American Journal of Gastroenterology ISSN 0002-9270

C
2007 by Am. Coll. of Gastroenterology doi: 10.1111/j.1572-0241.2007.01203.x
Published by Blackwell Publishing
Nonsurgical Approaches for the Treatment of Anal Fissures
CME
Sanju Dhawan, Ph.D. and Sunny Chopra, M. Pharm.
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
Chronic anal ssure (CAF) is usually associated with internal anal sphincter spasm, the relief of which is central to
provide ssure healing. The treatment for CAF has undergone a transformation in recent years from surgical to
medical. Both the approaches share the common goal of reducing the spasm. Though surgical treatment has a
high success rate, it can permanently impair fecal continence in a large number of patients. Smooth muscle
relaxation seems to be a novel way by which more than 60% of the patients can be cured with the topical use of
the agents. This treatment is in addition to the normalization of stools mostly. Smooth muscle relaxation is well
tolerated, can be administered on an outpatient basis, does not cause any lesion of the continence organ, and
subsequently, does not lead to any permanent latent or apparent fecal incontinence. This review encompasses
various agents that are used for smooth muscle relaxation. In addition, it describes various clinical studies
reported in the literature with their success rates and side effects.
(Am J Gastroenterol 2007;102:13121321)
INTRODUCTION
According to Antropoli et al., various pathologies of anal
canal are extremely common (1, 2). About 3040% of the
population suffers from proctologic pathologies at least once
in their lives. Anal ssure (AF) is present in about 1015%
of proctological patients (3). AF can be dened as a tear or
split in the distal anal canal, which if not treated appropri-
ately at an early stage causes considerable anal pain during
defecations (4, 5). It is associated with spasm of the internal
anal sphincter and a reduction in mucosal blood owwith de-
layed or nonhealing of the ulcer (6, 7). The primary cause of
chronic anal ssure (CAF) is increased resting anal pressure
(RAP). Other most frequent causes are infection, essentially
sexually transmitted diseases, and tumor, mainly anal epider-
moid cancer. Most AFs heal spontaneously with conservative
treatment, viz., stool softener and diet modication. Such AFs
are termed as acute but a proportion of them persists for a
longer period and is known as chronic. Chronicity is dened
by both chronology and morphology. Most surgeons consider
the persistence for 6 wk as a reasonable point when an AF, un-
likely to heal with conservative treatment, may be considered
chronic. Morphologically, the presence of visible transverse
internal anal sphincters bers at the base of a ssure typi-
es chronicity. Associated features include indurated edges,
a sentinel pile, and a hypertropical anal papilla. An acute s-
sure looks like a fresh tear in the skin, while in a CAF the
walls of the tear become thickened.
TREATMENT OF AF
The treatment for AF is based on reducing the spasm of the
internal anal sphincter, either by dilating the anal canal or
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sphincterotomy. It is postulated that spasm impedes mucosal
bloodowandimpairs healing. High-ber diet andincreasing
the volume of daily drinks are useful and very efcient in
treating AF (8). Analysis of the available literature shows
that by far, medical manipulation of the internal sphincter
should be the rst-line treatment in AF. A surgical therapy is
called for if the medical therapy fails or there is a recurrence
(9).
LATERAL INTERNAL SPHINCTEROTOMY (LIS)/SURGERY
LIS is a surgical technique to cure AF. It has been favored
by most of the surgeons, because it offers long-lasting relief
in sphincter spasm (10, 11). The most preferred options are
the manual dilatation with radiosurgery and subcutaneous
LIS. Both methods are easy to perform and no special setup
is needed (12, 13). Traditionally, LIS is considered as the
gold standard treatment for chronic ssures, but it perma-
nently weakens the internal sphincter and may lead to anal
deformity and incontinence in 830% of patients (14, 15).
Therefore, recently, nonsurgical treatment modalities have
been developed.
NONSURGICAL METHODS
Smooth muscle relaxation is an effective treatment for CAF
and has advantages over surgical treatment in avoiding long-
term complications. Additionally, it does not require hospi-
talization (16). The discovery of pharmacological agents that
effectively cause temporary sphincterotomy and heal most
ssures has led to approximately two-thirds of patients avoid-
ing surgery. Smooth muscle relaxation is also the rst option
in patients with a high risk of incontinence (17). Smooth mus-
cle relaxation has been tried using a variety of agents (18, 19).
