American Journal of Gastroenterology  C 2007 by Am. Coll. of Gastroenterology Published by Blackwell Publishing

ISSN 0002-9270 doi: 10.1111/j.1572-0241.2007.01203.x

CME

Nonsurgical Approaches for the Treatment of Anal Fissures Sanju Dhawan, Ph.D. and Sunny Chopra, M. Pharm. University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India

Chronic anal fissure (CAF) is usually associated with internal anal sphincter spasm, the relief of which is central to provide fissure healing. The treatment for CAF has undergone a transformation in recent years from surgical to medical. Both the approaches share the common goal of reducing the spasm. Though surgical treatment has a high success rate, it can permanently impair fecal continence in a large number of patients. Smooth muscle relaxation seems to be a novel way by which more than 60% of the patients can be cured with the topical use of the agents. This treatment is in addition to the normalization of stools mostly. Smooth muscle relaxation is well tolerated, can be administered on an outpatient basis, does not cause any lesion of the continence organ, and subsequently, does not lead to any permanent latent or apparent fecal incontinence. This review encompasses various agents that are used for smooth muscle relaxation. In addition, it describes various clinical studies reported in the literature with their success rates and side effects. (Am J Gastroenterol 2007;102:1312–1321)

INTRODUCTION According to Antropoli et al., various pathologies of anal canal are extremely common (1, 2). About 30–40% of the population suffers from proctologic pathologies at least once in their lives. Anal fissure (AF) is present in about 10–15% of proctological patients (3). AF can be defined as a tear or split in the distal anal canal, which if not treated appropriately at an early stage causes considerable anal pain during defecations (4, 5). It is associated with spasm of the internal anal sphincter and a reduction in mucosal blood flow with delayed or nonhealing of the ulcer (6, 7). The primary cause of chronic anal fissure (CAF) is increased resting anal pressure (RAP). Other most frequent causes are infection, essentially sexually transmitted diseases, and tumor, mainly anal epidermoid cancer. Most AFs heal spontaneously with conservative treatment, viz., stool softener and diet modification. Such AFs are termed as acute but a proportion of them persists for a longer period and is known as chronic. Chronicity is defined by both chronology and morphology. Most surgeons consider the persistence for 6 wk as a reasonable point when an AF, unlikely to heal with conservative treatment, may be considered chronic. Morphologically, the presence of visible transverse internal anal sphincters fibers at the base of a fissure typifies chronicity. Associated features include indurated edges, a sentinel pile, and a hypertropical anal papilla. An acute fissure looks like a fresh tear in the skin, while in a CAF the walls of the tear become thickened.

TREATMENT OF AF The treatment for AF is based on reducing the spasm of the internal anal sphincter, either by dilating the anal canal or To access a continuing medical education exam for this article, please visit www.acg.gi.org/journalcme.

sphincterotomy. It is postulated that spasm impedes mucosal blood flow and impairs healing. High-fiber diet and increasing the volume of daily drinks are useful and very efficient in treating AF (8). Analysis of the available literature shows that by far, medical manipulation of the internal sphincter should be the first-line treatment in AF. A surgical therapy is called for if the medical therapy fails or there is a recurrence (9).

LATERAL INTERNAL SPHINCTEROTOMY (LIS)/SURGERY LIS is a surgical technique to cure AF. It has been favored by most of the surgeons, because it offers long-lasting relief in sphincter spasm (10, 11). The most preferred options are the manual dilatation with radiosurgery and subcutaneous LIS. Both methods are easy to perform and no special setup is needed (12, 13). Traditionally, LIS is considered as the gold standard treatment for chronic fissures, but it permanently weakens the internal sphincter and may lead to anal deformity and incontinence in 8–30% of patients (14, 15). Therefore, recently, nonsurgical treatment modalities have been developed.

NONSURGICAL METHODS Smooth muscle relaxation is an effective treatment for CAF and has advantages over surgical treatment in avoiding longterm complications. Additionally, it does not require hospitalization (16). The discovery of pharmacological agents that effectively cause temporary sphincterotomy and heal most fissures has led to approximately two-thirds of patients avoiding surgery. Smooth muscle relaxation is also the first option in patients with a high risk of incontinence (17). Smooth muscle relaxation has been tried using a variety of agents (18, 19).

