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Topical 5% Minoxidil versus Topical 0.2% Glyceryl Trinitrate in Treatment of Chronic Anal Fissure: A Randomized Clinical Trial
Journal Pre-proof Topical 5% Minoxidil versus Topical 0.2% Glyceryl Trinitrate in Treatment of Chronic Anal Fissure: A Randomized Clinical Trial Sameh Hany Emile, Mohamed Anwar Abdel-Razik, Ayman Elshobaky, Samy Abbas Elbaz, Wael Khafagy, Mostafa Shalaby PII:
S1743-9191(20)30154-0
DOI:
https://doi.org/10.1016/j.ijsu.2020.01.143
Reference:
IJSU 5250
To appear in:
International Journal of Surgery
Received Date: 5 November 2019 Revised Date:
6 January 2020
Accepted Date: 24 January 2020
Please cite this article as: Emile SH, Abdel-Razik MA, Elshobaky A, Elbaz SA, Khafagy W, Shalaby M, Topical 5% Minoxidil versus Topical 0.2% Glyceryl Trinitrate in Treatment of Chronic Anal Fissure: A Randomized Clinical Trial, International Journal of Surgery, https://doi.org/10.1016/j.ijsu.2020.01.143. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.
Credit author statement Sameh Emile: Conceptualization, data curation, formal analysis, writing original draft, Mohamed Anwar Abdel-Razik: formal analysis, methodology, investigation, writing: review and editing, Ayman Elshobaky: data curation, methodology, writing: review and editing, Samy Elbaz: Data curation, investigation, resources, writing: review and editing, Wael Khafagy: formal analysis, supervision, writing: review and editing, Mostafa Shalaby: data curation, formal analysis, methodology, writing: review and editing
Title: Topical 5% Minoxidil versus Topical 0.2% Glyceryl Trinitrate in Treatment of Chronic Anal Fissure: A Randomized Clinical Trial Short running title: RCT on topical minoxidil versus topical GTN for chronic anal fissure Type: Original article Authors 1. Sameh Hany Emile, MD, MSc, PhD. [email protected] 2. Mohamed Anwar Abdel-Razik, MD, MSc, PhD. [email protected] 3. Ayman Elshobaky, MD, MSc, PhD. [email protected] 4. Samy Abbas Elbaz, MD, MSc, PhD. [email protected]. 5. Wael Khafagy, M.D, MSc, PhD. [email protected]. 6. Mostafa Shalaby, MD, MSc. PhD. [email protected] Affiliations Colorectal Surgery Unit, Department of General surgery, Mansoura Faculty of medicine, Mansoura University, Mansoura, Egypt. Authors’ contributions Sameh Hany Emile designed the study. Sameh Hany Emile, Mostafa Shalaby, and Mohamed Abdel-Razik, Ayman Elshobaky participated in data collection and analysis, writing and drafting of the manuscript. Samy Elbaz contributed to data collection and revision of the manuscript. Wael Khafagy supervised data collection and analysis and participated in critical revision of the manuscript. Correspondence to: •
Sameh Emile, MD. Colorectal Surgery Unit, General Surgery Department, Faculty of Medicine, Mansoura University Hospitals, 60 Elgomhuoria Street, Mansoura city, Egypt. PO: 35516
•
[email protected]
•
Tel: +20-1006267150, Fax: +20 (50) 239733.
Conflict of interest and sources of funding: None to be declared by the authors.
Topical 5% Minoxidil versus Topical 0.2% Glyceryl Trinitrate in Treatment of Chronic Anal Fissure: A Randomized Clinical Trial Abstract Background: Chronic anal fissure (CAF) is a common painful anal condition. Medical treatment of CAF involves the use of agents that induce chemical sphincterotomy. The present trial aimed to compare the efficacy and safety of topical minoxidil and glyceryl trinitrate (GTN) preparations in treatment of CAF. Methods: Adult patients with CAF were randomly assigned to one of two equal groups; group I received topical 5% minoxidil gel and group II received topical 0.2% GTN cream. The main outcome measures were healing of anal fissure, duration to healing, relief of symptoms, and adverse effects. Results: 62 patients (36 female and 26 male) were included to the study. Group I comprised 30 patients and group II comprised 32 patients. Healing of anal fissure was achieved in 23 (76.7%) patients in group I and 15 (46.9%) patients in group II (p=0.03). The average duration to healing in group I was significantly shorter than group II (4.1± 1.9 vs 5.3± 2.7 weeks, p=0.048). Adverse effects were recorded in 2 (6.6%) patients in group I and 13 (40.6%) patients in group II. The post-treatment pain score in the GTN group was significantly lower than the Minoxidil group. Conclusion: Topical 5% minoxidil gel achieved greater and quicker healing of CAF and fewer adverse effects than topical 0.2% GTN cream. Post-treatment pain scores after GTN were significantly lower than minoxidil. Keywords: Minoxidil; Glyceryl trinitrate; Chronic; Anal fissure; Randomized trial Trial registration number: NCT03528772.
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Introduction Chronic anal fissure (CAF) is one of the most common painful anal conditions. A sentinel pile at the distal end of the fissure with visible internal anal sphincter fibers (IAS) at its base usually indicates its chronicity. Patients with CAF usually complain of anal pain during defecation which may sometimes be associated with bleeding per rectum [1, 2]. Although various theories have been proposed to explain the pathogenesis of the CAF, the exact cause remains unknown. Nevertheless, IAS hypertonia and subsequent mucosal ischemia are the most prominent finding in typical CAF [1-3]. In contrast to acute anal fissure, CAF does not heal spontaneously and often requires relief of IAS spasm by either chemical or surgical sphincterotomy to promote healing and relieve anal pain [1, 2]. Lateral internal sphincterotomy (LIS) is considered the gold standard treatment for CAF because it is a simple and effective procedure with healing rates exceeding 90%. However, the major drawback of LIS is the risk of a degree of faecal incontinence (FI) which can occur in up to 9% of patients [4, 5]. Alternatives to LIS involve using pharmacologic agents that achieve reversible chemical sphincterotomy including nitric oxide donors such as glyceryl trinitrate (GTN); calcium channel blockers (CCB) such as diltiazem; and botulinum toxin injection [3-6]. While chemical sphincterotomy is not usually associated with the risk of continence disturbance, other adverse effects, particularly headache and postural hypotension, have been reported to be associated with topical application of GTN [2, 4]. Recently, topical minoxidil was introduced by Muthukumarassamy et al. [7] as a new emerging treatment for CAF. The authors reported good outcomes in terms of fissure healing and relief of anal pain with the use of a combination of 0.5% Minoxidil and 5%Lidocaine. Minoxidil has certain pharmacological properties that justify its use as a chemical sphincterotomy agent as it acts as an effective potassium channels agonist leading to smooth muscle hyperpolarization, in addition to reduced calcium influx through voltage-operated calcium channels [8]. Alvandipou et al. [8] conducted a randomized trial comparing topical 0.5% minoxidil with topical 2% Diltiazem in treatment of CAF. Topical minoxidil was well tolerated by the patients, alleviated symptoms effectively, and accelerated healing of the anal fissure in a comparable manner to diltiazem.
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In this prospective randomized trial we aimed to compare the efficacy and safety of topical minoxidil and GTN preparations in treatment of CAF with regard to healing of anal fissure, duration to healing, relief of symptoms, namely anal pain, and adverse effects.
