The Efficacy of Botulinum Toxin Alone Versus Combined Botulinum Toxin and Topical Diltiazem in Chronic Anal Fissure

Retrospective Analysis on the Efficacy of Botulinum Toxin Alone Versus Combined Botulinum Toxin and Topical Diltiazem in Chronic Anal Fissure: Short and Long-term Outcomes From a Single Center

Anal fissure (AF) is a painful tear extending from the anal canal to the dentate line. Although the exact pathophysiology is not known, an increase in anal tonus, decreased ano-dermal blood flow and local ischemia are possible mechanisms. The most effective treatment modality in chronic AF is lateral internal sphincterotomy however, incontinence rates are still reported as high as 8-30%. Topical diltiazem and botulinum toxin (BT) injection are good alternatives to surgery with lack of persistent side effects, easy applicability, and reproducibility, however, recurrence rates were reported up to 50% for each. A combination of BT with topical diltiazem may provide better results in terms of healing and recurrence. In this retrospective analysis a comparison of BT injection alone and BT injection combined with topical diltiazem treatment was performed.

Study Overview

• Status: Completed
• Conditions: Anal Fissure Chronic
• Intervention / Treatment: Drug: Botulinum Toxin Type A Injection [Botox]; Drug: Botulinum Toxin Type A Injection [Botox] + Diltiazem Hydrochloride 20 Mg/G Rectal Gel

• Study Type: Observational
• Enrollment (Actual): 217

Contacts and Locations

Study Locations

• Turkey
  • Other (Non U.s.)
    • Istanbul, Other (Non U.s.), Turkey, 34196
      • Istanbul Medipol University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Female and males older than 18 years old

Description

Inclusion Criteria:

• Patients with complaints longer than 8 weeks (chronic anal fissure)
• Patients who completed at least 24 months of follow-up (3rd day, 10th day, 1st-month, and 2nd-month face-to-face clinic visits and 6, 12, and 24 months phone calls)
• Patients who received conservative treatments including topical diltiazem and nitrites

Exclusion Criteria:

• Patients with previous anal surgery (lateral internal sphincterotomy, hemorrhoidectomy, anal fistula)
• Patients with inflammatory bowel diseases
• Patients with accompanying anorectal disease (hemorrhoids, anal fistula, abscess)
• Patients who underwent botulinum toxin injection within 1 year before recruitment
• Patients with anterior, lateral, or multiple fissures
• Comorbidities (AIDS, sexually transmitted disease, tuberculosis, leukemia)
• Pregnancy
• Prescription of calcium canal blockers or nitrites
• Hypersensitivity to diltiazem or botulinum toxin
• Patients without anal pain

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Botulinum toxin group; The procedures were performed at outpatient clinic without anesthesia. Lyophilized 100 IU BT Type-A (BOTOX, Alergan, CA, USA) was applied after diluted with 1 cc saline. A 26-G injector was used to inject 25 unit toxin in every 4 quadrants, to the alignment of clock 12, 3, 6, and 9 to internal anal sphincters.	Drug: Botulinum Toxin Type A Injection [Botox]
Botulinum toxin plus topical diltiazem group; The procedures were performed at outpatient clinic without anesthesia. Lyophilized 100 IU BT Type-A (BOTOX, Alergan, CA, USA) was applied after diluted with 1 cc saline. A 26-G injector was used to inject 25 unit toxin in every 4 quadrants, to the alignment of clock 12, 3, 6, and 9 to internal anal sphincters. After BT injection, topical 2% diltiazem gel was prescribed, applied 2 times per day for 10 days (2 doses of 1 gr each per day). No selection criteria were used when recommending this treatment; it was randomly suggested to some for a while during the cohort since the surgeon believed it might enhance the efficacy of BT.	Drug: Botulinum Toxin Type A Injection [Botox] + Diltiazem Hydrochloride 20 Mg/G Rectal Gel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fissure healing at 1 month	Evaluation of complete epithelization of the fissure by the principal investigator by rectal examination	1 month
Days to pain-free defecation	Patient reported time until pain-free defecation. This will be evaluated on 3rd day, 10th day and 1-month outpatient visits.	1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete healing at 48 months	Any recurrent symptoms evaluated by the surgeon within 2 months in the outpatient clinic and reported by the patient at phone call follow-up at 6 months, 12 months, 24 months, and 48 months.	48 months

Collaborators and Investigators

• Sponsor: Istanbul Medipol University Hospital
• Investigators: Principal Investigator: Naciye Cigdem Arslan, MD, Medipol University

Study record dates

Study Major Dates

• Study Start (Actual): November 4, 2016
• Primary Completion (Actual): June 30, 2020
• Study Completion (Actual): August 30, 2024

Study Registration Dates

• First Submitted: October 4, 2022
• First Submitted That Met QC Criteria: April 3, 2023
• First Posted (Actual): April 4, 2023

Study Record Updates

• Last Update Posted (Actual): September 4, 2024
• Last Update Submitted That Met QC Criteria: August 30, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: botulinum toxin, anal fissure, diltiazem
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases; Anus Diseases; Fissure in Ano; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Peripheral Nervous System Agents; Cholinergic Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Acetylcholine Release Inhibitors; Neuromuscular Agents; Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA; Diltiazem
• Other Study ID Numbers: E-10840098-772.02-786

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: I don not have a website to share IPD however if required I can share datasets, protocols and other information.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No