1. Comparison of captopril (0.5%) cream with diltiazem (2%)
cream for chronic anal fissure: a prospective randomized
double-blind two-centre clinical trial
S. Ala*, R. Enayatifard†, M. Alvandipour‡ and R. Qobadighadikolaei*
*Department of Clinical Pharmacy, Faculty of Pharmacy,Mazandaran University of Medical Sciences, Sari, Mazandaran, Iran, †Department of
Pharmaceutical Sciences, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Mazandaran, Iran and ‡Department of Surgery, Imam
Khomeini General Hospital affiliated to Mazandaran University of Medical Sciences, Sari, Mazandaran, Iran
Received 18 May 2015; accepted 17 July 2015; Accepted Article online 12 October 2015
Abstract
Aim This study compared the efficacy of topical capto-
pril with topical diltiazem in the treatment of chronic
anal fissure (CAF).
Method Fifty patients aged between 15 and 75 years
with CAF were included in a prospective randomized,
double-blind clinical trial. They were randomly allocated
to either captopril (0.5%) cream or diltiazem (2%) cream
in a dose of 2 cm of cream on the perianal skin every
12 h for 8 weeks. The intensity of pain upon defaeca-
tion was evaluated every 10 days using a visual analogue
scale. Bleeding on defaecation, pruritus and the pres-
ence of perianal irritation were also recorded before and
during the trial.
Results The average pain scores were lower in the dilti-
azem group on the 20th and 30th days. From day 40
to the end of the trial the average pain scores of the
two groups did not differ significantly. There were no
significant differences in bleeding or perianal irritation
between the groups, but the incidence of pruritus was
considerably higher in the captopril group, and at the
end of the trial 45.8% of the patients in this group still
suffered from pruritus.
Conclusion Topical captopril and diltiazem were found
to be equally effective in the management of pain,
bleeding and perianal irritation due to CAF, but due to
the high incidence of pruritus observed with topical
captopril this medication is not recommended for the
treatment of CAF.
Keywords Captopril, diltiazem, chronic anal fissure,
chemical sphincterotomy, pain upon defaecation
What does this paper add to the literature?
The present paper adds to the current body of informa-
tion on the potential indication of topical captopril for
chronic anal fissure. Our findings confirm the positive
results obtained by a previous pilot study, but also
demonstrate the adverse effect of pruritus which was
not shown by the pilot study.
Introduction
Anal fissure is a common perianal problem that causes
significant distress [1–3]. Its main symptom is pain on
defaecation, but pruritus, perianal irritation and prolapse
are also present in some patients [2–6]. Most acute anal
fissures heal spontaneously or with conservative treat-
ment [1–3], but a proportion become chronic. Chronic
anal fissure (CAF) is characterized by symptoms persist-
ing for more than 6–8 weeks, and some patients show
the presence of a sentinel tag at the external apex, a
hypertrophic anal papilla and visible fibres of the inter-
nal anal sphincter (IAS) in the base of the fissure [1–4].
CAF is usually treated medically and surgery is used
only if this is not successful owing to concern about
causing a disturbance of continence [4,7,8]. The use of
pharmacological agents has been likened by some to a
chemical sphincterotomy.
Agents used include glyceryl trinitrate (GTN),
isosorbide dinitrate, botulinum toxin, calcium-channel
blockers (CCBs) such as nifedipine and diltiazem, ligno-
caine and bethanecol [2–7]. In the present study we
have conducted a prospective randomized clinical trial
comparing the efficacy of captopril cream with that of
diltiazem cream in the treatment of CAF. The high
efficacy of topical diltiazem in drug-na€ıve patients
[9–15] and in patients unresponsive or noncompliant to
Correspondence to: Mina Alvandipour, Department of Surgery, Imam Khomeini
General Hospital, Amirmazandarani St, Sari, Mazandaran, Iran.
