How Effective Are Topical Calcium-Channel Blockers for Anal Fissure?

How Effective Are Topical Calcium-Channel Blockers for Anal Fissure?

Q&A 290.2

How effective are topical calcium-channel blockers for anal fissure?

Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals

Before using this Q&A, read the disclaimer at

Date prepared: 23January 2013

Background

Anal fissure is a tear in the squamous epithelium lining the distal anal canal near the mucocutaneous junction (1,2), Primary anal fissure is associated with increased anal tone and spasm of the anal sphincter (1,2) and pain so severe that it has been attributed to ischaemia (3), The aetiology of the typical or benign anal fissure is not clear but is thought to involve spasm, ischaemia, ulceration and inflammation (2), Increased anal tone impairs healing by inducing ischaemia (1), Causes of secondary anal fissure include constipation, inflammatory bowel disease, sexually transmitted disease, local or systemic malignancy, third trimester of pregnancy or childbirth, trauma or chemotherapy (1,2).

Symptoms include anal pain during and for several hours after defecation.Fresh blood loss and perianal itching may also be present (4).

Acute and chronic forms of the condition exist. Acute anal fissure is significantly more common than the chronic form; its prognosis is reported to be excellent with non-surgical conservative interventions such as increased fluid and fibre intake, stool softeners and analgesics/topical anaesthetics (1,5). Chronic anal fissure can be defined anatomically and by temporal association – a history of pain lasting for more than 4 – 6 weeks, or with pain of less duration but with similar past episodes (1,2).

Anal fissure is common, occurring mostly between the second and fourth decades of life with a lifetime incidence of 11%: frequency is approximately equal between men and women (5,6). Up to 11% of women develop the condition after childbirth (7).

The condition is also seen in children, but it is not certain that there is exact comparability to chronic fissure in adults (2). Initial management is similar, however (1).

Aims of treatment are to relieve the symptoms of pain, anal bleeding and irritation, heal the fissure, and minimise any adverse effects of treatment.Principal outcome measures are persistence of the fissure (measured by persistence of anal pain) and post treatment minor incontinence. The distinctionbetween persistence and recurrence is difficult to make, as the severity of symptoms fluctuates (2).

Answer

Guidance

In the UK, guidance on the medical management of anal fissure has been issued by PRODIGY (formerly the NHS Clinical Knowledge Summaries) and the Association of Coloproctology of Great Britain and Ireland (ACPGBI) (1,5), USA guidelines from the American Gastroenterological Association (AGA) were issued in 2003 (9) based on a technical review by the AGA (10), but have not been updated since.Updated practice parameters for the management of anal fissures were published by the American Society of Colon and Rectal Surgeons (ASCRS) in 2010(11), The AGA notes that topical therapy and botulinum toxin injection are acceptable options for the management of anal fissure: because of low morbidity profiles they may be considered as first line treatment, and not just salvage treatment for failed conservative care (9), The ACPGBI prefers topical diltiazem as it has similar efficacy to glyceryl trinitrate (GTN) but with fewer side effects (5). The ASCRS suggests conservative therapy as first-line; topical treatment is included as an acceptable option, using either a nitrate or calcium-channel blocker (11).

An updated evidence based review, “Non surgical therapy for anal fissure” was published by the Cochrane Collaboration in 2012(2), Conclusions from an analysis of the results of 75randomised controlled trials (n=5031) were that GTN therapy was statistically significantly better than placebo in healing anal fissure (48.9% vs. 35.5%, p < 0.0009) but late recurrence of fissure was common (in the range of 50% of those initially cured), Botulinum toxin and calcium channel blockers (diltiazem and nifedipine) were equivalent to GTN in efficacy and had fewer side effects. None of the medical treatments studied approached the efficacy of surgical sphincterectomy (>95%), but none were associated with incontinence (2).

Current advice from PRODIGY is that topical GTN should be offered to adults with primary anal fissure (unless pregnant or breastfeeding) if symptoms have been present for more than one week without improvement and they have been informed of associated benefits and harms, Treatment should be for up to 8 weeks or until the fissure is fully healed (1).

