Indian J Gastroenterol DOI 10.1007/s12664-015-0559-2
ORIGINAL ARTICLE
The effects of topical application of metronidazole for treatment of chronic anal fissure: A randomized, controlled pilot study Natalia Mihailovna Grekova 1 & Elena Anatolyevna Maleva 1 & Yuliana Lebedeva 1 & Viktor Nicolaevich Bordunovsky 1 & Larisa Fedorovna Telesheva 1 & Vladimir Anatolyevich Bychkovskikh 1
Received: 20 October 2014 / Accepted: 1 April 2015 # Indian Society of Gastroenterology 2015
Abstract Background Chronic anal fissures (CAFs) rarely heal with conservative management. Because they are associated with strong anal sphincter tone, most treatment aim to reduce anal pressure. Although infections can cause fissures, as can traumatic injury to the anal canal, antimicrobial treatment is not recommended. In a previous study, we reported identifying a wide spectrum of pathogenic microorganisms in the bases of CAFs, anaerobic bacteria being present in half the cases. We postulated that microbial colonization delays healing of CAF and aimed to determine whether decreasing the bacterial load with topical antibacterial treatment accelerates fissure healing. Methods We cultured fecal samples and swabs from the bases of CAFs in 103 patients. Patients in whose samples anaerobic bacteria were identified (47 patients) were then invited to participate in a prospective randomized clinical trial comparing topical metronidazole with conventional treatment. The primary endpoint was fissure healing confirmed on anoscopy. Secondary endpoints of maximum pain on defecation assessed by visual analog scale, maximum anal resting pressure, and rectal pH were recorded on entry and at 10, 21, and 28 days. Results The CAFs were colonized by mixtures of gram-positive/gram-negative anaerobic bacteria or gram-negative aerobic monocultures. Patients with anaerobic bacteria in their swabs who received topical metronidazole treatment experienced rapid relief of pain and anal sphincter spasm along with
* Yuliana Lebedeva [email protected] 1
Department of Surgery, South Ural State Medical University, Chelyabinsk, Russia
enhanced fissure healing (95.6 % healing rate compared with 70.8 % in the control group, p=0.048). Conclusion Topical antimicrobial treatment can be effective in patients with CAF provided the relevant microorganisms are correctly identified. Keywords Anal fissure . Anal pain . Metronidazole . Topical antimicrobial treatment
Introduction Anal fissures, a defect of the anoderm, are usually located in the posterior semicircle of the anal canal. Acute anal fissures heal either spontaneously or with the help of simple therapy. Chronic anal fissures (CAFs) are nonhealing ulcers located below the dentate line; they have morphological features that distinguish them from acute lesions [1]. Currently, most researchers agree that the cause(s) and pathophysiology of CAF are not completely understood [2, 3]. The starting point is rupture of the anoderm caused by the abrasive action of a fecal bolus with constipation or diarrhea [4]. The subsequent lack of healing and transformation of an acute fracture into a chronic ulcer is associated with several proven mechanisms. These include increased resting pressure in the anal canal resulting from spasm of the internal sphincter, which impairs intrasphincteric blood flow, causing local ischemia of the posterior commissure zone and local traumatic effects of fecal boluses, and lack of nitric oxide, which can intensify internal sphincter spasm [5, 6]. At present, breaking pre-epithelial defense is considered important in the pathogenesis of inflammatory diseases of the colon. Changes toward increased invasiveness and aggressiveness in the proportion and nature of microorganisms in the colon can result in damage to the pre-epithelial protective layer.
