Oral lacidipine in the treatment of anal fissure

Abstract

The aim of this prospective study was to assess the effectiveness in healing anal fissure (AF) of lacidipine, a calcium channel blocker with a better tolerability in comparison to other calcium antagonists. Twenty-one consecutive patients (16 women, 76.2%) with AF (16 chronic, situated posteriorly in 17 patients (81.0%), anteriorly in 4) with a mean age of 37.1 years (SD, 13.6, range, 20-6) were treated with oral lacidipine (6 mg daily) and warm sitz baths for 28 days, adding only stool softeners for patients with constipation. Blood pressure, pain scores (assessed from 0 to 10 on a visual analogue scale) and fissure healing were monitored at 14 days, 28 days and 2 months. At the 14-day and 28-day follow-ups, the mean systolic and diastolic pressures were not significantly different from pre-treatment levels. Seven patients (33.3%) developed side effects, but only one, who developed dyplopia, withdrew from the study at the 14-day control (non-compliance rate with treatment, 4.8%). Pain scores were significantly reduced after 14 days and continued to show a significant reduction throughout the treatment period. Three fissures (14.3%) healed by 14 days and a total of 19 (90.4%) after 28 days: among the healed AF no recurrences were seen at the 2-month control. Among the two treatment failures, one was the patient who withdrew from the study at the 14-day control due to dyplopia and the other was a patient who failed to heal up to the 2-month follow-up, although completely asymptomatic. Both patients underwent left lateral sphincterotomy and healed. In conclusion, oral lacedipine is quite well tolerated and may offer a promising alternative treatment for AF.

Full text

L. Ansaloni ()
Department of Emergency Surgery
S. Orsola-Malpighi Hospital
Via Massarenti 9
I-40138 Bologna, Italy
e-mail: so10790@iperbole.bologna.it
A. Bernabè •R. Ghetti •G. Gardini
Department of General Surgery
Lugo Hospital
Ravenna, Italy
R. Riccardi •R.M. Tranchino
Department of General Surgery
Faenza Hospital
Ravenna, Italy
the treatment period. Three fissures (14.3%) healed by 14
days and a total of 19 (90.4%) after 28 days: among the
healed AF no recurrences were seen at the 2-month control.
Among the two treatment failures, one was the patient who
withdrew from the study at the 14-day control due to dyplop-
ia and the other was a patient who failed to heal up to the 2-
month follow-up, although completely asymptomatic. Both
patients underwent left lateral sphincterotomy and healed. In
conclusion, oral lacedipine is quite well tolerated and may
offer a promising alternative treatment for AF.
Key words Fissure in ano •Calcium channel blockers
Introduction
Anal fissures (AF) are thought to arise as a consequence of
hypertonia of the internal anal sphincter (IAS), which
impedes blood flow to the anal mucosa [1]. It is well demon-
strated that in about 70%–80% of cases, AF are localised to
the posterior anal commissure [2, 3] where the anoderm is
less well perfused than other segments of the anal canal [4,
5] and its perfusion is strongly related to the anal pressure
[6]. AF are therefore considered to be ischaemic ulcers of the
anal canal, due to the increased activity of the IAS; therefore
the reduction of IAS tone is the most important step in the
treatment of AF [7, 8].
As calcium ions play an important role in muscle con-
traction, calcium channel blockers, such as nifedipine and
diltiazem, that inhibit smooth muscle excitation produced an
abolition of resting tone in IAS smooth muscle in vitro [9,
10] and reduced resting anal pressure. Thus calcium channel
blockers can heal AF, although with a high rate of side effects
[11–15]. The aim of this study was to assess the effectiveness
of lacidipine, a calcium channel blocker with a better tolera-
bility in comparison to nifedipine and other calcium antago-
nists [16, 17], in healing AF.
Tech Coloproctol (2002) 6:79–82 © Springer-Verlag 2002
L. Ansaloni •A. Bernabè •R. Ghetti •R. Riccardi •R.M. Tranchino •G. Gardini
Oral lacidipine in the treatment of anal fissure
Received: 8 January 2002 / Accepted: 20 May 2002
ORIGINAL ARTICLE
Abstract The aim of this prospective study was to assess the
effectiveness in healing anal fissure (AF) of lacidipine, a
calcium channel blocker with a better tolerability in com-
parison to other calcium antagonists. Twenty-one consecu-
tive patients (16 women, 76.2%) with AF (16 chronic, situ-
ated posteriorly in 17 patients (81.0%), anteriorly in 4) with
a mean age of 37.1 years (SD, 13.6, range, 20–65) were
treated with oral lacidipine (6 mg daily) and warm sitz baths
for 28 days, adding only stool softeners for patients with
constipation. Blood pressure, pain scores (assessed from 0
to 10 on a visual analogue scale) and fissure healing were
monitored at 14 days, 28 days and 2 months. At the 14-day
and 28-day follow-ups, the mean systolic and diastolic pres-
sures were not significantly different from pre-treatment
levels. Seven patients (33.3%) developed side effects, but
only one, who developed dyplopia, withdrew from the study
at the 14-day control (non-compliance rate with treatment,
4.8%). Pain scores were significantly reduced after 14 days
and continued to show a significant reduction throughout

