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ORIGINAL ARTICLE
Topical anal fissure treatment: placebo-controlled study
of mononitrate and trinitrate therapies
Ludmila Tankova &Krassimira Yoncheva &
Daniel Kovatchki &I. Doytchinova
Accepted: 9 December 2008 / Published online: 10 January 2009
#Springer-Verlag 2008
Abstract
Aim The present study aims to evaluate and compare the
efficacy of two nitrate gels, containing isosorbide-5-
mononitrate (ISMN) or glyceryl trinitrate (GTN), in the
therapy of chronic anal fissure.
Materials and methods The patients were randomly
assigned to three groups: 0.1% ISMN gel (21 patients),
0.1% GTN gel (21 patients) and a placebo group (ten
patients). The ethic committee of our hospital approved the
protocol and informed consent was obtained from all
participants. All patients underwent clinical examination,
visual inspection of the fissure and anal manometry prior to
and after therapy.
Results The chronic anal fissure was completely healed in
71% of the patients treated with ISMN, 67% with GTN and
in 30% from the placebo group. One patient in the ISMN
group reported mild headache. Three patients in the GTN
group had anal burning.
Conclusion Both topical nitrate treatments (ISMN and GTN)
were effective for chronic anal fissures. The reduction of the
anal pressure was slightly higher after ISMN treatment (28%)
than the treatment with GTN (23%). However, the statistical
difference was not significant (p>0.05).
Keywords Chronic anal fissure .Isosorbide mononitrate .
Glyceryl trinitrate .Topical gels
Introduction
Anal fissure appears to be a serious troubling condition
with severe pain, starting at the defecation and lasting up to
several hours afterward. The diagnosis is usually based on
typical clinical history confirmed by a visual inspection and
anoscopy. Anal fissures are most frequently idiopathic and
are generally located in the posterior midline of the anal
canal. Medical therapy is aimed at breaking the cycle of
sphincter spasm and at promoting the subsequent healing of
the fissure. If pharmacological treatment fails, surgical
management by means of internal lateral sphincterotomy to
reduce anal pressure can be performed. However, the main
disadvantage of the surgical sphincterotomy is the high
incidence of postoperative complications.
Various therapeutic alternatives (nitrates, botulinum
toxin, calcium channel blockers, cholinomimetics) have
been proposed to achieve reversible chemical anal sphinc-
terotomy [1]. Anal sphincter injection of botulinum toxin
leads to a satisfactory healing rate of up to 80% at the cost
of undesirable effects like perianal thrombosis [2]. Nitric
oxide is the most important inhibitory neurotransmitter in
the internal anal sphincter. Numbers of studies have
demonstrated that the topical ointment formulations con-
taining glyceryl trinitrate have provided sphincter relaxation
Int J Colorectal Dis (2009) 24:461–464
DOI 10.1007/s00384-008-0632-8
L. Tankova
Clinical Centre of Gastroenterology,
State University Hospital “Queen Joanna”,
8 Bialo more Str.,
1527 Sofia, Bulgaria
K. Yoncheva (*)
Department of Pharmaceutical Technology,
Faculty of Pharmacy, 2 Dunav Str.,
1000 Sofia, Bulgaria
e-mail: krassi.yoncheva@gmail.com
D. Kovatchki
Medical University of Vienna,
Vienna, Austria
I. Doytchinova
Department of Chemistry, Faculty of Pharmacy,
2 Dunav Str.,
1000 Sofia, Bulgaria
[3–9]. In a preliminary study, the potential of alternative
topical treatment using isosorbide mononitrate was inves-
tigated [10]. It was reported that mononitrate application
could facilitate the healing of chronic fissure without
serious side effects. However, the questions about its
appropriate dosage remained unanswered. The efficacy of
various topical nitrates for anal fissure treatment has not
been directly compared. The purpose of the study was to
perform placebo-controlled study for efficacy assessment of
two nitrate gels, containing isosorbide-5-mononitrate
(ISMN) or glyceryl trinitrate (GTN), in the therapy of
chronic anal fissure.
Materials and methods
Fifty two patients [30 women, 22 men; mean age (SD),
49±16.3 years; range, 17–77 years] with symptomatic
anal fissure lasting more than 6 weeks were enrolled in
the study. Anal fissures associated with other conditions
(Crohn’s disease, human immunodeficiency virus infec-
tion, fistula in ano, anal abscess and anal cancer) or
previous surgical procedures in the anal canal were
excluded. Pregnant women and patients using nitrate
derivatives were also ineligible for the study. The ethic
committee of our hospital approved the protocol and
informed consent was obtained from all participants.
