Low-Dose Amitriptyline Offers Viable Second-Line Treatment for IBS


Results from the phase 3 ATLANTIS study showed amitriptyline was superior to placebo across multiple symptom-based outcomes for patients with IBS.

Hazel Everitt, MSc, PhD | Credit: University of Southampton

Hazel Everitt, MSc, PhD

Credit: University of Southampton

Amitriptyline may be a safe and effective treatment for irritable bowel syndrome (IBS) when titrated according to symptom response and side effects, according to recent findings from the phase 3 ATLANTIS study.

Presented at United European Gastroenterology Week 2023, results showed patients treated with amitriptyline were nearly twice as likely to report an overall improvement in symptoms compared to those taking placebo, with investigators highlighting its viability as a second-line treatment for IBS if symptoms do not improve with first-line therapies.1

“[General practitioners] already prescribe low-dose amitriptyline for other conditions, such as chronic pain and poor sleep, and when we interviewed [general practitioners] as part of this research, they were willing to prescribe it for IBS if the research evidence supported this. Participants were also keen to have another option to try to help their IBS symptoms,” said Hazel Everitt, MSc, PhD, professor of primary care research at the Primary Care Research Centre at the University of Southampton.2

Dietary, pharmacologic, and behavioral approaches can be used to treat IBS and relieve symptoms, many of which are related to hypersensitivity of nerves found in the gastrointestinal tract. Low-dose antidepressants can be used to reduce reactivity to foods and emotional stress leading to IBS-related pain and diarrhea.3 A tricyclic antidepressant typically used to treat symptoms of depression, amitriptyline is also prescribed to treat certain types of pain and migraines, prompting further research into its viability as a treatment for IBS.4

Launched in 2019, ATLANTIS was a randomized, double-blind, placebo-controlled phase 3 trial conducted at 55 general practices across England. To be eligible for inclusion, patients were required to be > 18 years of age, have a primary care diagnosis of IBS of any subtype meeting Rome IV criteria, have tried first-line treatments without success, and score > 75 on the IBS Severity Scoring System (IBS-SSS). ​​Between Oct 18, 2019, and April 11, 2022, 15,672 potentially eligible patients were invited to take part and 1253 interested patients were screened.1

In total, 463 patients underwent randomization in a 1:1 ratio to receive amitriptyline (n=232) or placebo (n=231). More than 80% of participants had IBS-D or IBS-M, 84% had a normal Hospital Anxiety and Depression Scale score, and 85% had moderate to severe scores on the IBS-SSS. The mean IBS-SSS score in all participants was 272.8 (Standard deviation [SD], 90.3) and the median duration of IBS was 10 years.1

Participants received titrated low-dose oral amitriptyline or placebo tablets for 6 months and could modify the dose of both placebo and amitriptyline throughout the study in response to IBS symptoms and side effects. All participants completed electronic or postal questionnaires at baseline and at months 3, 6, and 12, also answering a weekly question, “Have you had adequate relief of your IBS symptoms?” for the entire 6-month study duration.1

The primary outcome of interest was global effect on IBS symptoms at 6 months. Investigators also established effect on relief of global IBS symptoms at 6 months as a key secondary outcome.1

In total, 73% of participants completed 6 months of treatment, including 75% (n = 173) in the amitriptyline group and 71% (n = 165) in the placebo group. Trial medication was discontinued by 23% of participants before 6 months, 20% (n = 46) in the amitriptyline group and 26% (n = 59) in the placebo group, with the most common reason for discontinuation attributed to adverse events.1

Upon analysis, amitriptyline was superior to placebo in IBS-SSS score at 6 months in the intention-to-treat analysis, with a significant mean difference between groups (–27.0; 95% confidence interval [CI], –46.9 to –7.1; P = .0079). Investigators also pointed out increased odds of subjective global assessment of relief of IBS symptoms were observed among patients treated with amitriptyline (Odds ratio [OR], 1.78; 95% CI, 1.19 to 2.66; P = .0050).1

Amitriptyline was also superior to placebo for adequate relief of IBS symptoms, indicating increased odds of adequate relief across all weeks during the 6-month treatment period (OR, 1.56; 95% CI, 1.20 to 2.03; P = .0008). Further analysis revealed more participants found amitriptyline acceptable than placebo and would have been willing to continue taking it at 6 months (1.60; 95% CI, 1.08 to 2.35; P = .018). Self-reported adherence at 3 months was similar between treatment groups, but at 6 months, 74% of participants in the amitriptyline group reported being adherent to trial medication compared to 68% in the placebo group.1

Investigators noted a significant increase in the total Antidepressant Side Effect Checklist score in the amitriptyline group compared to the placebo group at 3 months (mean difference, 1.39; 95% CI, 0.29 to 2.50; P = .013), but not at 6 months (mean difference, 0.26; 95% CI, –0.98 to 1.51; P = .68). Adverse events with amitriptyline were related mainly to its known anticholinergic effects, including dry mouth, drowsiness, blurred vision, and urination problems. Of note, few (<5%) were severe, except for constipation and diarrhea (<10%).1

“Amitriptyline is an effective treatment for IBS and is safe and well tolerated. This new rigorously conducted research indicates that general practitioners should support patients in primary care to try low-dose amitriptyline if their IBS symptoms haven’t improved with recommended first-line treatments,” concluded Alexander Ford, MD, MBChB, professor of gastroenterology at the University of Leeds School of Medicine.2


  1. Ford AC, Wright-Hughes A, Alderson SL, et al. 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. The Lancet. https://doi.org/10.1016/S0140-6736(23)01523-4
  2. University of Leeds. Amitriptyline helps relieve IBS symptoms. EurekAlert! October 16, 2023. Accessed October 17, 2023. https://www.eurekalert.org/news-releases/1004566
  3. Johns Hopkins Medicine. Irritable Bowel Syndrome (IBS). Conditions and Diseases. Accessed October 17, 2023. https://www.hopkinsmedicine.org/health/conditions-and-diseases/irritable-bowel-syndrome-ibs
  4. Mayo Clinic. Amitriptyline (Oral Route). Drugs and Supplements. October 1, 2023. Accessed October 17, 2023. https://www.mayoclinic.org/drugs-supplements/amitriptyline-oral-route/description/drg-20072061
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