Louis WC Liu University Health Network, Toronto, Ontario, Canada *Corresponding author: Email louis.liu@uhn.on.ca		John Marshall Department of Medicine and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
	Keith McIntosh Western University, London, Ontario, Canada		Phuong Nguyen Independent practice, Toronto, Ontario Canada
	Yvonne Tse University Health Network, Toronto, Ontario, Canada		Kathryn Woodman Department of Medicine and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada

Background

Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction that is characterized by abdominal pain and diarrhea or constipation.¹ Most individuals with IBS are frequently in pain, and one-quarter have constant pain.² The pathophysiology includes activation of the hypothalamic-pituitary-adrenal (HPA) axis and altered neurological circuitry leading to lowered thresholds for pain perception.^3-5 Disease subtypes include IBS with diarrhea (IBS-D), IBS with constipation (IBS-C), IBS with a mixed stool pattern (IBS-M), and unclassified IBS (IBS-U).^6-8 Estimates in Canada from a recent survey show an IBS prevalence of 4.2%.⁹

Family practitioners have integral roles in IBS management.¹⁰ The chronic nature of the condition requires continuity of care and a productive patient-physician relationship.^11-13 However, many primary care physicians (PCPs) lack confidence in diagnosing and treating IBS and associate the condition with complexity and uncertainty.¹⁴ The presentation overlaps with other gut-brain disorders, celiac disease, and inflammatory bowel disease (IBD)^14-16 and may exist on a continuum with other functional bowel disorders.¹⁷

American PCPs identified IBS as one of the most difficult chronic diseases to treat, and patients often receive therapies that lack proven efficacy.^18-19 These challenges indicate a need for greater clinician awareness of IBS diagnosis and treatment.²⁰ Although clinical practice guidelines (CPGs) are available, some are out of date, while others are discordant.²¹ Few guidelines have specifically aimed to improve the efficiency of IBS treatment in Canadian primary care. We developed a decision tool and practice pathway that incorporates high-quality evidence and supports non-gastroenterologists in improving IBS management with the objectives of:

1. obtaining a timely, positive diagnosis;


2. reducing the time to treatment;


3. reducing unnecessary testing;


4. integrating evidence-based therapies into practice;


5. increasing the efficiency of referral, including helping non-gastroenterologists to identify patients who require a referral for specialized care.

Methods

The development of practice recommendations was undertaken as a collaborative effort between practitioners, the authors of the study, at academic hospital centres in Ontario, including Toronto Western Hospital, St. Joseph’s Healthcare Hospital, and McMaster University. The goal was to assemble an expert panel of gastroenterologists and PCPs to discuss the unmet needs in IBS management in primary care. A steering committee was formed in November 2022, comprising five gastroenterologists and one PCP. Members of the panel practice in diverse geographical regions in Ontario and have expertise in gastric motility, demonstrated by their track records of peer-reviewed publications, academic appointments, leadership on clinical trials, and involvement in medical education.

The committee reviewed the latest evidence, aligned on the aims, and drafted the decision tool and practice pathway based on their expertise and clinical practice considerations. Two face-to-face meetings and several virtual meetings were conducted in the process of clinical practice pathway composition. Through two rounds of review, revision, and discussion, the group agreed on a practical tool to aid PCP management of IBS in October 2023. The final tool was developed through an iterative process and was reviewed and edited by all participants.

Results

A. IBS Treatment Pathway Overview

The recommended pathway for a patient with suspected IBS involves three visits (Figure 1):

• Visit 1: Assess for IBS symptoms and alarm features. Initiate, in parallel, investigations and treatments (nonpharmacological and pharmacological). Refer to a gastroenterologist if alarm features are present.
• Visit 2: Assess treatment response and discuss test results (refer to appropriate specialists for abnormal test results). Adjust therapy if necessary.
• Visit 3: Reassess treatment response. If symptoms are refractory, consider referral to a gastroenterologist.

