The use of a methylene blue and glyceryl trinitrate- based cream for the treatment of chronic anal fissures: a phase II randomized pilot trial from a referral coloproctological unit

The use of a methylene blue and glyceryl trinitrate- based cream for the treatment of chronic anal fissures: a phase II randomized pilot trial from a referral coloproctological unit | 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 The use of a methylene blue and glyceryl trinitrate- based cream for the treatment of chronic anal fissures: a phase II randomized pilot trial from a referral coloproctological unit Pierluigi Lobascio, Giovanni Tomasicchio, Noadia Cassetta, Donato Francesco Altomare, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4448360/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 03 Jan, 2025 Read the published version in Techniques in Coloproctology → Version 1 posted 8 You are reading this latest preprint version Abstract BACKGROUND (MAIN AIM): Chronic anal fissures (CAFs) are the second most common anorectal disease. Non-surgical treatment includes several options with controversial efficacy. The aim of this study was to evaluate the efficacy and safety of a new ointment based on methylene blue in addition to glyceryl trinitrate. METHODS: A phase II randomized single-centre triple-blinded study was carried out in a tertiary proctology unit on patients with CAF. The enrollment started after local ethical approval (Study n.6461, Protocol approval n. 0045085). Eligible consecutive patients were randomized to create three different groups, each receiving a different ointment. The efficacy of the treatment was evaluated with the REALISE score. RESULTS: Nine patients with Cream A (median age 47 years, IQR 40–56, 22% female), nine with B (median age 52 years, IQR 49–57, 33% female), and nine with C (median age 58 years, IQR 46–62, 55% female). In group A, REALISE scores decreased significantly from a median of 22 (IQR 12–25) to 6 (IQR 4–8) (p < 0.05) after 40 days. In group B, REALISE scores improved significantly from a median of 20 (IQR 17–22) to 5 (IQR 4–9) (p < 0.05). In group C, REALISE scores decreased significantly from a median of 19 (IQR 19–20) to 4 (4–5) (p < 0.05). No statistically differences were recorded. The healing rate was 77% with Creams A and C, while it was 44% with Cream B. CONCLUSION: Methylene blue-based ointments could be a new and innovative treatment for the non-operative management and healing of CAFs. anal fissure anal pain realise scoring system blue cream methylene blue glyceryl trinitrate Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Anal fissures were described for the first time by Lockhart-Mummery as a linear or over-shaped tear in the anoderm [ 1 ]. Chronic anal fissures (CAFs) are the second most common anorectal disease [ 2 ], causing significant morbidity and QoL deterioration [ 3 , 4 ]. The main symptom is intense burning anal pain and sometimes minor bleeding occurring during and after defecation. The usual location of anal fissures is the posterior midline [ 5 ], worsened by the spasm of the internal anal sphincter [ 6 ]. The treatment of anal sphincter spasms is considered a crucial target for curing the fissure [ 7 , 8 ]. Although surgery by lateral sphincterotomy is still the gold standard for curing anal fissures [ 9 – 11 ], in the last two decades, less invasive, conservative strategies have been considered as first-line treatments because of the fear of causing faecal incontinence, which is reported in up to 35% of patients [ 12 ]. The non-surgical treatment of anal fissures now includes several options [ 13 ]: glyceryl trinitrate ointment [ 14 ], anaesthetics (such as Lidocaine), steroids, calcium channel-blocking drugs (CCBs) [ 15 , 16 ], diltiazem ointments [ 17 , 18 ], and botulinum toxin injections [ 19 ]. The efficacy of these treatments is widely reported in the literature; however, several trials comparing their effectiveness report conflicting results [ 20 , 21 ]. Methylene blue is a non-toxic dye that inhibits soluble guanylate cyclase and nitric oxide synthase. Nitric oxide regulates physiological functions such as pain and analgesia by activating soluble guanylate cyclase to increase intracellular cyclic guanosine monophosphate [ 22 , 23 ]. It has been used intra-dermally in proctology, mainly for the treatment of intractable pruritus ani, because of its analgesic effect due to its interaction with nervous dermal receptors for pain and pruritus [ 24 , 25 ]; it has recently been used to minimize anal pain after lateral sphincterotomy for anal fissures [ 26 ], but it has never been used in as an adjunct to myorelaxant agents for the treatment of chronic fissures. The aim of this study was to evaluate the efficacy and safety of a new ointment based on methylene blue in addition to glyceryl trinitrate in the treatment of chronic anal fissures. Methods A phase II randomized single-centre triple-blinded study was carried out in a tertiary proctology unit on patients with chronic anal fissures between June 2022 and April 2023. After receiving approval from the local ethics committee (Study n.6461, Protocol approval n. 0045085/17.05.2022), patients of both sexes aged between 20 and 65 years with chronic anal fissures were enrolled. The exclusion criteria included previous medical or surgical treatment, acute anal fissure, infected or fistulized anal fissure, perineal Crohn’s disease, other proctological diseases, functional disorder of defecation and continence, severe liver and/or kidney disease, radiation proctitis, previous history of orthostatic hypotension, intolerance to nitrates, treatment with nitrate drugs for heart ischemia, sexually transmitted disease, cancer, those undergoing immunosuppressive treatment, pregnant or breastfeeding, or known allergy to one of the agents contained in the evaluating drugs. Acute fissures were defined as recently occurred (within 6 weeks) ulcerations of the anoderm, while chronic anal fissures were characterized as persisting for more than 6 weeks with the presence of the features proposed by Scholefield et al. [27]: a sentinel skin tag, hypertrophic anal papillae, an exposed internal anal sphincter, a fibrotic lateral fissure, or a fibrotic anal sphincter. Demographic data and detailed clinical histories were recorded, including information about anal pain intensity and duration, bowel habits, and stool consistency (using the Bristol stool scale) [28], before treatment. Patients were examined in the Sims position in an outpatient setting. The anal verge was inspected to confirm the presence of an anal fissure and to determine its location. When tolerated, digital rectal examination (DRE) to evaluate the anal sphincter tone and anoscopy were performed. In cases where it was impossible to perform both a DRE and anoscopy during enrolment, the anal fissure site was determined by inspecting the anal region by asking the patient to bear down during defaecation while spreading the glutei. In cases with a suspicious and unusual location, a colonoscopy was performed to rule out other neoplastic or inflammatory disorders. Eligible consecutive patients were randomized to create three different groups, each receiving a different ointment. The ointments were prepared in a pharmacy as follows: • Cream A: glyceryl trinitrate 0.4%, ialuronic acid 1%, soft white paraffin, ultramarine blue cosmetic pigment; • Cream B: glyceryl trinitrate 0.4%, methylene blue 2%, ialuronic acid 1%, soft white paraffin; • Cream C: glyceryl trinitrate 0.4%, methylene blue 0.4%, ialuronic Acid 1%, soft white paraffin. Different concentrations of methylene blue were used to prove and compare their efficacy and safety. Glyceryl trinitrate was used as a nitric oxide donor to promote muscle relaxation, thus leading to fissure healing [29]. Ialuronic acid has been demonstrated to play a crucial role in influencing the inflammatory, proliferative, or re-modelling phases of the healing process [30]. Soft white paraffin was added in variable quantities to reach the final weight of 30 g in each tube. Each ointment was kept in a tube labelled A, B or C, respectively, according to the randomization code produced by the pharmacist and unknown to the operators and patients. The study was designed specifically to prevent bias, applying a triple-blinded permuted block randomization method: surgeons, statistician, and patients were blinded to the administered treatment. The evaluation of safety in the procedure was considered with the notification of every ADR (adverse drug reaction), which would result in withdrawal from the study for the patient involved. After a clear and complete explanation of the study, possible side effects, and acceptance with written informed consent, approximately 200 mg of the ointment was applied directly on the anoderm. (Figures 1,2). Patients were tested for at least 20 minutes to evaluate any adverse effects, and they instructed to apply the ointment twice a day (every 12 h) for 30 days using the tip of their finger. In patients with constipation (according to the Roma IV criteria [31]), an oral laxative (PEG solution) was administered for at least 1 month. The efficacy of the treatment was evaluated using the REALISE score, a validated scoring system that rates the VAS for pain (score range: 0–10), NSAID use, pain duration, bleeding, and quality of life (QoL) on a scale of 1–5 [32] .The score was calculated during the first clinical evaluation, at day 10, at day 20 via a telephone interview, and at day 30 via an proctological outpatient evaluation. Furthermore, side effects were recorded. The degree of re-epithelization (healing) was evaluated and scored as follows: 0 = anal fissure still present; 1 = superficial fissure; 2 = partial re-epithelization; 3 = complete re-epithelization. Patient satisfaction was rated on a scale of 0 (failure) to 5 (excellent). The ointments were free-of-charge for all patients, while the production and preparation of the agents were based exclusively on the pharmacy’s rates. 