8 Fissure-In-Ano and Anal Stenosis
Abstract
Fissure-in-ano, or anal fissure, is a linear ulcer in the anal canal extending from below the dentate line to the level of the anal verge. They can be acute or chronic, and often cause symptoms and suffering out of proportion to the size and extent of the lesion. Fissures are a common reason that patients visit a colorectal surgeon, and recurrence rates are high following spontaneous healing. Anal stenosis occurs due to a loss of the physiologic capacity of the anal canal. Stenosis develops when the normally pliable tissues of the anus are replaced with scarred, fibrotic tissue. Although anal stenosis may occur in some congenital syndromes, the overwhelming majority of cases are secondary in nature, most of which are due to surgical trauma.
8.1 Fissure-In-Ano
Fissure-in-ano, or anal fissure, is a linear ulcer in the anal canal extending from below the dentate line to the level of the anal verge. They can be acute or chronic, and often cause symptoms and suffering out of proportion to the size and extent of the lesion. Fissures are a common reason that patients visit a colorectal surgeon, and recurrence rates are high following spontaneous healing.
8.1.1 Clinical Features
Fissures are more commonly encountered in younger and middle-aged adults, but may also occur in children and the elderly. 1 Both sexes are affected equally. Because many patients with acute fissures do not seek medical advice and improve without intervention, the exact incidence of fissures is not known. It has been suggested, however, that the lifetime incidence is 11%. 2
The vast majority of fissures occur as a single tear in the midline. Most (75–90%) occur in the posterior midline. In a review of 876 patients with fissure-in-ano, Hananel and Gordon 3 found the equal sex distribution (women, 51.1%; men, 49.9%) with a mean age of 39.9 years. The fissure was located in the posterior midline in 73.5%, the anterior midline in 16.4%, and in both in 2.6%. The fissure was located in the anterior midline in 12.6% of women and 7.7% of men. Other authors have also found that anterior fissures occur more commonly in female patients. 4 Up to 10% of acute anal fissures occur in the postpartum period, and many of these are located in the anterior midline. 5 In patients presenting with fissure that occurs off the midline, other underlying conditions must be considered (▶ Fig. 8.1).
8.1.2 Pathology
Acute anal fissures appear as a longitudinal or elliptical tear in the mucosal lining of the anal canal. While many fissures will heal spontaneously or with conservative treatment, some show considerable reluctance to heal. When symptoms are present for more than 8 to 12 weeks, the fissure often develops chronic features. This may include edema of the distal end of the fissure, which results in a tag or “sentinel pile.” The tag often has an inflamed, tense, and edematous appearance. Later, it may undergo fibrosis and persist as a permanent fibrous skin tag, even if the fissure heals. At the proximal end of the fissure at the level of the dentate line, swelling caused by edema and fibrosis may result in a hypertrophied anal papilla.
In longstanding cases, fibrous induration frequently develops in the lateral edges of the fissure. After several months without healing, the base of the ulcer, which is the internal sphincter, may become fibrosed, resulting in a spastic, fibrotic, tightly contracted internal sphincter. Infrequently, frank suppuration may occur and extend into the surrounding tissues, forming an intersphincteric or perianal abscess that may discharge through the anal canal or burst spontaneously externally and produce a low intersphincteric fistula. Usually, the external opening of this fistula is close to the midline and a short distance from the anus.
8.1.3 Etiology
The exact etiology of anal fissures is not completely understood; however, it is generally agreed that the initiating factor is trauma to the anal canal. This is often due to passage of a large or hard stool that tears the anal mucosa. In a case–control study, Jensen 6 found evidence to indicate that anal fissure is likely to result at least partly from an inappropriate diet and that dietary manipulation might reduce the incidence. A significantly decreased risk was associated with frequent consumption of raw fruits, vegetables, and whole-grain bread, and a significantly increased risk was related to frequent consumption of white bread, sauces thickened with roux, and bacon or sausages. Risk ratios for consumption of coffee, tea, and alcohol were not significantly different.
While most patients with anal fissure report constipation and hard stool, fissures may also develop following a bout of diarrhea or frequent defecation. Individuals with a longstanding condition of loose stools, usually resulting from chronic laxative abuse, may develop an anal stenosis with scarring, again predisposing to fissure formation. Fissures may also occur in the postpartum period and are thought to be secondary to shearing forces from the fetus on the anal canal. Perineal trauma leads to scarring and abnormal tethering of the anal submucosa, thus rendering it more susceptible to trauma because of its loss of laxity and mobility.
