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Recent Advances in the Pharmacotherapy of Chronic Anal Fissure: An Update
Review Article
Recent Advances in the Pharmacotherapy of Chronic Anal Fissure: An Update Bikash Medhi, Ramya Sankarnarayan Rao, Ajay Prakash, Om Prakash, Lileswar Kaman1 and Promila Pandhi, Departments of Pharmacology and 1General 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 1829. 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 10–14 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 160 012, India. E-mail: [email protected] ● Date of acceptance: 15 May 2007 © 2008 Elsevier. All rights reserved.
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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 20–25 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 10–15 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
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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.17–74
GTN Contraction of the internal anal smooth muscle depends on cytoplasmic calcium. Organic nitrates are prodrugs
155
156
2000
2000
2000
2000
2000
2001
Hyman & Cataldo
Palazzo et al24
Zuberi et al25
Altomare et al26
Hasegawa et al27
Richard et al28
29
7
8
9
10
11
12
13
2003
Ezri & Susmallian34
18
Simpson et al
Colak et al36
19
20
2003
2003
2003
Scholefield et al33
17
35
2002
Kocher et al32
2001
2001
16
31
Cundall et al
Pitt et al
30
Skinner et al
15
14
1999
Kennedy et al
6
1999
1999
22
Brisinda et al
5
23
1999
Carapeti et al
21
1997
4
Lund & Scholefield
3
1997
20
Oettle
2
19
1996
Lund et al17
1
18
Year
Reference
No.
89
15
52
200
52
48
64
65
39
56
132
42
45
33
50
50
70
80
24
21
Patients, n
6–12 wk
8 wk
6 wk
8 wk
6–8 wk
24 hr
Mean: 15.6 mo
4 wk
4 wk
4–8 wk
4 wk
8 wk
6 wk
Until symptoms completely resolved
4 wk
6 wk
8 wk
8 wk
22 mo
4–6 wk
Duration of treatment
Table. Different pharmacological agents used in clinical trials of chronic anal fissure
38 (73%) – TD, 24 (64%) – 6 wk GTN
7/7 – 0.05% ont. GTN 5/8 – 0.10% ont. GTN
58% GTN
46.9% – 0.1% GTN 40.4% – 0.2% GTN 54.1% – 0.4% GTN
0.2% GTN ont./ 2% Dil. cream
21.9% – 0.1% GTN 27.9% – 0.2% GTN 33.1% – 0.4% GTN
26/64 (40.6%) GTN
22/39 (43%) GTN
13/16 (81%) – AF, GTN 13/40 (33%) – CF
29/59 (49.2%) GTN
12/18 (66.7%) GTN
73% GTN
9/16 (56%) – AF 7/17 (41%) – CF, GTN
46% GTN
15/25 (60%) GTN
67% GTN
26/38 (68%) GTN
10/12 (83.33%) GTN
18/21 (85.71%) GTN
Drugs (% response)
Open trial
Open trial
89% NF
37.5%
RDB 2-centre trial
8.8%
Open trial
Open trial
Open trial
31/60 (51.7%)
12/19 (63.2%) NG
27%
Open trial
16%
24/25 (96%) BT
32%
3/39 (8%)
Open trial
Open trial
Control
TD patch more effective
Effective
NF effective
Effective
Not significant
Effective
Effective
Effective
Effective in acute fissure
MCRPCDB Comparable
Comparable
Effective
More often headache
Effective
BT more effective
Double-blind
Effective
Effective
Effective
Remarks
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ASIAN JOURNAL OF SURGERY VOL 31 • NO 3 • JULY 2008
2006
2006
2006
2005
41
Lindsey et al40
Gosselink et al
42
43
44
Mustafa et al
De Nardi et al
Thornton et al45
Jost & Schimrigk
24
25
26
27
28
29
30
ASIAN JOURNAL OF SURGERY VOL 31 • NO 3 • JULY 2008
56
1999
Brisinda et al21
36
2001
2002
Lysy et al
Madalinski et al54
Colak et al55
Wollina & Konrad
38
39
40
41
2002
2001
53
2000
Maria et al
37
52
1999
Minguez et al51
35
1998
Maria et al
1997
34
50
Jost
33
1996
1994
1994
49
Mason et al
32
48
Gui et al
31
47
46
2005
Weinstein et al
23
Fruehauf et al
2004
39
2004
2004
Boschetto et al
22
2004
38
Maan et al37
21
10
62
14
30
50
50
69
57
100
5
10
12
27
30
20
50
15
30
48
109
64
2 wk
2 mo
6 wk
6–12 wk
2 mo
6 wk
1 mo
2 mo
6 mo
1 wk
2 mo
6 mo
8–18 wk
8 wk
8 wk
2 wk
12–18 wk
16 wk
10–30 d
6 wk
Open trial
11/14 BT + NG 1/14 – NG 7/13 – 50 U BT
2/5: 20–25 U BT (IM inj.) 5/5: 30–50 U BT (IM + IC inj.)