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B. Visit 1

Patients with suspected IBS based on the Rome IV criteria^17,22 (Table 1) should undergo a physical examination and provide a detailed medical history. The IBS subtype should be assessed (Table 2) and the stool form should be described using the Bristol scale.^17,22,23 Abnormal stools, fecal urgency, and incomplete evacuation occur frequently in IBS.²⁴

Medications should be reviewed with attention to any that are associated with gastrointestinal (GI) symptoms. Alarm features that could indicate malignancy or a non-IBS etiology may require further investigation. These include a first presentation over 50 years old, nocturnal symptoms, unintended weight loss, unexplained rectal bleeding, unexplained iron deficiency anemia, and a family history of celiac disease, colorectal cancer (CRC) or IBD.²⁶ Patients with these features should be referred to a gastroenterologist. If alarm features are absent, investigation and treatment for IBS (including lifestyle modifications and pharmacological therapies) should be initiated in parallel to enable the patient to access treatment rapidly. To assess the response at subsequent visits, the patient may track symptom severity using a diary.²⁷ It is also important to discuss diet, sleep hygiene, and physical activity. Mental health issues should be addressed, and psychological interventions should be considered for all patients.^28-30

Finally, routine colonoscopy is not recommended, and patients should receive CRC screening according to the guidelines for the general population.^31,32

Recommended investigations

As part of the workup, we recommend a complete blood count (CBC) along with serum thyroid-stimulating hormone (TSH), ferritin, and calcium. The CBC and ferritin can exclude findings requiring additional investigation.¹⁰ Celiac disease symptoms overlap with those of IBS, and we recommend serologic testing.^26,33 Total IgA should be measured to exclude IgA deficiency as a cause of false-negative celiac serology.

For individuals with symptoms of IBS-D or IBS-M, we recommend tests for enteric infection (stool culture and sensitivity, ova and parasites, and Clostridium difficile toxin), fecal calprotectin (FC), C-reactive protein (CRP), and magnesium. Enteric infection can lead to post-infection IBS.^34,35 CRP and FC can be used to exclude inflammatory conditions such as IBD.^10,26

Recommended treatment – nonpharmacological

Nonpharmacological therapy is an essential component of treatment.^29,36 Recommendations include consuming adequate fluids and soluble fibre; and a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (low-FODMAP) should be considered.²⁶ Over half of individuals with IBS have food triggers, most commonly dairy, legumes, biogenic amines, and fatty foods.²⁶ These should be identified and minimized. Physical activity can improve symptoms, and we also recommend addressing sleep hygiene.^37-40

Psychological interventions are also recommended.^26,29 For example, cognitive behavioral therapy attenuates pain and improves mood in individuals with IBS.^28,30,41-45 Beneficial effects on mood and GI symptoms have also been reported for gut-directed hypnotherapy, meditation, and relaxation training.^{28,30,41,13,46,47}

Nonpharmacological therapies are, however, limited in managing global symptoms; pharmacological therapy is therefore necessary for most patients.²⁶

Recommended treatment – pharmacological

Treatment should be initiated while investigations are in progress. We recommend choosing one of the indicated therapies (Figure 1) approved by Health Canada, demonstrating benefits in reducing pain and global symptoms. Over-the-counter (OTC) medications and off-label therapies are also available, but these agents have limited benefits, and clinical trials have reported mixed results.⁵

For IBS-D, we recommend the opioid receptor agonist/antagonist eluxadoline or the antibiotic rifaximin. Other therapies, such as tricyclic antidepressants, loperamide, antispasmodics, probiotics, bile acid sequestrants, and peppermint oil may also be considered. For IBS-C, we recommend plecanatide, linaclotide, or tenapanor. An osmotic laxative, a stimulant laxative, or prucalopride may be considered for residual constipation, and peppermint oil or a selective serotonin reuptake inhibitor (SSRI) for individuals who continue to experience pain. The supporting evidence, mechanisms of action, and dosing information for the indicated pharmacological therapies are described in the Supplementary Information.

C. Visits 2 and 3

The second visit should take place after tests have been completed and after 4-8 weeks of treatment. If the results show celiac disease, anemia, or elevated FC, the patient should be referred to a gastroenterologist. If the patient has responded well, treatment should be continued. Otherwise, the agent may be changed, the dose adjusted, or additional agent(s) added.