Patients and methods Study design and setting This trial was designed as a prospective, randomized, double-blinded, controlled trial with two parallel groups. The study was conducted in the Colorectal Surgery Unit and General Surgery Department of our institution in the period of May 2018 through August 2019. Ethical approval for the study was obtained from the Institutional Review Board of our institution (ethical approval code: R/18.03.106). The trial was conducted in concordance with the Helsinki Declaration Principals and was reported in compliance with the CONSORT guidelines. The trial has been registered on www.clinicaltrials.gov. Selection criteria Adult patients of either gender aged between 18 and 65 years with CAF were included. Chronic anal fissure was defined based on the persistence of clinical symptoms for more than 6 weeks and the diagnosis was confirmed by detection of the signs of chronicity as indurated edges, visible IAS fibers through the base of the fissure, hypertrophic anal papilla, and sentinel pile [9]. We excluded pregnant female patients, patients with recurrent anal fissure after previous LIS; patients with coexisting anorectal diseases or inflammatory bowel diseases, patients with known allergy to GTN or Minoxidil, and patients unwilling to participate in the trial. Patient assessment Detailed history was taken from each patient regarding the anal pain and its onset and duration. Alongside this, associated symptoms including constipation and anal bleeding, previous medical or surgical treatments for the condition, and associated medical comorbidities were queried. Constipation was assessed before and after treatment using Wexner constipation score [10]. Initial assessment of the patients and decision on their eligibility for inclusion to the study was made by an attending surgeon (one of the study authors). Patients were examined in the left lateral position. The anal verge and perineum were carefully inspected to detect the number and location of anal fissure and to exclude other anal 3
lesions such as anal fistula and hemorrhoids. Digital rectal examination was done, if tolerated, to feel the induration at the fissure base and to exclude associated anorectal pathologies. Patients aging above 50 years old with anal bleeding were scheduled for colonoscopy to rule out colorectal cancer. Random sequence generation and allocation All participants who fulfilled the inclusion criteria and gave consent for participation in the trial were randomly assigned to either group I (5% Minoxidil gel) or group II (0.2% GTN cream) with a 1:1 allocation. Randomization was carried out using online software (Research Randomizer Version 4.0 at https://www.randomizer.org). Patients received the topical agent in unlabeled red or blue containers. The code of each color was known to a pharmacist who did not take part in patients’ care, follow-up, data collection/analysis or assessing the outcomes of the study. The investigators were not aware of the nature of the content of each container and the outcome assessors were unaware of the nature of the study. Interventions Signed informed consent was obtained from every patient before enrollment highlighting the possible future publication. Eligible patients were randomized into two equal groups: groups I received topical 5% Minoxidil gel (Minoxidil Forte 5% topical gel 60 gm; Pharmacare Egypt Co., Cairo, Egypt) and group II received topical 0.2% GTN cream (Nitroglycerine-Glycerile Tinitrate 0.2%, 30 gm; E.S.A.G Pharma Co., Cairo, Egypt).
In addition to the topical
treatments, patients in both groups were equally advised to increase dietary fiber intake and were prescribed laxatives to avoid constipation. The two topical agents were placed in identical 60 gm containers, labeled blue or red. The color code remained undefined until the end of trial, data analysis, and interpretation of results except for the same pharmacist. The containers were distributed to the patients by the outpatient department nurse in the hospital. Patients were advised to apply approximately 2 cm of the gel or cream on the perianal area three times per day for up to 6 weeks or until complete healing is confirmed clinically. During the first visit, patients were taught to self-administer the topical preparation. The patients were advised to increase water and dietary fiber intake and take laxatives (lactulose syrup) to avoid 4
constipation. Patients were also instructed to avoid using any other topical preparations during their treatment with minoxidil or GTN. Once complete healing of anal fissure was confirmed, the topical medications were stopped. Follow-up Patients were advised to visit the outpatient clinic every week for one month, then every two weeks for another month after starting treatment. In the case of intolerable adverse events patients were advised to visit the outpatient clinic at any other time point during the trial. At each visit, the extent of healing of the anal fissure was assessed by an attending surgeon and a resident with adequate training in colorectal surgery who were both unaware of the nature of the study.
Patients were asked about the improvement in their symptoms,
particularly anal pain and bleeding. Pain was measured at each visit by the Visual Analog Scale (VAS) ranging from no pain “0” to worst possible pain “10”. Adverse effects induced by the topical agents as itching, headache, palpitation, postural hypotension, dizziness, excess perianal hair growth, and hypersensitivity reaction were recorded. The continence state was assessed using Wexner incontinence score [11]. Study outcomes The primary outcome of the trial was healing of anal fissure and the duration needed to complete healing. Healing was defined as complete re-epithelialization of the anoderm at the site of the anal fissure. Patients who did not achieve complete healing by the end of the study period (2 months) were considered not healed. Secondary outcomes included improvement in symptoms such as anal pain, constipation, bleeding, changes in pain score and Wexner constipation score, and adverse effects of the treatments. Sample size calculation Using an online software (www.clincalc.com), the sample size was calculated based on the analysis of the primary endpoint of the study (healing of anal fissure at the end of treatment). In view of previous studies [3, 7, 8, 12] we assumed that healing rate of CAF will be 75% after topical minoxidil treatment and 40% after topical GTN treatment, thus a sample size of 60 patients equally divided across both groups was required to achieve a study power of 80% 5
with alpha level set at 5%. In order to compensate for drop-out and loss to follow-up, 66 patients were ultimately included.
Statistical analysis Data were collected in excel spreadsheet then analyzed with SPSS (Statistical Package for Social Science version 22 for Microsoft Windows; SPSS Inc., Chicago, Illinois, USA). Continuous data were expressed as a mean ± (SD) or median (range) according to normality. The Student-t test or Mann-Whitney U test was used to compare the continuous variables between the two groups. Chi-square test or Fisher's exact test was used for comparison of the qualitative data between the groups. P values less than < 0.05 were considered significant. Binary logistic regression analysis was used to determine the predictors for failure of healing of anal fissure. The odds ratio (OR) and 95% confidence interval (95%CI) of each of the significant variables were calculated. The area under the curve (AUC) was measured to determine the suitability of data to the statistical model.
