Objective: Assessment of the efficacy of topical 0.5% glyceryl trinitrate (GTN) paste in the treatment of chronic fissures in ano. Patients and Methods: Forty-five patients were treated with 0.5% GTN paste and reviewed at 3, 6 and 12 weeks to assess symptoms, side effects and fissure healing. Results: At 6 weeks, 73% of patients had no fissures. In 27% of cases treatment was unsuccessful. At three month follow up there was no early recurrence. The prevalence of headaches was 84% with 11% headache related non-compliance. Conclusions: The use of 0.5% GTN induces rapid healing of chronic anal fissures with a 73% healing rate in this study. Successful treatment may come at the expense of a high incidence of headaches and a lower compliance than found in studies involving a lower concentration of GTN. A balance is required between fissure healing and headache intolerance.
Keywords: Glyceryl trinitrate (GTN), anal fissure
J.R.Coll.Surg.Edinb., 45 June 2000, 168-170
Unlike acute anal fissures, chronic fissures-in-ano do not usually respond to dietary advice alone. The aim of treatment is to alleviate sphincter hypertonia and improve blood flow to the ulcerated area1. Lateral internal anal sphincterotomy has replaced anal stretching as the mainstay of treatment due to concerns over adverse effects on continence. Lateral sphincterotomy permanently lowers resting anal pressure and in doing so aids the healing of anal fissures. It may, however, be associated with minor temporary or permanent alterations in the control of gas, mucus and occasionally stool in up to 35% of patients2. This has led to alternative therapeutic approaches, in particular, pharmacological, reversible sphincterotomy using topical agents such as botulinum toxin, calcium channel blockers and glyceryl trinitrate (GTN).
The most widely used topical agent is GTN. The latter is metabolised to nitric oxide and leads to sphincter muscle relaxation and reduction in the maximum anal resting pressure. This results in a reversible improvement in pecten perfusion and eliminates the risk of permanent anal incontinence associated with surgery3. Existing data concerns mainly the efficacy of 0.2% GTN paste. Little is known about the use of higher doses. We present the results of one year's experience using 0.5% GTN paste as first line treatment of chronic anal fissures.
Forty-five consecutive patients with chronic anal fissure were included in the study. Chronicity was determined by a history longer than 3 months and/or the presence on examination of a sentinel tag or white muscular fibres at the base of the fissure.
Patients with inflammatory bowel disease, pregnant women and patients taking nitrates for other conditions were excluded. The Ethics Committee of Queen Elizabeth Hospital, King's Lynn, approved the study protocol. Informed consent was obtained from all patients.
At presentation, a pain score (0-10) was established as well as a symptom score (0-3) with one point each for bleeding, discharge and itching. The patients were started on a course of 0.5% GTN paste (prepared in the hospital pharmacy) which was applied digitally peri- and intra-anally three times daily, initially for 6 weeks. The amount applied was the smallest amount that could be rubbed into the anal area without leaving excess paste. All patients were reviewed at 3, 6, and 12 weeks to assess pain and symptoms scores and to assess fissure healing, complications and compliance. Patients that did not respond to treatment or who were unable to comply with the treatment were offered a lateral anal sphincterotomy.
The mean age of patients was 44 years (range 17-80 years). The mean length of anal fissure history was 10 months (range 4-36 months). The mean pain score at presentation was 8 (range 2-10).
The mean pain score at 3-week follow up was 3 with 15/45 (33%) patients experiencing no pain. At 6 weeks, 23/45 (51%) patients experienced no pain and 29/45 (64%) were pain free at 12 weeks.
At the time of presentation 32 out of 45 (71%) patients had two or more of the documented symptoms. At 3 weeks, 26 (58%) patients were symptom free. At 3 month follow up this was 31 (69%) patients.
Overall, at 12 weeks following treatment with 0.5% GTN paste, 33/45 (73%) patients had a clinically healed ulcer (Fig 1.). Four of these patients continued to experience pain in the absence of a fissure but were asymptomatic when reviewed at 18 weeks.
Figure 1: Outcome of treatment with 0.5% GTN paste at 12 weeks
In twelve (27%) patients, treatment with 0.5% GTN paste was unsuccessful. Of these, 7 patients were not compliant, 3 did not respond to treatment, 1 became pregnant during treatment and 1 did not attend follow-up. Of the 7 non-compliant patients, 5 (11%) stopped treatment due to the iatrogenic headaches, 1 experienced a peri-anal itch previously not present and one further patient - a police constable - found the application of GTN perianally not compatible with his daily duties.
