NIFEDIPINE CHEMICAL STRUCTURE

Fig. 2. Nifedipine chemical structure.

Nifedipine (Adalat) has a modulating effect on the microcirculation (Oshiro et al., 1995). The advent of this calcium channel blocker as nifedipine gel was a turning point and a major contribution to the healing of posterior anal fissures. Used to treat hypertension, angina pectoris, Raynaud's syndrome, congestive heart failure, and cardiomyopathies, it may cause side effects like headache, upset stomach, dizziness, tiredness, flushing, heartburn, tachycardia, muscle cramps, enlargement of gum tissue around teeth, constipation, nasal congestion, and cough. The first clinical study on the effects of calcium antagonists on resting

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

They improve fissure healing by inhibiting calcium ion entry through voltage-sensitive areas of vascular smooth muscle, causing muscle relaxation and vascular dilatation. Topical diltiazem (Cardizem) has similar efficacy to GNT, with fewer side effects, but the experience

NIFEDIPINE CHEMICAL STRUCTURE

Nifedipine (Adalat) has a modulating effect on the microcirculation (Oshiro et al., 1995). The advent of this calcium channel blocker as nifedipine gel was a turning point and a major contribution to the healing of posterior anal fissures. Used to treat hypertension, angina pectoris, Raynaud's syndrome, congestive heart failure, and cardiomyopathies, it may cause side effects like headache, upset stomach, dizziness, tiredness, flushing, heartburn, tachycardia, muscle cramps, enlargement of gum tissue around teeth, constipation, nasal congestion, and cough. The first clinical study on the effects of calcium antagonists on resting

healing without headache as a side effect (Gosselink et al., 2005).

**11.2 Calcium channel blockers** 

Fig. 2. Nifedipine chemical structure.

with children is small.

**11.3 Nifedipine** 

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.

#### **11.4 Botulinum toxin (Botox)**

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,

Nifedipine Gel with Lidocaine in the Treatment

fissures in children.

**11.9 Wonder remedies** 

immediate soothing relief.

swelling without skin irritation.

of Anal Fissure in Children: A Pilot Study and Review of the Literature 61

recurrences (Ali, 1988; Skobelkin et al., 1989). It involves laser vaporization of the fissure locally. Patient acceptance is remarkable, and the treatment can be carried out at a fraction of the cost of hospital surgical treatment. There are no reports of laser treatment for anal

Fig. 3a. Anal Fissures DX: a unique formula with anti-inflammatory properties, providing

Fig. 3b. H-Fissures: healing natural oil with anti-inflammatory properties, specially formulated to provide instant relief from the pain and discomfort of fissures, reducing the

Fig. 3c. Fissure Control: a breakthrough topical homeopathic treatment made of a blend of herbs (Chamomile, Lavandula Angustifolia, Helichrysum, and Hamamelis Virginiana).

hyperhidrosis, achalasia and chronic anal fissure (Jankovic & Brin, 1991). Botulinum toxin (Botox) is associated with a similar rate of healing of anal fissure as GTN, but is more expensive. The technique, dose and site of injection do not affect the rate of healing. The experience in children is very small. Jost & Schimrig (1993) first reported the use of botulin toxin (BT) for anal fissure in 1933. The commercially available agent prevents neural transmission by preventing acetylcholine release from presynaptic nerve terminals. BT exerts its effects on the acetylcholine releasing parasympathetic peripheral nerve endings as well as the ganglionic nerve endings, leading to flaccid paralysis of the internal anal sphincter (IAS). This effect stays for about 3 months, a period sufficient for most noncomplicated anal fissures to heal. Jost (1997) subsequently reported on a series of 100 patients treated with BT injection. In all, 78 patients became pain-free within 3 days, and healing rates at 3 and 6 months were 82% and 79%. BT injection was compared with topical GTN (0.2% twice daily) in a randomized trial of 50 chronic anal fissure patients (Brisinda et al., 1999). Resting anal pressure decreased in both groups, but did so to a greater extent in the BT group (29% with BT vs. 14% with GTN at 2 months). Healing rates were 96% in the BT group and 60% in the GTN group. No adverse effects were seen in the BT group.

#### **11.5 Hyperbaric oxygen**

Hyperbaric oxygen therapy provides a significant increase in tissue oxygenation in hypoperfused wounds. This increase in oxygen tension induces positive changes in the wound repair process by enhancing fibroblast replication, collagen synthesis and neovascularization. Cundall et al. (2003) reported a small series of adult patients with chronic anal fissure treated by hyperbaric oxygen. They found the procedure safe and appropriate in patients who have failed medical treatment, in those at risk of fecal incontinence, and in patients who are unfit for operation or in whom surgery has failed (Cundall et al., 2003).

#### **11.6 Naturopathic treatment**

Homeopathic medicines are excellent to alleviate the pain and spasm. Some of the more often indicated medicines are Chamomilla, Graphites, Nitric acid, Ratanhia, Sepia, Silicea and Thuja. Aesculus and Paeonia may be indicated if keynote symptoms are present. Homeopathic medicines often work faster and provide greater pain relief than analgesics and narcotics. In order to facilitate healing of the fissure, a topical cream consisting of Vitamins A and E, panthenol, calendula, goldenseal and Emu oil , can be used (Kruzel, 2006).
