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Khasawneh M, Mokhtare M, Moayyedi P, Black CJ, Ford AC. Efficacy of gut-brain neuromodulators in irritable bowel syndrome: an updated systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2025; 10:537-549. [PMID: 40258375 DOI: 10.1016/s2468-1253(25)00051-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 02/08/2025] [Accepted: 02/11/2025] [Indexed: 04/23/2025]
Abstract
BACKGROUND Gut-brain neuromodulators might be efficacious for irritable bowel syndrome (IBS), but there has been no synthesis of evidence from randomised controlled trials (RCTs) of some drug classes, and whether they have pain-modifying properties in IBS is unclear. We updated a previous systematic review and meta-analysis of RCTs examining these questions. METHODS We searched MEDLINE (from Jan 1, 1946, to Jan 1, 2025), Embase and Embase Classic (from Jan 1, 1947, to Jan 1, 2025), and the Cochrane Central Register of Controlled Trials (from database inception to Jan 1, 2025). Trials recruiting adults with IBS and that compared gut-brain neuromodulators versus placebo over at least 4 weeks of treatment were eligible. Dichotomous symptom data were pooled using a random effects model to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% CI. FINDINGS The search strategy identified 3625 citations. 28 RCTs were eligible containing 2475 patients. Ten RCTs were identified since our previous meta-analysis, containing 1348 patients. The RR of global IBS symptoms not improving with gut-brain neuromodulators versus placebo in 22 RCTs (2222 patients) was 0·77 (95% CI 0·69-0·87). The best evidence in terms of persistence of global IBS symptoms was for tricyclic antidepressants (TCAs) in 11 trials (1144 patients; RR 0·70, 0·62-0·80). The RR of abdominal pain not improving with gut-brain neuromodulators versus placebo in 19 RCTs (1792 patients) was 0·72 (95% CI 0·62-0·83). The best evidence was for TCAs in seven trials (708 patients; RR 0·69, 0·54-0·87), but there was also a benefit of selective serotonin reuptake inhibitors in seven RCTs (324 patients; RR 0·74, 0·56-0·99), and serotonin and norepinephrine reuptake inhibitors in two trials (94 patients; RR 0·22, 0·08-0·59). Adverse events were not significantly more common with gut-brain neuromodulators, although rates of withdrawal due to adverse events were significantly higher. The certainty in the evidence for tricyclic antidepressants for global IBS symptoms was moderate, but it was low to very low for all other endpoints and drug classes studied. INTERPRETATION Some gut-brain neuromodulators are efficacious in reducing global symptoms and abdominal pain in IBS. The findings support guidelines that recommend use of tricyclic antidepressants for ongoing global symptoms or abdominal pain but also highlight a potential for SSRIs to be modestly effective for abdominal pain. More data for SNRIs, azapirones, and tetracyclic antidepressants in IBS are required. FUNDING None.
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Affiliation(s)
- Mais Khasawneh
- Leeds Gastroenterology Institute, St James's University Hospital, Leeds, UK; Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK
| | - Marjan Mokhtare
- Department of Internal Medicine, School of Medicine Colorectal Research Center, Iran; University of Medical Sciences, Tehran, Iran
| | - Paul Moayyedi
- Gastroenterology Division, McMaster University, Health Sciences Center, Hamilton, ON, Canada
| | - Christopher J Black
- Leeds Gastroenterology Institute, St James's University Hospital, Leeds, UK; Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK
| | - Alexander C Ford
- Leeds Gastroenterology Institute, St James's University Hospital, Leeds, UK; Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK.
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Wright-Hughes A, Ow PL, Alderson SL, Ridd MJ, Foy R, Bishop FL, Chaddock M, Fernandez C, Guthrie EA, Muir DP, Taylor CA, Farrin AJ, Everitt HA, Ford AC. Predictors of response to low-dose amitriptyline for irritable bowel syndrome and efficacy and tolerability according to subtype: post hoc analyses from the ATLANTIS trial. Gut 2025; 74:728-739. [PMID: 39863398 PMCID: PMC7617491 DOI: 10.1136/gutjnl-2024-334490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 01/06/2025] [Indexed: 01/27/2025]
Abstract
BACKGROUND Low-dose amitriptyline, a tricyclic antidepressant (TCA), was superior to placebo for irritable bowel syndrome (IBS) in the AmitripTyline at Low-dose ANd Titrated for Irritable bowel syndrome as Second-line treatment (ATLANTIS) trial. OBJECTIVE To perform post hoc analyses of ATLANTIS for predictors of response to, and tolerability of, a TCA. DESIGN ATLANTIS randomised 463 adults with IBS to amitriptyline (232) or placebo (231). We examined the effect of baseline demographic and disease-related patient characteristics on response to amitriptyline and the effect of amitriptyline on individual symptoms and side effects by subtype. RESULTS There was a quantitative difference in amitriptyline effectiveness in those ≥50 years vs <50 on the IBS severity scoring system (IBS-SSS) (interaction p=0.048, mean difference in ≥50 years subgroup -46.5; 95% CI -74.2 to -18.8, p=0.0010), and subjective global assessment of relief (interaction p=0.068, OR in ≥50 years subgroup 2.59; 95% CI 1.47 to 4.55, p=0.0010), and those in the 70% most deprived areas of England compared with the 30% least deprived for a ≥30% improvement in abdominal pain (interaction p=0.021, OR in 70% most deprived subgroup 2.70; 95% CI 1.52 to 4.77, p=0.0007). Stronger treatment effects were seen in men, with higher Patient Health Questionnaire-12 scores, and with IBS with diarrhoea. Mean differences in individual IBS-SSS components favoured amitriptyline, and side effects were similar, across almost all IBS subtypes. CONCLUSION These exploratory analyses demonstrate there are unlikely to be deleterious effects of amitriptyline in any particular IBS subtype and could help identify patients in whom amitriptyline may be more effective. TRIAL REGISTRATION NUMBER ISRCTN48075063.
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Affiliation(s)
- Alexandra Wright-Hughes
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds, UK
| | - Pei-Loo Ow
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds, UK
| | - Sarah L Alderson
- Leeds Institute of Health Sciences, School of Medicine, University of Leeds, Leeds, UK
| | - Matthew J Ridd
- Population Health Sciences, University of Bristol, Bristol, UK
| | - Robbie Foy
- Leeds Institute of Health Sciences, School of Medicine, University of Leeds, Leeds, UK
| | - Felicity L Bishop
- Centre for Clinical and Community Applications of Health Psychology, School of Psychology, University of Southampton, Southampton, UK
| | | | - Catherine Fernandez
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds, UK
| | - Elspeth A Guthrie
- Leeds Institute of Health Sciences, School of Medicine, University of Leeds, Leeds, UK
| | - Delia P Muir
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds, UK
| | - Christopher A Taylor
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds, UK
| | - Amanda J Farrin
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds, UK
| | - Hazel A Everitt
- Primary Care and Population Sciences, University of Southampton, Southampton, UK
| | - Alexander C Ford
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
- Leeds Gastroenterology Institute, St James's University Hospital, Leeds, UK
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Teasdale EJ, Everitt HA, Alderson SL, Ford AC, Hanney J, Chaddock M, Williamson E, Cook H, Farrin AJ, Fernandez C, Guthrie EA, Hartley S, Herbert A, Howdon D, Muir D, Newman S, Ow PL, Ridd MJ, Taylor CM, Thornton R, Wright-Hughes A, Bishop FL. Low-dose amitriptyline for irritable bowel syndrome: a qualitative study of patients' and GPs' views and experiences. Br J Gen Pract 2025:BJGP.2024.0303. [PMID: 39191441 PMCID: PMC11920899 DOI: 10.3399/bjgp.2024.0303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 08/16/2024] [Indexed: 08/29/2024] Open
Abstract
BACKGROUND Irritable bowel syndrome (IBS) can cause troublesome symptoms, which impact 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 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). METHOD Semi-structured telephone interviews were conducted with 42 patients at 6 months post-randomisation, with 19 patients again at 12 months post-randomisation, and with 16 GPs between April 2020 and March 2022. 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, and 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. CONCLUSION Patients and GPs felt that the potential benefits of 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.
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Affiliation(s)
- Emma J Teasdale
- Centre for Clinical and Community Applications of Health Psychology, School of Psychology, University of Southampton, Southampton
| | - Hazel A Everitt
- Primary Care Research Centre, Faculty of Medicine, University of Southampton, Southampton
| | - Sarah L Alderson
- Leeds Institute of Health Sciences, School of Medicine, University of Leeds, Leeds
| | - Alexander C Ford
- Leeds Gastroenterology Institute, St James's University Hospital, Leeds; Leeds Institute of Medical Research at St James's, University of Leeds, Leeds
| | - James Hanney
- Centre for Clinical and Community Applications of Health Psychology, School of Psychology, University of Southampton, Southampton
| | | | | | - Heather Cook
- Exeter Clinical Trials Unit, University of Exeter, Exeter
| | - Amanda J Farrin
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds
| | - Catherine Fernandez
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds
| | - Elspeth A Guthrie
- Leeds Institute of Health Sciences, School of Medicine, University of Leeds, Leeds
| | - Suzanne Hartley
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds
| | - Amy Herbert
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol
| | - Daniel Howdon
- Leeds Institute of Health Sciences, School of Medicine, University of Leeds, Leeds
| | - Delia Muir
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds
| | - Sonia Newman
- Primary Care Research Centre, Faculty of Medicine, University of Southampton, Southampton
| | - Pei Loo Ow
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds
| | - Matthew J Ridd
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol
| | - Christopher M Taylor
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds
| | - Ruth Thornton
- Primary Care Research Centre, Faculty of Medicine, University of Southampton, Southampton
| | - Alexandra Wright-Hughes
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds
| | - Felicity L Bishop
- Centre for Clinical and Community Applications of Health Psychology, School of Psychology, University of Southampton, Southampton
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Iqbal M, Hira S, Saeed H, Shahid S, Butt ST, Rashid K, Ahmad M, Hussain H, Mughal A, Costa GPA, Gushken F, Nero N, Sengupta S, Anand A. Efficacy of Amitriptyline in Irritable Bowel Syndrome: A Systematic Review and Meta-analysis. J Neurogastroenterol Motil 2025; 31:28-37. [PMID: 39779201 PMCID: PMC11735204 DOI: 10.5056/jnm24084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 09/20/2024] [Accepted: 09/22/2024] [Indexed: 01/11/2025] Open
Abstract
Background/Aims Amitriptyline is prescribed off-label for irritable bowel syndrome (IBS). We conducted a meta-analysis to assess its efficacy. Methods A systematic literature review was conducted until November 10, 2023, using MEDLINE, Embase, Cochrane Library, and Web of Science to study the efficacy of amitriptyline in patients with IBS. We included all randomized controlled trials that compared amitriptyline to placebo. Revised Cochrane risk-of-bias tool was used to assess the quality of studies. Meta-analyses were performed using a bivariate random-effects model. Statistical analyses were performed using R Software 4.2.3 and heterogeneity was assessed with I2 statistics. Results Seven trials were included with 796 patients (61% female). Amitriptyline was associated with better treatment response (OR, 5.30; 95% CI, 2.47 to 11.39; P < 0.001), reduced Irritable Bowel Syndrome Symptom Severity Scores (MD, -50.72; 95% CI, -94.23 to -7.20; P = 0.020) and improved diarrhea (OR, 10.55; 95% CI, 2.90 to 38.41; P < 0.001). No significant difference between the 2 groups regarding the adverse effects was observed. Three trials showed an overall low risk of bias, 2 trials showed an overall high risk of bias due to randomization and missing data, and 2 trials had some concerns regarding missing data. Conclusions Amitriptyline was found to be well-tolerated and effective in treating IBS compared to placebo. These findings support the use of amitriptyline for the management of IBS, particularly among patients with the IBS diarrhea subtype. Future research should focus on the dose-dependent effects of amitriptyline in IBS to better guide clinicians in personalized titration regimens.
