Tricyclic Antidepressants

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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. The primary pain-relieving mechanism of TCAs is the inhibition of serotonin and norepinephrine reuptake, although they also block histamine, adrenaline, acetylcholine, and sodium channels, 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).[1]

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.[2] 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.[3] 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.[4][5]


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.


  1. Mu, Alex; Weinberg, Erica; Moulin, Dwight E.; Clarke, Hance (2017-11). "Pharmacologic management of chronic neuropathic pain: Review of the Canadian Pain Society consensus statement". Canadian Family Physician Medecin De Famille Canadien. 63 (11): 844–852. ISSN 1715-5258. PMC 5685445. PMID 29138154. Check date values in: |date= (help)
  2. Saarto, T.; Wiffen, P. J. (2007-10-17). "Antidepressants for neuropathic pain". The Cochrane Database of Systematic Reviews (4): CD005454. doi:10.1002/14651858.CD005454.pub2. ISSN 1469-493X. PMID 17943857.
  3. Sindrup, Søren H.; Otto, Marit; Finnerup, Nanna B.; Jensen, Troels S. (2005-06). "Antidepressants in the treatment of neuropathic pain". Basic & Clinical Pharmacology & Toxicology. 96 (6): 399–409. doi:10.1111/j.1742-7843.2005.pto_96696601.x. ISSN 1742-7835. PMID 15910402. Check date values in: |date= (help)
  4. Dworkin, Robert H.; O'Connor, Alec B.; Audette, Joseph; Baron, Ralf; Gourlay, Geoffrey K.; Haanpää, Maija L.; Kent, Joel L.; Krane, Elliot J.; Lebel, Alyssa A.; Levy, Robert M.; Mackey, Sean C. (2010-03). "Recommendations for the pharmacological management of neuropathic pain: an overview and literature update". Mayo Clinic Proceedings. 85 (3 Suppl): S3–14. doi:10.4065/mcp.2009.0649. ISSN 1942-5546. PMC 2844007. PMID 20194146. Check date values in: |date= (help)
  5. Bates, Daniel; Schultheis, B. Carsten; Hanes, Michael C.; Jolly, Suneil M.; Chakravarthy, Krishnan V.; Deer, Timothy R.; Levy, Robert M.; Hunter, Corey W. (2019-06-01). "A Comprehensive Algorithm for Management of Neuropathic Pain". Pain Medicine (Malden, Mass.). 20 (Suppl 1): S2–S12. doi:10.1093/pm/pnz075. ISSN 1526-4637. PMC 6544553. PMID 31152178.

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