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119
ound a healing rate of 7% (n = 1) in the indoramin group, and a rate of 22% (n = 2)
in the placebo group. Pulse and blood pressure values did not change, but about
one- half of the patients complained of a “blocked nose” after the intake of indora-
min. The trial was discontinued because the single one “healed” anal fissure recurred
after another 6 weeks.
11.2.6 Arginine
Arginine (L-arginine) is a water-soluble amino acid which is present in many food-
stuffs. For instance, 100 g peanuts contain 3.46 g arginine.
Arginine leads to the release of nitrogen monoxide (NO), which physiologically
causes vascular dilation.
In 2002, Griffin et al. were the first to report a relaxing effect of arginine. They
perianally applied 400 mg L-arginine gel to 25 healthy probands and afterwards
noticed a decrease in anal resting pressure by 46% on average for the duration of at
least 2 h. Side effects such as headache were not found. Later, Acheson et al. (2003)
carried out in vitro studies on isolated human internal anal sphincter muscles. They
found an average decline in the myogenic tone of 40.2%.
Fifteen anal fissure patients were treated intra-anally by Gosselink et al. (2005)
with 40% L-arginine gel five times a day. The healing rate after 18 weeks was 62%.
None of the patients complained of headache. Anal resting pressure was signifi-
cantly reduced, while anodermal blood flow was distinctly increased.
An oral dose of 15 g daily for 7 days led to a rise of the arginine plasma level in
healthy probands, but led neither to a reduction of the anal resting pressure nor to an
improvement of anodermal perfusion. Side effects were not observed (Prins et al. 2005).
Conclusion
Further randomized controlled clinical trials have to be carried out for the evalua-
tion of the arginine therapy.
11.2.7 Sildenafil
Sildenafil (Viagra
®
) is a drug intended to treat erectile dysfunction.
The release of cyclic guanosine monophosphate (cGMP) leads to smooth muscle
relaxation. The enzyme phosphodiesterase type 5 (PDE5) splits cGMP which is
thus inactivated. Sildenafil inhibits PDE5 selectively and thus ensures that also
small quantities of cGMP lead to a muscular relaxation.
In 2002, Jones and Mortensen carried out in vitro tests on the human internal
anal sphincter muscle and found a high reduction rate in the muscle tone after the
application of PDE5. These findings were confirmed by Ballester et al. (2007)
Having tested 32 in vitro samples of internal anal sphincter muscle fibers, they
found a significant muscular relaxation of a histamine-mediated contraction, caused
by an increase of cGMP.
11.2 Conservative Therapy
120
Aygen et al. (2005) carried out in vitro tests of isolated canine internal sphincter
muscle fibers and saw a significant dose-dependent inhibition of acetyl choline-
induced contraction after the application of sildenafil.
In 2004, Torrabadella et al. treated 19 chronic anal fissure patients and proved
also that the intra-anal dose of 0.75 ml sildenafil cream (10%) effected a significant
reduction by 18% on average in the anal resting pressure. Twenty-six percent of
patients had little or moderate anal complaints like pruritus ani and burning, but no
complications.
Conclusion
The question remains whether the topical application of sildenafil can have besides
muscular relaxation also a therapeutic effect in the treatment for chronic anal fis-
sure. It has to be answered in further clinical trials.
11.2.8 Bethanechol
Bethanechol is a direct parasympathomimetic agent, which as agonist immediately
stimulates the muscarinic acetylcholine receptor.
Carapeti et al. (1999) showed in healthy volunteers that topical application of
bethanechol significantly decreases resting anal sphincter tone.
In a further study, Carapeti et al. (2000) examined the effect of bethanechol in 15
chronic anal fissure patients. The topical perianal application of 0.1% gel three
times a day for 8 weeks resulted in complete healing of the anal fissure in 60% of
patients. Anal resting pressure was significantly reduced, blood flow had not
changed, and no headache or any other side effects were observed.
Conclusion
Randomized controlled clinical trials have to be carried out to evaluate local
bethanechol therapy.
11.2.9 Botulinum Toxin
Botulinum toxin (BTX) is a naturally occurring bacterial toxin, which is secreted as
exotoxin by Clostridium botulinum under anaerobic conditions. Seven subtypes
(A to G) have so far been identified, which do not only differ in their structure from
each other, but also in their immunological and pharmacological characteristics.