1312
Treatment of Anal Fissures 1313
Table 1. Details of the Clinical Trials Carried out Using Topical GTN
Clinical Dose of No. of Patients No. of Patients Recurrence Side
Trial (Ref.) GTN (%) Studied Healed (%) (%) Effects (%)
(26) 0.2 (twice a day for 6 wk) 21 61 (after 4 wk) 22 19 (mild headache)
90 (after 6 wk)
(27) 1 (N = 37), 0.5 (N = 6),
0.2 (N = 38)
81 (67 men, 64 acute, 47
CAFs)
69 (acute)
(for 18 months) 54 (chronic)
(28) 0.2 31 56 (after 6 months) 27 70 (headache)
10 (severe headache)
(29) 0.3 31 (16 acute, 15 CAFs) 56 (acute) 75 (headache)
41 (chronic)
(30) 0.2 56 (16 acute, 40 CAFs) 63 after 4 wk, 81 after 8
wk (acute cases)
9 61 (headache)
(500 mg) 33 after 8 wk, 50 after
12 wk (CAFs)
14 (severe headache)
(31) 0.5 45 73 (after 6 wk) 84 (headache)
(32) 0.2 GTN three times
a day for 8 wk
(Group A)
Group A (N = 34) 61 (Group A) 45 12
LIS (Group B) Group B (N = 31) 97 (Group B)
(33) 0.25 GTN (Group A) Group A (N = 22, 16
chronic, 6 acute)
Group A (75 chronic, 83
acute)
67 (group A, at 9
months)
77 (group A)
Dietary change
(group B)
Group B (N = 21, 16
chronic, 5 acute)
Group B (N = 21, 16
chronic, 5 acute)
(for 39 wk)
(34) Placebo (group A) 304 50 in all the cases 3.9 A 12.5 (headache)
0.1 (group B) 4.2 (severe headache)
0.1 group C) B 18.3 (headache)
0.4 (group D) 2 (severe headache)
(374 mg twice daily up
to 8 wk)
C 36.1 (headache)
6.3 (severe headache)
D 67.5 (headache)
24.3 (severe headache)
(35) 0.2 GTN (group A) Group A (N = 35) Group A (54) 9 (group A) Group A (N = 35)
LIS (group B) Group B (N = 35) 3 (group B) 3 Group B
(36) Placebo (group A) 200 24 (group A)
0.1 (group B) 50 (group B)
0.2 (group C) 36 (group C)
0.4 (group D) 57 (group D)
(220 mg twice a day)
(37) 0.2 (twice a day for 6 wk) 80 (34 men 46 women) 55 (after 4 wk) 61 (ushing)
78 (after 9 wk) 15 (severe headache)
Clinical Trials in Children
(38) 0.05 (group A) 15 (8 boys, average age
313 yr)
100 (group A) 13
0.1 (group B) 62.5 (group B)
N is the number of patients to whom the treatment was given
Smooth muscle relaxation is particularly suitable in patients
with associated inammatory bowel disease, in whom LIS
for AF is generally contraindicated (2023).
GLYCERYL TRINITRATE (GTN)
Topical GTN, a nitric oxide donor compound, has been shown
to cause relaxation of the anal sphincter and thus nds use in
the treatment of AF. It has been reported that blood ow at
the posterior midline of anoderm is inversely related to the
mean maximum anal resting pressure, and topical applica-
tion of GTN ointments increases the blood ow to posterior
midline (24). Fenton et al. reviewed the pharmacodynamic
and pharmacokinetic prole of GTN (0.4 % ointment) (25).
Nitroglycerin ointment is approved in the United Kingdom
as a prescription medicine for the treatment of CAF pain.
About 375 mg of 0.4% nitroglycerin rectal ointment is pre-
scribed twice a day, delivering 1.5 mg of nitroglycerin. Mean
bioavailability with 0.2% nitroglycerin ointment delivering
0.75 mg nitroglycerin dose is 50%. The values of C
max
, vol-
ume of distribution, clearance, and elimination half-life were
found to be 0.11 g/L, 3 L/kg, 1 L/kg/min, and 3 min, re-
spectively. Anumber of clinical trials conducted using topical
GTN are listed in Table 1.
1314 Dhawan and Chopra
Zuberi et al. randomized 42 consecutive patients with CAF
(more than 4 months duration) into three groups (39). Group
A(N=18) received GTN(0.2%) ointment, group Breceived
GTN patches (N = 19), and the control group (N = 12)
underwent LIS. Fissures healed completely in 66.7%, 63.2%,
and 91.7%in groups A, B, and C, respectively. No statistically
signicant difference (P = 0.7) was observed in the healing
rates with ointment or patches.