Secondary fissures may occur as a result of either an anatomic anal abnormality or inflammatory bowel disease, particularly Crohn’s disease. 7 When a fissure is encountered in a lateral location, the clinician should consider underlying inflammatory bowel disease or other inflammatory conditions such as tuberculosis, syphilis, and HIV infection. Previous anal surgery, especially hemorrhoidectomy, may result in anal scarring, skin loss, and stenosis. Fistula surgery may result in distortion of the anal canal with scarring and fixation of the anal skin. This decreased elasticity of the anal canal may then predispose to fissure formation. The presence of hemorrhoids is not likely a predisposing factor; it is more likely that an abnormality of the internal sphincter predisposes the patient to the formation of both hemorrhoids and fissures.
8.1.4 Pathogenesis
Many patients who suffer from an acute anal fissure will heal without any or with minimal intervention. If the concept that trauma to the anal canal is the initiating factor in the establishment of a fissure-in-ano is accepted, then why certain fissures proceed to and persist in a chronic state must be asked. Perpetuating factors might include infection, for example, but it is unlikely since sepsis is no more common in chronic fissures than in acute fissures. Persistently hard or large bowel movements, in addition to initiating the process, may continuously aggravate the anal canal and result in perpetuation of the fissure. This factor must be taken into account when planning treatment.
Studies have demonstrated that after the initiation of a tear in the anal canal, chronicity is perpetuated by an abnormality in the internal anal sphincter. Most investigators have found that resting pressures within the internal anal sphincter are higher in patients with fissures than in normal controls. 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 Nothmann and Schuster 13 demonstrated that after rectal distention there is a normal reflex relaxation of the internal sphincter. In patients with anal fissures, this relaxation is followed by an abnormal “overshoot” contraction. This may explain the pain that results from rectal stimulation during defecation and account for the sphincter spasm found in most patients with anal fissure. Furthermore, the authors demonstrated that after successful treatment of the fissure, the abnormal reflex contraction of the internal sphincter vanishes, a finding confirmed by others. 17
Keck et al 11 were not able to identify an overshoot contraction but did demonstrate hypertonic contraction of the internal sphincter. Several authors 9 , 15 , 17 have reported a significant reduction in mean resting pressure within the internal sphincter following lateral sphincterotomy and that the results persist for up to 1 year. Adequate internal sphincterotomy appears to permanently reduce anal canal pressure, which suggests that abnormal activity in the sphincter contributes to the development and persistence of a fissure. Farouk et al 10 found that following lateral internal sphincterotomy the number of internal sphincter relaxations increased, lending further evidence to the hypothesis that internal sphincter hypertonia may be relevant to the pathogenesis of this disorder. Abcarian et al 8 have suggested that the beneficial effect of internal sphincterotomy might be due to the anatomic widening of the anal canal, a concept supported by Olsen et al, 18 who failed to find a reduction in resting pressures after lateral sphincterotomy. Xynos et al 16 also found that following internal sphincterotomy, preoperative elevated resting pressures returned to normal. Patients with unhealed fissures showed the same pathologic manometric features as those before operation.
It has also been hypothesized that an inverse relationship exists between anal canal pressure and perfusion of the anoderm. This was first suggested by Gibbons and Read, 19 who documented increased resting pressures within the anal canal, whereas maximal pressures recorded during a voluntary contraction of the sphincter were no higher than in control subjects. They noted that it was unlikely that high resting pressures recorded in patients with chronic anal fissures were caused by spasm but probably represented a true increase in basal sphincter tone. They further proposed that elevated sphincter pressures may cause ischemia of the anal lining, resulting in the pain of anal fissures and failure to heal.
