Behavioural and new pharmacological treatments for constipation: getting the balance right

Abstract

Chronic constipation affects almost one in six adults and is even more frequent in the elderly. In the vast majority of patients, there is no obstructive mucosal or structural cause for constipation and, after excluding relatively rare systemic diseases (commonest of which is hypothyroidism), the differential diagnosis is quickly narrowed down to three processes: evacuation disorder of the spastic (pelvic floor dyssynergia, anismus) or flaccid (descending perineum syndrome) varieties, and normal or slow transit constipation. Treatment of chronic constipation based on identifying the underlying pathophysiology is generally successful with targeted therapy. The aims of this review are to discuss targeted therapy for chronic constipation: behavioural treatment for outlet dysfunction and pharmacological treatment for constipation not associated with outlet dysfunction. In particular, we shall review the evidence that behavioural treatment works for evacuation disorders, describe the new treatment options for constipation not associated with evacuation disorder, and demonstrate how 'targeting therapy' to the underlying diagnosis results in a balanced approach to patients with these common disorders.

Figure 1

Function of the pelvic floor and anal sphincters during defaecation. The coordinated relaxation of the pelvic floor and anal sphincters, together with propulsion of content in the distal colon and raised intra-abdominal pressure during straining allow the straightening of the recto-anal angle and comfortable, unimpeded evacuation of stool. Reproduced from Lembo T, Camilleri M.

Figure 2

Algorithm for managing patients with chronic constipation.

Figure 3

Example of radio-opaque marker colonic transit measurement. Plain x-ray obtained 4 days after ingestion of 72 radio-opaque markers on days 1–3 (ie, Metcalf technique) shows 22 markers scattered throughout the colon, suggestive of normal colonic transit.

Figure 4

Chloride secretory mechanisms in intestinal epithelial cells can be stimulated by increases in cyclic nucleotides (cAMP/cGMP) or cytosolic calcium ([Ca²⁺]_i). Major targets for regulation of secretion include channels in the apical membrane: CFTR, cystic fibrosis transmembrane conductance regulator; CaCC, calcium-activated chloride channel and ClC-2 (chloride channel type 2). Ion channels in the basolateral membrane deliver chloride into the enterocytes (NKCC1 (sodium/potassium/2 chloride co-transporter type 1) and ensure that obligatorily co-transported potassium and sodium ions are extruded by energy-dependent (eg, ATP) mechanisms, such as the sodium pump and different potassium transporters (eg, IK [intermediate conductance potassium channel]; K-cAMP channel, and KCNQ1/KCNE3 heteromeric K⁺ channels). Adapted from Barrett KE, Keely SJ, and reproduced from Camilleri M.