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Affiliation(s)
| | - Sara Hira
- Fatima Memorial Hospital, Lahore, Pakistan
| | - Humza Saeed
- Rawalpindi Medical University, Rawalpindi, Pakistan
| | - Sufyan Shahid
- Khawaja Muhammad Safdar Medical College, Sialkot, Pakistan
| | - Suha T Butt
- Rawalpindi Medical University, Rawalpindi, Pakistan
| | | | | | - Hammad Hussain
- Islamic International Medical College, Rawalpindi, Pakistan
| | - Anzalna Mughal
- Islamic International Medical College, Rawalpindi, Pakistan
| | - Gabriel P A Costa
- Faculty of Medicine, University of Ribeirão Preto, Ribeirão Preto, SP, Brazil
| | - Fernanda Gushken
- Faculdade Israelita de Ciências da Saúde Albert Einstein, São Paulo, SP, Brazil
| | - Neil Nero
- Floyd D. Loop Alumni Library, Cleveland Clinic, Cleveland, OH, USA
| | - Shreya Sengupta
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA
| | - Akhil Anand
- Department of Psychiatry and Psychology, Cleveland Clinic, Cleveland, OH, USA
- Department of Psychiatry, University Hospitals Medical Center, Cleveland, OH, USA
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Black CJ, Ford AC. Personalisation of therapy in irritable bowel syndrome: a hypothesis. Lancet Gastroenterol Hepatol 2024; 9:1162-1176. [PMID: 39521004 DOI: 10.1016/s2468-1253(24)00245-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 07/18/2024] [Accepted: 07/23/2024] [Indexed: 11/16/2024]
Abstract
Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction characterised by symptoms of abdominal pain, occurring at least 1 day per week, and a change in stool frequency or form. Individuals with IBS are usually subtyped according to their predominant bowel habit, which is used to direct symptom-based treatment. However, this approach is probably an oversimplification of a complex and multidimensional condition, and other factors, such as psychological health, are known to influence symptom severity and prognosis. We have previously used latent class analysis, a method of mathematical modelling, to show that people with IBS can be classified into seven unique clusters based on a combination of gastrointestinal symptoms, abdominal pain, extraintestinal symptoms, and psychological comorbidity. The clusters can be used to predict the prognosis of IBS (eg, symptom severity), health-care use (eg, consultation behaviour, prescribing, and costs), and impact (eg, quality of life, work and productivity, activities of daily living, and income). These clusters could also be used to increase the personalisation of IBS treatment that better recognises the heterogenous nature of the condition. We present new data providing additional validation of our seven-cluster model and conduct a comprehensive evidence-based review of IBS management. Based on this evidence, we propose a framework of first-line and second-line treatments according to IBS cluster. Finally, we discuss what further research is needed to implement this approach in clinical practice, including the need for randomised trials comparing cluster-based treatment with conventional treatment according to stool subtype.
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Affiliation(s)
- Christopher J Black
- Leeds Gastroenterology Institute, St James's University Hospital, Leeds, UK; Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
| | - Alexander C Ford
- Leeds Gastroenterology Institute, St James's University Hospital, Leeds, UK; Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
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Wright-Hughes A, Ford AC, Alderson SL, Ow PL, Ridd MJ, Foy R, Bishop FL, Chaddock M, Cook H, Cooper D, Fernandez C, Guthrie EA, Hartley S, Herbert A, Howdon D, Muir DP, Newman S, Taylor CA, Teasdale EJ, Thornton R, Everitt HA, Farrin AJ. Low-dose titrated amitriptyline as second-line treatment for adults with irritable bowel syndrome in primary care: the ATLANTIS RCT. Health Technol Assess 2024; 28:1-161. [PMID: 39397570 PMCID: PMC11491989 DOI: 10.3310/bfcr7986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2024] Open
Abstract
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.
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Affiliation(s)
- Alexandra Wright-Hughes
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds, UK
| | - Alexander C Ford
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, UK
| | - Sarah L Alderson
- Leeds Institute of Health Sciences, School of Medicine, University of Leeds, Leeds, UK
| | - Pei Loo Ow
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds, UK
| | - Matthew J Ridd
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Robbie Foy
- Leeds Institute of Health Sciences, School of Medicine, University of Leeds, Leeds, UK
| | - Felicity L Bishop
- Centre for Clinical and Community Applications of Health Psychology, School of Psychology, University of Southampton, Southampton, UK
| | | | - Heather Cook
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds, UK
| | - Deborah Cooper
- Leeds Institute of Health Sciences, School of Medicine, University of Leeds, Leeds, UK
| | - Catherine Fernandez
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds, UK
| | - Elspeth A Guthrie
- Leeds Institute of Health Sciences, School of Medicine, University of Leeds, Leeds, UK
| | - Suzanne Hartley
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds, UK
| | - Amy Herbert
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Daniel Howdon
- Leeds Institute of Health Sciences, School of Medicine, University of Leeds, Leeds, UK
| | - Delia P Muir
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds, UK
| | - Sonia Newman
- Primary Care Research Centre, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Christopher A Taylor
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds, UK
| | - Emma J Teasdale
- Centre for Clinical and Community Applications of Health Psychology, School of Psychology, University of Southampton, Southampton, UK
| | - Ruth Thornton
- Primary Care Research Centre, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Hazel A Everitt
- Primary Care Research Centre, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Amanda J Farrin
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds, UK
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Christoffersen T, Kornholt J, Riis T, Sonne DP, Klarskov N. Effect of Single-Dose Imipramine on Anal Sphincter Tone in Healthy Women: A Randomized, Placebo-Controlled Study Using Anal Acoustic Reflectometry. Int Urogynecol J 2024; 35:1873-1879. [PMID: 39167201 PMCID: PMC11420375 DOI: 10.1007/s00192-024-05890-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 07/14/2024] [Indexed: 08/23/2024]
Abstract
INTRODUCTION AND HYPOTHESIS Despite the high prevalence of fecal incontinence, existing treatment options may be inadequate. Drugs that enhance the tone of the anal sphincter complex could potentially be an effective pharmacological approach. This study investigated the effect of the tricyclic antidepressant imipramine on anal sphincter tone in healthy women, employing anal acoustic reflectometry as the evaluating method. METHODS In a double-blind, randomized, placebo-controlled crossover study, 16 healthy female volunteers were randomized to one of two treatment sequences. The participants attended two study visits separated by at least 7 days' washout. At each visit, they received a single dose of 50 mg imipramine or matching placebo, in alternating order. We assessed the anal opening pressure under the resting state and during voluntary squeezing of the pelvic floor. Measurements were performed pre-dose and 1 h after drug administration, corresponding to the estimated time of peak plasma concentration of imipramine. RESULTS All participants completed the study. In total, 44% of the participants reported at least one adverse effect, primarily anticholinergic. Compared with placebo, imipramine increased anal opening pressure by 15.2 cmH2O (95% confidence interval [CI] 2.0-28.2 cmH2O, p = 0.03) in the resting state and 15.1 (95% CI 4.2-26.0 cmH2O, p = 0.01) cmH2O during squeezing. CONCLUSIONS The findings indicate that imipramine increases anal sphincter tone in healthy women. However, further research is required to evaluate its clinical impact on individuals with fecal incontinence. This research also demonstrates the effectiveness of using anal acoustic reflectometry for assessing pharmacological effects on anal sphincter function.
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Affiliation(s)
- Thea Christoffersen
- Department of Clinical Pharmacology, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Bispebjerg Bakke 23, 2nd Floor, 2400, Copenhagen, Denmark.
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
| | - Jonatan Kornholt
- Department of Clinical Pharmacology, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Bispebjerg Bakke 23, 2nd Floor, 2400, Copenhagen, Denmark
- Novo Nordisk A/S, Bagsvaerd, Denmark
| | - Troels Riis
- Department of Clinical Pharmacology, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Bispebjerg Bakke 23, 2nd Floor, 2400, Copenhagen, Denmark
| | - David P Sonne
- Department of Clinical Pharmacology, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Bispebjerg Bakke 23, 2nd Floor, 2400, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Niels Klarskov
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Department of Gynecology and Obstetrics, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark
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Ihara E, Manabe N, Ohkubo H, Ogasawara N, Ogino H, Kakimoto K, Kanazawa M, Kawahara H, Kusano C, Kuribayashi S, Sawada A, Takagi T, Takano S, Tomita T, Noake T, Hojo M, Hokari R, Masaoka T, Machida T, Misawa N, Mishima Y, Yajima H, Yamamoto S, Yamawaki H, Abe T, Araki Y, Kasugai K, Kamiya T, Torii A, Nakajima A, Nakada K, Fukudo S, Fujiwara Y, Miwa H, Kataoka H, Nagahara A, Higuchi K. Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023. Digestion 2024; 105:480-497. [PMID: 39197422 PMCID: PMC11633876 DOI: 10.1159/000541121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 08/22/2024] [Indexed: 09/01/2024]
Abstract
The Japan Gastroenterological Association (JGA) published the first version of clinical guidelines for chronic diarrhea 2023. These guidelines describe the definition, classification, diagnostic criteria, diagnostic testing methods, epidemiology, pathophysiology, and treatment of chronic diarrhea, and provide flowcharts for the diagnosis and treatment of chronic diarrhea based on the latest evidence. Treatment for chronic diarrhea begins by distinguishing secondary chronic constipation with a clear etiology, such as drug-induced diarrhea, food-induced diarrhea, systemic disease-associated diarrhea, infection-associated diarrhea, organic disease-associated diarrhea, and bile acid diarrhea. The first line of treatment for chronic diarrhea in the narrow sense, defined in these guidelines as functional diarrhea in routine medical care, is lifestyle modification and dietary therapy. The first medicines to be considered for oral treatment are probiotics for regulating the gut microbiome and anti-diarrheals. Other medications, such as 5HT3 receptor antagonists, anticholinergics, Kampo medicine, psychotherapy, antibiotics, bulking agents, adrenergic agonists, and somatostatin analogs, lack sufficient evidence for their use, highlighting a challenge for future research. This Clinical Guidelines for Chronic Diarrhea 2023, which provides the best clinical strategies for treating chronic diarrhea in Japan, will also be useful for medical treatment worldwide.
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Affiliation(s)
- Eikichi Ihara
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Noriaki Manabe
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Hidenori Ohkubo
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Naotaka Ogasawara
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Haruei Ogino
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Kazuki Kakimoto
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Motoyori Kanazawa
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Hidejiro Kawahara
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Chika Kusano
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Shiko Kuribayashi
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Akinari Sawada
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Tomohisa Takagi
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Shota Takano
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Toshihiko Tomita
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Toshihiro Noake
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Mariko Hojo
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Ryota Hokari
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Tatsuhiro Masaoka
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Tomohiko Machida
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Noboru Misawa
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Yoshiyuki Mishima
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Hiroshi Yajima
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Sayuri Yamamoto
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Hiroshi Yamawaki
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Tatsuya Abe
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Yasumi Araki
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Kunio Kasugai
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Takeshi Kamiya
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Akira Torii
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Atsushi Nakajima
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Koji Nakada
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Shin Fukudo
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Yasuhiro Fujiwara
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Hiroto Miwa
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Hiromi Kataoka
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Akihito Nagahara
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Kazuhide Higuchi
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
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9
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Ford AC, Wright-Hughes A, Alderson SL, Ow PL, Ridd MJ, Foy R, Bianco G, Bishop FL, Chaddock M, Cook H, Cooper D, Fernandez C, Guthrie EA, Hartley S, Herbert A, Howdon D, Muir DP, Nath T, Newman S, Smith T, Taylor CA, Teasdale EJ, Thornton R, Farrin AJ, Everitt HA. 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; 402:1773-1785. [PMID: 37858323 DOI: 10.1016/s0140-6736(23)01523-4] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 06/30/2023] [Accepted: 07/20/2023] [Indexed: 10/21/2023]
Abstract
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).
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Affiliation(s)
- Alexander C Ford
- Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK; Leeds Gastroenterology Institute, St James's University Hospital, Leeds, UK.
| | - Alexandra Wright-Hughes
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Sarah L Alderson
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Pei-Loo Ow
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Matthew J Ridd
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Robbie Foy
- Leeds Institute of Health Sciences, School of Medicine, University of Leeds, Leeds, UK
| | - Gina Bianco
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Felicity L Bishop
- Centre for Clinical and Community Applications of Health Psychology, School of Psychology, University of Southampton, Southampton, UK
| | | | - Heather Cook
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Deborah Cooper
- Leeds Institute of Health Sciences, School of Medicine, University of Leeds, Leeds, UK
| | - Catherine Fernandez
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Elspeth A Guthrie
- Leeds Institute of Health Sciences, School of Medicine, University of Leeds, Leeds, UK
| | - Suzanne Hartley
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Amy Herbert
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Daniel Howdon
- Leeds Institute of Health Sciences, School of Medicine, University of Leeds, Leeds, UK
| | - Delia P Muir
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Taposhi Nath
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Sonia Newman
- Primary Care Research Centre, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Thomas Smith
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Christopher A Taylor
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Emma J Teasdale
- Centre for Clinical and Community Applications of Health Psychology, School of Psychology, University of Southampton, Southampton, UK
| | - Ruth Thornton
- Primary Care Research Centre, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Amanda J Farrin
- Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Hazel A Everitt
- Primary Care Research Centre, Faculty of Medicine, University of Southampton, Southampton, UK
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10
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Staudacher HM, Black CJ, Teasdale SB, Mikocka-Walus A, Keefer L. Irritable bowel syndrome and mental health comorbidity - approach to multidisciplinary management. Nat Rev Gastroenterol Hepatol 2023; 20:582-596. [PMID: 37268741 PMCID: PMC10237074 DOI: 10.1038/s41575-023-00794-z] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/02/2023] [Indexed: 06/04/2023]
Abstract
Irritable bowel syndrome (IBS) affects 5-10% of the global population. Up to one-third of people with IBS also experience anxiety or depression. Gastrointestinal and psychological symptoms both drive health-care use in people with IBS, but psychological comorbidity seems to be more important for long-term quality of life. An integrated care approach that addresses gastrointestinal symptoms with nutrition and brain-gut behaviour therapies is considered the gold standard. However, best practice for the treatment of individuals with IBS who have a comorbid psychological condition is unclear. Given the rising prevalence of mental health disorders, discussion of the challenges of implementing therapy for people with IBS and anxiety and depression is critical. In this Review, we draw upon our expertise in gastroenterology, nutrition science and psychology to highlight common challenges that arise when managing patients with IBS and co-occurring anxiety and depression, and provide recommendations for tailoring clinical assessment and treatment. We provide best practice recommendations, including dietary and behavioural interventions that could be applied by non-specialists and clinicians working outside an integrated care model.
