxin versus isosorbide dinitrate ointment for treatment of anal fissure. British Journal of Surgery. 96(12):1393-9, 2009 Dec. DOI: 10.1111/codi.12615 Algaithy ZK. Botulinum toxin versus surgical sphincterotomy in females with chronic anal fissure. Saudi Medical Journal. 29(9):1260-3, 2008 Sep. PMID: 18813408 Brisinda G; Cadeddu F; Bandara F; Marniga G; Maria G. Randomized clinical trial comparing botulinum toxin injections with 0.2 percent nitroglycerin ointment for chronic anal fissure. British Journal of Surgery. 94(2):162- 2007Feb. https://doi.org/10.1002/bjs.5514 Jones OM; Ramalingam T; Merrie A; Cunningham C; George BD; Mortensen NJ; Lindsey I. Randomized clinical trial of botulinum toxin plus glyceryl trinitrate vs. botulinum toxin alone for medically resistant chronic anal fissure: overall poor healing rates. Diseases of the Colon and rectum. 49(10):1574-80, 2006 Oct. DOI: 10.1007/s10350-006-0679-y Fruehauf H; Fried M; Wegmueller B; Bauerfeind P; Thumshirn M. Efficacy and safety of botulinum toxin injection compared with topical nitroglycerin ointment for the treatment of chronic anal fissure: a prospective randomized study. American Journal of Gastroenterology. 101(9):2107-12, 2006 Sep. DOI: 10.1111/j.1572-0241.2006.00722.x De Nardi P; Ortolano E; Radaelli G; Staudacher C. Comparison of glycerine trinitrate and botulinum toxin-a for the treatment of chronic anal fissure: long-term results. Diseases of the Colon and rectum. 49(4):427-32, 2006 Apr. DOI: 10.1007/s10350-005-0287-2 Massoud BW; Mehrdad V; Baharak T; Alireza Z. Botulinum toxin injection versus internal anal sphincterotomy for the treatment of chronic anal fissure. Annals of Saudi Medicine. 25(2):140-2, 2005 Mar-Apr. doi: 10.5144/0256-4947.2005.140 Arroyo Sebastian A; Perez Vicente F; Miranda Tauler E; Sanchez Romero A; Serrano Paz P; Calpena Rico R. Surgical (close lateral internal sphincterotomy) versus chemical (botulinum toxin) sphincterotomy as treatment of chronic anal fissure. Medicina Clinica. 124(15):573-5, 2005 Apr 23. Iswariah H; Stephens J; Rieger N; Rodda D; Hewett P. Randomized prospective controlled trial of lateral internal sphincterotomy versus injection of botulinum toxin for the treatment of idiopathic fissure in ano. ANZ Journal of Surgery. 75(7):553-5, 2005 Jul. https://doi.org/10.1111/j.1445-2197.2005.03427.x Brisinda G; Albanese A; Cadeddu F; Bentivoglio AR; Mabisombi A; Marniga G; Maria G. Botulinum neurotoxin to treat chronic anal fissure: results of a randomized "Botox vs. Dysport" controlled trial. Alimentary Pharmacology & Therapeutics. 19(6):695-701, 2004 Mar 15. doi: 10.3748/wjg.v18.i10.1021 Roka S., Langer F., Salat A., Jakesz R., Herbst F. Treatment of chronic anal fissure by injection of botulinum toxin A. European Surgery - Acta Chirurgica Austriaca. 36 (2) (pp 97-99), 2004. Date of Publication: April 2004. https://www.springermedizin.at/treatment-of-chronic-anal-fissure-by-injection-of-botulinum-toxi/14923488 Siproudhis L; Sebille V; Pigot F; Hemery P; Juguet F; Bellissant E. Lack of efficacy of botulinum toxin in chronic anal fissure. Alimentary Pharmacology & Therapeutics. 18(5):515-24, 2003 Sep 01. https://doi.org/10.1046/j.1365-2036.2003.01467.x Mentes BB; Irkorucu O; Akin M; Leventoglu S; Tatlicioglu E. Comparison of botulinum toxin injection and lateral internal sphincterotomy for the treatment of chronic anal fissure. Diseases of the Colon and rectum. 46(2):232-7, 2003 Feb. DOI: 10.1097/01.DCR.0000044712.58674.09 Madalinski MH; Slawek J; Duzynski W; Zbytek B; Jagiello K; Adrich Z; Kryszewski A. Side effects of botulinum toxin injection for benign anal disorders. European Journal of Gastroenterology & Hepatology. 14(8):853-6, 2002 Aug. DOI: 10.1097/00042737-200208000-00007 Wollina U; Konrad H. Botulinum toxin A in anal fissures: a modified technique. Journal of the European Academy of Dermatology & Venereology. 16(5):469-71, 2002 Sep. doi: 10.1046/j.1468-3083.2002.00490.x. Colak T; Ipek T; Kanik A; Aydin S. A randomized trial of botulinum toxin vs lidocaine pomade for chronic anal fissure. Acta Gastroenterologica Belgica. 65(4):187-90, 2002 Oct-Dec. PMID: 12619423 Lysy J; Israelit-Yatzkan Y; Sestiery-Ittah M; Weksler-Zangen S; Keret D; Goldin E. Topical nitrates potentiate the effect of botulinum toxin in the treatment of patients with refractory anal fissure. Gut. 48(2):221-4, 2001 Feb. doi: 10.1136/gut.48.2.221 Maria G; Brisinda G; Bentivoglio AR; Cassetta E; Gui D; Albanese A. Influence of botulinum toxin site of injections on healing rate in patients with chronic anal fissure. American Journal of Surgery. 179(1):46-50, 2000 Jan. DOI: 10.1016/s0002-9610(99)00255-x Brisinda G; Maria G; Bentivoglio AR; Cassetta E; Gui D; Albanese A. A comparison of injections of botulinum toxin and topical nitroglycerin ointment for the treatment of chronic anal fissure. New England Journal of Medicine. 341(2):65-9, 1999 Jul 08. DOI: 10.1056/NEJM199907083410201 Maria G; Brisinda G; Bentivoglio AR; Cassetta E; Gui D; Albanese A. Botulinum toxin injections in the internal anal sphincter for the treatment of chronic anal fissure: long-term results after two different dosage regimens. Annals of Surgery. 228(5):664-9, 1998 Nov. DOI: 10.1097/00000658-199811000-00005 P A Boland 1, M E Kelly 2, N E Donlon 2, J C Bolger 2, J O Larkin 2, B J Mehigan 2, P H McCormick 2, Management options for chronic anal fissure: a systematic review of randomized controlled trials. Int J Colorectal Dis 2020 Oct;35(10):1807-1815. DOI: 10.1007/s00384-020-03699-4 Brisinda G, Bianco G, Silvestrini N, Maria G. Cost considerations in the treatment of anal fissures. Expert Rev Pharmacoecon Outcomes Res. 2014;14(4):511–525. DOI: 10.1586/14737167.2014.924398 Andreevski V, Volkanovska A, Deriban G, Josifovic FL, Krstevski G, Nikolova D, et al. The value of injection therapy with botulinum toxin in pain treatment of primary chronic anal fissures compared to anal dilation, and local nifedipine in combination with lidocaine. Pril (Makedon Akad Nauk Umet Odd Med Nauki);44(2):89–97. DOI :10.2478/prilozi-2023-0029 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 09 Jan, 2025 Read the published version in Techniques in Coloproctology → Version 1 posted Editorial decision: Revision requested 08 Jun, 2024 Reviews received at journal 02 Jun, 2024 Reviewers agreed at journal 03 Apr, 2024 Reviews received at journal 10 Mar, 2024 Reviewers agreed at journal 09 Feb, 2024 Reviewers invited by journal 09 Feb, 2024 Editor assigned by journal 09 Feb, 2024 Submission checks completed at journal 25 Jan, 2024 First submitted to journal 22 Jan, 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3889351","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":269166785,"identity":"cee34d7b-d33c-4615-9157-eb475424115a","order_by":0,"name":"Kumarswamy Maradi Thippeswamy","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6klEQVRIiWNgGAWjYBACCRTeByBmYydBC2PjDJAWZlK0NPOAKEJaJGdkJ36u+HNYXndGdvpjm1/b5PmYGRg/fMzBrUVaInez5Nm2w4bbbuRubM7tu23YxszALDlzG24tchK5GyQbG24zQrT03GYEamFj5sWvZfPPhj+37cFaLHtu2xPUAnTYNskGttuJYC0MP24nEtQi2fN2m2Vj2//kbWfebpzZ23A7uY2ZsRmvXySO526+2fAnzXbb8dwNH378uW07v7354IePeLQggEACMGbaQCzGBmLUAwH/ASDxh0jFo2AUjIJRMKIAAHSiWYoymplWAAAAAElFTkSuQmCC","orcid":"","institution":"Prince Charles Hospital","correspondingAuthor":true,"prefix":"","firstName":"Kumarswamy","middleName":"Maradi","lastName":"Thippeswamy","suffix":""},{"id":269166786,"identity":"0247948a-c653-4d06-98a6-8d343c0b3864","order_by":1,"name":"Mei-yin Gruber","email":"","orcid":"","institution":"Prince Charles 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2","display":"","copyAsset":false,"role":"figure","size":32485,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFunnel plot for an overall response after the first injection\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-3889351/v1/ed7cefbd0393db8e105d1083.png"},{"id":50328530,"identity":"501e88d4-5ad9-4f42-8adb-8ee81b1ec551","added_by":"auto","created_at":"2024-01-29 20:54:14","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":69070,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plot for an overall response after the first injection\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-3889351/v1/6df64983aa4d1ba8a743357b.png"},{"id":50328529,"identity":"e6d07b11-5227-4061-b456-75bd5ddfc831","added_by":"auto","created_at":"2024-01-29 