Figure

The American College of Gastroenterology (ACG) released updated guidelines for the evaluation and management of patients with irritable bowel syndrome (IBS) in 2021. This is the first guideline from the ACG for IBS that utilizes the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) method to evaluate current science and offer evidence-based guidance to clinicians.

IBS is a chronic, quality of life–limiting, functional gastrointestinal (GI) disease. IBS is the most common functional GI disorder and is therefore a common reason patients present to primary and specialty care.1 The terminology relating to IBS has evolved in recent years, and the condition is now sometimes referred to as a disorder of gut-brain interaction.2 IBS more commonly affects women and people under the age of 50 years.3 Hallmark symptoms of IBS include chronic abdominal pain and altered bowel habits.4,5 The pathophysiology is largely uncertain but historically has been attributed to visceral hypersensitivity, alterations in intestinal microbiome, mucosal immune system activation, and disorganized bowel habits.5 Despite extensive study of the disease, there is not yet any specific testing available to make a diagnosis. A lack of diagnostic testing can make it difficult to convince patients that IBS is the root cause of their issues and that further workup is usually not indicated. Global IBS symptoms can be defined as abdominal pain, abdominal cramping, bloating, gas, and altered bowel habits.6,7

Criteria for diagnosis

The Rome IV Diagnostic Criteria for IBS is a set of symptom-based criteria that guides diagnosis.6,7 According to these criteria, IBS is defined as chronic abdominal pain, occurring at least 1 day per week in the last 3 months, that is associated with two or more of the following:

defecation change in stool frequency change in stool caliber (form, appearance).

Additionally, symptom onset needs to occur at least 6 months prior for the diagnosis to be made. When a diagnosis of IBS is made, it is important to determine by which subtype the patient is affected. Classification is important because it guides management. The four main subtypes of IBS are: 1) IBS with constipation (IBS-C), 2) IBS with diarrhea (IBS-D), 3) IBS with mixed or alternating bowel habits (IBS-M), and 4) IBS that does not have a significant identifiable pattern of abnormal stool (IBS-U).6 To accurately classify patients' subtypes, it is important to use a standardized approach. The Bristol Stool Form Scale (BSFS) is an objective way to classify stool caliber that should be used to help standardize patient history.8 Next, the patient should be asked to record any abnormal bowel movements over a 2-week period unless they are able to confidently report a strong pattern. After the pattern of stool consistency is determined, the Rome IV criteria should be used to diagnose the subtype.6 Rome IV criteria for IBS subtypes are listed below:

IBS-C (constipation): more than 25% of bowel movements are associated with BSFS 1 or 2, with BSFS 6 or 7 occurring less than 25% of the time IBS-D (diarrhea): more than 25% of bowel movements are associated with BSFS 6 or 7, with BSFS 1 or 2 occurring less than 25% of the time IBS-M (mixed): more than 25% of bowel movements are associated with BSFS 1 or 2 and more than 25% of bowel movements are associated with BSFS 6 or 7 IBS-U (unclassified): criteria for IBS are met but criteria for the other 3 subtypes are not met. Diagnostic evaluation and differential diagnosis

The following are recommendations for the diagnostic evaluation of patients who are suspected of having IBS. The overarching goal of the ACG guideline is that a diagnostic workup based on clinical history and physical exam should be initiated for patients who are suspected to have IBS rather than a diagnosis-of-exclusion approach.6

Routine colonoscopy evaluation is not indicated in patients younger than 45 years with IBS symptoms but without alarm signs.9 Common alarm signs that warrant evaluation with colonoscopy are GI bleeding, unintended weight loss, older age at onset of symptoms, and family history of IBD or colon cancer.10 If a patient is 45 years of age or older and has never had a colonoscopy, then they should be referred for routine colon cancer screening per current guidelines but not as part of a diagnostic workup for IBS.6,10 This distinction can have financial implications for the patient, as diagnostic colonoscopies are billed to insurance differently than screening colonoscopies. If a patient is older than 60 years of age, female, and experiencing frequent diarrhea, then a diagnostic colonoscopy with biopsies should be considered to evaluate for microscopic colitis.6 In some patients, symptoms may be exacerbated by the procedure due to the insufflation of air into the colon; thus, it is important to avoid the procedure unless the patient has alarm signs or risk factors.11,12

