medwireNews: Some gut–brain neuromodulators such as tricyclic antidepressants (TCAs), can be used to treat irritable bowel syndrome (IBS), suggests a meta-analysis.
"The findings support national management guidelines for IBS, which recommend use of tricyclic antidepressants for ongoing global symptoms or abdominal pain," write Alexander Ford (St James’s University Hospital, Leeds, UK) and colleagues in The Lancet Gastroenterology & Hepatology. They emphasize the need for further large-scale randomized controlled trials (RCTs) comparing drug classes and assessing IBS subtype-specific responses.
Gut–brain neuromodulators, which impact pain processing and gastrointestinal motility, have emerged as therapeutic options for IBS, say the authors, with treatments including: TCAs; selective serotonin reuptake inhibitors (SSRIs); serotonin and norepinephrine reuptake inhibitors (SNRIs); alpha-2-delta ligand agents such as gabapentin and pregabalin; azapirones; and tetracyclic antidepressants.
The study pooled data from 28 RCTs reporting either a global assessment of IBS symptom cure or improvement, or abdominal pain cure or improvement. These included 2475 patients aged 16 years and older with an IBS diagnosis based on a physician’s opinion or accepted symptom-based diagnostic criteria.
Patients were given either neuromodulators (n=1344) or placebo (n=1131). The most common treatments assessed included TCAs (11 RCTs), SSRIs (seven RCTs), and SNRIs (three RCTs).
The investigators used a random effects model to analyze the differences between the groups while accounting for between-study heterogeneity. Where direct dichotomous data were unavailable, they imputed response rates using a standardized statistical method. The researchers also downgraded the certainty of the evidence if there were signs of potential bias, inconsistency, or imprecision in the studies.
Across 22 RCTs assessing global IBS symptoms as a dichotomous endpoint, the researchers found that significantly fewer patients in the gut–brain neuromodulator group than the placebo group had unimproved global IBS symptoms following therapy, with rates of 52.2% and 64.9%, respectively. This gave a relative risk (RR) of 0.77 for no improvement with neuromodulator use with moderate heterogeneity between the studies.
Across 19 RCTs assessing abdominal pain, significantly fewer patients receiving gut–brain neuromodulators had no improvement following treatment than those given placebo (52.3 vs 66.2%), giving an RR of 0.72, again with moderate heterogeneity.
And among 11 RCTs comparing TCAs with placebo, significantly fewer patients given TCAs versus placebo had no improvement in their symptoms, with corresponding rates of 44.2% and 62.5%, and an RR of 0.70. The certainty of this finding increased to moderate compared with the previous meta-analysis.
TCAs also significantly reduced the risk for having no improvements in abdominal pain in an analysis of seven RCTs, with an RR of 0.69, albeit with a low certainty.
SSRIs did not significantly differ from placebo in terms of global IBS symptoms. However, patients given SSRIs were significantly less likely to have no abdominal pain improvement, with an RR of 0.74, although with very low certainty.
No significant efficacy for global IBS symptoms was seen in patients given SNRIs in two RCTs. However, such drugs significantly lowered the risk for no improvements in abdominal pain relative to placebo, with an RR of 0.22, albeit again with low certainty.
Alpha-2-delta ligand agents had no significant effect on global IBS symptoms and abdominal pain, while tandospirone and mirtazapine each showed benefits in a single RCT that require replication in larger studies, say the researchers.
According to 12 RCTs assessing treatment-emergent adverse events, these were not significantly more likely in patients given neuromodulators than placebo. However, patients given TCAs showed generally more drowsiness and dry mouth than those on placebo. Withdrawals due to adverse events were assessed in 23 RCTs and found to be significantly more frequent among those on gut–brain neuromodulators than placebo, with corresponding rates of 9.7% and 4.9% and a significant RR of 1.79 with no heterogeneity.
In a related editorial, Adrian Masclee, from Maastricht University Medical Center in the Netherlands, and Gwen Masclee, from Amsterdam University Medical Center in the Netherlands, write that the findings “provide us with an essential, clinically relevant update on the efficacy of gut–brain neuromodulatory drugs in IBS.”
Given potential negative and stigmatizing perceptions of antidepressants, they note that “[d]octors should realise that when a clear rationale for the use of gut–brain neuromodulators is provided, patients might become more willing to consider taking them.”
They conclude: “Gut–brain neuromodulators for the treatment of IBS are here to stay based on the consistency of their beneficial effects on IBS symptoms, although further work is needed to finetune the [selection of] those patients who would benefit from them the most.”
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Lancet Gastroenterol Hepatol 2025; doi:10.1016/S2468-1253(25)00051-2
Lancet Gastroenterol Hepatol 2025; doi:10.1016/S2468-1253(25)00100-1