Open trial
6/28 (21.42%) Lig.
Open trial
10/15 (66%) – BT + TN 3/15 (20%) – BT
24/34 (70.58%) BT
Open trial
15/25 (60%) NG
Open trial
Open trial
Open trial
Open trial
Open trial
Open trial
Open trial
Open trial
Open trial
Open trial
Open trial
Placebo
79.7–94.5%, HAD
4/11 (5% Lig.)
37/50 (74%) BT
24/25 (96%) BT
48% – 10 U BT 74% – 15 U BT 100% – 21 U BT
10/57 – 15 U, 20 U BT 23/57 – 20 U, 25 U BT
79% BT
3/5 (60%) BT
7/10 (70%) BT
9/12 (75%) BT
21/25 (84%) GTN
40% local GTN 33.3% parenteral GTN
7/10 – GTN, 6/10 – NF
13/25 (52%) GTN
8/13 (62%) GTN
28/30 (93%) GTN
0.2% (0.75 mg) NG/ 0.4% (1.5 mg) NG
38.9% GTN
15/16 (93.33%) GTN
48 (81%) – TD, 27 (79%) – 12 wk
Effective
Effective
(Continued)
Effective with combination
Effective with combination
Effective
Effective
Effective at high dose
Effective in large dose
Effective
Effective
Effective
Effective
Effective
Effective topical
Effective
Effective
Effective
Effective
No significant difference
Dilation more effective
Effective
■ PHARMACOTHERAPY OF CHRONIC ANAL FISSURE ■
157
158
68
Jonas et al
Dasgupta et al
50
51
1997
Perrotti et al
72
57
58
59
2000
2001
74
61
23
7
35
110
64
90
112
43
60
47
23
39
71
50
30
30 healthy volunteers
88
32
150
57
Patients, n
6 wk
3 hr
6 wk
6 wk
6 wk
6 wk
6 wk
8 wk
8 wk
8 wk
3 yr
8 wk
9 wk
8 wk
8 wk
4d
27 mo
14 mo
1 mo
6–42 mo
Duration of treatment
Indoramin (7%)
Indoramin 20 mg
Anaesthetic gel
Lig.
Xylocaine 5%
Lig.
80% Dil.
22/43 (86%) Dil.
31/60 (41%) Dil.
47/47 (48%) Dil.
11/23 (48%) Dil.
39/39 (48%) Dil.
71/71 (83%) Dil.
26/50 (52%) Dil.
15/30 (67%) Dil.
Placebo (22%)
Observational trial
GTN
NF
RDBCT: placebo better
Effective
+ GTN
RDBCT: + NF
RDBCT: + GTN
RDBCT: not significant
Minoxidil + Lig. GTN 0.2%
Effective
Comparable
Comparable
Effective
Effective
Effective
Effective
More effective than control
Comparable
Effective
Effective with combination
Effective
Effective with combination
Relapse rate high when concentration of drug decreased
Remarks
Open trial
21/43 (85%) healing (GTN)
29/60 (46%) healing (GTN)
Open trial
Open trial
Open trial
Open trial
24/50 (60 mg oral Dil.)
15/30 Healing 60%
Observational trial
Open trial
94% – NF + BT, 71% – control Dil.
Open trial
Open trial
Open trial
Control
24/32 (75%) BT
55 (73%) – 20 U BT 65 (87%) – 30 U BT + 50 U BT
Ratio of permanently healed and relapsed group after BT: ALF 6% vs. 45% LDD 38% vs. 68% NRI 26% vs. 59%
Drugs (% response)
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.