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Affiliation(s)
- Heidi M Staudacher
- Food & Mood Centre, IMPACT Institute, Deakin University Geelong, Melbourne, Victoria, Australia.
| | - Christopher J Black
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
- Leeds Gastroenterology Institute, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Scott B Teasdale
- Psychiatry and Mental Health, University of New South Wales, Sydney, New South Wales, Australia
| | | | - Laurie Keefer
- Department of Medicine and Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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11
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Bonetto S, Boano V, Valenzi E, Saracco GM, Pellicano R. Non-pharmacological strategies to treat irritable bowel syndrome: 2022 update. Minerva Gastroenterol (Torino) 2022; 68:475-481. [PMID: 36507830 DOI: 10.23736/s2724-5985.22.03202-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Irritable bowel syndrome (IBS) is a chronic functional disorder characterized by abdominal pain associated with changes in stool frequency or form, in absence of organic disease. The treatment of IBS is often challenging and should be individually adjusted according to the prevalent symptomatology. Pharmacological treatment for IBS with diarrhea includes peripheral opioid agonists, bile acid sequestrants and antibiotics, while IBS with constipation can be treated with soluble fibers, osmotic agents or prokinetics. In case of abdominal pain, the available pharmacological options are antispasmodics, peripheral opioid agonists or antidepressants. Along with pharmacotherapy, non-pharmacological interventions should be considered as they can play an important role in symptom control. The first-line approach includes lifestyle modifications and dietary advice. Microbiota manipulation through probiotics, prebiotics and symbiotics is a widely used strategy, although the evidence upon the most effective among these in specific IBS subtypes is still unclear. Fecal microbiota transplantation is still in experimental phase for IBS, but it is giving promising results. Psychological therapies may be effective in patients with IBS, despite their application can be limited by long duration, high costs and poor patient's acceptance. Alternative medicine approaches, such as acupuncture, body relaxation techniques, dietary supplements or Chinese herbs, have been proposed; however, the evidence upon their efficacy and safety is still controversial.
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Affiliation(s)
- Silvia Bonetto
- Unit of Gastroenterology and Endoscopy, Cardinal Massaia Hospital, Asti, Italy
| | - Valentina Boano
- Unit of Gastroenterology and Endoscopy, Cardinal Massaia Hospital, Asti, Italy
| | - Emiliano Valenzi
- Unit of Gastroenterology and Endoscopy, Cardinal Massaia Hospital, Asti, Italy
| | - Giorgio M Saracco
- Unit of Gastroenterology, Molinette Hospital, Turin, Italy
- Department of Medical Sciences, University of Turin, Turin, Italy
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12
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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. Trials 2022; 23:552. [PMID: 35804433 PMCID: PMC9264306 DOI: 10.1186/s13063-022-06492-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 06/24/2022] [Indexed: 11/12/2022] Open
Abstract
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. Supplementary Information The online version contains supplementary material available at 10.1186/s13063-022-06492-6.
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13
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Jeong B, Sung TS, Jeon D, Park KJ, Jun JY, So I, Hong C. Inhibition of TRPC4 channel activity in colonic myocytes by tricyclic antidepressants disrupts colonic motility causing constipation. J Cell Mol Med 2022; 26:4911-4923. [PMID: 35560982 PMCID: PMC9549500 DOI: 10.1111/jcmm.17348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 03/28/2022] [Accepted: 04/05/2022] [Indexed: 11/27/2022] Open
Abstract
Tricyclic antidepressants (TCAs) have been used to treat depression and were recently approved for treating irritable bowel syndrome (IBS) patients with severe or refractory IBS symptoms. However, the molecular mechanism of TCA action in the gastrointestinal (GI) tract remains poorly understood. Transient receptor potential channel canonical type 4 (TRPC4), which is a Ca2+‐permeable nonselective cation channel, is a critical regulator of GI excitability. Herein, we investigated whether TCA modulates TRPC4 channel activity and which mechanism in colonic myocytes consequently causes constipation. To prove the clinical benefit in patients with diarrhoea caused by TCA treatment, we performed mechanical tension recording of repetitive motor pattern (RMP) in segment, electric field stimulation (EFS)‐induced and spontaneous contractions in isolated muscle strips. From these recordings, we observed that all TCA compounds significantly inhibited contractions of colonic motility in human. To determine the contribution of TRPC4 to colonic motility, we measured the electrical activity of heterologous or endogenous TRPC4 by TCAs using the patch clamp technique in HEK293 cells and murine colonic myocytes. In TRPC4‐overexpressed HEK cells, we observed TCA‐evoked direct inhibition of TRPC4. Compared with TRPC4‐knockout mice, we identified that muscarinic cationic current (mIcat) was suppressed through TRPC4 inhibition by TCA in isolated murine colonic myocytes. Collectively, we suggest that TCA action is responsible for the inhibition of TRPC4 channels in colonic myocytes, ultimately causing constipation. These findings provide clinical insights into abnormal intestinal motility and medical interventions aimed at IBS therapy.
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Affiliation(s)
- Byeongseok Jeong
- Department of Physiology, Chosun University School of Medicine, Gwangju, South Korea
| | - Tae Sik Sung
- Department of Surgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea.,Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea
| | - Dongju Jeon
- Department of Physiology, Chosun University School of Medicine, Gwangju, South Korea
| | - Kyu Joo Park
- Department of Surgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Jae Yeoul Jun
- Department of Physiology, Chosun University School of Medicine, Gwangju, South Korea
| | - Insuk So
- Department of Physiology and Institute of Dermatological Science, Seoul National University College of Medicine, Seoul, South Korea
| | - Chansik Hong
- Department of Physiology, Chosun University School of Medicine, Gwangju, South Korea
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14
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Wollny T, Daniluk T, Piktel E, Wnorowska U, Bukłaha A, Głuszek K, Durnaś B, Bucki R. Targeting the Gut Microbiota to Relieve the Symptoms of Irritable Bowel Syndrome. Pathogens 2021; 10:1545. [PMID: 34959500 PMCID: PMC8705654 DOI: 10.3390/pathogens10121545] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/12/2021] [Accepted: 11/23/2021] [Indexed: 12/12/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a common, chronic, functional disorder with a large impact on world population. Its pathophysiology is not completely revealed; however, it is certain that dysregulation of the bidirectional communications between the central nervous system (CNS) and the gut leads to motility disturbances, visceral hypersensitivity, and altered CNS processing characterized by differences in brain structure, connectivity and functional responsiveness. Emerging evidence suggests that gut microbiota exerts a marked influence on the host during health and disease. Gut microbiome disturbances can be also important for development of IBS symptoms and its modulation efficiently contributes to the therapy. In this work, we review the current knowledge about the IBS therapy, the role of gut microbiota in pathogenesis of IBS, and we discuss that its targeting may have significant impact on the effectiveness of IBS therapy.
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Affiliation(s)
- Tomasz Wollny
- Holy Cross Oncology Center of Kielce, Artwińskiego 3, 25-734 Kielce, Poland;
| | - Tamara Daniluk
- Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Białystok, Mickiewicza 2c, 15-222 Białystok, Poland; (T.D.); (E.P.); (U.W.)
| | - Ewelina Piktel
- Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Białystok, Mickiewicza 2c, 15-222 Białystok, Poland; (T.D.); (E.P.); (U.W.)
| | - Urszula Wnorowska
- Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Białystok, Mickiewicza 2c, 15-222 Białystok, Poland; (T.D.); (E.P.); (U.W.)
| | - Anna Bukłaha
- Department of Microbiological Diagnostics and Infectious Immunology, Medical University of Białystok, Waszyngtona 15a, 15-269 Białystok, Poland;
| | - Katarzyna Głuszek
- Institute of Medical Science, Collegium Medicum, Jan Kochanowski University in Kielce, 25-734 Kielce, Poland; (K.G.); (B.D.)
| | - Bonita Durnaś
- Institute of Medical Science, Collegium Medicum, Jan Kochanowski University in Kielce, 25-734 Kielce, Poland; (K.G.); (B.D.)
| | - Robert Bucki
- Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Białystok, Mickiewicza 2c, 15-222 Białystok, Poland; (T.D.); (E.P.); (U.W.)
- Institute of Medical Science, Collegium Medicum, Jan Kochanowski University in Kielce, 25-734 Kielce, Poland; (K.G.); (B.D.)
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15
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Medical Therapies for Diarrhea-Predominant Irritable Bowel Syndrome. Gastroenterol Clin North Am 2021; 50:611-637. [PMID: 34304791 DOI: 10.1016/j.gtc.2021.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
Diarrhea-predominant irritable bowel syndrome is a common functional gastrointestinal disorder that manifests with abdominal pain and diarrheal bowel patterns, without structural explanation. Diarrhea-predominant irritable bowel syndrome is a heterogeneous condition resulting from diverse pathophysiologic processes. Treatment strategies with varied mechanisms of action are beneficial in its management. The clinician must become familiar with a multi-dimensional approach to irritable bowel syndrome. The 3 approved medications are central to disease management. Effective treatment uses off-label medications and emerging therapies and a growing number of over-the-counter and supplemental agents to optimize symptom improvement for the patient with diarrhea-predominant irritable bowel syndrome.
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16
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West M, McMaster CM, Staudacher HM, Hart S, Jacka FN, Stewart T, Loughman A, Rocks T, Ruusunen A. Gastrointestinal symptoms following treatment for anorexia nervosa: A systematic literature review. Int J Eat Disord 2021; 54:936-951. [PMID: 33529388 DOI: 10.1002/eat.23469] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 12/06/2020] [Accepted: 01/01/2021] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Gastrointestinal (GI) disturbances are a frequent and burdensome experience for patients with anorexia nervosa (AN). How GI symptoms respond to current interventions is not well characterized, yet is critical to facilitate treatment success, and to inform the development of new treatments for AN. Therefore, the aim of this systematic review was to identify which treatments are effective in improving GI symptoms in patients with AN. METHOD A systematic search for studies of AN treatments measuring GI symptoms pre- and post-treatment was conducted in May 2020 (PROSPERO ID: CRD42020181328). After removal of duplicates, title and abstracts of 3,370 studies were screened. Methodological quality was assessed using National Institute of Health Quality Assessment Tool. RESULTS Following full-text screening, 13 studies (12 observational studies and 1 randomized double-blind placebo-controlled trial) with 401 participants met eligibility criteria and were included. All observational studies included a component of nutritional rehabilitation, with half (n = 6) involving concurrent psychological treatment. The randomized controlled trial reported a drug therapy. Eleven studies reported an improvement in all (n = 6) or at least one (n = 5) patient-reported GI symptom following treatment. Two studies reported no change. Methodological quality was fair or poor across all studies. DISCUSSION This is the first systematic review to synthesize available evidence on the trajectory of patient-reported GI symptoms from commencement to end of treatment for AN. The results suggest that most studies showed improvement in one or more GI symptom in response to current treatments. Future therapeutic approaches should consider GI symptoms within their design for optimal treatment adherence and outcomes.
