Glyceryl trinitrate (GTN, glycerol trinitrate, glycerine trinitrate) is a rather unstable, poorly water-soluble liquid. The intake of 0.01 g of the substance leads to headache. GTN is especially used in the therapy of angina pectoris and cardiac insufficiency because of its vasodilating effect induced by the release of nitrogen monoxide. It is available in Germany as rectal ointment (0.4% Rectogesic®) for pain relief of chronic anal fissure. A comparative cost accounting was done under the assumption that Rectogesic® therapy achieves healing rates which are nearly as high as those after sphincterotomy. The result was that Rectogesic® treatment will cost £ 616 compared to £ 840 for sphincterotomy treatment (Christie and Guest 2002).

After topical application of glyceryl trinitrate, a decrease in anal resting pressure occurs, which provides therefore a better perfusion of the anoderm and pain relief. Since the effect lasts only for a few hours (Ciccaglione et al. 2000; Jonas et al. 2002), a more frequent application over a period of some weeks becomes necessary.

The clinical trials reviewed by us rest upon differing durations of treatment. The following authors applied GTN one to three times per day for 8 weeks: Bailey et al. (2002); Bielecki and Kolodziejczak (2003); Brisinda et al. (2007); Carapeti et al. (1999); De Nardi et al. (2006); Evans et al. (2001); Hashmat and Ishfaq (2007); Jonas et al. (2002); Jones et al. (2006); Libertiny et al. (2002); Lund and Scholefield (1997); Mustafa et al. (2005); Sileri et al. (2007); Zuberi et al. (2000). The following authors applied GTN for six weeks: Brisinda et al. (1999); Chaudhuri et al. (2001); Christie and Guest (2002); Colak et al. (2003); Hyman and Cataldo (1999); Jonas et al. (1999); Lund and Scholefield (1997); Maan et al. (2004); Mishra et al. (2005); Richard et al. (2000); Watson et al. (1996). But there are also reports of shorter or significantly longer periods of therapy. The long-term therapy with nitrates can lead to a weakening of the pharmacological effect (tachyphylaxis). The concentration of GTN in topical medication varies between 0.1% and 0.8%. Despite differing concentrations (0.1–0.4%), the healing rate in 304 anal fissure patients was always 50% after intra-anal application for a period of 8 weeks (Bailey et al. 2002). Carapeti et al. (1999) treated patients with increasing doses of 0.1–0.6% GTN and described similar effects. During a dose-finding study, Watson et al. (1996) treated 19 patients with 0.2–0.8% GTN ointment. To achieve the desired 25% decrease in anal resting pressure, 15 of the 19 patients required a concentration higher than 0.2%. After 6 weeks, nine patients were free of anal fissures. Scholefield et al. (2003) increased systematically the GTN doses in a placebo-controlled RCT. After 2 months, 37.5% of the patients in the placebo group were healed. The healing rate after the application of 0.1% GTN was 46.9%, 40.4% when 0.2% GTN was applied, and 54.1% after a dose of 0.4% GTN.

Differences arise also due to the variety of carriers used for the production of drugs for topical application. Thus, GTN is embedded in paraffin, be it yellow, white, or liquid (Altomare et al. 2000; Bassotti et al. 2000; Brisinda et al.; Carapeti et al.; Dorfman et al. 1999; Hasegawa et al. 2000; Hashmat and Ishfaq; Kennedy et al. 1999; Loder et al. 1994; Lund et al. 1996; Pitt et al. 2001; Watson et al.). GTN embedded in Vaseline was applied by Bacher et al. 1997; Hyman and Cataldo, in glycerin (Oettlé 1997); and in lanolin/Vaseline (Brown et al. 2007; Colak et al.; Richard et al.). Obviously, the magistral preparation of a GTN topical medication is difficult. Azarnoff et al. (2007) analyzed a 0.3% GTN ointment which had been prepared by 24 American pharmacies, and noticed nonconformity with US pharmacopeia in 46% of cases. The median concentration was only 0.2008%, for example.

Also, the sites of GTN application are not uniform. Some authors apply GTN perianally, some intra-anally, and others both perianally and intra-anally. Torrabadella and Salgado (2005) treated 11 patients intra-anally and 15 patients perianally by applying GTN ointment of the same dose. They found a higher healing rate and a significantly better decrease in the anal resting pressure when GTN was applied intra-anally.

Many questions remain unanswered on the basis of these findings. Which topical medication carrier combined with which GTN concentration is the best choice? How many times a day and for which period of time should therapy be carried out? Which is the best site of GTN application? Are there any exclusion criteria like secondary changes or migraine?

As already mentioned, anal fissure patients are characterized by a high degree of tolerance (Table 11.2). Eight trials comprising 491 patients, who have been treated with GTN, mention a period of suffering that lies between 1.9 and 240 months.

According to Brisinda et al. (1999), resting pressure in 25 patients dropped from 83.4 ± 15.0 to 69.5 ± 16.8 mm Hg after the application of a 0.2% GTN ointment for 1 month. Loder et al. (1994) were able to show a decrease in anal resting pressure of 27% after perianal application of 0.2% GTN in 10 patients. Lund et al. (1997) noticed a significant decrease in anal resting pressure in 23 anal fissure patients 20 min after the application of 0.2% GTN. In 95% of all anal fissure patients, 0.2% GTN ointment lowered anal resting pressure by 20% or more (Thornton et al. 2005). Only GTN reduced effectively the anal resting pressure, but not Vaseline, xylocaine, or hydrocortisone (Maan et al. 2004).

