**4.2 Calcium-channel blockers**

Topical application of calcium-channel blockers has been proven to effectively heal anal fissures with a lower risk of side effects [17]. Topically applied 0.5% nifedipine has been found to have healing rates of 93% in a duration of 19-month follow-up [18]. Also, Khan et al. have proved significantly higher healing rates (80.4%) with 2% topical diltiazem compared to GTN application [19]. Similarly, 0.5% topical minoxidil has been shown as equally effective as diltiazem [20].

#### **4.3 Botulinum toxin**

Botulinum toxin is an exotoxin produced by *Clostridium botulinum,* and its injection prevents the release of acetylcholine from the presynaptic nerve terminals, thus results resulting in temporary muscle paralysis. The first use of botulinum toxin in treating anal fissure was described in 1993 by Jost and Schimrigk [21, 22].

Although there is no standardized treatment with botulinum toxin regarding the dose and injection site, it is commonly injected directly into the internal anal sphincter on either side of the midline, with doses varying from 5 to 100 units [23, 24]. Pilkington et al. have revealed no significant differences between unilateral and bilateral injections in healing and fissure pain relief in a randomized prospective study [25]. In a retrospective review of patients who have been treated with high-dose (80–100 IU) and low-dose (20–40 IU) botulinum toxin, recurrence rates have been found significantly lower in a high-dose group during a mean follow-up of 25 months [26]. However, a meta-analysis has demonstrated no dose-dependent efficiency [27].

Several comparative studies have investigated the healing rates and symptomatic relief after botulinum toxin and topical agents [28–32]. Sajid et al. have shown that botulinum toxin injection has had similar healing rates with GTN but fewer side effects [33]. Also, another study has demonstrated that overall cure rates have been similar between diltiazem (53%), GTN (54%), and botulinum toxin (51%) [34]. A guideline published in 2017 has stated that botulinum toxin injection has similar results with topical agents as first-line therapy and modest improvement in healing rates as second-line therapy following treatment with topical agents [10].

The significant drawbacks of botulinum toxin injection are the risk of incontinence and its temporary effectiveness that usually lasts 3–6 months [35, 36]. Moreover, there are still unanswered questions: the following step when botulinum toxin fails if the second injection should be performed, the interval for repeat

*Sphincterotomy is the Gold-Standard Treatment of Chronic Anal Fissure: But How Should it be… DOI: http://dx.doi.org/10.5772/intechopen.104109*

injection, and the timing of surgery. A recent study has discussed some of those issues among colorectal surgeons on practice parameters of botulinum toxin treatment [37]. It has been shown that more than half of the clinicians perform the second injection in case of persistence of symptoms and recurrence, and the interval for repeat injection has usually been more than 2 months.
