UOA05-21: Nitric oxide: a new first-line treatment for the common and painful condition of anal fissure
Submitting InstitutionUniversity of Oxford
Unit of AssessmentBiological Sciences
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Cardiorespiratory Medicine and Haematology, Neurosciences, Medical Physiology
Summary of the impact
Collaboration between Professor Alison Brading at the University of
Oxford and her clinical colleague, Professor Neil Mortensen, translated
her pioneering research on the ability of nitric oxide to act as a
neurotransmitter in smooth muscle into a new treatment for the common,
painful, condition of anal fissure. For many years the principal treatment
was elective surgery, which carries a risk of faecal incontinence. Nitric
oxide donors are now used routinely to limit and resolve the development
of anal fissure, improving the lifestyle of sufferers and reducing the
economic costs associated with time off work and surgical intervention.
The treatment has been in existence since 2000, but since 2008 it has
repeatedly been confirmed as the most effective non-surgical intervention.
Anal fissure (a split in the lining of the anal canal) is very common. It
occurs mostly between age 20 and 50; the life-long incidence in the
general population is at least 11% and may be higher owing to
under-reporting of symptoms. Sufferers experience intense pain during and
after defecation, frequently accompanied by rectal bleeding. The condition
often becomes chronic, and in the past this has routinely been managed
surgically by lateral sphincterotomy. However, this is an expensive
intervention that is associated with a significant long-term risk of
faecal incontinence. There has therefore been a need to develop
alternative treatments for anal fissure, either as a bridge to surgery, as
an adjunct, or ideally as a replacement.
In 1993 Professor Alison Brading at the Department of Pharmacology and
colleagues including Professor Neil Mortensen, Consultant Colorectal
surgeon at Oxford's John Radcliffe Hospital, discovered strong evidence to
suggest that nitric oxide (NO) acts as a neurotransmitter in the human
anal sphincter. They showed that sodium nitroprusside, which is a NO
donor, caused potent relaxation in vitro in isolated muscle strips
from the human anal sphincter, and that stimulating the nerves to the anal
sphincter caused a relaxation that depended on the release and action of
NO1. It was immediately clear to Brading that it might prove
possible to manipulate NO neuro-transmission pharmacologically, and that
this could have important therapeutic implications in the management of
disordered anorectal function.
Brading and colleagues went on to develop these observations in studies
that characterised the endogenous pathways that link rectal stretch
(following filling) with anal dilation, a key requirement for successful
defecation. In the first of these studies, in vivo research was
conducted on 12 patients undergoing rectal surgery. NO is synthesised in
neurons which contain the enzyme nitric oxide synthase, and this study
enabled the structure and distribution of these neurons in the anorectum
to be determined. The distribution of NO-producing nerves was found to be
consistent with the role of NO in mediating the relaxation of the internal
anal sphincter2. This research provided compelling evidence
that NO was the neurotransmitter that mediates anal sphincter relaxation,
but did not directly demonstrate the existence of a nitrergic neuronal
pathway which could mediate the reflex. However, in a study using a
neuronal tracing technique in a guinea-pig model, Brading and colleagues
provided direct anatomical evidence of this neuronal pathway in the anal
sphincter, including additional evidence that the pathway is responsible
for relaxation of the sphincter when the rectum is filled3. A
further study in 1996 demonstrated that human rectal circular smooth
muscle also receives an inhibitory innervation, which is mediated by NO4.
In 2003 Brading and colleagues made some of the earliest observations
using neuronal nitric oxide knockout mice, a model that ultimately proved
to be of limited use in the study of normal sphincter relaxation. Although
in the normal mouse NO is an inhibitory neurotransmitter in the internal
sphincter, there are other inhibitory neurotransmitters which appear to
compensate for the absence of nitric oxide synthase in knockout mice so
that approximately normal function is maintained5.
During the period from 1993 onwards, Brading's research in this field
provided very strong evidence of the role of NO in the relaxation of the
anal sphincter, thus suggesting that NO donors could provide an effective
treatment for anal fissure. Initially it was thought that anal fissure was
caused by increased anal pressure resulting from the passage of a hard
stool, but more recently it was proposed that the pressure relates to the
restriction of blood flow, and that successful healing results from
treatments targeted at reducing resting anal pressure and increasing blood
flow. NO donors have subsequently been used routinely for this purpose
(see section 4). Most importantly, recent research demonstrated that the
intervention does not affect the adjacent urogenital tract6.
