AGA Clinical Practice Update on Management of Chronic Gastrointestinal Pain in Disorders of Gut–Brain Interaction: Expert Review

  • Laurie Keefer
    Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Cynthia W. Ko
    Reprint requests Address requests for reprints to: Cynthia W. Ko, MD, MS, Division of Gastroenterology, University of Washington, Box 356424, Seattle, Washington 98195. fax: (206) 685-8684.
    Division of Gastroenterology, University of Washington School of Medicine, Seattle, Washington
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  • Alexander C. Ford
    Leeds Gastroenterology Institute, St. James’s University Hospital, Leeds, United Kingdom

    Leeds Institute of Medical Research at St. James’s, University of Leeds, Leeds, United Kingdom
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      This expert review summarizes approaches to management of pain in disorders of gut–brain interaction. This review focuses specifically on approaches to pain that persist if first-line therapies aimed at addressing visceral causes of pain are unsuccessful. The roles of a therapeutic patient–provider relationship, nonpharmacologic and pharmacologic therapies, and avoidance of opioids are discussed.


      This was not a formal systematic review but was based on a review of the literature to provide best practice advice statements. No formal rating of the quality of evidence or strength of recommendation was performed. BEST PRACTICE ADVICE 1: Effective management of persistent pain in disorders of gut–brain interaction requires a collaborative, empathic, culturally sensitive, patient–provider relationship. BEST PRACTICE ADVICE 2: Providers should master patient-friendly language about the pathogenesis of pain, leveraging advances in neuroscience and behavioral science. Providers also must understand the psychological contexts in which pain is perpetuated. BEST PRACTICE ADVICE 3: Opioids should not be prescribed for chronic gastrointestinal pain because of a disorder of gut–brain interaction. If patients are referred on opioids, these medications should be prescribed responsibly, via multidisciplinary collaboration, until they can be discontinued. BEST PRACTICE ADVICE 4: Nonpharmacologic therapies should be considered routinely as part of comprehensive pain management, and ideally brought up early on in care. BEST PRACTICE ADVICE 5: Providers should optimize medical therapies that are known to modulate pain and be able to differentiate when gastrointestinal pain is triggered by visceral factors vs centrally mediated factors. BEST PRACTICE ADVICE 6: Providers should familiarize themselves with a few effective neuromodulators, knowing the dosing, side effects, and targets of each and be able to explain to the patient why these drugs are used for the management of persistent pain.


      Abbreviations used in this paper:

      5-HT (5-hydroxytryptamine), CAPS (centrally mediated abdominal pain syndrome), DGBI (disorders of gut–brain interaction), FD (functional dyspepsia), IBS (irritable bowel syndrome), PPI (proton pump inhibitor), RCT (randomized controlled trial), SNRI (serotonin-norepinephrine reuptake inhibitor), SSRI (selective serotonin reuptake inhibitor), TCA (tricyclic antidepressant)
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        • Sperber A.D.
        • Bangdiwala S.I.
        • Drossman D.A.
        • et al.
        Worldwide prevalence and burden of functional gastrointestinal disorders, results of Rome Foundation Global Study.
        Gastroenterology. 2021; 160: 99-114 e3
        • van Rensburg C.
        • Berghofer P.
        • Enns R.
        • et al.
        Efficacy and safety of pantoprazole 20 mg once daily treatment in patients with ulcer-like functional dyspepsia.
        Curr Med Res Opin. 2008; 24: 2009-2018
        • Kahrilas P.J.
        • Hughes N.
        • Howden C.W.
        Response of unexplained chest pain to proton pump inhibitor treatment in patients with and without objective evidence of gastro-oesophageal reflux disease.
        Gut. 2011; 60: 1473-1478
        • Ford A.C.
        • Moayyedi P.
        • Chey W.D.
        • et al.
        American College of Gastroenterology monograph on management of irritable bowel syndrome.
        Am J Gastroenterol. 2018; 113: 1-18
        • Cassar G.E.
        • Youssef G.J.
        • Knowles S.
        • et al.
        Health-related quality of life in irritable bowel syndrome: a systematic review and meta-analysis.
        Gastroenterol Nurs. 2020; 43: E102-E122
        • Chang L.
        Understanding the multidimensional nature of illness severity as measured by patient-reported outcome measures in irritable bowel syndrome.
        Clin Gastroenterol Hepatol. 2011; 9: 918-919
        • Parker C.H.
        • Naliboff B.D.
        • Shih W.
        • et al.
        The role of resilience in irritable bowel syndrome, other chronic gastrointestinal conditions, and the general population.
