Recent Advances in the Pharmacotherapy of Chronic Anal Fissure: An Update

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1 Review Article Recent Advances in the Pharmacotherapy of Chronic Anal Fissure: An Update Bikash Medhi, Ramya Sankarnarayan Rao, Ajay Prakash, Om Prakash, Lileswar Kaman 1 and Promila Pandhi, Departments of Pharmacology and 1 General Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India. Surgical sphincterotomy reduces anal tone and sphincter spasm and promotes ulcer healing. Because the surgery is associated with the side effect of faecal incontinence, pharmacological agents to treat chronic anal fissure have been explored recently. Glyceryl trinitrate (GTN) ointment (0.2%) has an efficacy of up to 68% in healing chronic anal fissure, but it is associated with headache as the major and most common side effect. Though botulinum toxin injected into the anal sphincter healed over 80% of chronic anal fissures, it is more invasive and expensive than GTN therapy. Diltiazem ointment achieved healing of chronic anal fissure comparable to 0.2% GTN ointment but was associated with fewer side effects. Other drugs that have been tried are lidocaine, the alpha-adrenergic antagonist indoramin, and the potassium channel opener minoxidil. [Asian J Surg 2008;31(3):154 63] Key Words: botulinum toxin, chronic anal fissure, diltiazem, glyceryl trinitrate Introduction Anal fissure is a tear in the anal mucosa extending from the anal verge toward the dentate line. It was first described by Recamier in It is common in people of all ages and especially in teenagers and young adults. Some studies suggest that as many as one in five people develop anal fissure during their lifetime. Anal fissure occurs predominantly in the midline and most commonly posterior (90%) with 10% anterior. After childbirth, women tend to have an anterior fissure, and less than 1% of patients have fissure both in the anterior and posterior positions. 1 Typically, symptoms are severe pain during and after defaecation and bright red rectal bleeding. Pain is described as tearing. It may last for minutes or up to an hour. As the fissure becomes chronic, the bleeding may stop, although the pain will persist. A minority complain of pruritis, swelling, prolapse and discharge. 2 Most anal fissures are acute and resolve spontaneously or with conservative medical management in days. It takes 6 8 weeks for the actual tear to heal. The fissure is said to be chronic if it is present for longer than 6 weeks. Fissures that fail to heal become chronic. They usually need further treatment or intervention to heal. When fissures become large, deep and chronic, they are called anal ulcers. 3 When a fissure is located in atypical locations or are multiple and fail to heal following treatment, other conditions such as inflammatory bowel disease, neoplasms, leukaemia, syphilis, tuberculosis, and HIV have to be ruled out. 4 6 Previously, anal fissure was thought to be due to severe constipation or straining at defaecation. However, current evidence suggests that anal fissure is due to high sphincter pressure and secondary local ischaemia. 7 The posterior commissure is not as well-perfused as other regions of the anal canal. Here, the inferior rectal artery has a perpendicular course through the septa of the internal anal sphincter. 8 Hence, increased intramuscular pressure compromises the blood flow, which is further aggravated by Address correspondence and reprint requests to Dr Bikash Medhi, Department of Clinical Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh , India. drbikashus@yahoo.com Date of acceptance: 15 May Elsevier. All rights reserved. 154 ASIAN JOURNAL OF SURGERY VOL 31 NO 3 JULY 2008

2 PHARMACOTHERAPY OF CHRONIC ANAL FISSURE increased intraluminal pressure. This endodermal ischaemia prevents small mechanical tears from healing in a timely fashion. Anal fissure is usually associated with constipation, laxative abuse, periods of diarrhoea, or sometimes has no obvious reason. Less commonly, fissures are caused by foreign body insertion or anal intercourse. In women, one in 10 cases occurs following childbirth. The diagnosis is made by the typical history of pain with defaecation associated with prior constipation. Chronic anal fissure is accompanied by an external skin tag and hypertrophied anal papilla. Ulcers can be inspected by gently parting the posterior anus. Digital and proctoscopic examination is to be avoided as it triggers severe pain and spasm of the underlying muscle. Histologically, one can see acute and chronic infection and granulation tissue. The sentinel tag is a fibroepithelial polyp covered by squamous mucosa. 