20:54:14","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":26688,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plot for response after repeated injection\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-3889351/v1/e594750222192356ec815dec.png"},{"id":50328322,"identity":"94e2d014-bdd1-4707-9a16-87bb214fc55c","added_by":"auto","created_at":"2024-01-29 20:46:14","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":7171,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFunnel plot for all reported complications\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Onlinefloatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-3889351/v1/02992f6af73d4f0817fc7283.png"},{"id":50328324,"identity":"458dddfb-e72f-44ca-9bc7-9ad6c922899b","added_by":"auto","created_at":"2024-01-29 20:46:14","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":65406,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plot for all reported complications\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-3889351/v1/ab44dcb92b17d3abb929d5b5.png"},{"id":50328321,"identity":"6c3808c2-1d74-4c08-ae07-cb89c668c6c3","added_by":"auto","created_at":"2024-01-29 20:46:14","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":304192,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTraffic plot showing the risk of bias in included studies\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-3889351/v1/2ddd4c4f4c57e3cf919a06c9.png"},{"id":73694266,"identity":"b774cd85-a846-429d-b305-5ad0031db8b4","added_by":"auto","created_at":"2025-01-13 16:12:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2235005,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3889351/v1/05793a72-66b9-4b16-9a41-8282df8ab74f.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy and Safety of Botulinum Toxin Injection in the Management of Chronic Symptomatic Anal Fissure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials","fulltext":[{"header":"What does this paper add to the literature?","content":"\u003cp\u003eThis study presents a comprehensive review of all published RCTs involving Botulinum Toxin A (BT) injection as a treatment option for anal fissure. It concluded the overall efficacy and safety of BT injection for anal fissure management together with looking at BT re-injection justification and efficacy.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eThe most common cause of severe anal pain in adults is anal fissures. There are various management options available for patients suffering from it. These options include topical nitrites, and calcium channel blockers as the conventional pharmacological treatment. Botulinum toxin injection can also be used and sphincterotomy is the most common surgical management option (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Recamier first described it in 1829 and recommended stretching the anal sphincter to treat anal fissures (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Peter Lord later popularized this procedure which is commonly known as Lord\u0026rsquo;s anal dilatation.\u003c/p\u003e \u003cp\u003eThe main pathology of chronic anal fissures is the spasm of internal anal sphincter (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Therefore, the main goal of treatment of this condition is to reduce the internal sphincter hypertonia. (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) Lateral internal sphincterotomy is the most frequently performed surgical procedure for treating chronic anal fissures resulting in a healing rate of 90 to 95% (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). It works by reducing the sphincter hypertonia which is the main etiological factor in the development of chronic anal fissures (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). However, it may cause minor but permanent incontinence (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Several therapeutic alternatives were proposed to reduce anal pressure leaving the sphincter ring intact to avoid incontinence (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). These therapeutic alternatives include CCB (diltiazem and nifedipine) and nitrites (nitroglycerin and nitrous oxide). Both of these classes of drugs act by relaxing the internal anal sphincter (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). There have been fewer reports of side effects with topical CCB or nitrites with the most common side effect being headache, however, their use is limited due to increased recurrence and lower efficacy than sphincterotomy and botulinum toxin (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Botulinum toxin A (BT) injection in the internal sphincter muscle has become an acceptable alternative to internal anal sphincterotomy (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). It eliminates the spasm of the internal anal sphincter temporarily by blockage of neurotransmission without internal anal sphincter muscle disruption (chemical sphincterotomy) (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Botulinum toxin has been preferred in some cases due to its higher efficacy despite being a minimally invasive procedure (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Possible side effects of using botulinum toxin include a small amount of anal bleeding up to 24 hours following the procedure. Other side effects can include mild flu-like symptoms, body aches, or headaches. Moreover, some of the patients also reported an increase in passing gas (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDespite years of research, there is still no common agreement on one single method for the treatment of anal fissures. Botulinum toxin and sphincterotomy are the two most efficacious methods to date. Sphincterotomy is routinely practiced, however, there has been increasing literature on the use of botulinum toxin for anal fissures. However, there have been contradicting views on its use and the literature has shown varying reports regarding its efficacy and safety.\u003c/p\u003e\n\u003ch3\u003eAims\u003c/h3\u003e\n\u003cp\u003eThus, this meta-analysis aims to assess the efficacy and safety of BT injection in the management of symptomatic chronic anal fissure through a systematic literature review and meta-analysis of published Randomised Controlled Trials (RCTs)\u003c/p\u003e"},{"header":"Methodology","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eSearch Strategy and Study Selection:\u003c/h2\u003e \u003cp\u003eA systematic search was conducted using the Embase and Medline search platforms in December 2023. The search included all MeSH and entry terms related anal fissures and botulinum toxin. No time filters were applied. The search included all publications between January 1974 to September 2020. Two authors (K.M.T and M.G) identified 264 published papers from the initial search. All abstracts were reviewed to ensure the relevance of the paper, avoid duplication, and include only RCTs, thus narrowing the search down to 100 papers after primary screening. These papers were all reviewed fully and 35 articles were included in the meta-analysis. Any disagreements between the two authors were resolved by the help of a third author (H.A). PRISMA guidelines were followed and the literature screening process is summarised in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eThe Inclusion Criteria of the studies were:\u003c/p\u003e \u003cp\u003e1- RCTs only included\u003c/p\u003e \u003cp\u003e2- English language studies\u003c/p\u003e \u003cp\u003e3- Studies where BT injection was the sole procedure\u003c/p\u003e \u003cp\u003e4- Studies with multiple arms where the data relevant to BT injection could be extracted separately.