        Clin Gastroenterol Hepatol. 2021; 19: 2549-2558
        • Jerndal P.
        • Ringstrom G.
        • Agerforz P.
        • et al.
        Gastrointestinal-specific anxiety: an important factor for severity of GI symptoms and quality of life in IBS.
        Neurogastroenterol Motil. 2010; 22 (646-e179)
        • Drossman D.A.
        2012 David Sun lecture: helping your patient by helping yourself--how to improve the patient-physician relationship by optimizing communication skills.
        Am J Gastroenterol. 2013; 108: 521-528
        • Di Palma J.A.
        • Herrera J.L.
        The role of effective clinician-patient communication in the management of irritable bowel syndrome and chronic constipation.
        J Clin Gastroenterol. 2012; 46: 748-751
        • Dorn S.D.
        • Morris C.B.
        • Schneck S.E.
        • et al.
        Development and validation of the irritable bowel syndrome satisfaction with care scale.
        Clin Gastroenterol Hepatol. 2011; 9 (1065–1071 e1-2)
        • Sharma S.
        • Ferreira-Valente A.
        • de C de C Williams A.
        • et al.
        Group differences between countries and between languages in pain-related beliefs, coping, and catastrophizing in chronic pain: a systematic review.
        Pain Med. 2020; 21: 1847-1862
        • Brady B.
        • Veljanova I.
        • Chipchase L.
        Are multidisciplinary interventions multicultural? A topical review of the pain literature as it relates to culturally diverse patient groups.
        Pain. 2016; 157: 321-328
        • Ford A.C.
        • Forman D.
        • Bailey A.G.
        • et al.
        Effect of dyspepsia on survival: a longitudinal 10-year follow-up study.
        Am J Gastroenterol. 2012; 107: 912-921
        • Melzack R.
        Evolution of the neuromatrix theory of pain. The Prithvi Raj lecture: presented at the third World Congress of World Institute of Pain, Barcelona 2004.
        Pain Pract. 2005; 5: 85-94
        • Auvray M.
        • Myin E.
        • Spence C.
        The sensory-discriminative and affective-motivational aspects of pain.
        Neurosci Biobehav Rev. 2010; 34: 214-223
        • Vlaeyen J.W.S.
        • Crombez G.
        • Linton S.J.
        The fear-avoidance model of pain.
        Pain. 2016; 157: 1588-1589
        • Probst T.
        • Baumeister H.
        • McCracken L.M.
        • et al.
        Baseline psychological inflexibility moderates the outcome pain interference in a randomized controlled trial on internet-based acceptance and commitment therapy for chronic pain.
        J Clin Med. 2018; 8: 24
        • Rogers A.H.
        • Garey L.
        • Bakhshaie J.
        • et al.
        Anxiety, depression, and opioid misuse among adults with chronic pain: the role of anxiety sensitivity.
        Clin J Pain. 2020; 36: 862-867
        • Dittmar O.
        • Baum C.
        • Schneider R.
        • et al.
        Effects of context and individual predispositions on hypervigilance to pain-cues: an ERP study.
        J Pain Res. 2015; 8: 507-521
        • Ballou S.
        • Keefer L.
        The impact of irritable bowel syndrome on daily functioning: characterizing and understanding daily consequences of IBS.
        Neurogastroenterol Motil. 2017;
        • Rhon D.I.
        • Lentz T.A.
        • George S.Z.
        Utility of catastrophizing, body symptom diagram score and history of opioid use to predict future health care utilization after a primary care visit for musculoskeletal pain.
        Fam Pract. 2020; 37: 81-90
        • Dorn S.D.
        • Meek P.D.
        • Shah N.D.
        Increasing frequency of opioid prescriptions for chronic abdominal pain in US outpatient clinics.
        Clin Gastroenterol Hepatol. 2011; 9: 1078-1085 e1
        • Chou R.
        • Hartung D.
        • Turner J.
        • et al.
        Opioid treatments for chronic pain.
        Agency for Healthcare Research and Quality, Rockville (MD)2020
        • Crocker J.A.
        • Yu H.
        • Conaway M.
        • et al.
        Narcotic use and misuse in Crohn's disease.
        Inflamm Bowel Dis. 2014; 20: 2234-2238
        • Sayuk G.S.
        • Kanuri N.
        • Gyawali C.P.
        • et al.
        Opioid medication use in patients with gastrointestinal diagnoses vs unexplained gastrointestinal symptoms in the US Veterans Health Administration.
