What medications are used to treat irritable bowel syndrome (IBS) with diarrhea?

Medications for IBS with Diarrhea (IBS-D)

For IBS-D, start with loperamide 4-12 mg daily for diarrhea control, combined with soluble fiber (ispaghula 3-4 g/day) and dietary modifications; if symptoms persist after 4 weeks, escalate to tricyclic antidepressants (amitriptyline 10-30 mg nightly) for global symptom relief and abdominal pain. 1, 2, 3

First-Line Pharmacological Approach

Loperamide (Primary Agent for Diarrhea Control)

• Loperamide is the preferred first-line medication for controlling stool frequency, urgency, and consistency in IBS-D 1, 3
• Dose: 4-12 mg daily, either as divided doses throughout the day or as a single 4 mg dose at night 1, 3
• Many patients learn to use loperamide prophylactically before situations where diarrhea would be problematic 1
• Important limitation: Loperamide improves stool consistency but has minimal effect on abdominal pain, which is a core IBS symptom 1, 3

Antispasmodics (For Abdominal Pain)

• Anticholinergic antispasmodics like dicyclomine effectively treat abdominal pain and global IBS symptoms, particularly when symptoms worsen after meals 1, 2, 4
• Common side effects include dry mouth, visual disturbances, and dizziness, which may limit tolerability 1, 2, 4
• Peppermint oil serves as an effective alternative antispasmodic with gastroesophageal reflux being the main side effect 2, 3

Dietary Modifications (Essential Adjunct)

• Start soluble fiber (ispaghula/psyllium) at 3-4 g/day and increase gradually to avoid bloating 2, 3
• Avoid insoluble fiber (wheat bran) as it worsens IBS-D symptoms 2, 3
• Reduce intake of lactose, fructose, sorbitol, caffeine, and alcohol as these commonly trigger diarrhea 3
• Consider low-FODMAP diet as second-line dietary therapy, but only under dietitian supervision 3

Second-Line Pharmacological Treatments

Tricyclic Antidepressants (Most Effective for Global Symptoms)

• TCAs are the most effective second-line treatment for global IBS symptoms and abdominal pain 1, 2, 3
• Start amitriptyline at 10 mg once nightly and titrate slowly (by 10 mg/week) up to 30-50 mg once daily based on response and tolerability 2, 3
• TCAs work through peripheral and central mechanisms affecting motility, secretion, and visceral sensation—not just mood effects 1
• Continue for at least 6 months if the patient reports symptomatic response 3
• When prescribing TCAs, clearly explain they are being used for gut-brain modulation, not depression 2, 3

5-HT3 Receptor Antagonists (For Refractory IBS-D)

Alosetron

• FDA-approved specifically for women with severe IBS-D 1
• Start at 0.5 mg once daily; if symptoms not controlled after 4 weeks, increase to 1 mg twice daily 1
• If constipation develops, discontinue until symptoms resolve, then restart at 0.5 mg once daily 1
• Discontinue if symptoms persist after 4 weeks at maximum dose 1

Ondansetron

• Start at 4 mg once daily and titrate to maximum 8 mg three times daily 2
• Highly efficacious for IBS-D as a second-line option 2, 4

Rifaximin (Non-Absorbable Antibiotic)

• FDA-approved for IBS-D treatment 5, 6
• Rifaximin has the most favorable safety profile among FDA-approved IBS-D agents 7, 8
• Effective for global IBS-D symptoms, though effect on abdominal pain is limited 2
• Systemic absorption is minimal, making it unsuitable for systemic infections but ideal for gut-targeted therapy 6

Eluxadoline (Mixed Opioid Receptor Modulator)

• FDA-approved for IBS-D in adults 5
• Dose: 100 mg twice daily 9
• Effective for both abdominal pain and stool consistency in patients with inadequate response to loperamide 9
• Critical contraindications: prior sphincter of Oddi problems, cholecystectomy, alcohol dependence, pancreatitis, or severe liver impairment 2, 5
• No cases of sphincter of Oddi spasm or pancreatitis were reported in patients with intact gallbladders 9

SSRIs (Alternative Neuromodulator)

• The AGA suggests against using SSRIs for IBS due to lower quality evidence compared to TCAs 1
• May be considered when TCAs are not tolerated, though evidence quality is lower 2, 3
• SSRIs increase gastric and intestinal motility but have less impact on visceral sensation compared to TCAs 1, 2

Alternative Agents for Specific Situations

Bile Acid Sequestrants

• Cholestyramine may benefit patients with bile acid malabsorption, particularly those with prior cholecystectomy 1, 3
• Effective only when SeHCAT retention is <5% 1
• Tolerability is poor; many patients prefer loperamide which is equally effective 1

Codeine

• Dose: 15-30 mg, 1-3 times daily 1
• Effective for functional diarrhea but more likely to cause sedation and drug dependency compared to loperamide 1

Treatment Algorithm

1. Start with loperamide 4-12 mg daily + soluble fiber + dietary modifications 1, 3
2. Add antispasmodic (dicyclomine or peppermint oil) if abdominal pain persists 2, 3
3. If inadequate response after 4 weeks, escalate to TCA (amitriptyline 10 mg nightly, titrate to 30-50 mg) 2, 3
4. For refractory symptoms despite TCA trial, consider:
   • Rifaximin (best safety profile) 7, 8
   • Eluxadoline 100 mg twice daily (if gallbladder intact and no contraindications) 2, 5, 9
   • 5-HT3 antagonists (ondansetron or alosetron) 1, 2

Critical Pitfalls to Avoid

• Do not use insoluble fiber (wheat bran) in IBS-D—it exacerbates symptoms 2, 3
• Screen for cholecystectomy before prescribing eluxadoline—it is contraindicated 2, 5
• Consider bile acid malabsorption in patients with nocturnal diarrhea or prior cholecystectomy 3
• When switching from TCAs to SSRIs, consider a washout period to avoid drug interactions 2
• Avoid IgG-based food elimination diets—they are not evidence-based 3
• Do not recommend gluten-free diet unless celiac disease is confirmed 3

Psychological Therapies (Adjunctive)

• Refer for IBS-specific cognitive behavioral therapy or gut-directed hypnotherapy when symptoms persist despite first-line treatments 3
• Strongly recommended when symptoms are refractory to drug treatment for 12 months 3