Pitt et al
Pitt et al
60
2004
73
Bacher et al
2002
71
Maan et al
56
2005
Muthukumarassamy et al
37
Nash et al
2006
2002
2002
2002
2002
2002
55
69
Bielecki & Kolodziejczak
54
32
Kocher et al
Griffin et al
53
52
65
67
Knight et al
49
70
2001
Jonas et al63
48
66
2000
Carapeti et al62
47
2001
1999
Carapeti et al
46
64
2006
61
2006
Witte & Klaase59
44
Tranqui et al
2002
Brisinda et al58
43
45
2002
Minguez et al57
42
60
Year
Reference
No.
Table. (Continued)
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■ 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 1994.76 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
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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
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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 = 0.0001). 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
160
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.84
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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, 7th edition. USA: McGraw Hill Health Professions Division, 1999:1265. 2. Gordan PH. Fissure in ano. In: Gordon PH, Nivatvongs S, eds. Principles and Practice of Surgery for the Colon, Rectum and Anus, 2nd edition. St Louis: Quality Medical Publishing, 1999:217–40. 3. Rosai J. In: Rosai and Ackerman’s Surgical Pathology, 9th edition. St Louis: Elsevier, 2004:858. 4. Nepomuceno OR, O’Grady JF, Eisenberg SW, et al. Tuberculosis of the anal canal: report of a case. Dis Colon Rectum 1971;14: 313–6. 5. Chapel TA, Prasad P, Chapel J, et al. Extragenital syphilitic chancres. J Am Acad Dermatol 1985;13:582–4. 6. Sweeney JL, Ritchie JK, Nicholls RJ. Anal fissure in Crohn’s disease. Br J Surg 1988;75:56–7.
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7. Gibbons CP, Read NW. Anal hypertonia in fissures: cause or effect? Br J Surg 1986;73:443–5. 8. Klosterhalfen B, Vogel P, Rixen H, et al. Topography of the inferior rectal artery: a possible cause of chronic, primary anal fissure. Dis Colon Rectum 1989;32:43–52. 9. Strugnell NA, Cooke SG, Lucarotti ME, et al. Controlled digital anal dilatation under total neuromuscular blockade for chronic anal fissure: a justifiable procedure. Br J Surg 1999;86:651–5. 10. Speakman CT, Burnett SJ, Kamm MA, et al. Sphincter injury after anal dilatation demonstrated by anal endosonography. Br J Surg 1991;78:1429–30. 11. Nielsen MB, Rasmussen OO, Pedersen JF, et al. Risk of sphincter damage and anal incontinence after anal dilatation for fissurein-ano. An endosonographic study. Dis Colon Rectum 1993;36: 677–80. 12. Garcia-Aguilar J, Belmonte C, Wong WD, et al. Open vs closed sphincterotomy for chronic anal fissure: long-term results. Dis Colon Rectum 1996;39:440–3. 13. Oh C, Divino CM, Steinhagen RM. Anal fissure, 20-year experience. Dis Colon Rectum 1995;38:378–82. 14. Samson RB, Stewart WR. Sliding skin grafts in the treatment of anal fissures. Dis Colon Rectum 1970;13:372–5. 15. Nyam DC, Wilson RG, Stewart KJ, et al. Island advancement flaps in the management of anal fissures. Br J Surg 1995;82:326–8. 16. Nyam DC, Pemberton JH. Long-term results of lateral internal sphincterotomy for chronic anal fissure with particular reference to incidence of fecal incontinence. Dis Colon Rectum 1999; 42:1306–10. 17. Lund JN, Armitage NC, Scholefield JH. Use of glyceryl trinitrate ointment in the treatment of anal fissure. Br J Surg 1996;83: 776–7. 18. Oettle GJ. Glyceryl trinitrate vs. sphincterotomy for treatment of chronic fissure-in-ano: a randomized, controlled trial. Dis Colon Rectum 1997;40:1318–20. 19. Lund JN, Scholefield JH. A randomized, prospective, doubleblind, placebo-controlled trial of glyceryl trinitrate ointment in treatment of anal fissure. Lancet 1997;349:11–4. 20. Carapeti EA, Kamm MA, McDonald PJ, et al. Randomized controlled trial shows that glyceryl trinitrate heals anal fissures, higher doses are not more effective, and there is a high recurrence rate. Gut 1999;44:727–30. 21. Brisinda G, Maria G, Bentivoglio AR, et al. A comparison of injections of botulinum toxin and topical nitroglycerin ointment for the treatment of chronic anal fissure. N Engl J Med 1999;341:65–9. 22. Kennedy ML, Sowter S, Nguyen H, et al. Glyceryl trinitrate ointment for the treatment of chronic anal fissure: results of a placebo-controlled trial and long-term follow-up. Dis Colon Rectum 1999;42:1000–6. 23. Hyman NH, Cataldo PA. Nitroglycerin ointment for anal fissures: effective treatment or just a headache? Dis Colon Rectum 1999;42:383–5. 24. Palazzo FF, Kapur S, Steward M, et al. Glyceryl trinitrate treatment of chronic fissure in ano: one year’s experience with 0.5% GTN paste. J R Coll Surg Edinb 2000;45:168–70.
