Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment in primary care (ATLANTIS): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Most patients with irritable bowel syndrome (IBS) are managed in primary care. When first-line therapies for IBS are ineffective, the UK National Institute for Health and Care Excellence guideline suggests considering low- dose tricyclic antidepressants as second-line treatment, but their effectiveness in primary care is unknown, and they are infrequently prescribed in this setting. METHODS: This randomised, double-blind, placebo-controlled trial (Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment [ATLANTIS]) was conducted at 55 general practices in England. Eligible participants were aged 18 years or older, with Rome IV IBS of any subtype, and ongoing symptoms (IBS Severity Scoring System [IBS-SSS] score ≥75 points) despite dietary changes and first-line therapies, a normal full blood count and C-reactive protein, negative coeliac serology, and no evidence of suicidal ideation. Participants were randomly assigned (1:1) to low-dose oral amitriptyline (10 mg once daily) or placebo for 6 months, with dose titration over 3 weeks (up to 30 mg once daily), according to symptoms and tolerability. Participants, their general practitioners, investigators, and the analysis team were all masked to allocation throughout the trial. The primary outcome was the IBS-SSS score at 6 months. Effectiveness analyses were according to intention-to-treat; safety analyses were on all participants who took at least one dose of the trial medication. This trial is registered with the ISRCTN Registry (ISRCTN48075063) and is closed to new participants. FINDINGS: Between Oct 18, 2019, and April 11, 2022, 463 participants (mean age 48·5 years [SD 16·1], 315 [68%] female to 148 [32%] male) were randomly allocated to receive low-dose amitriptyline (232) or placebo (231). Intention-to-treat analysis of the primary outcome showed a significant difference in favour of low-dose amitriptyline in IBS-SSS score between groups at 6 months (-27·0, 95% CI -46·9 to -7·10; p=0·0079). 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 6 months. 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. INTERPRETATION: To our knowledge, this is the largest trial of a tricyclic antidepressant 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 and well tolerated. General practitioners 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. FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme (grant reference 16/162/01).

Distinguishing emotional distress from mental disorder in primary care: a qualitative exploration of the Four-Dimensional Symptom Questionnaire.

BACKGROUND: Primary care clinicians see people experiencing the full range of mental health problems. Determining when symptoms reflect disorder is complex. The Four-Dimensional Symptom Questionnaire (4DSQ) uniquely distinguishes general distress from depressive and anxiety disorders. It may support diagnostic conversations and targeting of treatment. AIM: To explore peoples' experiences of completing the 4DSQ and their perceptions of their resulting score profile across distress, depression, anxiety, and physical symptoms. DESIGN AND SETTING: A qualitative study was conducted in the UK with people recruited from primary care and community settings. METHOD: Participants completed the 4DSQ then took part in semi-structured telephone interviews. They were interviewed about their experience of completing the 4DSQ, their perceptions of their scores across four dimensions, and the perceived utility if used with a clinician. Interviews were transcribed verbatim and data were analysed thematically. RESULTS: Twenty-four interviews were conducted. Most participants found the 4DSQ easy to complete and reported that scores across the four dimensions aligned well with their symptom experience. Distinct scores for distress, depression, and anxiety appeared to support improved self-understanding. Some valued the opportunity to discuss their scores and provide relevant context. Many felt the use of the 4DSQ with clinicians would be helpful and likely to support treatment decisions, although some were concerned about time-limited consultations. CONCLUSION: Distinguishing general distress from depressive and anxiety disorders aligned well with people's experience of symptoms. Use of the 4DSQ as part of mental health consultations may support targeting of treatment and personalisation of care.

Low-dose amitriptyline for irritable bowel syndrome (IBS): a qualitative study of patients' and GPs' views and experiences.