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Affiliation(s)
- Madeline West
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, Food & Mood Centre, School of Medicine, Barwon Health, Geelong, Victoria, Australia
| | - Caitlin M McMaster
- Boden Collaboration for Obesity, Nutrition, Exercise and Eating Disorders, University of Sydney, Sydney, New South Wales, Australia
| | - Heidi M Staudacher
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, Food & Mood Centre, School of Medicine, Barwon Health, Geelong, Victoria, Australia
| | - Susan Hart
- Boden Collaboration for Obesity, Nutrition, Exercise and Eating Disorders, University of Sydney, Sydney, New South Wales, Australia.,Nutrition and Dietetics Department, St Vincent's Hospital, Sydney, New South Wales, Australia
| | - Felice N Jacka
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, Food & Mood Centre, School of Medicine, Barwon Health, Geelong, Victoria, Australia.,Centre for Adolescent Health, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.,Black Dog Institute, Melbourne, New South Wales, Australia.,College of Public Health, Medical & Veterinary Sciences, James Cook University, Townsville, Queensland, Australia
| | - Tim Stewart
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, Food & Mood Centre, School of Medicine, Barwon Health, Geelong, Victoria, Australia.,Department of Dietetics, Human Nutrition and Sport, La Trobe University, Bundoora, Victoria, Australia
| | - Amy Loughman
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, Food & Mood Centre, School of Medicine, Barwon Health, Geelong, Victoria, Australia
| | - Tetyana Rocks
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, Food & Mood Centre, School of Medicine, Barwon Health, Geelong, Victoria, Australia
| | - Anu Ruusunen
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, Food & Mood Centre, School of Medicine, Barwon Health, Geelong, Victoria, Australia.,Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.,Department of Psychiatry, Kuopio University Hospital, Kuopio, Finland
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17
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Staudacher HM, Mikocka-Walus A, Ford AC. Common mental disorders in irritable bowel syndrome: pathophysiology, management, and considerations for future randomised controlled trials. Lancet Gastroenterol Hepatol 2021; 6:401-410. [PMID: 33587890 DOI: 10.1016/s2468-1253(20)30363-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 11/17/2020] [Accepted: 11/19/2020] [Indexed: 12/17/2022]
Abstract
The frequent co-occurrence of irritable bowel syndrome and the common mental disorders of anxiety and depression is well established. A range of biological and psychosocial disease mechanisms are common to both disorders, many of which contribute to a dysregulated gut-brain axis. Clinical and subthreshold psychological comorbidity adds to the functional impairment and disease burden in individuals with irritable bowel syndrome. Progress is being made with regard to understanding irritable bowel syndrome in the clinical setting from a biopsychosocial perspective. However, until now, most trials of irritable bowel syndrome treatment still consider the disease as a gut disorder in isolation, which leaves major gaps in knowledge about disease-disease interactions and treatment outcomes in irritable bowel syndrome. In this Viewpoint, we review the epidemiology, pathophysiology, and management of anxiety and depression in individuals with irritable bowel syndrome. We also provide methodological recommendations for future randomised controlled trials and outline guidance for research that better incorporates psychiatric comorbidity into its design, with a view to improve treatment outcomes for individuals with irritable bowel syndrome.
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Affiliation(s)
- Heidi M Staudacher
- IMPACT, Food & Mood Centre, School of Medicine, Barwon Health, Deakin University, Geelong, VIC, Australia.
| | | | - Alexander C Ford
- Leeds Gastroenterology Institute, St James's University Hospital, Leeds, UK; Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
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18
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Ford AC, Moayyedi P, Black CJ, Yuan Y, Veettil SK, Mahadeva S, Kengkla K, Chaiyakunapruk N, Lee YY. Systematic review and network meta-analysis: efficacy of drugs for functional dyspepsia. Aliment Pharmacol Ther 2021; 53:8-21. [PMID: 32936964 DOI: 10.1111/apt.16072] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/14/2020] [Accepted: 08/15/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Functional dyspepsia (FD) is a relapsing and remitting condition affecting between 5% and 10% of people. Efficacious therapies are available, but their relative efficacy is unknown. AIM To perform a systematic review with network meta-analysis to resolve this uncertainty. METHODS We searched the medical literature through July 2020 for randomised controlled trials (RCTs) assessing efficacy of drugs for adults with FD, compared with each other, or placebo. Trials reported a dichotomous assessment of symptom status after completion of therapy. We pooled data using a random effects model. Efficacy was reported as a pooled relative risk (RR) of remaining symptomatic with a 95% confidence interval (CI) to summarise efficacy of each comparison tested. Relative ranking was assessed with surface under the cumulative ranking curve (SUCRA) probabilities. RESULTS We identified 71 eligible RCTs (19 243 participants). Tricyclic antidepressants (TCAs) were ranked second for efficacy (RR of remaining symptomatic = 0.71; 95% CI 0.58-0.87, SUCRA 0.87), and first when only low risk of bias trials were included. Most RCTs that used TCAs recruited patients who were refractory to other drugs included in the network. Although sulpiride or levosulpiride were ranked first for efficacy (RR = 0.49; 95% CI 0.36-0.69, SUCRA 0.99), trial quality was low and only 86 patients received active therapy. TCAs were more likely to cause adverse events than placebo. CONCLUSIONS TCAs, histamine-2 receptor antagonists, standard- and low-dose proton pump inhibitors, sulpiride or levosulpiride, itopride and acotiamide were all more efficacious than placebo for FD.
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Affiliation(s)
- Alexander C Ford
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, UK.,Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
| | - Paul Moayyedi
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Christopher J Black
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, UK.,Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
| | - Yuhong Yuan
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Sajesh K Veettil
- Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
| | - Sanjiv Mahadeva
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Kirati Kengkla
- School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
| | - Nathorn Chaiyakunapruk
- Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
| | - Yeong Yeh Lee
- School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Malaysia.,Gut Research Group, Faculty of Medicine, National University of Malaysia, Kuala Lumpur, Malaysia.,St George and Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia
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19
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Ford AC, Sperber AD, Corsetti M, Camilleri M. Irritable bowel syndrome. Lancet 2020; 396:1675-1688. [PMID: 33049223 DOI: 10.1016/s0140-6736(20)31548-8] [Citation(s) in RCA: 433] [Impact Index Per Article: 86.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 06/26/2020] [Accepted: 07/03/2020] [Indexed: 12/11/2022]
Abstract
Irritable bowel syndrome is a functional gastrointestinal disorder with symptoms including abdominal pain associated with a change in stool form or frequency. The condition affects between 5% and 10% of otherwise healthy individuals at any one point in time and, in most people, runs a relapsing and remitting course. The best described risk factor is acute enteric infection, but irritable bowel syndrome is also more common in people with psychological comorbidity and in young adult women than in the rest of the general population. The pathophysiology of irritable bowel syndrome is incompletely understood, but it is well established that there is disordered communication between the gut and the brain, leading to motility disturbances, visceral hypersensitivity, and altered CNS processing. Other less reproducible mechanisms might include genetic associations, alterations in gastrointestinal microbiota, and disturbances in mucosal and immune function. In most people, diagnosis can be made on the basis of clinical history with limited and judicious use of investigations, unless alarm symptoms such as weight loss or rectal bleeding are present, or there is a family history of inflammatory bowel disease or coeliac disease. Once the diagnosis is made, an empathetic approach is key and can improve quality of life and symptoms, and reduce health-care expenditure. The mainstays of treatment include patient education about the condition, dietary changes, soluble fibre, and antispasmodic drugs. Other treatments tend to be reserved for people with severe symptoms and include central neuromodulators, intestinal secretagogues, drugs acting on opioid or 5-HT receptors, or minimally absorbed antibiotics (all of which are selected according to predominant bowel habit), as well as psychological therapies. Increased understanding of the pathophysiology of irritable bowel syndrome in the past 10 years has led to a healthy pipeline of novel drugs in development.
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Affiliation(s)
- Alexander C Ford
- Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK; Leeds Gastroenterology Institute, St James's University Hospital, Leeds, UK.
| | - Ami D Sperber
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Maura Corsetti
- National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK; Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK
| | - Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, MN, USA
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20
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Lu J, Shi L, Huang D, Fan W, Li X, Zhu L, Wei J, Fang X. Depression and Structural Factors Are Associated With Symptoms in Patients of Irritable Bowel Syndrome With Diarrhea. J Neurogastroenterol Motil 2020; 26:505-513. [PMID: 32675388 PMCID: PMC7547200 DOI: 10.5056/jnm19166] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Revised: 04/28/2020] [Accepted: 06/01/2020] [Indexed: 12/13/2022] Open
Abstract
Background/Aims A strong correlation between depression and irritable bowel syndrome with diarrhea (IBS-D) has been identified. The aim of this study is to identify the correlations among depression, structural factors, gastrointestinal (GI) and extra-GI symptoms, and efficacy of neuromodulators in patients with IBS-D. Methods Patients meeting the Rome III Diagnostic Criteria for IBS-D were enrolled. The intestinal symptoms and psychological states were evaluated using IBS-specific symptom questionnaires and Hamilton Depression Rating Scale. Results In total, 410 patients with IBS-D were enrolled, 28.8% (118/410) had comorbid depression. Patients with depression did not readily experience improvement in abdominal pain/discomfort after defecation, and had a higher prevalence of passing mucus, overlapping functional dyspepsia, and extra-GI symptoms. The structural factor “mental disorders” significantly correlated with main bowel symptom score and degree of pre-defecation abdominal pain/discomfort. No structural factor significantly correlated with bowel movements or stool form. Patients who had passing mucus, overlapping functional dyspepsia and extra-GI painful symptoms have higher score of “anxiety/somatization.” Patients with sexual dysfunction have higher score of “retardation symptoms.” In total, 28.3% of patients with IBS-D were prescribed neuromodulators. Baseline scores of “anxiety/somatization” and “retardation symptoms” positively correlated with improvement of diarrhea after paroxetine, and “sleep disturbances” positively correlated with improvement of abdominal pain/discomfort and diarrhea after mirtazapine. Conclusions Comorbid depression and higher scores of structural factors might aggravate GI and extra-GI symptoms other than bowel movements and stool form. Structural factors of Hamilton Depression Rating Scale correlated with efficacy of paroxetine and mirtazapine in patients with IBS-D.
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Affiliation(s)
- Jia Lu
- Departments of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lili Shi
- Departments of Psychological Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Dan Huang
- Department of Gastroenterology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Wenjuan Fan
- Departments of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaoqing Li
- Departments of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liming Zhu
- Departments of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jing Wei
- Departments of Psychological Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiucai Fang
- Departments of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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21
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Austhof E, Schaefer K, Faulkner J, Bach L, Riddle M, Pogreba-Brown K. Knowledge and practices of primary care physicians or general practitioners treating post-infectious Irritable Bowel Syndrome. BMC Gastroenterol 2020; 20:159. [PMID: 32450813 PMCID: PMC7249359 DOI: 10.1186/s12876-020-01305-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 05/13/2020] [Indexed: 02/07/2023] Open
Abstract
Background Post-infectious Irritable Bowel Syndrome (PI-IBS) is a functional bowel disorder which has significant impacts to a patient’s quality of life. No IBS-specific biomarker or treatment regimen for PI-IBS currently exists, therefore understanding practice patterns and variance is of interest. Methods This online survey of primary care physicians and general practitioners in the USA aimed to understand the knowledge and treatment of PI-IBS within the physician’s current practice. Summary statistics are provided with a commentary on implications for practices and treatment of PI-IBS. Results Most physician survey respondents (n = 50) were aware of PI-IBS, but less than half discussed this condition as a possible outcome in their patients with a recent gastrointestinal infection. Most physicians indicated that they would treat the patients themselves with a focus on managing IBS through different treatment modalities based on severity. Treatment for PI-IBS followed IBS recommendations, but most physicians also prescribed a probiotic for therapy. Physicians estimated that 4 out of 10 patients who develop PI-IBS will have life-long symptoms and described significant impacts to their patient’s quality of life. Additionally, physicians estimated a significant financial burden for PI-IBS patients, ranging from $100–1000 (USD) over the course of their illness. Most physicians agreed that they would use a risk score to predict the probability of their patients developing PI-IBS, if available. Conclusions While this survey is limited due to sample size, physician knowledge and treatment of PI-IBS was consistent across respondents. Overall, the physicians identified significant impacts to patient’s quality of life due to PI-IBS.
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Affiliation(s)
- Erika Austhof
- Department of Epidemiology & Biostatistics, University of Arizona, Mel and Enid Zuckerman College of Public Health, 1295 N Martin Ave, PO Box 245211, Tucson, 85721, AZ, USA.
| | - Kenzie Schaefer
- Department of Epidemiology & Biostatistics, University of Arizona, Mel and Enid Zuckerman College of Public Health, 1295 N Martin Ave, PO Box 245211, Tucson, 85721, AZ, USA.,College of Medicine, University of Arizona, 1501 N Campbell Ave, PO Box 245017, Tucson, 85724, AZ, USA
| | - Jaime Faulkner
- College of Medicine, University of Arizona, 1501 N Campbell Ave, PO Box 245017, Tucson, 85724, AZ, USA
| | - Laura Bach
- Division of Gastroenterology and Hepatology, College of Medicine, University of Arizona, 1501 N Campbell Ave, PO Box 245028, Tucson, 85724, AZ, USA
| | - Mark Riddle
- School of Medicine, University of Nevada Reno, 1664 N Virginia Street, Reno, 89557, NV, USA
| | - Kristen Pogreba-Brown
- Department of Epidemiology & Biostatistics, University of Arizona, Mel and Enid Zuckerman College of Public Health, 1295 N Martin Ave, PO Box 245211, Tucson, 85721, AZ, USA
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22
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Mikocka-Walus A, Ford AC, Drossman DA. Antidepressants in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2020; 17:184-192. [PMID: 32071420 DOI: 10.1038/s41575-019-0259-y] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/18/2019] [Indexed: 02/06/2023]
Abstract
Gut-brain dysregulation has been recognized by the scientific community as being crucial to the understanding of chronic gastrointestinal conditions, and this has translated into the practice of a newly established discipline, psychogastroenterology. Along with psychotherapy, antidepressants (a subtype of central neuromodulators) have been proposed as treatments for gut-brain disorders that might benefit both psychological and gastrointestinal health. Antidepressants have been found to be effective for the treatment of comorbid anxiety and depression, pain and impaired sleep. Although the efficacy of antidepressants is well established in disorders of gut-brain interaction (DGBI), evidence is only now emerging in IBD. This Perspective discusses the use of antidepressants in DGBI and IBD, focusing on how what we have learnt about the role of antidepressants in DGBI could be applied to help optimize the management of IBD.
