Low-dose amitriptyline found to be an effective second-line therapy for IBS

By Rebecca Jenkins

Low­-dose amitriptyline is safe and effective when offered as a second­-line therapy for irritable bowel syndrome (IBS) in primary care, a UK placebo-controlled study shows.

Writing in The Lancet, the study authors noted that therapeutic guidelines currently suggested considering low­-dose tricyclic antidepressants as second­-line treatment for IBS. However, most patients with IBS were managed in a primary care setting, where the drugs were infrequently prescribed and their effectiveness was unknown.

The randomised, double-blind, placebo­-controlled ATLANTIS (Amitriptyline at Low­-Dose and Titrated for Irritable Bowel Syndrome as Second­-Line Treatment) trial involved 463 participants with a mean age of 48.5 years from 55 general practices in England.

Patients were eligible if they were aged 18 years or over, with Rome IV IBS of any subtype and ongoing symptoms despite dietary changes and first­-line therapies (IBS Severity Scoring System [IBS­-SSS] score ≥75 points).

Participants were randomly assigned to low­-dose oral amitriptyline (10 mg daily) or placebo for six months, with dose titration over three weeks (up to 30 mg once daily), according to symptoms and tolerability.

At six months, intention­-to­-treat analysis showed a significant difference in favour of low­-dose amitriptyline in IBS­-SSS score at six months, with amitriptyline participants scoring a 99­-point improvement compared with a 69­-point improvement among the placebo group (−27).

‘We observed no effect of low­-dose amitriptyline on somato­ form symptom­-reporting, anxiety, or depression scores during the 6 months of treatment,’ the authors wrote.

‘This supports a benefit of low­-dose amitriptyline in IBS arising from its peripheral actions on gastrointestinal motility and pain sensation, rather than improvements in extra-­intestinal symptoms, anxiety, or depression which are often associated with IBS.’

The authors found 46 (20%) participants discontinued low­-dose amitriptyline (30 [13%] due to adverse events) and 59 (26%) discontinued placebo (20 [9%] due to adverse events) before six months.

Dr May Wong, Gastroenterologist at the Royal North Shore Hospital in Sydney and Senior Lecturer at The University of Sydney, said there was moderate use of amitriptyline for IBS in Australia, but prior to the ATLANTIS trial, its efficacy in IBS has predominantly been demonstrated in its use with specialist supervision.

‘Given the ATLANTIS findings, GPs, who provide care for the majority IBS patients in the community, can recommend this as second­-line [treatment] after dietary therapy for control of IBS­ related symptoms,’ she told Medicine Today.

‘Educating patients on the indications for the medication was key, with discussion about the involvement of the gut–brain axis.’

Dr Wong’s colleague, Dr Vithoo Sivanathan, Basic Physician Trainee at Royal North Shore Hospital, highlighted the need for patients to know how to titrate the medication to improve tolerability and minimise any potential side effects, which were known to include constipation, dry mouth, weight gain, urinary retention and insomnia.

‘Ensuring that comorbidities and potential drug interactions are assessed for prior to commencement will be important, together with regular follow­-up appointments,’ he added. 

Lancet 2023; 402: 1773-1785.