\u003c/p\u003e \u003cp\u003eThe exclusion criteria of the studies were:\u003c/p\u003e \u003cp\u003e1- Any publication that was not an RCT, non-relevant papers, and studies published in languages other than English\u003c/p\u003e \u003cp\u003e2- Studies in which BT injection was combined with another procedure\u003c/p\u003e \u003cp\u003e3- Studies with multiple arms where the data relevant to BT injection could not be extracted in isolation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData Extraction and Quality Assessment:\u003c/h2\u003e \u003cp\u003eA data collection sheet on Microsoft Excel was created for comprehensive outcomes and variables. Microsoft Excel was chosen due to the author's familiarity with the software. The authors documented study details such as first author, publication year, sample size, the proportion of anal fissure healing after the first and second injection, and all reported complications. The analysis utilized Open Meta Analyst v5.26.14, and the quality of RCTs was assessed using Cochrane\u0026rsquo;s Handbook for Systematic Reviews. A traffic plot was made to assess the bias in the studies using the RobVis 2.0 tool.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes and Statistical Analysis:\u003c/h2\u003e \u003cp\u003eThe primary outcome of efficacy was fissure healing (overall response) after the first BT injection. The secondary outcome of efficacy was the incidence of BT re-injection. The outcome of safety was all reported complications of BT injection. A meta-analysis of proportions was conducted for all outcomes. A binary random effects model was applied. The Freeman-Tukey double arcsine transformation was applied to stabilize variances of raw proportions. The transformed proportions were pooled using a random effects model with the DerSimonian Laird method. The pooled estimates were then back-transformed. Heterogeneity was assessed using the I2 statistics, with substantial heterogeneity being defined as I2 greater than 50%.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eAfter applying the inclusion and exclusion criteria, 35 RCTs were identified, and data was extracted and analyzed. There were 1532 patients (759 males and 773 females), aged 16\u0026ndash;80. The quantity of BT injected varied from 20\u0026ndash;100 IU when Botox\u0026reg; was used, 90\u0026ndash;100 IU when Dysport\u0026reg; was used, 20\u0026ndash;50 IU when Neuronox\u0026reg; was used and one study used Syposrt\u0026reg; 100 IU. All the above formulations are pharmacologically equivalent therefore, for this analysis, all the above have been treated as BT injections.\u003c/p\u003e\n\u003cp\u003eThere was variability in the aspects of the BT injection procedure as well. 32 studies reported injecting the BT into the Internal Anal Sphincter (IAS), 2 studies into the fissure edges and one study reported injection into the External Anal Sphincter (EAS). In 29 studies BT was injected into either side of the anal fissure, 4 studies reported injection at the 3 and 9 o\u0026rsquo;clock positions, 1 study injected into a single 9 o\u0026rsquo;clock position, and 1 study injected into 4 positions at 1, 5, 7, and 11 o\u0026rsquo;clock.\u003c/p\u003e\n\u003cp\u003eThe follow-up period in these studies varied from 2 to 60 months.\u003c/p\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003eOutcomes of Efficacy:\u003c/h2\u003e\n\u003cdiv id=\"Sec9\" class=\"Section3\"\u003e\n\u003ch2\u003ePrimary Outcome:\u003c/h2\u003e\n\u003cp\u003eThe primary outcome measure of fissure healing (overall response) after the first BT injection is summarized in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. As can be seen, the healing rate ranged from 18.92\u0026ndash;100%. 21 out of the 35 studies included reported statistically significant results whereas in 14 studies there was no statistically significant difference. Analysis using a random effect model showed that healing was observed in 1,117 patients out of 1532, with a proportion of 0.727, 95% CI\u0026thinsp;=\u0026thinsp;0.673\u0026ndash;0.781, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, I2\u0026thinsp;=\u0026thinsp;86.6%. Substantial heterogeneity was noted (I2\u0026thinsp;=\u0026thinsp;86.6%) and a subgroup analysis was performed to combat heterogeneity. Studies were divided into 3 subgroups based on either a follow-up period of up to 6 months, 6 to 12 months, or more than 12 months. However, even after the subgroup analysis, the data showed significant heterogeneity. This data is depicted as a funnel plot (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e) and a Forest plot (Fig.\u0026nbsp;3). The funnel plot showed minimal publication bias.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003ePooled analysis for overall response after first injection\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eStudy\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTotal\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePositive cases\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePercent\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e95% CI\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ez-value\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ep-value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eNour H., et al.,2020 (10)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e77.08\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e62.69 to 87.97\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.753\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003ePilkington SA et al.,2018(11)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e58\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e58\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e47.71 to 67.80\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.11\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eIqbal Z.,et al.,2016 (12)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e198\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e166\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e83.84\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e77.96 to 88.68\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.523\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eGandomkar H,et al.,2015(13)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e49\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e75.51\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e61.13 to 86.66\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.571\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0003\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eAhmad M.S.,et al.,2014 (14)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e80\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e66.28 to 89.97\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.243\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eAsim M,et al.,2014 (15)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e58.54\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e42.11 to 73.68\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.093\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.27\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eBerkel AE,et al.,2014 (16)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e66.67\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e46.04 to 83.48\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.732\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.083\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eKarabulut Z., et al.,2012 (17)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e90\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e68.30 to 98.77\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.578\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0003\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eValizadeh N,et al.,2012 (18)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27.8 to 68.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.84\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eSamim M,et al.,2012 (19)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e60\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e49\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e81.67\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e69.56 to 90.48\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.906\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eWitte ME,. et al.,2010 (20)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e90.48\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e69.62 to 98.83\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.147\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.25\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eNasr M,et al.,2010 (21)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e80\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e64.35 to 90.95\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.795\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eOthman I. et al.,2010 (22)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e87.