Results Patients’ characteristics Eighty-two patients with CAF were initially recruited, 16 patients did not meet the study criteria and were excluded. After including 66 patients to the study, four patients were lost to follow-up, thus 62 patients were available for the final analysis (Figure 1). Patients were 36 (58.1%) female and 26 (41.9%) male of a mean age of 37.8± 12.02 (range, 19-65) years. Thirteen (20.9%) patients had medical comorbidities (hypertension=10, diabetes mellitus= 1, ischemic heart disease=2) and seven (11.3%) were active smokers at the time of presentation. All patients complained of anal pain with a mean VAS of 7.66± 0.76. Fifty (80.6%) patients reported constipation before the start of treatment with a mean Wexner constipation score of 8.4± 3.66. Eighteen (29%) patients complained of bleeding per rectum, 12 (19.4%) of pruritus ani, and six (9.7%) of anal discharge. None of the patients had continence disturbance at their first presentation. The median duration of complaint was 6 (range, 3-120) months. Fifty-three (85.5%) patients had posterior anal fissure, four (6.4%) had anterior anal 6
fissure, and five (8.1%) both anterior and posterior anal fissures. Nine (14.5%) patients had history of previous anal surgery (hemorrhoidectomy= 6, anal fistulectomy= 3). Thirty patients received topical minoxidil treatment and 32 received topical GTN treatment. There were no significant differences between the two groups in regards patients’ demographics, clinical presentation, location of anal fissure, and history of previous anal surgery as shown in table 1. Outcome of treatment Healing of anal fissure (Figure 2) was achieved in 23 (76.7%) patients in the minoxidil group and 15 (46.9%) patients in the GTN group, the difference in healing rates between the two groups was statistically significant (p=0.03). The average duration to healing in the minoxidil group was significantly shorter than the GTN group (4.1± 1.9 vs 5.3± 2.7 weeks, p=0.048) (table 2). Adverse effects were recorded in 13 (40.6%) patients in the GTN group and 2 (6.6%) patients in the minoxidil group. Adverse effects of GTN cream included headache (n=7), postural hypotension (n=5), and palpitation (n=1). Adverse effects of minoxidil included itching in two patients. Continence was not affected in either group and the median Wexner incontinence score was zero in both groups. Both groups showed a significant decrease in pain scores and Wexner constipation scores at the end of treatment. The post-treatment pain score in the GTN group was significantly lower than the Minoxidil group (4± 1.2 vs 4.9± 1.25; p= 0.005). Both groups had comparable posttreatment constipation scores (5.7± 2.9 vs 4.8± 2.2; p=0.17) (Table 3). Analysis of the risk factors for failure of healing Patients’ characteristics including age, sex, location of anal fissure, duration of symptoms, diabetes mellitus, smoking status, and type of topical treatment were investigated by univariate analysis (table 4) which revealed that older age, active smoking, and topical GTN treatment were significantly associated with failure of healing. The significant factors were entered into multivariable regression analysis and GTN therapy (OR= 28.6, p=0.003) and active smoking (OR= 0.007, p=0.001) were found as significant independent predictors for failure of healing of anal fissure. Figure 3 illustrates the receiver operating characteristics (ROC) curve of the model used. ROC curve examines the accuracy of the test to discriminate patients with failure of healing from those with successful healing. The 7
AUC, a measure of how well the parameter can distinguish between the two groups, was 0.872 with standard error of 0.045 indicating adequate power of the statistical model used.
Discussion In the present trial we compared two topical agents in the treatment of CAF, minoxidil and GTN. GTN is a nitric oxide donor that releases nitric oxide radicals inside the fissure area. Nitric oxide acts by a dual mechanism through relaxation of the smooth muscles of the IAS and blood vessels resulting in relief of IAS spasm and increase in anodermal blood flow which alleviates ischemia [12]. On the other hand, minoxidil induces smooth muscle hyperpolarization by the opening of potassium channels and closure of voltage-operated calcium channels, resulting in relaxation of IAS and blood vessel smooth muscles [8]. Minoxidil is known to be a potent vasodilator agent that is mainly used in the treatment of alopecia by allowing more blood flow and nutrients to the hair follicles [14]. Minoxidil was first introduced as a treatment of CAF by Muthukumarassamy et al in 2005 [7]. The authors randomly assigned patients with CAF into three groups; the first received topical lignocaine, the second received topical minoxidil, and the third received a combination of both treatments. The study came to a conclusion that the combination of both topical agents conferred a higher rate of healing within a shorter time period and better relief of anal pain. However, the small sample size included to the study was its main limitation. Subsequently, two randomised trails [8, 15] compared topical minoxidil with topical diltiazem preparations. Alvandipour and colleagues [8] evaluated 44 patients who received topical minoxidil in comparison to a similar number of patients who received topical diltiazem. The conclusion of the study was that minoxidil is a potential chemical sphincterotomy agent that achieved comparable outcome to diltiazem in regards healing of anal fissure and relief of symptoms. However, the authors expressed their concern about itching at the beginning of minoxidil treatment which may affect compliance. Awan and coworkers [15] reported that minoxidil is a very effective topical treatment of CAF with significantly quick results and fewer side effects. Although the rate of healing of anal 8
fissure after the use of minoxidil was less than that of diltiazem (84% vs 90%), the average time to healing after minoxidil was significantly shorter than diltiazem (3.1 vs 4 weeks). Similar rates of pain relief was achieved in both groups (85% vs 83.3%) whereas the resolution of anal bleeding was higher after minoxidil compared to diltiazem (86% vs 64%).
To the best of our knowledge, the present trial is the first clinical trial to compare topical minoxidil with topical GTN preparations in the treatment of CAF. The trial included 62 patients, all of whom complained of anal pain which is the most common presentation of anal fissure. The average age of patients was 37.8 years in concordance with the literature. There was a slight female predominance of CAF as 58% of patients were women which may be attributed to cultural aspects as many women in our society tend to have constipation and withhold bowel motion when they are at school or work. About 80% of patients had chronic constipation which has a common association with CAF and is believed to factor in the development of the condition [16]. Less than 30% of patients complained of anal bleeding which may be due to underreporting of this symptom that can go unnoticed by many patients or due to the long duration of symptoms associated with fibrosis around the fissure base which can minimize bleeding. Both groups had similar patients’ demographics and baseline characteristics which may reflect absence of selection bias owing to adequate randomization [17]. The primary endpoint of the study was healing of CAF at the end of treatment which was achieved in more than three-quarter of patients after minoxidil treatment, significantly higher than the topical GTN group in which less than half of the patients achieved healing of CAF. These healing rates were similar to previous studies with minoxidil at 70-84% [7, 8, 15] and GTN at 4068% [17-21]. Despite the early promising results of GTN cream in treatment of CAF with healing rates reaching up to 85% [22-24], the collective evidence of a Cochrane review of 75 trials concluded an average healing rate of less than 50% [25]. The improved healing induced by minoxidil may be attributed to its potent vasodilator effect, promoting healing by increasing blood flow to the anal fissure (considered by Schouten to be an ischaemic ulcer [26]). The average duration to healing in our study was 5.3 weeks, consistent with previous studies reporting 4-8 weeks [12,18] and we report a mean time to healing after minoxidil at 4 weeks, again consistent with previous studies reporting between 3-6 weeks 9
[7,8, 15]. Healing after minoxidil treatment can probably be further improved and hastened by adding topical lignocaine cream as reported in a previous study [7]. Healing rates improved from 70 to 82% and healing time reduced from 3 to less than 2 weeks with combination therapy. Therefore, although not examined in the present study, a combination of both topical agents may be recommended to achieve better outcomes. Although both treatments conferred significant decrease in pain scores at the end of treatment, the post-treatment pain VAS in the GTN group was significantly lower than the minoxidil group. This may seem in contradiction to the greater healing induced by minoxidil; however; it can be explained in light of the idiopathic hypertensive anal canal theory [27]. The chief complaint of patients with hypertensive anal canal is anal pain that is associated with elevated resting anal pressure, yet with no evidence of anal fissure. We assume that minoxidil has a great healing promoting power, but is less effective in relaxation of the IAS spasm. Therefore, while minoxidil can manage to achieve healing, the residual IAS spasm might be the cause of increased pain score. Similarly, both groups showed a significant decrease in constipation scores at the end of treatment with no difference between minoxidil and GTN in regards post-treatment constipation scores. The improvement in constipation after either treatment may be attributed to the use of laxatives and increase dietary fiber intake. Nonetheless, the improvement in constipation may as well be explained by the relief of the IAS spasm and associated anal pain which help breaks the vicious circle of constipation causing pain, inducing IAS spasm, causing more pain and worsening the constipation [16]. Alvandipour et al. [8] reported headache, itching, and allergy after the use of topical minoxidil, the present study itching was recorded as adverse effect of minoxidil gel in two patients. On the other hand, about 40% of patients reported adverse effects after GTN applications. Headache was experienced by 23% and postural hypotension by 15.6% of patients in the GTN group. This was in line with previous studies which reported development of these side effects in up to 50% of patients [19, 21, 28, 29]. Limitations of the present study include its single-center nature, relatively small number of patients included, and short follow-up. Although the primary endpoint of the study that is the incidence of healing of anal fissure was adequately assessed within the follow-up period of the 10
study, longer follow-up may be needed to assess for recurrence of anal fissure after stoppage of topical treatment.
