Varenicline Shows Early Promise for Pain, Bowel Symptoms in IBS, With Ayah Matar, MD

Irritable bowel syndrome (IBS) is widely considered to be one of the most challenging conditions to treat in gastroenterology, with chronic abdominal pain representing a particularly difficult therapeutic target. Existing options for centrally mediated visceral pain in IBS are limited, and the mechanisms driving pain sensitivity remain incompletely understood.

Early-phase data presented at Digestive Disease Week (DDW) 2026 in Chicago, IL, by Ayah Matar, MD, a postdoctoral researcher at Mayo Clinic, suggest varenicline, a nicotinic acetylcholine receptor partial agonist currently approved for smoking cessation, may offer a novel mechanism for addressing both pain and bowel symptoms in non-constipation IBS.

"Pain might be due to sensitivity at the nicotinic receptors," Matar told HCPLive. "Since varenicline is a partial agonist at those receptors, we thought it might help with IBS — specifically the pain component."

Study Design

The study was a prospective, open-label, 8-day trial of oral varenicline at doses approved for smoking cessation in eight patients with non-constipation IBS and chronic abdominal pain. Each participant served as their own control, given the wide variance in rectal sensation in IBS patients.

A 2-week run-in period preceded treatment, during which daily diary data were collected; eligibility to proceed required an average pain score of ≥ 3 over 7 consecutive days. At baseline and end of treatment, participants underwent barostat-based rectal compliance and sensory testing, and completed daily symptom diaries and the Hospital Anxiety and Depression questionnaire.

Key Findings

After 8 days of varenicline treatment, participants showed significant improvements across multiple symptom domains compared to baseline. Abdominal pain decreased on both the 100mm visual analog scale and the 0–4 Likert scale, and anxiety scores also improved, though depression scores did not change significantly. Bowel symptoms including bloating, urgency, stool frequency, and ease of passage all improved at the end of treatment.

Of note, varenicline did not alter rectal compliance, a finding Matar described as clinically meaningful rather than a limitation.

"The minimal effect on rectal compliance suggests a central afferent modulation effect," she said. "That is really interesting, and addresses an unmet need when it comes to pain and IBS."

Varenicline did significantly decrease rectal sensation at 24 mmHg distension for gas, but not at other sensory thresholds, further supporting a centrally mediated rather than peripherally mediated mechanism of action.

Context and Next Steps

Matar said the rationale for investigating varenicline in IBS draws on prior evidence showing its efficacy for pain associated with opioid withdrawal, as well as preclinical data implicating nicotinic acetylcholine receptor signaling in visceral pain sensitivity. The current findings add a clinical signal to that mechanistic foundation, though the small sample size and open-label design require prospective confirmation.

She noted that next steps should include a placebo-controlled trial with a longer follow-up period to further characterize both efficacy and the safety profile beyond 8 days, a critical step before varenicline can be considered for broader clinical application in IBS.

Editor's note: Matar reports no relevant disclosures.

References

1. Matar A, Busciglio I, Linden DR, et al. Effect of Varenicline in Patients With Non-Constipation Irritable Bowel Syndrome and Pain. Presented at Digestive Disease Week (DDW) 2026; Chicago, IL; May 2–5, 2026.

2. Singh D, Saadabadi A. Varenicline. StatPearls. October 5, 2024. Accessed May 7, 2026. https://www.ncbi.nlm.nih.gov/books/NBK534846/