8 Treatment Initially, the patient is managed conservatively. The aim of treatment is to eliminate constipation, soften the stool and reduce anal sphincter spasm. Bulk is added to the diet and stool softener is prescribed. Increased fibre in the diet softens and bulks the stool. The recommended daily intake of fibre is g. Fibres are naturally found in fruit and vegetables. They can also be supplemented via commercially available preparations like psyllium seed, methylcellulose and calcium polycarbophil. Bulk-forming laxatives can be used safely. Side effects include flatulence and bloating. Analgesics relieve pain and a sitz bath relieves symptoms. A sitz bath is given by immersing the rectal area in warm water for minutes, 2 3 times daily. It improves blood flow and relaxes the internal anal sphincter. The patient is encouraged to drink water and avoid tea or coffee. A local anaesthetic can be prescribed to relieve pain and infection. Steroids decrease swelling and inflammation. This medical treatment is effective in patients with acute anal fissure. Chronic anal fissure requires surgical or pharmacological intervention. Surgery Digital anal dilatation is performed by controlled stretching around the anal circumference. It is done under general anaesthesia. By total neuromuscular blockade, the external anal sphincter is relaxed to avoid unintended contraction and damage. 9 Depending on the toughness of the internal sphincter force, the magnitude of stretch has to be tailored to the patient s requirement, but it is associated with sphincter damage and faecal incontinence. 10,11 The gold standard surgical procedure is internal sphincterotomy. Variations in the technique such as open or close, midline or lateral, single or multiple have been described. They provide immediate relief of pain, are simple to perform and are widely accepted by patients. However, the technique is associated with asymmetry of the anal canal, and irreversible anal sphincter damage and incontinence may be less frequent after closed sphincterotomy, while the complication rate and recurrence rate may be lower after open sphincterotomy. 12,13 In a small subgroup of patients with anal fissure and low maximal anal resting pressure (MARP), a V-Y anoplasty or an island advancement flap can be considered. 14,15 Nyam and Pemberton showed that lateral internal sphincterotomy healed and relieved symptoms in 96% of cases, while incontinence occurred frequently. 16 Most episodes of incontinence were minor and transient, but in a small subgroup, the incontinence seemed permanent. 16 Incontinence includes the inability to control flatus, mild faecal soiling, or loss of solid stool. Because anal fissure is more common in young adults, the long-term result of surgery is a concern. Recently, several pharmacological agents were investigated as an alternative to surgical therapy. The surgical approach to chronic anal fissure is reserved for patients who have tried medical treatment for at least 1 3 months, but have failed. The goal of lateral sphincterotomy is to relax the internal sphincter by cutting a small nick in the internal anal sphincter, which facilitates ulcer healing. Pharmacotherapy Drugs tried in the treatment of anal fissure include glyceryl trinitrate (GTN), isosorbide dinitrate, botulinum toxin, calcium channel antagonists (CCB) such as nifedipine and diltiazem, lidocaine, the cholinomimetic bethanecol, the alpha-adrenergic antagonist indoramin, and the potassium channel opener minoxidil. The different pharmacological agents that are used in the treatment of chronic anal fissure are summarized in the Table GTN Contraction of the internal anal smooth muscle depends on cytoplasmic calcium. Organic nitrates are prodrugs ASIAN JOURNAL OF SURGERY VOL 31 NO 3 JULY

