anal fssure nin surgical procudere

1. 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
CME
Nonsurgical Approaches for the Treatment of Anal Fissures
Sanju Dhawan, Ph.D. and Sunny Chopra, M. Pharm.
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
Chronic anal fissure (CAF) is usually associated with internal anal sphincter spasm, the relief of which is central to
provide fissure 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;102:1312–1321)
INTRODUCTION sphincterotomy. It is postulated that spasm impedes mucosal
blood flow and impairs healing. High-fiber diet and increasing
According to Antropoli et al., various pathologies of anal the volume of daily drinks are useful and very efficient in
canal are extremely common (1, 2). About 30–40% of the treating AF (8). Analysis of the available literature shows
population suffers from proctologic pathologies at least once that by far, medical manipulation of the internal sphincter
in their lives. Anal fissure (AF) is present in about 10–15% should be the first-line treatment in AF. A surgical therapy is
of proctological patients (3). AF can be defined as a tear or called for if the medical therapy fails or there is a recurrence
split in the distal anal canal, which if not treated appropri- (9).
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 flow with de- LATERAL INTERNAL SPHINCTEROTOMY (LIS)/SURGERY
layed or nonhealing of the ulcer (6, 7). The primary cause of
LIS is a surgical technique to cure AF. It has been favored
chronic anal fissure (CAF) is increased resting anal pressure
by most of the surgeons, because it offers long-lasting relief
(RAP). Other most frequent causes are infection, essentially
in sphincter spasm (10, 11). The most preferred options are
sexually transmitted diseases, and tumor, mainly anal epider-
the manual dilatation with radiosurgery and subcutaneous
moid cancer. Most AFs heal spontaneously with conservative
LIS. Both methods are easy to perform and no special setup
treatment, viz., stool softener and diet modification. Such AFs
is needed (12, 13). Traditionally, LIS is considered as the
are termed as acute but a proportion of them persists for a
gold standard treatment for chronic fissures, but it perma-
longer period and is known as chronic. Chronicity is defined
nently weakens the internal sphincter and may lead to anal
by both chronology and morphology. Most surgeons consider
deformity and incontinence in 8–30% of patients (14, 15).
the persistence for 6 wk as a reasonable point when an AF, un-
Therefore, recently, nonsurgical treatment modalities have
likely to heal with conservative treatment, may be considered
been developed.
chronic. Morphologically, the presence of visible transverse
internal anal sphincters fibers at the base of a fissure typi-
fies chronicity. Associated features include indurated edges, NONSURGICAL METHODS
a sentinel pile, and a hypertropical anal papilla. An acute fis-
Smooth muscle relaxation is an effective treatment for CAF
sure looks like a fresh tear in the skin, while in a CAF the
and has advantages over surgical treatment in avoiding long-
walls of the tear become thickened.
term complications. Additionally, it does not require hospi-
TREATMENT OF AF talization (16). The discovery of pharmacological agents that
effectively cause temporary sphincterotomy and heal most
The treatment for AF is based on reducing the spasm of the
fissures has led to approximately two-thirds of patients avoid-
internal anal sphincter, either by dilating the anal canal or
ing surgery. Smooth muscle relaxation is also the first option
in patients with a high risk of incontinence (17). Smooth mus-
To access a continuing medical education exam for this article, please visit
cle relaxation has been tried using a variety of agents (18, 19).
www.acg.gi.org/journalcme.
1312

2. 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)
1 (N = 37), 0.5 (N = 6), 81 (67 men, 64 acute, 47 69 (acute)
(27) – –
0.2 (N = 38) CAFs)
(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 9 61 (headache)
wk (acute cases)
(500 mg) 33 after 8 wk, 50 after 14 (severe headache)
12 wk (CAFs)
(31) 0.5 45 73 (after 6 wk) – 84 (headache)
Group A (N = 34)
(32) 0.2 GTN three times 61 (Group A) 45 12
a day for 8 wk
(Group A)
Group B (N = 31)
LIS (Group B) 97 (Group B)
Group A (N = 22, 16
(33) 0.25 GTN (Group A) Group A (75 chronic, 83 67 (group A, at 9 77 (group A)
chronic, 6 acute) acute) months)
Group B (N = 21, 16 Group B (N = 21, 16
Dietary change
(group B) chronic, 5 acute) 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 C 36.1 (headache)
to 8 wk)
6.3 (severe headache)
D 67.5 (headache)
24.3 (severe headache)
Group A (N = 35) Group A (N = 35)
(35) 0.2 GTN (group A) Group A (54) 9 (group A)
Group B (N = 35)
LIS (group B) 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 (flushing)
78 (after 9 wk) 15 (severe headache)
Clinical Trials in Children
(38) 0.05 (group A) 15 (8 boys, average age 100 (group A) 13
3–13 yr)
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 midline (24). Fenton et al. reviewed the pharmacodynamic
with associated inflammatory bowel disease, in whom LIS and pharmacokinetic profile of GTN (0.4 % ointment) (25).