An evidence-based algorithm for the treatment of anal fissure was devised by an international consensus group in 2006 (12), Separate algorithms are included for initial presentation in primary care and for treatment-resistant anal fissures in secondary care. Choice of medical treatment for first presentation of idiopathic anal fissure should take into account product licensing, availability, costs and contraindications (12).

There are currently no licensed topical presentations of any calcium-channel blocker in the UK.

Calcium has an important role in the maintenance of internal anal sphincter tone (13).Calcium channel blockers inhibit muscle contraction by preventing calcium influx into the cytoplasm via membrane channels. Both diltiazem and nifedipine have been studied for treatment of anal fissure: unless noted, studies were in chronic anal fissure (CAF).

Diltiazem

Diltiazem has been evaluated as an alternative treatment for CAF.

Healing rates of 75% have been reported in a series of 71 consecutive patients treated with topical 2% diltiazem gel twice daily for 8 weeks with minimal side effects (14).

Long term results of diltiazem treatment for CAF were reported for 112 adults given a 6 week course of 2% diltiazem cream twice daily (15).The initial success rate was 67.9% but 59% of patients required further treatment (medical or surgical) over the average two year period of follow up (surgery for 27,24.1%). Topical diltiazem was generally well tolerated: 24 patients reported adverse effects (most commonly perianal itch or soreness) but only six discontinued due to adverse effects.

In 39 patients with persistent CAF despite treatment with 0.2% GTN ointment, use of 2% diltiazem ointment twice daily for 8 weeks resulted in fissure healing in 49%.Side effects, including perianal itching, occurred in 4 of 39 patients.One patient discontinued therapy because of headaches, drowsiness and mood swings (16).

Comparative studies

A meta-analysis found five studies of topical diltiazem published up to December 2006, of which two were prospective randomised controlled trials comparing it with topical GTN (17). Only 103 patients were involved in total, 53 receiving diltiazem and 50 GTN. There was no statistically significant difference between the two treatments in efficacy, defined as healing/improvement (diltiazem relative risk [RR] 1.20; 95% CI 0.93 to 1.54; fixed-effect model). GTN was associated with a higher adverse effect rate (RR for diltiazem 0.45; 95% CI 0.28 to 0.73). This analysis has been updated but at date of writing the update had only been published as a conference abstract (18): the update included seven eligible comparative trials with 481 patients. Analysis confirmed similar efficacy (GTN:diltiazem RR 1.10; 95% CI 0.90 to 1.34; P=0.36; random effects model), and fewer adverse effects with diltiazem (overall p<0.01).

Threefurther randomised trials comparing diltiazem and GTN have been published since the original meta-analysis and were available in full.

In a comparison of topical diltiazem 2% with GTN 0.2% in 90 patients, all received advice to take a high-fibre diet:they were randomised to diltiazem, or GTN, or no additional treatment (19). Treatment was continued until healing. Patients in the two active treatment groups were more likely to have pain relief at six weeks, with no significant difference between diltiazem and GTN in healing (80%, 73%, respectively, control 33%; p=0.014 and 0.013 for diltiazem and GTN vs. control). Recurrence occurred in 12.5%, 32%, and 50% respectively (p=0.012 for diltiazem and p=0.013 for GTN vs. control; difference between active groups NS). No adverse effects were reported in the diltiazem group, whereas 67% of those using GTN reported headache

Diltiazem 2% and GTN 0.2% were compared in 80 patients (20). Healing rates at 8 weeks were similar in the two groups (77.5% vs. 82.5%, p=0.576), however more patients reported adverse effects in the GTN group (27 vs. 9, p<0.0001).

Similar results were obtained in a further study (21) involving 102 patients treated with GTN 0.2% or diltiazem 2% for 12 weeks: symptom relief and complete remission rates were statistically similar, although adverse effects (mainly headache) were more frequent with GTN.

