Journal of Cutaneous and Aesthetic Surgery

REVIEW ARTICLE
Year
: 2008  |  Volume : 1  |  Issue : 2  |  Page : 58--63

Pharmacological sphincterotomy for chronic anal fissures by botulinum toxin A


Uwe Wollina 
 Department of Dermatology and Allergology, Hospital Dresden-Friedrichstadt, Academic Teaching Hospital of the University of Dresden, Friedrichstrasse 41, Dresden, Germany

Correspondence Address:
Uwe Wollina
Department of Dermatology and Allergology, Hospital Dresden-Friedrichstadt, Academic Teaching Hospital of the University of Dresden, Friedrichstrasse 41, 01067 Dresden
Germany

Abstract

Chronic anal fissure is a common proctologic disease. Botulinum toxin (BTX) can be used for temporary chemical denervation to treat this painful disorder. Its application is by intramuscular injections into either the external or internal anal sphincter muscle. The mode of action, application techniques, and possible complications or adverse effects of BTX therapy are discussed in this report. The healing rate is dependent on the BTX dosage. The short-term healing rate (≤ 6 months) is 60-90%, whereas about 50% of the patients show a complete response in long-term follow-up studies (> 1 year). Adverse effects are generally mild, but relapses occur more often than with surgery. Conservative therapy is currently considered as a first-line treatment. With increasing evidence for its efficacy, BTX can now be considered among the first-line nonsurgical treatements. Although, surgical management by lateral sphincterotomy is the most effective treatment, it shows a higher incidence of incontinence and greater general morbidity rate than BTX. BTX is a useful alternative to surgery and in many cases, surgery can be avoided with the use of BTX.



How to cite this article:
Wollina U. Pharmacological sphincterotomy for chronic anal fissures by botulinum toxin A.J Cutan Aesthet Surg 2008;1:58-63


How to cite this URL:
Wollina U. Pharmacological sphincterotomy for chronic anal fissures by botulinum toxin A. J Cutan Aesthet Surg [serial online] 2008 [cited 2019 Oct 20 ];1:58-63
Available from: http://www.jcasonline.com/text.asp?2008/1/2/58/44160


Full Text

 Anal Fissures



An anal fissure is a defect in the epithelium of the anal canal from the ano-cutaneous border to the linea dentata. Chronic fissures are characterised by a sentinel tag, hypertophic anal papillae, anal spasm, and/or fibrosis of the inner sphincter muscle [Figure 1]. Chronic fissures are commonly seen at 6 o'clock with the patient in a recumbent position; fissures at any other position need further investigation as to the underlying cause. Possible causes are Crohn's disease, anal intercourse, sexually transmitted disease, or anal carcinoma [Table 1]. [1],[2]

Relaxation of the sphincter internus can be inhibited by nonadrenergic, noncholinergic enteric neurons, parasympathetic muscarinic receptors, sympathetic beta receptors, or by inhibition of intracellular calcium uptake. [3]

Acute anal fissures are extremely painful during defecation; the pain is cramp-like and may persist for hours. With chronic anal fissures, the pain may be less intense during defecation, but increases after that. Perianal eczema is often associated with chronic anal fissures. Hyperhidrosis of the anal fold aggravates these symptoms. [4]

The aetiopathogenesis of the chronic anal fissure is not well understood. There is increased intraanal pressure at rest that might contribute to an ischemic state of the anal sphincter muscles. Indeed, the anodermal blood flow of the posterior midline has been shown to be reduced. [1] On the other hand, there is an increased local innervation. [5] One's established a devil's circle of spasm and pain develops.

 Botulinum Toxin A



Botulinum toxin A (BTX A) is produced by Clostridium botulinum but can be synthesised as a single chain polypeptide of ~150 kDa that acts as a zinc-dependent endopeptidase. BTX A cleaves SNAP-25, a part of the SNARE complex that is responsible for acetylcholine transport from the nerve to the muscle end plate.

BTX action on hyperactive smooth muscles such as the anal sphincter is mediated by its action on the autonomic nervous system (as in striated muscles). The treatment goal for BTX is the interruption of the internal sphincter spasm and thereby, the ischemic state. Indeed, sphincter manometry after BTX injection has demonstrated a lowering of resting intranal pressure. [6]

 Selection of Patients



The diagnosis of a chronic anal fissure has to be established by proper examination and underlying diseases need appropriate therapy. None of the available BTX products on the market has been approved for the indication of anal fissures. Therefore, in its current status, this is an off-label use for BTX A. Hence, the patient should be properly counselled with an extensive verbal and written explanation, and his/her verbal and written consent obtained.