Conclusions Topical 5% minoxidil gel achieved greater and quicker healing of CAF in comparison with topical 0.2% GTN cream. Post-treatment pain scores were significantly lower after using GTN cream than minoxidil gel. While none of the patients experienced adverse effects related to the use of topical minoxidil, about 40% of patients reported side effects as headache and postural hypotension after using topical GTN.
Conflict of interests: None to be declared by the authors.
Provenance and peer review Not commissioned, externally peer-reviewed
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Tables Table 1. Baseline characteristics of patients in both groups. Variable
Minoxidil group
GTN group
P
(n=30)
(n=32)
value
Mean age in years
37.7± 11.5
37.9± 12.7
0.95
Male/Female
13/17
13/19
0.83
Location of
Posterior (%)
25 (83.3)
28 (87.5)
anal fissure
Anterior (%)
2 (6.6)
2 (6.2)
Multiple (%)
3 (10)
2 (6.2)
Constipation (%)
25 (83.3)
25 (78.1)
Bleeding (%)
11 (36.6)
7 (21.9)
Discharge (%)
3 (10)
3 (9.4)
Complaint
0.87
0.53
15
4 (13.3)
8 (25)
Median duration of complaint (months)
8
6
0.13
Baseline pain score
7.8± 0.76
7.5± 0.72
0.11
Baseline Wexner constipation score
9.1± 3.8
7.9± 3.5
0.2
Medical comorbidities (%)
8 (26.6)
5 (15.6)
0.45
Smokers (%)
4 (13.3)
3 (9.4)
0.7
History of previous anal surgery (%)
2 (6.6)
7 (21.9)
0.15
Pruritus (%)
*GTN= glyceryl trinitrate
Table 2. Outcome of patients in both groups. Variable
Minoxidil group
GTN group
P value
(n=30)
(n=32)
Healing (%)
23 (76.7)
15 (46.9)
0.03
Average time to healing in weeks
4.1± 1.9
5.3± 2.7
0.048
Adverse effects of treatment (%)
2 (6.6)
13 (40.6)
0.002
*GTN= glyceryl trinitrate
16
Table 3. Change in pain score and Wexner constipation score in the two groups Variable
Minoxidil group
GTN group
P
(n=30)
(n=32)
value
Mean baseline pain score
7.8± 0.76
7.5± 0.72
0.11
Mean post-treatment pain score
4.9± 1.25
4± 1.2
0.005
P value
<0.0001
<0.0001
Mean baseline Wexner constipation score
9.1± 3.8
7.9± 3.5
0.2
Mean post-treatment Wexner constipation score
5.7± 2.9
4.8± 2.2
0.17
P value
0.0003
<0.0001
*GTN= glyceryl trinitrate
17
Table 4. Univariate and multivariate analyses of risk factors for failure of healing of anal fissure Variable
Healing
No healing
(n=38) 35.7±
42.3±
12.2
11.9
Male
17
9
Female
21
15
Posterior
32
Anterior
4
Multiple
2
6
9
Mean age in years
Gender
Location of fissure
Median
(n=24)
duration
of
P*
Odds ratio
P **
value
(95%CI)
value
0.04
1.05
0.09
(0.99-1.11) 0.09 ------
0.25
------
------
------
0.37
18
symptoms (months)
------
------
Diabetes mellitus
0
1
0.99
------
------
Active smoking
1
6
0.01
0.007
0.001
(0.0001-.13) Constipation
32
18
Treatment
Minoxidil
23
GTN
15
0.57 0.03
------
------
1
0.003
28.6 (3.2-252.8)
* p value of univariate analysis (fisher exact or chi square test) ** p value of multivariate analysis
Figure Legends -
Figure 1. Consort flow diagram
-
Figure 2. Healing of chronic anal fissure after Minoxidil treatment.
-
Figure 3. Receiver operating characteristic (ROC) curve analysis demonstrating the area under the curve for the multivariate analysis model.
19
Highlights •
Adult patients with chronic anal fissure were randomly assigned to one of two equal groups
•
Group I received topical 5% minoxidil gel and group II received topical 0.2% GTN cream.
•
Healing of anal fissure was achieved in 76.7% of patients in group I and 46.9% of patients in group II (p=0.03).
•
The average duration to healing in group I was significantly shorter than group II (4.1 vs 5.3 weeks, p=0.048).
•
Post-treatment pain scores were significantly lower after using GTN cream than minoxidil gel
•
Adverse effects were recorded in 2 (6.6%) patients in group I and 13 (40.6%) patients in group II.
International Journal of Surgery Author Disclosure Form The following additional information is required for submission. Please note that failure to respond to these questions/statements will mean your submission will be returned. If you have nothing to declare in any of these categories then this should be stated. Please state any conflicts of interest
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Institutional review board of Mansoura Faculty of Medicine Code: R/18.03.106
Research Registration Unique Identifying Number (UIN) Please enter the name of the registry and the unique identifying number of the study. You can register your research at http://www.researchregistry.com to obtain your UIN if you have not already registered your study. This is mandatory for human studies only.
Clinical Trial NCT03528772 https://clinicaltrials.gov/ct2/show/NCT03528772
1
Author contribution Please specify the contribution of each author to the paper, e.g. study design, data collections, data analysis, writing. Others, who have contributed in other ways should be listed as contributors. Sameh Emile designed the study, shared in data collection and analysis and writing the manuscript. Mohamed Abdel-Razik contributed to, data acquisition and analysis, writing and revising the manuscript. Ayman Elshobaky contributed to data interpretation and analysis, writing and revision of the manuscript. Samy Elbaz contributed to data colllectio and analysis, drafting and critical revision of the manuscript. Wael Khafagy shared in interpretation of the results, supervision, writing parts of the manuscript and critical revision of the final version. Mostafa Shalaby contributed to, data acquisition and analysis, writing and revsing the manuscript
Guarantor The Guarantor is the one or more people who accept full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
Sameh Emile, M.D.
2
Data Statement Research data used in the study will be available on request
S1743-9191(20)30154-0
DOI:
https://doi.org/10.1016/j.ijsu.2020.01.143
Reference:
IJSU 5250
To appear in:
International Journal of Surgery
Received Date: 5 November 2019 Revised Date:
6 January 2020
Accepted Date: 24 January 2020
Please cite this article as: Emile SH, Abdel-Razik MA, Elshobaky A, Elbaz SA, Khafagy W, Shalaby M, Topical 5% Minoxidil versus Topical 0.2% Glyceryl Trinitrate in Treatment of Chronic Anal Fissure: A Randomized Clinical Trial, International Journal of Surgery, https://doi.org/10.1016/j.ijsu.2020.01.143. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.