Celiac disease

Patients with symptoms of IBS-D should be screened for celiac disease.6 Celiac disease is an immune-mediated inflammatory disease of the small intestine caused by a sensitivity to gluten in patients who have a genetic predisposition to the disease.6,13 Because there is considerable overlap in the symptoms of celiac disease and IBS, clinicians should take care to differentiate between celiac disease and gluten intolerance or non-celiac gluten sensitivity. Gluten intolerance and sensitivity are common in patients with IBS, but they are not the same as diagnostically proven celiac disease.13 It is important to exclude the presence of celiac disease in patients with IBS-D symptoms because the two disorders have different management goals, treatment, and preventive care. Evaluation for celiac disease can include starting with serologic testing with immunoglobulin A (IgA) tissue transglutaminase and total IgA levels. If the serologic workup for celiac disease is positive, then the patient should be referred for endoscopy with duodenal biopsies to confirm the diagnosis.

Inflammatory bowel disease

A fecal calprotectin or fecal lactoferrin and C-reactive protein (CRP) should be ordered in patients with suspected IBS-D to evaluate for inflammatory bowel disease (IBD).14 Currently, there are no biochemical tests to evaluate for IBS. There is significant overlap in the presentations of patients who have IBS-D and patients who have IBD. CRP is a nonspecific marker for inflammation that, when normal, can help to exclude the presence of IBD.6,10 Fecal calprotectin is a stool marker of inflammation; elevated levels are diagnostic for intestinal inflammation. This test can be used as a clinical tool to assess the degree of intestinal inflammation and to monitor response to therapy in IBD; normal values indicate disease remission and values above the reference range indicate active inflammation. Intestinal inflammation is not expected in patients with IBS.

Infectious diarrhea

Routine testing for infectious diarrheal pathogens in patients with chronic IBS symptoms is not recommended unless a patient has risk factors for exposure and/or acute symptoms.6 Common risk factors for development of infectious diarrhea include exposure to diarrheal pathogens; recent antibiotic use; immunocompromise; and work in food handling, healthcare, or day care. The presence of blood in diarrhea can occur for several reasons; however, if the patient reports abrupt or acute onset of bloody diarrhea, an evaluation for infectious diarrhea may be indicated. Most infectious diarrhea is self-limited and does not require treatment.

Food allergies

The ACG recommends that an individualized approach be taken in patients with IBS who exhibit food allergy symptoms. Up to 50% of patients with IBS will report intolerance to specific foods; however, only 1% to 3% of adults have food allergies.15-19 The diagnostic yield is low in evaluating all patients with IBS for food allergies, and such testing should be reserved for those who have significant risk factors or reproducible symptomatology for an allergy.6

Dyssynergic defecation

It can be difficult to differentiate between IBS, especially IBS-C, and dyssynergic defecation, as there is significant symptom overlap. Dyssynergic defecation is characterized by the inability of the puborectalis and external anal sphincter muscles to relax or contract.20 Due to the overlap, diagnostic testing should be offered to patients with IBS and symptoms of pelvic floor disorders or refractory constipation that has not been responsive to medication therapy.6 Biofeedback has been shown to improve pain and bowel symptoms in patients with pelvic floor dyssynergia and dyssynergic defecation.21,22 Therefore, anorectal diagnostic testing that identifies abnormalities amenable to biofeedback therapy should be pursued.6,20-23

Pharmacologic management

It is important for the clinician to understand that treatment of the bowel alteration alone will not address all the patient's symptoms. For example, use of loperamide may help diarrhea but not abdominal pain. Whenever possible, pharmacologic treatment should aim to address IBS global symptoms.