Their biological activity is given in mouse units (mu). One unit corresponds to the
amount of toxin which has a lethal effect on 50% of the mice tested (LD50).
In their clinical application, the units of the various BTX products are not equiva-
lent. Therefore, the dosages recommended by the respective manufacturers are not
applicable to other BTX preparations.
In Germany, botulinum toxin A is approved as injection solution in the treatment
of various diseases, but not in the therapy for anal fissure (Botox
®
, Vistabel
®
, Dysport
®
,
11 Therapy for Chronic Anal Fissure
121
and Xeomin
®
). Accordingly, the use of BTX is defined as a therapeutic or curative
attempt applying an approved drug for an unapproved indication (off-label use).
The choice of the injection site differs from author to author. Most authors inject
into the internal anal sphincter muscle, while others (Jost et al. 1995; Madalinski
et al. 1999) into the external anal sphincter muscle, and others again into the inter-
sphincteric groove (Thornton et al. 2005). Generally, the injections are tolerated
well. Rare complications such as anal thrombosis are described by Jost et al. (1995).
Botulinum toxin is a drug with a peripheral effect. It blocks the signal transmis-
sion at the neuromuscular junctions by inhibiting the release of acetylcholine. Its
application results in a temporary muscle relaxation, lasting about 2–3 months;
rarely, cases of permanent incontinence have been described (Brown et al. 2006;
Smith and Frizelle 2004).
BTX Studies
There are numerous studies which examine the effect of BTX injection used in the
treatment of chronic anal fissure, and there are some trials which compare this effect
with other drugs or surgical measures.
Table 11.16 shows in 22 studies with a total of 1013 patients that a healing rate
between 43% and 92% and a recurrence rate between 0.0% and 83% can be expected
in most cases after an early follow-up period of 2–6 months. But after a 3-year fol-
low- up, only 47% of anal fissures were healed, and the relapse rate was 53% (Arroyo
et al. 2005).
The behavior of the sphincter muscles is not clear. Whereas all authors observe a
reduction of the anal resting tone, the anal squeeze pressure remains unaltered in
some collectives, but is reduced in others.
Below, those controlled trials are presented which compare BTX therapy with
other therapy measures.
BTX Versus Lateral Sphincterotomy
The five trials in Table 11.17, too, suggest that the application of BTX produces a
similar trend: short-term healing in 41–88% of cases and a high relapse rate in the
long-term study.
BTX Versus GTN
After a short-term follow-up (2–6 months), healing rates of 20–96%, and no relapse
are observed in contrast to the longer follow-up period with a relapse rate of 33%
(De Nardi et al. 2006). A meta-analysis (Sajid et al. 2007) provides evidence that
BTX is just as efficient as GTN (Table 11.18).
BTX Versus Placebo
Siproudhis et al. (2003) treated 22 patients with BTX (one-time injection) who had
been suffering from anal fissure complaints for 8 months on average, and 22 patients
with placebos. After 4–12 weeks, the results did not differ; placebo and BTX had
the same therapeutic effect. Five patients in each group were healed, and five
patients in each group had to be given surgical treatment.