Patients and methods
Outpatients with AF seen in Lugo and Faenza Hospitals, Ravenna,
Italy, under the care of two colorectal units between September
2000 and May 2001 were studied prospectively. Patients with
Crohn’s disease were excluded. AF was considered to be present if
the patient presented with a history of anal pain on defecation and
the examination typically revealed a fissure. The AF was defined
chronic, when pain lasted for more than 2 months and the fissure
showed features of chronicity, such as exposure of the internal anal
sphincter, induration of the fissure edges, development of a large
sentinel pile and hypertrophied anal papilla.
A total of 21 consecutive patients (16 women, 76.2%) with AF
(16 chronic) with a mean age of 37.1 years (SD, 13.6; range, 20–65)
were treated with oral lacidipine (6 mg daily) and warm sitz baths
[18] for 28 days. Stool softeners were given to patients with consti-
pation. Although patients were not prescribed topical analgesic
creams for the duration of treatment, a high-fiber diet was encour-
aged. AF was situated posteriorly in 17 patients (81.0%), anteriorly
in 4. For 20 patients (95.2%) it was the first episode of AF (for the
remaining one, the second recurrence) and 9 patients (42.9%) had
already used other conservative treatments (topical anaesthetic
creams and stool softeners) without improvement. In 5 patients
(23.8%), haemorrhoids were present. Blood pressure, pain scores
(assessed from 0 to 10 on a visual analogue scale (VAS) ranging
from “no pain” to “worst pain imaginable”) and fissure healing
were monitored at 14 days, 28 days and 2 months. Healing was
defined by resolution of symptoms (anal pain and bleeding) and the
absence of a fissure on examination.
The statistical analysis was carried out using Epi Info, Version
6.02 software package (CDC, Atlanta, Georgia, USA, 1994). The
Kruskal-Wallis H test was used to compare mean pre- and post-
treatment values.
Results
At the 14-day and 28-day follow-up, the mean systolic and
diastolic blood pressures were not significantly different
from pretreatment levels (Table 1). Seven patients (33.3%)
developed side effects (headache in 2 patients, palpitations in
2, flushing, dizziness, colic abdominal pain, ankle oedema
and dyplopia in one each). Only the patient who developed
dyplopia withdrew from the study at the 14-day control
(non-compliance rate with treatment 4.8%).
Pain scores were significantly reduced after 14 days and
continued to show a significant reduction throughout the
80
treatment period (Table 2). Three fissures (14.3%) healed by
14 days and a total of 19 (90.4%) after 28 days: among the
AF healed no recurrences were seen at the 2-month control.
There were two treatment failures: the first patient withdrew
from the study at the 14-day control due to a side effect of
the drug treatment (dyplopia) and the other was a patient in
whom the fissure failed to heal up at the 2-month follow-up.
In the first case the VAS was 8 before the treatment and 1 at
the 14-day control; in the second the VAS was 0 at the 2-
month follow-up. Both patients underwent surgical left later-
al sphincterotomy, because the fissure was still present, and
both of them healed completely.
Discussion
As both clinical and manometric findings indicate an associ-
ation of AF with sustained hypertone of IAS [19], the treat-
ment is aimed at decreasing high sphincter pressure. Surgery
has been the traditional and accepted treatment [20, 21], but
all the operative techniques commonly used for AF, including
anal stretch, posterior and lateral sphincterotomies, show
obvious disadvantages, such as hospitalization and anesthetic
and surgery risks, and may result in an irreparable damage to
IAS. Therefore in the long-term outcome of all surgical pro-
cedures, a variable but consistent percentage of patients expe-
riences some form of incontinence [22–27]. This significant
complication and the improved knowledge of the neurophys-
iology of the IAS [28, 29] has led to a search for alternative
treatments for AF. Attempts have been made at reversible
reduction of anal pressure and some of them are effective,
like insertion of anal dilators [30], local injection of botu-
linum toxin [31], and “chemical sphincterotomy” with a phar-
macologic approach [32]. In the latter attempt two categories
of drugs have been used on clinical grounds to reduce the IAS
tone: nitric oxide donors and calcium antagonists [29]. Local
application of exogenous nitric oxide donors, such as isosor-
bide dinitrate [33] and glyceryl trinitrate [34], has been
shown to be effective in the management of anal fissure, but
with an high incidence of side effects, especially headache
[35]. Some patients experience tachyphylaxis, whereby
increasing concentration of paste are required to maintain an
effect [36].
L. Ansaloni et al.: Oral lacidipine and anal fissure
Table 1 Mean systolic and diastolic blood pressures at the 14-day
and 28-day follow-ups. Values are mean (SD)
Systolic pressure Diastolic pressure
Before treatment 121.9 (8.7) 77.1 (10.5)
14-day follow-up 120.5 (8.0) 71.9 (9.3)
28-day follow-up 118.5 (3.4) 71.5 (8.7)
Table 2 Pain scores at the 14-day, 28-day and 2-month follow-ups.
Values are mean (SD)
Pain score
Before treatment 6.8 (1.6)
14 days 0.8 (1.0)*
28 days 0 (0)
2 months 0 (0)
*p<0.000001 vs. pretreatment values (Kruskal-Wallis H test)

