Tricyclic Antidepressants with the Lowest Side Effect Profiles

Comparison of TCAs by Side Effect Profile

Secondary-amine TCAs are considered safer because of their lower affinity for muscarinic receptor antagonism 1
Tertiary-amine TCAs are associated with significant adverse anticholinergic effects and are considered potentially inappropriate medications in the American Geriatric Society's Beers Criteria 1
A meta-analysis comparing SSRIs with TCAs showed that patients receiving TCAs were more likely to withdraw from studies and discontinue drug therapy because of adverse reactions 1

Data from a large retrospective study showed an increased risk of sudden cardiac death associated with TCA doses >100 mg/day 2
Caution should be taken in any patient with a history of cardiovascular disease, and some authorities recommend an electrocardiogram before starting treatment 2

Common anticholinergic side effects include dry mouth, blurred vision, constipation, urinary retention, and cognitive impairment 3
Secondary amine TCAs (nortriptyline, desipramine) have significantly fewer anticholinergic effects than tertiary amine TCAs (amitriptyline, imipramine) 1

For painful diabetic peripheral neuropathy, amitriptyline and imipramine are commonly prescribed at doses of 25-75 mg/day, but secondary amine TCAs like nortriptyline and desipramine are better tolerated 2
For irritable bowel syndrome, TCAs have shown efficacy for global symptoms and abdominal pain, with secondary amine TCAs being preferred for IBS-C due to their lower anticholinergic effects 4
For chronic low back pain, tricyclic antidepressants were slightly to moderately more effective than placebo for pain relief 5

Start at a low dose, especially in older adults (approximately 50% of the adult starting dose) 1
Carefully titrate the dose to minimize side effects, using small increments at intervals that allow an adequate period of observation (usually at least a week at each dose level) 3
The analgesic dose is potentially lower than the antidepressant dose for TCAs 3
If treatment must be stopped, dose tapering is advisable to reduce the risk of a discontinuation syndrome 3