E-mail: minaalvh@yahoo.com
Colorectal Disease ª 2015 The Association of Coloproctology of Great Britain and Ireland. 18, 510–516510
Original article doi:10.1111/codi.13147

2. GTN [16–24] has been demonstrated in several studies.
For this reason it was used as the active control against
which the efficacy of captopril was determined. Capto-
pril is an angiotensin-converting enzyme (ACE) inhibi-
tor and has been found to decrease tone of the rat IAS
in vitro, possibly by inhibition of smooth muscle by
angiotensin II [25]. Following this observation, a
human pilot study on 10 healthy volunteers demon-
strated a considerable reduction in mean anal resting
pressure (MARP) in half of the subjects 20 min after
the application of captopril cream, with minimal side
effects [26]. To the best of our knowledge this is the
first randomized clinical trial to evaluate the effective-
ness of topical captopril for CAF.
Method
Preparation of the creams
Captopril and diltiazem creams were prepared by the
same method using water as a levigating agent. Both
preparations were prepared in identical tubes each con-
taining 50 g of product and labelled as Ala cream or
Alvand cream corresponding to captopril and diltiazem,
respectively. The concentration of captopril and dilti-
azem was quantified according to the United States
Pharmacopoeia (USP XXIX) as 0.5% and 2% [27]. The
physicochemical stability of the creams was evaluated at
50, 60, 70 and 80°C. Microbiological tests showed no
evidence of bacterial growth.
Patient selection
Consecutive patients newly diagnosed with CAF
referred to the Razi Educational Hospital and Tuba
Educational Polyclinics, both affiliated to Mazandaran
University of Medical Sciences, from March 2014 to
December 2014 were screened for the purpose of
enrolment in the study. Patients of both sexes aged
between 15 and 75 years were included. All were
diagnosed by the same surgeon based on the finding
on inspection of a typical midline CAF with the fea-
tures of chronicity described above. Subjects with a
history of previous anal surgery, the presence of addi-
tional anal or perianal disease including fistula-in-ano,
perianal abscess and haemorrhoids, a history of oral
diltiazem or captopril consumption, patients addicted
to opioids and pregnant women were excluded.
Trial design
After approval was obtained from the Ethical Commit-
tee at Mazandaran University of Medical Sciences
patients were randomized to receive diltiazem or capto-
pril and were followed prospectively. The trial was regis-
tered at the Iranian Registry of Clinical Trials (IRCT)
under the code IRCT 201308043014N7 (the full trial
protocol can be accessed at http://www.irct.ir/). The
study was performed according to the Declaration of
Helsinki, and written informed consent was obtained
from all patients before enrolment in the study. A sam-
ple size of 30 in each study arm was calculated to be
appropriate for a 90% power and 5% significance level
on the basis of a power analysis. The patients were ran-
domly allocated to either captopril cream or diltiazem
cream following a simple randomization procedure
using a computer-generated table of random numbers
(even numbers corresponded to code Ala cream and
odd numbers to code Alvand cream). The patients were
allocated to the intervention by an individual who was
not aware of the randomization code and was not
involved in the subsequent therapeutic procedure. The
patients and the investigators (healthcare providers, data
collectors and those assessing the outcomes) were
blinded to the allocation, and the randomization codes
were not available to either investigators or patients
until the end of the trial. The patients were required to
apply 2 cm of cream (equal to 3 g of the ointment,
which corresponds to 0.06 g of diltiazem and 0.015 g
of captopril) on the perianal skin, but not inside the
anus, every 12 h for 8 weeks. None of the patients
received opioid analgesics.
The primary outcomes were pain and bleeding on
defaecation. Pain intensity was evaluated using a visual
analogue scale (VAS), scored from 0 (no pain) to 10
(very severe pain). Bleeding was classified as grade I (no
haemorrhage on defaecation), grade II (occasional
haemorrhage on defaecation) and grade III (persistent
haemorrhage on defaecation). The pain intensity and
bleeding were assessed before commencement of the
trial and then every 10 days during the trial. In addi-
tion, the presence of pruritus and perianal irritation was
also recorded before and during the trial.