In a study carried out by Ciccaglione et al. (40), the effect
of GTN ([0.2%, N=6] and [2%, N=6]) on anal canal pres-
sure before and after 8 wk of treatment was observed. About
120 mg of GTN was applied on the external anal verge and
anal pressure was evaluated in 12 patients using an electronic
probe at three recording sites before and after application.
Both concentrations equally reduced basal anal canal pres-
sure in all three recording sites (P < 0.001) for a 60-min
period.
Another research team retrieved 10 randomized clinical
trials published up to July 2001 (41). In ve of six studies,
the healing rate for GTN was better than that of placebo or
lignocaine. However, headache was observed to be a com-
mon side effect of the treatment. LIS and topical GTN were
compared in four trials. The results suggested that with GTN
therapy surgery could be avoided in 3165% of patients. The
authors concluded that topically applied GTN (0.2% three
times a day) for 4 wk can be used for the treatment of AF.
All the above studies reported that GTN was benecial
for the treatment of CAF. However, in a very few studies, it
has been reported that GTN produced no benet regarding
healing or pain relief. In a randomized, double-blind study,
including 48 patients with CAF (42), three groups of patients
received 0%(placebo), 0.2%(0.75 mg), and 0.4%(1.5 mg) of
GTNointment. The study was completed by 69%of patients.
Other patients failed to complete the study due to headaches
and cooperation problems. No signicant difference (P <
0.05) was found between the groups with respect to patient
age, gender, past history, physical examination, amount of
ointment used, and adverse events. No signicant difference
was found between the groups regarding healing (P =0.952)
or pain relief (P = 0.4580.8 according to the type of pain
checked). According to this study, there was no benet re-
garding healing or pain relief, in treating patients suffering
from AF with GTN ointment in combination with stool soft-
eners and sitz baths compared to the same treatment without
GTN ointment.
DILTIAZEM (DTZ)
The internal anal sphincter has a calcium-dependent mecha-
nism to maintain tone, and also receives inhibitory extrinsic
cholinergic innervation. It may therefore be possible to lower
anal sphincter pressure using calcium channel blockers and
cholinergic agonists without side effects.
TOPICAL DTZ
In a study carried out by Knight et al., 71 consecutive pa-
tients with CAF were treated with DTZ (2%) ointment for 9
wk (43). About 88% of patients healed with DTZ ointment.
Four patients experienced perianal dermatitis and one patient
suffered from headache. After 32 wk completion of the treat-
ment, 27 of 41 patients available remained symptom-free.
Six of the seven patients with recurrent ssure were treated
successfully by repeating DTZ treatment.
In yet another study, patients with CAF were treated top-
ically with 2% DTZ gel (dose 8 mg) three times daily (44).
Twenty-three patients (12 women) with median age 45 yr had
a median 6 months history of ssures. These were associated
with a sentinel tag in 39%patients. The ssure healed in 48%
of patients, including 75% of patients who previously failed
to heal with GTN ointment. There were no recurrences at 3
months and no adverse effects.
ORAL AND TOPICAL DTZ
Some researchers have compared oral DTZwith topical DTZ.
A study performed by Jonas et al. assessed the effectiveness
of oral and topical DTZ in healing CAF (45). Fifty consecu-
tive patients with CAF were randomly included in the study.
Twenty-four patients received oral (60 mg) and 26 received
topical (2%gel) DTZtwice dailyfor upto8wk. Anal manom-
etry and blood pressure were recorded at 15-min intervals.
Every 15 days, patients were assessed on the basis of pain
alleviation, ssure healing, and side effects. After 8 wk, RAP
fell by 15 and 23% in the two groups, respectively. Fissure
healing was complete in 38% and 65% in patients with oral
and topical DTZ treatment by 8 wk, respectively. Side effects
including rashes, headache, nausea, and vomiting were ob-
served in eight patients of the oral DTZ group, whereas no
side effects were seen in those receiving topical therapy (P
= 0.001). Thus topical DTZ was found to be more effective
with no side effects.
Carapeti et al. conducted three studies each involving 10
healthy volunteers. In the rst study, subjects were given oral
DTZ (60 mg) or placebo on separate occasions. They were
then given DTZ once or twice daily for 4 days. In the sec-
ond and third studies, DTZ and bethenachol (BTN) gels of
increasing concentration were applied topically to lower anal
pressure (46). DTZ gel (2%), BTN (0.1%), and oral DTZ
twice daily produced 28%, 24%, and 17% reductions in anal
pressure, respectively.