IBS-C

There are several pharmacologic treatment options that can be considered for patients with IBS-C. Polyethylene glycol (Miralax and Glycolax) is an over-the-counter osmotic laxative used commonly for patients with constipation due to its efficacy, safety, and low cost. Unfortunately, current evidence does not support its use in the management of abdominal pain in patients with IBS.6 Although it should not be used to treat global IBS symptoms, it can have a role in the treatment of constipation in IBS.6

Chloride channel activators can be used to treat global IBS-C symptoms.24 Lubiprostone (Amitiza) is a prostaglandin E1 analogue that attaches to type-2 chloride channels located in intestinal epithelial cells and is approved for treatment of IBS-C in adult women.24 When these intestinal receptors are activated, they increase intestinal peristalsis and promote secretion.25 Patients treated with lubiprostone often see improvement in constipation and global IBS symptoms.6 The most common adverse reaction is nausea, which can usually be overcome by dose adjustments or consuming the medication with meals.6

Guanylate cyclase-C agonists are another option recommended in the ACG guideline for treatment of global IBS-C symptoms.26 Guanylate cyclase-C agonists target receptors in intestinal epithelial cells to increase intestinal fluid secretion and peristalsis and reduce activation of visceral nociceptive neurons.27 The two guanylate cyclase-C agonists available in the US are linaclotide (Linzess) and plecanatide (Trulance), which have been shown to relieve global symptoms of IBS-C and are effective in the management of constipation.6

The ACG guideline suggests the use of the serotonin-4 (5-HT4) receptor agonist tegaserod in IBS-C specifically for women younger than 65 years of age with one or fewer cardiovascular risk factors and who have previously failed secretagogues.28 Serotonin is an important neurotransmitter that regulates GI motor and sensory function.28 Stimulating 5-HT4 receptors initiates peristalsis, accelerates GI transit time, and reduces visceral hypersensitivity.29-33

Sodium/hydrogen exchanger 3 inhibitor tenapanor (Ibsrela) is another pharmacologic agent approved for the treatment of adults with IBS-C.34 This medication decreases the absorption of sodium in the small intestine and colon, thereby increasing intestinal fluid volume and transit time. Tenapanor has a boxed warning for dehydration in pediatric populations, so utilization in patients younger than 18 years of age is contraindicated.

IBS-D

Bile acid sequestrants such as cholestyramine (Questran) should not be used to treat global symptoms in IBS-D; however, they may be indicated for treatment of bile acid malabsorption (BAM) in patients with both BAM and IBS-D. Evidence supports treatment of IBS-D alone (without BAM) with cholestyramine, but it is an off-label use of the medication. BAM is a separate diagnosis in which there is an overproduction of secondary bile acids that increase colonic secretion of fluid, resulting in diarrhea.6,34

For patients with IBS-D, non-absorbed antibiotic rifaximin (Xifaxan) is instead recommended as an option to treat global symptoms and is approved for this indication. The drug is used in connection with the theory that patients with IBS-D have alterations in their gut microbiomes that increase their susceptibility to diarrhea.6 If a patient's symptoms improve with rifaximin treatment, then a repeat course can be given upon symptom recurrence.34

Alosetron (Lotronex) is a selective 5-HT3 receptor antagonist and works by slowing intestinal transit and relieving global IBS-D symptoms. It should be used to manage global IBS-D manifestations in women with severe symptoms who have failed first-line therapy.6,35 There is a risk of developing severe constipation or ischemic colitis necessitating hospitalization with alosetron; therefore, patients should be counseled about signs and symptoms that would warrant immediate discontinuation of the medication.35

- Pharmacologic management for global IBS symptoms6 IBS-C IBS-D

Eluxadoline

Alosetron

Rifaximin

Antispasmodics

TCAs∗

Abbreviations: IBS-C, IBS with constipation; IBS-D, IBS with diarrhea; TCAs, tricyclic antidepressants.

∗Off-label use for IBS.