for AF is generally contraindicated (20–23). 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-
GLYCERYL TRINITRATE (GTN)
scribed twice a day, delivering 1.5 mg of nitroglycerin. Mean
Topical GTN, a nitric oxide donor compound, has been shown bioavailability with 0.2% nitroglycerin ointment delivering
to cause relaxation of the anal sphincter and thus finds use in 0.75 mg nitroglycerin dose is 50%. The values of Cmax , vol-
the treatment of AF. It has been reported that blood flow at ume of distribution, clearance, and elimination half-life were
found to be 0.1–1 µg/L, 3 L/kg, 1 L/kg/min, and 3 min, re-
the posterior midline of anoderm is inversely related to the
mean maximum anal resting pressure, and topical applica- spectively. A number of clinical trials conducted using topical
tion of GTN ointments increases the blood flow to posterior GTN are listed in Table 1.

3. 1314 Dhawan and Chopra
TOPICAL DTZ
Zuberi et al. randomized 42 consecutive patients with CAF
(more than 4 months duration) into three groups (39). Group
In a study carried out by Knight et al., 71 consecutive pa-
A (N = 18) received GTN (0.2%) ointment, group B received
tients with CAF were treated with DTZ (2%) ointment for 9
GTN patches (N = 19), and the control group (N = 12)
wk (43). About 88% of patients healed with DTZ ointment.
underwent LIS. Fissures healed completely in 66.7%, 63.2%,
Four patients experienced perianal dermatitis and one patient
and 91.7% in groups A, B, and C, respectively. No statistically
suffered from headache. After 32 wk completion of the treat-
significant difference (P = 0.7) was observed in the healing
ment, 27 of 41 patients available remained symptom-free.
rates with ointment or patches.
Six of the seven patients with recurrent fissure were treated
In a study carried out by Ciccaglione et al. (40), the effect
successfully by repeating DTZ treatment.
of GTN ([0.2%, N = 6] and [2%, N = 6]) on anal canal pres-
In yet another study, patients with CAF were treated top-
sure before and after 8 wk of treatment was observed. About
ically with 2% DTZ gel (dose 8 mg) three times daily (44).
120 mg of GTN was applied on the external anal verge and
Twenty-three patients (12 women) with median age 45 yr had
anal pressure was evaluated in 12 patients using an electronic
a median 6 months’ history of fissures. These were associated
probe at three recording sites before and after application.
with a sentinel tag in 39% patients. The fissure healed in 48%
Both concentrations equally reduced basal anal canal pres-
of patients, including 75% of patients who previously failed
sure in all three recording sites (P < 0.001) for a 60-min
to heal with GTN ointment. There were no recurrences at 3
period.
months and no adverse effects.
Another research team retrieved 10 randomized clinical
trials published up to July 2001 (41). In five of six studies,
the healing rate for GTN was better than that of placebo or
ORAL AND TOPICAL DTZ
lignocaine. However, headache was observed to be a com-
mon side effect of the treatment. LIS and topical GTN were Some researchers have compared oral DTZ with topical DTZ.
compared in four trials. The results suggested that with GTN A study performed by Jonas et al. assessed the effectiveness
therapy surgery could be avoided in 31–65% of patients. The of oral and topical DTZ in healing CAF (45). Fifty consecu-
authors concluded that topically applied GTN (0.2% three tive patients with CAF were randomly included in the study.
times a day) for 4 wk can be used for the treatment of AF. Twenty-four patients received oral (60 mg) and 26 received
All the above studies reported that GTN was beneficial topical (2% gel) DTZ twice daily for up to 8 wk. Anal manom-
for the treatment of CAF. However, in a very few studies, it etry and blood pressure were recorded at 15-min intervals.
