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High-dose glyceryl trinitrate was no more effective than usual dose for chronic anal fissure

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Carapeti EA, Kamm MA, McDonald PJ, et al. Randomised controlled trial shows that glyceryl trinitrate heals anal fissures, higher doses are not more effective, and there is a high recurrence rate. Gut. 1999 May; 44:727-30.

Question

In patients with chronic anal fissure, does a higher dose of glyceryl trinitrate (GTN) prompt a faster or higher healing rate than the usual dose?

Design

10-week randomised (concealed), blinded (clinician and patient), placebo-controlled trial.

Setting

Surgical outpatient clinics in Harrow, England, UK.

Patients

70 patients who had anal fissure for 3 months with clinical features of chronicity (fibrosis of the base of the ulcer or sentinel pile). Exclusion criteria were fissures caused by Crohn disease or HIV, receipt of nitrate treatment for ischaemic heart disease, history of migraine, or pregnancy. 68 patients (97%) (median age 36 y, 51% men) completed the study.

Intervention

Patients were allocated to GTN ointment, 0.2% (usual dose) (n = 23); an escalating dose of GTN starting at 0.2% with weekly increments of 0.1% to a maximum of 0.6% (n = 23); or placebo (n = 22). The ointment was applied manually to the skin of the anal verge 3 times daily for 8 weeks.

Main outcome measures

Healing rate, pain, headache, and fissure recurrence.

Main results

More patients who received GTN had healed fissures at 10 weeks than did patients who received placebo (P = 0.008) (Table). Speed of healing did not differ between escalating-dose GTN and 0.2% GTN (healing within 6 weeks 39% vs 22%, P = 0.33). At 2 weeks, all 3 groups had a decrease from baseline in mean pain score (P £ 0.001) with no difference between the 2 GTN groups (P = 0.7) or between the 2 GTN groups and placebo (P = 0.4). More patients who received GTN had headache than patients who received placebo (P < 0.001); no difference in headache occurred between the GTN groups (P = 0.5) (Table). During a median 9-month follow-up, fissures recurred in 43% of those initially healed with placebo, 33% of those healed with 0.2% GTN, and 25% of those healed with escalating-dose GTN (P = 0.7).

Conclusion

In patients with chronic anal fissure, a higher dose of glyceryl trinitrate did not prompt a faster or higher healing rate than the usual 0.2% dose.

Source of funding: No external funding.

For correspondence: Prof. M.A. Kamm, St. Mark's Hospital, Northwick Park, Watford Road, Harrow, Middlesex HA1 3UJ, England, UK. FAX 44-181-235-4162.

0.2% glyceryl trinitrate (GTN), escalating-dose (ED) GTN, and placebo for anal fissure at 10 weeks*

Outcomes 0.2% ED 0.2% + Placebo RBI (95% CI) NNT (CI)

GTN GTN ED GTN

Healing 65% 32% 105% (8.9 to 319) 4 (2 to 26)

70% 32% 119% (18 to 343) 3 (2 to 12)

RRI (CI) NNH (CI)

Headache 72% 27% 163% (43 to 456) 3 (2 to 5)

65% 78% 20% (18 to 81) Not significant

*Abbreviations defined in Glossary; RBI, RRI, NNT, NNH, and CI calculated from data in article.

Commentary

The 2 studies by Carapeti and colleagues and Brisinda and colleagues provide useful information to guide treatment of chronic anal fissure. GTN ointment has been widely accepted as an efficacious treatment for a majority of patients presenting with a chronic anal fissure, providing relief of painful symptoms with little risk for long-term impairment of continence (1). However, GTN may have unpleasant side effects, particularly headache. Therefore, we need to know the minimum dose necessary to heal a fissure and the shortest effective duration of treatment. Local injection of botulinum toxin has emerged as another rapid and effective treatment option.

Carapeti and colleagues allocated patients to 8 weeks of treatment with GTN or placebo, and the results confirm that GTN is better. The authors also suggest that the higher doses of GTN were no more effective than the lower dose of 0.2%. To support this conclusion, however, perhaps more treatment groups should have received different doses rather than the escalating dose that was used. This would have increased both the number of patients required and the duration of the study, but the results would have been more reliable. Examination of these data reveals that a trend existed toward earlier healing (at 6 wk) in patients receiving the higher doses of GTN. However, at 6 weeks, they would have received only 4 weeks of higher-dose GTN, and there might be a threshold dose above 0.2% that maximises rapidity and effectiveness of healing. If this were the case, then patients could simply be started and maintained on that doseheadaches allowing. This question still needs to be answered. The study by Brisinda and colleagues pared a 6-week course of GTN ointment with 2 local injections of botulinum toxin. The results suggest that botulinum toxin is better than GTN. Botulinum did not cause the headaches associated with GTN, and it had better healing rates (at both 1 month and 2 months), which were sustained for a mean follow-up of 15 months. There was also the added advantage of a single treatment episode, albeit a local injection.

These results closely approximate those of previous publications (1, 2) and support a treatment algorithm in which GTN provides simple, widely available first-line treatment with few side effects in most patients. Botulinum toxin injection requires expertise to administer but has a high success rate, is effective in patients in whom GTN fails, and in some circumstances could be offered as first-line treatment. Both studies suggest that lateral sphincterotomy should no longer be used as first-line treatment and that neither placebo nor lateral sphincterotomy has a place as alternate treatment in future therapy trials. In addition, Brisinda and colleagues have provided a set of definitions for the study of chronic anal fissure that should be the standard for future trials.

John Monson, MD

University of Hull

Hull, England, UK

References

1. Lund JN, Scholefield JH. A randomised, prospective, double-blind, placebo-controlled trial of glyceryl trinitrate ointment in treatment of anal fissures. Lancet. 1997;349:11-4.

2. Maria G, Cassetta E, Gui D, et al. A comparison of botulinum toxin and saline for the treatment of chronic anal fissures. N Engl J Med. 1998;338:217-20.

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