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Treatment of Anal Fissures

1313

Table 1. Details of the Clinical Trials Carried out Using Topical GTN Clinical Trial (Ref.) (26)

Dose of GTN (%)

No. of Patients Studied

No. of Patients Healed (%)

(28)

61 (after 4 wk) 90 (after 6 wk) 1 (N = 37), 0.5 (N = 6), 81 (67 men, 64 acute, 47 69 (acute) 0.2 (N = 38) CAFs) (for 18 months) 54 (chronic) 0.2 31 56 (after 6 months)

(29)

0.3

31 (16 acute, 15 CAFs)

(30)

0.2

56 (16 acute, 40 CAFs)

(27)

0.2 (twice a day for 6 wk) 21

(33)

(34)

(35) (36)

(37)

0.5 0.2 GTN three times a day for 8 wk (Group A) LIS (Group B) 0.25 GTN (Group A) Dietary change (group B) (for 39 wk) Placebo (group A) 0.1 (group B) 0.1 group C) 0.4 (group D) (374 mg twice daily up to 8 wk)

0.2 GTN (group A) LIS (group B) Placebo (group A) 0.1 (group B) 0.2 (group C) 0.4 (group D) (220 mg twice a day) 0.2 (twice a day for 6 wk)

Clinical Trials in Children (38) 0.05 (group A)

19 (mild headache)

–

–

27

70 (headache) 10 (severe headache) 75 (headache)

9

61 (headache)

45 Group A (N = 34) Group B (N = 31) Group A (N = 22, 16 chronic, 6 acute) Group B (N = 21, 16 chronic, 5 acute)

97 (Group B) Group A (75 chronic, 83 67 (group A, at 9 acute) months) Group B (N = 21, 16 chronic, 5 acute)

304

50 in all the cases

Group A (N = 35) Group B (N = 35) 200

Group A (54) 24 (group A) 50 (group B) 36 (group C) 57 (group D)

Side Effects (%)

22

56 (acute) 41 (chronic) 63 after 4 wk, 81 after 8 wk (acute cases) 33 after 8 wk, 50 after 12 wk (CAFs) 73 (after 6 wk) 61 (Group A)

(500 mg) (31) (32)

Recurrence (%)

14 (severe headache) – 45

3.9

9 (group A) 3 (group B) –

84 (headache) 12

77 (group A)

A 12.5 (headache) 4.2 (severe headache) B 18.3 (headache) 2 (severe headache) C 36.1 (headache) 6.3 (severe headache) D 67.5 (headache) 24.3 (severe headache) Group A (N = 35) 3 Group B –

80 (34 men 46 women)

55 (after 4 wk) 78 (after 9 wk)

61 (flushing) 15 (severe headache)

15 (8 boys, average age 3–13 yr)

100 (group A)

13

0.1 (group B)

62.5 (group B)

N is the number of patients to whom the treatment was given

Smooth muscle relaxation is particularly suitable in patients with associated inflammatory bowel disease, in whom LIS for AF is generally contraindicated (20–23).

GLYCERYL TRINITRATE (GTN) Topical GTN, a nitric oxide donor compound, has been shown to cause relaxation of the anal sphincter and thus finds use in the treatment of AF. It has been reported that blood flow at the posterior midline of anoderm is inversely related to the mean maximum anal resting pressure, and topical application of GTN ointments increases the blood flow to posterior

midline (24). Fenton et al. reviewed the pharmacodynamic and pharmacokinetic profile of GTN (0.4 % ointment) (25). Nitroglycerin ointment is approved in the United Kingdom as a prescription medicine for the treatment of CAF pain. About 375 mg of 0.4% nitroglycerin rectal ointment is prescribed twice a day, delivering 1.5 mg of nitroglycerin. Mean bioavailability with 0.2% nitroglycerin ointment delivering 0.75 mg nitroglycerin dose is 50%. The values of Cmax , volume of distribution, clearance, and elimination half-life were found to be 0.1–1 µg/L, 3 L/kg, 1 L/kg/min, and 3 min, respectively. A number of clinical trials conducted using topical GTN are listed in Table 1.