DTZ VERSUS GTN
In a study reported by Jonas et al. (47), the efcacy of DTZ
for ssures that failed to heal with GTN was evaluated. Con-
secutive patients (N = 39, median age 42 yr) with persistent
CAF despite treatment with GTN ointment (0.2%) under-
went anal manometry before and for 1 h after application of
Treatment of Anal Fissures 1315
Table 2. Clinical Studies Where Effectiveness of Topical DTZ Has Been Compared With GTN and BTN
Clinical No. of Patients No of Patients Recurrence Side
Trial (Ref.) Dose Studied Healed (%) (%) Effects (%)
(49) BTN (0.1 %) 15 60 (BTN) Not reported Not reported
DTZ (2 %) 67 (DTZ)
(thrice daily for 8 wk)
(50) GTN (0.2 %) 52 86 (GTN) 22 72 (GTN)
DTZ (2 %) 83 (DTZ) 42 (DTZ)
(twice daily for 68 wk)
(51) GTN (0.5% N = 21) 43 85 (GTN) Not reported 33 (GTN)
DTZ (2%, N = 22) 86 (DTZ) 0 (DTZ)
(twice daily for 8 wk)
DTZ gel (700 mg of 2%) to the distal anal canal. The gel
was applied twice daily for 8 wk. Fissure healing and side
effects were noted every 15 days. Topical DTZ gel lowered
RAP by 20% and ssures healed in 49% of patients within 8
wk. Before DTZ, 69% had used a complete course of GTN
(0.5 g twice daily for 8 wk), and 44% of patients healed with
DTZ. Some of the patients had discontinued GTN prema-
turely because of headaches. Side effects including perianal
itching, headache, drowsiness, and mood swings occurred in
10% of patients during DTZ treatment. Hence, the authors
concluded that topical DTZ (2%) was effective treatment for
GTN-resistant CAF.
Grifn et al. (48) used topical DTZ gels to heal patients
with CAF that had failed previous treatment with topical
GTN (0.2%). Patients (N = 47) with CAF who had previ-
ously failed at least one course of topical GTNwere recruited
prospectively from a single center. They applied DTZ (700
mg of 2%) cream to the anal verge twice daily for 8 wk.
Forty-four percent of patients who completed treatment were
cured of ssures. Another 42% of patients with persistent
ssures were symptomatically improved. Thus surgery could
be avoided in 70% of patients. A few studies where topical
DTZ has been compared with GTN and bethenechol (BTN)
are included in Table 2.
NIFEDIPINE (NIF)
NIF has also been used in treatment of AFs as reported in a
number of studies (52). In a prospective, randomized, double-
blind, multicenter study, the efcacy of local application of
NIF gel (0.2%) in healing acute AF was determined (2). Pa-
tients (N =141) applied topical NIF gel every 12 h for 3 wk.
The control group (N=142) received topical lidocaine (1%)
and hydrocortisone acetate (1%) gel during therapy. Manom-
etry was performed before and after 14 and 21 days. After
21 days of therapy, 95% and 50% of patients were healed in
the NIF group and control group, respectively (P < 0.01). A
mean reduction of 30% (P < 0.01) and 188.8% (P < 0.01)
in anal pressure and squeeze pressure was observed.
In other studies reported by Merenstein and Rosenbaum
and Slawson, remarkable improvement in healing was ob-
servedwhen1.5%lidocaine and0.3%NIFwere appliedtwice
daily for 6 wk. Thus, a combination of lidocaine and NIF can
be a reliable nonsurgical method for treating CAF (53, 54).
Katsinelos et al. compared the efcacy of NIF ointment
(0.5%) with LIS for the treatment of CAF (55). Sixty-four
patients with symptomatic CAF were randomly assigned NIF
ointment (N = 32) every 8 h for 8 wk or LIS (N = 32).
In addition, both stool softeners and ber supplements were
prescribed. Patients were assessed at 2, 4, 6, and 8 wk. Long-
term outcomes were determined after a median follow-up of
19 and 20.5 months for the NIF and LIS group, respectively.
The overall healingrates at the endof follow-upwere 93%and
100% in the NIF and LIS groups, respectively (P = 0.48).
Fifty percent of patients developed side effects in the NIF
group compared with 18.7% in the LIS group.
LACIDIPINE
Lacidipine is a calcium channel blocker like nifedipine and
hence nds its use in the treatment of AFs. Twenty-one con-
secutive patients (16 women) with AF (16 chronic, situated
posteriorly in 17 patients, anteriorly in 4 patients) with a mean
age of 37.1 yr were treated with oral lacidipine (6 mg daily)
(56). Blood pressure, pain scores (assessed from 0 to 10 on a
visual analogue scale), and ssure healing were monitored af-
ter 2, 4, and 8 wk. However, about 33.3% patients developed
side effects. Pain scores were signicantly reduced after 2
wk and continued to show a signicant reduction throughout
the treatment period. Fourteen percent and 90.4% of ssures
were healed after 14 and 28 days, respectively. No recurrences
in ssures were reported.
