Amitriptyline can significantly improve symptoms of irritable bowel syndrome (IBS), according to a study led by the universities of Leeds, Southampton, and Bristol.
The researchers urged that the results of the ATLANTIS trial — the largest study of a tricyclic antidepressant in IBS ever conducted — should be used to update current guidelines.
They noted that the National Institute for Health and Care Excellence (NICE) guideline on IBS currently suggests considering low dose tricyclic antidepressants as second-line treatment in primary care — where most patients with IBS are seen — when first-line therapies are ineffective.
However, almost all trials have been conducted in specialist settings, where patients tend to have more severe symptoms, and their effectiveness in primary care is unknown. In fact, tricyclics are "infrequently prescribed" for IBS in this setting. The researchers commented that fewer than 10% of GPs prescribe tricyclics for IBS, compared with 95% who do so for insomnia, and said that this suggested that the reason was "uncertainty over the drug's efficacy in IBS, rather than concerns about side-effects".
NICE had in fact highlighted the need for a trial of tricyclic antidepressants in IBS in primary care. So they undertook a randomised, double-blind, placebo-controlled trial (Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment [ATLANTIS]) involving 463 patients with IBS (mean age 48·5 years [SD 16·1], 68% female) from 55 general practices in England.
Participants were randomly allocated to receive low-dose amitriptyline, 10 mg once daily, or placebo, for 6 months, with dose titration (up to 30 mg once daily) by patients over 3 weeks, according to symptoms and tolerability.
Symptom Severity Improvement Doubled Compared With Placebo
The results, published in The Lancet, and presented this week at UEG (United European Gastroenterology) Week 2023 in Copenhagen, showed that patients taking amitriptyline were almost twice as likely to report an overall improvement in IBS Severity Scoring System symptoms as those taking a placebo (mean score from baseline: –99·2 versus –68·9, a mean adjusted net effect of –27·0 (95% CI 46·9 to –7·10, p=0·0079).
Participants' anxiety or depression scores were not altered, suggesting that the beneficial effects of amitriptyline were gut-mediated and not because of any effect as an antidepressant per se.
In total, 46 (20%) participants in the active group stopped treatment before the trial end, 30 (13%) of which were due to adverse events, versus 59 (26%) — of which 20 (9%) were due to adverse events — in the placebo group. There were five serious adverse reactions, two in the amitriptyline group and three in the placebo group, and five serious adverse events unrelated to trial medication.
GPs Should Offer Low-dose Amitriptyline as Second Line Treatment
The team said that amitriptyline was "cheap and widely available", and that as most people with IBS were managed in primary care, the results of the trial were likely to be widely applicable. "GPs should offer low-dose amitriptyline to patients with IBS whose symptoms do not improve with first-line therapies," they said, advocating also for "appropriate support to guide patient-led dose titration" as had been developed for the trial.
Alexander Ford, professor of gastroenterology at the University of Leeds School of Medicine and co-chief investigator, said: "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."
Co-chief investigator Hazel Everitt, professor of primary care research at the University of Southampton, said: "When we interviewed GPs as part of this research, they were willing to prescribe it [amitriptyline] 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."
Professor Andrew Farmer, director of the National Institute for Health and Care Research (NIHR)'s Health Technology Assessment Programme, said that the results of the study were "hugely encouraging" in showing that a drug already widely available to treat a number of other conditions appeared to be safe and effective for people with IBS.
Asked to comment by Medscape News UK, Alison Reid, chief executive of the IBS Network, said the research was "great news" for people living with IBS. She noted that IBS is a complex, misunderstood, and debilitating condition, with "no one treatment that works for everyone".
The Network welcomed the evidence finding amitriptyline to be an effective treatment and encouraged GPs to consider other options such as tricyclics for their IBS patients when first line treatments such as diet, exercise and mindfulness, haven’t improved symptoms. "Some of our members who have already been prescribed amitriptyline have reported an improvement in their condition," she reported.
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Editor's note: This article was updated on 20 October to include comments from the IBS Network