        Aliment Pharmacol Ther. 2018; 47: 784-791
        • Tuteja A.K.
        • Biskupiak J.
        • Stoddard G.J.
        • et al.
        Opioid-induced bowel disorders and narcotic bowel syndrome in patients with chronic non-cancer pain.
        Neurogastroenterol Motil. 2010; 22 (e96): 424-430
        • Drossman D.A.
        • Morris C.B.
        • Edwards H.
        • et al.
        Diagnosis, characterization, and 3-month outcome after detoxification of 39 patients with narcotic bowel syndrome.
        Am J Gastroenterol. 2012; 107: 1426-1440
        • Manchikanti L.
        • Kaye A.M.
        • Knezevic N.N.
        • et al.
        Responsible, safe, and effective prescription of opioids for chronic non-cancer pain: American Society of Interventional Pain Physicians (ASIPP) Guidelines.
        Pain Physician. 2017; 20: S3-S92
        • Dowell D.
        • Haegerich T.M.
        • Chou R.
        CDC guideline for prescribing opioids for chronic pain - United States, 2016.
        MMWR Recomm Rep. 2016; 65: 1-49
        • Keefer L.
        • Palsson O.S.
        • Pandolfino J.E.
        Best practice update: incorporating psychogastroenterology into management of digestive disorders.
        Gastroenterology. 2018; 154: 1249-1257
        • Kinsinger S.W.
        Cognitive-behavioral therapy for patients with irritable bowel syndrome: current insights.
        Psychol Res Behav Manag. 2017; 10: 231-237
        • Ford A.C.
        • Lacy B.E.
        • Harris L.A.
        • et al.
        Effect of antidepressants and psychological therapies in irritable bowel syndrome: an updated systematic review and meta-analysis.
        Am J Gastroenterol. 2019; 114: 21-39
        • Vasant D.H.
        • Whorwell P.J.
        Gut-focused hypnotherapy for functional gastrointestinal disorders: evidence-base, practical aspects, and the Manchester Protocol.
        Neurogastroenterol Motil. 2019; 31: e13573
        • Moser G.
        • Tragner S.
        • Gajowniczek E.E.
        • et al.
        Long-term success of GUT-directed group hypnosis for patients with refractory irritable bowel syndrome: a randomized controlled trial.
        Am J Gastroenterol. 2013; 108: 602-609
        • Hasan S.S.
        • Pearson J.S.
        • Morris J.
        • et al.
        Skype hypnotherapy for irritable bowel syndrome: effectiveness and comparison with face-to-face treatment.
        Int J Clin Exp Hypn. 2019; 67: 69-80
        • Gaylord S.A.
        • Palsson O.S.
        • Garland E.L.
        • et al.
        Mindfulness training reduces the severity of irritable bowel syndrome in women: results of a randomized controlled trial.
        Am J Gastroenterol. 2011; 106: 1678-1688
        • Hughes L.S.
        • Clark J.
        • Colclough J.A.
        • et al.
        Acceptance and commitment therapy (ACT) for chronic pain: a systematic review and meta-analyses.
        Clin J Pain. 2017; 33: 552-568
        • Sebastian Sanchez B.
        • Gil Roales-Nieto J.
        • Ferreira N.B.
        • et al.
        New psychological therapies for irritable bowel syndrome: mindfulness, acceptance and commitment therapy (ACT).
        Rev Esp Enferm Dig. 2017; 109: 648-657
        • Trimble K.C.
        • Farouk R.
        • Pryde A.
        • et al.
        Heightened visceral sensation in functional gastrointestinal disease is not site-specific. Evidence for a generalized disorder of gut sensitivity.
        Dig Dis Sci. 1995; 40: 1607-1613
        • Verne N.G.
        • Robinson M.E.
        • Price D.D.
        Hypersensitivity to visceral and cutaneous pain in the irritable bowel syndrome.
        Pain. 2001; 93: 7-14
        • Ringel Y.
        • Drossman D.A.
        • Leserman J.L.
        • et al.
        Effect of abuse history on pain reports and brain responses to aversive visceral stimulation: an FMRI study.
        Gastroenterology. 2008; 134: 396-404
        • Icenhour A.
        • Langhorst J.
        • Benson S.
        • et al.
        Neural circuitry of abdominal pain-related fear learning and reinstatement in irritable bowel syndrome.
        Neurogastroenterol Motil. 2015; 27: 114-127
        • Black C.J.
        • Burr N.E.
        • Camilleri M.
        • et al.
        Efficacy of pharmacological therapies in patients with IBS with diarrhoea or mixed stool pattern: systematic review and network meta-analysis.