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Zuberi et al. randomized 42 consecutive patients with CAF (more than 4 months duration) into three groups (39). Group A (N = 18) received GTN (0.2%) ointment, group B received GTN patches (N = 19), and the control group (N = 12) underwent LIS. Fissures healed completely in 66.7%, 63.2%, and 91.7% in groups A, B, and C, respectively. No statistically significant difference (P = 0.7) was observed in the healing rates with ointment or patches. In a study carried out by Ciccaglione et al. (40), the effect of GTN ([0.2%, N = 6] and [2%, N = 6]) on anal canal pressure before and after 8 wk of treatment was observed. About 120 mg of GTN was applied on the external anal verge and anal pressure was evaluated in 12 patients using an electronic probe at three recording sites before and after application. Both concentrations equally reduced basal anal canal pressure in all three recording sites (P < 0.001) for a 60-min period. Another research team retrieved 10 randomized clinical trials published up to July 2001 (41). In five of six studies, the healing rate for GTN was better than that of placebo or lignocaine. However, headache was observed to be a common side effect of the treatment. LIS and topical GTN were compared in four trials. The results suggested that with GTN therapy surgery could be avoided in 31–65% of patients. The authors concluded that topically applied GTN (0.2% three times a day) for 4 wk can be used for the treatment of AF. All the above studies reported that GTN was beneficial for the treatment of CAF. However, in a very few studies, it has been reported that GTN produced no benefit regarding healing or pain relief. In a randomized, double-blind study, including 48 patients with CAF (42), three groups of patients received 0% (placebo), 0.2% (0.75 mg), and 0.4% (1.5 mg) of GTN ointment. The study was completed by 69% of patients. Other patients failed to complete the study due to headaches and cooperation problems. No significant difference (P < 0.05) was found between the groups with respect to patient age, gender, past history, physical examination, amount of ointment used, and adverse events. No significant difference was found between the groups regarding healing (P = 0.952) or pain relief (P = 0.458–0.8 according to the type of pain checked). According to this study, there was no benefit regarding healing or pain relief, in treating patients suffering from AF with GTN ointment in combination with stool softeners and sitz baths compared to the same treatment without GTN ointment.

TOPICAL DTZ

DILTIAZEM (DTZ)

DTZ VERSUS GTN

The internal anal sphincter has a calcium-dependent mechanism to maintain tone, and also receives inhibitory extrinsic cholinergic innervation. It may therefore be possible to lower anal sphincter pressure using calcium channel blockers and cholinergic agonists without side effects.

In a study reported by Jonas et al. (47), the efficacy of DTZ for fissures that failed to heal with GTN was evaluated. Consecutive patients (N = 39, median age 42 yr) with persistent CAF despite treatment with GTN ointment (0.2%) underwent anal manometry before and for 1 h after application of

In a study carried out by Knight et al., 71 consecutive patients with CAF were treated with DTZ (2%) ointment for 9 wk (43). About 88% of patients healed with DTZ ointment. Four patients experienced perianal dermatitis and one patient suffered from headache. After 32 wk completion of the treatment, 27 of 41 patients available remained symptom-free. Six of the seven patients with recurrent fissure were treated successfully by repeating DTZ treatment. In yet another study, patients with CAF were treated topically with 2% DTZ gel (dose 8 mg) three times daily (44). Twenty-three patients (12 women) with median age 45 yr had a median 6 months’ history of fissures. These were associated with a sentinel tag in 39% patients. The fissure healed in 48% of patients, including 75% of patients who previously failed to heal with GTN ointment. There were no recurrences at 3 months and no adverse effects.

ORAL AND TOPICAL DTZ Some researchers have compared oral DTZ with topical DTZ. A study performed by Jonas et al. assessed the effectiveness of oral and topical DTZ in healing CAF (45). Fifty consecutive patients with CAF were randomly included in the study. Twenty-four patients received oral (60 mg) and 26 received topical (2% gel) DTZ twice daily for up to 8 wk. Anal manometry and blood pressure were recorded at 15-min intervals. Every 15 days, patients were assessed on the basis of pain alleviation, fissure healing, and side effects. After 8 wk, RAP fell by 15 and 23% in the two groups, respectively. Fissure healing was complete in 38% and 65% in patients with oral and topical DTZ treatment by 8 wk, respectively. Side effects including rashes, headache, nausea, and vomiting were observed in eight patients of the oral DTZ group, whereas no side effects were seen in those receiving topical therapy (P = 0.001). Thus topical DTZ was found to be more effective with no side effects. Carapeti et al. conducted three studies each involving 10 healthy volunteers. In the first study, subjects were given oral DTZ (60 mg) or placebo on separate occasions. They were then given DTZ once or twice daily for 4 days. In the second and third studies, DTZ and bethenachol (BTN) gels of increasing concentration were applied topically to lower anal pressure (46). DTZ gel (2%), BTN (0.1%), and oral DTZ twice daily produced 28%, 24%, and 17% reductions in anal pressure, respectively.