In an effort to define perfusion of the anal canal, Klosterhalfen et al 20 performed angiography of the inferior rectal artery in a cadaver model. The authors demonstrated that in 85% of specimens, the posterior commissure is less perfused than the remainder of the anal canal, and postulated that this finding may play a role in the pathogenesis of fissure-in-ano. They also suggested that vessels passing through the sphincter muscle are subject to compression during periods of increased sphincter tone and that the resulting decrease in blood supply might lead to ischemia at the posterior commissure. In a landmark study, Schouten et al 21 used laser Doppler flowmetry to study perfusion of the anoderm in healthy subjects and demonstrated that perfusion of the posterior anal canal was lower than the rest of the anus. In addition, patients with fissure were evaluated and were found to have elevated mean maximum anal resting pressure and significantly lower anodermal blood flow at the fissure site when compared with flow at the posterior commissure of the healthy subjects. Both measurements were repeated 6 weeks after lateral internal sphincterotomy and compared with the measurements of the controls. In the patients with fissures, a significant decrease in resting pressure was noted (35%) that was accompanied by a consistent rise in blood flow (65%) at the previous fissure site. It is therefore believed that reduction of anal pressure by sphincterotomy improves anodermal blood flow at the posterior midline, resulting in fissure healing.
A primary internal anal sphincter disturbance may also be an etiologic factor. Internal anal smooth muscle relaxation occurs with stimulation of the β-adrenoreceptor, which induces the return of cytosolic calcium to the sarcoplasmic reticulum via cyclic adenosine monophosphate. Internal anal sphincter supersensitivity to β2 (beta-2) agonists has been observed in patients with chronic anal fissure. 22 Relaxation is also induced by nonadrenergic noncholinergic nitric oxide (NO), which is mediated via cyclic guanosine monophosphate (cGMP). 22 , 23 Sphincter contraction depends on an increase in cytoplasmic calcium and is enhanced by sympathetic adrenergic stimulation. Blocking direct influx of extracellular calcium through the membranes of the calcium channels may help inhibit contraction.
8.1.5 Symptoms
The most common symptom of a fissure is anal pain during and after defecation. Patients will often describe the pain as a sharp, cutting, “knifelike,” or tearing sensation during the passage of stool. Following defecation, the pain may be less severe and may be described as a burning or gnawing discomfort that may persist from a few minutes to several hours. Because of the anticipated pain, many patients may not defecate when the natural urge occurs. Such procrastination leads to harder stools, causing subsequent bowel movements to be more painful. A relentless cycle may ensue with the individual living from one bowel movement to the next.
Bleeding is very common with fissure but is not invariably present. The blood is typically bright red and is usually seen after wiping or may coat the outside of the stool. Some patients have a large sentinel pile and present complaining of a painful external hemorrhoid. Perianal itch is also very common in patients with fissure. Constipation is often an accompanying symptom as well as an initiating symptom of anal fissure. Infrequently, patients with an acutely painful fissure can develop urinary symptoms including dysuria, retention, or frequency.
8.1.6 Diagnosis
Examination
The diagnosis of a fissure is usually straightforward and is often made from the patient’s history alone. Physical examination confirms the suspicion of fissure and rules out other associated disease. The association between fissures and inflammatory bowel disease should always be remembered, and a careful history should be taken and followed, if indicated, by appropriate radiologic, hematologic, and biochemical investigations.
Inspection is the most important step in the examination for anal fissure (▶ Fig. 8.2). Because anal fissures are such extremely painful lesions, special care must be taken to make the examination as gentle as possible. Careful separation of the buttocks usually reveals the fissure; however, patient apprehension and involuntary spasm of the sphincter may keep the anal orifice closed. The coexistence of large hemorrhoids or skin folds may also hide the ulcer, and when the lesion cannot be visualized, the diagnosis may be made more by history and palpation than by visual appearance.
In patients with acute anal fissure, palpation often confirms the presence of sphincter spasm. The digital examination is uncomfortable, with maximal tenderness usually elicited in the posterior midline. If the diagnosis of fissure is made by inspection, digital examination may be omitted as the pain may be so intense. However, it is essential that the examination be performed at a later date to exclude other lesions of the lower rectum such as carcinoma or a polyp. With an acute fissure, anoscopic examination is usually impossible because of the severe pain.
