Randomised Clinical Trial: Linaclotide Vs Placebo-a Study of Bi-directional Gut and Brain Axis

Overview

Journal Aliment Pharmacol Ther

Specialties Gastroenterology
Pharmacology

Date 2020 May 15

PMID 32406112

Citations 13

Authors

Satish S C Rao

Xuelian Xiang

Yun Yan

Kulthep Rattanakovit

Tanisa Patcharatrakul

Rachael Parr

Deepak Ayyala

Amol Sharma

Affiliations

Soon will be listed here.

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.

Citing Articles

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Plecanatide Improves Abdominal Bloating and Bowel Symptoms of Irritable Bowel Syndrome with Constipation.

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The gut microbiota participates in the effect of linaclotide in patients with irritable bowel syndrome with constipation (IBS-C): a multicenter, prospective, pre-post study.

Zhou J, Wei H, Zhou A, Xiao X, Xie X, Tang B J Transl Med. 2024; 22(1):98.

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Gut liver brain axis in diseases: the implications for therapeutic interventions.

Yan M, Man S, Sun B, Ma L, Guo L, Huang L Signal Transduct Target Ther. 2023; 8(1):443.

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Cheng Z, Zhang L, Yang L, Chu H Front Endocrinol (Lausanne). 2022; 13:1025706.

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References

Chang L, Heitkemper M, Wiley J, Camilleri M . 2015 James W. Freston Single Topic Conference: A Renaissance in the Understanding and Management of Irritable Bowel Syndrome. Clin Gastroenterol Hepatol. 2016; 14(7):e77-86. DOI: 10.1016/j.cgh.2016.05.027. View

Chan Y, Herkes G, Badcock C, Evans P, Bennett E, Kellow J . Alterations in cerebral potentials evoked by rectal distension in irritable bowel syndrome. Am J Gastroenterol. 2001; 96(8):2413-7. DOI: 10.1111/j.1572-0241.2001.04088.x. View

Naliboff B, Derbyshire S, Munakata J, Berman S, Mandelkern M, Chang L . Cerebral activation in patients with irritable bowel syndrome and control subjects during rectosigmoid stimulation. Psychosom Med. 2001; 63(3):365-75. DOI: 10.1097/00006842-200105000-00006. View

Mayer E, Berman S, Derbyshire S, Suyenobu B, Chang L, Fitzgerald L . The effect of the 5-HT3 receptor antagonist, alosetron, on brain responses to visceral stimulation in irritable bowel syndrome patients. Aliment Pharmacol Ther. 2002; 16(7):1357-66. DOI: 10.1046/j.1365-2036.2002.01287.x. View

Grundy L, Harrington A, Castro J, Garcia-Caraballo S, Deiteren A, Maddern J . Chronic linaclotide treatment reduces colitis-induced neuroplasticity and reverses persistent bladder dysfunction. JCI Insight. 2018; 3(19). PMC: 6237488. DOI: 10.1172/jci.insight.121841. View

Rao S, Lembo A, Shiff S, Lavins B, Currie M, Jia X . A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol. 2012; 107(11):1714-24. PMC: 3504311. DOI: 10.1038/ajg.2012.255. View

Sinhamahapatra P, Saha S, Chowdhury A, Chakrabarti S, Ghosh A, Maiti B . Visceral afferent hypersensitivity in irritable bowel syndrome--evaluation by cerebral evoked potential after rectal stimulation. Am J Gastroenterol. 2001; 96(7):2150-7. DOI: 10.1111/j.1572-0241.2001.03952.x. View

Tantiphlachiva K, Attaluri A, Valestin J, Yamada T, Rao S . Translumbar and transsacral motor-evoked potentials: a novel test for spino-anorectal neuropathy in spinal cord injury. Am J Gastroenterol. 2011; 106(5):907-14. PMC: 3883059. DOI: 10.1038/ajg.2010.478. View

Pezzone M, Liang R, Fraser M . A model of neural cross-talk and irritation in the pelvis: implications for the overlap of chronic pelvic pain disorders. Gastroenterology. 2005; 128(7):1953-64. DOI: 10.1053/j.gastro.2005.03.008. View

10.

Barker A, Jalinous R, Freeston I . Non-invasive magnetic stimulation of human motor cortex. Lancet. 1985; 1(8437):1106-7. DOI: 10.1016/s0140-6736(85)92413-4. View

11.

Rao S, Xiang X, Yan Y, Rattanakovit K, Patcharatrakul T, Parr R . Randomised clinical trial: linaclotide vs placebo-a study of bi-directional gut and brain axis. Aliment Pharmacol Ther. 2020; 51(12):1332-1341. PMC: 7384154. DOI: 10.1111/apt.15772. View

12.

Camilleri M, Boeckxstaens G . Dietary and pharmacological treatment of abdominal pain in IBS. Gut. 2017; 66(5):966-974. DOI: 10.1136/gutjnl-2016-313425. View

13.

Patrick D, Drossman D, Frederick I, DiCesare J, Puder K . Quality of life in persons with irritable bowel syndrome: development and validation of a new measure. Dig Dis Sci. 1998; 43(2):400-11. DOI: 10.1023/a:1018831127942. View

14.

Hannig G, Tchernychev B, Kurtz C, Bryant A, Currie M, Silos-Santiago I . Guanylate cyclase-C/cGMP: an emerging pathway in the regulation of visceral pain. Front Mol Neurosci. 2014; 7:31. PMC: 3997039. DOI: 10.3389/fnmol.2014.00031. View

15.

Ligon C, Mohammadi E, Ge P, Hannig G, Higgins C, Greenwood-Van Meerveld B . Linaclotide inhibits colonic and urinary bladder hypersensitivity in adult female rats following unpredictable neonatal stress. Neurogastroenterol Motil. 2018; 30(10):e13375. DOI: 10.1111/nmo.13375. View

16.

Brierley S, Linden D . Neuroplasticity and dysfunction after gastrointestinal inflammation. Nat Rev Gastroenterol Hepatol. 2014; 11(10):611-27. DOI: 10.1038/nrgastro.2014.103. View

17.

Castro J, Harrington A, Hughes P, Martin C, Ge P, Shea C . Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3',5'-monophosphate. Gastroenterology. 2013; 145(6):1334-46.e1-11. DOI: 10.1053/j.gastro.2013.08.017. View

18.

Mayer E, Tillisch K, Gupta A . Gut/brain axis and the microbiota. J Clin Invest. 2015; 125(3):926-38. PMC: 4362231. DOI: 10.1172/JCI76304. View

19.

Remes-Troche J, Tantiphlachiva K, Attaluri A, Valestin J, Yamada T, Hamdy S . A bi-directional assessment of the human brain-anorectal axis. Neurogastroenterol Motil. 2010; 23(3):240-8, e117-8. PMC: 3035753. DOI: 10.1111/j.1365-2982.2010.01619.x. View

20.

Rao S, Hatfield R, Soffer E, Rao S, Beaty J, Conklin J . Manometric tests of anorectal function in healthy adults. Am J Gastroenterol. 1999; 94(3):773-83. DOI: 10.1111/j.1572-0241.1999.00950.x. View