Authors' objectives: Irritable 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. To evaluate the clinical and cost-effectiveness of low-dose titrated amitriptyline as a second-line treatment for irritable bowel syndrome in primary care. People with irritable bowel syndrome experience stomach (abdominal) pain and changes to their bowel movements. Irritable bowel syndrome can have a serious impact on people’s lives. Previous small trials suggest that a drug called amitriptyline used at a low dose may help irritable bowel syndrome. Amitriptyline is already used to treat other conditions. It is available for irritable bowel syndrome but is not used much by general practitioners. Irritable bowel syndrome (IBS) affects 5% of the population, accounting for > 3% of all consultations in primary care in England and Wales. Symptoms include abdominal pain in association with a change in stool form or frequency. The condition impacts on quality of life and ability to work and limits social activities. The medical management of IBS is unsatisfactory, with no therapy proven to alter the long-term natural history and, at best, modest symptom reduction. Previous meta-analyses of trials conducted in secondary and tertiary care suggest low-dose tricyclic antidepressants (TCAs) may be efficacious, probably because of their pain-modifying properties, as well as their influence on gut motility, rather than any effects on mood. Although National Institute for Health and Care Excellence guidelines for the management of IBS in primary care suggest considering low-dose TCAs as second-line treatment, their effectiveness in this setting is unknown and they are infrequently prescribed by general practitioners (GPs). Our objective was to determine the clinical and cost-effectiveness of low-dose titrated amitriptyline compared with placebo for 6 months as a second-line treatment in adults with IBS in primary care.

Authors' results and conclusions: Four 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 [−27.0, 95% confidence interval (CI) −46.9 to −7.10; p = 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 = 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. General 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–patient communication to distinguish amitriptyline for irritable bowel syndrome from use as an antidepressant and to support patients managing their own dose titration. Four hundred and sixty-three patients took part. Participants receiving amitriptyline reported a bigger improvement in their irritable bowel syndrome severity scores at 6 months, compared with patients on placebo. Amitriptyline was better across a range of irritable bowel syndrome symptom measures but did not impact anxiety, depression or ability to work. Forty-six people (19.8%) stopped taking amitriptyline and 59 (25.5%) stopped the placebo before 6 months. Patients liked being able to adjust their dose and valued contact with the research team. This study showed that amitriptyline is more effective than a placebo and is safe. General practitioners should offer low-dose amitriptyline to people with irritable bowel syndrome if symptoms do not improve with other standard treatments. Patients should be supported and helped to adjust their dose as needed. The dose adjustment sheet used in this trial will be made available. In the largest trial of a TCA in IBS ever conducted, titrated low-dose amitriptyline was superior to placebo as a second-line treatment for IBS in primary care across multiple outcomes and was safe. The results of ATLANTIS strongly support use of titrated low-dose amitriptyline in this setting. GPs 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, such as the self-titration document developed for this trial.