General contraindications for the use of BTX have to be considered before its use [Table 2]. [7]

 Procedure of BTX Administration



BTX is available in a freeze-dried form. Published studies have been performed with either Botox® (Allergan) or Dysport® (Ipsen-Speywood). One Botox®-unit translates into two or three Dysport®-units. The vials have to be resolved with sterile physiological sodium chloride solution (according to the manufacturer's instructions with 2-2.5 mL). Higher concentrations might be necessary in individual cases.

For injections, easy-to-use syringes such as the insulin syringes or those used for hyposensitization are preferred. They have a maximum capacity of 1 mL and markings that allow safe injections of volumes as low as 0.1 mL, which is the usual volume to inject per site. A fine and sharp needle of 27-32 gauge should be employed to minimize pain and bleeding. [2]

Injection should be done with the patient lying on one side or in a recumbent position. An intramuscular injection is performed after local disinfection. Injections into both the internal as well as the external sphincter muscles have been described in literature. For the former technique, the doctor has to put 2-3 fingers in ano for the exact localization of the needle. This technique causes more pain for the patient and also carries the risk of needle stick injury for the doctor as well. Therefore, sedation of the patient is often necessary. Injection into the external sphincter avoids these risks and sedation is not necessary. However, as the internal sphincter is also involved in the pathophysiology of anal fissures, injection into only the external sphincter may not be fully effective in releiving the spasm. However, BTX shows a three-dimensional diffusion of about 2 cm, which is considered adequate to reach the internal sphincter as well. [8]

The injections are usually placed along the fissure on both sides at a distance of 1-2 cm as fissure-associated ischaemia will prevent diffusion. In a recent study, Maria et al . demonstrated that a perifissural injection in the posterior-median localization is less effective than an injection along the anterior midline. They observed an increased relaxation effect by the latter technique. [9]

Different dosage schedules have been used. Most investors use higher dosages as the response rate is higher and the relapse rate is lower. Up to 100 U BTXA (Botox®) have been used without any severe adverse effects; the usual initial dosage is 20-40 U Botox® or 50-100 U Dysport®. [8]

 Outcome and Safety: Published Studies



BTX therapy of chronic anal fissures has been performed for more than ten years now and a number of mostly single-centre studies have been published [Table 3]. The healing rates (≤ 6 months) are 60-90% and partial responses are seen in many patients. However, nonresponders are rare (12 months) show complete healing rates of about 50%. [8]

Complications

Faecal incontinence is a severe adverse effect of surgery. With BTX, mild temporary incontinence of flatus has been reported in ≤ 6% of the patients. [10] Abscess formation is very rare, whereas this adverse effect is seen in about 13% of lateral sphincterotomy patients. [11] Jost et al . reported a single case of perianal thrombosis after BTX injection into the external sphincter muscle. [12] Radwan et al . reported two patients with temporary faecal soiling after BTX injection into the internal sphincter muscle. [13]

Comparison of BTX to other established treatments and combinations

The gold standard for the management of recalcitrant chronic anal fissures has been lateral sphincterotomy. In a retrospective evaluation of 562 chronic anal fissure patients, complete healing was achieved within 31 weeks compared to 56 weeks with BTX. The relapse rate in the BTX group was significantly higher (35%), with 7% eventually treated by surgery. [37]

In a meta-analysis, Sajid et al . compared surgical vs chemical sphincterotomy using BTX for the treatment of chronic anal fissures. Surgical sphincterotomy had a significantly higher healing rate [ P P P P et al . treated 40 patients with combined fissurectomy followed by injection of 10 U of Botox® into the internal anal sphincter on both sides of the fissure. At six weeks, 38 patients (95%) were free of symptoms and no adverse effects were detected. The response rate of questionnaires was 93%; the median follow-up was one year (0.9-1.6 years). In the long-term, recurrence was found in four patients who were treated successfully with repeated fissurectomy, BTX injections, and salvage procedures. The overall success rate of combined fissurectomy and BTX injection was 79%, this combined approach scoring as an excellent and safe procedure with low morbidity and a high healing rate for chronic fissures. [40]

Brisinda et al . evaluated the efficacy of BTX injection in the treatment of recurrent anal fissures following lateral internal sphincterotomy. Eighty patients were treated with botulinum toxin (30 U Botox® or 90 U Dysport®) injected into two sites of the internal sphincter. One month after injection, there was complete healing in 54 patients (68%). Eight patients (10%) reported mild incontinence of flatus that disappeared spontaneously within two months. At two months, 59 patients (74%) had a healing scar. Anorectal manometry at one month demonstrated a significant reduction in both resting anal pressure and maximum voluntary squeeze pressure ( P [41]