Credit author statement Sameh Emile: Conceptualization, data curation, formal analysis, writing original draft, Mohamed Anwar Abdel-Razik: formal analysis, methodology, investigation, writing: review and editing, Ayman Elshobaky: data curation, methodology, writing: review and editing, Samy Elbaz: Data curation, investigation, resources, writing: review and editing, Wael Khafagy: formal analysis, supervision, writing: review and editing, Mostafa Shalaby: data curation, formal analysis, methodology, writing: review and editing
Title: Topical 5% Minoxidil versus Topical 0.2% Glyceryl Trinitrate in Treatment of Chronic Anal Fissure: A Randomized Clinical Trial Short running title: RCT on topical minoxidil versus topical GTN for chronic anal fissure Type: Original article Authors 1. Sameh Hany Emile, MD, MSc, PhD. [email protected] 2. Mohamed Anwar Abdel-Razik, MD, MSc, PhD. [email protected] 3. Ayman Elshobaky, MD, MSc, PhD. [email protected] 4. Samy Abbas Elbaz, MD, MSc, PhD. [email protected]. 5. Wael Khafagy, M.D, MSc, PhD. [email protected]. 6. Mostafa Shalaby, MD, MSc. PhD. [email protected] Affiliations Colorectal Surgery Unit, Department of General surgery, Mansoura Faculty of medicine, Mansoura University, Mansoura, Egypt. Authors’ contributions Sameh Hany Emile designed the study. Sameh Hany Emile, Mostafa Shalaby, and Mohamed Abdel-Razik, Ayman Elshobaky participated in data collection and analysis, writing and drafting of the manuscript. Samy Elbaz contributed to data collection and revision of the manuscript. Wael Khafagy supervised data collection and analysis and participated in critical revision of the manuscript. Correspondence to: •
Sameh Emile, MD. Colorectal Surgery Unit, General Surgery Department, Faculty of Medicine, Mansoura University Hospitals, 60 Elgomhuoria Street, Mansoura city, Egypt. PO: 35516
•
[email protected]
•
Tel: +20-1006267150, Fax: +20 (50) 239733.
Conflict of interest and sources of funding: None to be declared by the authors.
Topical 5% Minoxidil versus Topical 0.2% Glyceryl Trinitrate in Treatment of Chronic Anal Fissure: A Randomized Clinical Trial Abstract Background: Chronic anal fissure (CAF) is a common painful anal condition. Medical treatment of CAF involves the use of agents that induce chemical sphincterotomy. The present trial aimed to compare the efficacy and safety of topical minoxidil and glyceryl trinitrate (GTN) preparations in treatment of CAF. Methods: Adult patients with CAF were randomly assigned to one of two equal groups; group I received topical 5% minoxidil gel and group II received topical 0.2% GTN cream. The main outcome measures were healing of anal fissure, duration to healing, relief of symptoms, and adverse effects. Results: 62 patients (36 female and 26 male) were included to the study. Group I comprised 30 patients and group II comprised 32 patients. Healing of anal fissure was achieved in 23 (76.7%) patients in group I and 15 (46.9%) patients in group II (p=0.03). The average duration to healing in group I was significantly shorter than group II (4.1± 1.9 vs 5.3± 2.7 weeks, p=0.048). Adverse effects were recorded in 2 (6.6%) patients in group I and 13 (40.6%) patients in group II. The post-treatment pain score in the GTN group was significantly lower than the Minoxidil group. Conclusion: Topical 5% minoxidil gel achieved greater and quicker healing of CAF and fewer adverse effects than topical 0.2% GTN cream. Post-treatment pain scores after GTN were significantly lower than minoxidil. Keywords: Minoxidil; Glyceryl trinitrate; Chronic; Anal fissure; Randomized trial Trial registration number: NCT03528772.
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Introduction Chronic anal fissure (CAF) is one of the most common painful anal conditions. A sentinel pile at the distal end of the fissure with visible internal anal sphincter fibers (IAS) at its base usually indicates its chronicity. Patients with CAF usually complain of anal pain during defecation which may sometimes be associated with bleeding per rectum [1, 2]. Although various theories have been proposed to explain the pathogenesis of the CAF, the exact cause remains unknown. Nevertheless, IAS hypertonia and subsequent mucosal ischemia are the most prominent finding in typical CAF [1-3]. In contrast to acute anal fissure, CAF does not heal spontaneously and often requires relief of IAS spasm by either chemical or surgical sphincterotomy to promote healing and relieve anal pain [1, 2]. Lateral internal sphincterotomy (LIS) is considered the gold standard treatment for CAF because it is a simple and effective procedure with healing rates exceeding 90%. However, the major drawback of LIS is the risk of a degree of faecal incontinence (FI) which can occur in up to 9% of patients [4, 5]. Alternatives to LIS involve using pharmacologic agents that achieve reversible chemical sphincterotomy including nitric oxide donors such as glyceryl trinitrate (GTN); calcium channel blockers (CCB) such as diltiazem; and botulinum toxin injection [3-6]. While chemical sphincterotomy is not usually associated with the risk of continence disturbance, other adverse effects, particularly headache and postural hypotension, have been reported to be associated with topical application of GTN [2, 4]. Recently, topical minoxidil was introduced by Muthukumarassamy et al. [7] as a new emerging treatment for CAF. The authors reported good outcomes in terms of fissure healing and relief of anal pain with the use of a combination of 0.5% Minoxidil and 5%Lidocaine. Minoxidil has certain pharmacological properties that justify its use as a chemical sphincterotomy agent as it acts as an effective potassium channels agonist leading to smooth muscle hyperpolarization, in addition to reduced calcium influx through voltage-operated calcium channels [8]. Alvandipou et al. [8] conducted a randomized trial comparing topical 0.5% minoxidil with topical 2% Diltiazem in treatment of CAF. Topical minoxidil was well tolerated by the patients, alleviated symptoms effectively, and accelerated healing of the anal fissure in a comparable manner to diltiazem.
2
In this prospective randomized trial we aimed to compare the efficacy and safety of topical minoxidil and GTN preparations in treatment of CAF with regard to healing of anal fissure, duration to healing, relief of symptoms, namely anal pain, and adverse effects.
