Factors Affecting Dissatisfaction to Treatments in Patients With Chronic Constipation and Irritable Bowel Syndrome With Constipation. Pooled Analysis of Multiple Prospective N-of-1 Treatment Optimization Trials

Introduction: Chronic constipation (CC) and Irritable Bowel Syndrome with Constipation (IBS-C) are two overlapping conditions in which the patients are dissatisfied of their bowel habit. In a non negligible proportion of patients, the dissatisfaction persists after a first line treatment with effective laxatives such as macrogol and bisacodyl. Prucalopride and linaclotide are two relatively new treatments that are used in these conditions. Prucalopride is a prokinetic drug licensed for patients with CC not responsive to standard laxative treatments. Linaclotide is a guanylate cyclase-C agonist that has been shown to improve both abdominal pain and bowel habits in patients with IBS-C. Despite these new treatments, a consistent number of patients remains dissatisfied suggesting that they complain of a "refractory" or "intractable" form of constipation.

Both IBS-C and CC are diseases defined by patients symptoms, as well as the lack of response to treatments. The Patient Assessment of Constipation-Symptoms (PAC-SYM) is a validated self-report questionnaire able to assess over time both general constipation severity and cluster of symptoms specific of this condition and to indicate the patient perspective on the disorder. Some limitations on the performances of this questionnaire have however emerged and it has recently been demonstrated that a Modified version of the PAC-SYM (M:PAC-SYM) is a better tool to assess constipation severity in patients recruited in tertiary referral centres. A change > 0.24 in the M:PAC-SYM score has been shown to define whether the response to treatment is adequate or not, but how this variation persists in the long term has not yet been investigated.

Several factors may influence the lack of response to treatments. Stool characteristics, psychological alterations (somatisation), delayed colonic transit and increased resting anal pressure may influence constipation severity, but the relative role of these factors is still unknown. On the other hand the bowel frequency, that is commonly believed to reflect constipation, does not seem to play a major role.

Aims: The purpose of this study will be to perform a pooled analysis of multiple prospective treatment optimization N-of-1 trials in patients with IBS-C and CC aimed at: 1) define how many patients achieve a sustained improvement; 2) define which factors are associated with a sustained improvement; 3) evaluate the suitability of M:PAC-SYM for treatment optimization among patients with CC or IBS-C 4) assess in a longitudinal follow up the natural history of IBS-C and CC submitted to standardised treatments.

Study design: All patients aged 18 - 80 years old with IBS-C and CC will be included in this observational multicentric national study. Patients with secondary causes of CC will be excluded. The diagnosis of CC and IBS-C will be defined according to Rome III criteria. All patients should undergo a thorough clinical examination including a rectal examination searching for both anatomical and functional defects. Dietary advices and supplementation with soluble fibres in those patients reporting insufficient dietary fibre intake will be given. Basic principles of defecation will be given to all patients and in particular to those with dyssynergic behaviour during straining.