The treatment response should be reassessed at the third visit. If satisfactory, no further adjustments are necessary. If there has been partial response, further optimization of treatment is recommended. However, if the symptoms are refractory, we recommend referral to a gastroenterologist.

Discussion

A. Choosing a pharmacological therapy

Family practitioners should be aware of the current therapies available for IBS and the clinical data supporting their use. Here we discuss the evidence supporting the recommended IBS therapies, and considerations for choosing a therapy.

Although OTC medications are frequently used, these agents have limited benefit for pain and global symptoms, and their long-term safety is unclear.^5,48 For example, in a randomized trial, polyethylene glycol relieved constipation but did not decrease pain.⁴⁹ Off-label therapies provide modest benefits, but symptom relief is often inadequate.^5,50,51 In a meta-analysis, peppermint oil and tricyclic antidepressants demonstrated efficacy for global symptoms and pain, but some trials were of short duration and lacked rigour, creating uncertainty (refer to Supplementary Information for details).⁵⁰ Therefore, we recommend first line therapies that are supported by clear evidence and approved by Health Canada.

IBS-D

Health Canada-indicated IBS-D therapies include rifaximin and eluxadoline. Rifaximin is a broad-spectrum antibiotic that alters gut permeability.⁵² Individuals treated with rifaximin experienced significant relief from IBS symptoms, including bloating and pain.⁵³ Its safety profile is similar to placebo,⁵³ with benefit lasting up to 22 weeks and no evidence of resistance.⁵⁴ The recommended dose is 550 mg orally three times a day for 14 days.⁵⁵

Eluxadoline is an opioid receptor agonist/antagonist that reduces GI motility and visceral hypersensitivity.⁵⁶ Phase 3 clinical trials showed decreases in pain and improvements in stool consistency.⁵⁷ There was no indication of symptom worsening or withdrawal after treatment was stopped.⁵⁷ The recommended dose is 100 mg orally twice daily, which may be reduced to 75 mg twice daily for tolerability.⁵⁸ Patients 65 years of age and older should start at 75 mg, increasing to 100 mg if well tolerated.⁵⁸ However, eluxadoline is contraindicated in patients with significant hepatic impairment, excessive alcohol consumption, or cholecystectomy; refer to Supplementary Information for details.⁵⁸

IBS-C

Health Canada-indicated IBS-C therapies include the guanylate cyclase-C (GC-C) agonists linaclotide and plecanatide, which accelerate intestinal transit,⁵⁹ and tenapanor, an inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3), which increases intestinal sodium and fluid.⁶⁰ The efficacy of linaclotide is supported by a phase 3, double-blind, placebo-controlled trial and two open-label trials of up to 78 weeks.^61,62 The recommended dose is 290 μg orally once daily.⁶³ Plecanatide has demonstrated efficacy in two phase 3 trials, and its long-term safety was demonstrated in a 53-week open-label trial.^64,65 The recommended dose is 3 mg orally once daily.⁶⁶ Finally, the long-term safety of tenapanor was demonstrated over 52 weeks in two phase 3 trials.^67-69 The recommended dose is 50 mg orally twice daily (refer to the Supplementary Information for details).⁷⁰

The benefits and safety of the indicated therapies have been established in randomized, placebo-controlled, phase 3 clinical trials.^{53,54,57,61,62,64,65,67-69} However, these drugs have not been compared in head-to-head trials, and the available meta-analyses offer limited support in choosing among the medications.^71-73 Given the current evidence, it is difficult to select a single best choice. Instead, the clinician and patient should participate in shared decision-making, considering the patient’s previous experiences, drug availability, routes and schedules of administration, and cost.