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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;15:243–5. 26. 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;43:174–9. 27. 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;82:27–30. 28. 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;43:1048–57. 29. 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;71:218–20. 30. Pitt J, Williams S, Dawson PM. Reasons for failure of glyceryl trinitrate treatment of chronic fissure-in-ano: a multivariate analysis. Dis Colon Rectum 2001;44:864–7. 31. Cundall JD, Gunn J, Easterbrook JR, et al. The dose response of the internal anal sphincter to topical application of glyceryl trinitrate ointment. Colorectal Dis 2001;3:259–62. 32. Kocher HM, Steward M, Leather AJ, et al. Randomized clinical trial assessing the side-effects of glyceryl trinitrate and diltiazem hydrochloride in the treatment of chronic anal fissure. Br J Surg 2002;89:413–7. 33. Scholefield JH, Bock JU, Marla B, et al. A dose finding study with 0.1%, 0.2%, and 0.4% glyceryl trinitrate ointment in patients with chronic anal fissures. Gut 2003;52:264–9. 34. Ezri T, Susmallian S. Topical nifedipine vs. topical glyceryl trinitrate for treatment of chronic anal fissure. Dis Colon Rectum 2003;46:805–8. 35. Simpson J, Lund JN, Thompson RJ, et al. The use of glyceryl trinitrate (GTN) in the treatment of chronic anal fissure in children. Med Sci Monit 2003;9:PI123–6. 36. Colak T, Ipek T, Urkaya N, et al. A randomised study comparing systemic transdermal treatment and local application of glyceryl trinitrate ointment in the management of chronic anal fissure. Eur J Surg Suppl 2003;588:18–22. 37. Maan MS, Mishra R, Thomas S, et al. Randomized, double-blind trial comparing topical nitroglycerine with xylocaine and proctosedyl in idiopathic chronic anal fissure. Indian J Gastroenterol 2004;23:91–3. 38. Boschetto S, Giovannone M, Tosoni M, et al. Hydropneumatic anal dilation in conservative treatment of chronic anal fissure: clinical outcomes and randomized comparison with topical nitroglycerin. Tech Coloproctol 2004;8:89–92. 39. Weinstein D, Halevy A, Negri M, et al. A prospective, randomized double-blind study on the treatment of anal fissures with nitroglycerin ointment. Harefuah 2004;143:713–7. 40. Lindsey I, Cunningham C, Jones OM, et al. Fissurectomybotulinum toxin: a novel sphincter-sparing procedure for
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medically resistant chronic anal fissure. Dis Colon Rectum 2004; 47:1947–52. 41. Gosselink MP, Darby M, Zimmerman DD, et al. Treatment of chronic anal fissure by application of l-arginine gel: a phase II study in 15 patients. Dis Colon Rectum 2005;48:832–7. 42. Fruehauf H, Fried M, Wegmueller B, et al. Efficacy and safety of botulinum toxin A injection compared with topical nitroglycerin ointment for the treatment of chronic anal fissure: a prospective randomized study. Am J Gastroenterol 2006;101:2107–12. 43. Mustafa NA, Cengiz S, Turkyilmaz S, et al. Comparison of topical glyceryl trinitrate ointment and oral nifedipine in the treatment of chronic anal fissure. Acta Chir Belg 2006;106:55–8. 44. De Nardi P, Ortolano E, Radaelli G, et al. Comparison of glycerine trinitrate and botulinum toxin-A for the treatment of chronic anal fissure: long-term results. Dis Colon Rectum 2006; 49:427–32. 45. Thornton MJ, Kennedy ML, King DW. Manometric effect of topical glyceryl trinitrate and its impact on chronic anal fissure healing. Dis Colon Rectum 2005;48:1207–12. 46. Jost WH, Schimrigk K. Therapy of anal fissure using botulin toxin. Dis Colon Rectum 1994;37:1321–4. 47. Gui D, Cassetta E, Anastasio G, et al. Botulinum toxin for chronic anal fissure. Lancet 1994;344:1127–8. 48. Mason PF, Watkins MJ, Hall HS, et al. The management of chronic fissure in-ano with botulinum toxin. J R Coll Surg Edinb 1996;41:235–8. 