Article Text

Botulinum toxin A injections were more effective than glyceryl trinitrate for complete healing of anal fissure

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Brisinda G, Maria G, Bentivoglio AR, et al. A comparison of injections of botulinum toxin and topical nitroglycerin ointment for the treatment of chronic anal fissure. N Engl J Med. 1999 Jul 8;341:65-9.

Question

In patients with chronic anal fissure, are botulinum toxin injections more ef-fective than nitroglycerin ointment (glyceryl trinitrate [GTN]) for increasing the healing rate?

Design

Randomised (concealed), blinded (outcome assessor), controlled trial with 1- and 2-month follow-up.

Setting

Clinical centres in Rome.

Patients

50 adults (mean age 42 y, 50% women) with symptomatic chronic anal fissure, which was defined as evidence of posterior circumscribed ulcer with a large sentinel tag of skin, induration at edges, and exposure of horizontal fibres of the internal anal sphincter; and symptoms of post-defecatory or nocturnal pain, bleeding, or both for 2 months. Exclusion criteria were acute fissure, fissure associated with other conditions, or previous surgery in the anal canal. Follow-up was complete.

Intervention

Patients were allocated to 2 injections of botulinum toxin A, 20 U in 0.4 mL of solution (n = 25), or 0.2% GTN (10 g of 2% nitroglycerin diluted to 100 g with soft paraffin) applied manually to the anus and anal canal twice daily for 6 weeks (n = 25).

Main outcome measure

Complete healing after treatment.

Main results

More patients in the botulinum-toxin group than in the GTN group had healed fissures at 1 month (P < 0.001) and 2 months (P = 0.005) after treatment (Table). More patients in the GTN group than in the botulinum-toxin group had transient moderate-to- severe headaches (P = 0.005) (Table). No patient in either group had relapses, complications, or side effects after a mean follow-up of 16 months.

Conclusion

In patients with anal fissure, botulinum toxin A injections were more effective than glyceryl trinitrate for complete healing of the fissure and led to fewer adverse effects.

Source of funding: Not stated.

For correspondence: Dr. G. Maria, Istituto di Clinica Chirurgica Generale, Policlinico Univer-sitario Agostino Gemelli, Largo Agostino Gemelli 8, 00168 Rome, Italy. E-mail gbrisin@tin.it.

Botulinum toxin A injections (Bot) vs glyceryl trinitrate (GTN) for anal fissure*

Outcomes Bot GTN RBI (95% CI) NNT (CI)

Healing at 1 mo 88% 40% 120% (41 to 281) 3 (2 to 5)

Healing at 2 mo 96% 60% 160% (121 to 237) 3 (2 to 7)

RRR (CI)

Treatment-related 0% 20% 100% (30 to 100) 5 (3 to 20)

headache

*Abbreviations defined in Glossary; RBI, RRR, NNT, 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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