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Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment in Primary Care
TAKE-HOME MESSAGE
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This large, placebo-controlled, randomised controlled trial evaluated the use of low-dose amitriptyline (10 mg daily) for irritable bowel syndrome and found a significant improvement in symptoms with amitriptyline compared with placebo. The drug was generally well-tolerated, with comparable rates of adverse events between the treatment and placebo groups.
- Amitriptyline should be considered a second-line therapy for irritable bowel syndrome, as this study suggests significant benefits at low doses.
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
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).
Additional Info
Disclosure statements are available on the authors' profiles:
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
Lancet 2023 Nov 11;402(10414)1773-1785, AC Ford, A Wright-Hughes, SL Alderson, PL Ow, MJ Ridd, R Foy, G Bianco, FL Bishop, M Chaddock, H Cook, D Cooper, C Fernandez, EA Guthrie, S Hartley, A Herbert, D Howdon, DP Muir, T Nath, S Newman, T Smith, CA Taylor, EJ Teasdale, R Thornton, AJ Farrin, HA EverittFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Amitriptyline for Irritable Bowel Syndrome
This is the largest study to date for the evaluation of amitriptyline compared with placebo for the secondary treatment of all types of irritable bowel syndrome (IBS). A total of 55 general primary care practices in England were used to recruit 463 patients with an IBS severity score of 75 or more whose symptoms persisted after first-line treatments were used. First-line treatments included dietary changes, fiber intake, antispasmodics, laxatives, and antidiarrheal medications. The patients were randomized to receive amitriptyline 10 mg titrated up to 30 mg if needed over 3 weeks or placebo for 6 months.
The side-effect dropout rate was 13% for amitriptyline and 9% for placebo. The main side effects were attributed to amitriptyline’s anticholinergic effects, including drowsiness, dry mouth, blurred vision, and urinary symptoms.
After 6 months, the amitriptyline group had a 27-point greater improvement in IBS severity score than the placebo group. This effect was mainly related to pain. There was no difference in bloating or mood-related symptoms, suggesting that amitriptyline’s known benefit on reducing pain severity was likely responsible for the improvement in IBS pain scores.
There is generally a high placebo response in IBS studies because of the strong mind–gut connection. This study was no different. For the placebo group, 45% of the participants had a somewhat, considerable, or complete resolution of IBS symptoms compared with 61% for the amitriptyline group.
Amitriptyline is a well-established, inexpensive therapy that can be used at a low dose with efficacy for IBS.
The value of tricyclic antidepressants in the management of IBS has been supported by multiple randomised controlled studies. Jackson et al reported a systematic review and meta-analysis that included 11 such studies, nine in IBS and two in functional dyspepsia.1 Tricyclic medications were used in 9 of 11 studies, including three with amitriptyline. Dichotomous outcome of symptom improvement was used in seven studies, and the continuous variable in pain score in eight studies. The odds ratio (OR) for improvement with antidepressant therapy was 4.2, and the mean pain improvement score was 0.9 SD units. The results of the meta-analysis were consistent with the mechanism of action subscribed to tricyclic antidepressants in the management of chronic neuropathic pain and fibromyalgia.2 Thus, the use of antidepressants in patients with IBS with troublesome pain has gained acceptance among many gastroenterologists.
The study by Ford et al is a large and well-designed study in primary practice that confirms the value of amitriptyline in the management of symptoms of IBS. This trial demonstrated a 10% difference in the IBS-SSS score for symptom severity at 6 months. There was also an increased prevalence of a greater than 30% improvement in pain with a significant OR of 1.66. Pain severity and frequency account for 170 of 470 total points in the IBS-SSS scale. Thus, the patients with troublesome pain might account for the improvement in outcomes. However, neither pain as a stratifying feature of the study group nor pain as a dominant symptom in responders was reported. The clinician must decide, then, to use amitriptyline only in patients with mostly troublesome pain, consistent with previous data, or to use the drug in all patients with moderate to severe IBS, however judged.
The study by Ford et al also demonstrated that amitriptyline produced the expected side effects of anticholinergic drugs, such as drowsiness, blurred vision, and altered urination, (but not constipation) and noted weight gain, a well-known problem of tricyclic medications. Prescription of amitriptyline for patients with IBS must balance expected efficacy and tolerance of side effects. The current study is a major achievement in providing the best data thus far on the value of amitriptyline for the management of IBS.
References