BACKGROUND: Irritable bowel syndrome (IBS) can cause troublesome symptoms impacting patients' quality of life and incur considerable health service resource use. Guidelines suggest low-dose amitriptyline for IBS as second line treatment, but this is rarely prescribed in primary care. AIM: To explore patients' and general practitioners' (GPs) views and experiences of using low-dose amitriptyline for IBS. DESIGN AND SETTING: Qualitative interview study with patients and GPs in England, nested within the ATLANTIS trial of low-dose amitriptyline versus placebo (ISRCTN48075063). METHODS: Semi-structured telephone interviews with 42 patients at 6-months post-randomisation, 19 patients again at 12-months post-randomisation, and 16 GPs. Reflexive thematic analysis was used to analyse patient and GP data separately, then together, to identify unique and cross-cutting themes. RESULTS: We found concerns about amitriptyline being an antidepressant, medicalising IBS, and side-effects. Perceived benefits included the low and flexible dose, ease of treatment, familiarity of amitriptyline and its potential to offer benefits beyond IBS symptom relief. These concerns and perceived benefits were expressed in the context of desire for a novel approach to IBS: GPs were keen to offer more options for IBS and patients sought a cure for their symptoms. CONCLUSIONS: Patients and GPs felt the potential benefits from trying low-dose amitriptyline for IBS outweighed their concerns. When offering low-dose amitriptyline for IBS, GPs could address patient concerns about taking an antidepressant for IBS, highlighting the low and flexible dosage and other potential benefits of amitriptyline such as improved sleep.

Low-dose titrated amitriptyline as second-line treatment for adults with irritable bowel syndrome in primary care: the ATLANTIS RCT.

Background: 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. Objective: To evaluate the clinical and cost-effectiveness of low-dose titrated amitriptyline as a second-line treatment for irritable bowel syndrome in primary care. Design: 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. Setting: Fifty-five general practices in three regions in England (Wessex, West of England, West Yorkshire). Participants: 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. Intervention: Amitriptyline 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 : 1 with most having the option to continue blinded treatment for a further 6 months. Main outcome measures: 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. Results: 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. Conclusions: 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. Study registration: This trial is registered as ISRCTN48075063. Funding: This 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 Vol. 28, No. 66. See the NIHR Funding and Awards website for further award information.

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. 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. 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.

Amitriptyline at low-dose and titrated for irritable bowel syndrome as second-line treatment (The ATLANTIS trial): protocol for a randomised double-blind placebo-controlled trial in primary care.

BACKGROUND: Irritable bowel syndrome (IBS) is a common functional bowel disorder that has a considerable impact on patient quality of life and substantial societal and health care resource costs. Current treatments are often ineffective. Tricyclic antidepressants have shown promise in secondary care populations but their effectiveness in a primary care setting remains unclear. METHODS: ATLANTIS is a randomised, multi-centre, parallel-group, two-arm, double-blind, placebo-controlled trial of low-dose amitriptyline as a second-line treatment for IBS in primary care. Participants will be invited by letter, or recruited opportunistically, from general practices in three regions of England (West Yorkshire, Wessex, and West of England) and screened for eligibility. A total of 518 adult patients with IBS, who are symptomatic despite first-line therapies, will be randomised 1:1 to amitriptyline or identical placebo for 6 months. Treatment will commence at a dose of 10 mg (or one placebo tablet) daily at night, with dose titration up to a maximum of 30 mg at night, depending on side effects and response to treatment. Participant-reported assessments will be conducted at baseline and 3, 6, and 12 months post-randomisation. The primary objective is to determine the effectiveness of amitriptyline, compared with placebo, in improving participant-reported global symptoms of IBS at 6 months (using the IBS Severity Scoring System). Secondary outcomes include relief of IBS symptoms, effect on IBS-associated somatic symptoms (Patient Health Questionnaire-12), anxiety and depression (Hospital Anxiety and Depression Scale), ability to work and participate in other activities (Work and Social Adjustment Scale), acceptability and tolerability of treatment, self-reported health care use, health-related quality of life (EQ-5D-3L), and cost-effectiveness. A nested, qualitative study will explore patient and general practitioner experiences of treatments and trial participation, including acceptability, adherence, unanticipated effects, and implications for wider use of amitriptyline for IBS in primary care. DISCUSSION: Determining the clinical and cost-effectiveness of low-dose amitriptyline as a second-line treatment for IBS in primary care will provide robust evidence to inform management decisions. TRIAL REGISTRATION: ISRCTN ISRCTN48075063 . Registered on 7th June 2019.