Patients and methods Study design and setting This trial was designed as a prospective, randomized, double-blinded, controlled trial with two parallel groups. The study was conducted in the Colorectal Surgery Unit and General Surgery Department of our institution in the period of May 2018 through August 2019. Ethical approval for the study was obtained from the Institutional Review Board of our institution (ethical approval code: R/18.03.106). The trial was conducted in concordance with the Helsinki Declaration Principals and was reported in compliance with the CONSORT guidelines. The trial has been registered on www.clinicaltrials.gov. Selection criteria Adult patients of either gender aged between 18 and 65 years with CAF were included. Chronic anal fissure was defined based on the persistence of clinical symptoms for more than 6 weeks and the diagnosis was confirmed by detection of the signs of chronicity as indurated edges, visible IAS fibers through the base of the fissure, hypertrophic anal papilla, and sentinel pile [9]. We excluded pregnant female patients, patients with recurrent anal fissure after previous LIS; patients with coexisting anorectal diseases or inflammatory bowel diseases, patients with known allergy to GTN or Minoxidil, and patients unwilling to participate in the trial. Patient assessment Detailed history was taken from each patient regarding the anal pain and its onset and duration. Alongside this, associated symptoms including constipation and anal bleeding, previous medical or surgical treatments for the condition, and associated medical comorbidities were queried. Constipation was assessed before and after treatment using Wexner constipation score [10]. Initial assessment of the patients and decision on their eligibility for inclusion to the study was made by an attending surgeon (one of the study authors). Patients were examined in the left lateral position. The anal verge and perineum were carefully inspected to detect the number and location of anal fissure and to exclude other anal 3
lesions such as anal fistula and hemorrhoids. Digital rectal examination was done, if tolerated, to feel the induration at the fissure base and to exclude associated anorectal pathologies. Patients aging above 50 years old with anal bleeding were scheduled for colonoscopy to rule out colorectal cancer. Random sequence generation and allocation All participants who fulfilled the inclusion criteria and gave consent for participation in the trial were randomly assigned to either group I (5% Minoxidil gel) or group II (0.2% GTN cream) with a 1:1 allocation. Randomization was carried out using online software (Research Randomizer Version 4.0 at https://www.randomizer.org). Patients received the topical agent in unlabeled red or blue containers. The code of each color was known to a pharmacist who did not take part in patients’ care, follow-up, data collection/analysis or assessing the outcomes of the study. The investigators were not aware of the nature of the content of each container and the outcome assessors were unaware of the nature of the study. Interventions Signed informed consent was obtained from every patient before enrollment highlighting the possible future publication. Eligible patients were randomized into two equal groups: groups I received topical 5% Minoxidil gel (Minoxidil Forte 5% topical gel 60 gm; Pharmacare Egypt Co., Cairo, Egypt) and group II received topical 0.2% GTN cream (Nitroglycerine-Glycerile Tinitrate 0.2%, 30 gm; E.S.A.G Pharma Co., Cairo, Egypt).
In addition to the topical
treatments, patients in both groups were equally advised to increase dietary fiber intake and were prescribed laxatives to avoid constipation. The two topical agents were placed in identical 60 gm containers, labeled blue or red. The color code remained undefined until the end of trial, data analysis, and interpretation of results except for the same pharmacist. The containers were distributed to the patients by the outpatient department nurse in the hospital. Patients were advised to apply approximately 2 cm of the gel or cream on the perianal area three times per day for up to 6 weeks or until complete healing is confirmed clinically. During the first visit, patients were taught to self-administer the topical preparation. The patients were advised to increase water and dietary fiber intake and take laxatives (lactulose syrup) to avoid 4
constipation. Patients were also instructed to avoid using any other topical preparations during their treatment with minoxidil or GTN. Once complete healing of anal fissure was confirmed, the topical medications were stopped. Follow-up Patients were advised to visit the outpatient clinic every week for one month, then every two weeks for another month after starting treatment. In the case of intolerable adverse events patients were advised to visit the outpatient clinic at any other time point during the trial. At each visit, the extent of healing of the anal fissure was assessed by an attending surgeon and a resident with adequate training in colorectal surgery who were both unaware of the nature of the study.
Patients were asked about the improvement in their symptoms,
particularly anal pain and bleeding. Pain was measured at each visit by the Visual Analog Scale (VAS) ranging from no pain “0” to worst possible pain “10”. Adverse effects induced by the topical agents as itching, headache, palpitation, postural hypotension, dizziness, excess perianal hair growth, and hypersensitivity reaction were recorded. The continence state was assessed using Wexner incontinence score [11]. Study outcomes The primary outcome of the trial was healing of anal fissure and the duration needed to complete healing. Healing was defined as complete re-epithelialization of the anoderm at the site of the anal fissure. Patients who did not achieve complete healing by the end of the study period (2 months) were considered not healed. Secondary outcomes included improvement in symptoms such as anal pain, constipation, bleeding, changes in pain score and Wexner constipation score, and adverse effects of the treatments. Sample size calculation Using an online software (www.clincalc.com), the sample size was calculated based on the analysis of the primary endpoint of the study (healing of anal fissure at the end of treatment). In view of previous studies [3, 7, 8, 12] we assumed that healing rate of CAF will be 75% after topical minoxidil treatment and 40% after topical GTN treatment, thus a sample size of 60 patients equally divided across both groups was required to achieve a study power of 80% 5
with alpha level set at 5%. In order to compensate for drop-out and loss to follow-up, 66 patients were ultimately included.
Statistical analysis Data were collected in excel spreadsheet then analyzed with SPSS (Statistical Package for Social Science version 22 for Microsoft Windows; SPSS Inc., Chicago, Illinois, USA). Continuous data were expressed as a mean ± (SD) or median (range) according to normality. The Student-t test or Mann-Whitney U test was used to compare the continuous variables between the two groups. Chi-square test or Fisher's exact test was used for comparison of the qualitative data between the groups. P values less than < 0.05 were considered significant. Binary logistic regression analysis was used to determine the predictors for failure of healing of anal fissure. The odds ratio (OR) and 95% confidence interval (95%CI) of each of the significant variables were calculated. The area under the curve (AUC) was measured to determine the suitability of data to the statistical model.
Results Patients’ characteristics Eighty-two patients with CAF were initially recruited, 16 patients did not meet the study criteria and were excluded. After including 66 patients to the study, four patients were lost to follow-up, thus 62 patients were available for the final analysis (Figure 1). Patients were 36 (58.1%) female and 26 (41.9%) male of a mean age of 37.8± 12.02 (range, 19-65) years. Thirteen (20.9%) patients had medical comorbidities (hypertension=10, diabetes mellitus= 1, ischemic heart disease=2) and seven (11.3%) were active smokers at the time of presentation. All patients complained of anal pain with a mean VAS of 7.66± 0.76. Fifty (80.6%) patients reported constipation before the start of treatment with a mean Wexner constipation score of 8.4± 3.66. Eighteen (29%) patients complained of bleeding per rectum, 12 (19.4%) of pruritus ani, and six (9.7%) of anal discharge. None of the patients had continence disturbance at their first presentation. The median duration of complaint was 6 (range, 3-120) months. Fifty-three (85.5%) patients had posterior anal fissure, four (6.4%) had anterior anal 6
fissure, and five (8.1%) both anterior and posterior anal fissures. Nine (14.5%) patients had history of previous anal surgery (hemorrhoidectomy= 6, anal fistulectomy= 3). Thirty patients received topical minoxidil treatment and 32 received topical GTN treatment. There were no significant differences between the two groups in regards patients’ demographics, clinical presentation, location of anal fissure, and history of previous anal surgery as shown in table 1. Outcome of treatment Healing of anal fissure (Figure 2) was achieved in 23 (76.7%) patients in the minoxidil group and 15 (46.9%) patients in the GTN group, the difference in healing rates between the two groups was statistically significant (p=0.03). The average duration to healing in the minoxidil group was significantly shorter than the GTN group (4.1± 1.9 vs 5.3± 2.7 weeks, p=0.048) (table 2). Adverse effects were recorded in 13 (40.6%) patients in the GTN group and 2 (6.6%) patients in the minoxidil group. Adverse effects of GTN cream included headache (n=7), postural hypotension (n=5), and palpitation (n=1). Adverse effects of minoxidil included itching in two patients. Continence was not affected in either group and the median Wexner incontinence score was zero in both groups. Both groups showed a significant decrease in pain scores and Wexner constipation scores at the end of treatment. The post-treatment pain score in the GTN group was significantly lower than the Minoxidil group (4± 1.2 vs 4.9± 1.25; p= 0.005). Both groups had comparable posttreatment constipation scores (5.7± 2.9 vs 4.8± 2.2; p=0.17) (Table 3). Analysis of the risk factors for failure of healing Patients’ characteristics including age, sex, location of anal fissure, duration of symptoms, diabetes mellitus, smoking status, and type of topical treatment were investigated by univariate analysis (table 4) which revealed that older age, active smoking, and topical GTN treatment were significantly associated with failure of healing. The significant factors were entered into multivariable regression analysis and GTN therapy (OR= 28.6, p=0.003) and active smoking (OR= 0.007, p=0.001) were found as significant independent predictors for failure of healing of anal fissure. Figure 3 illustrates the receiver operating characteristics (ROC) curve of the model used. ROC curve examines the accuracy of the test to discriminate patients with failure of healing from those with successful healing. The 7
AUC, a measure of how well the parameter can distinguish between the two groups, was 0.872 with standard error of 0.045 indicating adequate power of the statistical model used.