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Affiliation(s)
| | - Alexander C Ford
- Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.,Leeds Gastroenterology Institute, St James's University Hospital, Leeds, UK
| | - Douglas A Drossman
- Center for Functional Gastrointestinal and Motility Disorders, University of North Carolina, Chapel Hill, NC, USA.,Center for Education and Practice of Biopsychosocial Care and Drossman Gastroenterology, Chapel Hill, NC, USA
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23
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Ford AC, Lacy BE, Harris LA, Quigley EMM, Moayyedi P. Effect of Antidepressants and Psychological Therapies in Irritable Bowel Syndrome: An Updated Systematic Review and Meta-Analysis. Am J Gastroenterol 2019; 114:21-39. [PMID: 30177784 DOI: 10.1038/s41395-018-0222-5] [Citation(s) in RCA: 244] [Impact Index Per Article: 40.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Irritable bowel syndrome (IBS) is a chronic functional bowel disorder that is thought to be due to a disorder of brain-gut function. Drugs acting centrally, such as antidepressants, and psychological therapies may, therefore, be effective. METHODS We updated a previous systematic review and meta-analysis of randomized controlled trials (RCTs). MEDLINE, EMBASE, PsychINFO, and the Cochrane Controlled Trials Register were searched (up to July 2017). Trials recruiting adults with IBS, which compared antidepressants versus placebo, or psychological therapies versus control therapy or "usual management" were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% confidence interval (CI). RESULTS The search strategy identified 5316 citations. Fifty-three RCTs, reported in 51 separate articles, were eligible for inclusion: 17 compared antidepressants with placebo, 35 compared psychological therapies with control therapy or "usual management", and one compared both psychological therapy and antidepressants with placebo. Four of the trials of psychological therapies, and one of the RCTs of antidepressants, were identified since our previous meta-analysis. The RR of IBS symptoms not improving with antidepressants versus placebo was 0.66 (95% CI 0.57-0.76), with similar treatment effects for both tricyclic antidepressants and SSRIs, although with heterogeneity between RCTs of the latter (I(2) = 49%, P = 0.07). The RR of symptoms not improving with psychological therapies was 0.69 (95% CI 0.62-0.76). Cognitive behavioral therapy, relaxation therapy, multi-component psychological therapy, hypnotherapy, and dynamic psychotherapy were all beneficial when data from two or more RCTs were pooled. There was significant heterogeneity between studies (I(2) = 69%, P < 0.001) and significant funnel plot asymmetry. There were also issues regarding trial design, including lack of blinding. CONCLUSIONS Antidepressants are efficacious in reducing symptoms in IBS patients. Psychological therapies also appear to be effective treatments for IBS, although there are limitations in the quality of the evidence, and treatment effects may be overestimated as a result.
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Affiliation(s)
- Alexander C Ford
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, UK
- Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK
| | - Brian E Lacy
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA
| | - Lucinda A Harris
- Division of Gastroenterology and Hepatology, Mayo School of Medicine, Scottsdale, AZ, USA
| | - Eamonn M M Quigley
- Division of Gastroenterology and Hepatology, Lynda K and David M Underwood Center for Digestive Disorders, Houston Methodist Hospital and Weill Cornell Medical College, Houston, TX, USA
| | - Paul Moayyedi
- Gastroenterology Division, McMaster University, Health Sciences Center, Hamilton, ON, Canada
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24
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Rawla P, Sunkara T, Raj JP. Updated review of current pharmacological and non-pharmacological management of irritable bowel syndrome. Life Sci 2018; 212:176-181. [DOI: 10.1016/j.lfs.2018.10.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 09/27/2018] [Accepted: 10/01/2018] [Indexed: 02/07/2023]
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Ford AC, Moayyedi P, Chey WD, Harris LA, Lacy BE, Saito YA, Quigley EMM. American College of Gastroenterology Monograph on Management of Irritable Bowel Syndrome. Am J Gastroenterol 2018; 113:1-18. [PMID: 29950604 DOI: 10.1038/s41395-018-0084-x] [Citation(s) in RCA: 241] [Impact Index Per Article: 34.4] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Alexander C Ford
- Leeds Institute of Biomedical and Clinical Sciences, University of Leeds and Leeds Gastroenterology Institute, Leeds Teaching Hospitals Trust, Leeds, UK
| | - Paul Moayyedi
- Division of Gastroenterology, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - William D Chey
- Division of Gastroenterology, Department of Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
| | | | | | | | - Eamonn M M Quigley
- Division of Gastroenterology and Hepatology, Houston Methodist Hospital and Weill Cornell Medical College, Houston, TX, USA.
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26
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Drossman DA, Tack J, Ford AC, Szigethy E, Törnblom H, Van Oudenhove L. Neuromodulators for Functional Gastrointestinal Disorders (Disorders of Gut-Brain Interaction): A Rome Foundation Working Team Report. Gastroenterology 2018; 154:1140-1171.e1. [PMID: 29274869 DOI: 10.1053/j.gastro.2017.11.279] [Citation(s) in RCA: 259] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 11/13/2017] [Accepted: 11/24/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Central neuromodulators (antidepressants, antipsychotics, and other central nervous system-targeted medications) are increasingly used for treatment of functional gastrointestinal disorders (FGIDs), now recognized as disorders of gut-brain interaction. However, the available evidence and guidance for the use of central neuromodulators in these conditions is scanty and incomplete. In this Rome Foundation Working Team report, a multidisciplinary team summarized available research evidence and clinical experience to provide guidance and treatment recommendations. METHODS The working team summarized the literature on the pharmacology of central neuromodulators and their effects on gastrointestinal sensorimotor function and conducted an evidence-based review on their use for treating FGID syndromes. Because of the paucity of data for FGIDs, we included data for non-gastrointestinal painful disorders and specific symptoms of pain, nausea, and vomiting. This information was combined into a final document comprising a synthesis of available evidence and recommendations for clinical use guided by the research and clinical experience of the experts on the committee. RESULTS The evidence-based review on neuromodulators in FGID, restricted by the limited available controlled trials, was integrated with open-label studies and case series, along with the experience of experts to create recommendations using a consensus (Delphi) approach. Due to the diversity of conditions and complexity of treatment options, specific recommendations were generated for different FGIDs. However, some general recommendations include: (1) low to modest dosages of tricyclic antidepressants provide the most convincing evidence of benefit for treating chronic gastrointestinal pain and painful FGIDs and serotonin noradrenergic reuptake inhibitors can also be recommended, though further studies are needed; (2) augmentation, that is, adding a second treatment (adding quetiapine, aripiprazole, buspirone α2δ ligand agents) is recommended when a single medication is unsuccessful or produces side effects at higher dosages; (3) treatment should be continued for 6-12 months to potentially prevent relapse; and (4) implementation of successful treatment requires effective communication skills to improve patient acceptance and adherence, and to optimize the patient-provider relationship. CONCLUSIONS Based on systematic and selectively focused review and the consensus of a multidisciplinary panel, we have provided summary information and guidelines for the use of central neuromodulators in the treatment of chronic gastrointestinal symptoms and FGIDs. Further studies are needed to confirm and refine these recommendations.
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Affiliation(s)
- Douglas A Drossman
- Center for Functional Gastrointestinal and Motility Disorders, University of North Carolina, Chapel Hill, North Carolina; Center for Education and Practice of Biopsychosocial Care and Drossman Gastroenterology, Chapel Hill, North Carolina.
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - Alexander C Ford
- Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, United Kingdom; Leeds Gastroenterology Institute, St James's University Hospital, Leeds, United Kingdom
| | - Eva Szigethy
- Departments of Psychiatry and Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Hans Törnblom
- Departments of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Lukas Van Oudenhove
- Laboratory for Brain-Gut Axis Studies, Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
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27
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Radovanovic-Dinic B, Tesic-Rajkovic S, Grgov S, Petrovic G, Zivkovic V. Irritable bowel syndrome - from etiopathogenesis to therapy. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2018; 162:1-9. [PMID: 29358788 DOI: 10.5507/bp.2017.057] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 12/12/2017] [Indexed: 12/15/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a chronic and relapsing functional gastrointestinal disorder that affects 9-23% of the population across the world. Patients with IBS are often referred to gastroenterology, undergo various investigations, take various medicines, take time off work and have a poor quality of life. The pathophysiology of IBS is not yet completely understood and seems to be multifactorial. Many pathogenetic factors, in various combinations, and not all necessarily present in each patient, can play an important role. Discomfort or abdominal pain relieived by defacation, asociated with a change in stool form, is a typical clinical manifestation of IBS. Many factors, such as emotional stress and eating, may exacerbate the symptoms. A timely diagnosis of IBS is important so that treatment which will provide adequate symptomatic relief (diarrhoea, constipation, pain and boaring) can be introduced. The diagnosis of IBS is not confirmed by a specific test or structural abnormality. It is made using criteria based on clinical symptoms such as Rome criteria, unless the symptoms are thought to be atypical. Today the Rome Criteria IV is the current gold-standard for the diagnoses of IBS. Treatment of patients with IBS requires a multidisciplinary approach. Some patients respond well to non-pharmacological treatment, while others also require pharmacological treatment. This review will provide a summary of pathophysiology, diagnostic criteria and therapies for IBS.
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Affiliation(s)
- Biljana Radovanovic-Dinic
- Clinic for Gastroenterology and Hepatology, Clinical Centre Nis, Serbia.,Faculty of Medicine, University of Nis, Serbia
| | | | | | - Gordana Petrovic
- Clinic for Gastroenterology and Hepatology, Clinical Centre Nis, Serbia
| | - Valentina Zivkovic
- Faculty of Medicine, University of Nis, Serbia.,Institute for Treatment and Rehabilitation, Niska Banja, Serbia
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Kułak-Bejda A, Bejda G, Waszkiewicz N. Antidepressants for irritable bowel syndrome-A systematic review. Pharmacol Rep 2017; 69:1366-1379. [PMID: 29132094 DOI: 10.1016/j.pharep.2017.05.014] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 05/21/2017] [Accepted: 05/26/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND According to the multifactorial etiology of Irritable bowel syndrome (IBS), psychological factors play an important role. It is possible that antidepressant therapy may be more effective for patients with IBS. The aim of this study was a systematic review of the best available antidepressant therapies for IBS. METHODS The databases Medline, PubMed, EMBASE, and the Cochrane Controlled Trials Register for randomized controlled trials were searched for studies published before September 2016. Meta-analyses, randomized controlled trials, controlled trials, uncontrolled trials, cohort studies, and open-label studies were analyzed. RESULTS Of 513 articles, 29 fulfilled the inclusion criteria: 6 meta-analyses, 18 randomized controlled trials, and 5 studies without randomization. In these studies, the efficacy of tricyclics, selective serotonin reuptake inhibitors or serotonin-noradrenaline reuptake inhibitors, were analyzed in IBS. Different interventions were used, though in most studies their effect on global symptom relief in IBS as a primary outcome was investigated. Generally, patients' tolerance of the therapies was good. Only severe adverse events were observed as a result of the nature of the drug. CONCLUSIONS Generally, antidepressants improved IBS symptoms. In comparison with placebo, tricyclic therapy for IBS was more effective than selective serotonin reuptake inhibitors. Antidepressants might be an alternative therapy for patients suffering from IBS, especially diarrhea-predominant IBS.