BOTULINUM TOXIN (BTX)
BTXs comprise a family of neurotoxins designated as types A
to G, which are produced by the anerobic bacteriumClostrid-
ium botulinum. BTX-A blocks cholinergic transmission re-
sulting in accid paralysis and autonomous nerve dysfunc-
tion. CAFs are caused by anal sphincter hypertonia leading
to an ischemic ulcer. BTX-A injection into the internal or ex-
ternal anal sphincter causes relaxation of the anal sphincters,
enhances microcirculation at the ssure site, and promotes
ssure healing (57). Studies of BTX injection into the anal
1316 Dhawan and Chopra
Table 3. Clinical Trials Conducted Using BTX for Smooth Muscle Relaxation
Clinical Location of Dose of No. of No of Patients
Trial (Ref.) Application the Agent Patients Studied Healed (%)
(60) Bilaterally to the
ssure
2.55U (BTX) 100 (43 women,
average age 34.7)
79
(after 6 months)
(61) Anterior midline of
internal anal
sphincters)
Group A (BTX 20 U) 50 Group A (96)
GTN twice daily
for 6 wk
Group B (GTN 0.2 %) Group B (60)
(62) External anal
sphincter
15 U (BTX) 40 42 (at 3 months)
50 (at 6 months)
(63) Internal anal
sphincter
50U (BTX) 13 54 (after 1 month)
85 (after 2 months
(64) Laterally into
internal anal
sphincter
50U (BTX) 12 (8 women, 4
men)
25 (1 month)
58 (after 3 months)
(65) - Group A (BTX 20 U, N = 10) 21 Group A (70)
Group B (GTN 0.2 %, N = 11) Group B (82)
(66, 67) - 30 U (BTX) 51 79
(68) Internal sphincter 25 U (BTX) 100 47 (after 3 yr)
sphincter have reported excellent healing rates, although the
procedure is more invasive, and patients may nd it uncom-
fortable and less tolerable.
Brisinda et al. tried to optimize the dose of BTX. In their
study, 150 patients with posterior AF were treated with BTX
injected into the internal anal sphincter on each side of the
anterior midline (58). Subjects were randomized into two
treatment groups. Patients in group I were treated with 20
U of BTX and, if the ssure persisted, were retreated with
an additional 30 U. Patients in group II were treated with 30
U and retreated with an additional 50 U, if the ssure per-
sisted. One month after the injection, examinations revealed
complete healing in 73% from group I and 87% from group
II (P = 0.04). Five patients from group II reported mild in-
continence of atus that lasted 2 wk after the treatment and
disappeared spontaneously. The values of the RAP (P =0.3)
and the maximum voluntary pressure (P =0.2) did not differ
between the two groups. A recurrence of the ssure was ob-
served in 6 patients from the group. The authors conrmed
that with an increase in dose, the success rate increased with
little increase in side effects.
Another study proved the use of local inltration of BTX
into the internal anal sphincter as an effective treatment for
CAF. In a double-blind, placebo-controlled study, 30 consec-
utive symptomatic adults were enrolled (59). All the patients
received two injections (total volume 0.4 mL) into the in-
ternal anal sphincter. The treated group (N = 15) and the
control group (N = 15) received 20 U of BTX-A and saline,
respectively. After 2 months, 11 patients in the treated group
and two in the control group had healed ssures (P =0.003).
Thirteen and four patients in the treated and control group,
respectively, were relieved of symptoms (P = 0.003). The
MRAP was reduced by 25%in the treated group as compared
with the control group. Later on three patients in the control
group underwent LIS. The remaining 10 patients (control
group) received BTX injections (20 U). Seven patients had
healed ssures after 2 months; the other three left the study
and underwent surgery. Four patients in the treated group
were later retreated (with 25 U of BTX); all had healed s-
sures after 2 months. A few clinical studies carried out using
BTX have been encompassed in Table 3 too.
Sixty patients with CAF were recruited in a study con-
ducted by Thornton et al. (69). Fifty-seven patients (30
women) with median age 43 received 20 U of BTX in-
jected into the intersphincteric groove. Each parameter was
reassessed after 2 wk and 3 months. Physical healing and
symptom control were dependent on the baseline maximum
RAP and baseline ssure score (P = 0.003, P = 0.009, re-
spectively). Although maximum RAP fell by 17%, pressure
reduction did not correlate with clinical outcome (P > 0.2).
