**8. Differential diagnosis**

Pruritus ani, inflammatory bowel disease (mostly Crohn's disease), tuberculosis, immune system diseases, acquired immunodeficiency syndrome (AIDS), Chlamydia, venereal diseases, neoplasm, and sexual abuse.

Nifedipine Gel with Lidocaine in the Treatment

**11. Medical treatment** 

**11.1 Glyceryl trinitrate** 

of Anal Fissure in Children: A Pilot Study and Review of the Literature 57

Acute fissures often resolve within 10-14 days of conservative management. However, as long as 6-8 weeks may be necessary for the fissure to heal. Recurrence after conservative management can be observed in 27% of the cases. Dietary modification (increased fluid and fiber intake), stool softeners (lactulose) and warm baths are all part of the conservative treatment (Shafik, 1993). Conservative treatment is safe, has few side effects, and should usually be the first step in therapy. Shub et al. (1978) reported that 44% of fissure patients healed with sitz baths, a psyllium fiber supplement, and emollient suppositories. In 27% of

The optimal treatment for an anal fissure is to induce a temporary reduction of anal canal resting pressure to allow healing of the fissure without permanently disrupting normal sphincter function. Internal anal smooth muscle relaxation can be inhibited by stimulation of non-adrenergic non-cholinergic enteric neurons, parasympathetic muscarinic receptors, or

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

these "healed" patients, the fissures recurred over a 5-year follow-up period.

sympathetic beta adrenoceptors, and by inhibition of calcium entry into the cell.

### **9. Innervation and pharmacology of the internal sphincter**

The enteric nervous system consists of two major plexuses of interconnecting ganglia, the myenteric (Auerbach's) plexus and the submucous (Meissner's) plexus. The enteric nervous system contains entire reflex pathways that permit peristaltic contractions independent of extrinsic innervations. The internal anal sphincter receives its sympathetic innervations from the hypogastric pelvic plexuses. Parasympathetic innervation is from the first, second, and third sacral segments via the pelvic plexus. Internal anal smooth muscle relaxation can be inhibited by stimulation of nonadrenergic noncholinergic enteric neurons, parasympathetic muscarinic receptors, or sympathetic beta adrenoceptors, and by inhibition of calcium entry into the cell. Sphincter contraction depends on an increase in cytoplasmic calcium and is enhanced by sympathetic alpha adrenergic stimulation (Bhardwaj et al., 2000). A number of putative nonadrenergic transmitters have been suggested, the work being concentrated on the function of adenosine triphosphate (ATP), vasoactive intestinal peptide (VIP), and nitric oxide (NO) and their role in mediating the rectoanal inhibitory reflex (RAIR), as they are known to act together in mediating enteric inhibitory cotransmission in other areas of the gut. NO activates soluble guanylate monophosphate (cGMP) and relaxation of smooth muscle. NO has been widely demonstrated to be the main chemical neurotransmitting agent in the nonadrenergic neurons mediating relaxation of the internal anal sphincter. Working on the opposum internal anal sphincter, Rattan and Chakder suggested that NO was a nonadrenergic noncholinergic inhibitory neurotransmitter (Rattan & Chakder, 1992). NO caused tetrodotoxin-resistant relaxations of internal anal sphincter strips. The internal anal sphincter generates a high degree of tone in the resting state and is responsible for 50-85% of overall resting anal tone. This is due to both intrinsic myogenic activity and extrinsic adrenergic innervations. The effects of adrenergic agonists are well documented. Parks et al demonstrated that internal anal sphincter strips contracted to noradrenaline, had a variable response to adrenaline and relaxed in response to isoprenaline (Parks et al., 1969). Analysis of these responses using appropriate adrenoceptor antagonists has shown that contractions were mediated via alpha-receptors and relaxations via beta-receptors. Contractions to noradrenaline and adrenaline can be converted to relaxations by the addition of an alpha-receptor antagonist. Burleigh et al. (1979) have shown that acetylcholine has a predominantly inhibitory effect on internal anal sphincter smooth muscle acting through muscarinic receptors. Furthermore, electrical field stimulation of internal anal sphincter strips resulted in relaxation of the smooth muscle. These relaxations are abolished by tetrodotoxin, indicating that they are nerve mediated. Transient internal anal sphincter relaxation in response to rectal distension was first described by Gowers in 1877. O'Kelly et al. (1994) suggested that NO might be important in mediating the rectoanal inhibitory reflex. A review on the pharmacology of the internal anal sphincter was reported by Cook et al. (2001).

#### **10. Clinical picture**

The clinical picture involves a history of constipation in 20% of the cases, intense crying with bowel movements, streaks of bright red blood on the surface of hard stool, on the diaper, or on the toilet paper, following bowel movements, discharge and pruritus. The clinical hallmark of anal fissure is pain during, and especially some time after defecation. Inspection of the anal region reveals a posterior midline laceration, a sentinel skin tag, and signs of inflammation.