Treatment of Anal Fissures

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Table 2. Clinical Studies Where Effectiveness of Topical DTZ Has Been Compared With GTN and BTN Clinical Trial (Ref.) (49) (50) (51)

Dose BTN (0.1 %) DTZ (2 %) (thrice daily for 8 wk) GTN (0.2 %) DTZ (2 %) (twice daily for 6–8 wk) GTN (0.5% N = 21) DTZ (2%, N = 22) (twice daily for 8 wk)

No. of Patients Studied

No of Patients Healed (%)

Recurrence (%)

Side Effects (%)

15

60 (BTN) 67 (DTZ)

Not reported

Not reported

52

86 (GTN) 83 (DTZ)

22

72 (GTN) 42 (DTZ)

43

85 (GTN) 86 (DTZ)

Not reported

33 (GTN) 0 (DTZ)

DTZ gel (700 mg of 2%) to the distal anal canal. The gel was applied twice daily for 8 wk. Fissure healing and side effects were noted every 15 days. Topical DTZ gel lowered RAP by 20% and fissures healed in 49% of patients within 8 wk. Before DTZ, 69% had used a complete course of GTN (0.5 g twice daily for 8 wk), and 44% of patients healed with DTZ. Some of the patients had discontinued GTN prematurely because of headaches. Side effects including perianal itching, headache, drowsiness, and mood swings occurred in 10% of patients during DTZ treatment. Hence, the authors concluded that topical DTZ (2%) was effective treatment for GTN-resistant CAF. Griffin et al. (48) used topical DTZ gels to heal patients with CAF that had failed previous treatment with topical GTN (0.2%). Patients (N = 47) with CAF who had previously failed at least one course of topical GTN were recruited prospectively from a single center. They applied DTZ (700 mg of 2%) cream to the anal verge twice daily for 8 wk. Forty-four percent of patients who completed treatment were cured of fissures. Another 42% of patients with persistent fissures were symptomatically improved. Thus surgery could be avoided in 70% of patients. A few studies where topical DTZ has been compared with GTN and bethenechol (BTN) are included in Table 2.

NIFEDIPINE (NIF) NIF has also been used in treatment of AFs as reported in a number of studies (52). In a prospective, randomized, doubleblind, multicenter study, the efficacy of local application of NIF gel (0.2%) in healing acute AF was determined (2). Patients (N = 141) applied topical NIF gel every 12 h for 3 wk. The control group (N = 142) received topical lidocaine (1%) and hydrocortisone acetate (1%) gel during therapy. Manometry was performed before and after 14 and 21 days. After 21 days of therapy, 95% and 50% of patients were healed in the NIF group and control group, respectively (P < 0.01). A mean reduction of 30% (P < 0.01) and 188.8% (P < 0.01) in anal pressure and squeeze pressure was observed. In other studies reported by Merenstein and Rosenbaum and Slawson, remarkable improvement in healing was observed when 1.5% lidocaine and 0.3% NIF were applied twice

daily for 6 wk. Thus, a combination of lidocaine and NIF can be a reliable nonsurgical method for treating CAF (53, 54). Katsinelos et al. compared the efficacy of NIF ointment (0.5%) with LIS for the treatment of CAF (55). Sixty-four patients with symptomatic CAF were randomly assigned NIF ointment (N = 32) every 8 h for 8 wk or LIS (N = 32). In addition, both stool softeners and fiber supplements were prescribed. Patients were assessed at 2, 4, 6, and 8 wk. Longterm outcomes were determined after a median follow-up of 19 and 20.5 months for the NIF and LIS group, respectively. The overall healing rates at the end of follow-up were 93% and 100% in the NIF and LIS groups, respectively (P = 0.48). Fifty percent of patients developed side effects in the NIF group compared with 18.7% in the LIS group.