49. Jost WH. One hundred cases of anal fissure treated with botulin toxin: early and long-term results. Dis Colon Rectum 1997;40: 1029–32. 50. Maria G, Brisinda G, Bentivoglio AR, et al. Botulinum toxin injections in the internal anal sphincter for the treatment of chronic anal fissure: long-term results after two different dosage regimens. Ann Surg 1998;228:664–9. 51. Minguez M, Melo F, Espi A, et al. Therapeutic effects of different doses of botulinum toxin in chronic anal fissure. Dis Colon Rectum 1999;42:1016–21. 52. Maria G, Brisinda G, Bentivoglio AR, et al. Influence of botulinum toxin site of injections on healing rate in patients with chronic anal fissure. Am J Surg 2000;179:46–50. 53. Lysy J, Israelit-Yatzkan Y, Sestiery-Ittah M, et al. Topical nitrates potentiate the effect of botulinum toxin in the treatment of patients with refractory anal fissure. Gut 2001;48:221–4. 54. Madalinski MH, Slawek J, Zbytek B, et al. Topical nitrates and the higher doses of botulinum toxin for chronic anal fissure. Hepatogastroenterology 2001;48:977–9. 55. Colak T, Ipek T, Kanik A, et al. A randomized trial of botulinum toxin vs lidocain pomade for chronic anal fissure. Acta Gastroenterol Belg 2002;65:187–90. 56. Wollina U, Konrad H. Botulinum toxin A in anal fissures: a modified technique. J Eur Acad Dermatol Venereol 2002;16: 469–71. 57. Minguez M, Herreros B, Espi A, et al. Long-term follow-up (42 months) of chronic anal fissure after healing with botulinum toxin. Gastroenterology 2002;123:112–7.
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58. Brisinda G, Maria G, Sganga G, et al. Effectiveness of higher doses of botulinum toxin to induce healing in patients with chronic anal fissures. Surgery 2002;131:179–84. 59. Witte ME, Klaase JM. Favourable results with local injections of botulinum-A toxin in patients with chronic isosorbide dinitrate ointment-resistant anal fissures. NedTijdschr Geneeskd 2006;150: 1513–7. 60. Tranqui P, Trottier DC, Victor C, et al. Nonsurgical treatment of chronic anal fissure: nitroglycerin and dilatation versus nifedipine and botulinum toxin. Can J Surg 2006;49:41–5. 61. Carapeti EA, Kamm MA, Evans BK, et al. Topical diltiazem and bethanechol decrease anal sphincter pressure without side effects. Gut 1999;45:719–22. 62. Carapeti EA, Kamm MA, Phillips RK. Topical diltiazem and bethanechol decrease anal sphincter pressure and heal anal fissures without side effects. Dis Colon Rectum 2000;43:1359–62. 63. Jonas M, Neal KR, Abercrombie JF, et al. A randomized trial of oral vs topical diltiazem for chronic anal fissures. Dis Colon Rectum 2001;44:1074–8. 64. Knight JS, Birks M, Farouk R. Topical diltiazem ointment in the treatment of chronic anal fissure. Br J Surg 2001;88:553–6. 65. Jonas M, Speake W, Scholefield JH. Diltiazem heals glyceryl trinitrate-resistant chronic anal fissures: a prospective study. Dis Colon Rectum 2002;45:1091–5. 66. Dasgupta R, Franklin I, Pitt J, et al. Successful treatment of chronic anal fissure with diltiazem gel. Colorectal Dis 2002; 4:20–2. 67. Griffin N, Acheson AG, Jonas M, et al. The role of topical diltiazem in the treatment of chronic anal fissures that have failed glyceryl trinitrate therapy. Colorectal Dis 2002;4:430–5. 68. Bielecki K, Kolodziejczak M. A prospective randomized trial of diltiazem and glyceryltrinitrate ointment in the treatment of chronic anal fissure. Colorectal Dis 2003;5:256–7. 69. Nash GF, Kapoor K, Saeb-Parsy K, et al. The long-term results of diltiazem treatment for anal fissure. Int J Clin Pract 2006;60: 1411–3. 70. Muthukumarassamy R, Robinson SS, Sarath SC, et al. Treatment of anal fissures using a combination of minoxidil and lidocaine: a randomized, double-blind trial. Indian J Gastroenterol 2005;24: 158–60. 71. Perrotti P, Bove A, Antropoli C, et al. Topical nifedipine with lidocaine ointment vs active control for treatment of chronic anal fissure: results of a prospective, randomized, double-blind study. Dis Colon Rectum 2002;45:1468–75.