Mixed opioid agonists/antagonists are an option suggested by the ACG to treat global IBS-D symptoms. Eluxadoline (Viberzi) is a peripherally acting, mixed mu- and kappa-opioid receptor agonist/delta-opioid receptor antagonist that has been shown to improve global IBS-D symptoms.36 Eluxadoline is contraindicated in patients who have had a cholecystectomy and those who have known or suspected biliary obstruction, sphincter of Oddi disease or dysfunction, pancreatitis or a history of pancreatitis, severe hepatic impairment, and/or alcohol use disorder.37 Eluxadoline should be discontinued after 12 weeks if patients do not respond to therapy due to the increased risk of pancreatitis with the medication.37

Other pharmacologic considerations

Antispasmodics work by relaxing the smooth muscle of the intestines and are often used in IBS management. Although they should not be prescribed to treat global IBS symptoms and there are limited data to support their use, antispasmodics can be considered on an as-needed basis or when a patient is anticipating a known trigger to their symptoms, as these drugs are generally safe and usually well tolerated.6,38 Dicyclomine (Bentyl) and hyoscyamine (Levsin) are commonly prescribed antispasmodics. These agents should be used with caution in older adults due to their known anticholinergic adverse reactions, and they should also be avoided in patients with glaucoma, myasthenia gravis, and reflux esophagitis. Another less commonly used antispasmodic agent, chlordiazepoxide/clidinium (Librax), is also available. Use of chlordiazepoxide/clidinium should be limited to the short term (between 2 and 4 weeks) and should be avoided in patients with a history of substance use disorders, glaucoma, prostate hyperplasia, and bladder neck obstructions. Concomitant use of chlordiazepoxide/clidinium with opioids or other benzodiazepines should be avoided due to the risk of respiratory depression.

Most patients with IBS report abdominal pain, bloating, and urgency. Tricyclic antidepressants (TCAs), including amitriptyline, nortriptyline, imipramine, and desipramine, can be used to treat global symptoms of IBS; however, this is an off-label use of the medication.6 TCAs are neuromodulators that can improve visceral hypersensitivity by acting on norepinephrine and dopamine receptors.6,39 TCAs have also been thought to improve abdominal pain related to diarrhea due to their anticholinergic effects that slow GI transit in some patients.36,39,40 Patients should be started on low doses that are gradually increased until the patient achieves therapeutic relief of symptoms.40 For a summary of pharmacologic treatment options, see Pharmacologic management for global IBS symptoms.

Nonpharmacologic management

A low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet is frequently recommended in patients with IBS. Foods high in FODMAPs lead to increased GI water secretion and increased fermentation in the gut, which can cause distension, bloating, gas, and increased postprandial symptoms in patients with IBS.6 The ACG recommends a short trial of the diet, as it is very restrictive and difficult to maintain on a long-term basis. Patients who respond to the diet will note improvement within 2 to 6 weeks; after this period, they should be instructed to slowly reintroduce foods to better determine which foods are contributing to their GI symptoms. This reintroduction phase is important, as it allows patients to increase dietary options and avoid unnecessary restrictions. Referral to a specialized and trained GI nutritionist or dietary specialist is recommended, though this expertise is not always available due to resource scarcity or accessible due to lack of insurance coverage and/or patient financial limitations. If a referral is not possible, providers should give patients high-quality teaching materials to optimize patient education.6

The new ACG guideline recommends initiation of soluble fiber to treat patients with global IBS symptoms.6 Initiation of fiber supplementation is the first line of treatment in most patients with IBS-C; it is important that soluble fibers, such as psyllium, oat bran, barley, and beans, be recommended.6 On the other hand, insoluble fiber, found in wheat bran, whole grains, and vegetables such as cauliflower, does not dissolve in water or body fluids, instead absorbing them and adhering to other material to form stool. Insoluble fiber can exacerbate patient discomfort.

Patients with IBS can be referred for cognitive behavioral therapy (CBT) for treatment of global IBS symptoms.6 The brain-gut axis links the enteric and central nervous systems.6,41 CBT can improve symptoms of abdominal pain by managing the psychosomatic aspects of the disease, which can impact the enteric nervous system. It is important to counsel the patient on the reason for the referral and the role of therapy in managing IBS, as a patient may otherwise feel as though their physical symptoms are being invalidated if the connection and reason are not explained.