These observations are further supported by a recent study of Baraza et al . in females, who have an increased risk of incontinence after surgery. The authors combined BTX injection for anal fissures with fissurectomy. Forty-six female patients who had undergone excision of the fissure edges and injection of 25-100 U of BTX (Botox®, Dysport®) into the intersphincteric space, were followed up two months after the procedure and over a period of up to 39 months. No patient had any postoperative incontinence symptoms. There was a cure rate of 85% in 44 patients at a median follow-up period of 11 months. Fissurectomy and botulinum toxin injection for the treatment of chronic anal fissure in females seems to be effective in the medium-term, but there is a high rate of late recurrence. However, only a minority of patients proceed to more invasive surgical intervention, which may make it a useful option in patients who are not suitable for lateral sphincterotomy. [42],[43]

In a prospective, controlled, two-armed trial comparing 0.2% nitroglycerine nitrate ointment with 20 U Botox®, a complete healing was achieved in 66.7 or 57.1% of the patients, respectively after three months. Relapses were seen in 33% of the patients in both groups. After three years, complete healing was seen in 40.0 and 33.3% of the patients in the nitroglycerine and Botox arms, respectively. [44] The combination of nitroglycerine ointment and BTX seems to potentiate the healing effect. [45] The combination of nifedipin and BTX (30-100 U Botox®) resulted in a remarkable low relapse rate of 2% ( n = 47). [38]

In a meta-analysis, Sajid et al . compared the effectiveness of BTX and glyceryltrinitrate (GTN) for the pharmacological management of chronic anal fissures (CAF). BTX and GTN were equally effective in healing/improving chronic anal fissures. GTN was associated with a higher incidence of total side effects [ P = 0.0002], especially headache [ P = 0.0007]. Their conclusion was that BTX is as effective as GTN for the management of chronic anal fissures, but that it is associated with a lower complication rate. BTX has therefore been recommended as a first-line therapy for chemical sphincterotomy. [46]

 Guidelines for the Practice



The management of patients with chronic anal fissures involves both general and local measures. The treatment needs experience and skills and should be carried out only by those specialized in proctology. In Europe, proctology is performed by dermatologists, gastroenterologists, and specialized surgeons.

First-line therapy is always conservative and involves using appropriate nutrition, fluid intake, and exercises. Such treatment is easy, cheap, and safe but this remains the basis for all other treatments as well. [1]

Among conservative medical procedures, diltiazem, nifedipin, and nitroglycerine can be considered as first-line treatments. However, the effect is delayed with these treatments, and nitroglycerine has a significant risk of headaches. [46] If there is no response by eight weeks, BTX injections should be considered.

BTX is a safe and effective treatment for anal fissures. The effect is dose-dependent and technique-dependent. Doses of 20-40 U Botox® or 50-100 U Dysport® are useful as long as the patient does not suffer from anal fold hyperhidrosis, in which case, higher doses may be necessary. Both techniques: injections along both sides of a chronic fissure or along the anterior midline, are effective. There is some debate about the site of injection, as both internal and external sphincters have their advocates as mentioned earlier. The injection into the internal sphincter is supported by the pathophysiology of anal fissures, but is more difficult to give and more painful. Injection into the external sphincter is easier and less painful. [8] Combination of BTX with either nitroglycerine or nifedipin reduces relapse rates. The role of fissurectomy in conjuction with BTX needs further investigation. [47] Using this algorithm, lateral sphincterotomy can be avoided in most cases and BTX can also be used in patients with a relapse after surgical sphincterotomy.

In summary, BTX is a useful and safe alternative in the management of anal fissures. BTX does not cause any downtime for the patient and is more convenient than surgery. However, in some patients, particularly those with underlying pathologies, BTX may not be adequate and such patients may eventually need sphincterotomy.