2.1 Statistical Analysis The continuous parameters are reported as the median and interquartile ranges. The categorical variables were recorded as numbers and percentages where appropriate. Comparisons of the categorical variables were performed using the χ2 and Fisher’s exact test where appropriate. Comparisons between groups were made using the Kruskal–Wallis test with Bonferroni corrections. A p value < 0.05 was considered statistically significant. Statistical analyses were carried out using RStudio (R version 4.0.3 10/ 10/2020 Copyright© 2020, The R Foundation for Statistical Computing). 2.2 Ethical approval declarations 1. Local Ethical Committee form Hospital University of Bari approved this study with n.6461 and Protocol approval n. 0045085/17.05.2022) 2. The methods were carried out in accordance with the relevant guidelines and regulations 3. Informed consent was obtained from all participants and/or their legal guardian/s Results Thirty patients (median age 53 years, IQR 43–61, 35% female) with anterior (3, 10%), posterior (25, 83.3%), or antero-posterior (2, 6.6%) chronic anal fissures were entered into the study after giving informed consent. Twenty-seven patients completed both the telephone interviews and proctological evaluation at day 40. Three out of thirty (10%) patients discontinued the medical therapy: two patients due to headaches (one with Cream A and one with Cream B) and one due to anal itching (Cream C). Patients were divided in three groups and treated with the three different creams: nine patients with Cream A (median age 47 years, IQR 40–56, 22% female), nine with Cream B (median age 52 years, IQR 49–57, 33% female), and nine with Cream C (median age 58 years, IQR 46–62, 55% female), as is show in the CONSORT diagrams [ 33 ] (Fig. 3 ). Digital rectal examination (DRE) was performed in eight patients (88%) of group A, seven (78%) of group B, and nine (100%) of group C; no statistical differences were observed between the groups. Not all patients who underwent DRE tolerated anoscopy (55% of group A, 33% of group B, and 78% of group C), and no statistical differences were observed between the groups. The baseline characteristics of patients with chronic anal fissures are summarized in Table 1 . Table 1 Baseline characteristics of patients with chronic anal fissures Group A n = 9 Group B n = 9 Group C n = 9 p-value Sex - M - F 7 (78%) 2 (22%) 6 (67%) 3 (33%) 4 (45%) 5 (55%) 0.61 Age (years) 47 (40–56) 52 (49–57) 58 (46–62) 0.62 Side - Anterior - Posterior - Anterior + Posterior 0 8 1 1 7 1 2 7 0 0.25 DRE - Yes - No 8 (89%) 1 (11%) 7 (78%) 2 (22%) 9 0 0.33 Anoscopy - Yes - No 5 (55%) 4 (45%) 3 (33%) 6 (67%) 7 (78%) 2 (22%) 0.17 The anal pain, according to the visual analogue scale (VAS), had a median value ≥ 7 in all of the three groups at the base line evaluation (A: 7, IQR 5–10; B: 9, IQR 7–10; C: 8, IQR 7–10) without any statistical differences between the groups. At the proctological evaluation at day 40, the VAS scores significantly decreased with all three creams (A: 2, IQR 1–4; B: 1, IQR 0–4; C: 0, IQR 0–0), with a statistical difference observed between Creams A and C (p < 0.05). A significant reduction in NSAID intake was observed in groups B and C (B: 3, IQR 1–4 vs. 1, IQR 1–1; p < 0.05 and C: 3, IQR 1–3 vs. 1, IQR 1–1; p < 0.05), with no statistical differences observed between the groups. In group A, the REALISE scores decreased significantly from a median of 22 (IQR 12–25) to 6 (IQR 4–8) (p < 0.05) after 40 days. In group B, the REALISE scores improved significantly from a median of 20 (IQR 17–22) to 5 (IQR 4–9) (p < 0.05). In group C, the REALISE scores decreased significantly from a median of 19 (IQR 19–20) to 4 (4–5) (p < 0.05). No statistically differences were recorded between the groups (Fig. 4 ). The REALISE scores at the baseline, day 10, day 20, and day 40 are summarized in Table 2 . The healing rate was 77% with Creams A and C, while it was 44% with Cream B. At the last consultation, the satisfaction rating had a higher median score (excellent) with Creams B (5, IRQ 4–5) and C (5, IQR 5–5), while the median score with Cream A was 4 (IQR 3–5), with no statistical differences reported between the groups. No severe adverse events were recorded. Six (22%) patients (two different groups) reported transient headaches, while one patient from group A and two from group B reported itching after ointment application. Table 2 REALISE domains at the baseline, 10–20 and 40 days from the start of treatment. Cream A ( n = 9 ) Cream B ( n = 9 ) Cream C ( n = 9 ) p-value VAS - Baseline - 10 days - 20 days - 40 days p-value 7 (5–10) 4 (2–6) 1 (0–6) 2 (1–4) < 0.05 9 (7–10) 3 (2–5) 1 (1–4) 1 (0–4) < 0.05 8 (7–10) 2 (0–6) 0 (0–2) 0 (0–0) < 0.05 0.55 0.85 0.33 < 0.05 (1–3 = 0.02) Pain Duration - Baseline - 10 days - 20 days - 40 days p-value 3 (2–5) 2 (1–3) 1(1–1) 1(1–1) < 0.05 3 (2–3) 1(1–2) 1 (1–1) 1 (1–2) 0.06 2 (1–5) 1 (1–2) 1 (1–1) 1(1–1) < 0.05 0.55 0.50 0.70 0.41 NSAID use - Baseline - 10 days - 20 days - 40 days p-value 3 (1–4) 1 (1–2) 1 (1–2) 1 (1–1) 0.17 3(1–4) 2 (1–3) 1(1–2) 1 (1–1) < 0.05 3 (1–3) 1 (1–2) 1 (1–1) 1 (1–1) < 0.05 0.99 0.44 0.84 0.33 Bleeding - Baseline - 10 days - 20 days - 40 days p-value 1(1–5) 1(1–1) 1(1–1) 1(1–1) < 0.5 3 (1–4) 1(1–1) 1(1–1) 1(1–1) < 0.5 2 (1–3) 1 (1–1) 1(1–1) 1(1–1) 0.2 0.75 0.76 1 0.75 Qol - Baseline - 10 days - 20 days - 40 days p-value 4 (2–5) 2(1–3) 1(1–2) 1(1–1) < 0.05 4 (4–4) 2(2–2) 1(1–2) 1(1–1) < 0.05 4(4–5) 1(1–2) 1(1–1) 1(1–1) < 0.05 0.68 < 0.05 (1–3 = 0.03) 0.50 0.75 Defecation - Baseline - 10 days - 20 days - 40 days p-value 1(0–1) 1(1–1) 1(1–1) 1(1–1) 0.28 1(0–1) 1(1–1) 1(1–1) 1(1–1) 0.17 0(0–0) 1(1–1) 1(1–1) 1(1–1) < 0.05 0.1 0.36 0.35 0.84 Realise - Baseline - 10 days - 20 days - 40 days p-value 22 (12–25) 11(6–14) 5 (4–12) 6(4–8) < 0.05 20(17–22) 10(8–11) 6 (5–12) 5(4–9) < 0.05 19 (19–20) 8 (6–12) 6(4–6) 4(4–5) < 0.05 0.98 0.73 0.55 0.22 Discussion CAFs significantly affect patients’ QoL because of the pain caused by this distal anal condition. In the literature, the application of either operative or non-operative management of CAFs is still debated. Non-operative management is a well-defined approach, and it is the first-line approach for treating anal fissures, reducing the associated anal spasms with pain decreases, and fissure healing in up to 80% of the cases [ 18 ]. Balla et al. reported that for CAF treatment, colorectal surgeons consider lateral internal sphincterotomy as the first surgical option, only in 15.1% of cases, opting mostly for medical treatment [ 34 ]. The optimal non-operative CAF treatment has not yet been established, and this approach is deemed controversial in the literature; however, several topical ointments have been proposed as non-invasive treatments in the past few decades [ 16 ]. Several studies have reported the effect of topical nitrates in rapid pain relief and success in healing CAFs. In their randomized open-label multi-centre trial, Gagliardi et al. reported an overall success rate in CAF healing of 43% with topical trinitrate, underling that the optimal treatment duration for topical nitrate was 6 weeks [ 35 ]. In line with the literature, our data reported a healing rate of 77% with the 0.4% methylene blue ointment, exhibiting an excellent satisfaction score, significant reductions in anal pain, and no severe adverse events recorded. The design of this study considered a new ointment based on the addition of several components, including methylene blue, with the aim of healing and reducing pain during non-operative treatment of CAFs. In the literature, the analgesic properties of methylene blue is well known due to its temporary disruption of sensory nerve conduction. It is a non-toxic dye that inhibits soluble guanylate cyclase and nitric oxide synthase. Nitric oxide regulates physiological functions such as pain and analgesia by activating soluble guanylate cyclase to increase intracellular cyclic guanosine monophosphate [ 22 , 23 ]. Methylene blue, as an oxidizing–reducing agent, demonstrates a strong affinity for nerve tissues when applied locally, which can directly block the electrical conductivity of nerve fibres, thereby affecting neural excitability and impulse conductivity. Recent studies have shown that low doses (0.5 or 1%) of methylene blue may block peripheral nerve fibres at the incision. Local application of methylene blue could cause reversible damage to the incision and its surrounding subcutaneous nerve terminal medulla, thus achieving a long-acting post-operative analgesic effect. However, this damage will cause a burning sensation between 2 and 4 hours after injection. To eliminate this burning sensation, methylene blue can be combined with local anaesthetic drugs [ 36 , 37 ]. In their single-blind prospective randomized placebo-controlled trial, Sim et al. reported