Indian J Gastroenterol
Because defects caused initially by mechanical damage are constantly in contact with fecal flora, they cannot remain sterile and inevitably become infected. Changes in the microbial–tissue complex can cause nonspecific inflammation of the mucosa, leading to loss of elasticity and plasticity of the anoderm, making it easy to rupture [7]. They can also impair processes of healing and transform acute defects to chronic ulcers via proinflammatory cytokines or microbial metabolites that inhibit regeneration of the mucous membrane. Thus, the state of the microbiota in the rectum, anal canal, and anal fissure itself significantly influences the process of healing of anal fissures, as do spasm of the anal sphincter and local ischemia [8]. The problem of treatment of CAF has not yet been solved. Surgical treatment of anal fissures is an unsatisfactory option because it can lead to irreversible damage to the sphincter and varying degrees of incontinence [9, 10]. An alternative is pharmacological sphincterotomy, which is widely achieved by use of donors of nitric oxide, calcium channel blockers, or injections of botulinum toxin into the sphincter. However, pharmacological relaxation of the sphincter does not always lead to rapid and persistent healing of CAFs [11, 12]. We have not found any published studies about the presence and/or direct damaging effects of microorganisms on lesions of the anoderm in patients with CAF. However, a randomized study by Carapeti et al. showed that posthemorrhoidectomy surgical wounds are less painful and heal faster with topical metronidazole treatment [13]. Similarly, Nicholson and Armstrong concluded that topical 10 % metronidazole significantly reduces post-hemorrhoidectomy discomfort and postoperative edema and improves overall healing after Harmonic Scalpel hemorrhoidectomy [14]. Pelta et al. performed subcutaneous fissurotomies and administered topical 10 % metronidazole postoperatively in 109 patients with good results [15]. In contrast, Hosseini et al. performed a randomized clinical trial on the effect of oral metronidazole on wound healing and pain after anal sphincterotomy and found no significant differences between groups regarding postsurgical complications [16]. The aim of this study was to determine whether topical metronidazole treatment could accelerate healing of chronic anal fissure.
Methods Study design This study was conducted at the Chelyabinsk Railway Hospital from 2008 to 2011 and was approved by the Ethics Committee of the Chelyabinsk State Medical Academy. All procedures followed were in accordance with the ethical standards of the responsible committee and with the Helsinki
Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients for being included in the study. Patients of both sexes, aged 18 to 65 years, with chronic anal fissure and coexisting proctitis and without any exclusion criteria were included. A chronic fissure was identified by the presence of indurated edges, visible internal sphincter fibers at the base of the fissure, a sentinel polyp at the distal end of the fissure, or a fibroepithelial polyp at the apex. Proctitis was defined by the presence of two or more of the following criteria found on anoscopy: mucosal hyperemia, edema, punctate hemorrhages, contact vulnerability, focal or diffuse depletion or absence of vascular pattern, presence of mucus, fibrin, and presence of papillitis or cryptitis. Exclusion criteria were acute anal fissure (symptoms present for less than 6 weeks, no morphological signs of chronic lesion—17 patients), presence of only one or no endoscopic criteria of proctitis on rectoscopy (14 patients), Crohn’s disease or ulcerative colitis (1 patient), and anal sphincter fibrosis (1 patient). One hundred and three patients who satisfied the inclusion criteria underwent microbiological tests as described below. Patients with both aerobic and anaerobic species in swabs obtained from the bases of their fissures were included in a randomized clinical study. Patients with only aerobic microorganisms in their swabs underwent no further investigation (Fig. 1).
Microbiological examinations Microbial analysis was performed at the Microbiology Laboratory of Chelyabinsk State Hospital No. 6. Swabs from the bases of the fissures and fecal samples were simultaneously collected from each patient with CAF. After natural defecation into sterile containers, samples were collected from the center of the feces. To assess each colonic biocenosis, the frequencies of certain types of microbes were determined and quantitative indicators calculated based on 1 g of feces. The microflora colonizing the CAFs was assessed from the swabs taken from their bases. After application of a 10 % lidocaine anesthetic spray, the defects in the anoderm were exposed, washed with pulsating jets of saline, and dried. The perianal skin was treated twice with the antiseptic Bonaderm (an alcohol-based antiseptic with skin softening components; Novodez, Moscow, Russia). Material was taken from the base of the defects by circular movements of the swabs. The swabs were then placed in Amies transport media with charcoal (Transport Medium Swabs; Copan Diagnostics, Murrieta, CA, USA). Microbiological assessment of aerobic flora included identification of microorganisms using the nomenclature of DH Berg [17] and determining their sensitivity to antibiotics. Isolation and identification of anaerobic bacteria were performed using diagnostic tablets (MIKRO-LA-TEST, ANAEROtest 23; Erba Lachema, Brno, Czech Republic) for
Indian J Gastroenterol Fig. 1 Overview of study patients, therapy used, and follow up characteristics
Patients with anal fissure N=136 Patients without proctitis,with acute anal fissure or other exclusion criteria N= 33 Microbiological examinations
Patients without anaerobic bacteria in swabs obtained from fissure bottom N= 56
Patients with chronic anal fissures + proctitis colonized by anaerobic bacteria N=47
Metronidazole group N=23 Suppositories or therapeutic enema with 250 mg of metronidazole
Control group N=24 Suppositories with hydrocortisone 5 mg and cinchocaine hydrochloride 5 mg for 14 days + suppositories with sodium alginate 250 mg for another 14 days
Follow up visits: day 10, 21, 28
bacteriological analyzer iEMS Reader (Thermo Labsystem, Helsinki, Finland).