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72. Bacher H, Mischinger HJ, Werkgartner G, et al. Local nitroglycerin for treatment of anal fissures: an alternative to lateral sphincterotomy? Dis Colon Rectum 1997;40:840–5. 73. Pitt J, Craggs MM, Henry MM, et al. Alpha-1 adrenoreceptor blockade: potential new treatment for anal fissure. Dis Colon Rectum 2000;43:800–3. 74. Pitt J, Dawson M, Hallan RI, et al. A double-blind randomized placebo-controlled trial of oral indoramin to treat chronic anal fissure. Colorectal Dis 2001;3:165–8. 75. Murad F. The 1996 Albert Lasker Medical Research Awards. Signal transduction using nitric oxide and cyclic guanosine monophosphate. JAMA 1996;276:1189–92. 76. Loder PB, Kamm MA, Nicholls RJ, et al. Reversible chemical sphincterotomy by local application of glyceryl trinitrate. Br J Surg 1994;81:1386–9. 77. Watson SJ, Kamm MA, Nicholls RJ, et al. Topical glyceryl trinitrate in the treatment of chronic anal fissure. Br J Surg 1996;83:771–5. 78. Westfall TC, Westfall DP. Neurotransmission: the autonomic and somatic motor neuron systems. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gillman’s, The Pharmacological Basis of Therapeutics, 11th edition. New York: McGraw-Hill, 2006:137–81. 79. Mason PF, Watkins MJ, Hall HS, et al. The management of chronic fissure in-ano with botulinum toxin. J R Coll Surg Edinb 1996;41:235–8. 80. Jost WH, Schrank B. Repeat botulin toxin injections in anal fissure: in patients with relapse and after insufficient effect of first treatment. Dig Dis Sci 1999;44:1588–9. 81. Staneva-Stoytcheva D, Venkova K. Effects of the calcium antagonists diltiazem, verapamil and nitrendipine on the contractile responses of guinea-pig isolated ileum to electrical stimulation or carbachol. J Pharm Pharmacol 1992;44:321–5. 82. Morales-Olives FJ, Cortijo J, Esplugues JV, et al. Effect of verapamil and diltiazem on isolated gastro-esophageal sphincter of the rat. J Pharm Pharmacol 1985;37:208–9. 83. Jonard P, Essamri B. Diltiazem and internal anal sphincter. Lancet 1987;1:754. 84. Nelson R. A systematic review of medical therapy for anal fissure. Dis Colon Rectum 2004;47:422–31. 85. Mishra R, Thomas S, Maan MS, et al. Topical nitroglycerin versus lateral internal sphincterotomy for chronic anal fissure: prospective, randomized trial. ANZ J Surg 2005;75:1030–1. 86. Floyd ND, Kondylis L, Kondylis PD, et al. Chronic anal fissure: 1994 and a decade later—are we doing better? Am J Surg 2006; 191:344–8.
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Recent Advances in the Pharmacotherapy of Chronic Anal Fissure: An Update Bikash Medhi, Ramya Sankarnarayan Rao, Ajay Prakash, Om Prakash, Lileswar Kaman1 and Promila Pandhi, Departments of Pharmacology and 1General 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 1829. 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 10–14 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 160 012, India. E-mail: [email protected] ● Date of acceptance: 15 May 2007 © 2008 Elsevier. All rights reserved.