LACIDIPINE Lacidipine is a calcium channel blocker like nifedipine and hence finds its use in the treatment of AFs. Twenty-one consecutive patients (16 women) with AF (16 chronic, situated posteriorly in 17 patients, anteriorly in 4 patients) with a mean age of 37.1 yr were treated with oral lacidipine (6 mg daily) (56). Blood pressure, pain scores (assessed from 0 to 10 on a visual analogue scale), and fissure healing were monitored after 2, 4, and 8 wk. However, about 33.3% patients developed side effects. Pain scores were significantly reduced after 2 wk and continued to show a significant reduction throughout the treatment period. Fourteen percent and 90.4% of fissures were healed after 14 and 28 days, respectively. No recurrences in fissures were reported.

BOTULINUM TOXIN (BTX) BTXs comprise a family of neurotoxins designated as types A to G, which are produced by the anerobic bacterium Clostridium botulinum. BTX-A blocks cholinergic transmission resulting in flaccid paralysis and autonomous nerve dysfunction. CAFs are caused by anal sphincter hypertonia leading to an ischemic ulcer. BTX-A injection into the internal or external anal sphincter causes relaxation of the anal sphincters, enhances microcirculation at the fissure site, and promotes fissure healing (57). Studies of BTX injection into the anal

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Table 3. Clinical Trials Conducted Using BTX for Smooth Muscle Relaxation Clinical Trial (Ref.)

Location of Application

Dose of the Agent

No. of Patients Studied

(60)

Bilaterally to the fissure

2.5–5U (BTX)

100 (43 women, average age 34.7)

(61)

Anterior midline of internal anal sphincters) GTN twice daily for 6 wk External anal sphincter

Group A (BTX 20 U)

50

(62)

Group B (GTN 0.2 %)

No of Patients Healed (%) 79 (after 6 months) Group A (96) Group B (60)

15 U (BTX)

40

42 (at 3 months) 50 (at 6 months) 54 (after 1 month)

(63)

Internal anal sphincter

50U (BTX)

13

(64)

Laterally into internal anal sphincter

50U (BTX)

12 (8 women, 4 men)

(65)

-

21

(66, 67) (68)

Internal sphincter

Group A (BTX 20 U, N = 10) Group B (GTN 0.2 %, N = 11) 30 U (BTX) 25 U (BTX)

sphincter have reported excellent healing rates, although the procedure is more invasive, and patients may find it uncomfortable and less tolerable. Brisinda et al. tried to optimize the dose of BTX. In their study, 150 patients with posterior AF were treated with BTX injected into the internal anal sphincter on each side of the anterior midline (58). Subjects were randomized into two treatment groups. Patients in group I were treated with 20 U of BTX and, if the fissure persisted, were retreated with an additional 30 U. Patients in group II were treated with 30 U and retreated with an additional 50 U, if the fissure persisted. One month after the injection, examinations revealed complete healing in 73% from group I and 87% from group II (P = 0.04). Five patients from group II reported mild incontinence of flatus that lasted 2 wk after the treatment and disappeared spontaneously. The values of the RAP (P = 0.3) and the maximum voluntary pressure (P = 0.2) did not differ between the two groups. A recurrence of the fissure was observed in 6 patients from the group. The authors confirmed that with an increase in dose, the success rate increased with little increase in side effects. Another study proved the use of local infiltration of BTX into the internal anal sphincter as an effective treatment for CAF. In a double-blind, placebo-controlled study, 30 consecutive symptomatic adults were enrolled (59). All the patients received two injections (total volume 0.4 mL) into the internal anal sphincter. The treated group (N = 15) and the control group (N = 15) received 20 U of BTX-A and saline, respectively. After 2 months, 11 patients in the treated group and two in the control group had healed fissures (P = 0.003). Thirteen and four patients in the treated and control group, respectively, were relieved of symptoms (P = 0.003). The MRAP was reduced by 25% in the treated group as compared with the control group. Later on three patients in the control

51 100

85 (after 2 months 25 (1 month) 58 (after 3 months) Group A (70) Group B (82) 79 47 (after 3 yr)

group underwent LIS. The remaining 10 patients (control group) received BTX injections (20 U). Seven patients had healed fissures after 2 months; the other three left the study and underwent surgery. Four patients in the treated group were later retreated (with 25 U of BTX); all had healed fissures after 2 months. A few clinical studies carried out using BTX have been encompassed in Table 3 too. Sixty patients with CAF were recruited in a study conducted by Thornton et al. (69). Fifty-seven patients (30 women) with median age 43 received 20 U of BTX injected into the intersphincteric groove. Each parameter was reassessed after 2 wk and 3 months. Physical healing and symptom control were dependent on the baseline maximum RAP and baseline fissure score (P = 0.003, P = 0.009, respectively). Although maximum RAP fell by 17%, pressure reduction did not correlate with clinical outcome (P > 0.2). Seventeen patients reported a mean 17% increase in continence score. Daniel et al. (70) reviewed the published studies about the use of BTX injection in the management of CAF. The authors reported that healing occurred in more than 70% of fissures without irreversible incontinence.