At 6 month follow-up, the 33 patients successfully treated all remained symptom free with healed fissures. There were no fissure recurrences.
Thirty-eight out of the 45 patients (84.4%) experienced headaches on commencing treatment. Five (11%) patients did not comply with treatment due to this side effect.
Topical GTN paste is an effective alternative to surgery in the treatment of chronic fissures-in-ano. At a concentration of 0.2%, GTN has been shown to be better than placebo (68% vs 8%) in healing chronic anal fissures.4 A crescendo dosage of GTN from 0.2% to 0.6%, by 0.1% weekly increments, was associated with a consistently lower pain score and a better healing rate (70% vs 64%) compared with the 0.2% treatment group but this did not reach statistical significance.5
Most data to support the use of topical GTN has been based on the application of 0.2% GTN. Only one small uncontrolled study has previously assessed the use of topical 0.5% GTN ointment in the treatment of anal fissures.6 This study, however, included patients with Crohn's disease and thrombosed external piles; indeed only 12 patients in this series had primary fissures-in- ano. Relief of pain was shown to be rapid and complete but no physical examination was performed to assess fissure healing and follow-up was to 8 weeks only. Curiously, headaches were reported in only 7 of the 20 patients in Gorfine's (1995) study despite use of the 0.5% GTN paste 4 times a day.6 More recently, a randomised controlled trial that included a treatment arm of weekly increases in GTN ointment concentration of 0.1% - starting at 0.2% and progressing to 0.6% over an 8 week period -showed no statistically significant difference in outcome compared with a fixed 0.2% concentration5. Our series is unique in the use of 0.5% GTN paste ab initio. It shows that up to 73% of patients with chronic anal fissures can be successfully treated using topical 0.5% GTN paste as a primary measure. The effect of treatment appears to be almost immediate with symptomatic improvement evident at 3 weeks from the commencement of treatment. The rapid symptomatic improvement with 0.5% GTN compares favourably with the use of 0.2% GTN or weekly increments in GTN concentration. Whilst there is little difference in the overall outcome of treatment there does appear to be a trend towards a better outcome with the use of higher doses (73% with 0.5% vs 70% using incremental doses vs 64% with 0.2%)4,5. This benefit, however, occurs at the expense of more headaches and a lower compliance rate. Indeed, as in the use of GTN for angina, headaches are a significant side-effect of treatment. The use of 0.5% GTN is associated with an 83% incidence of headaches. In five patients (11%) headache intolerance was the cause for non-compliance or dis-continuation of treatment. This compares with a headache incidence of 58%, when using 0.2% GTN ointment, and 3% non-compliance due to this side effect4. What remains unclear in all published series is whether headaches are in part due to absorption of GTN via the finger, given that not all patients use gloves while applying the medication. Furthermore, given the absence of a reliable and reproducible dosage system the actual quantity applied to the anus is not standardised and may be different in each patient. This could indeed render the comparison of results and headache incidence, using different concentrations of GTN ointment, not comparable once the quantity applied is taken into account.
Of note is the minimal difference in the findings at 6 and 12 week follow-up. Symptom scores were nearly identical with partially healed ulcers at 6 weeks completing the healing process within 12 weeks. It would appear that compliant patients that respond to treatment do so within 6 weeks or probably not at all. This suggests that failure to respond to topical GTN at 6 weeks may be an indication for an alternative therapeutic approach.
Early recurrence does not appear to be a problem. Long- term recurrence and its' treatment options are currently the subject of a study in this hospital. A recent study has shown 11 symptomatic relapses in 44 patients treated with topical 0.2% GTN 3 months from termination of treatment.7 From a quarter to a third of patients in another study experienced recurrence at a median follow up of 9 months.5
Short-term follow up suggests that there is little justification in using a higher dose of GTN paste. Longer follow up series with various doses, however, are required in order to establish the optimal dosage. Standardisation of the method of application and the amount of ointment applied are also required to validate metanalysis in the future.
Copyright date: 25 April 2000
Correspondence: F.F. Palazzo, Surgical Research Fellow & Hon. Lecturer, Department of Immunology, St Bartholomew's & Royal London Hospitals, 38 Little Britain, London EC1 7BE, UK
©2000 The Royal College of Surgeons of Edinburgh, J.R.Coll.Surg.Edinb.