For Irritable Bowel Syndrome with Constipation (IBS-C), which Tricyclic Antidepressants (TCAs) are preferred?

TCAs for IBS-C: Use Secondary Amines (Nortriptyline or Desipramine) Over Tertiary Amines

For IBS-C specifically, secondary amine TCAs (nortriptyline or desipramine) are preferred over tertiary amines (amitriptyline or imipramine) due to their lower anticholinergic effects, which minimizes worsening of constipation. 1

Why TCAs Are Used in IBS-C

TCAs function as gut-brain neuromodulators with both peripheral and central actions affecting motility, secretion, and visceral sensation—not primarily as antidepressants in this context. 2 They demonstrate efficacy for:

• Global symptom relief (RR 0.67; 95% CI 0.54-0.82) 2
• Abdominal pain reduction (RR 0.76-0.94) 2
• TCAs ranked first among all treatments for IBS pain across all subtypes in network meta-analysis 2

The Critical Distinction: Secondary vs. Tertiary Amines

Secondary Amines (PREFERRED for IBS-C):

• Nortriptyline or desipramine 2, 1
• Lower anticholinergic burden means less constipation, dry mouth, and urinary retention 2, 1
• Better tolerated in IBS-C patients where constipation is already problematic 1

Tertiary Amines (AVOID in IBS-C):

• Amitriptyline or imipramine 2, 1
• Higher anticholinergic effects worsen constipation through muscarinic-1 receptor blockade 1
• More sedation and anticholinergic side effects (dry mouth, constipation, urinary retention) 2, 1

Practical Dosing Protocol

Start low and titrate slowly: 2, 1

• Begin at 10 mg at bedtime 2, 1
• Increase by 10 mg weekly or every 2 weeks based on response and tolerability 2, 1
• Target dose: 30-50 mg at bedtime (maximum) 2, 1
• Take with food to minimize GI side effects 3

Allow adequate trial duration: 1

• Requires 6-8 weeks total, including 2 weeks at the highest tolerated dose, for full therapeutic assessment 1
• Analgesic effects take several weeks as central sensitization pathways are modulated 1

When to Use TCAs in IBS-C Treatment Algorithm

TCAs are second-line therapy after first-line IBS-C treatments have failed: 2, 1

1. First-line for IBS-C: Secretagogues (linaclotide 290 mcg daily, lubiprostone, plecanatide, tenapanor) 2, 4
2. Second-line: TCAs (preferably secondary amines) when pain is the predominant refractory symptom 2, 1

Important Clinical Caveats

Cardiovascular Screening:

• Obtain ECG before initiating in patients >40 years or with cardiac risk factors 1
• TCAs cause QTc prolongation, arrhythmias, and conduction delays, particularly at doses >100 mg/day 1
• Keep doses <100 mg/day when possible in patients with cardiac risk 1

Elderly Patients (≥65 years):

• TCAs are potentially inappropriate due to strong anticholinergic effects 1
• Associated with falls, stroke, cognitive decline, and death in older adults 1
• Use lower doses and monitor carefully, or consider alternative neuromodulators 1

Side Effect Profile:

• Common: sedation, dry mouth, constipation (dose-dependent anticholinergic effects) 2, 1
• Withdrawal rate due to adverse effects is significantly higher than placebo (RR 2.11; 95% CI 1.35-3.28) 2

Alternative Neuromodulators if TCAs Fail or Are Contraindicated

If secondary amine TCAs are ineffective or poorly tolerated: 2

• SNRIs (duloxetine): Start 30 mg daily, titrate to 60 mg daily 2
• Mirtazapine: Start 15 mg daily, titrate to 45 mg daily 2
• Both have norepinephric effects providing better analgesia than SSRIs 2

Avoid SSRIs for IBS pain—they have minimal analgesic effect and the AGA suggests against their use for IBS 2

Key Pitfall to Avoid

Do not use amitriptyline as first-choice TCA in IBS-C. While amitriptyline is the most studied TCA in IBS trials 2, 1, its tertiary amine structure with high anticholinergic activity will exacerbate constipation in IBS-C patients. 1 The evidence supporting TCAs applies to the class, but clinical judgment dictates choosing the agent least likely to worsen the patient's predominant bowel pattern. 1