has been reported that GTN produced no benefit regarding Every 15 days, patients were assessed on the basis of pain
healing or pain relief. In a randomized, double-blind study, alleviation, fissure healing, and side effects. After 8 wk, RAP
including 48 patients with CAF (42), three groups of patients fell by 15 and 23% in the two groups, respectively. Fissure
received 0% (placebo), 0.2% (0.75 mg), and 0.4% (1.5 mg) of healing was complete in 38% and 65% in patients with oral
GTN ointment. The study was completed by 69% of patients. and topical DTZ treatment by 8 wk, respectively. Side effects
Other patients failed to complete the study due to headaches including rashes, headache, nausea, and vomiting were ob-
and cooperation problems. No significant difference (P < served in eight patients of the oral DTZ group, whereas no
0.05) was found between the groups with respect to patient side effects were seen in those receiving topical therapy (P
age, gender, past history, physical examination, amount of = 0.001). Thus topical DTZ was found to be more effective
ointment used, and adverse events. No significant difference with no side effects.
was found between the groups regarding healing (P = 0.952) Carapeti et al. conducted three studies each involving 10
or pain relief (P = 0.458–0.8 according to the type of pain healthy volunteers. In the first study, subjects were given oral
checked). According to this study, there was no benefit re- DTZ (60 mg) or placebo on separate occasions. They were
garding healing or pain relief, in treating patients suffering then given DTZ once or twice daily for 4 days. In the sec-
from AF with GTN ointment in combination with stool soft- ond and third studies, DTZ and bethenachol (BTN) gels of
eners and sitz baths compared to the same treatment without increasing concentration were applied topically to lower anal
GTN ointment. pressure (46). DTZ gel (2%), BTN (0.1%), and oral DTZ
twice daily produced 28%, 24%, and 17% reductions in anal
pressure, respectively.
DILTIAZEM (DTZ) DTZ VERSUS GTN
The internal anal sphincter has a calcium-dependent mecha- In a study reported by Jonas et al. (47), the efficacy of DTZ
nism to maintain tone, and also receives inhibitory extrinsic for fissures that failed to heal with GTN was evaluated. Con-
secutive patients (N = 39, median age 42 yr) with persistent
cholinergic innervation. It may therefore be possible to lower
anal sphincter pressure using calcium channel blockers and CAF despite treatment with GTN ointment (0.2%) under-
cholinergic agonists without side effects. went anal manometry before and for 1 h after application of

4. 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 6–8 wk)
GTN (0.5% N = 21)
(51) 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 daily for 6 wk. Thus, a combination of lidocaine and NIF can
was applied twice daily for 8 wk. Fissure healing and side be a reliable nonsurgical method for treating CAF (53, 54).
effects were noted every 15 days. Topical DTZ gel lowered Katsinelos et al. compared the efficacy of NIF ointment
RAP by 20% and fissures healed in 49% of patients within 8 (0.5%) with LIS for the treatment of CAF (55). Sixty-four
wk. Before DTZ, 69% had used a complete course of GTN patients with symptomatic CAF were randomly assigned NIF
ointment (N = 32) every 8 h for 8 wk or LIS (N = 32).
(0.5 g twice daily for 8 wk), and 44% of patients healed with
DTZ. Some of the patients had discontinued GTN prema- In addition, both stool softeners and fiber supplements were
turely because of headaches. Side effects including perianal prescribed. Patients were assessed at 2, 4, 6, and 8 wk. Long-
itching, headache, drowsiness, and mood swings occurred in term outcomes were determined after a median follow-up of
10% of patients during DTZ treatment. Hence, the authors 19 and 20.5 months for the NIF and LIS group, respectively.
concluded that topical DTZ (2%) was effective treatment for The overall healing rates at the end of follow-up were 93% and
100% in the NIF and LIS groups, respectively (P = 0.48).
GTN-resistant CAF.
Griffin et al. (48) used topical DTZ gels to heal patients Fifty percent of patients developed side effects in the NIF
with CAF that had failed previous treatment with topical group compared with 18.7% in the LIS group.
GTN (0.2%). Patients (N = 47) with CAF who had previ-
ously failed at least one course of topical GTN were recruited
prospectively from a single center. They applied DTZ (700 LACIDIPINE
mg of 2%) cream to the anal verge twice daily for 8 wk.