Peppermint oil is an evidence-based antispasmodic option suggested in the ACG guideline that is shown to reduce global IBS symptoms and abdominal pain.6 Of note, peppermint oil relaxes the lower esophageal sphincter and may worsen symptoms of indigestion in patients with gastroesophageal reflux disease; this population may benefit from enteric-coated formulations of peppermint oil.

Fecal transplants are not recommended for the treatment of global IBS symptoms.6 Previous research was driven by the hypothesis that dysbiosis within the gut microbiome drives symptoms of IBS and that related effects might be ameliorated by fecal transplant. Unfortunately, current data do not show that fecal transplants lead to improvement in symptoms in patients with IBS. For a summary of recommended nonpharmacologic management options, see Nonpharmacologic management of IBS.

Primary care management and gastroenterology referral

IBS is often managed successfully in primary care. Management can be optimized in this setting when there is an established long-term therapeutic relationship between the primary care provider and patient. Successful management of IBS in any setting requires building rapport, trust, and a therapeutic relationship with the patient. Management should be focused on an affirming, positive strategy rather than focusing on diagnosis based on exclusion.6 A focused clinical history that confirms Rome IV criteria and a lack of alarm features along with reassuring physical exam and limited diagnostic testing are sufficient to confidently diagnose patients with IBS and start working on treatment goals.

- Nonpharmacologic management of IBS6

Low FODMAP diet

Soluble fiber

CBT

Peppermint oil

Abbreviations: CBT, cognitive behavioral therapy; FODMAP, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols.

Referral to gastroenterology should be initiated for any alarm symptoms, including GI bleeding (melena, hematochezia), weight loss, nocturnal symptoms, iron-deficiency anemia, family history of GI malignancy, IBD, or celiac sprue. GI bleeding should not be minimized, even when it occurs in small volume or in a younger patient. Colorectal cancers are increasing in incidence among young adults, and any alarm sign should therefore prompt urgent referral to gastroenterology.9 Patients should also be referred to gastroenterology when the diagnostic workup reveals an alternative diagnosis. This can include (but is not limited to) an elevated fecal calprotectin, anemia, and positive celiac serologic testing. Patients without alarm symptoms who fail to improve with primary care management of IBS can also be referred to gastroenterology for further evaluation.

Conclusion

IBS is a common diagnosis encountered by both primary care providers and specialists in gastroenterology. Care of the patient with IBS should be centered on establishing trust and rapport. A multidisciplinary approach is optimal and should aim to foster collaboration among gastroenterology specialists, nutritionists, behavioral health specialists, and primary care providers. The journey to making a diagnosis should be focused on using a positive diagnostic approach rather than a paradigm that aims to diagnose by exclusion. A careful history and physical exam without alarm signs are sufficient to diagnose IBS, and a focused but limited diagnostic workup is usually indicated. After a diagnosis has been established, it is important to pinpoint the subtype of IBS by which the patient is affected because this information drives management of bowel alterations. It is also vital for the provider to treat global IBS symptoms, not just altered bowel habits. Management of bowel alterations alone is not sufficient in most patients with IBS to resolve their constellation of GI maladies.