a significant reduction in post-operative pain after open haemorrhoidectomy in patients treated with perianal intradermal injections of methylene blue due to the unique property of temporarily ablating dermal nerve endings [ 38 ]. The preparations with methylene blue used in our trial reported an increased healing rate and reduction in REALISE score with no statistical differences when compared to glyceryl trinitrate preparation. Cream C with 0.4% methylene blue showed a median VAS score of 0 at day 40, with a statistically significant difference when compared to Cream A without methylene blue. Furthermore, Cream C, with a lower percentage of methylene blue (0.4%), had a statistically significant reduction in the REALISE score, an excellent satisfaction score (5, IQR 5–5), and no noted side effects. Cream B, with a higher percentage of methylene blue (2%), reported itching in 22% of patients after the application, with complicated local dermatitis in 50% of them. The main limitation of this study is its small sample size, which is strict and could represent a possible selection bias; however, this is a pilot, single-centre study. Multi-centre studies are currently in progress to try to avoid these biases and to enrol a higher number of patients. Conclusion Methylene blue-based ointments are safe and effective for improving patient quality of life according to the REALISE score. Methylene blue-based ointments could be a new and innovative treatment for the non-operative management and healing of CAFs. Furthermore, multi-centre studies and shared guidelines are necessary to standardize the treatment and improve the patients’ quality of life. Declarations Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Conflict of interest: The authors have no conflicts of interest to declare. All co-authors have seen and agree with the contents of the manuscript and there is no financial interest to report. We certify that the submission is original work and is not under review at any other publication. Ethics approval and consent to participate: section 2.2 Consent for publication :Written informed consent was obtained from all participants. Data and materials availability: All data and materials can be acquired from the corresponding author. Author contribution: All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Pierluigi Lobascio, Gaetano Gallo, Angela Pezzolla, Donato Francesco Altomare, Noadia Cassetta. The first draft of the manuscript was written by Rita Laforgia and Giovanni Tomasicchio. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. References JP L-M. Diseases of the rectum and colon and their surgical treatment. 2nd ed London: Baillière, Tindall & Cox. 1934. Orsay C, Rakinic J, Perry WB, Hyman N, Buie D, Cataldo P, et al. Practice parameters for the management of anal fissures (revised). Dis Colon Rectum. 2004;47:2003–7. Lund JN, Scholefield JH. Aetiology and treatment of anal fissure. Br J Surg. 1996;83:1335–44. Griffin N, Acheson AG, Tung P, Sheard C, Glazebrook C, Scholefield JH. Quality of life in patients with chronic anal fissure. Colorectal Dis. 2004;6:39–44. American Gastroenterological A. American Gastroenterological Association medical position statement: Diagnosis and care of patients with anal fissure. Gastroenterology. 2003;124:233–4. Schouten WR, Briel JW, Auwerda JJ, De Graaf EJ. Ischaemic nature of anal fissure. Br J Surg. 1996;83:63–5. Steele SR, Madoff RD. Systematic review: the treatment of anal fissure. Aliment Pharmacol Ther. 2006;24:247–57. Lund JN, Nystrom PO, Coremans G, Herold A, Karaitianos I, Spyrou M, et al. An evidence-based treatment algorithm for anal fissure. Tech Coloproctol. 2006;10:177–80. Marby M, Alexander-Williams J, Buchmann P, Arabi Y, Kappas A, Minervini S, et al. A randomized controlled trial to compare anal dilatation with lateral subcutaneous sphincterotomy for anal fissure. Dis Colon Rectum. 1979;22:308–11. Jensen SL, Lund F, Nielsen OV, Tange G. Lateral subcutaneous sphincterotomy versus anal dilatation in the treatment of fissure in ano in outpatients: a prospective randomised study. Br Med J (Clin Res Ed). 1984;289:528–30. Abcarian H. Surgical correction of chronic anal fissure: results of lateral internal sphincterotomy vs. fissurectomy–midline sphincterotomy. Dis Colon Rectum. 1980;23:31–6. Khubchandani IT, Reed JF. Sequelae of internal sphincterotomy for chronic fissure in ano. Br J Surg. 1989;76:431–4. Cross KLR, Brown SR, Kleijnen J, Bunce J, Paul M, Pilkington S, et al. The Association of Coloproctology of Great Britain and Ireland guideline on the management of anal fissure. Colorectal Dis. 2023;25:2423–57. Bailey HR, Beck DE, Billingham RP, Binderow SR, Gottesman L, Hull TL, et al. A study to determine the nitroglycerin ointment dose and dosing interval that best promote the healing of chronic anal fissures. Dis Colon Rectum. 2002;45:1192–9. Perrotti P, Bove A, Antropoli C, Molino D, Antropoli M, Balzano A, et al. Topical nifedipine with lidocaine ointment vs. active control for treatment of chronic anal fissure: results of a prospective, randomized, double-blind study. Dis Colon Rectum. 2002;45:1468–75. Gallo G, Trompetto M, Fulginiti S, La Torre M, Tierno S, Cantarella F, et al. Efficacy and safety of Propionibacterium extract gel versus glyceryl trinitrate ointment in the treatment of chronic anal fissure: a randomized controlled trial. Colorectal Dis. 2023;25:1698–707. Knight JS, Birks M, Farouk R. Topical diltiazem ointment in the treatment of chronic anal fissure. Br J Surg. 2001;88:553–6. Tomasicchio G, Dezi A, Picciariello A, Altomare DF, Giove C, Martines G, et al. Safety and efficacy of Levorag emulgel in the treatment of anal fissures using a validated scoring system. Front Surg. 2023;10:1145170. Brisinda G, Maria G, Sganga G, Bentivoglio AR, Albanese A, Castagneto M. Effectiveness of higher doses of botulinum toxin to induce healing in patients with chronic anal fissures. Surgery. 2002;131:179–84. Altomare DF, Rinaldi M, Milito G, Arcana F, Spinelli F, Nardelli N, et al. Glyceryl trinitrate for chronic anal fissure–healing or headache? Results of a multicenter, randomized, placebo-controled, double-blind trial. Dis Colon Rectum. 2000;43:174–9; discussion 9–81. Karamanlis E, Michalopoulos A, Papadopoulos V, Mekras A, Panagiotou D, Ioannidis A, et al. Prospective clinical trial comparing sphincterotomy, nitroglycerin ointment and xylocaine/lactulose combination for the treatment of anal fissure. Tech Coloproctol. 2010;14 Suppl 1:S21-3. Mayer B, Brunner F, Schmidt K. Inhibition of nitric oxide synthesis by methylene blue. Biochem Pharmacol. 1993;45:367–74. Xu J, Pu M, Xu X, Xiang J, Rong X. The postoperative analgesic effect of intercostal nerve block and intravenous patient-controlled analgesia on patients undergoing lung cancer surgery. Am J Transl Res. 2021;13:9790–5. Fransiska D, Jeo WS, Moenadjat Y, Friska D. Methylene Blue Effectiveness as Local Analgesic after Anorectal Surgery: A Literature Review. Adv Med. 2017;2017:3968278. Sutherland AD, Faragher IG, Frizelle FA. Intradermal injection of methylene blue for the treatment of refractory pruritus ani. Colorectal Dis. 2009;11:282–7. Tan KY, Seow-Choen F. Methylene blue injection reduces pain after lateral anal sphincterotomy. Tech Coloproctol. 2007;11:68–9. Scholefield JH, Bock JU, Marla B, Richter HJ, Athanasiadis S, Prols M, et al. A dose finding study with 0.1%, 0.2%, and 0.4% glyceryl trinitrate ointment in patients with chronic anal fissures. Gut. 2003;52:264–9. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol. 1997;32:920–4. Lund JN, Scholefield JH. Glyceryl trinitrate is an effective treatment for anal fissure. Dis Colon Rectum. 1997;40:468–70. Abatangelo G, Vindigni V, Avruscio G, Pandis L, Brun P. Hyaluronic Acid: Redefining Its Role. Cells. 2020;9. Simren M, Palsson OS, Whitehead WE. Update on Rome IV Criteria for Colorectal Disorders: Implications for Clinical Practice. Curr Gastroenterol Rep. 2017;19:15. Picciariello A, Lobascio P, Spazzafumo L, Rinaldi M, Dibra R, Trigiante G, et al. The REALISE score: a new statistically validated scoring system to assess the severity of anal fissures. Tech Coloproctol. 2021;25:935–40. Schulz KF, Altman DG, Moher D, Group C. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Obstet Gynecol. 2010;115:1063–70. Balla A, Saraceno F, Shalaby M, Gallo G, Di Saverio S, De Nardi P, et al. Surgeons' practice and preferences for the anal fissure treatment: results from an international survey. Updates Surg. 2023;75:2279–90. Gagliardi G, Pascariello A, Altomare DF, Arcana F, Cafaro D, La Torre F, et al. Optimal treatment duration of glyceryl trinitrate for chronic anal fissure: results of a prospective randomized multicenter trial. Tech Coloproctol. 2010;14:241–8. Kim SH, Ahn SH, Cho YW, Lee DG. Effect of Intradiscal Methylene Blue Injection for the Chronic Discogenic Low Back Pain: One Year Prospective Follow-up Study. Ann Rehabil Med. 2012;36:657–64. Raines S, Hedlund C, Franzon M, Lillieborg S, Kelleher G, Ahlen K. Ropivacaine for continuous wound infusion for postoperative pain management: a systematic review and meta-analysis of randomized controlled trials. Eur Surg Res. 2014;53:43–60. Sim HL, Tan KY. Randomized single-blind clinical trial of intradermal methylene blue on pain reduction after open diathermy haemorrhoidectomy. Colorectal Dis. 2014;16:O283-7. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 03 Jan, 2025 Read the published version in Techniques in Coloproctology → Version 1 posted Editorial decision: Revision requested 10 Aug, 2024 Reviews received at journal 10 Aug, 2024 Reviewers agreed at journal 10 Aug, 2024 Reviewers agreed at journal 01 Jul, 2024 Reviewers invited by journal 10 Jun, 2024 Editor assigned by journal 09 Jun, 2024 Submission checks completed at journal 20 May, 2024 First submitted to journal 20 May, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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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-4448360","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":304526268,"identity":"016af92e-8e26-4db3-9b5f-ce621108fa7c","order_by":0,"name":"Pierluigi Lobascio","email":"","orcid":"","institution":"Hospital University of Bari","correspondingAuthor":false,"prefix":"","firstName":"Pierluigi","middleName":"","lastName":"Lobascio","suffix":""},{"id":304526269,"identity":"2358cf0c-0381-4790-93f9-0ec995ea3ade","order_by":1,"name":"Giovanni Tomasicchio","email":"","orcid":"","institution":"Hospital University of Bari","correspondingAuthor":false,"prefix":"","firstName":"Giovanni","middleName":"","lastName":"Tomasicchio","suffix":""},{"id":304526270,"identity":"bcb318a0-40ad-41d1-a52a-7212d15c236c","order_by":2,"name":"Noadia Cassetta","email":"","orcid":"","institution":"Farmacia Santelia","correspondingAuthor":false,"prefix":"","firstName":"Noadia","middleName":"","lastName":"Cassetta","suffix":""},{"id":304526271,"identity":"d5b804e8-5272-4bb9-8c58-7c478e0cf5bf","order_by":3,"name":"Donato Francesco Altomare","email":"","orcid":"","institution":"Hospital University of Bari","correspondingAuthor":false,"prefix":"","firstName":"Donato","middleName":"Francesco","lastName":"Altomare","suffix":""},{"id":304526272,"identity":"fe1ffad1-8144-4e05-8a31-d1773032e1c6","order_by":4,"name":"Gaetano Gallo","email":"","orcid":"","institution":"Sapienza University of Rome","correspondingAuthor":false,"prefix":"","firstName":"Gaetano","middleName":"","lastName":"Gallo","suffix":""},{"id":304526273,"identity":"d0393e61-6e78-4534-be85-b828d3eeda4f","order_by":5,"name":"Angela Pezzolla","email":"","orcid":"","institution":"Hospital University of Bari","correspondingAuthor":false,"prefix":"","firstName":"Angela","middleName":"","lastName":"Pezzolla","suffix":""},{"id":304526274,"identity":"3f99b03d-4789-4db8-a239-4d9381e281af","order_by":6,"name":"Rita Laforgia","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/UlEQVRIiWNgGAWjYDACZiB+wCAHJBkbGD42gIQYGw8wGODTAtSTwGAM1sI4s4FBAsQAasGrB6YFyOQFa2FgOMCAxxrzdv6DHxJqDOTM+xc3frbdYVOn234YaEvBH5xaZA4zM0skHDMwlrnxsFk690yahNmZRPwOkwD6RSKB7U/iDImDDdK5bYclzA4Q1sL8I+GfAUhL829LkJbzDwlqYZNIbANq4W9sk2YEablB2BYzi8Q+A2MJCcY2y962NMltN4C2JBgY49bCf/DxjQ/fDOQk+I8/vvGzzYbf7Hz6wwcf/sjh1IKkOQGJk4BDESrgP0CUslEwCkbBKBiBAAB1flVUihNpuAAAAABJRU5ErkJggg==","orcid":"","institution":"Hospital University of Bari","correspondingAuthor":true,"prefix":"","firstName":"Rita","middleName":"","lastName":"Laforgia","suffix":""}],"badges":[],"createdAt":"2024-05-20 10:11:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4448360/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4448360/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10151-024-03029-8","type":"published","date":"2025-01-03T15:57:44+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":57729122,"identity":"d8e641ed-8b0e-4041-9311-ccf58914ff5e","added_by":"auto","created_at":"2024-06-04 21:51:38","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":292284,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eOintment – blue cream\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4448360/v1/ad0423dca691b69544cc2fb5.jpg"},{"id":57729120,"identity":"9031b2dd-7dbd-4516-9dd1-3dff3c76b32d","added_by":"auto","created_at":"2024-06-04 21:51:38","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1382308,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eApplication of the ointment\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4448360/v1/140d4de4b0d93549536067b7.jpg"},{"id":57729119,"identity":"5ae9439a-5873-46f7-9edc-4115afa29e8c","added_by":"auto","created_at":"2024-06-04 21:51:38","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":83011,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eCONSORT diagrams - included patients flowchart\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure34.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4448360/v1/8a7bcb7f73efac99ebb6e668.jpg"},{"id":57730165,"identity":"8a73b5cd-3fa9-4230-80d3-ef18469031f9","added_by":"auto","created_at":"2024-06-04 21:59:38","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":44258,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eREALISE score at the baseline vs 40 days from the start of treatment with three different creams\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4448360/v1/f1aa80d1a7f55799b1b13a99.jpg"},{"id":73093368,"identity":"01b9f3a7-bfe9-464b-9a74-c82b61c88d84","added_by":"auto","created_at":"2025-01-06 16:15:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2324403,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4448360/v1/28f63b57-b432-48c8-90d6-a162b2831538.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The use of a methylene blue and glyceryl trinitrate- based cream for the treatment of chronic anal fissures: a phase II randomized pilot trial from a referral coloproctological unit","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAnal fissures were described for the first time by Lockhart-Mummery as a linear or over-shaped tear in the anoderm [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Chronic anal fissures (CAFs) are the second most common anorectal disease [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], causing significant morbidity and QoL deterioration [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The main symptom is intense burning anal pain and sometimes minor bleeding occurring during and after defecation. The usual location of anal fissures is the posterior midline [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], worsened by the spasm of the internal anal sphincter [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The treatment of anal sphincter spasms is considered a crucial target for curing the fissure [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Although surgery by lateral sphincterotomy is still the gold standard for curing anal fissures [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], in the last two decades, less invasive, conservative strategies have been considered as first-line treatments because of the fear of causing faecal incontinence, which is reported in up to 35% of patients [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe non-surgical treatment of anal fissures now includes several options [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]: glyceryl trinitrate ointment [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], anaesthetics (such as Lidocaine), steroids, calcium channel-blocking drugs (CCBs) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], diltiazem ointments [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], and botulinum toxin injections [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The efficacy of these treatments is widely reported in the literature; however, several trials comparing their effectiveness report conflicting results [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMethylene blue is a non-toxic dye that inhibits soluble guanylate cyclase and nitric oxide synthase. Nitric oxide regulates physiological functions such as pain and analgesia by activating soluble guanylate cyclase to increase intracellular cyclic guanosine monophosphate [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. It has been used intra-dermally in proctology, mainly for the treatment of intractable pruritus ani, because of its analgesic effect due to its interaction with nervous dermal receptors for pain and pruritus [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]; it has recently been used to minimize anal pain after lateral sphincterotomy for anal fissures [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], but it has never been used in as an adjunct to myorelaxant agents for the treatment of chronic fissures.\u003c/p\u003e \u003cp\u003eThe aim of this study was to evaluate the efficacy and safety of a new ointment based on methylene blue in addition to glyceryl trinitrate in the treatment of chronic anal fissures.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eA phase II randomized single-centre triple-blinded study was carried out in a tertiary proctology unit on patients with chronic anal fissures between June 2022 and April 2023. After receiving approval from the local ethics committee (Study n.6461, Protocol approval n. 0045085/17.05.2022), patients of both sexes aged between 20 and 65 years with chronic anal fissures were enrolled. The exclusion criteria included previous medical or surgical treatment, acute anal fissure, infected or fistulized anal fissure, perineal Crohn\u0026rsquo;s disease, other proctological diseases, functional disorder of defecation and continence, severe liver and/or kidney disease, radiation proctitis, previous history of orthostatic hypotension, intolerance to nitrates, treatment with nitrate drugs for heart ischemia, sexually transmitted disease, cancer, those undergoing immunosuppressive treatment, pregnant or breastfeeding, or known allergy to one of the agents contained in the evaluating drugs.