3 MEDHI et al Table. Different pharmacological agents used in clinical trials of chronic anal fissure No. Reference Year Patients, n Duration of treatment Drugs (% response) Control Remarks 1 Lund et al wk 18/21 (85.71%) GTN Open trial Effective 2 Oettle mo 10/12 (83.33%) GTN Open trial Effective 3 Lund & Scholefield wk 26/38 (68%) GTN 3/39 (8%) Effective 4 Carapeti et al wk 67% GTN 32% Double-blind 5 Brisinda et al wk 15/25 (60%) GTN 24/25 (96%) BT BT more effective 6 Kennedy et al wk 46% GTN 16% Effective 7 Hyman & Cataldo Until symptoms 9/16 (56%) AF Open trial More often headache completely resolved 7/17 (41%) CF, GTN 8 Palazzo et al wk 73% GTN 27% Effective 9 Zuberi et al wk 12/18 (66.7%) GTN 12/19 (63.2%) NG Comparable 10 Altomare et al wk 29/59 (49.2%) GTN 31/60 (51.7%) MCRPCDB Comparable 11 Hasegawa et al wk 13/16 (81%) AF, GTN Open trial Effective in acute fissure 13/40 (33%) CF 12 Richard et al wk 22/39 (43%) GTN Open trial Effective 13 Skinner et al wk 14 Pitt et al Mean: 15.6 mo 26/64 (40.6%) GTN Open trial Effective 15 Cundall et al hr 21.9% 0.1% GTN 8.8% Effective 27.9% 0.2% GTN 33.1% 0.4% GTN 16 Kocher et al wk 0.2% GTN ont./ RDB 2-centre trial Not significant 2% Dil. cream 17 Scholefield et al wk 46.9% 0.1% GTN 37.5% Effective 40.4% 0.2% GTN 54.1% 0.4% GTN 18 Ezri & Susmallian wk 58% GTN 89% NF NF effective 19 Simpson et al wk 7/7 0.05% ont. GTN Open trial Effective 5/8 0.10% ont. GTN 20 Colak et al wk 38 (73%) TD, Open trial TD patch more effective 24 (64%) 6 wk GTN 156 ASIAN JOURNAL OF SURGERY VOL 31 NO 3 JULY 2008

4 PHARMACOTHERAPY OF CHRONIC ANAL FISSURE 48 (81%) TD, 27 (79%) 12 wk 21 Maan et al wk 15/16 (93.33%) GTN 4/11 (5% Lig.) Effective 22 Boschetto et al d 38.9% GTN %, HAD Dilation more effective 23 Weinstein et al % (0.75 mg) NG/ Placebo No significant difference 0.4% (1.5 mg) NG 24 Lindsey et al wk 28/30 (93%) GTN Effective 25 Gosselink et al wk 8/13 (62%) GTN Open trial Effective 26 Fruehauf et al wk 13/25 (52%) GTN Open trial Effective 27 Mustafa et al wk 7/10 GTN, 6/10 NF Open trial Effective 28 De Nardi et al wk 40% local GTN Open trial Effective topical 33.3% parenteral GTN 29 Thornton et al wk 21/25 (84%) GTN Open trial Effective 30 Jost & Schimrigk mo 9/12 (75%) BT Open trial Effective 31 Gui et al mo 7/10 (70%) BT Open trial Effective 32 Mason et al wk 3/5 (60%) BT Open trial Effective 33 Jost mo 79% BT Open trial Effective 34 Maria et al mo 10/57 15 U, 20 U BT Open trial Effective in large dose 23/57 20 U, 25 U BT 35 Minguez et al mo 48% 10 U BT Open trial Effective at high dose 74% 15 U BT 100% 21 U BT 36 Brisinda et al wk 24/25 (96%) BT 15/25 (60%) NG Effective 37 Maria et al mo 37/50 (74%) BT Open trial Effective 38 Lysy et al wk 10/15 (66%) BT + TN Open trial Effective with combination 3/15 (20%) BT 39 Madalinski et al wk 11/14 BT + NG Open trial Effective with combination 1/14 NG 7/13 50 U BT 40 Colak et al mo 24/34 (70.58%) BT 6/28 (21.42%) Lig. Effective 41 Wollina & Konrad wk 2/5: U BT (IM inj.) Open trial Effective 5/5: U BT (IM + IC inj.) (Continued) ASIAN JOURNAL OF SURGERY VOL 31 NO 3 JULY

5 MEDHI et al Table. (Continued) No. Reference Year Patients, n Duration of treatment Drugs (% response) Control Remarks 42 Minguez et al mo Ratio of permanently healed and Open trial Relapse rate high when relapsed group after BT: concentration of drug ALF 6% vs. 45% decreased LDD 38% vs. 68% NRI 26% vs. 59% 43 Brisinda et al mo 55 (73%) 20 U BT Open trial Effective with combination 65 (87%) 30 U BT + 50 U BT 44 Witte & Klaase mo 24/32 (75%) BT Open trial Effective 45 Tranqui et al mo 94% NF + BT, 71% control Open trial Effective with combination 46 Carapeti et al healthy 4 d Dil. Observational trial Effective volunteers 47 Carapeti et al wk 15/30 (67%) Dil. 15/30 Comparable Healing 60% 48 Jonas et al wk 26/50 (52%) Dil. 24/50 (60 mg oral Dil.) More effective than control 49 Knight et al wk 71/71 (83%) Dil. Open trial Effective 50 Jonas et al wk 39/39 (48%) Dil. Open trial Effective 51 Dasgupta et al yr 11/23 (48%) Dil. Open trial Effective 52 Griffin et al wk 47/47 (48%) Dil. Open trial Effective 53 Kocher et al wk 31/60 (41%) Dil. 29/60 (46%) healing (GTN) Comparable 54 Bielecki & Kolodziejczak wk 22/43 (86%) Dil. 21/43 (85%) healing (GTN) Comparable 55 Nash et al wk 80% Dil. Open trial Effective 56 Muthukumarassamy et al wk Lig. Minoxidil + Lig. RDBCT: not significant 57 Maan et al wk Xylocaine 5% GTN 0.2% RDBCT: + GTN 58 Perrotti et al wk Lig. NF RDBCT: + NF 59 Bacher et al wk Anaesthetic gel GTN + GTN 60 Pitt et al hr Indoramin 20 mg Observational trial Effective 61 Pitt et al wk Indoramin (7%) Placebo (22%) RDBCT: placebo better GTN = glyceryl trinitrate; BT = botulinum toxin; AF = anal fissure; CF = chronic fissure; NG = nitroglycerine; MCRPCDB = multicentre randomized placebo-controlled double-blind; Dil. = diltiazem; RDB = randomized double-blind; NF = nifedipine; ont. = ointment; TD = transdermal; Lig. = lidocaine; HAD = hydropneumatic anal dilation; TN = topical nitrate; IM = intramuscular; inj. = injection; IC = intracutaneous; ALF = anterior location of fissure; LDD = longer duration of disease; NRI = need for re-injection; RDBCT = randomized double-blind controlled trial. 158 ASIAN JOURNAL OF SURGERY VOL 31 NO 3 JULY 2008