11.2 Conservative Therapy
122
Table 11.16 Details of 22 studies on BTX therapy with 1013 patients
Author (year)
Patients and
groups (n)
Duration of symptoms
before therapy (Months)
Healing rate
and duration
after BTX therapy
Recurrence rate
and lapse of time
Anal resting
pressure
Anal squeeze
pressure(%) (Months) (%) (Months)
Arroyo et al. (2005) 100 17 47 36 53.0 ↓ →
Bhardwaj et al. (2006) 10 12 80 3 ↓
Brisinda et al. (2002) 75/75 12/13 89/96 2 8.0 2 ↓ →
Brisinda et al. (2004) 50/50 13/13 92/94 2 0.0 22 ↓ ↓
Espi et al. (1997) 36 73 0.0
Fernandez Lopez et al. (1999) 76 37 67 3
Godevenos et al. (2004) 45 2–8 78 2 4.4
Gonzales Carro et al. (1999) 40 3+ 50 6
Gui et al. (1994) 10 13 70 2 10.0 1 ↓ →
Jost and Schimrigk (1994) 12 6–32 83 6 83.0 6
Jost (1997) 100 14 79 6 8.0 6
Jost et al. (1995 25 15 84 6 4.0 6
Lindsey et al. (2003) 40 12 43 2
Maria et al. (1998) 23/34 10/13 43/67 2 ↓ →
Maria et al. (2000) 50 16 60 2 ↓ →
Mason et al. (1996) 5 60 3 ↓ →
Minguez et al. (1999) 23/27/19 12/20/20 83/78/90 6 ↓ ↓
Simms et al. (2004) 47 10 79 27.0 16
Thornton et al. (2005) 56 66 2.5 ↓ ↓
Tranqui et al. (2006) 50 92 4.0
Trzcinski et al. (2002) 13 85 4 8.0 4 ↓ ↓
Witte and Klaase (2007) 100 77 10 14.0 ↓ ↓
11 Therapy for Chronic Anal Fissure
123
Table 11.17 Details of five BTX therapy versus lateral internal sphincterotomy (LIS) trials with 300 patients
Author (year)
Patients and therapy
Healing LIS (%)
BTX
Anal
resting
pressure
Anal
squeeze
pressureBTX (n) LIS (n) Healing (%)
Duration
(Months) Recurrence (%)
Lapse of time
(Months)
Arroyo (2005) 40 40 92 45 36 55 36 ↓ →
Giral et al (2004) 10 11 82 70 2 0 14 ↓ ↓
Iswariah (2005) 17 21 91 41 6.5 5 6 n/a n/a
Massoud (2005) 25 25 100 88 6 80 6 n/a n/a
Mentes et al. (2003) 61 50 94 75 12 11 6
Total 153 147
11.2 Conservative Therapy
124
Maria et al. (1998), however, described results in 15 anal fissure patients who had
been treated with a BTX injection and 15 controls who had received a saline solu-
tion injection. After 2 months, 11 anal fissures had healed in the verum group, but
only two anal fissures in the placebo group. A decrease in anal resting tone could be
shown in the verum group. At the end of 16 months, no relapse was observed in any
group.
BTX Versus Lidocaine Ointment
Colak et al. (2002) treated 24 patients with BTX and 28 patients with lidocaine oint-
ment. All the patients said to have been suffering from complaints for 12 months on
average. After 2 months of treatment, there was a healing rate of 70.58% in the first
patient group and of 21.42% in the second group. Different from lidocaine, treat-
ment with BTX resulted in a significantly reduced anal resting tone and in decreased
squeeze pressure rates.
BTX Combined with Lateral Internal Sphincterotomy (LIS)
Baraza et al. (2008) performed sphincterotomy in 46 anal fissure patients
combined with a simultaneous BTX injection. After an average of 11 months,
85% of anal fissures had healed. After 22 months, however, 50% of patients had
a relapse. The high relapse rate is probably due to the fact that the sentinel tag
was left intact. The authors state that “The sentinel pile if present was left
alone.”
Lindsey et al. (2004) performed sphincterotomy in 30 patients, and simultane-
ously injected BTX. After 4 months, 93% of anal fissures had healed.
Table 11.18 Details of seven tBTX versus GTN therapy trials with 314 patients
Author
(year)
Patients by
therapy
Duration
of
symptoms
before
(Months)
Healing after
BTX therapy
BTX therapy
and
recurrence
Anal
resting
pressure
Anal
squeeze
pressureBTX GTN
Rate
(%)
Duration
(Months)
Rate
(%)
After
(Months)
Brisinda
et al. (1999)
25 25 9.5 96 2 0 15 ↓ →
Brisinda
et al. (2007)
50 50 17 92 2 0 21 ↓ →
De Nardi
et al. (2006)
15 15 >3 33 36 33 36 n/a n/a
Fruehauf
et al. (2006)
25 25 >2 24 1/2 0 14 n/a n/a
Jones et al.
(2006)
15 15 +BTX 15 27 2 n/a n/a ↓ ↓
Lysy et al.
(2006)
15 15 +BTX 21 20 1.5 n/a n/a n/a n/a
Madalinski
et al. (2001)
13 11 +BTX n/a 55 n/a n/a n/a n/a n/a
Total 158 156
11 Therapy for Chronic Anal Fissure
125
Conclusion
The following findings can be gained from the trials on hand:
1. Since the BTX units of the individual products are differently defined and are not
equivalent, a comparison of results makes no sense.