The triad of a chronic fissure includes a sentinel pile, an anal ulcer, and a hypertrophied anal papilla. The sentinel pile is visible externally, and can sometimes be very large. The ulcer is often deep, with fibers of the internal anal sphincter visible at the base and induration of the base and the lateral edges. Just proximal to the ulcer, the hypertrophied anal papilla may be identified. A chronic fissure may be associated with anal stenosis of varying severity, especially if the patient has had a previous anal surgery such as a hemorrhoidectomy. Although there is no specific duration that defines a fissure as chronic, evaluation of the chronicity of the process is important. Once the entire internal sphincter is bared with scarring and fibrosis, and the history of problems is longstanding, the fissure is unlikely to heal without surgical intervention. Patients with chronic anal fissure tend to have less pain, which may permit anoscopy to rule out other conditions such as internal hemorrhoids or proctitis.
Sigmoidoscopy likewise may be impossible to perform during the initial examination, but it must be performed at a subsequent visit (or colonoscopy) to rule out an associated carcinoma or inflammatory bowel disease.
A biopsy should be performed on any fissure that fails to heal after treatment. Such biopsy may reveal unsuspected Crohn’s disease or an implanted adenocarcinoma. Squamous carcinoma of the anal canal may also be confused with fissure-in-ano.
Differential Diagnosis
Anal pain, swelling, and bleeding are common complaints that prompt evaluation by a colorectal surgeon. Many conditions may result in symptoms similar to those of a fissure. Thrombosed hemorrhoids or perianal abscesses are readily seen; however, certain other conditions may require more careful discrimination.
Anorectal Suppuration
Symptoms of an intersphincteric abscess may closely mimic those of a fissure. An intersphincteric fistulous abscess without an external opening is usually situated posteriorly in the midanal canal between the internal and external sphincter. It causes great pain that may last for many hours after defecation. A diagnostic clue that may help to identify an intersphincteric abscess is that unlike with a fissure, the pain associated with an abscess often does not completely go away. Little, if anything, is seen externally, but during the examination exquisite tenderness will be elicited over the abscess, which itself may not be palpable.
Pruritus Ani
Discerning pruritus ani with superficial cracks in the anal skin from anal fissure may sometimes prove difficult as many patients with anal fissure develop pruritus as a result of the discharge irritating the perianal skin. The skin in pruritus ani, however, shows only superficial cracks extending radially from the anus, and these cracks never extend up to the dentate line. Therefore, digital examination of the rectum does not elicit pain, and there is no true anal spasm or tenderness as seen in patients with fissure.
Fissures in Patients with Inflammatory Bowel Disease
Anal fissures may develop in patients with ulcerative colitis. These fissures are often situated off the midline and may be multiple. As well as being broad, the fissures are surrounded by inflamed skin. This inflammation should alert the surgeon to an associated proctocolitis, which can be diagnosed by sigmoidoscopy or colonoscopy.
Anal and perianal ulceration frequently occurs in patients with Crohn’s disease. The ulcer seen in Crohn’s is often much more extensive than an idiopathic fissure, and again may occur off the midline. Despite the opinion of some authors, Crohn’s fissures are not always painless. If a lesion is suspect, biopsy frequently reveals the histologic features of Crohn’s disease. Evaluation of the entire gastrointestinal tract is necessary, as sigmoidoscopy alone may, in fact, be normal because the involved intestine may be more proximal.
Anal Carcinoma
Squamous cell carcinoma of the anus or adenocarcinoma of the rectum may involve the anal skin, and patients may present with anal pain and bleeding. Palpation, however, may detect a greater degree of induration, and a biopsy of any suspect lesion along with endoscopic evaluation of the colon should be performed.
Specific Infectious Perianal Conditions
Syphilitic fissures may be caused by either primary chancres or condylomata lata. In its initial stage, a chancre may closely resemble an ordinary fissure but subsequently develops significant induration at its margin, and inguinal lymph nodes become enlarged. History of anoreceptive intercourse, location of the fissure off the midline, and a more external location away from the anal verge or internally above the dentate line help distinguish these lesions from idiopathic anal fissures. In addition, patients with syphilitic fissures may have multiple lesions that have irregular borders and appear opposite one another in a mirror image (“kissing”). Suspect lesions can be diagnosed by a dark-field examination. Anal condylomata lata may occur at the anal orifice, as well as in the perianal region, and may cause multiple anal fissures.
A tuberculous ulcer in the anal region is rare. When it occurs, it tends to enlarge and develop undermined edges. Differentiating this lesion from Crohn’s disease may be very difficult; however, the tuberculous ulcer is often associated with pulmonary tuberculosis. Performing a biopsy may be necessary. If the fissure remains after antituberculous chemotherapy has been administered, treatment is the same as with an idiopathic fissure.