6 PHARMACOTHERAPY OF CHRONIC ANAL FISSURE that release nitric oxide (NO). NO activates the soluble form of guanyl cyclase and increases intracellular cyclic GMP. It promotes dephosphorylation of the myosin light chain and the reduction of cytosolic calcium leading to relaxation of smooth muscle in a broad range of tissues. 75 Hence, GTN facilitates ulcer healing by dilating blood vessels, increasing blood flow to injured tissues and reducing the pressure in the internal anal sphincter. Loder et al showed a significant decrease in resting anal pressure using GTN ointment in Lund and Scholefield used 0.2% GTN ointment and showed that it decreased MARP by 33% and induced an increase in anodermal blood flow. 19 Studies have shown a healing rate of 33 68%. Higher doses of NO donor ointment induced faster initial healing of chronic anal fissures but did not result in a superior healing rate in the long term. Compliance was decreased due to severe headaches and orthostatic hypotension. 20,24 Other adverse effects include syncopal attack and tachyphylaxis that limit the use of topical GTN ointment. 26,28,77 The effect of GTN is temporary and the relapse rate is as high as 35%. GTN should not be used within 24 hours of erectile dysfunction medications such as sildenafil, tadalafil and vardenafil. GTN ointment (0.2%) is applied around the anal opening 2 3 times daily, as well as before and after bowel movement. Because GTN requires frequent application, a GTN patch was investigated by Zuberi et al to improve compliance and acceptability, and was found to be a suitable alternative. 25 Botulinum toxin The anaerobic bacterium Clostridium botulinum produces a family of toxins targeted to presynaptic proteins. Acetylcholine is stored in vesicles along with other cotransmitters such as adenosine triphosphate and vasoactive intestinal polypeptide at neuroeffector junctions. Release of acetylcholine occurs on depolarization of the varicosity, which allows the entry of calcium through voltage dependent calcium channels. Elevated calcium promotes fusion of the vesicular membrane with the cell membrane and exocytosis of the transmitter occurs. Botulinum toxin digests selected proteins in the plasma membrane (syntaxin and SNAP 25) and the synaptic vesicle (synaptobrevin), and blocks release of acetylcholine. 78 Botulinum toxin A produces flaccid paralysis of skeletal muscle and diminished activity of parasympathetic and sympathetic cholinergic synapses. Studies of injection of botulinum toxin reported a significant decrease in anal resting pressure of 18 30%. 21,79 The therapeutic effect starts within a few hours and lasts from several weeks to 3 4 months. When injected into the external anal sphincter, resolution of pain and ulcer healing occurred in 80% of cases. 49 It enabled treatment of chronic uncomplicated anal fissure with increased sphincter tone. It could be administered on an outpatient basis and did not cause any lesion or incontinence. 80 Higher doses were effective in producing long-term healing without complications. 50 A minority of patients had temporary incontinence. Other studies injected botulinum toxin into the internal anal sphincter. The intrasphincteric injection of toxin was a safe and effective new option with a healing rate related to the dose and to the number of puncture sites. 51 When injected into either side of the anterior midline, healing was improved. 52 When combined with GTN at 6 weeks, healing rates were superior, but no significant difference was seen at 12 weeks. 53 CCBs CCBs are effective in causing smooth muscle relaxation. Nifedipine was evaluated for treatment of anal fissure. With 0.2% nifedipine ointment, a mean reduction of 30% in MARP was observed. 81 Total remission of 95% was observed at 3 weeks and was 60% after 8 weeks. It was well tolerated except for flushing and mild headache. There was no episode of postural hypotension or incontinence. A calcium-dependent mechanism is required to maintain internal sphincter muscle tone. CCB causes relaxation of gastrointestinal smooth muscle. 