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e73.2 to 95.81\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.743\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMehrotra S. et al.,2009 (23)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e93.33\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e77.93 to 99.18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.747\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eAbd Elhady HM,et al.,2009(24)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e47.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31.51 to 63.87\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.32\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.75\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eFesten S, et al.,2009 (25)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18.92\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.96 to 35.16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-3.78\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0002\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eAlgaithy ZK. et al.,2008 (26)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e43\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e86\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e73.26 to 94.18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.091\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eBrisinda G;et al.,2007 (27)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e92\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e80.77 to 97.78\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.94\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eJones OM,et al.,2006 (28)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e76.67\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e57.72 to 90.07\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.921\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.003\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eFruehauf H,et al.,2006 (29)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e64\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e42.52 to 82.03\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.16\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eDe Nardi P,et al.,2006 (30)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e36.67\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19.93 to 56.14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.14\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMassoud BW,et al.,2005 (31)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e80\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e59.3 to 93.15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.003\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eArroyo Sebastian A,et al.,2005 (32)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37.90 to 58.22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.69\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eIswariah H,et al.,2005 (33)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e47.06\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22.98 to 72.19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.81\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eBrisinda G; et al.,2004 (34)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e93\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e93\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e86.11 to 97.14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eRoka S.,et al.,2004 (35)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e85.71\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e63.66 to 96.95\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.273\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eSiproudhis L,et al.,2003 (36)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27.2 to 72.80\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.99\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMentes BB, et al.,2003 (37)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e61\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e75.41\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e62.71 to 85.54\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.969\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMadalinski MH,et al.,2002 (38)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e96\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e96\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e96.23 to 100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.798\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eWollina U, et al.,2002 (39)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e80\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e44.39 to 97.48\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.897\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.057\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eColak T,et al.,2002 (40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e70.59\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e52.52 to 84.90\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.401\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.016\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eLysy J,et al.,2001 (41)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e63.33\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e43.86 to 80.07\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.461\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.14\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMaria G,et al.,2000 (42)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e74\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e59.66 to 85.37\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.394\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0006\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eBrisinda G, et al.,1999 (43)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e96\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e79.65 to 99.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMaria G,et al.,1998 (44)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e73.33\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e44.90 to 92.21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.807\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.07\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOverall effect:\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1532\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1117\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e72.7%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e67.3 to 78.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19.53\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003ch2\u003eSecondary Outcome:\u003c/h2\u003e\n\u003cp\u003eThe secondary outcome of efficacy was the response to repeat BT injection in patients who did not respond to the initial injection. 