Lacidipine is a calcium channel blocker like nifedipine and
Forty-four percent of patients who completed treatment were
hence finds its use in the treatment of AFs. Twenty-one con-
cured of fissures. Another 42% of patients with persistent
secutive patients (16 women) with AF (16 chronic, situated
fissures were symptomatically improved. Thus surgery could
posteriorly in 17 patients, anteriorly in 4 patients) with a mean
be avoided in 70% of patients. A few studies where topical
age of 37.1 yr were treated with oral lacidipine (6 mg daily)
DTZ has been compared with GTN and bethenechol (BTN)
(56). Blood pressure, pain scores (assessed from 0 to 10 on a
are included in Table 2.
visual analogue scale), and fissure healing were monitored af-
ter 2, 4, and 8 wk. However, about 33.3% patients developed
side effects. Pain scores were significantly reduced after 2
wk and continued to show a significant reduction throughout
NIFEDIPINE (NIF)
the treatment period. Fourteen percent and 90.4% of fissures
NIF has also been used in treatment of AFs as reported in a were healed after 14 and 28 days, respectively. No recurrences
number of studies (52). In a prospective, randomized, double- in fissures were reported.
blind, multicenter study, the efficacy 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.
BOTULINUM TOXIN (BTX)
The control group (N = 142) received topical lidocaine (1%)
and hydrocortisone acetate (1%) gel during therapy. Manom- BTXs comprise a family of neurotoxins designated as types A
etry was performed before and after 14 and 21 days. After to G, which are produced by the anerobic bacterium Clostrid-
21 days of therapy, 95% and 50% of patients were healed in ium botulinum. BTX-A blocks cholinergic transmission re-
the NIF group and control group, respectively (P < 0.01). A sulting in flaccid paralysis and autonomous nerve dysfunc-
mean reduction of 30% (P < 0.01) and 188.8% (P < 0.01) tion. CAFs are caused by anal sphincter hypertonia leading
in anal pressure and squeeze pressure was observed. to an ischemic ulcer. BTX-A injection into the internal or ex-
In other studies reported by Merenstein and Rosenbaum ternal anal sphincter causes relaxation of the anal sphincters,
and Slawson, remarkable improvement in healing was ob- enhances microcirculation at the fissure site, and promotes
served when 1.5% lidocaine and 0.3% NIF were applied twice fissure healing (57). Studies of BTX injection into the anal

5. 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 2.5–5U (BTX) 100 (43 women, 79
fissure average age 34.7)
(after 6 months)
(61) Anterior midline of Group A (BTX 20 U) 50 Group A (96)
internal anal
sphincters)
GTN twice daily Group B (GTN 0.2 %) Group B (60)
for 6 wk
(62) External anal 15 U (BTX) 40 42 (at 3 months)
sphincter
50 (at 6 months)
(63) Internal anal 50U (BTX) 13 54 (after 1 month)
sphincter
85 (after 2 months
(64) Laterally into 50U (BTX) 12 (8 women, 4 25 (1 month)
internal anal men)
sphincter
58 (after 3 months)
Group A (BTX 20 U, N = 10)
(65) - 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 group underwent LIS. The remaining 10 patients (control
procedure is more invasive, and patients may find it uncom- group) received BTX injections (20 U). Seven patients had
fortable and less tolerable. healed fissures after 2 months; the other three left the study
Brisinda et al. tried to optimize the dose of BTX. In their and underwent surgery. Four patients in the treated group
study, 150 patients with posterior AF were treated with BTX were later retreated (with 25 U of BTX); all had healed fis-
injected into the internal anal sphincter on each side of the sures after 2 months. A few clinical studies carried out using
anterior midline (58). Subjects were randomized into two BTX have been encompassed in Table 3 too.
treatment groups. Patients in group I were treated with 20 Sixty patients with CAF were recruited in a study con-
U of BTX and, if the fissure persisted, were retreated with ducted by Thornton et al. (69). Fifty-seven patients (30
an additional 30 U. Patients in group II were treated with 30 women) with median age 43 received 20 U of BTX in-
U and retreated with an additional 50 U, if the fissure per- jected into the intersphincteric groove. Each parameter was
sisted. One month after the injection, examinations revealed reassessed after 2 wk and 3 months. Physical healing and
complete healing in 73% from group I and 87% from group symptom control were dependent on the baseline maximum
II (P = 0.04). Five patients from group II reported mild in- RAP and baseline fissure score (P = 0.003, P = 0.009, re-
continence of flatus that lasted 2 wk after the treatment and spectively). Although maximum RAP fell by 17%, pressure
disappeared spontaneously. The values of the RAP (P = 0.3) reduction did not correlate with clinical outcome (P > 0.2).