81,82 Oral diltiazem has been shown to reduce the resting anal pressure. 83 Carapeti et al explored the possible use of CCB and a cholinomimetic to lower anal sphincter pressure. 61 Both oral diltiazem and a topical gel containing varying concentrations of bethanechol were tested on healthy adult volunteers to determine the dose response characteristics of these agents. They found that a single dose of 60 mg of diltiazem lowered MARP by a mean of 21%. Once-daily diltiazem produced a clinically insignificant effect, but a twice-daily regimen reduced anal pressure by a mean of 17%. Diltiazem gel (2%) produced a maximal 28% reduction, the effect lasting 3 5 hours. This presented a potential alternative with low side effects to topical nitrates for the treatment of anal fissure. 61 Carapeti et al conducted their study on patients with chronic anal fissure. 62 Patients were treated with 2% diltiazem gel 3 times daily for 8 weeks. The fissure healed ASIAN JOURNAL OF SURGERY VOL 31 NO 3 JULY

7 MEDHI et al in 67% of patients. There was no significant difference in maximum resting sphincter pressure between responders and nonresponders. There was a significant decrease in pain score after treatment with diltiazem (p = 0.002). MARP was significantly lowered (p = ). No headache or other side effects were reported. 62 Jonas et al assessed the efficacy of oral and topical diltiazem in healing chronic anal fissure. 63 MARP fell by 15% and 23% in the oral and topical application groups, respectively. Fissure healing was 38% in the oral group and 65% in the topical group after 8 weeks. Oral diltiazem caused side effects such as rash, headache, nausea, vomiting, decreased smell and taste, while topically treated groups showed no side effects. Knight et al studied the effects of 2% topical diltiazem in 71 patients. 64 Three-quarters experienced healing in 2 3 months and, in a further 2 months, 88% experienced healing. Minor side effects were perianal dermatitis, one patient had headache, and six of seven patients with recurrent fissure were treated successfully by repeat chemical sphincterotomy. Jonas et al did a study to determine the efficacy of diltiazem in anal fissures that failed to heal with GTN. 65 Thirty-nine patients with chronic anal fissure received GTN therapy, of which 27 patients completed the course and 12 patients discontinued it. Of the 27 patients who completed the GTN course, 44% were healed with topical diltiazem, and in 56% of the patients, the fissure persisted and surgical sphincterotomy was undertaken. Of the 12 patients who discontinued GTN therapy, 58% were healed with topical diltiazem. Dasgupta et al also evaluated the treatment of patients with anal fissure with diltiazem gel. 66 They found that the fissure healed in 48%, including 75% of the patients who previously failed to heal with GTN. There were no recurrences and no adverse effects. Griffin et al also studied the role of topical diltiazem in the treatment of chronic anal fissure in patients who did not respond to GTN therapy. 67 They concluded that topical 2% diltiazem is an effective and safe treatment for patients who have failed to heal with topical 0.2% GTN. Sphincterotomy could be avoided in 70% of cases. Kocher et al performed a randomized controlled trial assessing the side effects of GTN and diltiazem in the treatment of chronic anal fissure. 32 More headache occurred with GTN than with diltiazem (p = 0.01). There was no significant difference in healing and symptomatic improvement rates between the two groups. Bielecki and Kolodziejczak conducted a prospective randomized trial of diltiazem and GTN in the treatment of chronic anal fissure and concluded that diltiazem and GTN were equally effective in healing anal fissure. 68 However, the diltiazem trial reported fewer side effects compared to GTN topical therapy. Lidocaine and minoxidil Several studies suggest the topical use of lidocaine in chronic anal fissure. Muthukumarassamy et al, in a randomized, double-blind trial of 90 patients, reported that the healing rate with a combination of minoxidil (0.5%) and lidocaine (5%) was greater compared to control groups (p = 0.001), and the healing rates of minoxidil and lidocaine were not significantly different. 70 A study conducted by Maan et al reported that topical use of GTN was significantly better in reducing MARP and in relieving pain of patients with chronic anal fissure. 