There has been one comparative study in children (22): 93 patients with a mean age of 32.1 months were randomised to receive topical diltiazem 2%, lidocaine 10%, or GTN 0.2% for 8 weeks with a further 8 week course for non-responders. At 12 months, 82 were available for assessment. Overall healing rate was 79.8%. Response rate was higher in the diltiazem group after the first course (D=82% vs. L=25% vs. GTN=39%) and after the second course (92% vs. 64% vs. 82%). Recurrence rates at 12 months were 11%, 57%, and 37%.

Diltiazem has also been compared with botulinum toxin. A small pilot study in 51 patients with treatment-resistant CAFcompared twice-daily diltiazem 2% for eight weeks with a single injection of botulinum toxin 40units, both after fissurectomy (23). At eight weeks, symptom resolution rates were similar in the two groups (89.3% vs. 82.6%). Adverse effects were minor. In a larger study using a double-blind, double-dummy technique (24), healing rates at 3 months were similar in both groups (43%); as were the proportions of patients achieving >50% reduction in mean pain score (diltiazem 78%, botulinum toxin 82%). The only adverse effect noted was perianal itching in the diltiazem group (15%).

Contact allergy to diltiazem cream has been reported but appears to be uncommon (25).

Nifedipine

Both oral (26) and topical 0.2% nifedipine (27) have been shown to reduce anal pressure and promote healing of anal fissures.

Oral nifedipine 20mg twice daily was given to 15 patients with CAF for 8 weeks and to eight healthy volunteers acting as controls.After 5 days, maximum resting anal pressure was reduced by 35% (p<0.001) in patients with anal fissure compared to 28% (p<0.001) in the volunteer group. (26)

Comparative studies

Topical nifedipine was superior to 1% lidocaine plus 1% hydrocortisone in a randomized multicentre study in 283 patients.Fissure healing was seen in 95% of the nifedipine group vs. 50% of the comparator group (27).

In a prospective, randomized, double-blind study, 55 patients with anal fissure received treatment with topical nifedipine ointment 0.3% plus 1.5% lidocaine whilst 53 others received topical lidocaine 1.5% plus 1% hydrocortisone acetate applied 12 hourly for 6 weeks (28).Healing occurred in 94.5% of the nifedipine group compared to 16.4% of the control group (p=0.001).Fissure recurrence was seen in 3 of 52 patients in the nifedipine group after 1 year.

A randomised single-blind study compared topical nifedipine 0.5% with standard therapy using topical lidocaine 2% plus stool softeners for four weeks in 110 patients (29). After 4 weeks, healing occurred in 70% of the nifedipine group and 12% of the standard therapy group (p<0.005). At 12 months, recurrence rate for healed patients in the nifedipine group was 26%.

Nifedipine 0.5% has been compared with lateral internal sphincterotomy for CAF in 64 patients who were randomised to topical nifedipine 0.5% for eight weeks [n=32] or surgery [n=32] (30).Complete healing rates at 8 weeks were 30 (nifedipine) vs. 32 (surgery): 1 patient in the nifedipine group withdrew at 2 weeks due to headache, 1 had partial healing and proceeded to surgery. At long-term follow-up of 19 months (nifedipine) or 20.5 months (surgery), 2 patients in the nifedipine group had had recurrence compared to none in the surgery group. Adverse effects (headache, flushing, local irritation) were fairly common in the nifedipine group, but were tolerable apart from the 1 patient who withdrew; 4 patients in the surgery group (12.5%) had permanent incontinence to flatus.

Observational studies

A longer-term observational study followed-up 31 patients treated for acute anal fissure with topical nifedipine 0.5% for 8 weeks: 27 completed the course and 23 of these (74.2% of the total) had complete remission of symptoms (31).Two achieved remission with a further four weeks treatment. The 25 patients with remission were followed-up for an average of 22.9 (range 6-52) months: over this time, four had recurrence that was successfully treated with a further course of topical nifedipine. Two patients reported moderate headache. The authors suggest that aggressive treatment of acute fissures may reduce progression to chronicity.