Randomization and clinical study design To assess the effect of topical antibacterial treatment on CAF, patients whose CAFs were colonized by anaerobic bacteria were randomly allocated to treatment or control groups. Patients in both groups were encouraged to prevent hard stools by dietary measures and were administered oil enemas (50 mL sunflower oil) before defecation. In addition to this basic therapy, patients in the treatment group received rectal suppositories containing 250 mg of metronidazole or therapeutic 50 mL enemas containing 250 mg of metronidazole. Patients in the control group received suppositories containing hydrocortisone 5 mg and cinchocaine hydrochloride 5 mg for 14 days. If the CAFs had not healed within 14 days, patients in the control group received suppositories with sodium alginate 250 mg for another 14 days. Both patients and investigators were aware of the group allocated and the treatment received. Data were analyzed by a qualified statistician who was aware of the patients’ allocation. Baseline assessment included recording duration of symptoms and maximum severity of pain on defecation according to a visual analog scale (VAS), anoscopy, and manometric
measurement of maximum resting pressure using the Peritron perineometer (Cardiodesign; Oakleigh, Australia) measurement of rectal pH with standard litmus paper. Follow up visits were scheduled at 10, 21, and 28 days and included assessment of symptoms, recording of worst pain on a VAS, and maximum resting pressure on manometry, measuring rectal pH and anoscopy. The primary endpoint was fissure healing confirmed on anoscopy as finding a scar where the fissure was. Secondary endpoints were maximum pain on defecation assessed by VAS, maximum anal resting pressure, and rectal pH.
Table 1
Patient’s characteristics according to randomly allocated group
Age in years, mean (SD) Sex (F/M) Mean duration of symptoms, weeks Location of fissure Anterior Posterior Lateral Multiple
Metronidazole group (n=23)
Control group (n=24)
38.0 (2.4) 13:10 24.4
32.8 (1.8) 14:10 17.7
2 17 1 3
6 14 1 3
Indian J Gastroenterol
culturing feces sample does not provide correct information about microbial status of fissure.
Statistical analysis Statistical analysis was performed using Statistica software Version 6.0. Statistical tests used included the Mann– Whitney test, χ2 test, and Fisher test. The probability was 2tailed, p
ORIGINAL ARTICLE
The effects of topical application of metronidazole for treatment of chronic anal fissure: A randomized, controlled pilot study Natalia Mihailovna Grekova 1 & Elena Anatolyevna Maleva 1 & Yuliana Lebedeva 1 & Viktor Nicolaevich Bordunovsky 1 & Larisa Fedorovna Telesheva 1 & Vladimir Anatolyevich Bychkovskikh 1
Received: 20 October 2014 / Accepted: 1 April 2015 # Indian Society of Gastroenterology 2015
Abstract Background Chronic anal fissures (CAFs) rarely heal with conservative management. Because they are associated with strong anal sphincter tone, most treatment aim to reduce anal pressure. Although infections can cause fissures, as can traumatic injury to the anal canal, antimicrobial treatment is not recommended. In a previous study, we reported identifying a wide spectrum of pathogenic microorganisms in the bases of CAFs, anaerobic bacteria being present in half the cases. We postulated that microbial colonization delays healing of CAF and aimed to determine whether decreasing the bacterial load with topical antibacterial treatment accelerates fissure healing. Methods We cultured fecal samples and swabs from the bases of CAFs in 103 patients. Patients in whose samples anaerobic bacteria were identified (47 patients) were then invited to participate in a prospective randomized clinical trial comparing topical metronidazole with conventional treatment. The primary endpoint was fissure healing confirmed on anoscopy. Secondary endpoints of maximum pain on defecation assessed by visual analog scale, maximum anal resting pressure, and rectal pH were recorded on entry and at 10, 21, and 28 days. Results The CAFs were colonized by mixtures of gram-positive/gram-negative anaerobic bacteria or gram-negative aerobic monocultures. Patients with anaerobic bacteria in their swabs who received topical metronidazole treatment experienced rapid relief of pain and anal sphincter spasm along with
* Yuliana Lebedeva [email protected] 1
Department of Surgery, South Ural State Medical University, Chelyabinsk, Russia
enhanced fissure healing (95.6 % healing rate compared with 70.8 % in the control group, p=0.048). Conclusion Topical antimicrobial treatment can be effective in patients with CAF provided the relevant microorganisms are correctly identified. Keywords Anal fissure . Anal pain . Metronidazole . Topical antimicrobial treatment
Introduction Anal fissures, a defect of the anoderm, are usually located in the posterior semicircle of the anal canal. Acute anal fissures heal either spontaneously or with the help of simple therapy. Chronic anal fissures (CAFs) are nonhealing ulcers located below the dentate line; they have morphological features that distinguish them from acute lesions [1]. Currently, most researchers agree that the cause(s) and pathophysiology of CAF are not completely understood [2, 3]. The starting point is rupture of the anoderm caused by the abrasive action of a fecal bolus with constipation or diarrhea [4]. The subsequent lack of healing and transformation of an acute fracture into a chronic ulcer is associated with several proven mechanisms. These include increased resting pressure in the anal canal resulting from spasm of the internal sphincter, which impairs intrasphincteric blood flow, causing local ischemia of the posterior commissure zone and local traumatic effects of fecal boluses, and lack of nitric oxide, which can intensify internal sphincter spasm [5, 6]. At present, breaking pre-epithelial defense is considered important in the pathogenesis of inflammatory diseases of the colon. Changes toward increased invasiveness and aggressiveness in the proportion and nature of microorganisms in the colon can result in damage to the pre-epithelial protective layer.
