Anal Fissure PharmacologyJudd 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 pharmacologyChronic 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 pharmacologyPathogenesis

• 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 comparingsphincterotomy with medical therapy

0.01 0.1 1 10

TOTAL

Mentes 2003

Libertiny 2002

Evans 2001

Richard 2000

Oettle 1997

Favours Surgery Favours medical treatment

Nelson RDis Colon Rectum 2004; 47: 422-431

2.8%

16%

7.4%

0%

0%

Lateral internal sphincterotomyRisk 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 alBr J Surg 2004; 91: 270-279

Anal fissure pharmacologyRegulation of internal sphincter tone

• Intrinsic myogenic tone

• Enteric nervous systemNitric oxide is neuro-transmitter and relaxes

internal sphincter

• Autonomic nervous systemExcitatory sympathetic innervation

Inhibitory parasympathetic innervation

Lindsey et alBr 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

0.01 0.1 1 10 100

TOTALSonmez 2002

Bailey 2002Werre 2001

Oglesby 2001Kenny 2001

Chaudhuri 2001Altomare 2000

Tander 1999Kennedy 1999Carapeti 1999

Lund 1997

Favours treatment Favours control

Nelson RDis Colon Rectum 2004; 47: 422-431

0.01 0.1 1 10 100

TOTALBailey 2002Werre 2001

Oglesby 2001Kenny 2001

Chaudhuri 2001Altomare 2000

Tander 1999Kennedy 1999Carapeti 1999

Favours treatment Favours control

Meta-analysis of RCT comparing GTN with placebo

(Studies with abnormally low placebo response rates excluded)

Nelson RDis Colon Rectum 2004; 47: 422-431

• Limited clinical efficacyNelson Dis Colon Rectum 2004; 47: 422-431

• Headaches and dizzinessAltomare et al Dis Colon Rectum 2000; 43: 174-9

• TachyphylaxisWatson et al Br J Surg 1996; 83:771-5

• Mode of applicationLindsey et al Dis Colon Rectum 2003; 46: 361-6

• Significant reduction in MRP for 15-90 minsLindsey et al Br J Surg 2004; 91: 270-9

Anal fissure pharmacologyGTN Limitations

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-effectsCarapeti 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 GTN2% 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 GTN0.2% 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 alDis Colon Rectum 2003; 46: 805-808

Anal fissure pharmacology Botulinum neurotoxin A (Botox®)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®)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 rateJost 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®)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 ABotulinum neurotoxin APublished studiesPublished studies

Brisinda et alSurgery 2002; 131:179-84

*

• 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 Consultant experienceConsultant experience

• 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

Anal fissure pharmacologyConclusionsConclusions

Bradford

Obstructive

Defecation trial

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