8 out of the 35 studies reported that a second BT injection was administered to patients who did not respond after the first injection. As shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, the pooled analysis showed that the response after repeated injection was achieved in 29 out of 38 patients, (proportion\u0026thinsp;=\u0026thinsp;0.785, 95% CI\u0026thinsp;=\u0026thinsp;0.626 to 0.945, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, I2\u0026thinsp;=\u0026thinsp;50.97%). A moderate level of heterogeneity was observed and this was dealt with by making sub-groups based on the periods of follow-up. The studies were divided into three subgroups i.e. studies with follow-up periods of up to 6 months, up to 12 months, and more than 12 months. This decreased the heterogeneity significantly. Moreover, it was also seen that most of the studies that involved the outcome of repeated injections had a follow-up of more than 12 months. Statistical methodology as described above showed an overall efficacy of 73.19% after the second injection achieving statistical significance (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). No funnel plot was made because the number of studies included was less than 10 and the forest plot is depicted in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eMeta-analysis for response after repeated injection\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eStudy\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTotal\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePositive cases\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eProportion\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e95% CI\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ez-value\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ep-value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePilkington SA,et al.,2018 (11)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.417\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15.17 to 72.33\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.57\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.56\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eKarabulut Z., et al.,2012(17)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15.81 to 100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.414\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.157\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOthman I. et al.,2010 (22)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e29.24 to 100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.732\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.08\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBrisinda G, et al.,2007 (27)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e39.76 to 100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.045\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIswariah H,et al.,2005 (33)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.50 to 100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.317\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMentes BB,et al.,2003 (37)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e69.15 to 100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.162\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMaria G, et al.,1998 (44)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.76 to 93.24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.99\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMehrotra S. et al.,2009 (23)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.945\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15.81 to 100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.414\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.157\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOverall effect\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e38\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.785\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.626 to 0.945\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.674\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003eThe outcome of Safety:\u003c/h2\u003e\n\u003cp\u003eSafety was assessed by the number of reported complications in the patients. Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e shows the different complications reported in the patients in the included studies.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eSummary of reported complications\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eComplication\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNumber of patients\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePercentage %\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIncontinence to flatus 78 (4.8%),\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e70\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.8%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIncontinence to faeces 10 (0.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.6%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAnal haematoma 17 (1%),\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eThrombosed Haemorrhoids 4 (0.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.2%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFlu-like symptoms 5 (0.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.3%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEpididymitis 2 (0.12%),\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.12%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eProtrusion of hemorrhoids 2(0.12%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.12%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePerianal itching 2(0.12%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.12%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFistula in ano 3 (0.18%).\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.18%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eThe data showed that there was a wide variation in the reported complication rate ranging from 0% to 27% as depicted in Table 4. Upon pooling the data, complications were reported in 88 out of 1532, with a proportion of 0.042, 95% CI= 0.028 \u0026ndash; 0.055, p\u0026lt;0.001, and I2=60.27%. The results showed significant heterogeneity and thus a subgroup analysis was performed with the studies divided into 3 subgroups based on the period of follow-up. These subgroups were studies with a follow-up period of up to 6 months, 6 to 12 months, or more than 12 months. This significantly decreased the heterogeneity especially in the subgroups with 6 and 12 months follow-up. There was still significant heterogeneity in the group with more than 12 months follow-up period and it can be attributed to the wide range (from 18 to 60 months) of follow-up periods pooled in that subgroup. The funnel and forest plots are shown in Figures 5 and 6 respectively. The funnel plot showed minimal publication bias.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab4\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003ePooled analysis for all reported complications\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eStudy\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTotal\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eComplications\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePercent\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e95% CI\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ez-value\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ep-value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNour H., et al.,2020 (10)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.67\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.48 to 30.22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.62\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePilkington SA et al.,2018(11)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.62 to 8.52\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-9.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIqbal Z.,et al.,2016 (12)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e198\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.00 to 1.85\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-14.07\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGandomkar H,et al.,2015(13)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e49\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.08\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.5 to 13.98\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-6.429\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAhmad M.S.,et al.,2014(14)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.32\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.54 to 19.93\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-5.466\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAsim M,et al.,2014 (15)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11.11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.35 to 29.16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-4.041\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBerkel AE,et al.,2014 (16)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.26 to 16.55\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-6.223\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eKarabulut Z., et al.,2012 (17)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.13 to 24.87\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-4.025\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eValizadeh N,et al.,2012 (18)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.55 to 31.22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-3.