The largest published study is a prospective observational study reporting outcomes for 455 (of 473 identified) patients treated non-surgically at one academic centre over a five-year period (32). Treatment protocol started with topical isosorbide dinitrate using a spray; if this was ineffective or not tolerated the next step was nifedipine 0.2% gel topically, with botulinum toxin used in those still not responding. Healing rate at 4 months was 84.4% (384/455). At a median follow-up of 47.43 months, 33.6% had healed with no recurrence, 37.4% had recurrence one or more recurrences responding to medical therapy, and 29% did not heal and were referred for surgery. The authors identified two factors prognostic of poor response, older age, and prolonged time between appearance of symptoms and initiation of treatment.

Summary

Topical diltiazem 2% is at least as effective as topical GTN, with short-term healing rates between 68% and 80%.

Nifedipine 0.2% to 0.5% is also effective, with reported short-term healing rates up to 95%. There are no published comparative studies with current medical treatments, although a small trial found 0.5% usedfor 8 weeks to be approaching the effectiveness of surgery (87.5%) after two years.

Adverse effects are considerablyless frequent with calcium-channel blockers than with GTN, particularly headache.

Longer-term observational data suggest thatwith optimum medical therapy, roughly a third of patients will heal without recurrence; around a third will heal, have a relapse, and respond to further medical therapy; and around a third will require surgery for permanent relief.

There are no licensed topical formulations of calcium-channel blockers at the time of publication.

Limitations
This document focuses on the medical management of chronic anal fissures with topical calcium-channel blockers in adults, Data on the use of this form of therapy in children are very limited,.