REFERENCES 1. Palsson OS, Whitehead W, Tornblom H, Sperber AD, Simren M. Prevalence of Rome IV functional bowel disorders among adults in the United States, Canada, and the United Kingdom. Gastroenterology. 2020;158(5):1262–1273. 2. Grad S, Dumitrascu DL. Irritable bowel syndrome subtypes: new names for old medical conditions. Dig Dis. 2020;38(2):122–127. 3. Ford AC, Lacy BE, Talley NJ. Irritable bowel syndrome. N Engl J Med. 2017;376(26):2566–2578. 4. Ford AC, Moayyedi P, Lacy BE, et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol. 2014;109(suppl 1):S2–26. 5. Camilleri M. Peripheral mechanisms in irritable bowel syndrome. N Engl J Med. 2012;367(17):1626–1635. 6. Lacy BE, Pimentel M, Brenner DM, et al. ACG Clinical Guideline: management of irritable bowel syndrome. Am J Gastroenterol. 2021;116(1):17–44. doi:10.14309/ajg.0000000000001036. 7. Lacy BE, Mearin F, Chang L, et al. Bowel disorders. Gastroenterology. 2016;150(6):1393–1407. 8. Blake MR, Raker JM, Whelan K. Validity and reliability of the Bristol Stool Form Scale in healthy adults and patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2016;44(7):693–703. doi:10.1111/apt.13746. 9. Loomans-Kropp HA, Umar A. Increasing incidence of colorectal cancer in young adults. J Cancer Epidemiol. 2019;2019. doi:10.1155/2019/9841295. 10. Shaukat A, Kahi CJ, Burke CA, Rabeneck L, Sauer BG, Rex DK. ACG Clinical Guidelines: Colorectal Cancer Screening 2021. Am J Gastroenterol. 2021;116(3):458–479. doi:10.14309/ajg.0000000000001122. 11. Cullingford GL, Coffey JF, Carr-Locke DL. Irritable bowel syndrome: can the patient's response to colonoscopy help with diagnosis. Digestion. 1992;52(3–4):209–213. 12. Mayer EA, Gebhart GF. Basic and clinical aspects of visceral hyperalgesia. Gastroenterology. 1994;107(1):271–293. 13. Barone M, Gemello E, Viggiani MT, et al. Evaluation of non-celiac gluten sensitivity in patients with previous diagnosis of irritable bowel syndrome: a randomized double-blind placebo-controlled crossover trial. Nutrients. 2020;12(3):705. doi:10.3390/nu12030705. 14. Menees SB, Powell C, Kurlander J, Goel A, Chey WD. A meta-analysis of the utility of C-reactive protein, erythrocyte sedimentation rate, fecal calprotectin, and fecal lactoferrin to exclude inflammatory bowel disease in adults with IBS. Am J Gastroenterol. 2015;110(3):444–454. 15. Lacy BE, Weiser K, Noddin L, et al. Irritable bowel syndrome: patients' attitudes, concerns and level of knowledge. Aliment Pharmacol Ther. 2007;25(11):1329–1341. 16. Bohn L, Storsrud S, Tornblom H, Bengtsson U, Simren M. Self-reported food-related gastrointestinal symptoms in IBS are common and associated with more severe symptoms and reduced quality of life. Am J Gastroenterol. 2013;108(5):634–641. 17. Monsbakken KW, Vandvik PO, Farup PG. Perceived food intolerance in subjects with irritable bowel syndrome: etiology, prevalence and consequences. Eur J Clin Nutr. 2006;60(5):667–672. 18. Rona RJ, Keil T, Summers C, et al. The prevalence of food allergy: a meta-analysis. J Allergy Clin Immunol. 2007;120(3):638–646. 19. Liu AH, Jaramillo R, Sicherer SH, et al. National prevalence and risk factors for food allergy and relationship to asthma: results from the National Health and Nutrition Examination Survey 2005-2006. J Allergy Clin Immunol. 2010;126(4):798–806. 20. Rao SS, Welcher KD, Leistikow JS. Obstructive defecation: a failure of rectoanal coordination. Am J Gastroenterol. 1998;93(7):1042–1050. 21. Patcharatrakul T, Gonlachanvit S. Outcome of biofeedback therapy in dyssynergic defecation patients with and without irritable bowel syndrome. J Clin Gastroenterol. 2011;45(7):593–598. 22. Baker J, Eswaran S, Saad R, et al. Abdominal symptoms are common and benefit from biofeedback therapy in patients with dyssynergic defecation. Clin Transl Gastroenterol. 