Statistical analysis
Data were analysed using SPSS software (version 12;
SPSS Inc., Chicago, Illinois, USA). The paired t-test,
and Wilcoxon’s signed rank test were used for compar-
ison between the two groups and a P-value of < 0.05
was considered significant.
Results
The flow diagram is shown in Fig. 1. Sixty-three
patients met the inclusion criteria and were randomized
Colorectal Disease ª 2015 The Association of Coloproctology of Great Britain and Ireland. 18, 510–516 511
S. Ala et al. Captopril and anal fissure

3. to receive diltiazem (29) and captopril (34). During the
trial five patients were were excluded owing to their
irregular use of the cream and eight were excluded due
to noncompliance owing to intolerable pruritus. This
left 26 (mean age 34.4 Æ 11.0 years; 19 female)
patients in the diltiazem and 24 (33.7 Æ 10.0; 17
female) in the captopril group (Table 1). There were no
statistical differences in mean age (P = 0.823), female/
male ratio (P = 0.861) or mean duration of symptoms
(P = 0.880) between the two groups.
The results are summarized in Tables 2–5. As can be
seen in Table 2, at the beginning of the trial there were
no significant differences in the average pain scores,
incidence of bleeding, pruritus or perianal irritation
between the two groups. Before day 20, there was no
significant difference in pain reduction between the
groups, but on days 20 and 30 posttreatment, consider-
ably lower pain scores were observed in the diltiazem
group. From day 40 to the end of the trial the average
pain scores of the two groups did not differ significantly
and by the end of the trial both groups had very mild
pain.
The incidence of bleeding did not differ considerably
between the two groups throughout the trial (Table 3).
At the end of the trial none of the patients in either
group suffered from any bleeding. Similarly perianal irri-
tation was reduced throughout the trial period with no
significant between-group differences at any time. At
the end of the trial all but three patients were relieved
of irritation (Table 4). For pruritus however, it can be
seen in Table 5, that from day 20 onwards, the inci-
dence of pruritus in the diltiazem group was markedly
lower than in the captopril group (0 vs 11/24, 45.8%).
The incidence of adverse drug reactions among the
patients treated with diltiazem was low, with two
having experienced mild headache, one vertigo and one
Enrolment
Diltiazem group
Allocated to intervention (n = 29)
Randomized (n = 63)
Allocation
Follow-Up
Analysed (n = 24)
Analysis
Analysed (n = 26)
Lost to follow-up (n = 0) Lost to follow-up (n = 0)
Discontinued intervention due to pruritus (n = 8)Discontinued intervention due to irregular use
of the medication (n = 3)
Discontinued intervention due to irregular use
of the medication (n = 2)
Allocated to intervention (n = 34)
Captopril group
Assessed for eligibility (n = 73)
Excluded (n = 10)
♦ Not meeting inclusion criteria (n = 7)
♦ Declined to participate (n = 3)
♦ Received allocated intervention (n = 34)♦ Received allocated intervention (n = 29)
Figure 1 Flow diagram of participants (prepared in accordance with the CONSORT guidelines, 2010).
Colorectal Disease ª 2015 The Association of Coloproctology of Great Britain and Ireland. 18, 510–516512
Captopril and anal fissure S. Ala et al.

4. constipation. In the captopril group no side effects
other than pruritus were observed.
Discussion
Surgical treatments such as manual anal dilatation, open
or closed lateral sphincterotomy and posterior midline
sphincterotomy have been used for the management of
anal fissure [5,6]. In the past two decades reversible
chemical sphincterotomy with pharmacological agents
has emerged as an alternative to avoid the risk of conti-
nence disturbance associated with sphincterotomy [4–
8]. Despite promising results following the application
of various pharmacological agents [2–7], adverse drug
reactions and recurrence of fissure, the search for more
acceptable pharmacological agents continues. In the
present study captopril was not found to be superior to
diltiazem.
Table 1 The demographic data of the patients in the two study arms.