2. The optimal injection site (either internal or external anal sphincter muscle, or
intersphincteric groove) is not known.
3. The relapse rates after BTX therapy are low after a short observation period, yet
very high after 3 years.
4. “The Australian as well as the Canadian drug surveillance authorities point out
that BTX should only be used in approved indications in the recommended dos-
age and in knowledge of the anatomical structures and injection techniques”
(Quoted from Rheinisches Ärzteblatt of 3 November 2009; translation from the
German original). The reason for these recommendations was a variety of effects,
unwanted and systemic, and lasting mostly for a limited period of time, such as
allergies, diplopia, and hypotonia (differing according to the field of use).
However, there were single cases of systemic side effects which were life-threat-
ening, for example, aspiration pneumonia. Five reports referred to cases of death,
among them a case of botulism. Except for one case, the complications occurred
under medical indications, and partly after off-label use.
5. The findings of most of the trials are of no value because of their methodical
shortcomings, especially because of the inexact definition of chronic anal
fissure.
11.2.10 Further Therapeutic Agents
Muthukumarassamy et al. (2005) treated a total of 90 chronic anal fissure patients
with 5% lignocaine or with 0.5% minoxidil ointment or with a combination of both
topical applications for 6 weeks three times a day. Lignocaine is a local anesthetic,
and minoxidil is a calcium channel opener which releases nitrogen monoxide (NO)
as a muscle relaxant and vasodilator. Minoxidil is applied as an antihypertensive
agent which is also topically used as the therapy for androgenetic alopecia (Regaine
topical solution or foam). In their noncontrolled, nonrandomized study, the authors
found that the combination therapy resulted in healing anal fissure in 32% of cases
and that the combination was more effective than the therapy using the substances
individually.
Ansaloni et al. (2002) treated 21 anal fissure patients with a daily oral dose of 6 mg
lacidipine (Motens) for a period of 28 days. In addition, patients took warm sitz baths.
Lacidipine is a calcium channel blocker drug belonging to the 1,4-Dihydropyridine
class. It leads to the relaxation of vascular and smooth musculature. The relaxant
effect persists longer than under the therapy with nifedipine. In 90.4% of cases, the
authors found a complete healing of anal fissure. A change in the systolic or diastolic
blood pressure was not observed. In 33% of cases, however, severe side effects such
as headache, flush, abdominal pain, or ankle edemata occurred.
11.2 Conservative Therapy
126
The oral dose of 5-aminosalicylic acid (1500 mg Claversal per day) for 14 days
seems to have no effect on either the acute or chronic anal fissure. According to
Bornschein (1987), there was no significant difference in regard to the healing rate
between the verum (n = 24) and placebo group (= 25).
Gonyautoxin belongs to the group of paralytic shellfish toxins (PST) and is a
metabolic product of algae accumulated in shellfish. Garrido et al. (2005) injected
100 units of gonyautoxin into the internal anal sphincter muscle of 50 patients with
acute or chronic anal fissure. They noticed a decrease in anal resting tone of 43.8%
on average. After 28 days, 98% of anal fissures had healed. Side effects were not
observed.
Hyperbaric oxygen is assumed to heal chronic wounds due to additional tissue
oxygenation. Cundall et al. (2003) saw eight anal fissure patients in 15 treatment
sessions for a period of 3 weeks. After 3 months, five anal fissures (33%) had healed.
11.3 Surgical Treatment
11.3.1 Lateral Internal Sphincterotomy (LIS)
According to many authors, the increase of the internal anal sphincter tone
stands in the focus to explain the pathogenesis of anal fissure. The partial sever-
ance of the internal anal sphincter muscle with the intention to reduce anal
sphincter tonus is therefore regarded as a surgical procedure which is looked
upon as first-choice therapy because of its assumed safety. Sphincterotomy was
described first time ever by Alexis Boyer in his monumental work “Traitë des
Maladies Chirugicales” 1818–1826.
The internal anal sphincter is an important muscle of the continence organ.
Especially English and American authors, however, assume that the anal sphincter
is of only minor importance for fecal continence. Therefore, the sphincter muscle
could safely be partially severed.
Yet, we are convinced that the internal anal sphincter is not an insignificant mus-
cle, but extremely important for the closure of the anus (cf. Chap. 1).