Patients were randomly assigned toone of the three groups:
with ISMN therapy (21 patients), with GTN therapy (21
patients) and placebo (ten patients; Table 1). The therapy was
carried out by application of rectal hydrogels containing
0.1% of nitrates or placebo gel. The gels were prepared using
the non-toxic and biocompatible gelling polymer Carbopol
940 (Goodrich, Brecksville, USA). The hydrogels were
placed in small numerically labelled boxes and looked the
same. The patients were instructed to apply a bean size
volume of the hydrogel by passing the fingertip within the
anal canal twice daily for 6 weeks. This amount represents
approximately1gofthegel,which,fordrug-loadedgels,
corresponds to 1 mg of the active agent.
Patients underwent clinical examination, visual inspec-
tion of the fissure and anal manometry prior to and after the
treatment course. Anal tonic activity was assessed by an
ordinary manometric gauge for arterial pressure. The
evaluation was based on the flow of air in an open circuit
using a rubber probe with an opening at one end. By this
simple method, resting anal pressure was measured when
the patient was asked to relax anal sphincter. Squeeze
pressure was assessed when the patient was straining.
Manometric values were compared to the normal range for
our laboratory [10].
Anal pain was assessed before starting treatment and at
the end of the therapy (6 weeks from the therapy start). The
method of pain scaling is the verbal rating scale with four
categories—no pain, mild pain, moderate and severe pain.
Patients were asked to select the category that best
describes their anal pain. A questionnaire was used to
determine the patient compliance with the therapy, paying
special attention to headache, arterial blood pressure and
faecal incontinence. The primary end point was complete
healing of anal fissure, defined as presence of a scar at
6 weeks of treatment. The second outcome was a
persistence of fissure but with pain relief. Fissure healing
was assessed by an observer blinded to the allocation of
active compounds and placebo. Patients were followed up
for at least 3 months (3 to 6 months).
Data analysis add-on of MS Office Excel 2003 (Micro-
soft Corporation, USA) was used for statistical analysis.
Paired ttest was used to compare the mean resting anal
pressure (RAP) before and after treatment in the three
groups. Value of P< 0.05 was considered significant.
Results
The patients in both nitrate groups reported marked relief of
the anal pain following topical application of the gels
lasting from 2 to 4 h. The fissure-related pain was resolved
in all of these patients at 6 weeks. Four patients in the
placebo group (40%) also reported pain reduction (mild
pain according to the scale).
The chronic anal fissure was completely healed in 15 of
21 patients (71%) of the ISMN group, in 14 of 21 patients
(67%) in the GTN group and only in three of ten patients
(30%) in the placebo group (Fig. 1). There were differences
in the clinical outcome between the two treatment groups,
but they could not underscore the significance level of 0.05.
As compared with baseline values, the resting anal pressure
was significantly reduced by 28% in the ISMN group and
by 23% in the GTN treated patients (Table 2). No
significant difference was found in the mean resting anal
pressure before and after placebo therapy (p= 0.12).
One patient in the ISMN group reported a mild transient
headache. None of the GTN-treated patients suffered
headache, though three of them had anal burning. Side
effects were not reported by patients in the placebo group.
Faecal incontinence was not observed. None of the patients
developed recurrent symptoms at short follow-up.
Table 1 Characteristics of the three patient groups
Patients ISMN
(n=21)
GTN
(n=21)
Placebo
(n=10)
Mean age (SD, years) 50 (17.1) 48 (15.5) 46 (10.8)
Sex (men/women) 7/14 11/10 4/6
462 Int J Colorectal Dis (2009) 24:461–464
Discussion
Topical treatment with nitric oxide donors is aimed at
reducing the resting anal pressure by decreasing the anal
sphincter tone and by improving the blood supply at the site
of the fissure. Clinical studies have shown that 60–83% of
the chronic anal fissures can be healed by a GTN treatment
course [3–9]. On the other hand, a multicentre randomised
controlled trial failed to demonstrate any superiority of
topical 0.2% GTN treatment versus placebo [11]. The
questions regarding its appropriate therapeutic dosage, one
that causes minimal side effects and brings long term
benefit, have remained unanswered [1,12].
