1. Anal Fissure Pharmacology
Judd Davies
Bradford Royal Infirmary
Bill Bryson quotes from his 1995 book Notes from a small island
Radical change in the management of chronic fissure-in-ano in my surgical life-time from over 10,000 sphincterotomy in 1996/1997 to 5,500 procedures in 1999/2000.
“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

2. 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
Need to exclude uncommon causes for atypical fissure-in-ano including Crohn’s disease, HIV/AIDS, tuberculosis, syphilis and anal carcinoma.

3. 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

4. Meta-analysis of RCT comparing sphincterotomy with medical therapy0% 0%
7.4%
2.8%
16%
Oettle form South Africa, Multi-centre study from Canada by Richards et al, Evans from Australia, multicentre study from Uk by Libertiny, and mentes from Turkey
2.8% Libertiny incontinent to flatus (1/35)
16% Mentes incontinent to flatus (8/50)
7.4% Evans incontinent to flatus (2/33)
Nelson R
Dis Colon Rectum 2004; 47:

5. 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
Systemic review of randomised trials concluded an incidence of faecal incontinence of 10%, this is mostly to flatus but there on only limited reports as to duration, and similarly publications describing treatment for incontinent after sphincterotomy for fissure are strikingly obvious.
Lindsey et al
Br J Surg 2004; 91:

6. 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
Intrinsic myogenic tone, is spontaneous, poorly understood and dependant on extra-cellular calcium levels entering via L-type calcium channels. Second is the enteric nervous system, the third division of the autonomic nervous system. These neural pathways are located in Auerbach and Meissner’s plexi within the wall of the gut. They are responsible for for peristalsis and local reflexes such as the ano-rectal inhibitory reflex. The neuro-transmitter is nitric oxide.
Sympathetic input (originating from the thoracolumbar spinal cord) is conveyed via the celiac and hypogastric plexus, whereas the parasympathetic input is conveyed via the splanchnic plexus.
Lindsey et al
Br J Surg 2004; 91:

7. 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®)

8. Meta-analysis of RCT comparing GTN with placebo
This is a meta-analysis of randomised controlled trials comparing GTN with placebo for treatment of anal fissure using odds ratios and 95% confidence intervals.Placebo healing rate of 35% across the board, which is fairly standard.
First Study was performed by Lund and schofield on 80 patients who has GTN 0.2% bd for 8 weeks. Healing rates were significantly higher 68% versus 8%. Headaches were relatively common 58% versus 18%. Resting reduced in order of 35%.
Nelson R
Dis Colon Rectum 2004; 47:

9. Meta-analysis of RCT comparing GTN with placebo
(Studies with abnormally low placebo response rates excluded)
This is the same meta-analysis performed with certain studies excluded as the placebo response rates were lower than 2 SD below the mean for the placebo group.
Nelson R
Dis Colon Rectum 2004; 47:

10. Anal fissure pharmacology GTN Limitations
Limited clinical efficacy
Nelson Dis Colon Rectum 2004; 47:
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 mins
Lindsey et al Br J Surg 2004; 91: 270-9
Italian multi-centre trial with 132 participants found 34% of patients in GTN versus placebo group developed head-aches.
Ambulatory manometry sowed MRP was reduced for between mins.

11. 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:
10 of 15 (67%) patients healed at 3 months
No side-effects
Carapeti et al Dis Colon rectum 2000; 43:
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:
Calcium and its entry through L-type calcium channels is important for the maintenance of the tone and spontaneous activity of the IAS. Diltiazem acts as a calcium channel inhibitor decreasing intra-cellular availability of calcium. Minimal side-effects in 71 patients with x4 contact dermatitis, and x1 headache

12. 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
Interestingly in this study they used 0.5% GTN which may explain high side-effect profile and relatively short follow-up at 8 weeks.

13. 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:

14. 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
Work from animal models suggest in works by reducing myogenic tone and contractile response to sympathetic stimulation, by acting either directly on smooth muscle or indirectly on the nerves , perhaps through acetylcholine at ganglionic level.

15. Botulinum neurotoxin A (Botox®)
Prospective audit of 100 patients treated with units of Botox showed 79% healing at 6 months
7% transient incontinence rate
Jost Dis Colon Rectum 1997; 40:
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:

16. 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

17. Botulinum neurotoxin A Published studies*
Brisinda et al
Surgery 2002; 131:179-84

18. 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
From the economic modelling study by Christie et al, cost from treatment with GTN in 2002 £616, compared with £840 for a sphincterotomy.

19. 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

20. Bradford Obstructive Defecation trial Double-blind
Comparing Botox with saline
Puborectalis injection
40 patients