What medications are recommended for an adult with irritable bowel syndrome, tailored to diarrhea‑predominant (IBS‑D), constipation‑predominant (IBS‑C), or mixed (IBS‑M) subtypes?

Medications for Irritable Bowel Syndrome

For IBS-D, start with loperamide or an antispasmodic as first-line therapy, then escalate to tricyclic antidepressants (amitriptyline 10 mg nightly, titrated to 30-50 mg) if symptoms persist; for IBS-C, use linaclotide as the most effective second-line agent after fiber fails; for IBS-M, tricyclic antidepressants are the preferred pharmacologic option. 1

IBS-D (Diarrhea-Predominant) Treatment Algorithm

First-Line Agents

• Loperamide is effective for diarrhea but does not reliably improve abdominal pain; titrate the dose carefully (typically 2-6 mg before breakfast, with additional doses as needed) to avoid constipation, bloating, and nausea 1, 2
• Antispasmodics (dicyclomine, hyoscyamine) provide relief for global symptoms and abdominal pain, though dry mouth, visual disturbance, and dizziness are common; use intermittently during symptom flares rather than continuously 1, 3

Second-Line Agents (Moderate to High Quality Evidence)

• Tricyclic antidepressants are the strongest recommendation for IBS-D with abdominal pain; start amitriptyline 10 mg at bedtime and titrate by 10 mg weekly to a maximum of 30-50 mg daily (strong recommendation, moderate quality evidence) 1, 4

  • Explain to patients this is a "gut-brain neuromodulator" rather than treatment for depression to improve acceptance 1, 5
  • Common side effects include dry mouth, sedation, and constipation; benefits may take 3-4 weeks to manifest 4, 3
  • Screen patients over 40 years with ECG before initiating, as doses >100 mg/day can cause QTc prolongation 4

• 5-HT3 receptor antagonists are likely the most efficacious drug class for IBS-D 1

  • Ondansetron 4 mg once daily, titrated to maximum 8 mg three times daily, is a reasonable option when alosetron/ramosetron are unavailable 1
  • Constipation is the most common side effect 1
  • Alosetron is FDA-approved but has restricted use due to ischemic colitis risk (conditional recommendation, moderate evidence) 1

• Eluxadoline 100 mg twice daily is effective (27.2% vs 16.7% FDA endpoint responders compared to placebo), but is contraindicated in patients without a gallbladder or those consuming >3 alcoholic beverages daily due to pancreatitis and sphincter of Oddi spasm risk (conditional recommendation, moderate evidence) 1, 6

• Rifaximin 550 mg three times daily for 14 days is effective, with retreatment recommended if symptoms recur (conditional recommendation, moderate evidence); however, its effect on abdominal pain is limited 1

Agents to Avoid in IBS-D

• SSRIs are NOT recommended for IBS-D or general IBS populations; the American Gastroenterological Association suggests against their use (conditional recommendation, low certainty evidence) as they did not significantly improve symptoms (RR 0.74; 95% CI 0.52-1.06) and may worsen gastrointestinal motility 1, 7, 5

IBS-C (Constipation-Predominant) Treatment Algorithm

First-Line Agents

• Fiber supplements (ispaghula/psyllium) should be introduced gradually; synthetic fiber is often better tolerated than natural fiber, but excessive supplementation can worsen bloating and cramps 1, 3
• Polyethylene glycol laxatives are reasonable first-line options 1

Second-Line Agents (High Quality Evidence)

• Linaclotide (guanylate cyclase-C agonist) is the most efficacious secretagogue for IBS-C and has the strongest recommendation (strong recommendation, high quality evidence); diarrhea is a common side effect 1, 5

• Lubiprostone (chloride channel activator) is less likely to cause diarrhea than other secretagogues, but nausea is a frequent side effect (strong recommendation, moderate evidence) 1

• Plecanatide (guanylate cyclase-C agonist) is effective but diarrhea rates are similar to linaclotide 1

• Tenapanor is another option for IBS-C 1

Neuromodulators for IBS-C

• SSRIs may be considered in IBS-C if secretagogues fail, though evidence is weak (conditional recommendation, low certainty); start citalopram 20 mg daily or paroxetine 10 mg daily 5, 3

  • SSRIs increase gastrointestinal motility, which theoretically benefits constipation, but clinical evidence remains inconsistent 7, 5

• Avoid tertiary amine TCAs (amitriptyline) in IBS-C due to anticholinergic effects worsening constipation 5, 4

  • If a TCA must be used, choose desipramine or nortriptyline (secondary amines with lower anticholinergic effects) 5, 4

IBS-M (Mixed Pattern) Treatment

• Tricyclic antidepressants are the preferred pharmacologic option for IBS-M, as they address abdominal pain and global symptoms without specifically targeting bowel pattern (conditional recommendation, low evidence) 1
• Start amitriptyline 10 mg nightly, titrate to 30-50 mg based on response 1, 4
• Antispasmodics can be used intermittently for pain flares 1

Universal Considerations Across All IBS Subtypes

Probiotics

• Probiotics as a group may improve global symptoms and abdominal pain, but no specific species or strain can be recommended; advise a 12-week trial and discontinue if no improvement (weak recommendation, very low evidence) 1

Critical Pitfalls to Avoid

• Never use eluxadoline in post-cholecystectomy patients—5 cases of pancreatitis occurred in clinical trials, with risk particularly elevated in those without gallbladders 1, 6
• Do not use SSRIs as primary therapy for IBS—they lack efficacy and may worsen symptoms through increased GI motility 1, 7
• Avoid amitriptyline in elderly patients (≥65 years) due to strong anticholinergic effects, fall risk, and cognitive decline; if already prescribed, taper over 2-4 weeks 4
• Screen for alarm features (age >50 with new symptoms, rectal bleeding, unintentional weight loss, iron deficiency anemia, nocturnal diarrhea, family history of colon cancer/IBD/celiac disease) before diagnosing IBS 1

Dosing Timelines and Expectations

• TCAs require 6-8 weeks for adequate therapeutic trial, including 2 weeks at the highest tolerated dose 4
• SSRIs take 3-4 weeks to show benefit, with initial anxiety and sleep disturbance common in the first 10 days 4, 3
• Antispasmodics work acutely; use dicyclomine before meals for predictable postprandial symptoms or sublingual hyoscyamine for unpredictable severe pain episodes 3

When to Refer to Gastroenterology

• Failure of first-line therapies (loperamide, antispasmodics, fiber) warrants consideration of second-line prescription agents, which may require specialty initiation 1
• Eluxadoline, 5-HT3 antagonists, rifaximin, and secretagogues are typically initiated in secondary care 1