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Affiliation(s)
| | - Grzegorz Bejda
- Medical University of Białystok, Department of Integrated Medical Care, Białystok, Poland
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Abstract
BACKGROUND The use of psychotropic medications, particularly antidepressants, is common in patients with inflammatory bowel disease (IBD) in spite of a lack of their robust efficacy in this population. This review provides an overview of the use trends of different classes of antidepressant and anti-anxiety medication and their effects on mood, nervous system function, gastrointestinal physiology and immunity drawing from the literature available in the general population, other medical conditions, and when available, patients with IBD. It also covers the evidence base for the actions, efficacy, and potential complications of antidepressants organized by different classes. METHODS We conducted a PubMed search of articles relating the different drug classes probed to the terms above in different populations of interest. All types of articles were accepted including case reports and series, open and randomized trials, reviews, and expert opinion. We also examined the reference lists of the publications found. RESULTS Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) are the most commonly prescribed agents for anxiety and depression in patients with IBD, though their efficacy for these conditions in the general population are mild to moderate at best. SSRIs are generally well tolerated, though at higher doses, they, like most antidepressant classes, can be associated with activation, serotonergic syndrome, and increased suicidal ideation. TCAs have many more serious side effects but have some shown efficacy for functional GI symptoms. A newer class, the serotonin noradrenergic reuptake inhibitors (SNRIs), can be effective for refractory depression, anxiety and chronic pain syndromes with a side effect profile similar to both SSRIs and more mild manifestations of TCAs. Mirtazapine has moderate efficacy for depression if sedation and weight gain side effects are tolerated and some small support for use in nausea and vomiting. Bupropion targets dopamine and noradrenaline reuptake and has moderate efficacy for depression, and some small support for use in fatigue and smoking cessation. Buspirone has an indication for generalized anxiety disorder though studies show only a minimal benefit. It has some growing evidence for use in functional dyspepsia. Most of these agents have physiological effects on the brain, immune system, and gastrointestinal tract (with the exception of bupropion) hence their therapeutic and side effects manifested in these systems. CONCLUSION Antidepressant medications are frequently prescribed for depression, anxiety disorders, and chronic pain syndromes, but overall support for their efficacy is modest at best. Psychological interventions have growing support for having much more robust effects without the side effects of antidepressants and should be considered first-line treatment or at least an adjunct to psychotropic medications for these conditions.
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Abstract
Accurately measuring the complex motor behaviors of the gastrointestinal tract has tremendous value for the understanding, diagnosis and treatment of digestive diseases. This review synthesizes the literature regarding current tests that are used in both humans and animals. There remains further opportunity to enhance such tests, especially when such tests are able to provide value in both the preclinical and the clinical settings.
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Key Words
- acute pancreatitis
- biliary pancreatitis
- necroptosis
- apoptosis
- pancreatic cell death
- ac, ascending colon
- cf6, filling the colon at 6 hours
- ct, computed tomography
- gebt, gastric emptying breath test
- hdam, high-definition anorectal pressure manometry/topography
- hram, high-resolution anorectal manometry
- ht, hydroxytryptophan
- iqr, interquartile range
- mmc, migrating motor complex
- mri, magnetic resonance imaging
- 99mtc, technetium-99m
- spect, single-photon emission computed tomography
- 13c, carbon-13
- 3-d, 3-dimensional
- wmc, wireless motility capsule
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Chronic Pain Syndromes, Mechanisms, and Current Treatments. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2015; 131:565-611. [DOI: 10.1016/bs.pmbts.2015.01.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Saha L. Irritable bowel syndrome: pathogenesis, diagnosis, treatment, and evidence-based medicine. World J Gastroenterol 2014; 20:6759-6773. [PMID: 24944467 PMCID: PMC4051916 DOI: 10.3748/wjg.v20.i22.6759] [Citation(s) in RCA: 286] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2013] [Revised: 12/26/2013] [Accepted: 02/17/2014] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a chronic and debilitating functional gastrointestinal disorder that affects 9%-23% of the population across the world. The percentage of patients seeking health care related to IBS approaches 12% in primary care practices and is by far the largest subgroup seen in gastroenterology clinics. It has been well documented that these patients exhibit a poorer quality of life and utilize the health care system to a greater degree than patients without this diagnosis. The pathophysiology of IBS is not clear. Many theories have been put forward, but the exact cause of IBS is still uncertain. According to the updated ROME III criteria, IBS is a clinical diagnosis and presents as one of the three predominant subtypes: (1) IBS with constipation (IBS-C); (2) IBS with diarrhea (IBS-D); and (3) mixed IBS (IBS-M); former ROME definitions refer to IBS-M as alternating IBS (IBS-A). Across the IBS subtypes, the presentation of symptoms may vary among patients and change over time. Patients report the most distressing symptoms to be abdominal pain, straining, myalgias, urgency, bloating and feelings of serious illness. The complexity and diversity of IBS presentation makes treatment difficult. Although there are reviews and guidelines for treating IBS, they focus on the efficacy of medications for IBS symptoms using high-priority endpoints, leaving those of lower priority largely unreported. Therefore, the aim of this review is to provide a comprehensive evidence-based review of the diagnosis, pathogenesis and treatment to guide clinicians diagnosing and treating their patients.
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Abstract
The understanding of irritable bowel syndrome (IBS) has undergone a rapid evolution with scientific advancement. IBS is a common functional bowel disorder that generates a significant health care burden and is the most commonly diagnosed gastrointestinal condition. There are well-established diagnostic criteria and algorithms for the initial evaluation of patients presenting with the symptoms of IBS. The symptoms can be targeted for therapy with a variety of pharmaceutical and nonpharmaceutical agents. Therapy should be individualized for the patient, and the cornerstone for any effective treatment strategy should be the solid patient-physician relationship.
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Affiliation(s)
- Kaitlin Occhipinti
- Department of Gastroenterology, Ochsner Clinic Foundation, New Orleans, Louisiana
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Mozaffari S, Esmaily H, Rahimi R, Baeeri M, Sanei Y, Asadi-Shahmirzadi A, Salehi-Surmaghi MH, Abdollahi M. Effects of Hypericum perforatum extract on rat irritable bowel syndrome. Pharmacogn Mag 2012. [PMID: 21969792 DOI: 10.4103/0973-1296] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
CONTEXT In irritable bowel syndrome (IBS), disturbance of bowel motility is associated with infiltration of inflammatory mediators and cytokines into the intestine, such as neutrophils, myeloperoxidase (MPO), tumor necrosis factor alfa (TNF-α), and lipid peroxide. AIMS Regarding promising anti-inflammatory and anti-oxidative effects of Hypericum perforatum (HP) extract, besides its anti-depressant effect, this study was designed to evaluate the effects of HP in an experimental model of IBS. SETTINGS AND DESIGN IBS was induced by a 5-day restraint stress in rats. The HP extract was administered by gavage in doses of 150, 300, and 450 mg/kg for 26 days. Fluoxetine and loperamide were used as positive controls. Gastric emptying and small bowel and colon transit, besides the levels of TNF-α, MPO, lipid peroxidation, and antioxidant power, were determined in colon homogenates. STATISTICAL ANALYSIS USED Data were analyzed by one-way ANOVA followed by Tukey's post hoc test for multiple comparisons. RESULTS A significant reduction in small bowel and colonic transit (450 mg/kg), TNF-α, MPO, and lipid peroxidation and an increase in antioxidant power in all HP-treated groups (150, 300, and 450 mg/kg) were seen as compared with the control group. Gastric emptying did not alter significantly when compared with the control group. Treatment with loperamide (10 mg/kg) significantly inhibited gastric emptying and small bowel and colonic transit, while flouxetine (10 mg/kg) decreased gastric emptying, TNF-α, MPO, and lipid peroxidation and increased the antioxidant power of the samples in comparison with the control group. CONCLUSIONS HP diminished the recruitment of inflammatory cells and TNF-α following restraint stress not in a dose-dependent manner, possibly via inhibition of MPO activity and increasing colon antioxidant power, without any difference with fluoxetine. The HP extract inhibits small bowel and colonic transit acceleration like loperamide but has minimal effect on gastric emptying.
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Affiliation(s)
- Shilan Mozaffari
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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Abstract
Transit assessment of the small intestine and colon is relevant in the study of physiology, pathophysiology, and pharmacodynamics, and there is increasing use of small-bowel and colonic transit measurements in clinical practice as well. The main methods that are applied in clinical practice are substrate-hydrogen breath tests for small-bowel transit and radiopaque markers for colonic transit. Over the past 2-3 decades, scintigraphy has become the preferred standard in research studies, particularly for studies of pathophysiology and pharmacodynamics. New approaches include experimental stable isotope measurement of orocecal transit and the recently approved method using a wireless motility capsule that is validated as an accurate measurement of small-bowel and colonic transit.
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Affiliation(s)
- Lawrence A Szarka
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA
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Sinagra E, Romano C, Cottone M. Psychopharmacological treatment and psychological interventions in irritable bowel syndrome. Gastroenterol Res Pract 2012; 2012:486067. [PMID: 22956940 PMCID: PMC3432371 DOI: 10.1155/2012/486067] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2012] [Revised: 05/28/2012] [Accepted: 07/04/2012] [Indexed: 12/11/2022] Open
Abstract
Irritable bowel syndrome (IBS) accounts for 25% of gastroenterology output practice, making it one of the most common disorders in this practice. Psychological and social factors may affect the development of this chronic disorder. Furthermore, psychiatric symptoms and psychiatric diseases are highly prevalent in this condition, but the approach to treating these is not always straightforward. As emphasized in the biopsychosocial model of IBS, with regard to the modulatory role of stress-related brain-gut interactions and association of the disease with psychological factors and emotional state, it proves useful to encourage psychopharmacological treatments and psychosocial therapies, both aiming at reducing stress perception. The aim of this paper is to analyze the effectiveness of psychopharmacological treatment and psychological interventions on irritable bowel syndrome.
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Affiliation(s)
- Emanuele Sinagra
- Division of Internal Medicine “Villa Sofia-V. Cervello” Hospital, University of Palermo, Via Trabucco 180, 90146 Palermo, Italy
| | - Claudia Romano
- Division of Internal Medicine “Villa Sofia-V. Cervello” Hospital, University of Palermo, Via Trabucco 180, 90146 Palermo, Italy
| | - Mario Cottone
- Division of Internal Medicine “Villa Sofia-V. Cervello” Hospital, University of Palermo, Via Trabucco 180, 90146 Palermo, Italy
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Ruepert L, Quartero AO, de Wit NJ, van der Heijden GJ, Rubin G, Muris JWM. Bulking agents, antispasmodics and antidepressants for the treatment of irritable bowel syndrome. Cochrane Database Syst Rev 2011; 2011:CD003460. [PMID: 21833945 PMCID: PMC8745618 DOI: 10.1002/14651858.cd003460.pub3] [Citation(s) in RCA: 166] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is a common chronic gastrointestinal disorder. The role of pharmacotherapy for IBS is limited and focused mainly on symptom control. OBJECTIVES The objective of this systematic review was to evaluate the efficacy of bulking agents, antispasmodics and antidepressants for the treatment of irritable bowel syndrome. SEARCH STRATEGY Computer assisted structured searches of MEDLINE, EMBASE, The Cochrane library, CINAHL and PsychInfo were conducted for the years 1966-2009. An updated search in April 2011 identified 10 studies which will be considered for inclusion in a future update of this review. SELECTION CRITERIA Randomized controlled trials comparing bulking agents, antispasmodics or antidepressants with a placebo treatment in patients with irritable bowel syndrome aged over 12 years were considered for inclusion. Only studies published as full papers were included. Studies were not excluded on the basis of language. The primary outcome had to include improvement of abdominal pain, global assessment or symptom score. DATA COLLECTION AND ANALYSIS Two authors independently extracted data from the selected studies. Risk Ratios (RR) and Standardized Mean Differences (SMD) with 95% confidence intervals (CI) were calculated. A proof of practice analysis was conducted including sub-group analyses for different types of bulking agents, spasmolytic agents or antidepressant medication. This was followed by a proof of principle analysis where only the studies with adequate allocation concealment were included. MAIN RESULTS A total of 56 studies (3725 patients) were included in this review. These included 12 studies of bulking agents (621 patients), 29 of antispasmodics (2333 patients), and 15 of antidepressants (922 patients). The risk of bias was low for most items. However, selection bias is unclear for many of the included studies because the methods used for randomization and allocation concealment were not described. No beneficial effect for bulking agents over placebo was found for improvement of abdominal pain (4 studies; 186 patients; SMD 0.03; 95% CI -0.34 to 0.40; P = 0.87), global assessment (11 studies; 565 patients; RR 1.10; 95% CI 0.91 to 1.33; P = 0.32) or symptom score (3 studies; 126 patients SMD -0.00; 95% CI -0.43 to 0.43; P = 1.00). Subgroup analyses for insoluble and soluble fibres also showed no statistically significant benefit. Separate analysis of the studies with adequate concealment of allocation did not change these results. There was a beneficial effect for antispasmodics over placebo for improvement of abdominal pain (58% of antispasmodic patients improved compared to 46% of placebo; 13 studies; 1392 patients; RR 1.32; 95% CI 1.12 to 1.55; P < 0.001; NNT = 7), global assessment (57% of antispasmodic patients improved compared to 39% of placebo; 22 studies; 1983 patients; RR 1.49; 95% CI 1.25 to 1.77; P < 0.0001; NNT = 5) and symptom score (37% of antispasmodic patients improved compared to 22% of placebo; 4 studies; 586 patients; RR 1.86; 95% CI 1.26 to 2.76; P < 0.01; NNT = 3). Subgroup analyses for different types of antispasmodics found statistically significant benefits for cimteropium/ dicyclomine, peppermint oil, pinaverium and trimebutine. Separate analysis of the studies with adequate allocation concealment found a significant benefit for improvement of abdominal pain. There was a beneficial effect for antidepressants over placebo for improvement of abdominal pain (54% of antidepressants patients improved compared to 37% of placebo; 8 studies; 517 patients; RR 1.49; 95% CI 1.05 to 2.12; P = 0.03; NNT = 5), global assessment (59% of antidepressants patients improved compared to 39% of placebo; 11 studies; 750 patients; RR 1.57; 95% CI 1.23 to 2.00; P < 0.001; NNT = 4) and symptom score (53% of antidepressants patients improved compared to 26% of placebo; 3 studies; 159 patients; RR 1.99; 95% CI 1.32 to 2.99; P = 0.001; NNT = 4). Subgroup analyses showed a statistically significant benefit for selective serotonin releasing inhibitors (SSRIs) for improvement of global assessment and for tricyclic antidepressants (TCAs) for improvement of abdominal pain and symptom score. Separate analysis of studies with adequate allocation concealment found a significant benefit for improvement of symptom score and global assessment. Adverse events were not assessed as an outcome in this review. AUTHORS' CONCLUSIONS There is no evidence that bulking agents are effective for treating IBS. There is evidence that antispasmodics are effective for the treatment of IBS. The individual subgroups which are effective include: cimetropium/dicyclomine, peppermint oil, pinaverium and trimebutine. There is good evidence that antidepressants are effective for the treatment of IBS. The subgroup analyses for SSRIs and TCAs are unequivocal and their effectiveness may depend on the individual patient. Future research should use rigorous methodology and valid outcome measures.