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSamim M,et al.,2012 (19)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e60\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.04 to 13.92\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-6.971\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWitte ME,. et al.,2010 (20)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.79 to 23.66\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-5.06\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNasr M,et al.,2010 (21)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.00 to 8.81\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-6.325\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOthman I. et al.,2010 (22)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.52\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.18 to 30.38\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-3.71\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0002\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMehrotra S. et al.,2009 (23)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.33\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.08 to 17.22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-5.112\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAbd Elhady HM,et al.,2009(24)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.57 to 20.39\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-5.376\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFesten S, et al.,2009 (25)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.07 to 14.16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-5.754\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlgaithy ZK. et al.,2008 (26)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10.03 to 33.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-4.243\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBrisinda G;et al.,2007 (27)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.26 to 16.55\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-6.223\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eJones OM,et al.,2006 (28)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.10 to 20.35\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-4.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFruehauf H,et al.,2006 (29)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.71 to 38.57\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-3.286\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDe Nardi P,et al.,2006 (30)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.00 to 11.57\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-5.477\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMassoud BW,et al.,2005 (31)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.00 to 13.72\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eArroyo Sebastian A,et al.,2005 (32)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11.77\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.46 to 36.44\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-3.153\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIswariah H,et al.,2005 (33)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.62 to 18.83\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-7.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBrisinda G; et al.,2004 (34)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.52\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.18 to 30.38\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-3.71\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0002\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRoka S.,et al.,2004 (35)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11.84 to 28.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-6.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSiproudhis L,et al.,2003 (36)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e61\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.00 to 5.87\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-7.81\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMentes BB, et al.,2003 (37)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.00 to 16.84\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-4.472\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMadalinski MH,et al.,2002 (38)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.25 to 44.50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-2.53\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.011\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWollina U, et al.,2002 (39)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.00 to 10.28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-5.831\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eColak T,et al.,2002 (40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e96\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27.08\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18.52 to 37.11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-4.491\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLysy J,et al.,2001 (41)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.00 to 11.57\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-5.477\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMaria G,et al.,2000 (42)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.00 to 7.11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-7.071\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBrisinda G, et al.,1999 (43)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.00 to 13.72\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMaria G,et al.,1998 (44)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.00 to 21.80\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-3.873\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003ch2\u003eRisk of Bias:\u003c/h2\u003e\n\u003cp\u003eThe risk of bias was assessed using the Cochrane\u0026rsquo;s handbook for systemic reviews and a traffic plot was created using the Robvis visualisation tool. The traffic plot is shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003e. It assesses the risk of bias in RCTs on 5 domains i.e. selection (D1), performance (D2), detection (D3), attrition (D4), and reporting (D5). The assessment showed a high risk of bias in the studies Pilkington et al (\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e), Berkel et al (\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e), Valizadeh et al (\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e), Abd el Hady et al (\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e), Festen et al (\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e), Jones OM et al (\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e), De Nardi et al (\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e), Brisinda G et al (\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e), Roka S et al (\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e), Siproudhis et al (\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e), Madalinski et al (\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e), and Brisinda G et al (\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e). This can account for the high amounts of heterogeneity present in the results as well.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study presents a comprehensive review of all published RCTs involving BT injection as a treatment option for anal fissure.