What about using nortriptyline for Irritable Bowel Syndrome with Mixed diarrhea and constipation (IBS-M)?

Nortriptyline for IBS-M

Nortriptyline is a reasonable second-line treatment option for IBS-M, potentially better tolerated than amitriptyline due to lower anticholinergic effects that are less likely to worsen constipation during mixed bowel habit phases. 1, 2

Why Nortriptyline Makes Sense for IBS-M

Secondary amine TCAs like nortriptyline have lower anticholinergic activity compared to tertiary amines (amitriptyline), making them preferable when constipation is a concern. 1, 2 This is particularly relevant in IBS-M where patients alternate between diarrhea and constipation—the reduced anticholinergic burden means less risk of exacerbating constipation phases while still providing pain relief. 1

The British Society of Gastroenterology gives TCAs a strong recommendation with moderate quality evidence for global IBS symptoms and abdominal pain, explicitly noting that secondary amines may be better tolerated in patients prone to constipation. 1

Practical Prescribing Approach

Start nortriptyline at 10 mg once daily at bedtime and titrate slowly over 3 weeks up to a maximum of 30-50 mg once daily, based on symptom response and tolerability. 1, 3

• The low starting dose minimizes side effects while the gradual titration allows patients to find their optimal dose. 4, 5
• Most patients in the landmark ATLANTIS trial (which used amitriptyline) achieved benefit at doses between 10-30 mg daily. 4, 5
• Counsel patients that this is being used as a "gut-brain neuromodulator" rather than an antidepressant—this explanation significantly improves acceptance and adherence. 1, 3

Expected Benefits and Timeline

Therapeutic effects may take several weeks to manifest, with optimal assessment requiring 6-8 weeks including at least 2 weeks at the highest tolerated dose. 3

The mechanism involves:

• Sodium channel blockade providing analgesic effects for visceral pain 3
• Inhibition of serotonin and norepinephrine reuptake modulating gut-brain signaling 1, 3
• Mild anticholinergic effects that can help with diarrhea phases without being as constipating as amitriptyline 1, 2

Side Effect Profile

Common side effects include dry mouth, mild sedation, and some degree of constipation, though these are less pronounced with nortriptyline than amitriptyline. 1, 3

• In the ATLANTIS trial using amitriptyline, only 13% discontinued due to adverse events versus 9% on placebo—a relatively modest difference. 4
• Screen patients over 40 years with an ECG before initiating therapy, as TCAs can cause QTc prolongation, particularly at doses >100 mg/day. 3
• Avoid in patients with cardiac conduction abnormalities, recent myocardial infarction, or uncontrolled narrow-angle glaucoma. 3

Evidence Quality and Strength

While the highest quality recent trial (ATLANTIS, 2023) specifically studied amitriptyline rather than nortriptyline, the class effect of TCAs is well-established. 4, 5 The trial demonstrated a clinically meaningful 27-point reduction in IBS-SSS scores at 6 months (p=0.0079) and superior subjective global relief (OR 1.78, p=0.005). 4, 5

The American Gastroenterological Association gives TCAs a conditional recommendation with LOW certainty evidence overall, but notes they showed clinically meaningful global relief responses. 1 The British Society gives a strong recommendation with moderate quality evidence. 1

When Nortriptyline May Be Particularly Effective

Post hoc analyses suggest stronger treatment effects in:

• Patients ≥50 years old (mean difference -46.5 points on IBS-SSS, p=0.0010) 6
• Those with higher somatic symptom burden 6
• Men showed numerically stronger effects 6

Important Caveats

TCAs work best as second-line therapy after first-line treatments (dietary modification, fiber, antispasmodics, probiotics) have failed. 1, 4, 5

If the patient has concurrent moderate-to-severe depression or anxiety requiring treatment, standard antidepressant doses of an SSRI may be more appropriate, as low-dose TCAs (10-30 mg) used for IBS are unlikely to adequately address psychiatric symptoms. 2

In elderly patients (≥65 years), use nortriptyline with caution at the lowest effective dose due to anticholinergic cognitive effects and fall risk. 3