Parameter Captopril group (n = 24) Diltiazem group (n = 26) P-value
Age (years) Mean Æ SD 10.03 Æ 33.75 34.42 Æ 11.02 0.823
Range 15–57 20–58
Female/male 17/7 19/7 0.861
Duration of symptoms (days) Mean Æ SD 74 Æ 44.10 72.12 Æ 43.22 0.880
Range 21–180 20–150
Table 2 Average pain scores in the two study groups at differ-
ent time points during the trial.
Time
(days)
Average pain score (mean Æ SD)
P-value
Captopril
group (n = 24)
Diltiazem
group
(n = 26)
0 5.9 Æ 2.3 5.9 Æ 1.7 0.988
10 3.7 Æ 1.3 3.5 Æ 1.9 0.532
20 2.5 Æ 1.7 1.6 Æ 1.4 0.033*
30 1.6 Æ 1.3 1.1 Æ 0.7 0.009*
40 1.5 Æ 1.1 1.4 Æ 0.5 0.155
50 1.3 Æ 0.7 1.2 Æ 0.3 0.270
60 1.2 Æ 0.6 1.4 Æ 0.3 0.327
*Statistically significant difference.
Table 3 Incidence of bleeding among the two study groups at
different time points throughout the trial.
Time (days)
Number of patients with bleeding
P-value
Captopril group
(n = 24)
Diltiazem group
(n = 26)
0 16 21 0.369
10 9 14 0.158
20 1 3 0.342
30 0 0 1.000
40 1 0 0.298
50 1 1 0.954
60 0 0 1.000
Table 4 Incidence of pruritus among the two study groups at
different time points throughout the trial.
Time (days)
Number of patients with pruritus
P-value
Captopril group
(n = 24)
Diltiazem group
(n = 26)
0 15 10 0.165
10 12 8 0.124
20 10 0 0.000*
30 11 0 0.000*
40 14 1 0.000*
50 9 2 0.003*
60 11 0 0.000*
*Statistically significant difference.
Table 5 The incidence of perianal irritation among the two
study groups at different time points throughout the trial.
Time (days)
Number of patients with perianal
irritation
P-value
Captopril group
(n = 24)
Diltiazem group
(n = 26)
0 15 18 0.716
10 5 8 0.878
20 1 1 0.954
30 0 2 0.170
40 1 3 0.342
50 0 3 0.089
60 1 2 0.524
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S. Ala et al. Captopril and anal fissure

5. A recent Cochrane Review by Nelson et al. [6] has
combined the results from 75 randomized controlled
trials (RCT) concerning the efficacy of different phar-
macological agents including GTN, isosorbide, botuli-
num toxin, diltiazem, nifedipine, hydrocortisone,
lignocaine, bran, indoramin, minoxidil, clove oil, L-argi-
nine, sildenafil and healer cream and surgical sphinc-
terotomy in a total of 5031 patients with CAF.
Lignocaine, bran and hydrocortisone were no better
than placebo. GTN was the most frequently studied
agent and was found to be significantly more effective
than placebo in curing the fissure in the combined anal-
ysis and in all sensitivity analyses, but despite the higher
overall healing rate for GTN (48.9%) compared with
placebo (35.5%) the advantage was marginal. Further-
more, two case series with a long follow-up reported
high recurrence rates for GTN, and when compared
with sphincterotomy GTN was found to be less effec-
tive. Injection of botulinum toxin into the internal
sphincter did not show any statistical advantages over
placebo or surgery in combined analyses, and was asso-
ciated with a higher recurrence rate compared with sur-
gical therapy. Calcium channel blockers were found to
be considerably more effective than lignocaine and
hydrocortisone, but less effective than surgical sphinc-
terotomy. There were no studies with long follow-up to
determine the recurrence rates associated with calcium
channel blockers. Indoramin, minoxidil and L-arginine
were also tested in small RCTs but none were effective
in healing fissure, whereas promising results for clove
oil, sildenifil and healer cream suggest that further stud-
ies of these agents should be performed [6].