References

  1. PRODIGY (2011) Anal Fissure. (accessed23/01/2013)
  2. Nelson RL, Thomas K, Morgan J, Jones A. Non surgical therapy for anal fissure. Cochrane Database of Systematic Reviews 2012, Issue 2. Art. No.: CD003431. DOI: 10.1002/14651858.CD003431.pub3. (accessed 23/01/2013)
  3. Schouten WR, Briel JW, Auwerda JJ. Relationship between anal pressure and anodermal blood flow. The vascular pathogenesis of anal fissure. Dis Colon Rectum 1994;37:664-669
  4. Mayo Clinic staff, Anal fissure. August 8 2008. (accessed 23/01/2013)
  5. Cross KLR, Massey EJD, Fowler AL and Monson JRT. The management of anal fissure: ACPGBI Position Statement, Colorectal Dis 2008;10:1-7
  6. Lock MR, Thompson JPS. Fissure-in-ano: the initial management and prognosis. Br J Surg 1977;64:355-358
  7. Martin JD. Postpartum anal fissure, Lancet 1953;1:271-273
  8. Filingeri V, Giudiceandrea F, Vennarecci G et al. Anal fissure in children, (accessed 8.6.09 and 31.1.09)
  9. American Gastroenterological Association. Medical position statement: Diagnosis and care of patients with anal fissure. Gastroenterology 2003;124;233-234
  10. Madoff RD, FleshmanJW for the American Gastroenterological Association. AGA technical review on the diagnosis and care of patients with anal fissure, Gastroenterology 2003;124:235-245
  11. Perry WB, Dykes SL, Buie WD, et al. Practice Parameters for the Management of Anal Fissures (3rd Revision). Dis Colon Rectum 2010; 53: 1110-5
  12. Lund JN, Nystrom PO, Coremans G et al. An evidence-based treatment algorithm for anal fissure, Tech Coloproctol2006;10;177-180
  13. Jones OM, Brading AF, Mortenson N. The physiology, pharmacology and therapeutic manipulation of the internal anal sphincter. Can J Gastroenterol 2002;16:249-257
  14. Knight JS, Birks K, Farouk R. Topical diltiazem ointment in the treatment of chronic anal fissure. Br J Surg 2001; 88: 553-6
  15. Nash GF, Kapoor K, Saeb-Parsy K, et al. The long-term results of diltiazem treatment for anal fissure. Int J Clin Pract 2006; 60: 1411-3
  16. Jonas M, Speake W, Scholefield JH. Diltiazem heals glyceryl trinitrate-resistant chronic anal fissures: a prospective study. Dis Colon Rectum 2002;45:1091-5
  17. Sajid MS, Rimple J, Cheek E, Baig MK. The efficacy of diltiazem and glyceryl trinitrate for the medical management of chronic anal fissure: a meta-analysis. Int J Colorectal Dis 2008; 23: 1-6
  18. Sajid MS, Parampalli U, Baig MK. An updated meta-analysis on the topical application of diltiazem versus glyceryltrinitrate for the pharmacological management of chronic anal fissure. Colorectal Dis 2011; 13(Suppl 6): 13
  19. Shrivistava UK, Jain BK, Kumar P, Saifee Y. A comparison of the effects of diltiazem and glyceryl trinitrate ointment in the treatment of chronic anal fissure: a randomised clinical trial. Surg Today 2007; 37: 483-5
  20. Jawaid M, Masood Z, Salim M. Topical diltiazem hydrochloride and glyceryl trinitrate in the treatment of chronic anal fissure. J Coll Phys Surg Pakistan 2009; 19: 614-7
  21. Sanei B, Mahmoodieh M, Masoudpour H. Comparison of topical glyceryl trinitrate with diltiazem ointment for the treatment of chronic anal fissure : A randomized clinical trial. Act Chir Belg 2009; 109: 727-30
  22. Cevik M, Boleken ME, Koruk I, et al. A prospective, randomized, double-blind study comparing the efficacy of diltiazem, glyceryl trinitrate, and lidocaine for the treatment of anal fissure in children. Pediatric Surg Int 2012; 28: 411-6
  23. Arthur JD, Makin CA, El-Sayed TY, Walsh CJ. A pilot comparative study of fissurectomy/diltiazem and fissurectomy/botulinum toxin in the treatment of chronic anal fissure. Tech Coloproctol 2008; 12: 331-6
  24. Samim M, Twigt B, Stoker L, Pronk A. Topical diltiazem cream versus botulinum toxin a for the treatment of chronic anal fissure: A double-blind randomized clinical trial. Ann Surg 2012; 255: 18-22
  25. Leinonen PT, Riekki R, Oikarinen A. Contact allergy to diltiazem cream. Contact Dermatitis 2010; 63: 228-30
  26. Cook TA, Smilgrin Humphreys MM, Mortensen NJl. Oral nifedipine reduces resting anal pressure and heals chronic anal fissures. Br J Surg 1999; 86: 1269-73
  27. Antropoli C, Perrotti P, Rubino M et al. Nifedipine for local use in conservative treatment of anal fissures: preliminary results of a multicenter study. Dis Colon Rectum 1999; 42: 1011-5
  28. Perrotti P, Bove A, Carmine A et al. Topical nifedipine with lidocaine ointment vs. active control for treatment of chronic anal fissure: results of a prospective, randomized, double-blind study. Dis Colon Rect 2002; 45: 1468-75
  29. Golfam F, Golfam P, Khalaj A, Mortaz SSS. The effect of topical nifedipine in treatment of chronic anal fissure. Act Med Iranica 2010; 48: 295-9
  30. Katsinelos P, Papaziogas B, Koutelidakis I, et al. Topical 0.5% nifedipine vs. lateral internal sphincterotomy for the treatment of chronic anal fissure: long-term follow-up. Int J Colorectal Dis 2006; 21:179-83
  31. Katsinelos P, Kountouras J, Paroutoglou G, et al. Aggressive treatment of acute anal fissure with 0.5% nifedipine ointment prevents its evolution to chronicity. World J Gastroenterol 2006; 12: 6203-6
  32. Lysy J, Israeli E, Levy S, et al. Long term results of "chemical sphincterectomy" for chronic anal fissure. Dis Colon Rectum 2006; 49: 858-64

Quality Assurance

Top View