\u003c/p\u003e \u003cp\u003eA recent systematic review conducted by Poland et al. (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e) included a total of 775 patients of which the Botox injection arm included 132 patients. The study compared the outcomes of different modalities of treatment of anal fissure. At 8 weeks, healing rates were 95.13% in those treated with sphincterotomy, 66.7% in the botulinum toxin group, 63.8% in the nitrate group, 52.3% for topical diltiazem and 50% for topical minoxidil. There was a risk of permanent incontinence with sphincterotomy (2.3%). In our meta-analysis, the success following a single BT injection was pooled to be 72.7% and thus, the Botox arm results of this systematic review are similar to our results. The risk of permanent incontinence with sphincterotomy emphasizes the need for a ladder approach in the management of anal fissures starting with the least invasive options of topical applications first, then BT injections, and reserving the operative solutions for the last. The heterogeneity in the groups for the outcome of efficacy (overall response after the first BT injection) can be attributed to the different follow-up periods of the study. The studies had a follow-up period ranging from 2 months in Colak et al (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e) to 60 months in Abd El Hady et al (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Subgroups were made to combat the heterogeneity however they did not provide satisfactory results. Another possible reason for heterogeneity could be the different doses used in each study. The dose of BT injection used ranged from 20 IU to 100 IU. Such differences in studies can impact significant heterogeneity in the results. Festen et al (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) used a dose of 20 mg and reported results in only 14 out of 37 patients, whereas Othman et al (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) used 80 mg and showed a response in 35 out of 40 patients. However, subgroup analysis by stratifying data based on follow-up yielded better results than stratifying on doses (especially for the outcome of safety). Moreover, some of the studies had a high risk of bias as well and thus, they can also contribute to the heterogeneity. Overall, the pooled analysis showed that BT injection is an efficacious method for treatment of chronic anal fissures.\u003c/p\u003e \u003cp\u003ePilkington et al. (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) reported an RCT conducted to compare unilateral with bilateral BT injections. In the group who failed to have a resolution of their symptoms after the first injection, twelve patients had repeat BT injections administered in the same manner as their initial randomization: 5 in the bilateral injection group and 7 in the unilateral group. The healing rate after repeat BT was 2/5 (40%) in the bilateral group and 3/7 (43%) in the unilateral group, overall 5/12 (41.6%). This evidence seems to suggest that the site of injection or whether the injection was unilateral or bilateral appears to have very little impact on the effectiveness of this treatment. However, other studies such as Othman et al (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) and Brisinda G (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) showed a 100% success rate in patients having repeat injections. The meta-analysis presented here included 38 patients who had a repeat BT injection reported through 5 different studies with an overall healing of 78.5%. This result lies between that reported by Pilkington et al and Othman et al/Brisinda et al. A possible explanation for this could be the period of follow-up. Amongst the included studies, only Pilkington (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) had a significantly decreased efficacy of repeat BT injection This could be attributed to the type of BT injection used. Other studies such as Othman et al (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) used Botox, but Pilkington (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) used Dysport or Syposrt. The data seems to suggest that a repeat injection may be beneficial before proceeding with surgical alternatives.\u003c/p\u003e \u003cp\u003eThere is some variability in the perception and reporting of complications following BT injection. Madaliński et al., (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e) presented their experience of complications after BT in 105 chronic anal fissure patients in 2002. They reported incontinence to flatus 5%, incontinence to feces 2.8%, anal hematoma 2.8% thrombosed hemorrhoids 1.1% flu-like symptoms 1.7% epididymitis 0.5%, and protrusion of hemorrhoids 0.5%. This is almost certainly due to reporting bias as most of these side effects are only temporary and require little active intervention. Our meta-analysis has shown complications in only 88 out of 1532 (4.2%) of the patients and it is a lower incidence than some of the studies. Studies with 6 and 12-month follow-up periods showed a lower incidence of complications (2.1% and 2.5% respectively), however, studies with a follow-up period of more than 12 months showed a higher rate (8.9%) and heterogeneity amongst complications. Thus, it is logical to conclude that with increased time, there is an increased time of developing complications. This is further solidified by the results of studies like Al Gaithy et al (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) and Roka et al (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e) with complications occurring in 20% and 19% of patients respectively and follow-up times of 24 months. This coupled with the increased rate of repeat injection in studies with longer follow-up periods (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e) reinforces the fact that even though BT injection is a suitable first-line, minimally invasive treatment option, it should be augmented with repeat injection after sufficient time. However, for a definite and permanent solution, other treatment options might be considered. Moreover, recently, the efficacy of BT injection is superior to nifedipine with lignocaine and anal dilation as well, thus further reinforcing its use for the treatment of chronic anal fissures (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHowever, every article is bound by some limitations. A meta-analysis is only as good as the studies included in it and some of the studies included in this analysis showed a high risk of bias and were not as robust. This affects the results and has resulted in significant heterogeneity, especially in the primary outcome of efficacy. Moreover, broad inclusion criteria which included all drug types of BT injection can affect the results. Lastly, this meta-analysis also suffers from a low publication bias in the outcome of efficacy.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eBT injection for chronic anal fissures is an effective, safe, and less invasive treatment option for chronic anal fissures, and offering a repeat injection for recurrent/ persistent symptoms after the first injection can lead to very good results.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAcknowledgements:\u003c/h2\u003e\n\u003cp\u003eThe authors would like to acknowledge the authors of the original studies and their participants.\u003c/p\u003e\n\u003ch2\u003eFunding:\u003c/h2\u003e\n\u003cp\u003eNo external funding was provided for this article.\u003c/p\u003e\n\u003ch2\u003eConflicts of Interest:\u003c/h2\u003e\n\u003cp\u003eThe authors have no conflicts of interest to disclose.\u003c/p\u003e\n\u003ch2\u003eEthical Statement:\u003c/h2\u003e\n\u003cp\u003eSince this is a review article, no ethical approval is required.\u003c/p\u003e\n\u003ch2\u003eData availability Statement:\u003c/h2\u003e\n\u003cp\u003eData is provided within the supplementary information files.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution:\u003c/h2\u003e\n\u003cp\u003eK.M.T: Data collection, Data analysis and manuscript preparation M.G: Data Collection H.A: Statistical analysis of data M.A.D: Project supervision, review of results, and manuscript preparation.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKodner IJ, Fry RD, Fleshman JW, Birnbaum EH, Read TE. 