COMBINED TREATMENT APPROACH The use of BTX is associated with hyperhidrosis (syndrome associated with excessive sweating). Wollina and Konrad (71) compared the traditional BTX-A treatment of muscular spasticity in AFs with combined treatment of spasticity and focal treatment of the anal fold and perianal skin. Ten patients with CAF (of more than 6 months’ duration who failed to respond to conservative treatment and who had refused surgery) associated with focal hyperhidrosis as assessed by Minor’s sweat test were investigated in an open, two-armed trial.

Treatment of Anal Fissures

Intramuscular injections of 20–25 U BTX-A were given in group A (N = 5). In group B (N = 5), injections were combined with intracutaneous injection of 30–50 U BTX-A to treat focal hyperhidrosis. The mean follow-up was 5 months. All the patients in group B and two of the five patients in group A experienced a complete remission despite the fact that relief of pain was evident in eight of 10 patients within 2 wk. Patient satisfaction with treatment was high in group B. The study suggested that combined therapy of both muscular spasticity and focal hyperhidrosis may provide better results than intramuscular injections alone in AF therapy with BTX-A. In another study carried out by Bhardwaj et al. (72), 10 patients (5 men) with median age 40.5 yr were injected with 20 U BTX at the site of the fissure. The optimal angle for injection of BTX-A was 60◦ . Assessment was made on the basis of a visual analogue pain scale, incontinence score, and anal manometry preinjection, at 48 h postinjection and at 6 and 12 wk postinjection. All the patients attended the 48 h follow-up visit, but only seven attended the 6- and 12-wk visits. In six of seven patients, the fissures were healed. The remaining three were contacted by telephone at 6 months postinjection and two of three remained asymptomatic without further treatment. In seven patients, the median pain score preinjection was 5.5 out of 10 (range 1–10) and this dropped to a median of 1 at 12 wk. The median drop in resting pressure was 37% at 6 wk.

BTX VERSUS GTN In a prospective, nonrandomized, open-label study, patients (N = 40) with CAF who failed a course of GTN were treated with 20 U of BTX-A (73). Symptomatic relief, visual healing of fissures, side effects, and patient preference were assessed at an 8-wk follow-up. About 73% patients had improved symptomatically and avoided surgery. Forty-three percent of fissures were healed, whereas 57% of fissures remained unhealed. Of the unhealed fissures, 12%, 18%, and 27% were asymptomatic, symptomatic, and came to surgery, respectively. Transient minor incontinence symptoms were noted in 18% of patients. Thus, authors concluded that second-line BTX injection improved symptoms in approximately threequarters of patients after failed primary GTN therapy.

ISOSORBIDES Isosorbide Mononitrate (ISM) Tankova et al. (74) conducted a study to assess the efficacy and patient compliance of topical mononitrate hydrogel for the treatment of AF. ISM (0.2%) was applied to the anal canal twice daily for 3 wk. Anal pressure was determined using anal manometry before and after the therapy. At the end of therapy, 88% and 22% fissures were healed in treated and control group patients, respectively. Twenty percent of patients suffered from mild heart attack. No fecal incontinence and recurrence occurred during 3 months of follow-up.

