In primary care, second-line IBS therapy with amitriptyline vs. placebo reduced symptoms at 6 mo

A randomized trial indicated that titrated low-dose amitriptyline is safe and effective as a second-line treatment for irritable bowel syndrome (IBS) in the primary care setting. Four hundred sixty-three patients at 55 general practices in England were randomly assigned to receive 10 mg of amitriptyline or placebo once daily for six months. Oral doses were titrated over three weeks, to a maximum of 30 mg daily, based on symptom response and side effects. After six months, patients in the intervention group had significantly improved mean IBS-severity scores (–27.0 [95% CI, –46.9 to –7.10]; P=0.0079) and increased odds of relief of IBS symptoms according to the subjective global assessment (odds ratio, 1.78 [95% CI, 1.19 to 2.66]; P=0.0050).

The study was published Oct. 16, 2023, by The Lancet and was summarized in the October 2023 ACP Gastroenterology Monthly. The following commentary by Tanvi Gupta, MD, ACP Resident/Fellow Member, and Brooks D. Cash, MD, FACP, was published Feb. 6 in the ACP Journal Club section of Annals of Internal Medicine.

IBS guidelines recommend diet and lifestyle modification and over-the-counter therapies as first-line approaches for IBS, followed by prescription medications. Although multiple prescription medications are approved for both IBS with diarrhea and IBS with constipation, these therapies can be difficult for patients to access due to costs, coverage policies, and differing approval status worldwide. TCAs [tricyclic antidepressants] are a more accessible prescription therapy option for IBS, but this class of medications has not been rigorously evaluated in a primary care setting in adequately powered, well-designed clinical trials.

The ATLANTIS trial by Ford and colleagues found that, in primary care patients whose first-line therapies for moderate-to-severe IBS had failed, low-dose titrated amitriptyline improved IBS-SSS [IBS Severity Scoring System] scores and the subjective global assessment and increased the likelihood of adequate relief of IBS symptoms vs. placebo. Amitriptyline appeared to exert its effects on IBS symptoms independently of any effect on anxiety or depressive symptoms and was well tolerated.

ATLANTIS was a well-executed, adequately powered, blinded randomized controlled trial assessing a widely available and affordable therapy for a common and costly problem in a clinically relevant patient population where previous studies had not provided definitive estimates of benefit.

The results of this high-quality trial provide pragmatic guidance on amitriptyline dosing and expectations for use in patients with IBS and strengthen recommendations for amitriptyline as an option in primary care after failure of first-line therapies. Although the data are not entirely applicable to tertiary or specialty care settings, these results should be considered by providers in those settings who may have been reticent to prescribe TCAs. Additional evaluation of the mechanisms and effects of other TCAs and neuromodulators for IBS and other disorders of gut–brain interaction is needed given the lack of access and increasingly restrictive insurance coverage of other medications specifically approved for these indications.