37 The result of this randomized, double-blind trial showed a better healing rate with GTN (93.75%), lidocaine (68.75%) and proctosedyl (75%) in comparison with the control group given Vaseline (25%). Perrotti et al, in a randomized, double-blind trial of 110 patients, showed that nifedipine (0.3%) had a far better healing rate of 94.5% than the 16.4% in lidocainetreated patients (1.5%). 71 In the trial done by Bacher et al, local application of GTN in both acute and chronic anal fissure had a significantly superior healing rate (80%) compared to locally applied anaesthetic gel (40%). 72 Indoramin The emerging alpha-adrenergic antagonist indoramin reduced anal pressure in chronic anal fissure patients. The work was done by Pitt et al in seven patients who had a reduction in anal pressure by a mean of > 35%. 73 In a double-blind, randomized, placebo-controlled trial, the authors found that after 6 weeks of treatment with oral indoramin (20 mg), healing had occurred in one (7%) patient in the indoramin group and in two (22%) in the placebo group (p > 0.1). Additionally, after 3 months, chronic anal fissure in the indoramin group had recurred and the trial was terminated early because of poor healing rates. 74 A meta-analysis of medical therapy for chronic anal fissure showed that acute fissure and fissure in children may have a rate of healing that is only marginally better than placebo, and for chronic fissure, medical therapy is far less effective than surgery ASIAN JOURNAL OF SURGERY VOL 31 NO 3 JULY 2008

8 PHARMACOTHERAPY OF CHRONIC ANAL FISSURE Conclusion Although surgical sphincterotomy reduces anal tone and sphincter spasm and promotes ulcer healing, it is associated with cases of faecal incontinence. A pharmacological means to treat chronic anal fissure is an interesting alternative. GTN 0.2% ointment has an efficacy of up to 68% in healing chronic anal fissures, but it is associated with headache as a major side effect. Botulinum toxin injected into the anal sphincter healed over 80% of chronic anal fissures, but it was more invasive and expensive than GTN therapy. Recently, Mishra et al concluded that both treatments may be considered as first-line treatment even if less effective than surgery. 85 Diltiazem ointment achieved healing of chronic anal fissure comparable to GTN 0.2% ointment and was associated with fewer side effects. Topical treatment is effective for patients with chronic anal fissure in the short-term and long-term, but for many patients, it is not a definitive treatment. It can be offered to those who are ready to take repeated treatments. A longer interval between appearance of symptoms and treatment initiation negatively affects fissure healing and recurrence rate. Floyd et al documented a significant change in the medical approach to chronic fissure management. 86 The addition of multiple treatment modalities prolonged time to healing from initial evaluation, but allowed 72% of patients to avoid the need for permanent sphincter division while maintaining the highest rates of healing. Other drugs that have been tried are lidocaine, the alpha-adrenergic antagonist indoramin, and the potassium channel opener minoxidil. References 1. Kodner IJ, Fry RD, Fleshman JW, et al. Colon rectum and anus. In: Schwartz s Principles of Surgery, 7 th edition. 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9 MEDHI et al 25. Zuberi BF, Rajput MR, Abro H, et al. A randomized trial of glyceryl trinitrate ointment and nitroglycerin patch in healing of anal fissures. Int J Colorectal Dis 2000;15: Altomare DF, Rinaldi M, Milito G, et al. Glyceryl trinitrate for chronic anal fissure healing or headache? Results of a multicenter, randomized, placebo-controlled, double-blind trial. Dis Colon Rectum 2000;43: Hasegawa H, Radley S, Morton DG, et al. Audit of topical glyceryl trinitrate for treatment of fissure-in-ano. Ann R Coll Surg Engl 2000;82: Richard CS, Gregoire R, Plewes EA, et al. Internal sphincterotomy is superior to topical nitroglycerin in the treatment of chronic anal fissure: results of a randomized, controlled trial by the Canadian Colorectal Surgical Trials Group. Dis Colon Rectum 2000;43: Skinner SA, Polglase AL, Le CT, et al. Treatment of anal fissure with glyceryl trinitrate in patients referred for surgical management. ANZ J Surg 2001;71: Pitt J, Williams S, Dawson PM. 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