8.1.7 Treatment
Acute Fissure
Avoidance of constipation is probably the single most important nonoperative treatment. The aim of treatment of an acute fissure-in-ano is to break the cycle of a hard stool, pain, and reflex spasm. This result often can be accomplished with simple measures such as addition of bulk-forming agents, increase in water intake, and warm baths to help relieve the sphincter spasm. Ingestion of bulk-forming foods (e.g., adequate amounts of unprocessed bran) or stool softeners such as psyllium seed preparations can be used to create a soft stool that hopefully will not further tear the anal canal. In addition, a large bulky stool may result in physiologic dilatation of the anal sphincter. Warm sitz baths several times a day as well as following bowel movements may help with symptomatic relief and may result in relaxation of the sphincter muscles. 24
Shub et al 25 followed 393 patients with fissure-in-ano for 5 years and found that 44% healed within 4 to 8 weeks with nonoperative treatment consisting of an emollient suppository, a psyllium seed preparation, and sitz baths. The recurrence rate was 27%, and one-third of those lesions healed after further nonoperative treatment. Hananel and Gordon 3 reviewed 876 patients who presented with fissure-in-ano with a mean follow-up of 26 months (range, 0.5–215 months). Forty-four percent of patients responded to nonoperative therapy (consisting of bulk-forming agents and sitz baths), 62.4% of them in the first 2 months. Recurrent symptoms developed in 18.6% of patients whose fissures healed; 60% responded to further medical therapy. Of the patients who initially did not respond to medical treatment, lateral internal sphincterotomy was recommended. The authors found that of those patients that responded to nonoperative treatment, there was an increase in healing rates from 62.4% at 2 months to 86.2% at 6 months. Therefore, depending upon the severity of the patient’s symptoms, it may be worthwhile to continue medical treatment for up to 6 months if the patient demonstrates steady improvement.
In a double-blind, placebo-controlled trial, Jensen 26 found that the use of unprocessed bran in doses of 5 g three times per day resulted in a decreased recurrence rate. Patients were randomized to receive three daily doses of a placebo or unprocessed bran at 2.5- or 5-g doses. After a 1-year follow-up, the recurrence rate in patients receiving 5 g of bran was 16%, 60% in patients receiving 2.5 g, and 68% in the placebo group (p < 0.01). Patients in this study were also followed for 6 months after therapy was stopped. Recurrent fissures developed in 25% of patients, suggesting that maintenance therapy of fiber should be continued for life.
Topical anesthetic agents and hydrocortisone have also been used in the treatment of acute anal fissures. In a prospective trial, patients with acute fissure were randomized into one of three treatment categories: lidocaine ointment, hydrocortisone ointment, or warm sitz baths combined with an intake of unprocessed bran. 27 After 1 and 2 weeks of treatment, symptomatic relief was significantly better among patients treated with sitz baths and bran than among patients in the other treatment arms. After 3 weeks, there was no significant difference in symptomatic relief among the three groups, but patients treated with lidocaine had significantly fewer healed fissures (60%) than did patients treated with hydrocortisone (82.4%) or warm sitz baths and bran (87%).
Chronic Anal Fissure
A fissure that persists for at least 6 to 8 weeks is typically considered a chronic fissure. Unlike acute fissures, the majority of chronic fissures will not heal spontaneously or with conservative treatment. 1 In fact, a recent Cochrane review of 70 randomized trials of nonoperative treatment for chronic anal fissure demonstrated a combined healing rate in the placebo group of only 35%. 28 Anatomic features of chronicity include exposure of the internal sphincter at the base of the fissure, induration of the fissure edges, development of a large sentinel pile, and hypertrophied anal papilla. Lock and Thomson 2 reported that once these features were present, it was unlikely that spontaneous healing will occur and early recognition of these associated problems was very important for the institution of the correct treatment.
Sphincter Relaxants
Because of the relationship between hypertonicity of the anal sphincter and anal fissure, pharmacologic therapies have been used to create a reversible reduction in sphincter pressure until the fissure has healed. Topical agents include nitroglycerin and calcium channel blockers (diltiazem or nifedipine) that aim to cause relaxation of the muscle, and injectable botulinum toxin that results in chemical denervation of the muscle. A wide variation of results have been reported with the use of these agents, in part due to the fact that some studies have included acute fissures, some chronic fissures, and often both. The dosage of medication, the frequency of administration of the medication, and the length of follow-up also account for the wide variation of results.
