Thanks to Ben Gold for this reference.

AC Ford et al. The Lancet 2023; DOI:https://doi.org/10.1016/S0140-6736(23)01523-4. Open Access! Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment in primary care (ATLANTIS): a randomised, double-blind, placebo-controlled, phase 3 trial

In this randomized, double-blind, placebo-controlled study of 463 adults (median age 48 yrs), the authors compared low-dose oral amitriptyline (10 mg once daily) or placebo for 6 months, with dose titration over 3 weeks (up to 30 mg once daily). The use of the Rome IV criteria resulted in the selection of a group of patients with higher symptom severity,⁵⁰ borne out by the mean IBS-SSS scores at baseline, which were in the moderate to severe range. The median duration of IBS among participants was 10 years.

Key findings:

• Intention-to-treat analysis of the primary outcome showed a significant difference in favour of low-dose amitriptyline in IBS-SSS score between groups at 6 months (–27·0, 95% CI –46·9 to –7·10; p=0·0079)
• 46 (20%) participants discontinued low-dose amitriptyline (30 [13%] due to adverse events), and 59 (26%) discontinued placebo (20 [9%] due to adverse events) before 6 months.

In their discussion, the authors note that “this is the largest trial of a tricyclic antidepressant in IBS ever undertaken and the first based entirely in a primary care setting…low-dose amitriptyline met the primary outcome, with a mean decrease in IBS-SSS of almost 100 points at both months 3 and 6 compared with baseline, and also met the key secondary outcome for effectiveness, as well as other IBS symptom measures.”

“There was no effect of low-dose amitriptyline on somatoform symptom-reporting scores, or anxiety or depression scores, during 6 month follow-up, nor was there any impact on work and social activities.:

My take (borrowed from authors): Titrated low-dose amitriptyline was superior to placebo as a second-line treatment for IBS in primary care across multiple outcomes, and was safe and well tolerated.

Related blog posts:

• “How to Approach a Patient with Difficult-to-Treat IBS” (2021)
• Topamax and Amitriptyline Did Not Work for Pediatric Migraines
• A 6-Year Study of Amitriptyline, Escitalopram, and Functional Dyspepsia
• Patient Information on Irritable Bowel (Rome Foundation)
• Advice on Abdominal Pain for Everyone Who Cares for Children | gutsandgrowth
• Brave New World: Psychotropic Medications and Pediatric Functional GI Disorders
• NY Times: “Millions Take Gabapentin for Pain. But There’s Scant Evidence It Works.” | gutsandgrowth
• Gut-Brain Modulators for Functional GI Disorders: Irritable Bowel, Dyspepsia, Functional Heartburn, and Cyclic Vomiting Syndrome

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