Mechanistic Randomized Controlled Trial (RCT) of Mesalazine in Symptomatic Diverticular Disease
Mechanistic Randomized Controlled Trial (RCT) of Mesalazine in Symptomatic Diverticular Disease
Diverticulosis (bulges in the bowel wall) affects two third of the elderly population in the
 UK. Diverticular disease and its complications are responsible for 68000 hospital admissions
 and 2000 deaths per year. It commonly produces recurrent short lived abdominal pain, changes
 in bowel habit and incontinence. The causes of symptoms are not known and the treatments
 unsatisfactory. Recent studies have found an association between inflammation, alteration of
 bowel nerves and symptoms. Mesalazine is an anti-inflammatory drug used in inflammatory bowel
 conditions, such as ulcerative colitis and crohn's disease. We plan to perform a randomized
 double blind (neither the patients or the doctors known which treatment the patient is
 taking) placebo (sham medication) controlled trial of mesalazine in symptomatic diverticular
 disease patients. We anticipate a reduction in the amount of inflammation, bowel nerve
 changes and symptoms in patients taking mesalazine compare to those taking the placebo.
Diverticular disease affects two thirds of the elderly population in the United Kingdom. Only
 a small fraction of individuals with diverticulosis develop symptoms, perhaps 1 in 10, for
 reasons which are not well understood. The symptoms however are quite disabling as we found
 in a recent survey which indicated that around 36% suffered recurrent abdominal pain.
 Surprisingly, given the severity of the disability there has been very little research into
 the factors predicting the development of painful diverticular disease. Recent studies have
 indicated however that there may be an inflammatory component since the best predictor of
 recurrent abdominal pain is a previous episode of acute diverticulitis.

 Just what initiates an attack of acute diverticulitis is poorly understood but may include
 the inspissation of fecal material in the diverticulum which then leads to pressure on the
 lining epithelium and a break down of barrier function. This allows colonic bacteria to enter
 the lamina propria where they cause acute inflammation, attracting pus cells from the
 circulating blood and creating micro-abscesses. The resolution of this involves fibrosis and
 scaring together with muscular hypertrophy which may well lead to secondary motor
 abnormalities. Patients with symptomatic diverticular disease are known to have higher
 intraluminal pressures, both at baseline and in response to stimuli such as a meal or
 prostigmine.

 A recent report in which patients admitted with acute diverticulitis were followed for two
 years found that a very high proportion of such individuals subsequently develop recurrent
 chronic abdominal pain. Recent work has indicated that this leaves a permanent change in
 mucosal innervation. Markers of nerve injury including galanin and substance P are
 upregulated in patients with symptoms as opposed to those without. This is the first time
 that an objective marker has been shown to distinguish patients on the basis of symptoms.

 While acute diverticulitis may be the initiating insult, a chronic low level inflammation may
 also be required to maintain visceral hypersensitivity. Where detailed quantitative histology
 has been performed in diverticular disease, some individuals have been identified with a
 lymphocytic infiltration. In other circumstances, chronic inflammation sensitises mucosal
 nerves and is associated with visceral hypersensitivity, something which has also been noted
 in symptomatic diverticular disease.

 Whether anti-inflammatory agents could reverse this process is as yet unknown but there are
 currently available safe and effective treatments for inflammatory bowel disease such as 5
 amino-salicylic acid or budesonide which might well be effective and allow further evaluation
 of the role of low grade inflammation in symptomatic diverticular disease.

 This study aims to investigate the inflammatory, neurological and symptomatic effects of
 mesalazine in diverticular disease.
Inclusion Criteria:

 -  Symptomatic diverticular disease with short lived recurrent abdominal pain on 3 or
 more days a month.

 -  18 - 85 years of age.

 -  Signed informed consent

 -  Presence of at least one diverticulum in the left colon

 Exclusion Criteria:

 -  Pregnant or lactating women.

 -  Severe co-morbidity, alcoholism or drug dependence or inability to give informed
 consent.

 -  Contraindications to use of Mesalazine as detailed in SmPC.

 -  Inability to stop NSAIDs (non-steroidal anti-inflammatory agents) or long term
 antibiotics.

 -  The use of specific concomitant medications as detailed in the section below.

 -  Presence of other gastrointestinal inflammatory conditions such as ulcerative colitis,
 Crohn's disease and Coeliac disease.