Indian J Gastroenterol
Because defects caused initially by mechanical damage are constantly in contact with fecal flora, they cannot remain sterile and inevitably become infected. Changes in the microbial–tissue complex can cause nonspecific inflammation of the mucosa, leading to loss of elasticity and plasticity of the anoderm, making it easy to rupture [7]. They can also impair processes of healing and transform acute defects to chronic ulcers via proinflammatory cytokines or microbial metabolites that inhibit regeneration of the mucous membrane. Thus, the state of the microbiota in the rectum, anal canal, and anal fissure itself significantly influences the process of healing of anal fissures, as do spasm of the anal sphincter and local ischemia [8]. The problem of treatment of CAF has not yet been solved. Surgical treatment of anal fissures is an unsatisfactory option because it can lead to irreversible damage to the sphincter and varying degrees of incontinence [9, 10]. An alternative is pharmacological sphincterotomy, which is widely achieved by use of donors of nitric oxide, calcium channel blockers, or injections of botulinum toxin into the sphincter. However, pharmacological relaxation of the sphincter does not always lead to rapid and persistent healing of CAFs [11, 12]. We have not found any published studies about the presence and/or direct damaging effects of microorganisms on lesions of the anoderm in patients with CAF. However, a randomized study by Carapeti et al. showed that posthemorrhoidectomy surgical wounds are less painful and heal faster with topical metronidazole treatment [13]. Similarly, Nicholson and Armstrong concluded that topical 10 % metronidazole significantly reduces post-hemorrhoidectomy discomfort and postoperative edema and improves overall healing after Harmonic Scalpel hemorrhoidectomy [14]. Pelta et al. performed subcutaneous fissurotomies and administered topical 10 % metronidazole postoperatively in 109 patients with good results [15]. In contrast, Hosseini et al. performed a randomized clinical trial on the effect of oral metronidazole on wound healing and pain after anal sphincterotomy and found no significant differences between groups regarding postsurgical complications [16]. The aim of this study was to determine whether topical metronidazole treatment could accelerate healing of chronic anal fissure.
Methods Study design This study was conducted at the Chelyabinsk Railway Hospital from 2008 to 2011 and was approved by the Ethics Committee of the Chelyabinsk State Medical Academy. All procedures followed were in accordance with the ethical standards of the responsible committee and with the Helsinki
Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients for being included in the study. Patients of both sexes, aged 18 to 65 years, with chronic anal fissure and coexisting proctitis and without any exclusion criteria were included. A chronic fissure was identified by the presence of indurated edges, visible internal sphincter fibers at the base of the fissure, a sentinel polyp at the distal end of the fissure, or a fibroepithelial polyp at the apex. Proctitis was defined by the presence of two or more of the following criteria found on anoscopy: mucosal hyperemia, edema, punctate hemorrhages, contact vulnerability, focal or diffuse depletion or absence of vascular pattern, presence of mucus, fibrin, and presence of papillitis or cryptitis. Exclusion criteria were acute anal fissure (symptoms present for less than 6 weeks, no morphological signs of chronic lesion—17 patients), presence of only one or no endoscopic criteria of proctitis on rectoscopy (14 patients), Crohn’s disease or ulcerative colitis (1 patient), and anal sphincter fibrosis (1 patient). One hundred and three patients who satisfied the inclusion criteria underwent microbiological tests as described below. Patients with both aerobic and anaerobic species in swabs obtained from the bases of their fissures were included in a randomized clinical study. Patients with only aerobic microorganisms in their swabs underwent no further investigation (Fig. 1).
