Anal Fissure Pharmacology

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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
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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

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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

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Meta-analysis of RCT comparingsphincterotomy
with medical therapy
0
0
7.4
2.8
16
Nelson R Dis Colon Rectum 2004 47 422-431
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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 al Br J Surg 2004 91 270-279
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Anal fissure pharmacologyRegulation 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
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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)

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Meta-analysis of RCT comparing GTN with placebo
Nelson R Dis Colon Rectum 2004 47 422-431
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Meta-analysis of RCT comparing GTN with
placebo (Studies with abnormally low placebo
response rates excluded)
Nelson R Dis Colon Rectum 2004 47 422-431
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Anal fissure pharmacologyGTN 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 83771-5
• 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

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Diltiazem ointment 2Applied 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 200188553-556
• 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

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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

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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 al Dis Colon Rectum 2003 46 805-808
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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

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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

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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

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Botulinum neurotoxin APublished studies

Brisinda et al Surgery 2002 131179-84
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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 n1543
• EUA and Botox n46
• EUA and Rotation flap n42
• Lateral sphincterotomy n5

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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

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• Bradford
• Obstructive
• Defecation trial

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