Botulinum toxin in the treatment of anal fissure

Introduction: anal fissure and its treatment

La anal fissure is an ulceration that can open in the skin lining the anal canal. It occurs in both sexes, with about equal incidence, and it predominates in young adults. Acute fissures largely heal without the need for any therapeutic intervention, but in a percentage of cases they evolve to a chronic form and tend to no longer heal spontaneously. Typical symptoms are postdefecatory pain, which can be very intense and last for hours, the presence of bright red spots of blood on the toilet paper, and itching. The majority of fissures is localized at the level of the posterior midline of the anal canal, although in about 10% of cases in women, and about 1% in men, the site may be the anterior midline. The predominantly posterior localization is likely due to the poorer arterial vascularization of the posterior anal commissura which, associated with thesphincter hypertone, results in ischemia and subsequent ulceration of the area. The component due to sphincter hypertone, however, is not constant, which may have important implications in the indication for surgical treatment of the fissure. The internal anal sphincter, which receives sympathetic innervation through the hypogastric nerves, is, under normal conditions, in a state of partial contraction, and relaxes in response to the distention of the rectal ampulla in the so-called rectosphinteric reflex. Normal resting pressure values of the anal sphincter system vary depending on the instrumentation and technique employed, but generally range from 60 to 80 mm H g(average 72 mm Hg), with significantly higher pressures in the male sex than in the female.

Since time immemorial, anal fissure therapy has been based on reducing the pressure of the internal anal sphincter to promote increased arterial flow and promote healing of the fissure. These results, initially achieved by the surgical procedure of internal lateral sphincterotomy (SLI), are now achievable by local application of drugs (chemical sphincterotomy); and it is in this direction that the use of botulinum toxin in the treatment of anal fiss ure plays a leading role.

Botulinum toxin in the treatment of anal fissure

Botulinum toxin is a neurotoxin of a polypeptide nature produced by Clostridium botulinum, a Gram + sporigenous bacterium of the Clostridiaceae family whose spores are found in soil and plants (and indeed one of the main causes of C. botulinum intoxication is the ingestion of contaminated food and n

botulinum toxin, botox, anal fissure, anal fissure therapy, botulinum toxin in the treatment of anal fissure
from Nature Reviews Microbiology 12, 535-549 (2014)

on well cooked or of canned goods, especially those prepared at home, within which the bacterium had a chance to develop).

Botulinum toxin is the most potent toxin known to date: 75 ng of pure toxin is capable of killing a man weighing 75 kg1.

The mechanism of action of botulinum toxin occurs at synapses, where the toxin inhibits the release of acetylcholine causing flaccid paralysis of the muscles served by them. Clinical manifestations of intoxication include flaccid paralysis, muscle weakness, diplopia, difficulty of movement, and pharyngeal and voluntary muscle uncoordination; death occurs from paralysis of respiratory muscles2. There are seven types of botulinum toxin, labeled with letters A through G.

Botulinum toxin type A has been used for decades in cynics for the treatment of spasms and dystonias, including cervical dystonia or spastic torticollis, blepharospasm,severe primitive axillary hyperhidrosis, and strabismus. In aesthetic medicine, botulinum toxin is widely used for the treatment of facial and neck wrinkles.
The use of botulinum toxin in the treatment of anal fiss ure was first reported in 1993 by W. Jost et al. Since then, studies on the efficacy, both from the point of view of overall cost, outcome, and post-treatment complications compared with local medical therapy with NO (nitric oxide) donors and surgery (internal lateral sphincterotomy) have multiplied, and have led some Authors to state that the introduction of botulinum toxin in the treatment of anal fiss ure is comparable to the introduction of laparoscopy in surgery.

The main data can be summarized as follows:

Our experience with botulinum toxin in the treatment of anal fissure

Between 2009 and 2015, we subjected 63 patients diagnosed with chronic anal fissure to botulinum toxin treatment. The mean age of the patients was 62 years (48 to 83 years) and the inclusion criterion was failure of medical therapy with NO donors. All patients had resting pressures of the anal sphincter system measured before treatment and two months after treatment, obtaining the following results:

  • Pre-treatment P: 83.15 (75.08 - 89.21) mm Hg
  • P at 2 months after infiltration: 61.04 (46.01 - 71.06)
botulinum toxin, botox, anal fissure, anal fissure therapy, botulinum toxin in the treatment of anal fissure
Injection of botulinum toxin into the sides of the fissure

In all cases, pre-infiltration local anesthesia was administered by application, 30 minutes before the injections, of a lidocaine-prilocaine cream (Emla 2.5% + 2.5% cream). The procedure, which was well tolerated in all cases, consisted of the administration of 30 Allergan units of toxin, divided as follows: 10 U to either side of the fissure, about 1 cm from the fissure; and 10 U in the commisure contra-lateral to the fissure.

The therapeutic effect, in terms of the onset of remission of pain symptoms, began to occur about 48 hours after the administration of botulinum toxin.

botulinum toxin, botox, anal fissure, anal fissure therapy, botulinum toxin in the treatment of anal fissure
Scheme of administration of botulinum toxin

At 30 days after administration, complete remission of symptoms, associated with complete or advanced healing of the fissure, was observed in 41 patients (65.07%). The remaining 22 patients underwent a new infiltrative procedure of 50 U Allergan toxin (17 U to both sides of the fissure and 16 U in the contralateral commisure.

At 60 days after the first administration, complete healing of the fissure was observed in 47 patients, accounting for 74.60% of the total number of patients undergoing treatment. Therefore, 6 patients (12% of the total, 27.27% of nonresponders after the first administration) benefited from the second dose of botulinum toxin. Of the remaining 16 patients, 13 underwent surgery, while 3 escaped follow-up. Of the 13 patients who underwent surgery, 12 (92.30%) recovered; 1 of them (8.33%), at follow-up, showed a persistent degree of anal incontinence, with pressure values, at manometric checks at 6 and 12 months, stably below 38 mm Hg.

No complications were observed in patients undergoing botulinum toxin treatment.

CONCLUSIONS

In Italy, anal fissure represents the second most frequent cause of request for proctological specialist examination.

Its treatment, from surgical-although internal lateral sphincterotomy remains the gold standard in the treatment of this condition, it is burdened by a limited but concrete incidence of serious complications, such asanal incontinence-has now become predominantly medical, thanks to the development of drugs capable of inducing relaxation of the muscle fibers of the anal sphincter system. Among them, botulinum toxin plays a leading role because of the intensity and duration of relaxation it is able to induce.

Today, there is a growing consensus in the Medical Community toward the use of botulinum toxin in the treatment of anal fissure, and its use as a test for predicting the risk of occurrence of anal incontinence after surgery is gaining ground.

Despite this, and despite the amount of data over time demonstrating the efficacy and safety of botulinum toxin in the treatment of anal fissure, this indication is off-label to date, and the treatment is not available in National Health Service hospitals.

(1) Diane O. Fleming, Debra Long Hunt: Biological Safety: principles and practice. ASM Press, 2000, p. 267

(2) Giampietro Schiavo, Ornella Rossetto, and Cesare Montecucco: The molecular basis of tetanus and botulism. The Sciences (Scientific American) 1993;304:40-44