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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 20–25 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 10–15 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
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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.17–74
GTN Contraction of the internal anal smooth muscle depends on cytoplasmic calcium. Organic nitrates are prodrugs
155
156
2000
2000
2000
2000
2000
2001
Hyman & Cataldo
Palazzo et al24
Zuberi et al25
Altomare et al26
Hasegawa et al27
Richard et al28
29
7
8
9
10
11
12
13
2003
Ezri & Susmallian34
18
Simpson et al
Colak et al36
19
20
2003
2003
2003
Scholefield et al33
17
35
2002
Kocher et al32
2001
2001
16
31
Cundall et al
Pitt et al
30
Skinner et al
15
14
1999
Kennedy et al
6
1999
1999
22
Brisinda et al
5
23
1999
Carapeti et al
21
1997
4
Lund & Scholefield
3
1997
20
Oettle
2
19
1996
Lund et al17
1
18
Year
Reference
No.
89
15
52
200
52
48
64
65
39
56
132
42
45
33
50
50
70
80
24
21
Patients, n
6–12 wk
8 wk
6 wk
8 wk
6–8 wk
24 hr
Mean: 15.6 mo
4 wk
4 wk
4–8 wk
4 wk
8 wk
6 wk
Until symptoms completely resolved
4 wk
6 wk
8 wk
8 wk
22 mo
4–6 wk
Duration of treatment
Table. Different pharmacological agents used in clinical trials of chronic anal fissure
38 (73%) – TD, 24 (64%) – 6 wk GTN
7/7 – 0.05% ont. GTN 5/8 – 0.10% ont. GTN
58% GTN
46.9% – 0.1% GTN 40.4% – 0.2% GTN 54.1% – 0.4% GTN
0.2% GTN ont./ 2% Dil. cream
21.9% – 0.1% GTN 27.9% – 0.2% GTN 33.1% – 0.4% GTN
26/64 (40.6%) GTN
22/39 (43%) GTN
13/16 (81%) – AF, GTN 13/40 (33%) – CF
29/59 (49.2%) GTN
12/18 (66.7%) GTN
73% GTN
9/16 (56%) – AF 7/17 (41%) – CF, GTN
46% GTN
15/25 (60%) GTN
67% GTN
26/38 (68%) GTN
10/12 (83.33%) GTN
18/21 (85.71%) GTN
Drugs (% response)
Open trial
Open trial
89% NF
37.5%
RDB 2-centre trial
8.8%
Open trial
Open trial
Open trial
31/60 (51.7%)
12/19 (63.2%) NG
27%
Open trial
16%
24/25 (96%) BT
32%
3/39 (8%)
Open trial
Open trial
Control
TD patch more effective
Effective
NF effective
Effective
Not significant
Effective
Effective
Effective
Effective in acute fissure
MCRPCDB Comparable
Comparable
Effective
More often headache
Effective
BT more effective
Double-blind
Effective
Effective
Effective
Remarks
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ASIAN JOURNAL OF SURGERY VOL 31 • NO 3 • JULY 2008
2006
2006
2006
2005
41
Lindsey et al40
Gosselink et al
42
43
44
Mustafa et al
De Nardi et al
Thornton et al45
Jost & Schimrigk
24
25
26
27
28
29
30
ASIAN JOURNAL OF SURGERY VOL 31 • NO 3 • JULY 2008
56
1999
Brisinda et al21
36
2001
2002
Lysy et al
Madalinski et al54
Colak et al55
Wollina & Konrad
38
39
40
41
2002
2001
53
2000
Maria et al
37
52
1999
Minguez et al51
35
1998
Maria et al
1997
34
50
Jost
33
1996
1994
1994
49
Mason et al
32
48
Gui et al
31
47
46
2005
Weinstein et al
23
Fruehauf et al
2004
39
2004
2004
Boschetto et al
22
2004
38
Maan et al37
21
10
62
14
30
50
50
69
57
100
5
10
12
27
30
20
50
15
30
48
109
64
2 wk
2 mo
6 wk
6–12 wk
2 mo
6 wk
1 mo
2 mo
6 mo
1 wk
2 mo
6 mo
8–18 wk
8 wk
8 wk
2 wk
12–18 wk
16 wk
10–30 d
6 wk
Open trial
11/14 BT + NG 1/14 – NG 7/13 – 50 U BT
2/5: 20–25 U BT (IM inj.) 5/5: 30–50 U BT (IM + IC inj.)
Open trial
6/28 (21.42%) Lig.