and the maximum voluntary pressure (P = 0.2) did not differ Seventeen patients reported a mean 17% increase in conti-
between the two groups. A recurrence of the fissure was ob- nence score.
served in 6 patients from the group. The authors confirmed Daniel et al. (70) reviewed the published studies about the
that with an increase in dose, the success rate increased with use of BTX injection in the management of CAF. The authors
little increase in side effects. reported that healing occurred in more than 70% of fissures
Another study proved the use of local infiltration of BTX without irreversible incontinence.
into the internal anal sphincter as an effective treatment for
CAF. In a double-blind, placebo-controlled study, 30 consec-
COMBINED TREATMENT APPROACH
utive symptomatic adults were enrolled (59). All the patients
received two injections (total volume 0.4 mL) into the in- The use of BTX is associated with hyperhidrosis (syndrome
ternal anal sphincter. The treated group (N = 15) and the associated with excessive sweating). Wollina and Konrad (71)
control group (N = 15) received 20 U of BTX-A and saline, compared the traditional BTX-A treatment of muscular spas-
respectively. After 2 months, 11 patients in the treated group ticity in AFs with combined treatment of spasticity and focal
and two in the control group had healed fissures (P = 0.003). treatment of the anal fold and perianal skin. Ten patients
Thirteen and four patients in the treated and control group, with CAF (of more than 6 months’ duration who failed to re-
respectively, were relieved of symptoms (P = 0.003). The spond to conservative treatment and who had refused surgery)
MRAP was reduced by 25% in the treated group as compared associated with focal hyperhidrosis as assessed by Minor’s
with the control group. Later on three patients in the control sweat test were investigated in an open, two-armed trial.

6. Treatment of Anal Fissures 1317
Intramuscular injections of 20–25 U BTX-A were given in Isosorbide Dinitrate (ISDN)
group A (N = 5). In group B (N = 5), injections were com- In a randomized, prospective, double-blind, placebo con-
bined with intracutaneous injection of 30–50 U BTX-A to trolled trial, 37 consecutive subjects with AF were enrolled
treat focal hyperhidrosis. The mean follow-up was 5 months. (75). The subjects were divided into two groups. One group
(N = 20) received ISDN and the other group (N = 17) was
All the patients in group B and two of the five patients in
group A experienced a complete remission despite the fact given placebo. Both groups were treated for a median of 5
that relief of pain was evident in eight of 10 patients within 2 wk. After this period, 17 subjects in the isosorbide group
had healed compared with 6 controls (P < 0.003). The fis-
wk. Patient satisfaction with treatment was high in group B.
The study suggested that combined therapy of both muscu- sure recurred in 2 patients who had an initial good response to
lar spasticity and focal hyperhidrosis may provide better re- isosorbide, and in 2 patients of the control group. Side effects
sults than intramuscular injections alone in AF therapy with (particularly headache) were more common after ISDN.
In a study carried out by Songun et al., patients (N = 100)
BTX-A.
In another study carried out by Bhardwaj et al. (72), 10 pa- with AF were treated with ISDN, the primary healing rate of
tients (5 men) with median age 40.5 yr were injected with 20 AFs was 93% with ISDN (76). In case of recurrence (13%),
U BTX at the site of the fissure. The optimal angle for injec- 54% could again be treated successfully with ISDN but a
tion of BTX-A was 60◦ . Assessment was made on the basis complication (temporary headache) was observed in about
of a visual analogue pain scale, incontinence score, and anal 7% of patients.
manometry preinjection, at 48 h postinjection and at 6 and 12
wk postinjection. All the patients attended the 48 h follow-up L-Arginine (LA)
visit, but only seven attended the 6- and 12-wk visits. In six of Nitric oxide produced from the cellular metabolism of LA
seven patients, the fissures were healed. The remaining three also causes relaxation of the internal anal sphincter. A study
were contacted by telephone at 6 months postinjection and investigated by Griffin et al. reported that topical LA can
two of three remained asymptomatic without further treat- be used as a possible alternative treatment for CAF (77). In
a two-center study, volunteers (N = 25) received LA (400
ment. In seven patients, the median pain score preinjection
was 5.5 out of 10 (range 1–10) and this dropped to a median mg) or placebo. Anal manometry was performed 2 h after
of 1 at 12 wk. The median drop in resting pressure was 37% application of LA gel or placebo gel. It was found that LA
at 6 wk. gel significantly lowered MRAP. LA gel had a rapid onset of
action with a duration of action of more than 2 h (P < 0.01).
