10.1111_codi.13147 (1)

Comparison of captopril (0.5%) cream with diltiazem (2%)cream for chronic anal fissure: a prospective randomizeddouble-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 forchronic anal fissure. Our findings confirm the positiveresults obtained by a previous pilot study, but alsodemonstrate the adverse effect of pruritus which wasnot 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: [email protected]

Colorectal Disease ª 2015 The Association of Coloproctology of Great Britain and Ireland. 18, 510–516510

Original article doi:10.1111/codi.13147

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

http://www.irct.ir/

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 � 11.0 years; 19 female)

patients in the diltiazem and 24 (33.7 � 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 useof the medication (n = 3)

Discontinued intervention due to irregular useof 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).


Captopril and anal fissure S. Ala et al.

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 � SD 10.03 � 33.75 34.42 � 11.02 0.823

Range 15–57 20–58

Female/male 17/7 19/7 0.861

Duration of symptoms (days) Mean � SD 74 � 44.10 72.12 � 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 � SD)

P-value

Captopril

group (n = 24)

Diltiazem

group

(n = 26)

0 5.9 � 2.3 5.9 � 1.7 0.988

10 3.7 � 1.3 3.5 � 1.9 0.532

20 2.5 � 1.7 1.6 � 1.4 0.033*

30 1.6 � 1.3 1.1 � 0.7 0.009*

40 1.5 � 1.1 1.4 � 0.5 0.155

50 1.3 � 0.7 1.2 � 0.3 0.270

60 1.2 � 0.6 1.4 � 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



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.



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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10.1111_codi.13147 (1)