{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T13:55:02Z","timestamp":1783950902392,"version":"3.55.0"},"reference-count":90,"publisher":"National Institute for Health and Care Research","license":[{"start":{"date-parts":[[2024,10,1]],"date-time":"2024-10-01T00:00:00Z","timestamp":1727740800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000664","name":"Health Technology Assessment programme","doi-asserted-by":"publisher","award":["16\/162\/01"],"award-info":[{"award-number":["16\/162\/01"]}],"id":[{"id":"10.13039\/501100000664","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journalslibrary.nihr.ac.uk"],"crossmark-restriction":false},"short-container-title":["Health Technol Assess"],"abstract":"Background<\/jats:title>\nIrritable bowel syndrome, characterised by abdominal pain and a change in stool form or frequency, is most often managed in primary care. When first-line therapies are ineffective, National Institute for Health and Care Excellence guidelines suggest considering low-dose tricyclic antidepressants as second-line treatment, but their effectiveness in primary care is unknown and they are infrequently prescribed by general practitioners.<\/jats:p>\n<\/jats:sec>\nObjective<\/jats:title>\nTo evaluate the clinical and cost-effectiveness of low-dose titrated amitriptyline as a second-line treatment for irritable bowel syndrome in primary care.<\/jats:p>\n<\/jats:sec>\nDesign<\/jats:title>\nA pragmatic, randomised, multicentre, two-arm, double-blind, placebo-controlled trial. A nested, qualitative study explored participant and general practitioner experiences of treatments and trial participation, and implications for wider use of amitriptyline for irritable bowel syndrome in primary care.<\/jats:p>\nParticipants, clinicians, investigators and analysts were masked to allocation.<\/jats:p>\n<\/jats:sec>\nSetting<\/jats:title>\nFifty-five general practices in three regions in England (Wessex, West of England, West Yorkshire).<\/jats:p>\n<\/jats:sec>\nParticipants<\/jats:title>\nPatients aged \u2265 18 years meeting Rome IV criteria for irritable bowel syndrome with ongoing symptoms after trying first-line treatments and no contraindications to TCAs.<\/jats:p>\n<\/jats:sec>\nIntervention<\/jats:title>\nAmitriptyline 10 mg once-daily, self-titrated by participants to a maximum of 30 mg once-daily or matched placebo for 6 months. Participants randomised 1\u2002:\u20021 with most having the option to continue blinded treatment for a further 6 months.<\/jats:p>\n<\/jats:sec>\nMain outcome measures<\/jats:title>\nThe primary participant-reported outcome was the effect of amitriptyline on global irritable bowel syndrome symptoms at 6 months, measured using the irritable bowel syndrome Severity Scoring System, with a 35-point between-group difference defined as the minimum clinically important difference. The key secondary outcome was the proportion of participants reporting subjective global assessment of relief at 6 months, defined as somewhat, considerable, or complete relief of symptoms. Other secondary outcomes included: effect on global symptoms, via the irritable bowel syndrome Severity Scoring System, and subjective global assessment of relief of irritable bowel syndrome symptoms at 3 and 12 months; effect on somatic symptom-reporting at 6 months; anxiety an\u2013d depression scores; ability to work and participate in other activities at 3, 6 and 12 months; acceptability, tolerability and adherence to trial medication.<\/jats:p>\n<\/jats:sec>\nResults<\/jats:title>\nFour hundred and sixty-three participants were randomised to amitriptyline (232) or placebo (231). An intention-to-treat analysis of the primary outcome showed a significant difference in favour of amitriptyline for irritable bowel syndrome Severity Scoring System score between arms at 6 months [\u221227.0, 95% confidence interval (CI) \u221246.9 to \u22127.10; p<\/jats:italic> = 0.008]. For the key secondary outcome of subjective global assessment of relief of irritable bowel syndrome symptoms, amitriptyline was superior to placebo at 6 months (odds ratio 1.78, 95% CI 1.19 to 2.66; p<\/jats:italic> = 0.005). Amitriptyline was superior to placebo across a range of other irritable bowel syndrome symptom measures but had no impact on somatoform symptom-reporting, anxiety, depression, or work and social adjustment scores. Adverse event trial withdrawals were more common with amitriptyline (12.9% vs. 8.7% for placebo) but most adverse events were mild. The qualitative study thematically analysed 77 semistructured interviews with 42 participants and 16 GPs. Most participants found the self-titration process acceptable and empowering.<\/jats:p>\n<\/jats:sec>\nConclusions<\/jats:title>\nGeneral practitioners should offer low-dose amitriptyline to patients with irritable bowel syndrome whose symptoms do not improve with first-line therapies. Guidance and resources should support GP\u2013patient communication to distinguish amitriptyline for irritable bowel syndrome from use as an antidepressant and to support patients managing their own dose titration.<\/jats:p>\n<\/jats:sec>\nStudy registration<\/jats:title>\nThis trial is registered as ISRCTN48075063.<\/jats:p>\n<\/jats:sec>\nFunding<\/jats:title>\nThis award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16\/162\/01) and is published in full in Health Technology Assessment<\/jats:italic> Vol. 28, No. 66. See the NIHR Funding and Awards website for further award information.<\/jats:p>\n<\/jats:sec>","DOI":"10.3310\/bfcr7986","type":"journal-article","created":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T08:28:25Z","timestamp":1728894505000},"page":"1-161","update-policy":"https:\/\/doi.org\/10.3310\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Low-dose titrated amitriptyline as second-line treatment for adults with irritable bowel syndrome in primary care: the ATLANTIS RCT"],"prefix":"10.3310","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8839-6756","authenticated-orcid":true,"given":"Alexandra","family":"Wright-Hughes","sequence":"first","affiliation":[{"name":"Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6371-4359","authenticated-orcid":true,"given":"Alexander 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