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

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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.