To our knowledge, there are no studies concerning
isosorbide mononitrate as an alternative nitrate agent in the
therapy of anal fissures. Because ISMN is hard to metabolise
by the hepatic cells, its therapeutic plasma level can be
sustained for a longer period without development of drug
tolerance [13]. A preliminary study with isosorbide mono-
nitrate has demonstrated successful healing of chronic anal
fissures and good patient compliance [10]. At the end of the
therapy, the fissures were healed in 80% of the patients
compared with 22% of the patients in the placebo group. The
current study provides further evidence for this approach.
Two nonsurgical therapies with ISMN or with GTN were
examined and compared. Low concentration of both
pharmacological compounds (0.1%) was investigated tak-
ing into account that higher concentrations of glyceryl
trinitrate did not significantly improve the therapy [4]. It
should not be underestimated that the more the GTN, the
higher the risk to provoke drug adverse effects. Both
nitrates were administered in the form of rectal hydrogels,
which may provide gradual drug delivery and longer
residence at the treated area. Jonas et al. [14]have
demonstrated that 0.2% GTN ointment significantly lowers
anal resting pressure but only for 90 min.
Pain relief lasting up to 4 h was reported from patients in
both nitrate groups following the local treatment. The long-
lasting relief was probably a consequence of the gradual
reduction of anal pressure. The values of the resting anal
pressure significantly decreased in the patients in both
treated groups compared to the values in the placebo group
(Table 2). However, the reduction of the anal pressure was
more pronounced in the ISMN group (28%) than in the
GTN group (23%). Probably due to technical reasons, the
manometric values in our laboratory are generally lower
compared to all reported data.
The healing rate of the 0.1% ISMN therapy reached 71% at
6 weeks and it was slightly lower than the rate of the 0.2%
ISMN therapy (80%) [10]. The healing rate achieved with
0.1% GTN therapy was 67%, which is in accordance with
the previously reported rate following the same dosage [15].
During the therapy, only one patient treated with ISMN
experienced a transit headache, which responded to para-
cetamol (Table 2). Surprisingly, headache was not observed
in any patients of GTN group in this study. These results
probably were due to the gradual drug delivery from the gels.
Transient mild anal burning after application of the gel
appeared in three patients (14%) of the GTN group during
therapy. Anal burning has been previously reported as a result
of treatment with 0.2% GTN ointment [3,5]. This side effect
seems to appear often with GTN regardless of its low dosage.
High recurrent rates of 33% to 67% for chronic anal
fissures are reported at 9 months after initial fissure healing
[5,6]. However, there are reports without relapses during
the mean follow-up period of 16 to 22 months [4,9]. None
of the patients in our series developed recurrent symptoms
during follow-up. The low relapse rate in our series is likely
to be due to the short follow-up period (3 to 6 months).
Conclusion
In this study, both mono- and trinitrate treatments (ISMN and
GTN, respectively) were effective for chronic fissures therapy.
Table 2 Values of RAP before and after the therapy with 0.1% ISMN
gel, 0.1% GTN gel and placebo gel
Parameters ISMN GTN Placebo
Mean baseline RAP
(SD, mmHg)
38.5 (6.9) 37.4 (6.7) 35.9 (3.9)
Mean RAP after therapy
(SD, mmHg)
27.7 (8.6)* 28.8 (6.0)* 33.8 (6.3)*
95% Confidence interval
of the difference
−12,89; −8.64 −12,86; −4,28 −0,71; 4,91
Mean RAP decrease (%) 28% 23% 6%
Side effects: headache 1 ––
Side effects: local
burning
–3–
*p<0.000001 for ISMN; p<0.001 for GTN; p=0,12 for placebo
0
15
30
45
60
75
90
Clinical values (%)
Fissure healing
RAP decrease
ISMN GTN Placebo
Fig. 1 Clinical outcome of the treatment with 0.1% ISMN gel, 0.1%
GTN gel and placebo gel (p<0.05)
Int J Colorectal Dis (2009) 24:461–464 463
However, the reduction of anal pressure was higher after
treatment with ISMN than after GTN therapy. In addition, the
relatively low occurrence of adverse effects may be marked as
advantage of the mononitrate topical therapy. Future inves-
tigations with long-term follow-up and a standard assay for
this topical nitrate preparation are needed for the precise
assessment of its therapeutic efficacy.
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