Concerning calcium antagonists, in 1987 it was showed
that anal resting pressure decreased shortly after oral admin-
istration of 60 mg diltiazem; based on this finding, treatment
with this calcium channel blocker was advocated in patients
with proctalgia fugax [37]. More recently, two calcium chan-
nel blockers, nifedipine and diltiazem, have been used topi-
cally with a good rate of AF healing [12–15, 38]. In topical
treatments, there may be confusion as to whether paste
should be applied around the anal margin or within the anal
canal, and the volume of paste that should be applied is also
unclear. As an oral preparation could overcome some of the
potential confusion with site of application and dose, Cook
and colleagues showed that oral administration of 20 mg
nifedipine twice daily reduced resting anal pressure and
healed AF [11], although with a high side effect rate [39].
Unlike most of the other calcium antagonists, including
nifedipine, that have a relatively short duration of action and
need to be administered 2–3 times daily, lacidipine is a cal-
cium antagonist with a long duration of action, allowing a
once-daily administration [40]. Moreover lacidipine is better
tolerated in comparison to nifedipine and other calcium
antagonists [16, 17]. Our study has demonstrated that
lacidipine, given orally in single daily dosage of 6 mg, with
a healing rate of 90% at the 28-day follow-up, may be used
successfully to treat AF. The significant reduction in pain
scores within the first two weeks of treatment (which con-
tinued throughout the period of study) and the alleviation of
symptoms in the only patient in whom the AF failed to heal
provide further support for a role for lacidipine in the treat-
ment of AF. Follow-up measurements of systolic and dias-
tolic blood pressure were not significantly different from
pretreatment levels and only 33% of patients experienced
side effects. We conclude that, although further prospective
randomized controlled trials with long-term follow-ups are
needed, oral lacidipine is quite well tolerated and offers a
promising alternative treatment for AF.
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Invited comment
This is one of several papers dealing with medical treat-
ment of anal fissure by “chemically induced sphincteroto-
my” that have appeared in surgical journals in the last 3–4
years. A new selective calcium channel blockers has been
tested after oral instead of topical administration. The
paper, however, belongs to the lowest category of quality of
scientific evidence as listed by the British Medical Council
as there are no controls and the treatment was not ran-
domised to minimize any bias in the study. To demonstrate
a cause-effect of lacipidine on anal tone and then on the fis-
sure healing, anal manometric data cannot be set aside like
in this paper. On the other hand, the authors could not doc-
ument any effect of this drug on blood pressure using the
dosages reported. One could argue that even the anal rest-
ing tone did not change in these patients. In that case why
should the fissures heal? Finally the follow-up period,
which is the true Achille’s heel of these papers, is indeed
very short and insufficient to exclude any recurrence of the
fissure. The Authors are encouraged to continue this inter-
esting and thought provoking study in a larger series with
longer follow-up.
D.F. Altomare
University of Bari,
Bari, Italy
L. Ansaloni et al.: Oral lacidipine and anal fissure