Seventeen patients reported a mean 17% increase in conti-
nence score.
Daniel et al. (70) reviewed the published studies about the
use of BTXinjection in the management of CAF. The authors
reported that healing occurred in more than 70% of ssures
without irreversible incontinence.
COMBINED TREATMENT APPROACH
The use of BTX is associated with hyperhidrosis (syndrome
associated with excessive sweating). Wollina and Konrad (71)
compared the traditional BTX-Atreatment of muscular spas-
ticity in AFs with combined treatment of spasticity and focal
treatment of the anal fold and perianal skin. Ten patients
with CAF (of more than 6 months duration who failed to re-
spondtoconservative treatment andwhohadrefusedsurgery)
associated with focal hyperhidrosis as assessed by Minors
sweat test were investigated in an open, two-armed trial.
Treatment of Anal Fissures 1317
Intramuscular injections of 2025 U BTX-A were given in
group A (N = 5). In group B (N = 5), injections were com-
bined with intracutaneous injection of 3050 U BTX-A to
treat focal hyperhidrosis. The mean follow-up was 5 months.
All the patients in group B and two of the ve patients in
group A experienced a complete remission despite the fact
that relief of pain was evident in eight of 10 patients within 2
wk. Patient satisfaction with treatment was high in group B.
The study suggested that combined therapy of both muscu-
lar spasticity and focal hyperhidrosis may provide better re-
sults than intramuscular injections alone in AF therapy with
BTX-A.
In another study carried out by Bhardwaj et al. (72), 10 pa-
tients (5 men) with median age 40.5 yr were injected with 20
U BTX at the site of the ssure. The optimal angle for injec-
tion of BTX-A was 60

. Assessment was made on the basis

of a visual analogue pain scale, incontinence score, and anal
manometry preinjection, at 48 h postinjection and at 6 and 12
wk postinjection. All the patients attended the 48 h follow-up
visit, but only seven attended the 6- and 12-wk visits. In six of
seven patients, the ssures were healed. The remaining three
were contacted by telephone at 6 months postinjection and
two of three remained asymptomatic without further treat-
ment. In seven patients, the median pain score preinjection
was 5.5 out of 10 (range 110) and this dropped to a median
of 1 at 12 wk. The median drop in resting pressure was 37%
at 6 wk.
BTX VERSUS GTN
In a prospective, nonrandomized, open-label study, patients
(N=40) with CAF who failed a course of GTN were treated
with 20 Uof BTX-A(73). Symptomatic relief, visual healing
of ssures, side effects, and patient preference were assessed
at an 8-wk follow-up. About 73% patients had improved
symptomatically and avoided surgery. Forty-three percent of
ssures were healed, whereas 57% of ssures remained un-
healed. Of the unhealed ssures, 12%, 18%, and 27% were
asymptomatic, symptomatic, and came to surgery, respec-
tively. Transient minor incontinence symptoms were noted
in 18% of patients. Thus, authors concluded that second-line
BTX injection improved symptoms in approximately three-
quarters of patients after failed primary GTN therapy.
ISOSORBIDES
Isosorbide Mononitrate (ISM)
Tankova et al. (74) conducted a study to assess the efcacy
and patient compliance of topical mononitrate hydrogel for
the treatment of AF. ISM (0.2%) was applied to the anal
canal twice daily for 3 wk. Anal pressure was determined us-
ing anal manometry before and after the therapy. At the end
of therapy, 88% and 22% ssures were healed in treated and
control group patients, respectively. Twenty percent of pa-
tients suffered from mild heart attack. No fecal incontinence
and recurrence occurred during 3 months of follow-up.
Isosorbide Dinitrate (ISDN)
In a randomized, prospective, double-blind, placebo con-
trolled trial, 37 consecutive subjects with AF were enrolled
(75). The subjects were divided into two groups. One group
(N = 20) received ISDN and the other group (N = 17) was
given placebo. Both groups were treated for a median of 5
wk. After this period, 17 subjects in the isosorbide group
had healed compared with 6 controls (P < 0.003). The s-
sure recurred in 2 patients who had an initial good response to
isosorbide, and in 2 patients of the control group. Side effects
(particularly headache) were more common after ISDN.
In a study carried out by Songun et al., patients (N =100)
with AF were treated with ISDN, the primary healing rate of
AFs was 93% with ISDN (76). In case of recurrence (13%),
54% could again be treated successfully with ISDN but a
complication (temporary headache) was observed in about
7% of patients.