References

1Utzig MJ, Kroesen AJ, Buhr HJ. Concepts in pathogenesis and treatment of chronic anal fissure: A review of the literature. Am J Gastroenterol 2003;98:968-74.
2Wollina U, Konrad H, Petersen S. Botulinumtoxin in dermatology-beyond wrinkles and sweat. J Cosmet Dermatol 2005;4:223-7.
3Bhardwaj R, Vaizey CJ, Boulos PB, Hoyle CH. Neuromyogenic properties of the internal anal sphincter: Therapeutic rationale for anal fissures. Gut 2000;46:861-8.
4Wollina U, Konrad H. Botulinum toxin A in anal fissures: A modified technique. J Eur Acad Dermatol Venereol 2002;16:469-71.
5Horsch D, Kirsch JJ, Weihe E. Elevated density and plasticity of nerve fibres in anal fissures. Int J Colorectal Dis 1998;13:134-40.
6Wollina U. Botulinum toxin: Non-cosmetic indications and possible mechanisms of action. J Cutan Aesth Surg 2008;1:3-6.
7Wollina U, Konrad H. Managing adverse effects associated with botulinum toxin type A. Am J Clin Dermatol 2005,6:141-50.
8Wollina U. Behandlung der Analfissur mit Botulinumtoxin. Zentralbl Chir 2008;133:123-8.
9Maria G, Brisidina G, Bentivoglio AR, Cassetta E, Gui D, Albanese A. Influence of botulinum toxin site of injections on healing rate in patients with chronic anal fissure. Am J Surg 2000;179:46-50.
10Arroyo A, Pιrez F, Serrano P, Candela F, Calpena R. Long-term results of botulinum toxin for the treatment of chronic anal fissure: Prospective clinical and manometric study. Int J Colorectal Dis 2005;20:267-71.
11Floyd ND, Kondylis L, Kondylis PD, Reilly JC. Chronic anal fissure: 1994 and a decade later - are we doing better? Am J Surg 2006;191:344-8.
12Jost WH, Schannes S, Mlitz H, Schimrigk K. Perianal thrombosis following injection therapy into the external sphincter using botulinum toxin. Dis Colon Rectum 1995;38:781.
13Radwan MM, Ramdan K, Abu-Azab I, Abu-Zidan FM. Botulinum toxin treatment for anal fissure. Afr Health Sci 2007;7:14-7.
14Gui D, Cassetta E, Anastasio G, Bentivoglo AR, Maria G, Albanese A. Botulinum toxin for chronic anal fissure. Lancet 1994;344:1127-8.
15Jost WH, Schimrigk K. Therapy of anal fissure using botulinum toxin. Dis Colon Rectum 1994;37:1340.
16Jost WH, Schannes S, Mlitz H, Schimrigk K. Perianal thrombosis following injection therapy into the external sphincter using botulinum toxin. Dis Colon Rectum 1995;38:781.
17Jost WH, One hundred cases of anal fissure treated with botulinum toxin: Early and long-term results. Dis Colon Rectum 1997;40:1029-32.
18Maria G, Casetta E, Gui D, Brisinda G, Bentivoglio AR, Albanese A. A comparison of botulin toxin and saline for the treatment of chronic anal fissure. N Engl J Med 1998;338:217-20.
19Maria G, Brisinda G, Bentivoglio AR, Cassetta E, Gui D, Albanese A. 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.
20Minguez M, Melo F, Espi A, Garcia-Granero E, Mora F, Lledo S, Benages A. Therapeutic effects of different doses of botulinum toxin in chronic anal fissure. Dis Colon Rectum 1999;42:1016-21.
21Brisinda G, Maria G, Bentivoglio AR, Cassetta E, Gui D, Albanese A. A comparison of injections of botulinum toxin and topical nitroglycerine ointment for the treatment of chronic anal fissure. N Engl J Med 1999;341:65-9.
22Fernandez-Lopez F, Conde Freire R, Rios Rios A, Carcia Iglesias J, Cainzos Fernandez M, Potel Lesquereux J. Botulinum toxin for the treatment of anal fissure. Dig Surg 1999;16:515-8.
23Lysy J, Israelit-Ytzkan Y, Sestiery-Ittah M, Weksler-Zangen S, Keret D, Goldin E. Topical nitrates potentiate the effect of botulinum toxin in the treatment of patients with refractory anal fissure. Gut 2001;48:221-24.
24Madalinski MH, Slawek J, Zbytek B, Duzynski W, Adrich Z, Jagiello K, et al. Topical nitrates and the higher doses of botulinum toxin for chronic anal fissure. Hepatogastroenterology 2001;48:977-9.
25Brisinda G, Maria G, Sganga G, Bentivoglio AR, Albanese A, Castagneto M. Effectiveness of higher doses of botulinum toxin to induce healing in patients with chronic anal fissures. Surgery 2002;131:179-84.