B. Applying the pathway in practice

The significance of PCPs in alleviating the impact of IBS within the community is pivotal and cannot be overemphasized.⁷⁴ However, PCPs are often challenged to reach a timely, positive diagnosis.¹⁴ On average, it takes four years for a patient to receive a definitive diagnosis and up to six years from the onset of symptoms.^2,19 As a result, many patients report feelings of stigma, and a lack of support and empathy.^19,75

The Canadian Association of Gastroenterology (CAG) has published CPGs,²⁶ and guidance for PCPs is available.^8,76-79 Yet, not all are applicable to primary care.²¹ The pathway described herein will increase clinicians’ awareness of the best practices for IBS management in Canada, including the optimal use of nonpharmacological and pharmacological therapies, which should both be implemented early during treatment. The focus on symptom-based criteria, along with limited testing and recommendations for newer therapies that are supported by strong evidence will help PCPs to handle diagnosis and treatment confidently.^19,36

A unique feature of this pathway is that tests and treatment will be carried out in parallel. It is safe to initiate treatment without waiting for test results, which may be time-consuming. Furthermore, exhaustive diagnostic testing is not necessary.^26,78,79 Hence, we recommend limited testing and use of the symptom-based Rome IV criteria (Table 1); no imaging is necessary except in specific circumstances. Treatment should be adjusted based on the test results and treatment responses. We also support building a strong patient-provider relationship based on empathy and education.^26,79

While this pathway is designed for PCPs, who manage most IBS patients, referral to a gastroenterologist is recommended if a patient has alarm features or if tests indicate celiac disease, anemia, IBD, possible malignancy, or if symptoms are refractory to therapy, including changing agents and optimizing dosing.

C. Limitations

These recommendations are based on expert opinion and clinical experience in Ontario as well as recent clinical data. Although the decision tool may apply throughout Canada, some recommendations may not be congruent with local best practices. The application of some of the recommendations will depend on regional resources, including specialist availability, access to therapeutic agents, and insurance coverage.

Conclusions

We report an evidence-based decision tool and treatment pathway for IBS diagnosis and treatment in Canadian primary care. The pathway is simple and practical such that it can be efficiently integrated into practice.

LIST OF ABBREVIATIONS

CBC: Complete blood count

CPG: Clinical practice guideline

CRC: Colorectal cancer

CRP: C-reactive protein

FC: Fecal calprotectin

GI: Gastrointestinal

IBS: Irritable bowel syndrome

IBD: Inflammatory bowel disease

IBS-C: IBS with constipation

IBS-D: IBS with diarrhea

IBS-M: IBS with mixed symptoms

IBS-U: unclassified IBS

OTC: Over the counter

PCP: Primary care physician

DECLARATIONS

COMPETING INTERESTS

LWCL received honoraria for academic lectures from AbbVie, Bausch Health,Knight Therapeutics Inc, Lupin Pharmaceutical, Avir Pharma, and Medtronic; and participated on advisory boards for AbbVie, Bausch Health, and Knight Therapeutics Inc. JM received consulting fees from AbbVie, Amgen, Astra Zeneca, Bausch Health, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Fresenius Kabi, Janssen, Lupin Pharmaceutical, Organon, Paladin, Pfizer, Pharmascience, Roche, Sandoz, Takeda, Teva, and Viatris; and honoraria for academic lectures from AbbVie, Amgen, Bausch Health, Ferring, Fresenius Kabi, Janssen, Lupin Pharmaceutical, Organon, Pfizer, Pharmascience, Roche, Takeda, Viatris. KM received honoraria for academic lectures from Knight Therapeutics Inc and Lupin Pharmaceutical. PN received honoraria for academic lectures from AbbVie, Alexion, AstraZeneca, Bausch Health, Bayer, Boehringer Ingelheim, Eisai, Eli Lilly, GSK, HLS, Janssen, Knight Therapeutics Inc., Merck, Novo Nordisk, Pfizer, and Sanofi; and participated on advisory boards for AbbVie, AstraZeneca, Bausch Health, Boehringer Ingelheim, Eli Lilly, GSK, HLS, Knight Therapeutics Inc., Merck, Novo Nordisk. YT received consulting fees from Knight Therapeutics Inc. and Medtronic; honoraria for academic lectures from Bausch Health and Knight Therapeutics Inc.; and participated on advisory boards for Knight Therapeutics Inc. KW received honoraria for consultancy from Bausch Health.

FUNDING

Funding for assistance with writing and editing the manuscript was provided by Bausch Health Canada.

ACKNOWLEDGEMENTS

The authors extend their gratitude to Margaret Johnson, Ph.D., and STA Healthcare Communications (Montréal, Canada) for their assistance with writing and editing.

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