Nitroglycerin
Nitric oxide is the principal nonadrenergic, noncholinergic neurotransmitter mediating neurogenic relaxation of the internal sphincter. Glyceryl trinitrate (GTN) acts as a nitric oxide donor that promotes healing of anal fissure by two mechanisms. Nitric oxide stimulates guanylate cyclase, leading to formation of cGMP, which in turn activates protein kinases that then dephosphorylate myosin light chains, resulting in muscle fiber relaxation. 23 When applied as a topical ointment, it diffuses across the skin barrier and causes a reduction in internal sphincter pressure as well as improving anodermal blood flow through its vasodilatory effect on the anal vessels.
Studies have shown that GTN effectively reduces mean resting anal pressure. 29 , 30 , 31 In a controlled trial, Loder et al 30 demonstrated a significant reduction in anal sphincter pressure from the topical application of 0.2% GTN, a finding confirmed by others. 32 Lund and Scholefield 31 conducted a prospective randomized double-blind, placebo-controlled study to determine the efficacy of topical GTN 0.2% applied twice a day. After 8 weeks, healing was observed in 68% of patients compared to 8% of controls, and maximum anal resting pressures fell significantly from 115.9 to 75.9 cm H2O in the treatment group.
Schouten et al 33 evaluated the influence of the topical application of isosorbide dinitrate on anal anodermal blood flow and fissure healing. Before treatment and at 3 and 6 weeks, 22 patients underwent conventional anal manometry and laser Doppler flowmetry of the anoderm. Maximum resting anal pressures were significantly reduced, there was a significant increase in anodermal blood flow, and fissure healing occurred in 88% of patients at 12 weeks.
McLeod and Evans 34 reviewed the literature with respect to the use of nitroglycerin in the management of patients with anal fissure. A total of nine randomized controlled trials have studied the efficacy of GTN in chronic anal fissure. In four out of five trials, GTN was significantly more effective than placebo in healing fissures. 29 , 31 , 32 , 35 , 36 The healing rates in the GTN group varied from 46 to 70% and healing in the placebo group ranged from 8 to 51%. Two trials have reported results of long-term follow-up with symptomatic recurrence rates ranging from 27 to 62%. 29 , 37 Three trials compared 0.2 to 0.5% GTN to lateral sphincterotomy. 38 , 39 , 40 Sphincterotomy was superior in two of these trials.
Conflicting results with the use of GTN have been reported in the literature with respect to healing rate, recurrence rate, and side effects (▶ Table 8.1). Differences in reported healing rates may relate to the difficulty in administering a standardized dose to all patients. Most published studies of topical GTN have used 0.2 to 0.3% preparations. Dosing frequencies varied from two to three times a day and durations varied from 4 to 8 weeks. Healing rates may well be affected by alteration of any of these dosing variables.
The major drawback of treatment with GTN is that a significant proportion of patients experience adverse effects. The high incidence of side effects interferes with quality of life and may result in poor patient compliance. Headaches are the primary adverse event and have been reported in 29 to 72% of patients. 29 , 32 Most were transient (lasting roughly 15 minutes) and dose related, and only 3 to 20% of patients discontinued treatment because of headaches. 29 , 31 , 39 Educating patients prior to initiation of treatment, beginning with a lower dose and escalating over several days, using a glove during application to avoid absorption through the skin of the finger, and remaining in a recumbent position for 15 minutes after application may help to reduce symptoms. 54 , 55
Pitt et al 48 conducted a study to identify factors associated with treatment failure of GTN. The authors cited risk factors of constipation, recent childbirth, colonoscopy, and anal receptive intercourse. Fissures in patients who had an associated sentinel pile were significantly less likely to heal initially, more likely to recur, and more likely to remain unhealed in the long term. Fissures with a history of more than 6 months were also less likely to heal initially.