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Diseases of the Colon and rectum. 46(2):232-7, 2003 Feb. DOI: 10.1097/01.DCR.0000044712.58674.09\u003c/li\u003e\n\u003cli\u003eMadalinski MH; Slawek J; Duzynski W; Zbytek B; Jagiello K; Adrich Z; Kryszewski A. Side effects of botulinum toxin injection for benign anal disorders. European Journal of Gastroenterology \u0026amp; Hepatology. 14(8):853-6, 2002 Aug. DOI: 10.1097/00042737-200208000-00007 \u003c/li\u003e\n\u003cli\u003eWollina U; Konrad H. Botulinum toxin A in anal fissures: a modified technique. Journal of the European Academy of Dermatology \u0026amp; Venereology. 16(5):469-71, 2002 Sep. doi: 10.1046/j.1468-3083.2002.00490.x.\u003c/li\u003e\n\u003cli\u003eColak T; Ipek T; Kanik A; Aydin S. A randomized trial of botulinum toxin vs lidocaine pomade for chronic anal fissure. Acta Gastroenterologica Belgica. 65(4):187-90, 2002 Oct-Dec. PMID: 12619423 \u003c/li\u003e\n\u003cli\u003eLysy J; Israelit-Yatzkan Y; Sestiery-Ittah M; Weksler-Zangen S; Keret D; Goldin E. Topical nitrates potentiate the effect of botulinum toxin in the treatment of patients with refractory anal fissure. Gut. 48(2):221-4, 2001 Feb. doi: 10.1136/gut.48.2.221\u003c/li\u003e\n\u003cli\u003eMaria G; Brisinda G; Bentivoglio AR; Cassetta E; Gui D; Albanese A. Influence of botulinum toxin site of injections on healing rate in patients with chronic anal fissure. American Journal of Surgery. 179(1):46-50, 2000 Jan. DOI: 10.1016/s0002-9610(99)00255-x\u003c/li\u003e\n\u003cli\u003eBrisinda G; Maria G; Bentivoglio AR; Cassetta E; Gui D; Albanese A. A comparison of injections of botulinum toxin and topical nitroglycerin ointment for the treatment of chronic anal fissure. New England Journal of Medicine. 341(2):65-9, 1999 Jul 08. DOI: 10.1056/NEJM199907083410201\u003c/li\u003e\n\u003cli\u003eMaria G; Brisinda G; Bentivoglio AR; Cassetta E; Gui D; Albanese A. Botulinum toxin injections in the internal anal sphincter for the treatment of chronic anal fissure: long-term results after two different dosage regimens. Annals of Surgery. 228(5):664-9, 1998 Nov. DOI: 10.1097/00000658-199811000-00005\u003c/li\u003e\n\u003cli\u003eP A Boland 1, M E Kelly 2, N E Donlon 2, J C Bolger 2, J O Larkin 2, B J Mehigan 2, P H McCormick 2, Management options for chronic anal fissure: a systematic review of randomized controlled trials. Int J Colorectal Dis 2020 Oct;35(10):1807-1815. DOI: 10.1007/s00384-020-03699-4\u003c/li\u003e\n\u003cli\u003eBrisinda G, Bianco G, Silvestrini N, Maria G. Cost considerations in the treatment of anal fissures. \u003cem\u003eExpert Rev Pharmacoecon Outcomes Res. \u003c/em\u003e2014;14(4):511\u0026ndash;525. DOI: 10.1586/14737167.2014.924398 \u003c/li\u003e\n\u003cli\u003eAndreevski V, Volkanovska A, Deriban G, Josifovic FL, Krstevski G, Nikolova D, et al. The value of injection therapy with botulinum toxin in pain treatment of primary chronic anal fissures compared to anal dilation, and local nifedipine in combination with lidocaine. Pril (Makedon Akad Nauk Umet Odd Med Nauki);44(2):89\u0026ndash;97. DOI :10.2478/prilozi-2023-0029\u003c/li\u003e\n\u003c/ol\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":"techniques-in-coloproctology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tcol","sideBox":"Learn more about [Techniques in Coloproctology](http://link.springer.com/journal/10151)","snPcode":"10151","submissionUrl":"https://submission.nature.com/new-submission/10151/3","title":"Techniques in Coloproctology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Anal fissure, Fissure-in-ano, Botox, Botulinuma Toxin A, Perianal fissure, Randomized controlled trial, Botulinum Toxin, meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-3889351/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3889351/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground:\u003c/b\u003e\u003c/p\u003e \u003cp\u003ePerianal fissure is one of the most painful anal conditions. Various management options are available, including topical nitrites, calcium channel blockers, botulinum toxin injection, and sphincterotomy.\u003c/p\u003e\u003cp\u003e\u003cb\u003eAim:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTo assess the efficacy and safety of Botulinum Toxin A (BT) injection in the management of symptomatic chronic anal fissure by conducting a systematic review of literature and meta-analysis of published Randomised Controlled Trials (RCTs)\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethodology:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eSystematic search conducted using Embase and Medline search platforms, extending from January 1974 to September 2020. The search identified 264 published papers, of which 35 RCTs were identified. Meta-analysis was performed on the collected data with a random effects model using the Freeman-Tukey arcsine transformed proportions. A p-value less than 0.05 was deemed significant. The I2 test was used to test for heterogeneity.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA total of 1532 patients were included. Upon pooling of the data, 1117 patients out of 1532 (72.7%) demonstrated healing of the fissure after the first injection with BT (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, I2\u0026thinsp;=\u0026thinsp;86.6%). Subgroup analysis was done based on the follow-up period in months. 9 studies reported that a second BT injection was needed in patients who did not respond after the initial injection. 29 out of 38 patients (78.5%) showed a response to the second injection (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, I2\u0026thinsp;=\u0026thinsp;50.6%). Complications were observed in 88 out of 1532 patients (4.02%) with p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, I2\u0026thinsp;=\u0026thinsp;60.2%.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eBT injection for chronic symptomatic anal fissures is effective and safe with minor temporary complications. There is evidence to support offering a repeat injection for recurrent/ persistent symptoms.\u003c/p\u003e","manuscriptTitle":"Efficacy and Safety of Botulinum Toxin Injection in the Management of Chronic Symptomatic Anal Fissure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-29 20:46:09","doi":"10.21203/rs.3.rs-3889351/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-06-08T08:45:04+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-02T16:22:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"33704362-5aa7-4bb7-83f1-c043a47b7b56","date":"2024-04-03T13:35:34+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-03-11T00:27:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"6bbc7eda-07df-48ee-8b7b-237533a2375e","date":"2024-02-09T18:32:48+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-02-09T16:09:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-02-09T16:05:14+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-01-25T05:18:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"Techniques in Coloproctology","date":"2024-01-22T23:59:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"techniques-in-coloproctology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tcol","sideBox":"Learn more about [Techniques in Coloproctology](http://link.springer.com/journal/10151)","snPcode":"10151","submissionUrl":"https://submission.nature.com/new-submission/10151/3","title":"Techniques in Coloproctology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"0ee2aff9-a3d9-4112-b151-dc7fb655081a","owner":[],"postedDate":"January 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-13T16:07:11+00:00","versionOfRecord":{"articleIdentity":"rs-3889351","link":"https://doi.org/10.1007/s10151-024-03087-y","journal":{"identity":"techniques-in-coloproctology","isVorOnly":false,"title":"Techniques in Coloproctology"},"publishedOn":"2025-01-09 15:57:53","publishedOnDateReadable":"January 9th, 2025"},"versionCreatedAt":"2024-01-29 20:46:09","video":"","vorDoi":"10.1007/s10151-024-03087-y","vorDoiUrl":"https://doi.org/10.1007/s10151-024-03087-y","workflowStages":[]},"version":"v1","identity":"rs-3889351","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3889351","identity":"rs-3889351","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}