The resting tone of the anal closure apparatus is maintained by both the smooth
musculature (M. sphincter ani int.), accounting for 55–70%, and the striated muscu-
lature (M. sphincter ani ext. and M. puborectalis), accounting for 30–45% (Jostarndt
et al. 1986; Schweiger 1982; cf. Chap. 5.2.1). Both muscles degenerate with increas-
ing age. Therefore, sphincterotomy bears the risk of an additional functional deficit
in old age (Fig. 11.1).
This does not seem to be a general understanding. According to a survey on suit-
able surgical therapies, 85% of the surgeons interviewed favored anal sphincterot-
omy (Kraemer et al. 1998). In the year 2000, Argov and Levandovsky headlined
“Open lateral sphincterotomy is still the best treatment for chronic anal fissure.”.
Also, the American guideline of 2010 calls lateral sphincterotomy the method of
choice (Perry et al. 2010).
11 Therapy for Chronic Anal Fissure
127
Indication
The majority of authors sees the indication for partial sphincterotomy in the chronic
anal fissure with secondary changes existing for several months already.
Contraindication
Sphincterotomy is contraindicated for all types of fecal incontinence. Preoperative
manometry and endoanal sonography give information about possibly existing defi-
ciencies of the sphincter muscle. These tests are recommended for older women and
multipara.
Sphincterotomy Techniques
The open lateral sphincterotomy, according to Parks (1967), is performed either
under regional or general anesthesia. As a rule, a Parks’ anal retractor is inserted in
the anal canal. Then, a left lateral arcuate incision is made above the palpable inter-
sphincteric groove between 2 and 4 o’clock supine positions. The optimal incision
size is wide enough so that the internal anal sphincter muscle becomes visible. The
surgical scissors are spread to expose the intersphincteric groove and the subanoder-
mal area. Then, the internal anal sphincter muscle can be severed under view (open
technique) with scissors in its distal part. In this way, the risk of injuring the anoderm
is minimized. The incision wound is finally closed with a dermal suture (Fig. 11.2).
100
90
80
70
60
50
40
30
20
10
Youth Seniority Seniority +
sphincterotomy
Total capacity (%)
Loss of continence in the elderly
Loss of continence in the elderly
Loss due to
sphincterotomy
Capacity m. sph. ani ext.
at rest (%)
Capacity m. sph. ani int.
at rest (%)
15%
15%30%
30%
30%
60%
10%
70%
10%
15%
15%
100% 75% 45%
Fig. 11.1 Loss of anal continence due to aging and lateral internal sphincterotomy
11.3 Surgical Treatment
128
Fig. 11.2 Open lateral
sphincterotomy according
to Parks, incision of M.
sphincter ani int. under
view
The closed lateral sphincterotomy was described by Notaras in 1971. As a rule,
it is carried out under local anesthesia. A small radiate incision of the skin is made
at the anal edge at 3 o’clock. The intersphincteric groove is located by palpation
under control of the index finger inserted in the anal canal (closed technique). A
special scalpel – similar to the one used in cataract surgery – is advanced with its flat
side in the intersphincteric groove. It is then rotated by 90° with its cutting edge
perpendicular to the internal anal sphincter muscle, which is severed on retraction.
This incision can also be done with scissors. In doing so, the unintentional opening
of an anal crypt or an incision of the anoderm can be avoided. Injuring a crypt with
subsequent formation of a fistula is looked upon as a complication dependent on the
technique. Control by the index finger inserted in the anal canal should prevent this
complication. Notaras inaugurated his technique as an ambulatory surgery possible
under local anesthesia (Figs. 11.3 and 11.4). This operation technique has already
been described by Blandin (1855) in the first half of the 19th century (cf. Chap. 9.5).
A major problem regarding healing rates after lateral sphincterotomy lies in the
management of coexistent secondary changes such as skin tags, hypertrophied anal
papillae, anal crypts, or marginal fistulae. Some authors remove them, others leave
them in place, and others again give no details. In any case, secondary changes delay
healing and favor recurrence (Brühl and Krause 1985; Gupta 2004; Table 11.19).
Local or General Anesthesia?
Hiltunen and Matikainen recommend local anesthesia for the Notaras procedure,
whereas Keighley et al. (1981) advocate general anesthesia for the Parks’ technique.
11 Therapy for Chronic Anal Fissure