Although GTN is effective in healing one-half to two-thirds of patients with chronic anal fissure, long-term follow-up symptoms may recur in 15 to 63% (▶ Table 8.1). The risk of long-term recurrence, in addition to poor patient compliance, has diminished the role of nitrates in the treatment of anal fissure. In addition, randomized trials have demonstrated that GTN is inferior to both botulinum toxin 42 and lateral internal sphincterotomy in providing symptomatic relief and fissure healing. 38 , 40
Calcium Channel Blockers
Calcium channel blockers inhibit voltage-dependent calcium channels within the plasma membrane of electrically excitable muscle cells. This results in a decrease in the calcium ion concentration within the sarcoplasmic reticulum, which interferes with calcium-mediated signal transduction and phosphorylation. This disruption decreases contraction of the muscle cells and results in relaxation of the muscle fibers. 23 Both diltiazem and nifedepine have been used in the treatment of chronic anal fissures.
Nifedipine, a dihydropyridine, is a calcium antagonist that causes smooth muscle relaxation and vasodilatation. Chrysos et al 56 demonstrated that anal resting pressure was reduced by 30% following a sublingual dose of 20 mg. Other studies have also demonstrated a reduction in mean resting pressures between 21 and 36% in healthy volunteers 57 , 58 , 59 and 11 to 36% in patients with fissures. 57 , 59 , 60 Topical application has also been shown to lower resting pressure, relieve pain, and heal acute fissures. 57 Perrotti et al 60 performed a prospective randomized double-blind study in 110 patients to test the efficacy of local application of nifedipine and lidocaine ointment in healing chronic anal fissure. Patients treated with nifedipine used topical 0.3% nifedipine and 1.5% lidocaine ointment every 12 hours for 6 weeks. The control group received topical 1.5% lidocaine and 1% hydrocortisone acetate ointment during therapy. After a median follow-up of 18 months, healing of chronic anal fissure was achieved after 6 weeks of therapy in 94.5% of the nifedipine-treated patients in comparison to 16.4% of the controls. Mean anal resting pressure decreased by 11%. Recurrence of the fissure was observed in 3 of 52 patients in the nifedipine group within 1 year of treatment, and 2 of these patients healed with an additional course of topical nifedipine ointment. Antropoli et al 57 showed very similar results.
Ezri and Susmallian compared the use of 0.2% topical nifedipine to 0.2% topical GTN. 61 Healing of fissures was higher in the nifedipine group (89 vs. 58%) and side effects of headache and flushing were lower (5 vs 40%). Recurrence rates were similar between the two groups. Results with the use of nifedipine in the treatment of fissure-in-ano both in the cream form and in the oral form are noted in ▶ Table 8.2.
Diltiazem is another calcium channel blocker that reduces resting anal sphincter pressures. This agent was introduced because of the previously noted side effects of the topical GTN. Jonas et al 66 evaluated the efficacy of diltiazem for fissures that failed to heal with GTN. Diltiazem 2% was applied twice daily for 8 weeks or until the fissure healed. Fissures healed in 49% of patients within 8 weeks. Side effects occurred in 10% of patients and included perianal itching, but they continued with treatment as they were generally well tolerated. Knight et al 67 treated 71 patients with 2% diltiazem gel and reported healing in 75% of these patients. Carapeti et al 58 compared the use of diltiazem 2% with 0.1% bethanechol thrice daily. Fissures healed in 67% of patients with diltiazem and 60% of those treated with 0.1% bethanechol gel. Both diltiazem and bethanechol substantially reduced anal sphincter pressure and achieved fissure healing in a similar degree reported with topical nitrates but without side effects. Results with the use of diltiazem are listed in ▶ Table 8.3.
Jonas et al 74 further assessed the effectiveness of oral versus topical diltiazem in the healing of chronic fissures. Healing was noted to be complete in 38% of patients who received 60 mg of oral diltiazem compared to 65% of those receiving 2% topical gel. Oral diltiazem caused side effects of headaches, nausea, vomiting, and reduced smell and taste, whereas no side effects were seen in those receiving topical therapy. The authors concluded that topical diltiazem is more effective, achieving healing rates comparable to those reported with topical nitrates with significantly fewer side effects. Kocher et al 50 conducted a prospective double-blind randomized trial to compare the incidence of side effects with 0.2% GTN ointment and 2% DTZ cream in the treatment of chronic anal fissure. Treatments were applied perianally, twice daily for 6 to 8 weeks. There were more side effects with GTN (72%) than with DTZ (42%). In particular, more headaches occurred with GTN (59%).
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