Amitriptyline Use Nearly Doubles Symptom Improvement in IBS

GLASGOW, United Kingdom ― Amitriptyline, titrated at low dose, was superior to placebo as a second-line treatment for irritable bowel syndrome (IBS) across multiple outcomes in what the researchers call the largest randomized controlled trial (RCT) of a tricyclic antidepressant in the condition.

Patients who took low-dose amitriptyline were almost twice as likely to report an overall improvement in symptoms as those taking placebo, according to investigators of the Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment (ATLANTIS) trial. Low-dose amitriptyline appeared safe and well tolerated, they reported.

Hazel Everitt, PhD, professor of primary care research at the University of Southampton, UK, presented the findings at the Royal College of General Practitioners (RCGP) Annual Conference 2023.

The data were also published in The Lancet and were presented at the recent United European Gastroenterology (UEG) Week 2023.

Clinicians "should offer low-dose amitriptyline to patients with IBS whose symptoms do not improve with first-line therapies, with appropriate support to guide patient-led dose titration," the researchers wrote in the journal article.

Despite first-line treatments such as diet, fiber, and antispasmodics, many patients with IBS continue to have troublesome symptoms, Everitt told Medscape Medical News. "GPs haven't often prescribed amitriptyline for IBS ― probably because of the lack of research evidence for its use in primary care."

Everitt added that primary care physicians and patients interviewed for the study welcomed low-dose amitriptyline as a potential additional option, especially with increased patient-led care. "The dose titration document that was developed with patients specifically for the trial enables patients to be more empowered to manage their IBS by helping them to titrate their dose up or down depending on their symptoms and side effects."

Judith Danby, MBBS, a retired GP who moderated the session at which the ATLANTIS results were presented, said, "Self-titration of the dose equals patient empowerment, and if patients can be helped to manage their own medication, then they will also be more empowered to think about lifestyle change, too."

RCT Across 55 Practices

The UK's National Institute for Health and Care Excellence guidance for the management of IBS in primary care say clinicians should "consider" using low-dose tricyclic antidepressants as a second-line treatment but highlight the need for an RCT of these drugs carried out solely in primary care.

The ATLANTIS trial was conducted across 55 general practices in England and included adults with Rome IV IBS of any subtype and ongoing symptoms (IBS Severity Scoring System [IBS-SSS] score ≥75 points) despite dietary changes and first-line therapies. Participants had normal full blood counts and C-reactive protein measures, negative celiac serology, and no evidence of suicidal ideation. The mean age was 48.5 years, and 68% were female. The mean IBS-SSS score in all participants was 272.8 at baseline.

Patients were randomly assigned in a 1:1 ratio to receive either low-dose oral amitriptyline (10 mg once daily; n = 232) with dose titration over 3 weeks (up to a maximum dose of 30 mg once daily) as determined by a participant's symptoms and tolerability; or placebo (n = 231). Both groups participated for 6 months. The primary outcome was the IBS-SSS score at 6 months.

Amitriptyline

Three quarters of participants adhered to the therapy over the 6 months, which was particularly notable given that the trial was conducted during the COVID-19 pandemic, according to the researchers.

An intent-to-treat analysis found that at 6 months, amitriptyline was superior to placebo, with a significant mean difference in IBS-SSS score between groups of –27.0 (95% CI, –46.9 to –7.1; P =.0079; mean IBS-SSS, 170.4 vs 200.1 with amitriptyline and placebo). A secondary outcome showed an increased likelihood of relief of IBS symptoms by subjective global assessment (odds ratio [OR], 1.78; 95% CI. 1.19 – 2.66; P = .0050).

At 3 months, the difference in mean change in IBS-SSS score between groups was also significant, at –23.3 (95% CI, -42.0 to -4.6; P = .014), the researchers reported.

People who took the drug were 70% more likely to report relief of symptoms on SGA than those who took placebo (P = .08), according to the researchers.

The researchers reported no effect of low-dose amitriptyline on psychiatric symptoms, such as distressing thoughts, anxiety, and depression, during the 6-month follow-up, nor was there any effect on ability to work or go about social activities.

"This was a pragmatic trial performed in a large number of participants with IBS, with an average duration of symptoms of 10 years and with 80% having moderate to severe symptoms at baseline," Alexander Ford, MD, professor of gastroenterology at the University of Leeds, UK, and a co-investigator on the study, told Medscape. "The fact that amitriptyline showed such a strong effect over placebo in this group of patients, with a mean decrease in IBS-SSS of almost 100 points at both 3 and 6 months, is therefore all the more impressive."

Mild adverse events, such as dry mouth and drowsiness, were more frequent with low-dose amitriptyline than with placebo,

Everitt said the ATLANTIS findings could change practice. Previous trials of low-dose amitriptyline for IBS had mostly been small and were conducted in secondary care settings such as gastroenterology clinics with relatively short follow-up times.

"This is a problem for a long-term condition that fluctuates over time and is diagnosed and managed mostly in primary care," she said. "The ATLANTIS trial is the largest trial of low-dose amitriptyline for IBS undertaken worldwide and was rigorously conducted with 6 months follow-up, providing reliable results that can help inform GPs and patients' treatment decision making in usual clinical practice."

On a pragmatic level, the research group developed a dose titration document for use by patients and GPs. "Both the GPs and participants found the ATLANTIS dose titration document acceptable and helpful," Everitt pointed out. She noted, "We've made the dose titration document freely available to support patients and clinicians to try low dose amitriptyline for IBS."

Ford and Everitt received grant funding (institutional) from the National Institute for Health and Care Research.

Royal College of General Practitioners (RCGP) Annual Conference 2023: Abstract OP222. Presented October. 19, 2023.

Lancet. Published online October 17, 2023. Full text

Becky McCall is a freelance medical journalist based in London, UK. She has written for Medscape for nearly 15 years.

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Cite this: Amitriptyline Use Nearly Doubles Symptom Improvement in IBS - Medscape - Oct 19, 2023.