Advice
Overview for healthcare professionals
Overview for healthcare professionals
Botulinum toxin is a protein complex derived from Clostridium botulinum. In botulinum toxin type A, the protein consists of type A neurotoxin and several other proteins. The protein complex blocks the release of acetyl choline at presynaptic cholinergic nerve terminals (see Botox summaries of product characteristics).
Regulatory status of botulinum toxin type A injection
Botulinum toxin type A injection is not currently licensed in the UK for treating chronic anal fissure in any age group. Different brands of botulinum toxin type A (Azzalure, Bocouture, Botox, Dysport, Vistabel and Xeomin) have UK licences for a variety of other indications, such as managing muscle spasticity and frown lines. Therefore, use of botulinum toxin type A to treat chronic anal fissure is off-label.
In line with the guidance from the General Medical Council (GMC), it is the responsibility of the prescriber to determine the clinical need of the patient and the suitability of using botulinum toxin type A injection outside its authorised indications.
The only currently licensed non-surgical treatment for chronic anal fissure in the UK is topical 0.4% glyceryl trinitrate (GTN) ointment (brand name Rectogesic 4 mg/g rectal ointment). This is licensed for the relief of pain associated with chronic anal fissure in adults for a maximum of 8 weeks (see Rectogesic 4 mg/g rectal ointment summary of product characteristics). It is not indicated for the healing of chronic anal fissure. It is not recommended for use in children and young people aged under 18 years because of a lack of data on safety and efficacy.
Evidence statements
-
No randomised controlled trials (RCTs) or systematic reviews were identified that assessed the use of botulinum toxin type A injection in children with chronic anal fissure.
-
For the outcome of fissure healing in adults a Cochrane systematic review of RCTs found botulinum toxin type A injection was no better than placebo or lidocaine (3 RCTs, 136 patients); no better or worse than topical GTN ointment (mostly 0.2%) or isosorbide dinitrate 1% ointment (6 RCTs, 334 patients, including 1 RCT of isosorbide dinitrate) and not as effective as lateral internal sphincterotomy (5 RCTs, 365 patients). Most RCTs were small (fewer than 100 participants in each trial), often with short follow-up periods (typically less than 6 months).
-
An additional systematic review of RCTs and non-randomised studies (Yiannakopoulou et al. 2012) and 4 additional RCTs (Valizadeh et al. 2012, Soliman 2006, Samim et al. 2012 and Sahakitrungruang et al. 2011) provided further evidence in line with the conclusions of the Cochrane review.
-
Importantly, none of the studies in the 2 systematic reviews looking at GTN used 0.4% GTN ointment (the only licensed treatment); instead, most used unlicensed 0.2% GTN ointment or surgery as the main comparator.
-
No RCTs or systematic reviews were identified that looked specifically at botulinum toxin type A as a second-line treatment after first-line 0.4% GTN ointment had failed to heal the fissure.
-
One non-randomised study (Lindsey et al. 2003) provided limited evidence that botulinum toxin type A may be effective at avoiding the need for surgery in the very short term (up to 8 weeks) after previous treatment failure using the unlicensed 0.2% GTN ointment.
-
Evidence was available from 1 RCT (Samim et al. 2012) that indicated botulinum toxin type A injection may be of comparable efficacy to unlicensed topical 2% diltiazem cream for healing chronic anal fissure.
-
In 1 systematic review (Yiannakopoulou et al. 2012) the main adverse events associated with botulinum toxin type A injection for anal fissure were temporary incontinence to flatus in approximately 10% of patients, and to liquids and faeces in approximately 5% of patients.
-
The Medicines and Healthcare products Regulatory Agency (MHRA) advises 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.
Summary of the evidence
This section gives a brief summary of the main evidence. A more thorough analysis is given in the Evidence review section.
Two systematic reviews (Yiannakopoulou et al. 2012 and a Cochrane Review [Nelson et al. 2012]), 4 additional RCTs not included in either review (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 document. All related to adults only because no RCTs or systematic reviews were identified that recruited children or young people under the age of 18 years. Most studies were small (fewer than 100 participants in each trial) and many had short follow-up periods (typically less than 6 months).
All the research reviewed for this summary described using botulinum toxin type A injection; no instances of using botulinum toxin type B injection for treating chronic anal fissure were identified.
Efficacy
The evidence reviewed was consistent in concluding that botulinum toxin type A injection was not as effective as surgery for healing chronic anal fissure. The evidence for its effectiveness relative to placebo or GTN (mostly 0.2% ointment) was less consistent and yielded no statistically significant differences in healing rates compared with placebo or GTN when the RCTs were pooled in a meta-analysis.
Importantly, none of the studies in the 2 systematic reviews, nor any of the 5 additional studies identified, compared botulinum toxin type A with 0.4% GTN ointment, which is the only licensed treatment for chronic anal fissure in the UK. Unlicensed 0.2% GTN ointment was the main comparator in the majority of studies (a small minority used 1% isosorbide dinitrate ointment or 0.3% GTN). In addition, no RCTs or systematic reviews were identified that considered use of botulinum toxin type A injection after treatment failure using the licensed 0.4% GTN ointment.
The overall healing rate with botulinum toxin type A injection was 76.8% in the Cochrane review (doses and follow-up periods varied). However, when 2 studies with abnormally high healing rates (greater than 90%) were excluded, the overall healing rate was 67.5%.
The evidence for the effectiveness of botulinum toxin type A injection showed large variations between studies in reported fissure healing and recurrence rates. This may be partly because of variations between studies in the specific toxin brand used, injection site, unit dose, volume of solution injected, and possibly most importantly, the length of follow-up to assess fissure outcomes.
The systematic review by Yiannakopoulou et al. (2012) (18 studies, not all RCTs) reported follow-up periods ranging from 6 months to 5 years with recurrence of fissure in the botulinum study arms ranging from 0% (24-month follow-up ) to 52.5% (5-year follow-up). The Cochrane review reported a rate of fissure recurrence, after botulinum toxin type A injection had initially healed the fissure, exceeding 50% after 1 year in 1 RCT (Arroyo et al. 2005) and exceeding 40% after 42 months in a case series (Minguez et al. 2002). Recurrence rate is likely to be heavily influenced by the length of follow-up, with longer follow-up periods capturing more realistic rates of recurrence.
Safety
No serious adverse events or safety concerns were highlighted in either systematic review or additional RCTs reviewed for this summary. A systematic review including RCT and non-RCT evidence to bolster safety data (Yiannakopoulou et al. 2012) concluded that, in general, low levels of adverse events were reported in clinical trials and most of them were localised. One of the expected adverse events highlighted was temporary incontinence to flatus in approximately 10% of patients, and to liquids and faeces in approximately 5% of patients. This compares with reports of up to 30% of patients having difficulty controlling flatus, 20% soiling and 3–10% having episodes of leakage after surgery (Cross et al. 2008), although other reports (Nelson et al. 2011) suggest lower rates of usually no more than 5% of patients having anal incontinence after surgery in more recent years.
The Medicines and Healthcare products Regulatory Agency (MHRA) advises 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.
Cost effectiveness and cost
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 on 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 an approximate drug only cost of £77.50 per patient assuming wastage. This does not include cost of administration, which may be large, because the botulinum injections are often performed in a hospital operating theatre with the patient under general or regional anaesthetic. This looks likely to be more expensive than the licensed alternative, which is a self-administered course of 0.4% topical GTN ointment (applied intra-anally every 12 hours for up to 8 weeks) costing approximately £78.60 assuming wastage.