Satish S C Rao ¹, Xuelian Xiang ¹, Yun Yan ¹, Kulthep Rattanakovit ¹, Tanisa Patcharatrakul ¹, Rachael Parr ¹, Deepak Ayyala ¹, Amol Sharma ¹

Aliment Pharmacol Ther. 2020 May 13.doi: 10.1111/apt.15772. Online ahead of print.

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¹Division of Neurogastroenterology/Motility, Medical College of Georgia, Augusta University, Augusta, GA, USA.

Abstract

Background: Linaclotide, a guanylate cyclase C agonist relieves irritable bowel syndrome with predominant constipation (IBS-C) symptoms, but how it improves pain in humans is unknown.

Aims: To investigate the effects of linaclotide and placebo on the afferent and efferent gut-brain-gut signalling in IBS-C patients, in a randomised clinical trial.

Methods: Patients with IBS-C (Rome III) and rectal hypersensitivity were randomised (2:1) to receive linaclotide (290 µg) or placebo for 10 weeks and undergo bi-directional gut and brain axis assessment using anorectal electrical stimulations and transcranial/transspinal-anorectal magnetic stimulations. Rectal sensations were examined by balloon distention. Assessments included abdominal pain, bowel symptoms and quality of life (QOL) scores. Primary outcomes were latencies of recto-cortical and cortico-rectal evoked potentials.

Results: Thirty-nine patients participated; 26 received linaclotide and 13 received placebo. Rectal cortical evoked potentials latencies (milliseconds) were significantly prolonged with linaclotide compared to baseline (P1:Δ 19 ± 6, P < 0.005; N1:Δ 20 ± 7, P < 0.02) but not with placebo (P1:Δ 3 ± 5; N1:Δ 4.7 ± 5,P = 0.3) or between groups. The efferent cortico-anorectal and spino-anorectal latencies were unchanged. The maximum tolerable rectal volume (cc) increased significantly with linaclotide compared to baseline (P < 0.001) and placebo (Δ 29 ± 10 vs 4 ± 20, (P < 0.03). Abdominal pain decreased (P < 0.001) with linaclotide but not between groups. Complete spontaneous bowel movement frequency increased (P < 0.001), and IBS-QOL scores improved (P = 0.01) with linaclotide compared to baseline and placebo. There was no difference in overall responders between linaclotide and placebo (54% vs 23%, P = 0.13).

Conclusions: Linaclotide prolongs afferent gut-brain signalling from baseline but both afferent and efferent signalling were unaffected compared to placebo. Linaclotide significantly improves rectal hypersensitivity, IBS-C symptoms and QOL compared to placebo. These mechanisms may explain the effects of linaclotide on pain relief in IBS-C patients. ClinicalTrials.Gov: Registered at Clinical trials.gov no NCT02078323.