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Affiliation(s)
- Lisa Ruepert
- University Medical Center UtrechtP.O. Box 850603508 AB UtrechtNetherlands
| | - A Otto Quartero
- Huisartspraktijk DiepenveenDorpsstraat 16DiepenveenNetherlands7431 CK
| | - Niek J de Wit
- University Medical Center UtrechtJulius Center for Health Sciences and Primary CarePO Box 85500UtrechtNetherlands3508 GA
| | - Geert J van der Heijden
- University Medical Center UtrechtDepartment of Otorhinolaryngology & Julius Center for Health Sciences and Primary CarePO Box 85500Internal postal address STR 6.131UtrechtNetherlands3508 GA
| | - Gregory Rubin
- Durham UniversitySchool of Medicine and Health, Wolfson Research InstituteQueen's Campus, University BoulevardStockton on TeesUKTS17 6BH
| | - Jean WM Muris
- Maastricht UniversityDepartment of General PracticeMaastricht University Medical Centre, Care and Public Health Research Institute (CAPHRI)PO Box 616MaastrichtNetherlands6200 MD
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Foisy M, Ali S, Geist R, Weinstein M, Michail S, Thakkar K. The Cochrane Library and the Treatment of Chronic Abdominal Pain in Children and Adolescents: An Overview of Reviews. ACTA ACUST UNITED AC 2011. [DOI: 10.1002/ebch.818] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Mozaffari S, Esmaily H, Rahimi R, Baeeri M, Sanei Y, Asadi-Shahmirzadi A, Salehi-Surmaghi MH, Abdollahi M. Effects of Hypericum perforatum extract on rat irritable bowel syndrome. Pharmacogn Mag 2011; 7:213-23. [PMID: 21969792 PMCID: PMC3173896 DOI: 10.4103/0973-1296.84235] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2010] [Revised: 03/16/2011] [Accepted: 08/25/2011] [Indexed: 12/13/2022] Open
Abstract
CONTEXT In irritable bowel syndrome (IBS), disturbance of bowel motility is associated with infiltration of inflammatory mediators and cytokines into the intestine, such as neutrophils, myeloperoxidase (MPO), tumor necrosis factor alfa (TNF-α), and lipid peroxide. AIMS Regarding promising anti-inflammatory and anti-oxidative effects of Hypericum perforatum (HP) extract, besides its anti-depressant effect, this study was designed to evaluate the effects of HP in an experimental model of IBS. SETTINGS AND DESIGN IBS was induced by a 5-day restraint stress in rats. The HP extract was administered by gavage in doses of 150, 300, and 450 mg/kg for 26 days. Fluoxetine and loperamide were used as positive controls. Gastric emptying and small bowel and colon transit, besides the levels of TNF-α, MPO, lipid peroxidation, and antioxidant power, were determined in colon homogenates. STATISTICAL ANALYSIS USED Data were analyzed by one-way ANOVA followed by Tukey's post hoc test for multiple comparisons. RESULTS A significant reduction in small bowel and colonic transit (450 mg/kg), TNF-α, MPO, and lipid peroxidation and an increase in antioxidant power in all HP-treated groups (150, 300, and 450 mg/kg) were seen as compared with the control group. Gastric emptying did not alter significantly when compared with the control group. Treatment with loperamide (10 mg/kg) significantly inhibited gastric emptying and small bowel and colonic transit, while flouxetine (10 mg/kg) decreased gastric emptying, TNF-α, MPO, and lipid peroxidation and increased the antioxidant power of the samples in comparison with the control group. CONCLUSIONS HP diminished the recruitment of inflammatory cells and TNF-α following restraint stress not in a dose-dependent manner, possibly via inhibition of MPO activity and increasing colon antioxidant power, without any difference with fluoxetine. The HP extract inhibits small bowel and colonic transit acceleration like loperamide but has minimal effect on gastric emptying.
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Affiliation(s)
- Shilan Mozaffari
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hadi Esmaily
- Department of Clinical Pharmacy, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Roja Rahimi
- Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Baeeri
- Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Yara Sanei
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Azar Asadi-Shahmirzadi
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad-Hossein Salehi-Surmaghi
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Abdollahi
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
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Evolution of clinical trials for irritable bowel syndrome: issues in end points and study design. Am J Gastroenterol 2010; 105:731-5. [PMID: 20372121 DOI: 10.1038/ajg.2010.12] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Irritable bowel syndrome (IBS) involves a broad range of physiological and psychological alterations that may affect brain-gut dysregulation, gut function, visceral perception, and mucosal integrity and function. Despite advances in our understanding of basic neuroenteric mechanisms and the role of effectors and transmitters in the brain-gut axis, a reliable biologic marker of IBS has yet to be identified. IBS diagnosis and status depend entirely on an assessment of IBS signs and symptoms. This has made development of optimal end points and study design for evaluation of efficacy of IBS drugs a challenge. This article addresses three main topics: the evolution of primary end points for IBS clinical trials; a potential path forward for IBS end points in new clinical trials; and recommendations for the future development of patient-reported outcome (PRO) instruments for use in IBS clinical trials.
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Marciani L, Cox EF, Hoad CL, Pritchard S, Totman JJ, Foley S, Mistry A, Evans S, Gowland PA, Spiller RC. Postprandial changes in small bowel water content in healthy subjects and patients with irritable bowel syndrome. Gastroenterology 2010; 138:469-77, 477.e1. [PMID: 19909743 DOI: 10.1053/j.gastro.2009.10.055] [Citation(s) in RCA: 155] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2009] [Revised: 10/14/2009] [Accepted: 10/21/2009] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Postprandial symptoms are common in patients with irritable bowel syndrome with diarrhea (IBS-D) and could be diet related. We studied postprandial changes in distribution of water in the upper gastrointestinal tract of healthy volunteers (HVs) and patients with IBS-D after contrasting meals. METHODS In study 1, 11 HVs consumed 350-mL test meals with 5% mannitol (unabsorbable) or 5% glucose (readily absorbed). In study 2, 17 HVs consumed a 331-kcal meal, with or without 15 g bran. In study 3, 26 patients with IBS-D consumed the study 2 diet with bran meal. All subjects underwent serial magnetic resonance imaging analysis. RESULTS In study 1, subjects' small bowel water content (SBWC) increased after the mannitol but not glucose meals, reaching 381 mL (interquartile range, 343-491 mL) and 47 mL (18-78 mL), respectively, 40 minutes after eating (P < .001). In study 2, SBWC initially decreased after both meal types and then increased, plateauing at 180-405 minutes and was greater after the bran meal (P = .02). In study 3, fasting and postprandial SBWC was lower in IBS-D than in HVs (P < .05 and P < .0001, respectively). Patients with IBS-D had faster orocecal transit times (135 minutes; 90-180 minutes) compared with HVs (225 minutes; 203-293 minutes; P < .0001) and reduced terminal ileum diameter (P < .003). CONCLUSIONS Postprandial SBWC initially decreases, because of rapid, nutrient-driven fluid absorption, and then increases after a mixed liquid/solid meal. Patients with IBS-D have reduced fasting and postprandial SBWC with faster transit, possibly indicating increased small intestinal tone.
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Affiliation(s)
- Luca Marciani
- Nottingham Digestive Diseases Centre NIHR Biomedical Research Unit, Queen's Medical Centre Campus, Nottingham University Hospitals NHS Trust, University of Nottingham, Nottingham, United Kingdom
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Bechmann LP, Best J, Haag S, Leineweber K, Gerken G, Holtmann G. Serotoninergic and non-serotoninergic effects of two tricyclic antidepressants on visceral nociception in a rat model. Scand J Gastroenterol 2009; 44:680-6. [PMID: 19396660 DOI: 10.1080/00365520902767272] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Tricyclic antidepressants (TCAs) are well established in the treatment of patients with irritable bowel syndrome (IBS). The effects are believed to be linked to serotoninergic antinociceptive properties, but data on the antinociceptive effects of various TCAs with variable serotoninergic and non-serotoninergic properties have not been investigated. The aim of this study was to compare the antinociceptive effects of different TCAs. MATERIAL AND METHODS Colorectal distension (CRD) using a barostat device was carried out in rats and the visceromotor response (VMR) to CRD was quantified by abdominal wall electromyography. Prior to CRD, saline (control), amitriptyline (AM), desipramine (DES), reserpine (RES) or a combination of TCAs and RES (AM + RES or DES + RES) was applied intraperitoneally. Serum 5-HT levels were determined using high-performance liquid chromatography (HPLC). RES was used to antagonize the serotoninergic actions of TCAs in order to discriminate between these effects and others. RESULTS Both TCAs decreased the VMR compared to placebo. After RES application without TCAs, the VMR was increased compared to controls (6403 microV+/-1772 microV). Co-administration of AM and RES resulted in a modest decrease in VMR (5774 microV+/-1953 microV), while in rats treated with RES and DES the VMR again was significantly lower (3446 microV (+/-1347 microV; p <0.05)). 5-HT levels were higher in TCA pretreated rats than those in controls and significantly lower 5-HT levels were found in all rats pretreated with RES. CONCLUSIONS AM and DES have antinociceptive properties while RES is pro-nociceptive. The antinociceptive effects of DES are not abolished by RES pretreatment, while AM only attenuates the pro-nociceptive effects of RES. The non-serotoninergic properties of TCAs substantially contribute to the differences in the antinococeptive effects of various TCAs.
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Affiliation(s)
- Lars P Bechmann
- Department of Gastroenterology, University of Essen, Germany
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Abdul-Baki H, El Hajj II, ElZahabi L, Azar C, Aoun E, Skoury A, Chaar H, Sharara AI. A randomized controlled trial of imipramine in patients with irritable bowel syndrome. World J Gastroenterol 2009; 15:3636-3642. [PMID: 19653341 PMCID: PMC2721237 DOI: 10.3748/wjg.15.3636] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2009] [Revised: 06/18/2009] [Accepted: 06/25/2009] [Indexed: 02/06/2023] Open
Abstract
AIM To study the efficacy of low-dose imipramine in relieving symptoms associated with the irritable bowel syndrome (IBS). METHODS A randomized, double-blind trial of 25 mg imipramine vs matched placebo for 12 wk was performed. Doubling the dose was allowed once at week 2 in case of an unsatisfactory early response. Primary efficacy variables were subjective global symptom relief and quality of life (QoL) using SF-36 at week 12. RESULTS One hundred and seven patients were enrolled by advertisement or referral by general practitioners and 56 (31 imipramine: 25 placebo) completed the 16-wk study. Baseline characteristics were comparable. A high overall dropout rate was noted in the imipramine and placebo arms (47.5% vs 47.9%, P > 0.05), a mean of 25.0 and 37.4 d from enrollment, respectively (P < 0.05). At the end of 12 wk, there was a significant difference in global symptom relief with imipramine over placebo (per-protocol: 80.6% vs 48.0%, P = 0.01) and a trend on intent-to-treat (ITT) analysis (42.4% vs 25.0%, P = 0.06). This improvement was evident early and persisted to week 16 (P = 0.024 and 0.053 by per-protocol and ITT analyses, respectively). Mean cumulative and component-specific SF-36 scores improved in the imipramine group only (per-protocol, P < 0.01). Drug-related adverse events leading to patient dropout were more common in the imipramine group (25.4% vs 12.5%, P > 0.05). CONCLUSION Imipramine may be effective in the treatment of IBS patients and is associated with improved QoL. Careful patient selection, initiation of a low dose with gradual escalation and monitoring for side effects may result in an improved therapeutic response.