The behavior of anal squeeze pressure under GTN therapy is not uniform (Table 11.3).

The following controlled trials deal with the effect of GTN ointment in comparison with other therapeutic measures.

Sajid et al. (2008, 2012) proved by meta-analysis that both substances are similarly effective and have the same recurrence rates. GTN, however, produces more side effects.

Isosorbide dinitrate (ISDN) is used in the prevention and long-term therapy for angina pectoris. It is not approved for use in the local treatment of anal fissure. In Germany, it is available in pharmacies as Isoket ointment or TD spray Iso Mack®. Only Lysy et al. (1998) use an officinal Isoket spray in their clinical trials. Schouten et al. (1996) and Songun et al. (2003) embedded ISDN in lanolin, white Vaseline, or liquid paraffin, while Parellada (2004) incorporated it in white Vaseline. Werre et al. (2001) gave no details on the ointment carrier they employed. ISDN must be dissolved in an acid environment to ensure its full effect. It is therefore uncertain whether the preparations mentioned above have any effect at all.

ISDN releases nitrogen monoxide and has a relaxing effect on the internal anal sphincter muscle (Parellada 2004; Lysy et al. 1998; Schouten et al. 1996; Werre et al. 2001). It has a vasodilatory effect, too, and leads to a better perfusion (Schouten et al.). This relaxation should facilitate a “reversible chemical sphincterotomy.” Headache frequently occurs in the course of treatment. It generally stops some days after further application. Table 11.11 shows the details of five ISDN therapy studies.

However, the trials as such are hardly comparable because chronic anal fissures, for instance, and also both acute and chronic anal fissures are dealt with simultaneously, or no details whatsoever are given to explain the type of anal fissure. Differing concentrations (0.2–1.0%) of the topical medication were used, which were applied between three and eight times per day. The duration of therapy varied between 4 and 12 weeks. Healing rates lay between 67% and 100%, and the relapse rate could reach 14.6% (Table 11.12).

Diltiazem is a calcium channel blocker which leads to relaxation of smooth musculature and vascular dilation.

Carapeti et al. (2000) and Jonas et al. (2001) noticed a significant drop in anal resting pressure after local application of 2% diltiazem gel. Headache, frequently observed after employment of GTN and ISDN, does not seem to play a role in the use of diltiazem. Only one author (Kocher et al. 2002) reports this side effect. However, perianal pruritus is described in 7% of cases after diltiazem treatment, probably caused by the basic component of the topical medication (Knight et al. 2001; Jonas et al. 2001). Therefore, diltiazem should be incorporated in basic cream DAC (Neues Rezeptur-Formularium 2007).

Table 11.13 shows that the relapse rate after diltiazem therapy seems to be lower than that after GTN application: 12.5% vs. 32% (Shrivastava et al. 2007) and 0.0% vs. 2.5% (Kocher et al. 2002).

Nifedipine is a calcium antagonist. The agent has an effect particularly on the smooth musculature and leads to a vascular dilation. An oral dose of 20 mg nifedipine results in a significant reduction in anal resting pressure in healthy as well as in anal fissure patients, but not in squeeze pressure (Agaoglu et al. 2003; Cook et al. 1999; Mustafa et al. 2005). The active agent is highly sensitive to light. In Germany, nifedipine is approved for the treatment of both chronic stable and vasospastic angina, and also of essential hypertension. Depending on the dose, there have been hints at an increase of complications of the cardiovascular system, like myocardial infarction, and at rising mortality rates. Headache, flush and peripheral edemata are very often reported in the course of the treatment.

Therefore, an oral dose administered for the treatment of chronic anal fissure is unjustified because of low healing rates and partly grave side effects. The local application of 0.2–0.5% nifedipine, however, appears to result in a high healing rate and a lower complication rate (Tables 11.14 and 11.15).

Indoramin is an alpha-1-adrenoreceptor blocker which is used in the treatment for hypertension.

In 2000, Pitt et al. treated chronic anal fissure patients and healthy controls with an oral dose of indoramin, and afterwards found a significant reduction of anal resting pressure for the duration of 3 h.

A year later, they saw a significant drop in anal resting pressure in a double-blind randomized placebo-controlled trial with a total of 23 patients. Six weeks later, they 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 indoramin. The trial was discontinued because the single one “healed” anal fissure recurred after another 6 weeks.

Arginine (L-arginine) is a water-soluble amino acid which is present in many foodstuffs. 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 significantly 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).

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.

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.

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.

In their clinical application, the units of the various BTX products are not equivalent. 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®, 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 intersphincteric 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 transmission 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).

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 follow-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.

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 solution 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.

Lindsey et al. (2004) performed sphincterotomy in 30 patients, and simultaneously injected BTX. After 4 months, 93% of anal fissures had healed.

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.

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.

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 severance 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 muscle, 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 musculature (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 increasing 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 suitable surgical therapies, 85% of the surgeons interviewed favored anal sphincterotomy (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).

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).