BTX VERSUS GTN
Minoxidil and Lignocaine
In a prospective, nonrandomized, open-label study, patients In a prospective, randomized, double-blind study, 90 patients
(N = 40) with CAF who failed a course of GTN were treated with AF were recruited. Patients received local applications
of ointments containing 5% lignocaine (N = 28), 0.5% mi-
with 20 U of BTX-A (73). Symptomatic relief, visual healing
noxidil (N = 36), or both (N = 26) (78). Healing of AF at 6 wk
of fissures, side effects, and patient preference were assessed
at an 8-wk follow-up. About 73% patients had improved was considered as the primary end point. The healing rate was
symptomatically and avoided surgery. Forty-three percent of similar in the three groups. However, the mean time taken for
fissures were healed, whereas 57% of fissures remained un- complete healing with combination treatment (1.9 wk) was
healed. Of the unhealed fissures, 12%, 18%, and 27% were significantly shorter than that with minoxidil alone (3.1 wk,
P = 0.001) or with lignocaine alone (3.3 wk, P = 0.002).
asymptomatic, symptomatic, and came to surgery, respec-
tively. Transient minor incontinence symptoms were noted Thus, a combination of minoxidil and lignocaine helped in
in 18% of patients. Thus, authors concluded that second-line faster healing of AF and provided better symptomatic relief
BTX injection improved symptoms in approximately three- than either drug alone.
quarters of patients after failed primary GTN therapy.
Gonyautoxin
All the above treatments mentioned for AF, viz., LIS, GTN,
ISOSORBIDES
LA, NIF, and BTX, focused on reducing the tone of the inter-
nal anal sphincter. In a recent publication, Garrido and col-
Isosorbide Mononitrate (ISM)
Tankova et al. (74) conducted a study to assess the efficacy leagues (79) have described the successful use of a new agent,
and patient compliance of topical mononitrate hydrogel for gonyautoxin, in patients with acute AF and CAF. Gonyau-
the treatment of AF. ISM (0.2%) was applied to the anal toxin is a paralyzing phytotoxin produced by dinoflagellates.
canal twice daily for 3 wk. Anal pressure was determined us- It breaks the vicious circle of pain and spasm that leads to
ing anal manometry before and after the therapy. At the end AF. Fifty recruited patients received clinical examination, in-
of therapy, 88% and 22% fissures were healed in treated and cluding proctoscopy and questionnaire to evaluate the symp-
control group patients, respectively. Twenty percent of pa- toms (80). Anal manometry was performed before and after
tients suffered from mild heart attack. No fecal incontinence Gonyautoxin (100 U/mL) injection into both sides of the AF
and recurrence occurred during 3 months of follow-up. in the internal anal sphincter. Total remission of acute AF

7. 1318 Dhawan and Chopra
and CAF was achieved within 15 and 28 days, respectively. ies, participants were randomized to a nonsurgical therapy
Ninety-eight percent of the patients healed before 28 days for AF. Comparison included an operative procedure, an al-
with a mean time healing of 17.6 ± 9 days. Only one relapsed ternate medical therapy, or placebo. Dichotomous outcome
during 14 months of follow-up. There was about a 56% de- measures included nonhealing of the fissure (a combination
crease in resting pressure when compared with baseline. No of persistence and recurrence), and adverse events (including
side effects were observed. 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
OTHER TECHNIQUES
therapies to heal AF were reported in 31 retrospective charts
Sitz Bath (84). Nine agents (GTN, ISDN, BTX, DTZ, NIF, hydrocorti-
In addition to chemical agents used above, sitz baths have sone, lignocaine, bran, placebo) as well as anal dilators and
been used to provide relief to patients with CAF. Shafik con- surgical sphincterotomy were used. GTN was compared with
ducted a study on 18 healthy volunteers and 28 patients with a placebo group (0.78, 0.56–1.08), in children (0.96, 0.48–
painful anorectal diseases (18 patients with fissures and 10 1.92), and adults (0.73, 0.50–1.07). It was observed that GTN
with hemorrhoids) (81). All of them used sitz baths to allevi- was not significantly better than placebo in curing AF. When
ate pain. Investigations were comprised of measuring rectal calcium channel blockers were tested against GTN, they were
and interstitial sphincter temperature, rectal and rectal neck found to be equivalent in their ability to cure fissure (odds
pressures, and electromyographic activity of both the exter- ratio 0.66, 0.22–2.01). BTX when compared with placebo
nal and internal anal sphincters before and after the subjects (0.75, 0.32–1.77) and GTN (0.48, 0.21–1.10) showed no sig-
sat in a warm-water bath at temperatures of 40, 45, and 50o C nificant advantage in efficacy. The authors also concluded
for 10 min. Pain relief was more evident and lasted longer at that a number of more studies are required to establish the
higher bath temperatures. There was no change in the rectal efficacy of calcium channel blockers.