26Trcinski R, Dziki A, Tchórzewski A. Injections of botulinum A toxin for the treatment of anal fissures. Eur J Surg 2002;168:720-3.
27Colak T, Ipek T, Kanik A, Aydin S. A randomized trial of botulinum toxin vs lidocain pomade for chronic anal fissure. Acta Gastroenterol Belg 2002;65:187-90.
28Mentes BB, Írkφrücü, Akin M, Leventoglu S, Tatlicioglu E. Comparison of botulinum toxin injection and lateral internal sphincterotomy for the treatment of chronic anal fissure. Dis Colon Rectum 2003;46:232-7.
29Siproudhis L, Sebille V, Pigot F, Hemery P, Juguet F, Bellisant E. Lack of efficacy of botulinum toxin in chronic anal fissure. Aliment Pharmacol Ther 2003;18:515-24.
30Lindsey I, Jones OM, Cinningham C, George BD, Mostensen NJ. Botulinum toxin as second-line therapy for chronic anal fissure failing 0.2 percent glyceryl trinitrate. Dis Colon Rectum 2003;46:361-6.
31Giral A, Memisoglu K, Gültekin Y, Imeryüz N, Kalayc C, Ulusoy NB, et al. Botulinum toxin injection versus lateral internal sphincterotomy in the treatment of chronic anal fissure: A non-randomized controlled trial. BMC Gastroenterol 2004;4:7.
32Godevenos D, Pikoulis E, Pavlakis E, Daskalakis P, Stathoulopoulos A, Gavrielatou E, et al. The treatment of chronic anal fissure with botulinum toxin. Acta Chir Belg 2004;104:577-80.
33Arroyo A, Pιrez F, Serrano P, Candela F, Lacueva J, Calpena R. Surgical versus chemical (botulinum toxin) sphincterotomy for chronic anal fissure: Long-term results of a prospective randomized clinical and manometric study. Am J Surg 2005;189:429-34.
34Iswariah H, Stephens J, Rieger N, Rodda D, Hewett P. Randomized propective controlled trial of lateral internal sphincterotomy versus injections of botulinum toxin for the treatment of idiopathic fissure in ano. ANZ J Surg 2005;75:553-5.
35Massoud BW, Mehrdad V, Baharak T, Alireza Z. A comparison of botulinum toxin injection versus internal anal sphincterotomy for the treatment of chronic anal fissure. Ann Saudi Med 2005;25:140-2.
36Kinney TP, Shah AG, Rogers BH, Ehrenpreis ED. Retrograde endoscopic delivery of botulinum toxin for anal fissures. Endoscopy 2006;38:654.
37Floyd ND, Kondylis L, Kondylis PD, Reilly JC. Chronic anal fissure: 1994 and a decade later - are we doing better? Am J Surg 2006;191:344-8.
38Tranqui P, Trottier DC, Victor JC, Freeman JB. Nonsurgical treatment of chronic anal fissure: Nitroglycerin and dilatation versus nifedipine and botulinum toxin. Can J Surg 2006;49:41-5.
39Witte ME, Klaase JM. Botulinum toxin A injection in ISDN ointment-resistant chronic anal fissures. Dig Surg 2007;24:197-201.
40Scholz T, Hetzer FH, Dindo D, Demartines N, Clavien PA, Hahnloser D. Long-term follow-up after combined fissurectomy and Botox injection for chronic anal fissures. Int J Colorectal Dis 2007;22:1077-81.
41Sajid MS, Hunte S, Hippolyte S, Kiri VA, Maringe C, Baig MK. Comparison of surgical vs chemical sphincterotomy using botulinum toxin for the treatment of chronic anal fissure: A meta-analysis. Colorectal Dis 2008;10:547-52.
42Brisinda G, Cadeddu F, Brandara F, Marniga G, Vanella S, Nigro C, et al. Botulinum toxin for recurrent anal fissure following lateral internal sphincterotomy. Br J Surg 2008;95:774-8.
43Baraza W, Boereboom C, Shorthouse A, Brown S. The long-term efficacy of fissurectomy and botulinum toxin injection for chronic anal fissure in females. Dis Colon Rectum 2008;51:239-43.
44Sileri P, Mele A, Stolfi VM, Grande M, Sica G, Gentileschi P, et al. Medical and surgical treatment of chronic anal fissure: A prospective study. J Gastrointest Surg 2007;11:1541-8.
45De Nardi P, Ortolano E, Radaelli G, Stadacher C. Comparison of glycerine trinitrate and botulinum toxin-A for the treatment of chronic anal fissures: Long-term results. Dis Colon Rectum 2006;49:427-32.
46Sajid MS, Vijaynagar B, Desai M, Cheek E, Baig MK. Botulinum toxin vs glyceryltrinitrate for the medical management of chronic anal fissure: A meta-analysis. Colorectal Dis 2008;10:541-6.
47Acheson AG, Scholefield JH. Pharmacological advancements in the treatment of chronic anal fissure. Expert Opin Pharmacother 2005;6:2475-81.