Anal Fissure Pharmacology

Judd Davies Bradford Royal Infirmary “Bradford” role in life is to make every place in the world look better in comparison and it does this pretty well.” Bill Bryson 1995

Anal fissure pharmacology Chronic fissure-in-ano

• Ulcer in squamous epithelium just distal to mucocutaneous junction • Intermittent pain during defecation and for up to 2 hours after • Roughly same sex incidence • 60% fissures posterior • Anterior fissures more common in women

Anal fissure pharmacology Pathogenesis

• Most consistent finding is elevated resting pressure on manometry Gibbons et al 1986 • Using angiography, posterior commissure less well perfused Klosterhalfen et al 1989 • Findings duplicated using doppler flowmetric studies Schouten et al 1994

Meta-analysis of RCT comparing sphincterotomy with medical therapy

Oettle 1997 Richard 2000 Evans 2001 Libertiny 2002 Mentes 2003 TOTAL 0.01

0.1

1 10 Favours Surgery Favours medical treatment

0% 0% 7.4% 2.8% 16%

Nelson R Dis Colon Rectum 2004; 47: 422-431

Lateral internal sphincterotomy

Risk of incontinence • 0-36% incontinence to flatus • 0-21% incontinence to liquid stool • 0-5% incontinence to solid stool • Women at more risk due to shorter anal sphincter and occult obstetric sphincter defects Lindsey et al Br J Surg 2004; 91: 270-279

Anal fissure pharmacology

Regulation of internal sphincter tone • Intrinsic myogenic tone • Enteric nervous system Nitric oxide is neuro-transmitter and relaxes internal sphincter • Autonomic nervous system Excitatory sympathetic innervation Inhibitory parasympathetic innervation Lindsey et al Br J Surg 2004; 91: 270-279

Agents used to treat chronic anal fissure

• • • • • • • • GTN Other nitric oxide donors (isosorbide dinitrate, L arginine) Calcium channel blockers ( Diltiazem, nifedipine ) Botulinum toxin ( Botox ® and Dysport ® ) Cholinergic agonists (bethanechol)  1-adrenoceptor antagonists (indoramin) Hyperbaric oxygen Sildenafil (Viagra ® )

Meta-analysis of RCT comparing GTN with placebo

Lund 1997 Carapeti 1999 Kennedy 1999 Tander 1999 Altomare 2000 Chaudhuri 2001 Kenny 2001 Oglesby 2001 Werre 2001 Bailey 2002 Sonmez 2002 TOTAL 0.01

0.1

1 10 Favours treatment Favours control 100 Nelson R Dis Colon Rectum 2004; 47: 422-431

Meta-analysis of RCT comparing GTN with placebo

(Studies with abnormally low placebo response rates excluded)

Carapeti 1999 Kennedy 1999 Tander 1999 Altomare 2000 Chaudhuri 2001 Kenny 2001 Oglesby 2001 Werre 2001 Bailey 2002 TOTAL 0.01

0.1

1 10 Favours treatment Favours control 100 Nelson R Dis Colon Rectum 2004; 47: 422-431

Anal fissure pharmacology

GTN Limitations • • • • • Limited clinical efficacy Nelson Dis Colon Rectum 2004; 47: 422-431 Headaches and dizziness Altomare et al Dis Colon Rectum 2000; 43: 174-9 Tachyphylaxis Watson et al Br J Surg 1996; 83:771-5 Mode of application Lindsey et al Dis Colon Rectum 2003; 46: 361-6 Significant reduction in MRP for 15-90 mins Lindsey et al Br J Surg 2004; 91: 270-9

Diltiazem ointment 2%

Applied three times per day for 8 weeks • • • • Prospective audit of 71 patients showed 75% healing after 2-3 months Knight et al Br J Surg 2001;88:553-556 10 of 15 (67%) patients healed at 3 months No side-effects Carapeti et al Dis Colon rectum 2000; 43: 1359-62 Randomised trial of 50 patients, topical diltiazem demonstrated better healing (65% versus 33%) than oral diltiazem with fewer side-effects (0% versus 33%) Jonas et al Dis Colon Rectum 2001; 44: 1074-8

Diltiazem versus GTN

2% diltiazem ointment applied twice per day for 8 weeks • Randomised trial of 43 patients showed similar rates of healing with diltiazem and GTN ( 86% versus 85% ) with better side-effect profile ( 0% versus 33% ) Bielecki et al Colorectal Disease 2003; 5: 256-7 • Randomised trial of 60 patients showed similar rates of healing with diltiazem and GTN ( 86% versus 77% ) with better side-effect profile ( 41% versus 72% ) Kocher et al Br J Surg 2002; 89; 413-7

Nifedipine versus GTN

0.2% nifedipine ointment applied four times daily • • • Prospective double-blind study 52 patients randomised Significantly higher healing rates at 6 months (89% versus 58%) • Significantly fewer side-effects (5% versus 40%) • Recurrence frequent in both groups

Ezri et al Dis Colon Rectum 2003; 46: 805-808

Anal fissure pharmacology

Botulinum neurotoxin A (Botox®) •

Clostridium botulinum

• Prevents pre-synaptic acetylcholine release in skeletal muscle • Mechanism of action poorly understood in internal sphincter • 3 month duration • 30% reduction in maximum resting anal pressure

Botulinum neurotoxin A (Botox®)

• • • Prospective audit of 100 patients treated with 2.5-5 units of Botox showed 79% healing at 6 months 7% transient incontinence rate Jost Dis Colon Rectum 1997; 40: 1029-32 Double-blind study compared Botox and saline in 30 patients using 20iu Botox and found significantly better healing (73% versus 13%) at 2 months Maria et al N Engl J Med 1998; 338: 217-20

Botulinum neurotoxin A (Botox®)

• Double-blind study compared Botox with GTN in 50 patients and showed superior healing rates ( 96% versus 60% ) at 2 months.No relapses at 15 months Brisinda et al New Engl J Med 1999; 341: 65-9 • High late recurrence rates (42%) Minguez Gastroenterology 2002; 123: 112-7

Botulinum neurotoxin A

Published studies * Brisinda et al Surgery 2002; 131:179-84

Anal fissure pharmacology

Consultant experience • • • • GTN ointment 0.2% cost £13.52

Diltiazem cream 2% cost £40.92

Botox ® vial (100 units) cost £160.15

Lateral sphincterotomy cost £560 • • • • Total number of procedures performed n=1543 EUA and Botox ® n= 46 EUA and Rotation flap n= 42 Lateral sphincterotomy n= 5

Anal fissure pharmacology

Conclusions • GTN of only marginal benefit in treating chronic fissure in ano • Diltiazem has minimal side-effects and should probably be used as first-line treatment • Botox ® should be used for those failing diltiazem • Lateral sphincterotomy should be reversed for patients who have failed medical and sphincter conservative treatment options

B

radford

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bstructive

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efecation trial

• • • • Double-blind Comparing Botox with saline Puborectalis injection 40 patients