Authors' methods: A 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. Participants, clinicians, investigators and analysts were masked to allocation. Fifty-five general practices in three regions in England (Wessex, West of England, West Yorkshire). Patients aged ≥ 18 years meeting Rome IV criteria for irritable bowel syndrome with ongoing symptoms after trying first-line treatments and no contraindications to TCAs. The 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–d depression scores; ability to work and participate in other activities at 3, 6 and 12 months; acceptability, tolerability and adherence to trial medication. We recruited adults aged ≥ 18 years with irritable bowel syndrome from UK general practices who did not have any issues preventing the use of amitriptyline. Patients received either low-dose amitriptyline or placebo (a dummy tablet) for 6 months. Patients could adjust the dose according to symptoms and side effects. Neither the researchers nor the patients knew which treatment they were getting. Participants recorded symptoms using a questionnaire containing an irritable bowel syndrome severity score. We looked at the difference in average irritable bowel syndrome severity score between patients receiving amitriptyline and placebo. We also looked at effects of amitriptyline on mood, ability to work, and non-gut symptoms related to irritable bowel syndrome, as well as safety and acceptability. Some patients and general practitioners were interviewed about their experiences. ATLANTIS was a pragmatic, randomised, multicentre, parallel-group, two-arm, double-blind, placebo-controlled trial. A nested, qualitative study explored participant and GP experiences of treatments and trial participation. A within-study cost-effectiveness analysis was planned but, due to the coronavirus disease discovered in 2019 (COVID-19) pandemic, health economic analyses were removed after obtaining additional funding to complete the trial to prioritise funds for participant recruitment. These will be subject to further funding. Participants, their GPs, investigators, the research team, and the analysis team were all masked to treatment allocation throughout the trial. Patients meeting Rome IV criteria for IBS who had tried first-line treatments and with ongoing IBS symptoms [score of ≥ 75 on the IBS Severity Scoring System (IBS-SSS)] were recruited via mail-out from 55 general practices in three regions in England. Participants were randomised 1 : 1 to receive either low-dose titrated amitriptyline or placebo. Both treatments were supplied for 6 months, with the dose commenced at 10 mg o.d. and titrated to a maximum of 30 mg o.d. or a minimum of 10 mg alternate days. Dose titration was participant-led according to IBS symptoms and side effects, with support from the trial team and a dose titration document developed with input via patient and public involvement. Participants recruited earlier to the trial had the option to continue blinded treatment for an additional 6 months. The primary outcome was the effect of amitriptyline on global IBS symptom scores at 6 months. The key secondary outcome was the proportion of participants with relief of IBS symptoms at 6 months. Other secondary outcomes included effect on global IBS symptoms and relief of IBS symptoms at 3 and 12 months, effect on IBS-associated somatic symptoms at 6 months, effect on quality of life, anxiety, and depression scores, and ability to work and participate in other activities at 3, 6 and 12 months, as well as acceptability and tolerability of, and adherence to, treatment. Patient-reported questionnaires at baseline and 3, 6 and 12 months post randomisation (unless otherwise indicated) were used to assess IBS symptom severity (measured via the IBS-SSS), relief of IBS symptoms [measured by subjective global assessment (SGA) of relief], adequate relief of IBS symptoms (measured by a weekly response to the question ‘Have you had adequate relief of your IBS symptoms?’), IBS-associated somatic symptoms [using the Patient Health Questionnaire-12 (PHQ-12)], mood [using the Hospital Anxiety and Depression Scale (HADS)], ability to work and participate in other activities [using the Work and Social Adjustment Scale (WSAS)], quality of life (using the EQ-5D-3L), healthcare use (using a bespoke health resource use questionnaire), and tolerability [using the Antidepressant Side-Effect Checklist (ASEC)]. Numbers of participants reporting serious adverse events (SAEs), including serious adverse reactions (SARs), were reported for each treatment group. An evaluable sample size of 414 participants would provide 90% power to detect a minimum clinically important difference of 35 points between amitriptyline and placebo at 6 months on the IBS-SSS. This sample size provided at least 85% power to detect a 15% absolute difference in the key secondary outcome of SGA of relief of IBS symptoms at 6 months. We planned to recruit 518 participants, allowing for 20% loss to follow-up. Effectiveness outcomes were analysed in the intention-to-treat population, defined as all participants randomised, regardless of adherence. All statistical testing used two-sided 5% significance levels. The primary outcome was analysed using a linear regression model, adjusted for minimisation variables and baseline IBS-SSS score. Missing data were imputed by treatment arm, via multiple imputation, and results were expressed as point estimates with 95% confidence intervals (CIs). Secondary binary outcomes were analysed in logistic or ordinal regression models, with results expressed as odds ratios (ORs) with 95% CIs. Continuous secondary outcomes, including PHQ-12, HADS and WSAS scores, were analysed as for the primary outcome, adjusted for the respective baseline score. All participants receiving at least one dose of trial medication, according to medication received, were included in the safety analysis. The nested, qualitative study aimed to identify factors that would facilitate or impede prescribing of, acceptability of, and adherence to, low-dose amitriptyline in IBS, to identify participants’ and GPs’ perspectives on the broader impact of the trial, and to explore psychosocial and contextual factors that might shape wider use of amitriptyline for IBS. Familiarity with amitriptyline may both hinder uptake, given its association with depression, and facilitate it, given that it is a known drug, taken in a low dose distinct from the antidepressant dose, already used for a range of other painful conditions and has comparatively mild, and in some cases potentially beneficial, side effects such as on sleep. Semi-structured audio-recorded telephone interviews were conducted with a diverse sub-sample of trial participants and GPs involved in the trial and transcribed verbatim. The final sample size was dependent on saturation, to achieve a rigorous, credible analysis in relation to the aims. Topic guides allowed flexible exploration of all required topics, while remaining open to participants’ individual experiences and perspectives. To enhance trustworthiness of the analysis, all qualitative study team members contributed to avoid producing idiosyncratic interpretations, a negative case analysis was undertaken, and an audit trail was produced to enhance transparency, including detailed coding manuals and interviewer field notes. Reflexive thematic analysis, incorporating techniques from grounded theory, was used to analyse the qualitative data. Data collection and initial analyses proceeded iteratively, and informed subsequent interviews. Analysis was primarily inductive, with researchers identifying themes in the data rather than imposing any pre-existing interpretive framework. Qualitative findings were related to the main trial findings by comparing themes across subgroups and against the quantitative data.

Project Status: Completed

URL for project: https://www.journalslibrary.nihr.ac.uk/programmes/hta/16/162/01

Year Published: 2024

URL for published report: https://www.journalslibrary.nihr.ac.uk/hta/BFCR7986

URL for additional information: English

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: England, United Kingdom

DOI: 10.3310/BFCR7986

Organisation Name: NIHR Health Technology Assessment programme

Contact Address: NIHR Journals Library, National Institute for Health and Care Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK

Contact Name: journals.library@nihr.ac.uk

Contact Email: journals.library@nihr.ac.uk