**11.1 Glyceryl trinitrate**

Glyceryl trinitrate (GTN) is a vasodilator and causes relaxation of smooth muscle. Relaxation of the internal sphincter tone is achieved by the reduction of intracellular calcium in the smooth muscle cells by nitric oxide donation. Topical GTN heals anal fissures better than a placebo, irrespective of dose, but is associated with headache in around 25% of the patients. During the late 90's, GTN ointment was the best one could offer for a child with anal fissure. Exogenous nitrates release nitric oxide in vivo and have been used clinically as nitric oxide donors. Loder et al. (1994) demonstrated that topical application of 0.2% GTN led to decreased resting anal pressure. Chemical sphincterotomy using GTN with adjunctive stool softeners has been demonstrated to be quite effective at relieving symptoms and promoting healing. They significantly decrease pain during the therapy period. A study of 80 patients reported in the Lancet in 1997 showed healing in 26/38 (68%) after GTN, compared with 3/30 (8%) after placebo (Lund & Scholefield, 1997). Another study comparing GTN, lidocaine and placebo, was reported in the Journal of Pediatric Surgery in 1999. Complete healing was observed in 26/31 (83.9%) after GTN, 7/14 (50%) after lidocaine, and 6/11 (35.3%) after placebo (Tander et al., 1999). Kenny et al. (2001) questioned the healing power of GTN, reporting 31 children with an overall fissure healing rate of 84%, but with no differences being observed between GTN and placebo. Bacher et al. (1997) conducted a randomized trial of 0.2% GTN vs. 2% lidocaine gel, each applied 3 times daily, in a mixed group of acute and chronic fissure patients. After 1 month, healing rates were higher with GTN in both the acute (91.6%, GTN vs. 50%, lidocaine) and chronic (62.5%, GTN vs. 20%, lidocaine) fissure groups. A randomized, placebo-controlled treatment of anal fissure by lidocaine, EMLA, and GTN in 102 children, showed faster response rates by GTN application, and similar and high success rates by 8 weeks of EMLA treatment (Sönmez et al., 2002). The average age of patients was 3 years (range, 2.5 months to 15 years). Symptoms at admission consisted of hard stools in 90% of patients, pain or crying during defecation in 87%, bleeding in 84%, excessive straining at defecation in 35%, and mucosal prolapse in 9%. Despite the encouraging results reported with topical nitrates, severe headaches and noted relapse rates are major drawbacks. Dorfman et al. (1999) reported a 27% symptomatic relapse rate (median follow-up, 6 months). Associated side-effects were observed in 78% of

Nifedipine Gel with Lidocaine in the Treatment

**11.4 Botulinum toxin (Botox)** 

of Anal Fissure in Children: A Pilot Study and Review of the Literature 59

anal pressure showed that pressures were reduced with sublingual nifedipine in both healthy volunteers and patients with hypertonic sphincters (Chrysos et al., 1996). A medline database literature search concerning the non-surgical treatment of chronic anal fissures, including 282 patients, called the attention to nifedipine gel. The study compared nifedipine with lidocaine with hydrocortisone acetate, showing 98% complete healing after nifedipine and 61% complete healing in the control group. Nifedipine reduced MRAP by 30% and maximum squeeze pressure by 16.8% (McCallion & Gardiner, 2001). Another large study by Perroti et al. (2002) comparing nifedipine and lidocaine with hydrocortisone and lidocaine, showed complete healing in 94.5% of the nifedipine treated patients and only 16.4% of the control patients.

Preliminary results of a multicenter study on nifedipine for local use in conservative treatment of anal fissures was reported by Antropoli in 1999. Total remission from acute anal fissure was achieved after 21 days of therapy in 95% of the nifedipine-treated patients, with a mean reduction of 30% in maximum resting anal pressures. A randomized controlled double-blind trial comparing nifedipine gel plus lidocaine, topical lidocaine alone and hydrocortisone acetate ointment, showed topical nifedipine plus lidocaine gel to be effective and well tolerated in the treatment of chronic anal fissures (Perroti et al., 2002). In other studies reported by Merenstein & Rosenbaum (2003) and Slawson (2003), remarkable improvement in healing was observed when 1.5% lidocaine and 0.3% nifedipine were applied twice daily for 6 weeks. Ezra & Susmalliam (2003) showed a better healing rate with topical nifedipine than with GTN. Katsinelos et al. (2006) reported that aggressive treatment of acute anal fissure with 0.5% nifedipine gel ointment prevents its evolution to chronicity. Twenty-seven of their 31 patients achieved complete remission and healing of the anal fissure following an 8-week treatment course (85.2%). Recurrence was observed in 16% of their patients. A systematic review of medical therapy for anal fissure including 31 trials from 1966 to 2002 returned the black shadow of pessimism to most physicians' minds. Nine agents were studied: GTN, isosorbide dinitrate, botulinum toxin, diltiazem, nifedipine, hydrocortisone, lidocaine, bran, and placebo. The results were only marginally better than placebo (R. Nelson, 2004)! A Cochrane Collaboration Review from 2009, by the same author, showed no better results. GNT was found to be marginally, but significantly, better than placebo in healing anal fissure (48.6% vs. 37%, p < 0.004), but late recurrence of the fissure was common, in the range of 50% of those initially cured! Botox and calcium channel blockers were equivalent to GNT in efficacy, with fewer adverse effects. No medical therapy was found to come close to the efficacy of surgical sphincterotomy (R.L. Nelson, 2006). Combined treatments have also been reported. The combination of nifedipine and botulinum toxin was superior to nitroglycerin and pneumatic dilatation with respect to both healing (94% v. 71%) and recurrence rate (2% v. 27%) (Tranqui et al., 2006). Headache is the most common complication of administering topical nifedipine in adults, but not in children. Nifedipine gel in the treatment of anal fissure has now been accepted even in China, with good results (Hong-yu et al., 2004). Reversible chemical sphincterotomy with nifedipine gel looks now as the most promising development in the treatment of anal fissures in children. The outcome is extremely good and side effects almost nonexistent.

Botulinum neurotoxin is a lethal biological substance produced by the anaerobic bacterium Clostridium botulinum. Serotype A is commercially available and has proven to be of therapeutic value in a variety of clinical conditions such as strabismus, torticollis,

patients, including headaches in 63% and light-headedness in 52%. Carapeti et al. (1999) noted relapse rates of 33% with 0.2% GNT and 25% with escalating-dose GTN (mean followup, 9 months). Headaches were observed in 72% of the patients. More recent studies have shown lower healing rates with GTN than were initially reported. Patient non-compliance and tachyphylaxis are also major drawnbacks to this treatment. Local application of another precursor of nitric oxide, L-arginine, has been reported as effective in promoting fissure healing without headache as a side effect (Gosselink et al., 2005).
