Comparison of dose and injection sites of botulinum toxin for chronic anal fissure: a systematic review and network meta-analysis of randomized controlled trials.

Background: There are no consensus guidelines on the optimal dose or injection site of botulinum toxin (BT) for chronic anal fissure (CAF). The objective of this study was to determine the appropriate dose and injection site of BT for CAF by comparing healing rate and adverse effects (incontinence and recurrence). Methods: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and Scopus were searched from inception through May 31, 2021. Randomized controlled trials evaluating healing and adverse effects of BT injection for CAF published in any language were selected. Multiple treatment comparisons and ranking were performed using a two-stage network meta-analysis, and results were graded by Confidence in Network Meta-Analysis tool. Results: Twenty-seven trials involving 1880 patients were included. The results demonstrated that high-dose-BT had significantly higher short-term healing when injected out of the fissure (OF) site than each side of the fissure (SF) site, with a risk ratio (RR) of 2.12 (1.08, 4.15); low-dose-BT did not show any difference across OF and SF site with RR of 1.20 (0.85, 1.68). High-dose-BT at the OF site showed similar healing to low-dose-BT at the same site (RR of 1.02 (0.79, 1.31)) but with a higher risk of incontinence with RR of 3.54 (0.85, 14.76). In contrast, high-dose-BT at the SF site showed lower healing compared to low-dose-BT at the same site with RR of 0.57 (0.29, 1.14). Both high-dose-BT and low-dose-BT at the OF site had higher recurrence than high-dose-BT or low-dose-BT at the SF site with RR of 2.08 (0.33, 13.11) and 1.89 (0.60, 5.94), respectively. Conclusions: Given moderate level of evidence, low-dose BT is optimal; injection out of the fissure site improves short-term outcomes while injection each side of the fissure site tends to reduce recurrence in the longer term.