This study presents a comprehensive review of all published RCTs involving BT injection as a treatment option for anal fissure.
A recent systematic review conducted by Poland et al. (45) included a total of 775 patients of which the Botox injection arm included 132 patients. The study compared the outcomes of different modalities of treatment of anal fissure. At 8 weeks, healing rates were 95.13% in those treated with sphincterotomy, 66.7% in the botulinum toxin group, 63.8% in the nitrate group, 52.3% for topical diltiazem and 50% for topical minoxidil. There was a risk of permanent incontinence with sphincterotomy (2.3%). In our meta-analysis, the success following a single BT injection was pooled to be 72.7% and thus, the Botox arm results of this systematic review are similar to our results. The risk of permanent incontinence with sphincterotomy emphasizes the need for a ladder approach in the management of anal fissures starting with the least invasive options of topical applications first, then BT injections, and reserving the operative solutions for the last. The heterogeneity in the groups for the outcome of efficacy (overall response after the first BT injection) can be attributed to the different follow-up periods of the study. The studies had a follow-up period ranging from 2 months in Colak et al (40) to 60 months in Abd El Hady et al (24). Subgroups were made to combat the heterogeneity however they did not provide satisfactory results. Another possible reason for heterogeneity could be the different doses used in each study. The dose of BT injection used ranged from 20 IU to 100 IU. Such differences in studies can impact significant heterogeneity in the results. Festen et al (25) used a dose of 20 mg and reported results in only 14 out of 37 patients, whereas Othman et al (22) used 80 mg and showed a response in 35 out of 40 patients. However, subgroup analysis by stratifying data based on follow-up yielded better results than stratifying on doses (especially for the outcome of safety). Moreover, some of the studies had a high risk of bias as well and thus, they can also contribute to the heterogeneity. Overall, the pooled analysis showed that BT injection is an efficacious method for treatment of chronic anal fissures.
Pilkington et al. (11) reported an RCT conducted to compare unilateral with bilateral BT injections. In the group who failed to have a resolution of their symptoms after the first injection, twelve patients had repeat BT injections administered in the same manner as their initial randomization: 5 in the bilateral injection group and 7 in the unilateral group. The healing rate after repeat BT was 2/5 (40%) in the bilateral group and 3/7 (43%) in the unilateral group, overall 5/12 (41.6%). This evidence seems to suggest that the site of injection or whether the injection was unilateral or bilateral appears to have very little impact on the effectiveness of this treatment. However, other studies such as Othman et al (22) and Brisinda G (27) showed a 100% success rate in patients having repeat injections. The meta-analysis presented here included 38 patients who had a repeat BT injection reported through 5 different studies with an overall healing of 78.5%. This result lies between that reported by Pilkington et al and Othman et al/Brisinda et al. A possible explanation for this could be the period of follow-up. Amongst the included studies, only Pilkington (11) had a significantly decreased efficacy of repeat BT injection This could be attributed to the type of BT injection used. Other studies such as Othman et al (22) used Botox, but Pilkington (11) used Dysport or Syposrt. The data seems to suggest that a repeat injection may be beneficial before proceeding with surgical alternatives.
There is some variability in the perception and reporting of complications following BT injection. Madaliński et al., (38) presented their experience of complications after BT in 105 chronic anal fissure patients in 2002. They reported incontinence to flatus 5%, incontinence to feces 2.8%, anal hematoma 2.8% thrombosed hemorrhoids 1.1% flu-like symptoms 1.7% epididymitis 0.5%, and protrusion of hemorrhoids 0.5%. This is almost certainly due to reporting bias as most of these side effects are only temporary and require little active intervention. Our meta-analysis has shown complications in only 88 out of 1532 (4.2%) of the patients and it is a lower incidence than some of the studies. Studies with 6 and 12-month follow-up periods showed a lower incidence of complications (2.1% and 2.5% respectively), however, studies with a follow-up period of more than 12 months showed a higher rate (8.9%) and heterogeneity amongst complications. Thus, it is logical to conclude that with increased time, there is an increased time of developing complications. This is further solidified by the results of studies like Al Gaithy et al (26) and Roka et al (35) with complications occurring in 20% and 19% of patients respectively and follow-up times of 24 months. This coupled with the increased rate of repeat injection in studies with longer follow-up periods (22, 27, 33, 44) reinforces the fact that even though BT injection is a suitable first-line, minimally invasive treatment option, it should be augmented with repeat injection after sufficient time. However, for a definite and permanent solution, other treatment options might be considered. Moreover, recently, the efficacy of BT injection is superior to nifedipine with lignocaine and anal dilation as well, thus further reinforcing its use for the treatment of chronic anal fissures (47).
However, every article is bound by some limitations. A meta-analysis is only as good as the studies included in it and some of the studies included in this analysis showed a high risk of bias and were not as robust. This affects the results and has resulted in significant heterogeneity, especially in the primary outcome of efficacy. Moreover, broad inclusion criteria which included all drug types of BT injection can affect the results. Lastly, this meta-analysis also suffers from a low publication bias in the outcome of efficacy.