Discussion In the present trial we compared two topical agents in the treatment of CAF, minoxidil and GTN. GTN is a nitric oxide donor that releases nitric oxide radicals inside the fissure area. Nitric oxide acts by a dual mechanism through relaxation of the smooth muscles of the IAS and blood vessels resulting in relief of IAS spasm and increase in anodermal blood flow which alleviates ischemia [12]. On the other hand, minoxidil induces smooth muscle hyperpolarization by the opening of potassium channels and closure of voltage-operated calcium channels, resulting in relaxation of IAS and blood vessel smooth muscles [8]. Minoxidil is known to be a potent vasodilator agent that is mainly used in the treatment of alopecia by allowing more blood flow and nutrients to the hair follicles [14]. Minoxidil was first introduced as a treatment of CAF by Muthukumarassamy et al in 2005 [7]. The authors randomly assigned patients with CAF into three groups; the first received topical lignocaine, the second received topical minoxidil, and the third received a combination of both treatments. The study came to a conclusion that the combination of both topical agents conferred a higher rate of healing within a shorter time period and better relief of anal pain. However, the small sample size included to the study was its main limitation. Subsequently, two randomised trails [8, 15] compared topical minoxidil with topical diltiazem preparations. Alvandipour and colleagues [8] evaluated 44 patients who received topical minoxidil in comparison to a similar number of patients who received topical diltiazem. The conclusion of the study was that minoxidil is a potential chemical sphincterotomy agent that achieved comparable outcome to diltiazem in regards healing of anal fissure and relief of symptoms. However, the authors expressed their concern about itching at the beginning of minoxidil treatment which may affect compliance. Awan and coworkers [15] reported that minoxidil is a very effective topical treatment of CAF with significantly quick results and fewer side effects. Although the rate of healing of anal 8
fissure after the use of minoxidil was less than that of diltiazem (84% vs 90%), the average time to healing after minoxidil was significantly shorter than diltiazem (3.1 vs 4 weeks). Similar rates of pain relief was achieved in both groups (85% vs 83.3%) whereas the resolution of anal bleeding was higher after minoxidil compared to diltiazem (86% vs 64%).
To the best of our knowledge, the present trial is the first clinical trial to compare topical minoxidil with topical GTN preparations in the treatment of CAF. The trial included 62 patients, all of whom complained of anal pain which is the most common presentation of anal fissure. The average age of patients was 37.8 years in concordance with the literature. There was a slight female predominance of CAF as 58% of patients were women which may be attributed to cultural aspects as many women in our society tend to have constipation and withhold bowel motion when they are at school or work. About 80% of patients had chronic constipation which has a common association with CAF and is believed to factor in the development of the condition [16]. Less than 30% of patients complained of anal bleeding which may be due to underreporting of this symptom that can go unnoticed by many patients or due to the long duration of symptoms associated with fibrosis around the fissure base which can minimize bleeding. Both groups had similar patients’ demographics and baseline characteristics which may reflect absence of selection bias owing to adequate randomization [17]. The primary endpoint of the study was healing of CAF at the end of treatment which was achieved in more than three-quarter of patients after minoxidil treatment, significantly higher than the topical GTN group in which less than half of the patients achieved healing of CAF. These healing rates were similar to previous studies with minoxidil at 70-84% [7, 8, 15] and GTN at 4068% [17-21]. Despite the early promising results of GTN cream in treatment of CAF with healing rates reaching up to 85% [22-24], the collective evidence of a Cochrane review of 75 trials concluded an average healing rate of less than 50% [25]. The improved healing induced by minoxidil may be attributed to its potent vasodilator effect, promoting healing by increasing blood flow to the anal fissure (considered by Schouten to be an ischaemic ulcer [26]). The average duration to healing in our study was 5.3 weeks, consistent with previous studies reporting 4-8 weeks [12,18] and we report a mean time to healing after minoxidil at 4 weeks, again consistent with previous studies reporting between 3-6 weeks 9
[7,8, 15]. Healing after minoxidil treatment can probably be further improved and hastened by adding topical lignocaine cream as reported in a previous study [7]. Healing rates improved from 70 to 82% and healing time reduced from 3 to less than 2 weeks with combination therapy. Therefore, although not examined in the present study, a combination of both topical agents may be recommended to achieve better outcomes. Although both treatments conferred significant decrease in pain scores at the end of treatment, the post-treatment pain VAS in the GTN group was significantly lower than the minoxidil group. This may seem in contradiction to the greater healing induced by minoxidil; however; it can be explained in light of the idiopathic hypertensive anal canal theory [27]. The chief complaint of patients with hypertensive anal canal is anal pain that is associated with elevated resting anal pressure, yet with no evidence of anal fissure. We assume that minoxidil has a great healing promoting power, but is less effective in relaxation of the IAS spasm. Therefore, while minoxidil can manage to achieve healing, the residual IAS spasm might be the cause of increased pain score. Similarly, both groups showed a significant decrease in constipation scores at the end of treatment with no difference between minoxidil and GTN in regards post-treatment constipation scores. The improvement in constipation after either treatment may be attributed to the use of laxatives and increase dietary fiber intake. Nonetheless, the improvement in constipation may as well be explained by the relief of the IAS spasm and associated anal pain which help breaks the vicious circle of constipation causing pain, inducing IAS spasm, causing more pain and worsening the constipation [16]. Alvandipour et al. [8] reported headache, itching, and allergy after the use of topical minoxidil, the present study itching was recorded as adverse effect of minoxidil gel in two patients. On the other hand, about 40% of patients reported adverse effects after GTN applications. Headache was experienced by 23% and postural hypotension by 15.6% of patients in the GTN group. This was in line with previous studies which reported development of these side effects in up to 50% of patients [19, 21, 28, 29]. Limitations of the present study include its single-center nature, relatively small number of patients included, and short follow-up. Although the primary endpoint of the study that is the incidence of healing of anal fissure was adequately assessed within the follow-up period of the 10
study, longer follow-up may be needed to assess for recurrence of anal fissure after stoppage of topical treatment.