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Isosorbide Dinitrate (ISDN) In a randomized, prospective, double-blind, placebo controlled trial, 37 consecutive subjects with AF were enrolled (75). The subjects were divided into two groups. One group (N = 20) received ISDN and the other group (N = 17) was given placebo. Both groups were treated for a median of 5 wk. After this period, 17 subjects in the isosorbide group had healed compared with 6 controls (P < 0.003). The fissure recurred in 2 patients who had an initial good response to isosorbide, and in 2 patients of the control group. Side effects (particularly headache) were more common after ISDN. In a study carried out by Songun et al., patients (N = 100) with AF were treated with ISDN, the primary healing rate of AFs was 93% with ISDN (76). In case of recurrence (13%), 54% could again be treated successfully with ISDN but a complication (temporary headache) was observed in about 7% of patients. L-Arginine (LA) Nitric oxide produced from the cellular metabolism of LA also causes relaxation of the internal anal sphincter. A study investigated by Griffin et al. reported that topical LA can be used as a possible alternative treatment for CAF (77). In a two-center study, volunteers (N = 25) received LA (400 mg) or placebo. Anal manometry was performed 2 h after application of LA gel or placebo gel. It was found that LA gel significantly lowered MRAP. LA gel had a rapid onset of action with a duration of action of more than 2 h (P < 0.01). Minoxidil and Lignocaine In a prospective, randomized, double-blind study, 90 patients with AF were recruited. Patients received local applications of ointments containing 5% lignocaine (N = 28), 0.5% minoxidil (N = 36), or both (N = 26) (78). Healing of AF at 6 wk was considered as the primary end point. The healing rate was similar in the three groups. However, the mean time taken for complete healing with combination treatment (1.9 wk) was significantly shorter than that with minoxidil alone (3.1 wk, P = 0.001) or with lignocaine alone (3.3 wk, P = 0.002). Thus, a combination of minoxidil and lignocaine helped in faster healing of AF and provided better symptomatic relief than either drug alone. Gonyautoxin All the above treatments mentioned for AF, viz., LIS, GTN, LA, NIF, and BTX, focused on reducing the tone of the internal anal sphincter. In a recent publication, Garrido and colleagues (79) have described the successful use of a new agent, gonyautoxin, in patients with acute AF and CAF. Gonyautoxin is a paralyzing phytotoxin produced by dinoflagellates. It breaks the vicious circle of pain and spasm that leads to AF. Fifty recruited patients received clinical examination, including proctoscopy and questionnaire to evaluate the symptoms (80). Anal manometry was performed before and after Gonyautoxin (100 U/mL) injection into both sides of the AF in the internal anal sphincter. Total remission of acute AF

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and CAF was achieved within 15 and 28 days, respectively. Ninety-eight percent of the patients healed before 28 days with a mean time healing of 17.6 ± 9 days. Only one relapsed during 14 months of follow-up. There was about a 56% decrease in resting pressure when compared with baseline. No side effects were observed.

OTHER TECHNIQUES Sitz Bath In addition to chemical agents used above, sitz baths have been used to provide relief to patients with CAF. Shafik conducted a study on 18 healthy volunteers and 28 patients with painful anorectal diseases (18 patients with fissures and 10 with hemorrhoids) (81). All of them used sitz baths to alleviate pain. Investigations were comprised of measuring rectal and interstitial sphincter temperature, rectal and rectal neck pressures, and electromyographic activity of both the external and internal anal sphincters before and after the subjects sat in a warm-water bath at temperatures of 40, 45, and 50o C for 10 min. Pain relief was more evident and lasted longer at higher bath temperatures. There was no change in the rectal and interstitial sphincter temperatures before and after bath in both the healthy volunteers and patients. The rectal neck pressure and internal and sphincter electromyographic activity dropped significantly in the bath, but increased gradually to pretest levels 25–70 min after exiting the bath. Comparison of Nonsurgical Approaches A few studies are reported where the comparison among DTZ, BTX, NIF, and GTN has been carried out. Tranqui et al. enrolled 88 patients with CAF (82). During the first half of the study period, patients were treated with topical GTN and pneumatic dilatation. Subsequent patients received topical NIF and BTX injections (30–100 U). LIS was reserved for patients who failed medical treatment. In 98% of patients, the fissure healed with conservative (using laxatives and stool softeners) nonsurgical treatment. The combination of NIF and BTX was superior to GTN and pneumatic dilatation with respect to both healing (94% vs 71%, P < 0.05) and recurrence rate (2% vs 27%, P < 0.01). At an average follow-up of 27 months, 92% of patients reported having no pain or only mild occasional pain with bowel movements. Thus, topical NIF and BTX injections were found to be an excellent combination, associated with a low recurrence rate and minimal side effects. All the studies reported above interpret that smooth muscle relaxation can be used as an alternative to LIS. However, in the study carried out by Nelson it has been reported that medical therapy for CAF, acute fissure, and fissure in children may be applied with a chance of cure that is only marginally better than placebo, and, for chronic fissure in adults, far less effective than surgery (83). Efficacy and morbidity of various medical therapies for AF were assessed from the studies abstracted from published reports. In these stud-