and interstitial sphincter temperatures before and after bath Based on the reports of the clinical trials, we opine that
in both the healthy volunteers and patients. The rectal neck smooth muscle relaxation using chemical agents should be
pressure and internal and sphincter electromyographic activ-
ity dropped significantly in the bath, but increased gradually
to pretest levels 25–70 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 first
half of the study period, patients were treated with topical
GTN and pneumatic dilatation. Subsequent patients received
topical NIF and BTX injections (30–100 U). LIS was re-
served for patients who failed medical treatment. In 98% of
patients, the fissure 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 fissure, and fissure in
children may be applied with a chance of cure that is only
marginally better than placebo, and, for chronic fissure in
adults, far less effective than surgery (83). Efficacy and mor-
bidity of various medical therapies for AF were assessed from Figure 1. Algorithm for the treatment of anal fissures from available
the studies abstracted from published reports. In these stud- clinical trials.

8. Treatment of Anal Fissures 1319
tried first and if the fissures do not heal then surgery should 5. Acheson AG, Scholefield JH. Pharmacological advance-
ments in the treatment of chronic anal fissure. Expert Opin
be performed. The possible algorithm for the treatment of
Pharmacother 2005;6:2475–81.
AFs is provided in Figure 1.
6. Lubowski DZ. Anal fissures. Aust Fam Physician
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8. Hager T. Anal fissure. Ther Umsch 1997;54:190–2.
This review describes nonsurgical treatment modalities of- 9. Gupta PJ. A review of conservative and surgical manage-
ment of anal fissure. Acta Gastroenterol Belg 2005;68:446–
fered for CAF. Until now, lateral internal sphincterotomy has
50.
been considered to be the gold standard treatment for CAF.
10. Haq Z, Rahman M, Chowdhury RA, et al. Chemical
In the last decade, lateral internal sphincterotomy has been sphincterotomy–first line of treatment for chronic anal fis-
replaced by smooth muscle relaxation in most cases. This sure. Mymensingh Med J 2005;14:88–90.
medical option aims to achieve the effectiveness of surgery 11. Gupta PJ. Current treatment options for fissure-in-ano. J
Med Liban 2004;52:33–8.
without side effects by means of a temporary decrease of anal
12. Gupta PJ. Current trends of management for fissure in ano.
pressures that allows fissures to heal. Topical applications of
Rom J Gastroenterol 2002;11:25–7.
various agents, viz., glyceryl trinitrate (0.2%), diltiazem (2%), 13. Gupta PJ. Treatment of fissure in ano—revisited. Afr Health
nifedipine (0.2%), L-arginine (400 mg), minoxidil (0.5%), Sci 2004;4:58–62.
lignocaine (5%), and isosorbides (0.2%) are being exploited 14. Nyam D. Long-term results of lateral internal sphinctero-
tomy for chronic anal fissure with particular reference
for the treatment of AFs. Diltiazem (60 mg) and lacidip-
to incidence of fecal incontinence. Dis Colon Rectum
ine (6 mg) have also been tried orally. In addition to these
1999;42:1306–10.
approaches, injections of botulinum toxin (30 U-50 U) and 15. Garcia-Aguilar J, Belmonte C, Wong WD, et al. Open vs.
gonyautoxin (100 U) have also been reported. More than 80 closed sphincterotomy for chronic anal fissure. Dis Colon
clinical studies have been reported in the literature, wherein Rectum 1996;39:440–3.
16. McCallion K, Gardiner KR. Progress in the understand-
efficacy of smooth muscle relaxation has been assessed. All
ing and treatment of chronic anal fissure. Postgrad Med J
of these studies have shown that surgery can be avoided in
2001;77:753–8.