Conclusions Topical 5% minoxidil gel achieved greater and quicker healing of CAF in comparison with topical 0.2% GTN cream. Post-treatment pain scores were significantly lower after using GTN cream than minoxidil gel. While none of the patients experienced adverse effects related to the use of topical minoxidil, about 40% of patients reported side effects as headache and postural hypotension after using topical GTN.
Conflict of interests: None to be declared by the authors.
Provenance and peer review Not commissioned, externally peer-reviewed
References 1. Evans J, Luck A, Hewett P. Glyceryl trinitrate vs. lateral sphincterotomy for chronic anal fissure: prospective, randomized trial. Diseases of the colon and rectum. 2001;44(1):93-7. 2. Gandomkar H, Zeinoddini A, Heidari R, Amoli HA. Partial lateral internal sphincterotomy versus combined botulinum toxin A injection and topical diltiazem in the treatment of chronic anal fissure: a randomized clinical trial. Diseases of the colon and rectum. 2015;58(2):228-34.
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doi:10.4240/wjgs.v2.i7.231 19. Lund JN, Scholefield JH. A randomised, prospective, double-blind, placebo-controlled trial of glyceryl trinitrate ointment in treatment of anal fissure. Lancet. 1997;349:11–14. 20. Kennedy ML, Sowter S, Nguyen H, Lubowski DZ. Glyceryl trinitrate ointment for the treatment of chronic anal fissure: results of a placebo-controlled trial and long-term followup. Dis Colon Rectum. 1999;42:1000–1006. 21. Altomare DF, Rinaldi M, Milito G, Arcanà F, Spinelli F, Nardelli N, Scardigno D, PulvirentiD'Urso A, Bottini C, Pescatori M, et al. Glyceryl trinitrate for chronic anal fissure--healing or headache? Results of a multicenter, randomized, placebo-controled, double-blind trial. Dis Colon Rectum. 2000;43:174–179; discussion 179-181.
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Tables Table 1. Baseline characteristics of patients in both groups. Variable
Minoxidil group
GTN group
P
(n=30)
(n=32)
value
Mean age in years
37.7± 11.5
37.9± 12.7
0.95
Male/Female
13/17
13/19
0.83
Location of
Posterior (%)
25 (83.3)
28 (87.5)
anal fissure
Anterior (%)
2 (6.6)
2 (6.2)
Multiple (%)
3 (10)
2 (6.2)
Constipation (%)
25 (83.3)
25 (78.1)
Bleeding (%)
11 (36.6)
7 (21.9)
Discharge (%)
3 (10)
3 (9.4)
Complaint
0.87
0.53
15
4 (13.3)
8 (25)
Median duration of complaint (months)
8
6
0.13
Baseline pain score
7.8± 0.76
7.5± 0.72
0.11
Baseline Wexner constipation score
9.1± 3.8
7.9± 3.5
0.2
Medical comorbidities (%)
8 (26.6)
5 (15.6)
0.45
Smokers (%)
4 (13.3)
3 (9.4)
0.7
History of previous anal surgery (%)
2 (6.6)
7 (21.9)
0.15
Pruritus (%)
*GTN= glyceryl trinitrate
Table 2. Outcome of patients in both groups. Variable
Minoxidil group
GTN group
P value
(n=30)
(n=32)
Healing (%)
23 (76.7)
15 (46.9)
0.03
Average time to healing in weeks
4.1± 1.9
5.3± 2.7
0.048
Adverse effects of treatment (%)
2 (6.6)
13 (40.6)
0.002
*GTN= glyceryl trinitrate
16
Table 3. Change in pain score and Wexner constipation score in the two groups Variable
Minoxidil group
GTN group
P
(n=30)
(n=32)
value
Mean baseline pain score
7.8± 0.76
7.5± 0.72
0.11
Mean post-treatment pain score
4.9± 1.25
4± 1.2
0.005
P value
<0.0001
<0.0001
Mean baseline Wexner constipation score
9.1± 3.8
7.9± 3.5
0.2
Mean post-treatment Wexner constipation score
5.7± 2.9
4.8± 2.2
0.17
P value
0.0003
<0.0001
*GTN= glyceryl trinitrate
17
Table 4. Univariate and multivariate analyses of risk factors for failure of healing of anal fissure Variable
Healing
No healing
(n=38) 35.7±
42.3±
12.2
11.9
Male
17
9
Female
21
15
Posterior
32
Anterior
4
Multiple
2
6
9
Mean age in years
Gender
Location of fissure
Median
(n=24)
duration
of
P*
Odds ratio
P **
value
(95%CI)
value
0.04
1.05
0.09
(0.99-1.11) 0.09 ------
0.25
------
------
------
0.37
18
symptoms (months)
------
------
Diabetes mellitus
0
1
0.99
------
------
Active smoking
1
6
0.01
0.007
0.001
(0.0001-.13) Constipation
32
18
Treatment
Minoxidil
23
GTN
15
0.57 0.03
------
------
1
0.003
28.6 (3.2-252.8)
* p value of univariate analysis (fisher exact or chi square test) ** p value of multivariate analysis
Figure Legends -
Figure 1. Consort flow diagram
-
Figure 2. Healing of chronic anal fissure after Minoxidil treatment.
-
Figure 3. Receiver operating characteristic (ROC) curve analysis demonstrating the area under the curve for the multivariate analysis model.
19
Highlights •
Adult patients with chronic anal fissure were randomly assigned to one of two equal groups
•
Group I received topical 5% minoxidil gel and group II received topical 0.2% GTN cream.
•
Healing of anal fissure was achieved in 76.7% of patients in group I and 46.9% of patients in group II (p=0.03).
•
The average duration to healing in group I was significantly shorter than group II (4.1 vs 5.3 weeks, p=0.048).
•
Post-treatment pain scores were significantly lower after using GTN cream than minoxidil gel
•
Adverse effects were recorded in 2 (6.6%) patients in group I and 13 (40.6%) patients in group II.
International Journal of Surgery Author Disclosure Form The following additional information is required for submission. Please note that failure to respond to these questions/statements will mean your submission will be returned. If you have nothing to declare in any of these categories then this should be stated. Please state any conflicts of interest
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Institutional review board of Mansoura Faculty of Medicine Code: R/18.03.106
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Clinical Trial NCT03528772 https://clinicaltrials.gov/ct2/show/NCT03528772
1
Author contribution Please specify the contribution of each author to the paper, e.g. study design, data collections, data analysis, writing. Others, who have contributed in other ways should be listed as contributors. Sameh Emile designed the study, shared in data collection and analysis and writing the manuscript. Mohamed Abdel-Razik contributed to, data acquisition and analysis, writing and revising the manuscript. Ayman Elshobaky contributed to data interpretation and analysis, writing and revision of the manuscript. Samy Elbaz contributed to data colllectio and analysis, drafting and critical revision of the manuscript. Wael Khafagy shared in interpretation of the results, supervision, writing parts of the manuscript and critical revision of the final version. Mostafa Shalaby contributed to, data acquisition and analysis, writing and revsing the manuscript
Guarantor The Guarantor is the one or more people who accept full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
Sameh Emile, M.D.
2
Data Statement Research data used in the study will be available on request