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Camilleri M, Chang L. Challenges to the therapeutic pipeline for irritable bowel syndrome: end points and regulatory hurdles. Gastroenterology 2008; 135:1877-91. [PMID: 18848833 PMCID: PMC2671226 DOI: 10.1053/j.gastro.2008.09.005] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2008] [Revised: 08/26/2008] [Accepted: 09/04/2008] [Indexed: 12/14/2022]
Abstract
Recent advances in our understanding of basic neuroenteric mechanisms and the role of effectors and transmitters in the brain-gut axis have provided opportunities to develop new therapeutic agents for irritable bowel syndrome (IBS). Furthermore, human pharmacodynamic studies utilizing transit, colonic, or rectal sensitivity and brain imaging have been useful in determining therapeutic efficacy (particularly for drugs that act on motor function). This review provides an overview of medications that have not yet been approved for treatment of patients with IBS yet have shown promise in phase IIB trials. These include drugs that act on the serotonin receptor and transporter system: antidepressants, norepinephrine reuptake inhibitors, opioids, cholecystokinin antagonists, neurokinin-antagonists, chloride channel activators, guanylate cyclase C agonists, atypical benzodiazepines, probiotics, and antibiotics. The changing landscape in the regulatory approval process has impacted the development of IBS drugs. Guidance documents from regulatory agencies in Europe and the United States have focused on patients' reported outcomes and associated quality of life. After a decade of experience with different end points that have generated some data on psychometric validation and unprecedented information about responsiveness of the binary or global end points to drug therapy, it is necessary to pursue further validation studies before or during pivotal phase IIB or III trials. The hope of providing relief to patients should galvanize all parties to achieve these goals.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
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Choung RS, Cremonini F, Thapa P, Zinsmeister AR, Talley NJ. The effect of short-term, low-dose tricyclic and tetracyclic antidepressant treatment on satiation, postnutrient load gastrointestinal symptoms and gastric emptying: a double-blind, randomized, placebo-controlled trial. Neurogastroenterol Motil 2008; 20:220-7. [PMID: 18031471 DOI: 10.1111/j.1365-2982.2007.01029.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Antidepressants are commonly prescribed for patients with functional dyspepsia. However, the effect of tricyclic antidepressants on satiation and gastric emptying remains unclear, and there are no data for tetracyclic compounds. To compare the effects of nortriptyline (maximum dose: 50 mg daily) and mirtazapine (30 mg daily) vs placebo on gastric emptying, gastric satiation and postprandial symptoms after a nutrient load in healthy volunteers. Randomized, double-blind, placebo-controlled study evaluated gastric function before and after 14 days of nortriptyline (n = 13), mirtazapine (n = 13), or placebo (n = 14) in healthy volunteers. Validated methods were used to study gastric emptying ((13)C-octanoate) and satiation postnutrient drink test. The three arms were comparable with regard to age, gender, body mass index and hospital anxiety/depression scale. There were no statistically significant effects of mirtazapine or nortriptyline on gastric emptying compared to placebo (P = 0.34). Maximum tolerated volume was similar on drug and placebo (P = 0.56). Aggregate symptom score 30 min postmaximum tolerated volume after nutrient drink challenge on placebo was 132 (+/-21), vs 165 (+/-21) on mirtazapine, and 126 (+/-21) on nortriptyline 50 mg respectively (P = 0.28). Tricyclic and tetracyclic antidepressant agents do not appear to have significant effects on gastric motor or satiation postnutrient challenge in healthy individuals at the doses tested.
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Affiliation(s)
- R S Choung
- Mayo Clinic Division of Gastroenterology and Hepatology, and Clinical Enteric Neuroscience, Translational & Epidemiological Research Program (CENTER), Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN, USA
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Abstract
Based on a systematic PubMed search, this short review addresses why intestinal permeability may be important in the pathobiology of irritable bowel syndrome (IBS), the evidence of abnormal permeability in patients with IBS, and the pros and cons of the different probe molecules available to assess intestinal permeability. While a subgroup of patients with IBS appears to have evidence of increased intestinal permeability, improvements in the methods and validation are key to further research in this field in order to better understand intestinal barrier functions in IBS.
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Affiliation(s)
- M Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research Group, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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Braun T, Voland P, Kunz L, Prinz C, Gratzl M. Enterochromaffin cells of the human gut: sensors for spices and odorants. Gastroenterology 2007; 132:1890-901. [PMID: 17484882 DOI: 10.1053/j.gastro.2007.02.036] [Citation(s) in RCA: 186] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2006] [Accepted: 01/30/2007] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Release of serotonin from mucosal enterochromaffin cells triggered by luminal substances is the key event in the regulation of gut motility and secretion. We were interested to know whether nasal olfactory receptors are also expressed in the human gut mucosa by enterochromaffin cells and whether their ligands and odorants present in spices, fragrances, detergents, and cosmetics cause serotonin release. METHODS Receptor expression was studied by the reverse-transcription polymerase chain reaction method in human mucosal enterochromaffin cells isolated by laser microdissection and in a cell line derived from human enterochromaffin cells. Activation of the cells by odorants was investigated by digital fluorescence imaging using the fluorescent Ca(2+) indicator Fluo-4. Serotonin release was measured in culture supernatants by a serotonin enzyme immunoassay and amperometry using carbon fiber microelectrodes placed on single cells. RESULTS We found expression of 4 olfactory receptors in microdissected human mucosal enterochromaffin cells and in a cell line derived from human enterochromaffin cells. Ca(2+) imaging studies revealed that odorant ligands of the identified olfactory receptors cause Ca(2+) influx, elevation of intracellular free Ca(2+) levels, and, consequently, serotonin release. CONCLUSIONS Our results show that odorants present in the luminal environment of the gut may stimulate serotonin release via olfactory receptors present in human enterochromaffin cells. Serotonin controls both gut motility and secretion and is implicated in pathologic conditions such as vomiting, diarrhea, and irritable bowel syndrome. Thus, olfactory receptors are potential novel targets for the treatment of gastrointestinal diseases and motility disorders.
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Affiliation(s)
- Thomas Braun
- Institute of Anatomy, Ludwig Maximilian University Munich, Munich, Germany
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Huang WW, Zhou FS, Bushnell DM, Diakite C, Yang XH. Cultural adaptation and application of the IBS-QOL in China: a disease-specific quality-of-life questionnaire. Qual Life Res 2007; 16:991-6. [PMID: 17440830 DOI: 10.1007/s11136-006-9141-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2006] [Accepted: 10/13/2006] [Indexed: 12/18/2022]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is a chronic and episodic illness characterized by altered bowel habits and associated abdominal pain. At present, IBS is one of the most common functional gastrointestinal and motility disorders affecting countries around the world. Surveys have found that patients with IBS have a significantly lower health-related quality of life. OBJECTIVES The aim of this study was to translate and examine the validity of the Irritable Bowel Syndrome-Quality of Life questionnaire (IBS-QOL) in patients suffering from IBS in China. METHODS A structured procedure was used for the translation and cultural adaptation of the original English IBS-QOL into Chinese. The questionnaire was administered to 73 clinical patients with IBS and 70 healthy individuals. Psychometric testing for reliability, validity and responsiveness followed standardized procedures. Test-retest reliability (10-20 hours) was assessed using the clinical patients. Follow-up (4 weeks) was collected for 61 clinical patients. All enrolled patients also completed the Short Form-36 Health Survey (SF-36) at the baseline visit. Responsiveness to treatment (Venlafaxine and traditional Chinese herbal medicine) was assessed by one-way ANOVA methods. RESULTS The average length of time required to complete the questionnaire was short (5.63 min for IBS patients and 5.54 min for healthy subjects by self-administration). Internal consistency (Cronbach's alpha) values ranged from 0.722 to 0.914 for the Chinese IBS-QOL subscales and test-retest reliability coefficients were higher than 0.920 on all subscales. The convergent and discriminate validity results comparing the Chinese translation of the IBS-QOL overall score and the SF-36 subscales confirmed our predicted hypotheses. The Chinese IBS-QOL scores are more highly correlated with social functioning, vitality and general health (SF-36) and show weaker associations with physical functioning, role physical, mental health, and bodily pain (SF-36). The Chinese translation of the IBS-QOL was responsive to treatment. CONCLUSION In general, the Chinese translation of the IBS-QOL, after cultural adaptation and revision, possesses good reliability, validity and responsiveness. It is a reliable and valid instrument to assess the quality of life in Chinese patients suffering from IBS and is an appropriate measure to use in further clinical trials or for related research projects in China.
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Affiliation(s)
- Wen-Wei Huang
- Piwei Institute, Guangzhou University of Chinese Medicine, 12#, Jichang Road, Guangzhou City, Guangdong Province 510405, China.
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Sawhney MS, Prakash C, Lustman PJ, Clouse RE. Tricyclic antidepressants for chronic vomiting in diabetic patients. Dig Dis Sci 2007; 52:418-24. [PMID: 17195923 DOI: 10.1007/s10620-006-9378-8] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2006] [Accepted: 04/05/2006] [Indexed: 12/17/2022]
Abstract
Chronic vomiting in diabetic patients often is unresponsive to prokinetic agents and poorly explained by delayed gastric emptying or neuropathy. This retrospective study examines clinical response to tricyclic antidepressants, a treatment of reported benefit in nondiabetic patients with unexplained vomiting syndromes. Outcomes were studied in 24 diabetic outpatients who had been treated with tricyclic antidepressants specifically for nausea and vomiting after an unsatisfactory response to prokinetic therapy. Symptom patterns and treatment response were determined from chart review and telephone interview. Ten patients (42%) had recurrent, stereotypical vomiting episodes with symptom-free intervals suggesting cyclic vomiting syndrome; 14 (58%) had persistent symptoms. By chart review, at least moderate symptom response to tricyclic antidepressant treatment (median dosage, 50 mg/day) occurred in 88% of subjects, with complete or nearly complete resolution of symptoms in one-third. At follow-up interview, 77% self-reported at least moderate symptom improvement during therapy and 68% rated tricyclic antidepressants the most effective treatment received. Duration of diabetes, presence of neuropathy, and psychiatric status were not predictive of treatment outcome in multivariate analysis, but a cyclical symptom pattern attenuated antidepressant response (P< 0.05). In this retrospective review, the majority of diabetic patients with chronic vomiting and incomplete response to prokinetic therapy benefited from tricyclic antidepressants in low-dose, open-label regimens and rated them the most effective treatment received. This therapeutic option should be further studied in diabetic patients considering the morbidity of chronic vomiting in this population.
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Affiliation(s)
- Mandeep S Sawhney
- Division of Gastroenterology, Washington University School of Medicine, St Louis, MO 63110, USA
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Limsui D, Pardi DS, Camilleri M, Loftus EV, Kammer PP, Tremaine WJ, Sandborn WJ. Symptomatic overlap between irritable bowel syndrome and microscopic colitis. Inflamm Bowel Dis 2007; 13:175-81. [PMID: 17206699 DOI: 10.1002/ibd.20059] [Citation(s) in RCA: 99] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Microscopic colitis is diagnosed on the basis of histologic criteria, and irritable bowel syndrome (IBS) is diagnosed by symptom-based criteria. There has been little investigation into the symptomatic overlap between these conditions. Our aim was to assess the prevalence of symptoms of irritable bowel syndrome in a population-based cohort of patients with microscopic colitis. METHODS The Rochester Epidemiology Project (REP), a medical records linkage system providing all health care data for the defined population of Olmsted County, Minnesota, was used to identify all county residents with a diagnosis of microscopic colitis between 1985 and 2001. The medical records of these individuals were reviewed to ascertain symptoms consistent with Rome, Rome II, and Manning criteria for irritable bowel syndrome. RESULTS One hundred thirty-one cases of microscopic colitis were identified. Median age at diagnosis was 68 years (range, 24-95); 71% were women. Sixty-nine (53%) and 73 (56%) met Rome and Rome II criteria for irritable bowel syndrome, respectively. Fifty-four (41%) had three or more Manning criteria. Forty-three (33%) had previously been diagnosed with irritable bowel syndrome. CONCLUSIONS In this population-based cohort of histologically confirmed microscopic colitis, approximately one-half met symptom-based criteria for the diagnosis of irritable bowel syndrome. The clinical symptom-based criteria for irritable bowel syndrome are not specific enough to rule out the diagnosis of microscopic colitis. Therefore, patients with suspected diarrhea-predominant irritable bowel syndrome should undergo biopsies of the colon to investigate for possible microscopic colitis if symptoms are not well controlled by antidiarrheal therapy.
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Affiliation(s)
- David Limsui
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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