References to the research
1. O'Kelly T, Brading A, Mortensen N. (1993) Nerve mediated relaxation of
the human internal anal sphincter: the role of nitric oxide. Gut 34:
689-693. doi: 10.1136/gut.34.5.689 The first demonstration
in vitro of a functionally important nitrergic relaxation in
the human anal sphincter.
2. O'Kelly TJ, Davies JR, Brading AF, Mortensen NJ. (1994) Distribution
of nitric oxide synthase containing neurons in the rectal myenteric plexus
and anal canal: Morphologic evidence that nitric oxide mediates the
rectoanal inhibitory reflex. Dis Colon Rectum 37: 350-357. doi:
10.1007/BF02053596 Together with reference 3 below, this paper
provided the first demonstration of signalling between rectum and anal
sphincter involving nitrergic innervation. The studies showed how this
pathway can link rectal filling to anal sphincter relaxation.
3. Stebbing JF, Brading AF, Mortensen NJ. (1996) Nitric oxide and the
rectoanal inhibitory reflex: retrograde neuronal tracing reveals a
descending nitrergic rectoanal pathway in a guinea-pig model. Br J Surg
83: 493-498. doi: 10.1002/bjs.1800830417 See paper 2 above.
4. Stebbing JF, Brading AF, Mortensen NJ. (1996) Nitrergic innervation
and relaxant response of rectal circular smooth muscle. Dis Colon Rectum
39: 294-299. doi: 10.1007/BF02049471 Paper demonstrating a rectal
nitrergic innervation in humans.
5. Jones OM, Brading AF, Mortensen NJ. (2003) Role of nitric oxide in
anorectal function of normal and neuronal nitric oxide synthase knockout
mice: a novel approach to anorectal disease. Dis Colon Rectum 46: 963-970.
doi: 10.1007/s10350-004-6694-y The first use of nNOS knockout mice
to explore anorectal signalling with a view to translation.
6. Ramalingam T, Durlu-Kandilci NT, Brading AF. (2010) A comparison of
the contractile properties of smooth muscle from pig urethra and internal
anal sphincter. Neurourology and Urodynamics 29: 1326-1331.
doi:10.1002/nau.20863 The first demonstration that targeting
nitrergic neurotransmission in the anal sphincter does not impair
Funding for research: This work was funded between 1993-2004 by
grants of ~£1.2M from the British Heart Foundation, GlaxoSmithKline,
Pfizer and the Wellcome Trust.
Details of the impact
Professor Brading and colleagues' research has led directly to the
development of new NO-based treatments for anal fissure. NO donor
treatments were available before the start of the impact period, but since
2008 they have repeatedly been confirmed as the most effective
non-surgical treatment available by leading bodies including the NHS and
British Medical Journal (BMJ).
Route to impact
Dissemination of the original research results, through publications in
peer-reviewed literature, and through the clinical contacts of Professor
Mortensen, gave the impetus needed for a move to clinical trials of NO
donors such as glyceryl trinitrate (GTN) for the topical treatment of anal
fissure. These included the first randomised controlled trials of GTN from
1994-99. The results were extremely encouraging; Lund & Scholefield,
for example, showed that two-thirds of patients treated with topical GTN
avoided surgery that would otherwise have been required for fissure
healing. They suggested that GTN should become the first-line treatment
for anal fissures, with surgery reserved for those not responding to
pharmacological treatment7. An independent study in 2004
provided evidence that the pain associated with anal fissure can affect
health-related quality of life, and confirmed that successful non-surgical
interventions such as GTN treatment can lead to a lessening of pain and
improvements in vitality, physical functioning and general health8.
In addition to the investigation of nitric oxide donors, in 2001 Brading
and Mortensen were also responsible for early characterisation of another
set of agents that they showed could potentially relax the anal sphincter,
including botulinum toxin and calcium channel blockers9.
However, they found that nitric oxide donors were the pharmacological
treatment for which there was most evidence of effectiveness. Subsequent
clinical trials have largely confirmed that other agents are less
effective than the nitric oxide donors.
