Tricyclic antidepressant for IBS worth a try

The tricyclic antidepressant amitriptyline, when used at low dose in the second-line treatment setting and titrated according to symptom response and side-effects, is safe and provides relief from symptoms of irritable bowel syndrome (IBS), as shown in the phase III ATLANTIS* trial.

During 6 months of treatment, low-dose amitriptyline, titrated from 10 mg to a maximum of 30 mg once daily, produced greater reductions in the primary endpoint of IBS Severity Scoring System (IBS-SSS) score compared with placebo (mean difference, –27.0, 95 percent confidence interval [CI], –46.9 to –7.10; p=0.0079). [Lancet 2023;402:1773-1785]

The same was true for the key secondary endpoint, with amitriptyline associated with 78-percent greater odds of subjective global assessment (SGA) of relief of IBS symptoms at 6 months (odds ratio [OR], 1.78, 95 percent confidence interval [CI], 1.19–2.66; p=0.0050).

Results at 3 months were already significantly better with low-dose amitriptyline, with the IBS-SSS score being lower by 23.3 points (95 percent CI, –42.0 to –4.6; p=0.014) and the odds of experiencing symptom relief being greater by 70 percent (OR, 1.70, 95 percent CI, 1.15–2.53; p=0.0080) than with placebo.

“More participants found low-dose amitriptyline acceptable to take compared with placebo, and almost three-quarters of participants adhered to the drug during the 6-month trial,” according to UK-based investigators led by Prof Alexander Ford from the University of Leeds’s School of Medicine and Prof Hazel Everitt from the Primary Care Research Centre at the University of Southampton.

A higher proportion of patients on amitriptyline expressing their willingness to continue taking it at 6 months (OR, 1.60, 95 percent CI, 1.08–2.35, p=0.018). Self-reported adherence was also higher in the amitriptyline group than in the placebo group (74 percent vs 68 percent). 

Although more frequent in the amitriptyline group than in the placebo group, most adverse events (AEs) were mild and consistent with the known anticholinergic effects of amitriptyline. The most common AEs were dry mouth (54 percent vs 37 percent) and drowsiness (53 percent vs 34 percent), followed by problems with urination (22 percent vs 13 percent) and blurred vision (17 percent vs 9 percent). AEs led to treatment discontinuation in 13 percent of patients on amitriptyline and in 26 percent of those on placebo.

A total of five serious adverse reactions (two in the amitriptyline group and three in the placebo group) and five serious adverse events unrelated to trial medication (four and one in the respective groups) were recorded.

Primary care use

In primary care practice, the UK National Institute for Health and Care Excellence (NICE) acknowledges that common first-line treatments for IBS—including dietary changes and lifestyle advice, soluble fibre, laxatives, and antispasmodic or antidiarrhoeal drugs—have modest effects. As such NICE guideline recommends considering low-dose tricyclic antidepressants as a second-line option owing to the analgesic effect of the drugs, albeit with limited evidence for their effectiveness. [BMJ 2015;350:h701; Gut 2022;71:1117-1126; Lancet Gastroenterol Hepatol 2020;5:117-131]

The ambiguity surrounding the benefit of tricyclic antidepressants in IBS is reflected in the low prescribing rates by primary care practitioners. Less than 10 percent of them prescribe tricyclic antidepressants regularly, with many expressing scepticism about the drugs’ effectiveness. [Prim Health Care Res Dev 2015;16:263-269]

“Amitriptyline is an effective treatment for IBS and is safe and well tolerated. [ATLANTIS] indicates that general practitioners (GPs) should support patients in primary care to try low-dose amitriptyline if their IBS symptoms haven’t improved with recommended first-line treatments,” Ford said.

“When we interviewed GPs 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 and most were happy to self-adjust their dose depending on symptoms and side effects,” Everitt added.

Additional efficacy data

Aside from the primary and key secondary endpoints, amitriptyline also showed superiority to placebo in terms of providing “adequate relief” of IBS symptoms across all weeks during the 6 months of treatment (OR, 1.56, 95 percent CI, 1.20–2.03; p=0.0008) and in the number of patients reporting symptom relief for 50 percent of the trial duration (41 percent vs 30 percent). 

“We observed no effect of low-dose amitriptyline on somatoform symptom-reporting, anxiety, or depression scores during the 6 months of treatment,” Ford and Everitt noted.

“This supports a benefit of low-dose amitriptyline in IBS arising from [the drug’s] peripheral actions on gastrointestinal motility and pain sensation, rather than improvements in extra-intestinal symptoms, anxiety, or depression, which are often associated with IBS,” they added. [Dig Dis Sci 1995;40:86-95; Gut 2005;54:601-607; Aliment Pharmacol Ther 2015;41:449-458; Aliment Pharmacol Ther 2019;50:132-143]

Moreover, daily functioning regarding work or social activities remained unchanged for both groups, despite the negative trend reflected by higher Work and Social Adjustment Scale scores at 6 months with low-dose amitriptyline.

ATLANTIS included 463 adult patients (mean age 48.5 years, 68 percent women, 97.4 percent White) seen at 55 general practices in England. Inclusion criteria were Rome IV IBS of any subtype, ongoing symptoms (IBS-SSS score ≥75 points) despite dietary changes and first-line therapies, normal full blood count and C-reactive protein, negative coeliac serology, and no evidence of suicidal ideation.

Of the patients, 232 were assigned to receive amitriptyline and 231 to receive placebo for 6 months. GPs prescribed the drug, and patients managed their own dose based on the severity of their symptoms using an adjustment document designed for the trial.

“To our knowledge, this is the largest trial of a tricyclic antidepressant in IBS ever conducted, and the first based entirely in primary care,” the investigators said.

“We recruited participants with IBS, irrespective of predominant stool pattern, with symptoms of varying severity, from a broad range of general practices in three different regions of the UK, meaning our results are likely to be generalisable to many patients in this setting,” they added.

Strong placebo response

In an accompanying editorial, Professors Niek de Wit of University Medical Center Utrecht and Daniel Keszthelyi of Maastricht University Medical Center, both in the Netherlands, commended ATLANTIS’ rigorous design and pointed to another noteworthy finding—the potent effect of placebo in IBS—which has been shown in previous studies. [Lancet 2023;402:1727-1728; World J Gastroenterol 2017;23:2223-2233; Lancet Gastroenterol Hepatol 2021;6:459-473]

Notably, IBS-SSS score dropped substantially in both the amitriptyline and placebo groups, from a mean of 272.8 at baseline to 170.4 and 200.1 at 6 months, respectively, with a third of placebo-treated patients having adequate symptom relief during half of the trial duration, de Wit and Keszthelyi pointed out.

“Although this placebo response might be partially related to the high frequent contact with research and practice staff during the trial, it underlines the potential power of adequate patient–doctor communication and the limited additional benefit of active drug therapy,” they wrote.

Nevertheless, de Wit and Keszthelyi highlighted the potential of low-dose tricyclic antidepressants as a safe and effective therapy for IBS patients in primary care settings, while stressing the drugs’ suitability as an optional, not standard, treatment approach and the complexities of managing IBS effectively.

“Optimal IBS management requires a personalized approach, with treatment steps dependent on the type of IBS symptoms, disease history, treatment response in the past, and sensitivity to side-effects,” the authors said.

“Perhaps it is therefore more sensible to begin to refer to tricyclic antidepressants in the context of IBS as neuromodulators, rather than as antidepressants. This could help mitigate certain negative perceptions and facilitate therapeutic conversations,” they added.

*Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment in primary care