More recently, ACE inhibitors have been suggested
as a potential agent for chemical sphincterotomy based
on findings that suggest a key role for the renin–an-
giotensin system in the regulation of myogenic tone in
the IAS [28–30]. Subsequently, De Godoy et al. evalu-
ated the effects of the ACE inhibitor captopril and the
angiotensin II receptor subtype 1 antagonist losartan
on IAS pressure in spontaneously hypertensive rats.
They observed a concentration-dependent contraction
of IAS smooth muscle caused by angiotensin II, and a
higher resting anal pressure in hypertensive rats com-
pared with normotensive animals, which was decreased
and normalized by captopril and losartan [25]. The first
human pilot study evaluating the effects of captopril on
the MRAP was carried out by Khaikin et al. on 10
healthy volunteers. They observed a decrease in MRAP
shortly after topical application of 0.28% captopril
cream in 50% of the subjects, although the changes
from the baseline values were not statistically significant
[26]. These findings suggested a potential indication
for ACE inhibitors and angiotensin II receptor antago-
nists in the treatment of CAF. Diltiazem, has demon-
strated high efficacy in pain reduction and alleviation of
the symptoms of CAF in several studies [9–24] and was
selected as the control treatment in the study. Bleeding
resolved in both groups and only three patients contin-
ued to have anal irritation, but pruritus was far higher
in the captopril group than the diltiazem group
throughout the trial, resulting in discontinuation of its
application by eight patients and at the end of the trial
nearly half of the patients still had some degree of
pruritus. Thus in clinical practice diltiazem was more
effective.
Pruritus with captopril is thought to be due to the
presence of a sulfhydryl (SH) group in the structure of
captopril which is capable of inducing a skin reaction
[31]. Although the frequency of skin reaction with oral
captopril is low [31], the results of the present study
indicate a high rate of pruritus when captopril is used
topically.
The results of the present study could not be directly
compared with those reported in the review by Nelson
et al., nevertheless comparing our results with other
RCTs that have assessed pain reduction after treatment
with topical diltiazem, a number of studies [10,14–
16,20] have reported values approximately equal to the
pain reduction we observed in the diltiazem group,
although other studies reported higher [22,24] or lower
values [17,18]. Since the observed fall in the pain levels
after treatment with captopril was close to the value
observed for diltiazem the same comparison applies to
captopril. The same inconsistency exists in the literature
on pain reduction by GTN, showing superiority of cap-
topril to GTN in some studies [20,22,32–34], and vice
versa in others [18,22,24]. These inconsistencies, which
may in part be due to differences in the study design
and the topical agents, make it difficult to draw a defi-
nite conclusion. Overall, the results of the present study
demonstrate that captopril is equally as effective as dilti-
azem in the management of pain, bleeding and perianal
irritation caused by CAF, but the high incidence of pru-
ritus is a major drawback of this medication and under-
mines our initial hypothesis that topical captopril could
be a suitable treatment for CAF.
One main limitation of the present study is the small
number of patients included in the final analysis.
Although initially we enrolled adequate number of
patients according to the power calculation, the number
who completed the trial was smaller than expected. This
may cast some doubt on the results, but the fact that a
large number of patients in the captopril group were
noncompliant mainly owing to pruritus further confirms
the conclusion that topical captopril is not a good treat-
ment for CAF.
Colorectal Disease ª 2015 The Association of Coloproctology of Great Britain and Ireland. 18, 510–516514
Captopril and anal fissure S. Ala et al.

6. Acknowledgements
This study was funded by a grant from the Vice Chan-
cellor for Research at Mazandaran University of Medical
Sciences and registered as the doctoral thesis of Roja
Qobadighadikolaei. The authors would like to acknowl-
edge the staff of Dr Ala pharmacy for their help in allo-
cation of the patients to the interventions and Dr Roja
Hadianamrei for writing assistance.
Conflicts of interest
None to declare.
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