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAcute fissures were defined as recently occurred (within 6 weeks) ulcerations of the anoderm, while chronic anal fissures were characterized as persisting for more than 6 weeks with the presence of the features proposed by Scholefield et al. [27]: a sentinel skin tag, hypertrophic anal papillae, an exposed internal anal sphincter, a fibrotic lateral fissure, or a fibrotic anal sphincter.\u003c/p\u003e\n\u003cp\u003eDemographic data and detailed clinical histories were recorded, including information about anal pain intensity and duration, bowel habits, and stool consistency (using the Bristol stool scale) [28], before treatment. Patients were examined in the Sims position in an outpatient setting. The anal verge was inspected to confirm the presence of an anal fissure and to determine its location. When tolerated, digital rectal examination (DRE) to evaluate the anal sphincter tone and anoscopy were performed. In cases where it was impossible to perform both a DRE and anoscopy during enrolment, the anal fissure site was determined by inspecting the anal region by asking the patient to bear down during defaecation while spreading the glutei. In cases with a suspicious and unusual location, a colonoscopy was performed to rule out other neoplastic or inflammatory disorders.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEligible consecutive patients were randomized to create three different groups, each receiving a different ointment. The ointments were prepared in a pharmacy as follows:\u003c/p\u003e\n\u003cp\u003e\u0026bull;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Cream A: glyceryl trinitrate 0.4%, ialuronic acid 1%, soft white paraffin, ultramarine blue cosmetic pigment;\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Cream B: glyceryl trinitrate 0.4%, methylene blue 2%, ialuronic acid 1%, soft white paraffin;\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Cream C: glyceryl trinitrate 0.4%, methylene blue 0.4%, ialuronic Acid 1%, soft white paraffin.\u003c/p\u003e\n\u003cp\u003eDifferent concentrations of methylene blue were used to prove and compare their efficacy and safety. Glyceryl trinitrate was used as a nitric oxide donor to promote muscle relaxation, thus leading to fissure healing [29]. Ialuronic acid has been demonstrated to play a crucial role in influencing the inflammatory, proliferative, or re-modelling phases of the healing process [30]. Soft white paraffin was added in variable quantities to reach the final weight of 30 g in each tube. Each ointment was kept in a tube labelled A, B or C, respectively, according to the randomization code produced by the pharmacist and unknown to the operators and patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study was designed specifically to prevent bias, applying a triple-blinded permuted block randomization method: surgeons, statistician, and patients were blinded to the administered treatment. The evaluation of safety in the procedure was considered with the notification of every ADR (adverse drug reaction), which would result in withdrawal from the study for the patient involved.\u003c/p\u003e\n\u003cp\u003eAfter a clear and complete explanation of the study, possible side effects, and acceptance with written informed consent, approximately 200 mg of the ointment was applied directly on the anoderm. (Figures 1,2). Patients were tested for at least 20 minutes to evaluate any adverse effects, and they instructed to apply the ointment twice a day (every 12 h) for 30 days using the tip of their finger. In patients with constipation (according to the Roma IV criteria [31]), an oral laxative (PEG solution) was administered for at least 1 month.\u003c/p\u003e\n\u003cp\u003eThe efficacy of the treatment was evaluated using the REALISE score, a validated scoring system that rates the VAS for pain (score range: 0\u0026ndash;10), NSAID use, pain duration, bleeding, and quality of life (QoL) on a scale of 1\u0026ndash;5 [32] .The score was calculated during the first clinical evaluation, at day 10, at day 20 via a telephone interview, and at day 30 via an proctological outpatient evaluation. Furthermore, side effects were recorded. The degree of re-epithelization (healing) was evaluated and scored as follows: 0 = anal fissure still present; 1 = superficial fissure; 2 = partial re-epithelization; 3 = complete re-epithelization. Patient satisfaction was rated on a scale of 0 (failure) to 5 (excellent). The ointments were free-of-charge for all patients, while the production and preparation of the agents were based exclusively on the pharmacy\u0026rsquo;s rates.\u003c/p\u003e\n\u003ch2\u003e2.1 Statistical Analysis\u003c/h2\u003e\n\u003cp\u003eThe continuous parameters are reported as the median and interquartile ranges. The categorical variables were recorded as numbers and percentages where appropriate. Comparisons of the categorical variables were performed using the \u0026chi;2 and Fisher\u0026rsquo;s exact test where appropriate. Comparisons between groups were made using the Kruskal\u0026ndash;Wallis test with Bonferroni corrections. A p value \u0026lt; 0.05 was considered statistically significant. Statistical analyses were carried out using RStudio (R version 4.0.3 10/ 10/2020 Copyright\u0026copy; 2020, The R Foundation for Statistical Computing).\u003c/p\u003e\n\u003ch2\u003e2.2 Ethical approval declarations\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003e1. Local Ethical Committee form Hospital University of Bari approved this study with n.6461 and \u0026nbsp;Protocol approval n. 0045085/17.05.2022)\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp;\u0026nbsp;The methods were carried out in accordance with the relevant guidelines and regulations\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp;\u0026nbsp;Informed consent was obtained from all participants and/or their legal guardian/s\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThirty patients (median age 53 years, IQR 43\u0026ndash;61, 35% female) with anterior (3, 10%), posterior (25, 83.3%), or antero-posterior (2, 6.6%) chronic anal fissures were entered into the study after giving informed consent. Twenty-seven patients completed both the telephone interviews and proctological evaluation at day 40. Three out of thirty (10%) patients discontinued the medical therapy: two patients due to headaches (one with Cream A and one with Cream B) and one due to anal itching (Cream C). Patients were divided in three groups and treated with the three different creams: nine patients with Cream A (median age 47 years, IQR 40\u0026ndash;56, 22% female), nine with Cream B (median age 52 years, IQR 49\u0026ndash;57, 33% female), and nine with Cream C (median age 58 years, IQR 46\u0026ndash;62, 55% female), as is show in the CONSORT diagrams [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Digital rectal examination (DRE) was performed in eight patients (88%) of group A, seven (78%) of group B, and nine (100%) of group C; no statistical differences were observed between the groups. Not all patients who underwent DRE tolerated anoscopy (55% of group A, 33% of group B, and 78% of group C), and no statistical differences were observed between the groups. The baseline characteristics of patients with chronic anal fissures are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of patients with chronic anal fissures\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup A\u003c/p\u003e \u003cp\u003e\u003cem\u003en\u0026thinsp;=\u0026thinsp;9\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup B\u003c/p\u003e \u003cp\u003e\u003cem\u003en\u0026thinsp;=\u0026thinsp;9\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup C\u003c/p\u003e \u003cp\u003e\u003cem\u003en\u0026thinsp;=\u0026thinsp;9\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep-value\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003cp\u003e- M\u003c/p\u003e \u003cp\u003e- F\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (78%)\u003c/p\u003e \u003cp\u003e2 (22%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (67%)\u003c/p\u003e \u003cp\u003e3 (33%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (45%)\u003c/p\u003e \u003cp\u003e5 (55%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.61\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47 (40\u0026ndash;56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52 (49\u0026ndash;57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58 (46\u0026ndash;62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSide\u003c/b\u003e\u003c/p\u003e \u003cp\u003e- Anterior\u003c/p\u003e \u003cp\u003e- Posterior\u003c/p\u003e \u003cp\u003e- Anterior\u0026thinsp;+\u0026thinsp;Posterior\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e8\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e7\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e7\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDRE\u003c/b\u003e\u003c/p\u003e \u003cp\u003e- Yes\u003c/p\u003e \u003cp\u003e- No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (89%)\u003c/p\u003e \u003cp\u003e1 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (78%)\u003c/p\u003e \u003cp\u003e2 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAnoscopy\u003c/b\u003e\u003c/p\u003e \u003cp\u003e- Yes\u003c/p\u003e \u003cp\u003e- No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (55%)\u003c/p\u003e \u003cp\u003e4 (45%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (33%)\u003c/p\u003e \u003cp\u003e6 (67%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (78%)\u003c/p\u003e \u003cp\u003e2 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe anal pain, according to the visual analogue scale (VAS), had a median value\u0026thinsp;\u0026ge;\u0026thinsp;7 in all of the three groups at the base line evaluation (A: 7, IQR 5\u0026ndash;10; B: 9, IQR 7\u0026ndash;10; C: 8, IQR 7\u0026ndash;10) without any statistical differences between the groups. At the proctological evaluation at day 40, the VAS scores significantly decreased with all three creams (A: 2, IQR 1\u0026ndash;4; B: 1, IQR 0\u0026ndash;4; C: 0, IQR 0\u0026ndash;0), with a statistical difference observed between Creams A and C (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). A significant reduction in NSAID intake was observed in groups B and C (B: 3, IQR 1\u0026ndash;4 vs. 1, IQR 1\u0026ndash;1; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 and C: 3, IQR 1\u0026ndash;3 vs. 1, IQR 1\u0026ndash;1; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), with no statistical differences observed between the groups. In group A, the REALISE scores decreased significantly from a median of 22 (IQR 12\u0026ndash;25) to 6 (IQR 4\u0026ndash;8) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) after 40 days. In group B, the REALISE scores improved significantly from a median of 20 (IQR 17\u0026ndash;22) to 5 (IQR 4\u0026ndash;9) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). In group C, the REALISE scores decreased significantly from a median of 19 (IQR 19\u0026ndash;20) to 4 (4\u0026ndash;5) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). No statistically differences were recorded between the groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The REALISE scores at the baseline, day 10, day 20, and day 40 are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The healing rate was 77% with Creams A and C, while it was 44% with Cream B. At the last consultation, the satisfaction rating had a higher median score (excellent) with Creams B (5, IRQ 4\u0026ndash;5) and C (5, IQR 5\u0026ndash;5), while the median score with Cream A was 4 (IQR 3\u0026ndash;5), with no statistical differences reported between the groups. No severe adverse events were recorded. Six (22%) patients (two different groups) reported transient headaches, while one patient from group A and two from group B reported itching after ointment application.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eREALISE domains at the baseline, 10\u0026ndash;20 and 40 days from the start of treatment.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCream A\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u0026thinsp;=\u0026thinsp;9\u003c/em\u003e)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCream B\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u0026thinsp;=\u0026thinsp;9\u003c/em\u003e)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCream C\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u0026thinsp;=\u0026thinsp;9\u003c/em\u003e)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep-value\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVAS\u003c/p\u003e \u003cp\u003e- Baseline\u003c/p\u003e \u003cp\u003e- 10 days\u003c/p\u003e \u003cp\u003e- 20 days\u003c/p\u003e \u003cp\u003e- 40 days\u003c/p\u003e \u003cp\u003e\u003cem\u003ep-value\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (5\u0026ndash;10)\u003c/p\u003e \u003cp\u003e4 (2\u0026ndash;6)\u003c/p\u003e \u003cp\u003e1 (0\u0026ndash;6)\u003c/p\u003e \u003cp\u003e2 (1\u0026ndash;4)\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (7\u0026ndash;10)\u003c/p\u003e \u003cp\u003e3 (2\u0026ndash;5)\u003c/p\u003e \u003cp\u003e1 (1\u0026ndash;4)\u003c/p\u003e \u003cp\u003e1 (0\u0026ndash;4)\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (7\u0026ndash;10)\u003c/p\u003e \u003cp\u003e2 (0\u0026ndash;6)\u003c/p\u003e \u003cp\u003e0 (0\u0026ndash;2)\u003c/p\u003e \u003cp\u003e0 (0\u0026ndash;0)\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003cp\u003e0.85\u003c/p\u003e \u003cp\u003e0.33\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.05 (1\u0026ndash;3\u0026thinsp;=\u0026thinsp;0.02)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePain Duration\u003c/p\u003e \u003cp\u003e- Baseline\u003c/p\u003e \u003cp\u003e- 10 days\u003c/p\u003e \u003cp\u003e- 20 days\u003c/p\u003e \u003cp\u003e- 40 days\u003c/p\u003e \u003cp\u003e\u003cem\u003ep-value\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (2\u0026ndash;5)\u003c/p\u003e \u003cp\u003e2 (1\u0026ndash;3)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (2\u0026ndash;3)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;2)\u003c/p\u003e \u003cp\u003e1 (1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e1 (1\u0026ndash;2)\u003c/p\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (1\u0026ndash;5)\u003c/p\u003e \u003cp\u003e1 (1\u0026ndash;2)\u003c/p\u003e \u003cp\u003e1 (1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003cp\u003e0.50\u003c/p\u003e \u003cp\u003e0.70\u003c/p\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNSAID use\u003c/b\u003e\u003c/p\u003e \u003cp\u003e- Baseline\u003c/p\u003e \u003cp\u003e- 10 days\u003c/p\u003e \u003cp\u003e- 20 days\u003c/p\u003e \u003cp\u003e- 40 days\u003c/p\u003e \u003cp\u003e\u003cem\u003ep-value\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (1\u0026ndash;4)\u003c/p\u003e \u003cp\u003e1 (1\u0026ndash;2)\u003c/p\u003e \u003cp\u003e1 (1\u0026ndash;2)\u003c/p\u003e \u003cp\u003e1 (1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3(1\u0026ndash;4)\u003c/p\u003e \u003cp\u003e2 (1\u0026ndash;3)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;2)\u003c/p\u003e \u003cp\u003e1 (1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (1\u0026ndash;3)\u003c/p\u003e \u003cp\u003e1 (1\u0026ndash;2)\u003c/p\u003e \u003cp\u003e1 (1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e1 (1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.99\u003c/p\u003e \u003cp\u003e0.44\u003c/p\u003e \u003cp\u003e0.84\u003c/p\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBleeding\u003c/b\u003e\u003c/p\u003e \u003cp\u003e- Baseline\u003c/p\u003e \u003cp\u003e- 10 days\u003c/p\u003e \u003cp\u003e- 20 days\u003c/p\u003e \u003cp\u003e- 40 days\u003c/p\u003e \u003cp\u003e\u003cem\u003ep-value\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(1\u0026ndash;5)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (1\u0026ndash;4)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (1\u0026ndash;3)\u003c/p\u003e \u003cp\u003e1 (1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003cp\u003e0.76\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eQol\u003c/b\u003e\u003c/p\u003e \u003cp\u003e- Baseline\u003c/p\u003e \u003cp\u003e- 10 days\u003c/p\u003e \u003cp\u003e- 20 days\u003c/p\u003e \u003cp\u003e- 40 days\u003c/p\u003e \u003cp\u003e\u003cem\u003ep-value\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (2\u0026ndash;5)\u003c/p\u003e \u003cp\u003e2(1\u0026ndash;3)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;2)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (4\u0026ndash;4)\u003c/p\u003e \u003cp\u003e2(2\u0026ndash;2)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;2)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4(4\u0026ndash;5)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;2)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.68\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.05 (1\u0026ndash;3\u0026thinsp;=\u0026thinsp;0.03)\u003c/p\u003e \u003cp\u003e0.50\u003c/p\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDefecation\u003c/b\u003e\u003c/p\u003e \u003cp\u003e- Baseline\u003c/p\u003e \u003cp\u003e- 10 days\u003c/p\u003e \u003cp\u003e- 20 days\u003c/p\u003e \u003cp\u003e- 40 days\u003c/p\u003e \u003cp\u003e\u003cem\u003ep-value\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(0\u0026ndash;1)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(0\u0026ndash;1)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0(0\u0026ndash;0)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e1(1\u0026ndash;1)\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003cp\u003e0.36\u003c/p\u003e \u003cp\u003e0.35\u003c/p\u003e \u003cp\u003e0.84\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRealise\u003c/b\u003e\u003c/p\u003e \u003cp\u003e- Baseline\u003c/p\u003e \u003cp\u003e- 10 days\u003c/p\u003e \u003cp\u003e- 20 days\u003c/p\u003e \u003cp\u003e- 40 days\u003c/p\u003e \u003cp\u003e\u003cem\u003ep-value\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (12\u0026ndash;25)\u003c/p\u003e \u003cp\u003e11(6\u0026ndash;14)\u003c/p\u003e \u003cp\u003e5 (4\u0026ndash;12)\u003c/p\u003e \u003cp\u003e6(4\u0026ndash;8)\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20(17\u0026ndash;22)\u003c/p\u003e \u003cp\u003e10(8\u0026ndash;11)\u003c/p\u003e \u003cp\u003e6 (5\u0026ndash;12)\u003c/p\u003e \u003cp\u003e5(4\u0026ndash;9)\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 (19\u0026ndash;20)\u003c/p\u003e \u003cp\u003e8 (6\u0026ndash;12)\u003c/p\u003e \u003cp\u003e6(4\u0026ndash;6)\u003c/p\u003e \u003cp\u003e4(4\u0026ndash;5)\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003cp\u003e0.73\u003c/p\u003e \u003cp\u003e0.55\u003c/p\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eCAFs significantly affect patients\u0026rsquo; QoL because of the pain caused by this distal anal condition. In the literature, the application of either operative or non-operative management of CAFs is still debated. Non-operative management is a well-defined approach, and it is the first-line approach for treating anal fissures, reducing the associated anal spasms with pain decreases, and fissure healing in up to 80% of the cases [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Balla et al. reported that for CAF treatment, colorectal surgeons consider lateral internal sphincterotomy as the first surgical option, only in 15.1% of cases, opting mostly for medical treatment [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe optimal non-operative CAF treatment has not yet been established, and this approach is deemed controversial in the literature; however, several topical ointments have been proposed as non-invasive treatments in the past few decades [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSeveral studies have reported the effect of topical nitrates in rapid pain relief and success in healing CAFs. In their randomized open-label multi-centre trial, Gagliardi et al. reported an overall success rate in CAF healing of 43% with topical trinitrate, underling that the optimal treatment duration for topical nitrate was 6 weeks [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. In line with the literature, our data reported a healing rate of 77% with the 0.4% methylene blue ointment, exhibiting an excellent satisfaction score, significant reductions in anal pain, and no severe adverse events recorded. The design of this study considered a new ointment based on the addition of several components, including methylene blue, with the aim of healing and reducing pain during non-operative treatment of CAFs. In the literature, the analgesic properties of methylene blue is well known due to its temporary disruption of sensory nerve conduction. It is a non-toxic dye that inhibits soluble guanylate cyclase and nitric oxide synthase. Nitric oxide regulates physiological functions such as pain and analgesia by activating soluble guanylate cyclase to increase intracellular cyclic guanosine monophosphate [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Methylene blue, as an oxidizing\u0026ndash;reducing agent, demonstrates a strong affinity for nerve tissues when applied locally, which can directly block the electrical conductivity of nerve fibres, thereby affecting neural excitability and impulse conductivity. Recent studies have shown that low doses (0.5 or 1%) of methylene blue may block peripheral nerve fibres at the incision. Local application of methylene blue could cause reversible damage to the incision and its surrounding subcutaneous nerve terminal medulla, thus achieving a long-acting post-operative analgesic effect. However, this damage will cause a burning sensation between 2 and 4 hours after injection. To eliminate this burning sensation, methylene blue can be combined with local anaesthetic drugs [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. In their single-blind prospective randomized placebo-controlled trial, Sim et al. reported a significant reduction in post-operative pain after open haemorrhoidectomy in patients treated with perianal intradermal injections of methylene blue due to the unique property of temporarily ablating dermal nerve endings [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. The preparations with methylene blue used in our trial reported an increased healing rate and reduction in REALISE score with no statistical differences when compared to glyceryl trinitrate preparation. Cream C with 0.4% methylene blue showed a median VAS score of 0 at day 40, with a statistically significant difference when compared to Cream A without methylene blue. Furthermore, Cream C, with a lower percentage of methylene blue (0.4%), had a statistically significant reduction in the REALISE score, an excellent satisfaction score (5, IQR 5\u0026ndash;5), and no noted side effects. Cream B, with a higher percentage of methylene blue (2%), reported itching in 22% of patients after the application, with complicated local dermatitis in 50% of them. The main limitation of this study is its small sample size, which is strict and could represent a possible selection bias; however, this is a pilot, single-centre study. Multi-centre studies are currently in progress to try to avoid these biases and to enrol a higher number of patients.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eMethylene blue-based ointments are safe and effective for improving patient quality of life according to the REALISE score. Methylene blue-based ointments could be a new and innovative treatment for the non-operative management and healing of CAFs. Furthermore, multi-centre studies and shared guidelines are necessary to standardize the treatment and improve the patients\u0026rsquo; quality of life.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eFunding: \u0026nbsp;This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003eConflict of interest: The authors have no conflicts of interest to declare. All co-authors have seen and agree with the contents of the manuscript and there is no financial interest to report. We certify that the submission is original work and is not under review at any other publication.\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate: section 2.2\u003c/p\u003e\n\u003cp\u003eConsent for publication :Written informed consent was obtained from all participants.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData and materials availability: All data and materials can be acquired from the corresponding author.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAuthor contribution: All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Pierluigi Lobascio, Gaetano Gallo, Angela Pezzolla, Donato Francesco Altomare, Noadia Cassetta. The first draft of the manuscript was written by Rita Laforgia and Giovanni Tomasicchio. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eJP L-M. Diseases of the rectum and colon and their surgical treatment. 2nd ed London: Bailli\u0026egrave;re, Tindall \u0026amp; Cox. 1934.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOrsay C, Rakinic J, Perry WB, Hyman N, Buie D, Cataldo P, et al. Practice parameters for the management of anal fissures (revised). Dis Colon Rectum. 2004;47:2003\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLund JN, Scholefield JH. Aetiology and treatment of anal fissure. Br J Surg. 1996;83:1335\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGriffin N, Acheson AG, Tung P, Sheard C, Glazebrook C, Scholefield JH. Quality of life in patients with chronic anal fissure. Colorectal Dis. 2004;6:39\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmerican Gastroenterological A. American Gastroenterological Association medical position statement: Diagnosis and care of patients with anal fissure. Gastroenterology. 2003;124:233\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchouten WR, Briel JW, Auwerda JJ, De Graaf EJ. Ischaemic nature of anal fissure. Br J Surg. 1996;83:63\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSteele SR, Madoff RD. Systematic review: the treatment of anal fissure. Aliment Pharmacol Ther. 2006;24:247\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLund JN, Nystrom PO, Coremans G, Herold A, Karaitianos I, Spyrou M, et al. An evidence-based treatment algorithm for anal fissure. Tech Coloproctol. 2006;10:177\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarby M, Alexander-Williams J, Buchmann P, Arabi Y, Kappas A, Minervini S, et al. A randomized controlled trial to compare anal dilatation with lateral subcutaneous sphincterotomy for anal fissure. Dis Colon Rectum. 1979;22:308\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJensen SL, Lund F, Nielsen OV, Tange G. Lateral subcutaneous sphincterotomy versus anal dilatation in the treatment of fissure in ano in outpatients: a prospective randomised study. Br Med J (Clin Res Ed). 1984;289:528\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbcarian H. Surgical correction of chronic anal fissure: results of lateral internal sphincterotomy vs. fissurectomy\u0026ndash;midline sphincterotomy. Dis Colon Rectum. 1980;23:31\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhubchandani IT, Reed JF. Sequelae of internal sphincterotomy for chronic fissure in ano. Br J Surg. 1989;76:431\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCross KLR, Brown SR, Kleijnen J, Bunce J, Paul M, Pilkington S, et al. The Association of Coloproctology of Great Britain and Ireland guideline on the management of anal fissure. Colorectal Dis. 2023;25:2423\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBailey HR, Beck DE, Billingham RP, Binderow SR, Gottesman L, Hull TL, et al. A study to determine the nitroglycerin ointment dose and dosing interval that best promote the healing of chronic anal fissures. Dis Colon Rectum. 2002;45:1192\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerrotti P, Bove A, Antropoli C, Molino D, Antropoli M, Balzano A, et al. Topical nifedipine with lidocaine ointment vs. active control for treatment of chronic anal fissure: results of a prospective, randomized, double-blind study. Dis Colon Rectum. 