        Gut. 2020; 69: 74-82
        • Black C.J.
        • Burr N.E.
        • Quigley E.M.M.
        • et al.
        Efficacy of secretagogues in patients with irritable bowel syndrome with constipation: systematic review and network meta-analysis.
        Gastroenterology. 2018; 155: 1753-1763
        • Black C.J.
        • Yuan Y.
        • Selinger C.P.
        • et al.
        Efficacy of soluble fibre, antispasmodic drugs, and gut-brain neuromodulators in irritable bowel syndrome: a systematic review and network meta-analysis.
        Lancet Gastroenterol Hepatol. 2020; 5: 117-131
        • Vakil N.
        • Laine L.
        • Talley N.J.
        • et al.
        Tegaserod treatment for dysmotility-like functional dyspepsia: results of two randomized, controlled trials.
        Am J Gastroenterol. 2008; 103: 1906-1919
        • Tan V.P.
        • Liu K.S.
        • Lam F.Y.
        • et al.
        Randomised clinical trial: rifaximin versus placebo for the treatment of functional dyspepsia.
        Aliment Pharmacol Ther. 2017; 45: 767-776
        • Drossman D.A.
        • Tack J.
        • Ford A.C.
        • et al.
        Neuromodulators for functional gastrointestinal disorders (disorders of gut-brain interaction): a Rome Foundation working team report.
        Gastroenterology. 2018; 154: 1140-1171.e1
        • Lacy B.E.
        • Pimentel M.
        • Brenner D.M.
        • et al.
        ACG clinical guideline: management of irritable bowel syndrome.
        Am J Gastroenterol. 2021; 116: 17-44
        • Weinberg D.S.
        • Smalley W.
        • Heidelbaugh J.J.
        • et al.
        American Gastroenterological Association Institute guideline on the pharmacological management of irritable bowel syndrome.
        Gastroenterology. 2014; 147: 1146-1148
        • Limsrivilai J.
        • Charatcharoenwitthaya P.
        • Pausawasdi N.
        • et al.
        Imipramine for treatment of esophageal hypersensitivity and functional heartburn: a randomized placebo-controlled trial.
        Am J Gastroenterol. 2016; 111: 217-224
        • Viazis N.
        • Keyoglou A.
        • Kanellopoulos A.K.
        • et al.
        Selective serotonin reuptake inhibitors for the treatment of hypersensitive esophagus: a randomized, double-blind, placebo-controlled study.
        Am J Gastroenterol. 2012; 107: 1662-1667
        • Ford A.C.
        • Moayyedi P.
        • Black C.J.
        • et al.
        Systematic review and network meta-analysis: efficacy of drugs for functional dyspepsia.
        Aliment Pharmacol Ther. 2021; 53: 8-21
        • van Kerkhoven L.A.
        • Laheij R.J.
        • Aparicio N.
        • et al.
        Effect of the antidepressant venlafaxine in functional dyspepsia: a randomized, double-blind, placebo-controlled trial.
        Clin Gastroenterol Hepatol. 2008; 6: 746-752
        • Brennan B.P.
        • Fogarty K.V.
        • Roberts J.L.
        • et al.
        Duloxetine in the treatment of irritable bowel syndrome: an open-label pilot study.
        Hum Psychopharmacol. 2009; 24: 423-428
        • Lunn M.P.
        • Hughes R.A.
        • Wiffen P.J.
        Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia.
        Cochrane Database Syst Rev. 2014; 1: CD007115
        • Skljarevski V.
        • Ossanna M.
        • Liu-Seifert H.
        • et al.
        A double-blind, randomized trial of duloxetine versus placebo in the management of chronic low back pain.
        Eur J Neurol. 2009; 16: 1041-1048
        • Tack J.
        • Ly H.G.
        • Carbone F.
        • et al.
        Efficacy of mirtazapine in patients with functional dyspepsia and weight loss.
        Clin Gastroenterol Hepatol. 2016; 14: 385-392
        • Khalilian A.
        • Ahmadimoghaddam D.
        • Saki S.
        • et al.
        A randomized, double-blind, placebo-controlled study to assess efficacy of mirtazapine for the treatment of diarrhea predominant irritable bowel syndrome.
        Biopsychosoc Med. 2021; 15: 3
        • Kariv R.
        • Tiomny E.
        • Grenshpon R.
        • et al.
        Low-dose naltreoxone for the treatment of irritable bowel syndrome: a pilot study.
        Dig Dis Sci. 2006; 51: 2128-2133