The causes of constipation. Reclassifying constipation using MRI and high resolution manometry to define mechanism of disease and target treatment.

Constipation is a common problem affecting up to 1 in 7 of the population but treatment is unsatisfactory for over half the patients treated. One reason may be that the current system of classification which determines doctors' choice of treatment is based on symptoms rather than underlying causes. This is because defining the causes, which include abnormal contractions within the large bowel, is difficult at present as this can only be done by emptying the colon and measuring contraction pressure with small probes (a technique called manometry) within the bowel. This is time consuming, technically difficult and requires highly specialist staff to perform. Also, it requires a camera test (colonoscopy) to actually put the probe in the right place. This is expensive and unpleasant for patients.

The traditional theory of constipation is that it is due to underactivity of the colon i.e. reduced or absent contractions. We have recently developed a new magnetic resonance imaging (MRI) technique, which is non-invasive (does not involve putting anything up the bowel), acceptable to patients and potentially more widely available as it can be performed using standard MRI scanners. We have applied this MRI method to a group of patients with constipation. Surprisingly some patients have normal or increased numbers of bowel contractions (motility) in the right half of the colon where the small intestinal contents enter the colon. We see this in around half our patients despite finding slow movement throughout the colon (called slow transit). Recently advances in directly measuring pressure using manometry have shown that colonic contractions in patients with constipation-type irritable bowel syndrome may be uncoordinated or may actually serve to propel fluid backwards (retrograde contractions) rather than forwards as one would normally expect. An increase in such contractions would impede movement through the bowel (prolonging transit time) and by separating fluid from solid make the stool harder. This is a new and radically different view of the cause of constipation.

At 3 leading University Hospitals in Nottingham and London we propose to study up to 80 patients with constipation and 40 healthy volunteers, using MRI and manometry to determine if our new MRI methods can be used to detect abnormal contractions as well as manometry can. Our first aim is to confirm our original findings. We will also compare motility in both the right and left side of the colon using MRI to see if activity is similar on the two sides. We will also assess the motility of the left colon using a new highly sensitive manometry technique to see if classifying patients in this way identifies the same patients as the MRI test. We will then invite subjects who have had their colonic contractions assessed to take part in a trial of two very different treatments given in random order, one which increases contractions (called a prokinetic) and one which reduces contractions (muscle relaxant). During the trial neither the subject nor investigator will know which treatment has been given. We want to know if our new motility test will predict which treatment works to reduce symptoms (constipation and pain). We hypothesise that giving a prokinetic to patients with normal or increased contractions will aggravate symptoms but improve symptoms in those with underactive contractions. Conversely giving a muscle relaxant to reduce contractions will improve those with increased or abnormal contractions but not help those with normal or underactive contractions.

If successful we hope that future treatment of constipation unresponsive to simple measures will be based on objective assessment using the new MRI test rather than the current unsatisfactory symptom-based methods. This should substantially increase the proportion of patients who are satisfied with their treatment, thereby reducing doctor visits, investigations and time off work.

Chronic constipation is characterised by abdominal discomfort, pain and difficult or infrequent defaecation. The current clinical criteria subdivide patients based on symptoms into painful irritable bowel syndrome with constipation (IBS-C) or painless functional constipation (FC). However the current classification system fails to predict treatment response, which is unsatisfactory in 50%. While in some cases colonic hypomotility is the underlying problem this does not explain the abdominal pain which we hypothesize is due to abnormally increased retrograde/ uncoordinated colonic motility. Our recently developed cine MRI technique can noninvasively quantify colonic motility in response to distension of the ascending colon by means of the osmotic laxative, Moveprep. This shows that a subgroup of IBS-C have increased motility compared to FC. We wish to develop this observation using recent advances in high resolution manometry (HRM) made by our collaborator Dr Dinning (Adelaide) which have demonstrated the importance of cyclical retrograde propagated contractions (CRPCs) and/ or uncoordinated motility in the sigmoid colon in constipation.
We will validate the MRI assessment of colonic motility in constipation against the manometry gold standard and test the hypothesis that constipated patients with normal/hypermotility of either the right or left colon shown by MRI will show normal/increased CRPCs or uncoordinated motility in the left colon shown by manometry. We will then perform an RCT comparing an antispasmodic with a prokinetic to test the hypothesis that a) constipated patients with paradoxical normal/increased motility will respond better (in terms of reduced pain) to a smooth muscle relaxant than to a stimulant prokinetic and b) that patients with hypomotility will do better with a prokinetic. We will thus develop a simple MRI test to predict response to treatment in patients with constipation resistant to simple laxative treatment.

The main beneficiaries will be patients, clinicians, academics and the pharmaceutical industry.
Benefit to patients and clinicians
Constipation is an extremely common condition, affecting on average 14% of the population. It is responsible for 4.3 million GP consultations per year in England and Wales and according to the NHS Information Centre in 2011 there were 15.9 million prescriptions for laxatives at an estimated cost of £70.6 million per year. The condition is characterized by abdominal discomfort / pain and difficult defaecation which if severe can come to dominate patients' lives significantly impairing their quality of life. The health related quality of life impairment is similar to that seen with dermatitis, ulcerative colitis, depression, allergies, and chronic back pain. Our patients are dissatisfied by their treatments and our patient focus group felt that the medical community is dismissive of their problem and nihilistic as to better treatments. Improved understanding has the potential to significantly improve this undesirable situation.
Our proposed studies have the potential to radically change the way gastroenterologists and radiologists deal with this important clinical problem which can, in severe cases, appear intractable. The majority of patients with constipation have a disorder of function rather than anatomy yet such patients are currently are subjected to fruitless expensive investigations of anatomy (colonoscopy/ barium enema) without assessing function. This wastes resources and reflects the lack of useful clinical tests of colonic function. Our studies will compare the gold standard for assessing colonic motility with a simple MRI test which could be widely disseminated throughout the NHS, requiring only a standard MRI scanner.
If our study confirms that we can assess colonic motility non-invasively and the results can identify important mechanisms of constipation and predict response to different treatments then this could ensure more effective targeting of treatments to those who will benefit. It will also provide objective evidence of colonic function and identify the few who have profoundly inert colons for whom no drug will work and who could be saved from years of suffering by having a colectomy. Most importantly it will also identify the many who think they need a colectomy but actually either have disordered defaecation or the irritable bowel syndrome for whom surgery would be a disaster.
Benefit to academics
Our studies will indicate whether the abnormalities seen in the ascending colon in constipation are also a feature of the descending colon. They will also provide for the first time a large data set of high resolution manometry in constipation. By quantifying the role of retrograde cyclical contractions in the sigmoid colon we will address the issue of how hard stools can be seen despite apparently normal transit. This will open up a whole new area of research encouraging academics to define the way in which sigmoid motility is controlled and hence better understanding of the underlying causes of constipation.
Benefit to industry
The number needed to treat in most trials is >8 indicating considerable patient heterogeneity which is inevitable since currently trial entry is based on symptoms which are unreliable and subjective. Patients stratified using our Moviprep challenge will be much more homogeneous and as we hope to show in study 2 this will lead to a larger treatment effect and hence allow smaller more speedy trials during the development of new treatments for constipation.