ies, participants were randomized to a nonsurgical therapy for AF. Comparison included an operative procedure, an alternate medical therapy, or placebo. Dichotomous outcome measures included nonhealing of the fissure (a combination of persistence and recurrence), and adverse events (including incontinence, headache, infection, anaphylaxis). Continuous outcome measures of the study included measures of pain relief and anorectal manometry. In a study carried out by Nelson, 21 different comparisons of the ability of medical therapies to heal AF were reported in 31 retrospective charts (84). Nine agents (GTN, ISDN, BTX, DTZ, NIF, hydrocortisone, lignocaine, bran, placebo) as well as anal dilators and surgical sphincterotomy were used. GTN was compared with a placebo group (0.78, 0.56–1.08), in children (0.96, 0.48– 1.92), and adults (0.73, 0.50–1.07). It was observed that GTN was not significantly better than placebo in curing AF. When calcium channel blockers were tested against GTN, they were found to be equivalent in their ability to cure fissure (odds ratio 0.66, 0.22–2.01). BTX when compared with placebo (0.75, 0.32–1.77) and GTN (0.48, 0.21–1.10) showed no significant advantage in efficacy. The authors also concluded that a number of more studies are required to establish the efficacy of calcium channel blockers. Based on the reports of the clinical trials, we opine that smooth muscle relaxation using chemical agents should be

Figure 1. Algorithm for the treatment of anal fissures from available clinical trials.

Treatment of Anal Fissures

tried first and if the fissures do not heal then surgery should be performed. The possible algorithm for the treatment of AFs is provided in Figure 1.

CONCLUSIONS This review describes nonsurgical treatment modalities offered for CAF. Until now, lateral internal sphincterotomy has been considered to be the gold standard treatment for CAF. In the last decade, lateral internal sphincterotomy has been replaced by smooth muscle relaxation in most cases. This medical option aims to achieve the effectiveness of surgery without side effects by means of a temporary decrease of anal pressures that allows fissures to heal. Topical applications of various agents, viz., glyceryl trinitrate (0.2%), diltiazem (2%), nifedipine (0.2%), L-arginine (400 mg), minoxidil (0.5%), lignocaine (5%), and isosorbides (0.2%) are being exploited for the treatment of AFs. Diltiazem (60 mg) and lacidipine (6 mg) have also been tried orally. In addition to these approaches, injections of botulinum toxin (30 U-50 U) and gonyautoxin (100 U) have also been reported. More than 80 clinical studies have been reported in the literature, wherein efficacy of smooth muscle relaxation has been assessed. All of these studies have shown that surgery can be avoided in 33–98% of patients by using smooth muscle relaxation. Glyceryl trinitrate has been reported to heal 33–78% of patients with CAF. However, use of glyceryl trinitrate is accompanied by side effects, viz., headache, low blood pressure. Oral diltiazem caused a lot of side effects while with topical diltiazem application side effects were low. When nifedipine was used, the healing rate (95%) was high but side effects were observed in 50% patients. A few studies have also documented the use of isosorbides and L-arginine for the treatment of CAF. The healing rate with botulinum toxin injection was found to be higher (98%), but it is invasive therapy and less convenient than topical application. Considering the various pros and cons, we opine that treatment of CAF must be individualized, depending on the clinical condition of patients. Smooth muscle relaxation should be tried first and if there is no relief, then lateral internal sphincterotomy can be used. Reprint requests and correspondence: Sanju Dhawan, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160014, India. Received August 21, 2006; accepted January 18, 2007.

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CONFLICT OF INTEREST Guarantor of the article: Sanju Dhawan, Ph.D. Specific author contributions: Sanju Dhawan conceived the idea to review the clinical trials in order to contribute to the society. Sunny Chopra collected the literature from the journals and libraries. He compiled a draft of the reported clinical trials. The manuscript was extensively edited, interpreted, and revised by Sanju Dhawan. Financial support: Sunny Chopra worked as a Junior Research Fellow in the Postgraduate Program of University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. He was admitted to the Program under industry-sponsored candidate quota approved by All India Council of Technical Education, New Delhi, India. Potential competing interests: None.