Evidence review: safety

The main adverse effect related to glyceryl trinitrate use is headache. Of particular relevance to patient care is where headache is of such severity that it leads to treatment discontinuation (Nelson et al. 2012). The combined risk of headaches using glyceryl trinitrate in the Cochrane review was 30%, which covered all strengths and comparisons with other treatments included in the review. However, the effect of glyceryl trinitrate strength on headache was not assessed in the Cochrane review. See the evidence summary Chronic anal fissure: 2% topical diltiazem hydrochloride for a discussion of randomised controlled trials (RCTs) comparing glyceryl trinitrate with unlicensed 2% topical diltiazem hydrochloride on headache.

It is important to note that, whilst each of the following RCTs attempted to standardise the dose of glyceryl trinitrate (that is, the amount of ointment applied), this was not the same in each RCT. It is not known whether applying less ointment of the same strength, rather than reducing the strength of ointment applied, might have an effect on the incidence or headache.

Randomised controlled trial by Scholefield et al. (2003)

Frequency of headache and frequency of severe headache appeared to be related to glyceryl trinitrate ointment strength in the Scholefield et al. (2003) trial. From the intention-to-treat data, headaches were reported in 12.5% (6/48) of patients using placebo, 18.3% (9/49) using 0.1% glyceryl trinitrate ointment, 36.1% (17/47) using 0.2% glyceryl trinitrate ointment, and 67.5% (25/37) using 0.4% glyceryl trinitrate ointment for 8 weeks. This increase in the frequency of reported headaches with increasing glyceryl trinitrate strength was statistically significant (p value for trend less than 0.01).

The frequency of severe headaches showed a less clear pattern at a rate of 4.2% (2/48) with placebo, 2.0% (1/49) with 0.1% glyceryl trinitrate ointment; 6.4% (3/47) with 0.2% glyceryl trinitrate ointment, and 24.3% (9/37) with 0.4% glyceryl trinitrate ointment (no statistical test for trend reported). Headache was the only adverse event reported in the study; however, the authors commented that no other side effects were correlated with glyceryl trinitrate strength.

Randomised controlled trial by Bailey et al. (2002)

Bailey et al. (2002) pooled the results of twice and 3 times daily use of glyceryl trinitrate ointment and reported only the headache results associated with the 0.4% ointment. This showed that 3.3% of patients discontinued treatment because of headache (no patient numbers reported).

Randomised controlled trial by Carapeti et al. (1999)

In the trial by Carapeti et al. (1999), there was no statistically significant difference (p=0.5) in the number of patients reporting headaches in the 0.2% glyceryl trinitrate ointment group (65%, 15/23) compared with the escalating strength (0.2% up to 0.6% ointment) group (78%, 18/23). None of the patients in the study reported permanent loss of flatus or faecal continence, although 13% (6/46) using glyceryl trinitrate ointment (0.2% and escalating strength group combined) noted some temporary loss of flatus control while using the treatment.

Pilot randomised controlled trial by Simpson et al. (2003)

Out of 15 children, 2 experienced headache in the first few days of the trial by Simpson et al. (2003) (1 in each of the 0.05% and 0.1% glyceryl trinitrate ointment trial arms). These were short-lived (less than 20 minutes), resolved spontaneously and did not affect treatment adherence.