Chronic anal fissure: botulinum toxin type A injection

Summary

Evidence from 2 systematic reviews and 4 further randomised controlled trials (RCTs) suggests that botulinum toxin type A injection is less effective than surgery, no better or worse than topical glyceryl trinitrate (GTN; mostly 0.2% ointment) or isosorbide dinitrate, and no better than placebo or lidocaine at healing anal fissure. The Medicines and Healthcare products Regulatory Agency (MHRA) has warned healthcare professionals about the rare but serious risk of toxin spread when using all types of botulinum toxin.

Regulatory status: off-label

Key points

All the research reviewed for this summary used botulinum toxin type A injection to treat chronic anal fissure; no studies using botulinum toxin type B injection were found.

Currently, 0.4% glyceryl trinitrate (GTN) rectal ointment (Rectogesic 4 mg/g rectal ointment, ProStrakan) is the only licensed non-surgical treatment for chronic anal fissure in the UK. It is indicated for the relief of pain associated with chronic anal fissure in adults, but is not licensed for children or young people aged under 18 years.

Botulinum toxin type A injection is not licensed for treating chronic anal fissure in the UK. Its use for this indication is off-label because different botulinum toxin type A brands (Azzalure, Bocouture, Botox, Dysport, Vistabel and Xeomin) are licensed to treat other conditions in the UK, including muscle spasticity and frown lines. Doses of botulinum toxin type A injection are not interchangeable between different brands.

A Cochrane systematic review of randomised controlled trials (RCTs) (Nelson et al. 2012), a systematic review of RCTs and non-randomised studies (Yiannakopoulou et al. 2012), 4 additional RCTs (Valizadeh et al. 2012, Soliman 2006, Samim et al. 2012 and Sahakitrungruang et al. 2011) and 1 non-randomised trial (Lindsey et al. 2003) formed the body of evidence for this summary. All related to adults because no RCTs or systematic reviews were identified in children or young people under the age of 18 years. Most RCTs were small (fewer than 100 participants in each trial), often with short follow-up periods (typically less than 6 months).

Importantly, no studies were identified that compared botulinum toxin type A with 0.4% GTN ointment, the only licensed treatment for chronic anal fissure. Most studies in the 2 systematic reviews used unlicensed 0.2% GTN ointment or surgery as the main comparator.

The 2012 Cochrane review found botulinum toxin type A injection was no better at healing anal fissure than placebo or local lidocaine (3 RCTs, 136 patients), and no better or worse than topical GTN or isosorbide dinitrate 1% ointment (6 RCTs, 334 patients, including 1 RCT of isosorbide dinitrate). The most consistent finding was that botulinum toxin type A injection was not as effective at healing anal fissure as lateral internal sphincterotomy (5 RCTs, 365 patients). Additional evidence reviewed supported the Cochrane review findings.

There were large variations between studies in reported fissure healing and recurrence rates with botulinum toxin type A injection. This may be partly because of differences in the specific toxin brand used, injection site, unit dose, volume of solution injected, and most importantly, length of follow-up used to assess fissure outcomes.

The overall fissure healing rate estimated in the 2012 Cochrane review was approximately 67.5% after botulinum toxin type A injection. Yiannakopoulou et al. (2012) suggested recurrence rates after botulinum toxin type A injection ranged from 0% (24-month follow-up) to 52.5% (5-year follow-up) depending on the length of follow-up.

Botulinum toxin type A injection appeared well tolerated, with temporary incontinence to flatus in approximately 10% of patients, and to liquids and faeces in approximately 5% of patients being the main adverse effects reported.

However, in March 2013, the Medicines and Healthcare products Regulatory Agency advised that all patients receiving any product containing botulinum toxin should be warned of the signs and symptoms of toxin spread, such as muscle weakness and breathing difficulties. They should be advised to seek medical attention immediately if they experience breathing difficulties, choking, or any new or worsening swallowing difficulties, as such side effects may be life-threatening.

Some studies of botulinum toxin A used a single injection given in either side of the fissure, whereas others used 2 injections given as 1 injection in each side of the fissure. The most typical dose included in the studies in the Cochrane review was a single injection of 20 units of the Botox brand of botulinum toxin type A. This would give a drug-only cost of approximately £77.50 per patient, assuming wastage. This does not include the cost of administration, which is likely to include general or regional anaesthesia in a hospital operating theatre.