What is the recommended treatment for an adult with irritable bowel syndrome with predominant diarrhea (IBS‑D)?

Treatment of IBS-D (Irritable Bowel Syndrome with Diarrhea)

Start with dietary modifications and loperamide as first-line therapy, then escalate to tricyclic antidepressants if symptoms persist after 4-6 weeks, reserving 5-HT3 antagonists (ondansetron) and rifaximin as the most effective second-line options for refractory cases. 1

First-Line Treatment Approach

Dietary Interventions

• Begin with soluble fiber supplementation using ispaghula (psyllium) 3-4 g/day, building up gradually to avoid bloating, as this improves global IBS symptoms and abdominal pain with strong evidence. 1, 2
• Completely avoid insoluble fiber (wheat bran) as it consistently worsens symptoms, particularly bloating and diarrhea. 1, 2
• Advise regular meal patterns, adequate hydration, and limiting caffeine, alcohol, and gas-producing foods as foundational dietary advice. 2
• Regular physical exercise should be encouraged as it improves global IBS symptoms and forms the foundation of treatment. 2

First-Line Pharmacotherapy for Diarrhea Control

• Loperamide 2-4 mg up to four times daily is the first-line medication to reduce stool frequency, urgency, and fecal soiling. 1, 2
• Titrate the dose carefully starting at 2 mg once daily and increase gradually, as abdominal pain, bloating, nausea, and constipation are common side effects that may limit tolerability. 1, 3
• Reassess after 4-6 weeks; if constipation develops, discontinue immediately and may restart at lower dose only after symptoms resolve. 3, 4

Antispasmodics for Abdominal Pain

• Consider antispasmodics with anticholinergic properties for abdominal pain and global symptoms, though warn patients about common side effects including dry mouth, visual disturbance, and dizziness. 1, 2
• These can be used concomitantly with loperamide if both diarrhea and pain are prominent. 1

Probiotics as Alternative First-Line Option

• A 12-week trial of probiotics may be effective for global symptoms and abdominal pain, though no specific species or strain can be recommended; discontinue if no improvement occurs. 1, 2

Second-Line Dietary Therapy (Before Escalating Medications)

• If first-line treatments fail after 4-6 weeks, implement a low-FODMAP diet supervised by a trained dietitian with planned reintroduction of foods according to tolerance. 1, 2, 4
• This is effective for global symptoms and abdominal pain with approximately 52-86% of patients achieving symptom reduction. 4
• Never use IgG antibody-based food elimination diets as they lack evidence and may lead to unnecessary dietary restrictions. 1, 2
• Do not recommend gluten-free diets unless celiac disease has been confirmed. 1, 2, 4

Second-Line Pharmacotherapy (Most Critical Decision Point)

Tricyclic Antidepressants (TCAs) - First Choice for Most Patients

• TCAs are the most effective second-line drug for global symptoms and abdominal pain in IBS-D, with strong evidence and moderate quality. 1, 2
• Start amitriptyline 10 mg once daily at bedtime, titrate slowly by 10 mg every 1-2 weeks to a maximum of 30-50 mg once daily. 1, 2, 4
• Provide careful explanation that TCAs are used as gut-brain neuromodulators, not for depression, and counsel about side effects including dry mouth, drowsiness, and constipation. 1, 2
• Continue for at least 6 months if symptomatic response occurs. 4

SSRIs - Alternative When TCAs Not Tolerated

• The 2022 AGA guideline makes a conditional recommendation AGAINST SSRIs for IBS-D (low certainty evidence), representing a shift from prior recommendations. 1
• However, the 2021 British Society of Gastroenterology guideline suggests SSRIs may be effective as second-line gut-brain neuromodulators, particularly if psychological symptoms (anxiety, depression) are prominent. 1, 4
• This represents contradictory evidence; in clinical practice, reserve SSRIs for patients who cannot tolerate TCAs or have significant comorbid anxiety/depression. 1, 4

Most Effective Second-Line Options for Refractory IBS-D

5-HT3 Receptor Antagonists - Highest Efficacy

• 5-HT3 receptor antagonists are likely the most efficacious drug class for IBS-D, with moderate to high quality evidence. 1
• Ondansetron is the most practical option: start at 4 mg once daily, titrate to a maximum of 8 mg three times daily based on response. 1, 4
• Alosetron and ramosetron have strong efficacy but are unavailable in many countries; alosetron is restricted in the US due to ischemic colitis risk. 1
• Constipation is the most common side effect and requires dose adjustment. 1

Rifaximin - Effective for Global Symptoms

• Rifaximin 550 mg three times daily for 14 days is efficacious for IBS-D in secondary care, though its effect on abdominal pain is limited. 1, 5
• Patients who experience symptom recurrence can be retreated up to two times with the same dosage regimen. 5
• The drug is FDA-approved for IBS-D in the USA but is not available for this indication in many countries. 1, 5
• This is a non-absorbable antibiotic with minimal systemic effects. 1, 5

Eluxadoline - For Combined Pain and Diarrhea

• Eluxadoline (mixed opioid receptor drug) is efficacious for IBS-D when both abdominal pain and diarrhea are prominent. 1, 4
• It is contraindicated in patients with prior sphincter of Oddi problems or cholecystectomy, alcohol dependence, pancreatitis, or severe liver impairment. 1
• The 2022 AGA guideline gives this a conditional recommendation with moderate certainty evidence. 1

Algorithm for Treatment Escalation

1. Weeks 0-6: Soluble fiber (ispaghula 3-4 g/day) + loperamide (2-4 mg up to QID) + dietary advice + regular exercise 1, 2

2. Weeks 6-12: If inadequate response, add low-FODMAP diet (supervised by dietitian) OR initiate TCA (amitriptyline 10 mg at bedtime, titrate to 30-50 mg) 1, 2, 4

3. After 12 weeks: If still refractory, escalate to:

   • Ondansetron 4-8 mg daily (most efficacious) 1, 4
   • OR rifaximin 550 mg TID for 14 days (if global symptoms predominate) 1, 5
   • OR eluxadoline (if both pain and diarrhea are severe and no contraindications) 1, 4

4. After 6-12 months: If symptoms persist despite pharmacological treatment, consider IBS-specific cognitive behavioral therapy or gut-directed hypnotherapy. 2, 4

Critical Pitfalls to Avoid

• Never start with insoluble fiber as it will worsen diarrhea and bloating. 1, 2
• Do not use loperamide chronically without reassessing the underlying diagnosis, as the patient may have inflammatory bowel disease, bile acid diarrhea, or other conditions requiring specific treatment. 3
• Avoid promising complete symptom resolution; the goal is symptom relief and improved quality of life, not cure. 1, 2
• Do not prescribe eluxadoline to patients with prior cholecystectomy or sphincter of Oddi dysfunction due to pancreatitis risk. 1
• Discontinue loperamide immediately if constipation develops, as fecal impaction can occur after 3 days without bowel movement. 3
• Do not ignore psychological comorbidity, as anxiety and depression are major risk factors for IBS development and maintenance, particularly in post-infectious IBS. 4

When to Refer to Gastroenterology

• Refer when there is diagnostic doubt, severe symptoms, or symptoms refractory to first-line treatments after 12 weeks. 2
• Atypical features requiring specialist evaluation include: nocturnal diarrhea, prior cholecystectomy (consider bile acid diarrhea testing with SeHCAT scanning or serum 7α-hydroxy-4-cholesten-3-one), age >50 years with new-onset symptoms, unintentional weight loss, or family history of colon cancer or inflammatory bowel disease. 1