Transcript Anal Fissure Pharmacology

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
0%
0%
7.4%
Oettle 1997
Richard 2000
Evans 2001
2.8%
16%
Libertiny 2002
Mentes 2003
TOTAL
0.01
0.1
1
10
Favours Surgery Favours medical treatment
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, Larginine)
• 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
Nelson R
Dis Colon Rectum 2004; 47: 422-431
100
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
Nelson R
Dis Colon Rectum 2004; 47: 422-431
100
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 sphincterconservative treatment options
Bradford
Obstructive
Defecation trial
•
•
•
•
Double-blind
Comparing Botox with saline
Puborectalis injection
40 patients