Impact since 2008
The fundamental research of Brading and Mortensen means that nitric oxide
donors are now in routine clinical use as a principal first-line treatment
for anal fissure, and remain the best available medical therapy apart from
surgery. Use is by topical application to the anus 3-4 times a day for a
period of several weeks, which removes or delays the need for surgical
intervention. Nitric oxide donors (in particular GTN) offer an effective
and inexpensive (off patent and cheap to produce) therapy compared with
the medical and surgical alternatives. The BMJ's Best Practice site
currently recommends GTN as an initial treatment for anal fissure10,
as does the NHS Choices website11, demonstrating that NO donor
treatment has become standard in the UK. In 2012, a Cochrane systematic
review on the treatment of anal fissure identified nitric oxide donors as
the only effective non-surgical treatment12, indicating the
lasting and effective clinical translation that has arisen from the
pioneering work of Brading and Mortensen on the role of nitric oxide in
the human anal sphincter. A BMJ review in 2009 drew similar conclusions;
of the available non-surgical treatments, only nitric oxide donors were
deemed `likely to be beneficial'13. Since 2008, the increasing
use of GTN in developing countries as a cheap and effective alternative to
surgery is evidenced by papers such as those published by researchers at
the Suez Canal Hospital in Egypt14 and in India15,
both of which recommend that GTN be used as a first-line treatment.
The impact of these therapies is particularly important as a bridge to
surgery and in developing countries where access to surgical treatment is
limited. In the UK, with a hospitalisation rate of 1.56 per 10,000
inhabitants per year, surgical intervention for anal fissure represents a
significant financial burden, so the provision of medical alternatives has
significant financial advantages. The age profile of the patients with
anal fissures overlaps with their period of strong economic activity, so
time missed from work owing to surgery is a significant consideration, and
thus there is also a strong economic impact of treatment.
Sources to corroborate the impact
- Lund JN, Scholefield JH. (1997) A randomised, prospective,
double-blind, placebo-controlled trial of glyceryl trinitrate ointment
in treatment of anal fissure. Lancet 349: 11-14. doi:
10.1016/S0140-6736(96)06090-4 Clinical trial demonstrating the
effectiveness of nitric oxide donors in the treatment of anal
- Griffin N, Acheson AG, Tung P, Sheard C, Glazebrook C, Scholefield JH.
(2004) Quality of life in patients with chronic anal fissure. Colorectal
Disease 6: 39-44. doi: 10.1111/j.1463-1318.2004.00576.x Study
demonstrating significantly improved quality of life results for
patients with anal fissure who receive non-surgical treatments such
- Cook TA, Brading AF, Mortensen NJ. (2001) The pharmacology of the
internal anal sphincter and new treatments of ano-rectal disorders.
Aliment Pharmacol Ther 15: 887-898. doi:
10.1046/j.1365-2036.2001.00995.x A review of available
non-surgical treatments for anal fissure and their effectiveness,
confirming nitric oxide donors as the most reliable option.
- Best Practice. Anal fissure. BMJ Publishing; 25 Mar 2013. Available
best practice advice for the treatment of anal fissure, provided by
BMJ Best Practice; GTN is recommended as an appropriate initial
- NHS Choices. Anal Fissure - Treatment. Department of Health; 23 May
2012. Available from:
NHS advice for patients outlining treatment options for anal
fissure; GTN is again recommended.
- Nelson RL, Thomas K, Morgan J, Jones A. (2012) Non-surgical therapy
for anal fissure. Cochrane Database Syst Rev 2: CD003431. doi:
10.1002/14651858 2012 review concluding that although surgery
remains overall the most effective treatment for anal fissure,
nitric oxide donors represent the most effective non-surgical
- Nelson R. (2010) Anal fissure (chronic). Clinical Evidence. BMJ
publishing; Mar 2010. Available from:
Clinical Evidence review of the effectiveness of available
treatments for anal fissure, concluding that nitric oxide donors are
the only non-surgical treatment likely to be beneficial.
- Ellabban G, Elkazaz G, Hokam E. (2010) Local glyceryl trinitrate
versus lateral internal sphincterotomy in management of anal fissure.
World J of Colorectal Surgery 2: Available from:
http://services.bepress.com/wjcs/vol2/iss1/art12 Paper by researchers at the Suez Canal Hospital, Egypt,
recommending the use of GTN as a first-line treatment for anal
- Medhi B, Rao RS, Prakash A, Prakash O, Kaman L, Pandhi P. (2008)
Recent advances in the pharmacotherapy of chronic anal fissure: An
update. Asian Journal of Surgery 31: 154-163. doi:
10.1016/S1015-9584(08)60078-0 Paper by researchers in Chandigarh,
India, recommending the use of GTN as a first-line treatment for