33–98% of patients by using smooth muscle relaxation. Glyc- 17. Garcia-Granero E, Munoz-Forner E, Minguez M, et al.
eryl trinitrate has been reported to heal 33–78% of patients Treatment of chronic anal fissure. Cir Esp 2005;78:
with CAF. However, use of glyceryl trinitrate is accompanied 24–7.
18. De Nardi P, Ortolano E, Radaelli G, et al. Comparison of
by side effects, viz., headache, low blood pressure. Oral dilti-
glycerine trinitrate and botulinum toxin-a for the treatment
azem caused a lot of side effects while with topical diltiazem
of chronic anal fissure: Long-term results. Dis Colon Rec-
application side effects were low. When nifedipine was used, tum 2006;49:427–32.
the healing rate (95%) was high but side effects were ob- 19. Kassai M, Illenyi L, Horvath OP. Current treatment of anal
served in 50% patients. A few studies have also documented fissure. Orv Hetil 2001;142:1565–8.
20. Jonas M, Scholefield JH. Anal fissure. Gastroenterol Clin
the use of isosorbides and L-arginine for the treatment of
North Am 2001;30:167–81.
CAF. The healing rate with botulinum toxin injection was
21. Lund JN, Scholefield JH. Aetiology and treatment of anal
found to be higher (98%), but it is invasive therapy and less fissure. Br J Surg 1996;83:1335–44.
convenient than topical application. Considering the various 22. Minguez M, Herreros B, Benages A. Chronic anal fissure.
pros and cons, we opine that treatment of CAF must be in- Curr Treat Options Gastroenterol 2003;6:257–62.
23. Lindsey I, Jones OM, Cunningham C, et al. Chronic anal
dividualized, depending on the clinical condition of patients.
fissure. Br J Surg 2004;91:270–9.
Smooth muscle relaxation should be tried first and if there is
24. Ehrenpreis ED, Rubin DT, Ginsburg PM, et al. Treatment of
no relief, then lateral internal sphincterotomy can be used. anal fissures with topical nitroglycerin. Expert Opin Phar-
macother 2001;2:41–5.
Reprint requests and correspondence: Sanju Dhawan, Uni- 25. Fenton C, Wellington K, Easthope SE. 0.4% nitroglycerin
versity Institute of Pharmaceutical Sciences, Panjab University, ointment: In the treatment of chronic anal fissure pain. Drugs
Chandigarh-160014, India. 2006;66:343–9.
Received August 21, 2006; accepted January 18, 2007. 26. Lund JN, Armitage NC, Scholefield JH. Use of glyceryl
trinitrate ointment in the treatment of anal fissure. Br J Surg
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27. Manookian CM, Fleshner P, Moore B, et al. Topical nitro-
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CONFLICT OF INTEREST
2001;167:382–5.
76. Songun I, Boutkan H, Delemarre JB, et al. Effect of
Guarantor of the article: Sanju Dhawan, Ph.D.
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2003;20:122–6. Specific author contributions: Sanju Dhawan conceived the
77. Griffin N, Zimmerman DD, Briel JW, et al. Topical L- idea to review the clinical trials in order to contribute to the
arginine gel lowers resting anal pressure: Possible treatment society. Sunny Chopra collected the literature from the jour-
for anal fissure. Dis Colon Rectum 2002;45:1332–6.
nals and libraries. He compiled a draft of the reported clinical
78. Muthukumarassamy R, Robinson SS, Sarath SC, et al. Treat-
trials. The manuscript was extensively edited, interpreted, and
ment of anal fissures using a combination of minoxidil and
lignocaine: A randomized, double-blind trial. Indian J Gas- revised by Sanju Dhawan.
troenterol 2005;24:158–60. Financial support: Sunny Chopra worked as a Junior Re-
79. New toxin treatment for anal fissures. Nat Clin Pract Gas- search Fellow in the Postgraduate Program of University
troenterol Hepatol 2005;2:126–7.
Institute of Pharmaceutical Sciences, Panjab University,
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Chandigarh, India. He was admitted to the Program under
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Colon Rectum 2005;48:335–40; discussion 340-3. industry-sponsored candidate quota approved by All India
81. Shafik A. Role of warm-water bath in anorectal condi- Council of Technical Education, New Delhi, India.
tions. The ”thermosphincteric reflex.” J Clin Gastroenterol Potential competing interests: None.
1993;16:304–8.