2015;6(7):e105. 23. Chiarioni G, Whitehead WE, Pezza V, Morelli A, Bassotti G. Biofeedback is superior to laxatives for normal transit constipation due to pelvic floor dyssynergia. Gastroenterology. 2006;130(3):657–664. 24. Lacy BE, Levy LC. Lubiprostone: a chloride channel activator. J Clin Gastroenterol. 2007;41(4):345–351. 25. Lembo A, Sultan S, Chang L, Heidelbaugh JJ, Smalley W, Verne GN. AGA Clinical Practice Guideline on the pharmacological management of irritable bowel syndrome with diarrhea. Gastroenterology. 2022;163(1):137–151. doi:10.1053/j.gastro.2022.04.017. 26. Currie MG, Fok KF, Kato J, et al. Guanylin: an endogenous activator of intestinal guanylate cyclase. Proc Natl Acad Sci U S A. 1992;89(3):947–951. 27. Brenner DM, Fogel R, Dorn SD, et al. Efficacy, safety, and tolerability of plecanatide in patients with irritable bowel syndrome with constipation: results of two phase 3 randomized clinical trials. Am J Gastroenterol. 2018;113:735–745. 28. Prather CM, Camilleri M, Zinsmeister AR, McKinzie S, Thomforde G. Tegaserod accelerates orocecal transit in patients with constipation-predominant irritable bowel syndrome. Gastroenterology. 2000;118(3):463–468. 29. Sun Y-N, Luo J-Y. Effects of tegaserod on Fos, substance P and calcitonin gene-related peptide expression induced by colon inflammation in lumbarsacral spinal cord. World J Gastroenterol. 2004;10(12):1830–1883. 30. Jiao H-M, Xie P-Y. Tegaserod inhibits noxious rectal distention induced responses and limbic system c-Fos expression in rats with visceral hypersensitivity. World J Gastroenterol. 2004;10(19):2836–2841. 31. Coffin B, Farmachidi J-P, Rueegg P, Bastie A, Bouhassira D. Tegaserod, a 5-HT4 receptor partial agonist, decreases sensitivity to rectal distension in healthy subjects. Aliment Pharmacol Ther. 2003;17(4):577–585. 32. Langaker KJ, Morris D, Pruitt R, et al. The partial 5-HT4 agonist (HTF 919) improves symptoms in constipation-predominant irritable bowel syndrome (C-IBS). Digestion. 1998;59(suppl 3):20. 33. Lembo AJ, Lacy BE, Zuckerman MJ, et al. Eluxadoline for irritable bowel syndrome with diarrhea. N Engl J Med. 2016;374(3):242–253. 34. Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel syndrome. 2002;123(6):2108–2131. doi:10.1053/gast.2002.37095. 35. Ford AC, Moayyedi P, Lacy BE, et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol. 2014;109(suppl 1):S2–26. 36. Wade PR, Palmer JM, McKenney S, et al. Modulation of gastrointestinal function by MuDelta, a mixed mu opioid receptor agonist/delta opioid receptor antagonist. Br J Pharmacol. 2012;167(5):1111–1125. 37. Eluxadoline. In: Lexi-drugs online [database on the Internet]. Hudson, OH: Lexicomp; 2022. http://online.lexi.com/. Accessed June 2, 2022. 38. Gorard DA, Libby GW, Farthing MJ. Influence of antidepressants on whole gut and orocaecal transit times in health and irritable bowel syndrome. Aliment Pharmacol Ther. 1994;8(2):159–166. 39. Chang L, Sultan S, Lembo A, Verne GN, Smalley W, Heidelbaugh JJ. AGA Clinical Practice Guideline on the pharmacological management of irritable bowel syndrome with constipation. Gastroenterology. 2022;163(1):118–136. doi:10.1053/j.gastro.2022.04.016. 40. Drossman DA, Tack J, Ford AC, Szigethy E, Tornblom H, Van Oudenhove L. Neuromodulators for functional gastrointestinal disorders (disorders of gut-brain interaction): a Rome Foundation Working team report. Gastroenterology. 2018;154(4):1140–1171. 41. Laird KT, Tanner-Smith EE, Russell AC, Hollon SD, Walker LS. Comparative efficacy of psychological therapies for improving mental health and daily functioning in irritable bowel syndrome: a systematic review and meta-analysis. Clin Psychol Rev. 2017;51:142–152.