L-Arginine (LA)
Nitric oxide produced from the cellular metabolism of LA
also causes relaxation of the internal anal sphincter. A study
investigated by Grifn et al. reported that topical LA can
be used as a possible alternative treatment for CAF (77). In
a two-center study, volunteers (N = 25) received LA (400
mg) or placebo. Anal manometry was performed 2 h after
application of LA gel or placebo gel. It was found that LA
gel signicantly lowered MRAP. LA gel had a rapid onset of
action with a duration of action of more than 2 h (P <0.01).
Minoxidil and Lignocaine
In a prospective, randomized, double-blind study, 90 patients
with AF were recruited. Patients received local applications
of ointments containing 5% lignocaine (N = 28), 0.5% mi-
noxidil (N=36), or both (N=26) (78). Healing of AFat 6 wk
was considered as the primary end point. The healing rate was
similar in the three groups. However, the mean time taken for
complete healing with combination treatment (1.9 wk) was
signicantly shorter than that with minoxidil alone (3.1 wk,
P = 0.001) or with lignocaine alone (3.3 wk, P = 0.002).
Thus, a combination of minoxidil and lignocaine helped in
faster healing of AF and provided better symptomatic relief
than either drug alone.
Gonyautoxin
All the above treatments mentioned for AF, viz., LIS, GTN,
LA, NIF, and BTX, focused on reducing the tone of the inter-
nal anal sphincter. In a recent publication, Garrido and col-
leagues (79) have described the successful use of a newagent,
gonyautoxin, in patients with acute AF and CAF. Gonyau-
toxin is a paralyzing phytotoxin produced by dinoagellates.
It breaks the vicious circle of pain and spasm that leads to
AF. Fifty recruited patients received clinical examination, in-
cluding proctoscopy and questionnaire to evaluate the symp-
toms (80). Anal manometry was performed before and after
Gonyautoxin (100 U/mL) injection into both sides of the AF
in the internal anal sphincter. Total remission of acute AF
1318 Dhawan and Chopra
and CAF was achieved within 15 and 28 days, respectively.
Ninety-eight percent of the patients healed before 28 days
with a mean time healing of 17.6 9 days. Only one relapsed
during 14 months of follow-up. There was about a 56% de-
crease in resting pressure when compared with baseline. No
side effects were observed.
OTHER TECHNIQUES
Sitz Bath
In addition to chemical agents used above, sitz baths have
been used to provide relief to patients with CAF. Shak con-
ducted a study on 18 healthy volunteers and 28 patients with
painful anorectal diseases (18 patients with ssures and 10
with hemorrhoids) (81). All of them used sitz baths to allevi-
ate pain. Investigations were comprised of measuring rectal
and interstitial sphincter temperature, rectal and rectal neck
pressures, and electromyographic activity of both the exter-
nal and internal anal sphincters before and after the subjects
sat in a warm-water bath at temperatures of 40, 45, and 50
o
C
for 10 min. Pain relief was more evident and lasted longer at
higher bath temperatures. There was no change in the rectal
and interstitial sphincter temperatures before and after bath
in both the healthy volunteers and patients. The rectal neck
pressure and internal and sphincter electromyographic activ-
ity dropped signicantly in the bath, but increased gradually
to pretest levels 2570 min after exiting the bath.
Comparison of Nonsurgical Approaches
A few studies are reported where the comparison among
DTZ, BTX, NIF, and GTN has been carried out. Tranqui
et al. enrolled 88 patients with CAF (82). During the rst
half of the study period, patients were treated with topical
GTN and pneumatic dilatation. Subsequent patients received
topical NIF and BTX injections (30100 U). LIS was re-
served for patients who failed medical treatment. In 98% of
patients, the ssure healed with conservative (using laxatives
and stool softeners) nonsurgical treatment. The combination
of NIF and BTX was superior to GTN and pneumatic dilata-
tion with respect to both healing (94% vs 71%, P < 0.05)
and recurrence rate (2% vs 27%, P < 0.01). At an average
follow-up of 27 months, 92% of patients reported having no
pain or only mild occasional pain with bowel movements.
Thus, topical NIF and BTX injections were found to be an
excellent combination, associated with a low recurrence rate
and minimal side effects.
