Editorial: Alpha2-Delta Ligands in Irritable Bowel Syndrome

Abstract

Irritable bowel syndrome (IBS) is a highly prevalent disorder of gut–brain interaction associated with increased healthcare spending and reduced quality of life. IBS subtypes are defined by bowel patterns, but abdominal pain is a hallmark feature. Few IBS pharmacotherapies specifically target pain. Among these therapies are neuromodulators, particularly tricyclic antidepressants (TCAs), which are recognised for their effects on visceral and central pain. Multiple studies, including a large randomised trial, have demonstrated that TCAs improve global symptoms and pain in IBS [1]. However, responses are variable and may be limited for some due to a lack of efficacy or adverse effects, highlighting a need for novel therapies.

Houghton et al. [2] presented the results of a multi-centre phase II trial examining the efficacy of an investigational alpha₂-delta ligand, PD-217014, for the treatment of abdominal pain in IBS. The study was conducted from 2004 to 2005 and patients were identified using Rome II criteria, with 321 also meeting Rome IV criteria. Results showed no significant differences between active treatment and placebo for the primary and secondary endpoints pertaining to patient-reported abdominal pain, bloating, bowel habits, and global symptoms in both the Rome II- and Rome IV-defined cohorts. Baseline pain, anxiety and depression did not influence treatment responses.

Other alpha₂-delta ligands, such as pregabalin and gabapentin, are commonly used to treat pain disorders due to their anti-nociceptive effects [3]. Studies in IBS populations have suggested that response rates may vary according to IBS subtype, dosing scheme and treatment duration with more promising results reported in patients with IBS-D and in studies with longer treatment periods. Thus, the efficacy of alpha₂-delta ligands may be influenced by treatment protocols and patient-specific characteristics [4, 5]. Similarly, preclinical studies of PD-217014 found baseline visceral hypersensitivity to be a predictor of response [6], which may be present in many but not all patients with IBS. Although Houghton et al. did not find baseline pain severity to affect treatment response, abdominal pain is a subjective experience. Moreover, while pain is correlated with visceral hypersensitivity, it can also be affected by central processing, psychosocial variables, sex hormones and environmental factors [7-9]. Multiple processes including immune activation, barrier dysfunction, the gut microbiota, neurotransmitter- and peptide-mediated mechanisms, dysregulation of the hypothalamic–pituitary–adrenal axis and the endocannabinoid system may further contribute to visceral sensitisation [10]. Thus, pain-modifying agents may exhibit variable degrees of efficacy across individuals with IBS in whom common symptoms can arise from a complex combination of independent and/or related mechanisms. This complexity makes it particularly challenging to identify the biological pathways that should be targeted to treat IBS-related pain.

With these considerations, the negative findings of Houghton et al. should not be interpreted as dismissing the potential role of alpha₂-delta ligands in IBS. Rather, they highlight the need for longer treatment durations, dose titration protocols and comprehensive assessments of baseline traits that correspond to visceral sensitisation in future studies. Importantly, these observations underscore the crucial need for validated, non-invasive biomarkers of visceral hypersensitivity to guide the development and application of novel pharmacotherapies for pain in IBS.

Andrea Shin: conceptualization, writing – original draft, writing – review and editing.

A.S. serves as a consultant for Ardelyx and has served on an Advisory Board for Gemelli Biotech.

This article is linked to Houghton et al paper. To view this article, visit https://doi.org/10.1111/apt.18487.