Microbiological examinations Microbial analysis was performed at the Microbiology Laboratory of Chelyabinsk State Hospital No. 6. Swabs from the bases of the fissures and fecal samples were simultaneously collected from each patient with CAF. After natural defecation into sterile containers, samples were collected from the center of the feces. To assess each colonic biocenosis, the frequencies of certain types of microbes were determined and quantitative indicators calculated based on 1 g of feces. The microflora colonizing the CAFs was assessed from the swabs taken from their bases. After application of a 10 % lidocaine anesthetic spray, the defects in the anoderm were exposed, washed with pulsating jets of saline, and dried. The perianal skin was treated twice with the antiseptic Bonaderm (an alcohol-based antiseptic with skin softening components; Novodez, Moscow, Russia). Material was taken from the base of the defects by circular movements of the swabs. The swabs were then placed in Amies transport media with charcoal (Transport Medium Swabs; Copan Diagnostics, Murrieta, CA, USA). Microbiological assessment of aerobic flora included identification of microorganisms using the nomenclature of DH Berg [17] and determining their sensitivity to antibiotics. Isolation and identification of anaerobic bacteria were performed using diagnostic tablets (MIKRO-LA-TEST, ANAEROtest 23; Erba Lachema, Brno, Czech Republic) for
Indian J Gastroenterol Fig. 1 Overview of study patients, therapy used, and follow up characteristics
Patients with anal fissure N=136 Patients without proctitis,with acute anal fissure or other exclusion criteria N= 33 Microbiological examinations
Patients without anaerobic bacteria in swabs obtained from fissure bottom N= 56
Patients with chronic anal fissures + proctitis colonized by anaerobic bacteria N=47
Metronidazole group N=23 Suppositories or therapeutic enema with 250 mg of metronidazole
Control group N=24 Suppositories with hydrocortisone 5 mg and cinchocaine hydrochloride 5 mg for 14 days + suppositories with sodium alginate 250 mg for another 14 days
Follow up visits: day 10, 21, 28
bacteriological analyzer iEMS Reader (Thermo Labsystem, Helsinki, Finland).
Randomization and clinical study design To assess the effect of topical antibacterial treatment on CAF, patients whose CAFs were colonized by anaerobic bacteria were randomly allocated to treatment or control groups. Patients in both groups were encouraged to prevent hard stools by dietary measures and were administered oil enemas (50 mL sunflower oil) before defecation. In addition to this basic therapy, patients in the treatment group received rectal suppositories containing 250 mg of metronidazole or therapeutic 50 mL enemas containing 250 mg of metronidazole. Patients in the control group received suppositories containing hydrocortisone 5 mg and cinchocaine hydrochloride 5 mg for 14 days. If the CAFs had not healed within 14 days, patients in the control group received suppositories with sodium alginate 250 mg for another 14 days. Both patients and investigators were aware of the group allocated and the treatment received. Data were analyzed by a qualified statistician who was aware of the patients’ allocation. Baseline assessment included recording duration of symptoms and maximum severity of pain on defecation according to a visual analog scale (VAS), anoscopy, and manometric
measurement of maximum resting pressure using the Peritron perineometer (Cardiodesign; Oakleigh, Australia) measurement of rectal pH with standard litmus paper. Follow up visits were scheduled at 10, 21, and 28 days and included assessment of symptoms, recording of worst pain on a VAS, and maximum resting pressure on manometry, measuring rectal pH and anoscopy. The primary endpoint was fissure healing confirmed on anoscopy as finding a scar where the fissure was. Secondary endpoints were maximum pain on defecation assessed by VAS, maximum anal resting pressure, and rectal pH.
Table 1
Patient’s characteristics according to randomly allocated group
Age in years, mean (SD) Sex (F/M) Mean duration of symptoms, weeks Location of fissure Anterior Posterior Lateral Multiple
Metronidazole group (n=23)
Control group (n=24)
38.0 (2.4) 13:10 24.4
32.8 (1.8) 14:10 17.7
2 17 1 3
6 14 1 3
Indian J Gastroenterol
culturing feces sample does not provide correct information about microbial status of fissure.
Statistical analysis Statistical analysis was performed using Statistica software Version 6.0. Statistical tests used included the Mann– Whitney test, χ2 test, and Fisher test. The probability was 2tailed, p