2002;45:1468\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGallo G, Trompetto M, Fulginiti S, La Torre M, Tierno S, Cantarella F, et al. Efficacy and safety of Propionibacterium extract gel versus glyceryl trinitrate ointment in the treatment of chronic anal fissure: a randomized controlled trial. Colorectal Dis. 2023;25:1698\u0026ndash;707.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKnight JS, Birks M, Farouk R. Topical diltiazem ointment in the treatment of chronic anal fissure. Br J Surg. 2001;88:553\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTomasicchio G, Dezi A, Picciariello A, Altomare DF, Giove C, Martines G, et al. Safety and efficacy of Levorag emulgel in the treatment of anal fissures using a validated scoring system. Front Surg. 2023;10:1145170.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrisinda G, Maria G, Sganga G, Bentivoglio AR, Albanese A, Castagneto M. Effectiveness of higher doses of botulinum toxin to induce healing in patients with chronic anal fissures. Surgery. 2002;131:179\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAltomare DF, Rinaldi M, Milito G, Arcana F, Spinelli F, Nardelli N, et al. Glyceryl trinitrate for chronic anal fissure\u0026ndash;healing or headache? Results of a multicenter, randomized, placebo-controled, double-blind trial. Dis Colon Rectum. 2000;43:174\u0026ndash;9; discussion 9\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaramanlis E, Michalopoulos A, Papadopoulos V, Mekras A, Panagiotou D, Ioannidis A, et al. Prospective clinical trial comparing sphincterotomy, nitroglycerin ointment and xylocaine/lactulose combination for the treatment of anal fissure. Tech Coloproctol. 2010;14 Suppl 1:S21-3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMayer B, Brunner F, Schmidt K. Inhibition of nitric oxide synthesis by methylene blue. Biochem Pharmacol. 1993;45:367\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu J, Pu M, Xu X, Xiang J, Rong X. The postoperative analgesic effect of intercostal nerve block and intravenous patient-controlled analgesia on patients undergoing lung cancer surgery. Am J Transl Res. 2021;13:9790\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFransiska D, Jeo WS, Moenadjat Y, Friska D. Methylene Blue Effectiveness as Local Analgesic after Anorectal Surgery: A Literature Review. Adv Med. 2017;2017:3968278.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSutherland AD, Faragher IG, Frizelle FA. Intradermal injection of methylene blue for the treatment of refractory pruritus ani. Colorectal Dis. 2009;11:282\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTan KY, Seow-Choen F. Methylene blue injection reduces pain after lateral anal sphincterotomy. Tech Coloproctol. 2007;11:68\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScholefield JH, Bock JU, Marla B, Richter HJ, Athanasiadis S, Prols M, et al. A dose finding study with 0.1%, 0.2%, and 0.4% glyceryl trinitrate ointment in patients with chronic anal fissures. Gut. 2003;52:264\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol. 1997;32:920\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLund JN, Scholefield JH. Glyceryl trinitrate is an effective treatment for anal fissure. Dis Colon Rectum. 1997;40:468\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbatangelo G, Vindigni V, Avruscio G, Pandis L, Brun P. Hyaluronic Acid: Redefining Its Role. Cells. 2020;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSimren M, Palsson OS, Whitehead WE. Update on Rome IV Criteria for Colorectal Disorders: Implications for Clinical Practice. Curr Gastroenterol Rep. 2017;19:15.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePicciariello A, Lobascio P, Spazzafumo L, Rinaldi M, Dibra R, Trigiante G, et al. The REALISE score: a new statistically validated scoring system to assess the severity of anal fissures. Tech Coloproctol. 2021;25:935\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchulz KF, Altman DG, Moher D, Group C. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Obstet Gynecol. 2010;115:1063\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBalla A, Saraceno F, Shalaby M, Gallo G, Di Saverio S, De Nardi P, et al. Surgeons' practice and preferences for the anal fissure treatment: results from an international survey. Updates Surg. 2023;75:2279\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGagliardi G, Pascariello A, Altomare DF, Arcana F, Cafaro D, La Torre F, et al. Optimal treatment duration of glyceryl trinitrate for chronic anal fissure: results of a prospective randomized multicenter trial. Tech Coloproctol. 2010;14:241\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim SH, Ahn SH, Cho YW, Lee DG. Effect of Intradiscal Methylene Blue Injection for the Chronic Discogenic Low Back Pain: One Year Prospective Follow-up Study. Ann Rehabil Med. 2012;36:657\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaines S, Hedlund C, Franzon M, Lillieborg S, Kelleher G, Ahlen K. Ropivacaine for continuous wound infusion for postoperative pain management: a systematic review and meta-analysis of randomized controlled trials. Eur Surg Res. 2014;53:43\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSim HL, Tan KY. Randomized single-blind clinical trial of intradermal methylene blue on pain reduction after open diathermy haemorrhoidectomy. Colorectal Dis. 2014;16:O283-7.\u003c/span\u003e\u003c/li\u003e\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, anal pain, realise scoring system, blue cream, methylene blue, glyceryl trinitrate","lastPublishedDoi":"10.21203/rs.3.rs-4448360/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4448360/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBACKGROUND (MAIN AIM): Chronic anal fissures (CAFs) are the second most common anorectal disease. Non-surgical treatment includes several options with controversial efficacy. The aim of this study was to evaluate the efficacy and safety of a new ointment based on methylene blue in addition to glyceryl trinitrate.\u003c/p\u003e \u003cp\u003eMETHODS: A phase II randomized single-centre triple-blinded study was carried out in a tertiary proctology unit on patients with CAF. The enrollment started after local ethical approval (Study n.6461, Protocol approval n. 0045085). Eligible consecutive patients were randomized to create three different groups, each receiving a different ointment. The efficacy of the treatment was evaluated with the REALISE score.\u003c/p\u003e \u003cp\u003eRESULTS: Nine patients with Cream A (median age 47 years, IQR 40\u0026ndash;56, 22% female), nine with B (median age 52 years, IQR 49\u0026ndash;57, 33% female), and nine with C (median age 58 years, IQR 46\u0026ndash;62, 55% female). In group A, REALISE scores decreased significantly from a median of 22 (IQR 12\u0026ndash;25) to 6 (IQR 4\u0026ndash;8) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) after 40 days. In group B, REALISE scores improved significantly from a median of 20 (IQR 17\u0026ndash;22) to 5 (IQR 4\u0026ndash;9) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). In group C, REALISE scores decreased significantly from a median of 19 (IQR 19\u0026ndash;20) to 4 (4\u0026ndash;5) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). No statistically differences were recorded. The healing rate was 77% with Creams A and C, while it was 44% with Cream B.\u003c/p\u003e \u003cp\u003eCONCLUSION: Methylene blue-based ointments could be a new and innovative treatment for the non-operative management and healing of CAFs.\u003c/p\u003e","manuscriptTitle":"The use of a methylene blue and glyceryl trinitrate- based cream for the treatment of chronic anal fissures: a phase II randomized pilot trial from a referral coloproctological unit","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-04 21:51:33","doi":"10.21203/rs.3.rs-4448360/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-10T14:23:39+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-10T14:13:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"113718329309026861591054630351793732760","date":"2024-08-10T14:11:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"270213827886512318827535049834366909684","date":"2024-07-02T03:52:58+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-10T23:00:37+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-09T19:22:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-20T11:50:41+00:00","index":"","fulltext":""},{"type":"submitted","content":"Techniques in Coloproctology","date":"2024-05-20T10:09:55+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":"3cf85b05-bd45-4005-8e74-81430091eea8","owner":[],"postedDate":"June 4th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-06T16:03:29+00:00","versionOfRecord":{"articleIdentity":"rs-4448360","link":"https://doi.org/10.1007/s10151-024-03029-8","journal":{"identity":"techniques-in-coloproctology","isVorOnly":false,"title":"Techniques in Coloproctology"},"publishedOn":"2025-01-03 15:57:44","publishedOnDateReadable":"January 3rd, 2025"},"versionCreatedAt":"2024-06-04 21:51:33","video":"","vorDoi":"10.1007/s10151-024-03029-8","vorDoiUrl":"https://doi.org/10.1007/s10151-024-03029-8","workflowStages":[]},"version":"v1","identity":"rs-4448360","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4448360","identity":"rs-4448360","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}