All the studies reported above interpret that smooth mus-
cle relaxation can be used as an alternative to LIS. How-
ever, in the study carried out by Nelson it has been reported
that medical therapy for CAF, acute ssure, and ssure in
children may be applied with a chance of cure that is only
marginally better than placebo, and, for chronic ssure in
adults, far less effective than surgery (83). Efcacy and mor-
bidity of various medical therapies for AFwere assessed from
the studies abstracted from published reports. In these stud-
ies, participants were randomized to a nonsurgical therapy
for AF. Comparison included an operative procedure, an al-
ternate medical therapy, or placebo. Dichotomous outcome
measures included nonhealing of the ssure (a combination
of persistence and recurrence), and adverse events (including
incontinence, headache, infection, anaphylaxis). Continuous
outcome measures of the study included measures of pain
relief and anorectal manometry. In a study carried out by
Nelson, 21 different comparisons of the ability of medical
therapies to heal AF were reported in 31 retrospective charts
(84). Nine agents (GTN, ISDN, BTX, DTZ, NIF, hydrocorti-
sone, lignocaine, bran, placebo) as well as anal dilators and
surgical sphincterotomy were used. GTNwas compared with
a placebo group (0.78, 0.561.08), in children (0.96, 0.48
1.92), and adults (0.73, 0.501.07). It was observed that GTN
was not signicantly better than placebo in curing AF. When
calciumchannel blockers were tested against GTN, they were
found to be equivalent in their ability to cure ssure (odds
ratio 0.66, 0.222.01). BTX when compared with placebo
(0.75, 0.321.77) and GTN (0.48, 0.211.10) showed no sig-
nicant advantage in efcacy. The authors also concluded
that a number of more studies are required to establish the
efcacy of calcium channel blockers.
Based on the reports of the clinical trials, we opine that
smooth muscle relaxation using chemical agents should be
Figure 1. Algorithmfor the treatment of anal ssures fromavailable
clinical trials.
Treatment of Anal Fissures 1319
tried rst and if the ssures do not heal then surgery should
be performed. The possible algorithm for the treatment of
AFs is provided in Figure 1.
CONCLUSIONS
This review describes nonsurgical treatment modalities of-
fered for CAF. Until now, lateral internal sphincterotomy has
been considered to be the gold standard treatment for CAF.
In the last decade, lateral internal sphincterotomy has been
replaced by smooth muscle relaxation in most cases. This
medical option aims to achieve the effectiveness of surgery
without side effects by means of a temporary decrease of anal
pressures that allows ssures to heal. Topical applications of
various agents, viz., glyceryl trinitrate (0.2%), diltiazem(2%),
nifedipine (0.2%), L-arginine (400 mg), minoxidil (0.5%),
lignocaine (5%), and isosorbides (0.2%) are being exploited
for the treatment of AFs. Diltiazem (60 mg) and lacidip-
ine (6 mg) have also been tried orally. In addition to these
approaches, injections of botulinum toxin (30 U-50 U) and
gonyautoxin (100 U) have also been reported. More than 80
clinical studies have been reported in the literature, wherein
efcacy of smooth muscle relaxation has been assessed. All
of these studies have shown that surgery can be avoided in
3398%of patients by using smooth muscle relaxation. Glyc-
eryl trinitrate has been reported to heal 3378% of patients
with CAF. However, use of glyceryl trinitrate is accompanied
by side effects, viz., headache, low blood pressure. Oral dilti-
azem caused a lot of side effects while with topical diltiazem
application side effects were low. When nifedipine was used,
the healing rate (95%) was high but side effects were ob-
served in 50% patients. A few studies have also documented
the use of isosorbides and L-arginine for the treatment of
CAF. The healing rate with botulinum toxin injection was
found to be higher (98%), but it is invasive therapy and less
convenient than topical application. Considering the various
pros and cons, we opine that treatment of CAF must be in-
dividualized, depending on the clinical condition of patients.
Smooth muscle relaxation should be tried rst and if there is
no relief, then lateral internal sphincterotomy can be used.
Reprint requests and correspondence: Sanju Dhawan, Uni-
versity Institute of Pharmaceutical Sciences, Panjab University,
Chandigarh-160014, India.
Received August 21, 2006; accepted January 18, 2007.
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CONFLICT OF INTEREST
Guarantor of the article: Sanju Dhawan, Ph.D.
Specic author contributions: Sanju Dhawan conceived the
idea to review the clinical trials in order to contribute to the
society. Sunny Chopra collected the literature from the jour-
nals and libraries. He compiled a draft of the reported clinical
trials. The manuscript was extensively edited, interpreted, and
revised by Sanju Dhawan.
Financial support: Sunny Chopra worked as a Junior Re-
search Fellow in the Postgraduate Program of University
Institute of Pharmaceutical Sciences, Panjab University,
Chandigarh, India. He was admitted to the Program under
industry-sponsored candidate quota approved by All India
Council of Technical Education, New Delhi, India.
Potential competing interests: None.