Tricyclic Antidepressants

Written by: Dr Jeremy Steinberg – created: 29 March 2023; last modified: 23 April 2025

This article is still missing information.

Tricyclic Antidepressants (TCAs) are well-studied and widely recommended as a first-line therapy for neuropathic pain. They have proven efficacy in managing peripheral neuropathy, post-herpetic neuralgia, and neuropathic pain following spinal cord injury, and exhibit limited efficacy for radiculopathy, HIV, and chemotherapy-induced peripheral neuropathy.

Mechanism

The primary pain-relieving mechanism of TCAs is the inhibition of presynaptic uptake of serotonin (5-HT) and noradrenaline thereby increasing the concentraiton of these monoamines in the synaptic cleft, particularly in the spinal cord dorsal horn. This action enhances the activity of descending inhibitory pain pathways originating from the locus coeruleus (NE) and raphe nuclei (5-HT/NE).

TCAs possess additional mechanisms that may contribute to analgesia and side effects. They also block H1 receptors and muscarinic acetylcholine receptors (amitriptyline more than nortriptyline), adrenaline, acetylcholine, and sodium channels (contributing to anti-hyperexcitability effects), weak antagonism of NMDA receptors, which contributes to their broad side effect profile. Notably, their analgesic effect is independent of their antidepressant effect and occurs at a lower dosage (20-30% of the antidepressant dosage).

Evidence

A Cochrane review of 61 randomized controlled trials found that TCAs had a number needed to treat (NNT) of 3.6 to achieve moderate pain relief, with a number needed to harm (NNH) of 28 for major adverse effects and 9 for minor adverse effects. A separate trial determined that high-dose TCAs had an NNT of 7.6 and an NNH of 9.2 in neuropathic pain associated with spinal cord injury. It is recommended to trial TCAs for four to eight weeks; inadequate pain relief should prompt consideration of alternative first-line medications or combination therapy.

Prescribing

For nortriptyline and amitriptyline, start at 10–25 mg at dinner time. The maximum daily dose is 150mg.

Caution is advised when prescribing TCAs to elderly and frail patients due to potential adverse effects, such as falls, cardiac arrhythmias, orthostasis, urinary retention, and dry mouth. Also further caution with autonomic neuropathy, urinary retension, glaucoma, or if also taking an SNRI, SSRI, MAOI, and/or tramadol.

Adverse Effects

Tolerability is a major limiting factor for TCAs. Common side effects include anticholinergic effects (dry mouth, constipation, urinary retention, blurred vision, cognitive impairment), antihistaminic effects (sedation, weight gain), and cardiovascular effects (orthostatic hypotension, tachycardia, potential for cardiac conduction abnormalities, particularly at higher doses). Due to these risks, TCAs should be used cautiously, especially in elderly patients and those with pre-existing cardiac conditions, glaucoma, or urinary retention. There is also a significant risk of serotonin syndrome when combined with other serotonergic agents like MAOIs, SSRIs, or SNRIs.⁴¹ TCAs have numerous potential drug interactions.

Literature Review

Literature Review

Reviews from the last 7 years: review articles, free review articles, systematic reviews, meta-analyses, NCBI Bookshelf

Articles from all years: PubMed search, Google Scholar search.

TRIP Database: clinical publications about evidence-based medicine.

Other Wikis: Radiopaedia, Wikipedia Search, Wikipedia I Feel Lucky, Orthobullets,