Open trial
10/15 (66%) – BT + TN 3/15 (20%) – BT
24/34 (70.58%) BT
Open trial
15/25 (60%) NG
Open trial
Open trial
Open trial
Open trial
Open trial
Open trial
Open trial
Open trial
Open trial
Open trial
Open trial
Placebo
79.7–94.5%, HAD
4/11 (5% Lig.)
37/50 (74%) BT
24/25 (96%) BT
48% – 10 U BT 74% – 15 U BT 100% – 21 U BT
10/57 – 15 U, 20 U BT 23/57 – 20 U, 25 U BT
79% BT
3/5 (60%) BT
7/10 (70%) BT
9/12 (75%) BT
21/25 (84%) GTN
40% local GTN 33.3% parenteral GTN
7/10 – GTN, 6/10 – NF
13/25 (52%) GTN
8/13 (62%) GTN
28/30 (93%) GTN
0.2% (0.75 mg) NG/ 0.4% (1.5 mg) NG
38.9% GTN
15/16 (93.33%) GTN
48 (81%) – TD, 27 (79%) – 12 wk
Effective
Effective
(Continued)
Effective with combination
Effective with combination
Effective
Effective
Effective at high dose
Effective in large dose
Effective
Effective
Effective
Effective
Effective
Effective topical
Effective
Effective
Effective
Effective
No significant difference
Dilation more effective
Effective
■ PHARMACOTHERAPY OF CHRONIC ANAL FISSURE ■
157
158
68
Jonas et al
Dasgupta et al
50
51
1997
Perrotti et al
72
57
58
59
2000
2001
74
61
23
7
35
110
64
90
112
43
60
47
23
39
71
50
30
30 healthy volunteers
88
32
150
57
Patients, n
6 wk
3 hr
6 wk
6 wk
6 wk
6 wk
6 wk
8 wk
8 wk
8 wk
3 yr
8 wk
9 wk
8 wk
8 wk
4d
27 mo
14 mo
1 mo
6–42 mo
Duration of treatment
Indoramin (7%)
Indoramin 20 mg
Anaesthetic gel
Lig.
Xylocaine 5%
Lig.
80% Dil.
22/43 (86%) Dil.
31/60 (41%) Dil.
47/47 (48%) Dil.
11/23 (48%) Dil.
39/39 (48%) Dil.
71/71 (83%) Dil.
26/50 (52%) Dil.
15/30 (67%) Dil.
Placebo (22%)
Observational trial
GTN
NF
RDBCT: placebo better
Effective
+ GTN
RDBCT: + NF
RDBCT: + GTN
RDBCT: not significant
Minoxidil + Lig. GTN 0.2%
Effective
Comparable
Comparable
Effective
Effective
Effective
Effective
More effective than control
Comparable
Effective
Effective with combination
Effective
Effective with combination
Relapse rate high when concentration of drug decreased
Remarks
Open trial
21/43 (85%) healing (GTN)
29/60 (46%) healing (GTN)
Open trial
Open trial
Open trial
Open trial
24/50 (60 mg oral Dil.)
15/30 Healing 60%
Observational trial
Open trial
94% – NF + BT, 71% – control Dil.
Open trial
Open trial
Open trial
Control
24/32 (75%) BT
55 (73%) – 20 U BT 65 (87%) – 30 U BT + 50 U BT
Ratio of permanently healed and relapsed group after BT: ALF 6% vs. 45% LDD 38% vs. 68% NRI 26% vs. 59%
Drugs (% response)
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.
Pitt et al
Pitt et al
60
2004
73
Bacher et al
2002
71
Maan et al
56
2005
Muthukumarassamy et al
37
Nash et al
2006
2002
2002
2002
2002
2002
55
69
Bielecki & Kolodziejczak
54
32
Kocher et al
Griffin et al
53
52
65
67
Knight et al
49
70
2001
Jonas et al63
48
66
2000
Carapeti et al62
47
2001
1999
Carapeti et al
46
64
2006
61
2006
Witte & Klaase59
44
Tranqui et al
2002
Brisinda et al58
43
45
2002
Minguez et al57
42
60
Year
Reference
No.
Table. (Continued)
■ MEDHI et al ■
ASIAN JOURNAL OF SURGERY VOL 31 • NO 3 • JULY 2008
■ 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 1994.76 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
ASIAN JOURNAL OF SURGERY VOL 31 • NO 3 • JULY 2008
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
159
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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 = 0.0001). 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
160
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.84
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■ 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.
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