Background   Tricyclic antidepressants (TCAs) are a class of drugs largely developed as antidepressants but are also used, mostly off-label, for analgesic indications including postherpetic neuralgia, diabetic neuropathy (DN), fibromyalgia, back pain, and cancer related pain. Amitriptyline is the most well-studied TCA for pain (1,2); doxepin, imipramine, nortriptyline, and desipramine have been used as analgesics as well. This Fast Fact reviews the analgesic role of TCAs as a medication class.

Mechanism   TCAs have analgesic effects via inhibition of norepinephrine and serotonin reuptake in the central nervous system. This is in addition to their antidepressant effects which some postulate helps with pain perception and expectations (3-6). TCAs are categorized into secondary (nortriptyline, desipramine) and tertiary (amitriptyline, imipramine) amines. Secondary amines have less antihistaminergic and anticholinergic activity than tertiary amines (7,8). While antihistaminic and anticholinergic effects may be desirable in those with sleep issues, they increase the risk of delirium. In general, tertiary amines especially should be avoided in patients at risk for delirium (e.g., age >65, cognitive impairment). 

Clinical trial data     The most robust supporting data for the analgesic use of TCAs has been in patients with non-cancer related neuropathic pain.

• Non-cancer, neuropathic pain: Systematic reviews and meta-analyses of antidepressants and antiepileptic drugs suggest that the number needed to treat for 50% pain reduction in non-cancer, neuropathic pain is 2.1-3 for TCAs (compared to 4-4.6 for serotonin norepinephrine reuptake inhibitors (SNRI) and 4.1-5.1 for gabapentin) (8,9). However, the number needed to harm was 13.6 for TCAs vs 21.5 for SNRIs and 26.1 for gabapentin (9,10). Data regarding more specific non-cancer neuropathic pain conditions are below.
  • Post-herpetic neuralgia: several studies demonstrated analgesic efficacy of amitriptyline and nortriptyline (11-13). However, additional randomized trials suggest that amitriptyline and nortriptyline’s analgesic efficacy is non-superior to gabapentin and pregabalin and gabapentin and pregabalin may be better tolerated (14,15). 
  • DN: randomized, blinded, placebo-controlled crossover trials found amitriptyline and desipramine to be effective analgesics (16,17). There is not clear evidence TCAs improve quality of life for patients with DN and furthermore, comparative data are insufficient to recommend TCAs over other established DN analgesics such as duloxetine and venlafaxine (18).
• Fibromyalgia: Approximately 30-47% report moderate improvement in pain from amitriptyline, however, subsequent data suggest this treatment effect wanes after a few months and may not be superior to other antidepressants, NSAIDs, exercise, or physical therapy (19,20).
• Chronic back pain:  a meta-analysis suggested TCAs along with other antidepressants can have a small but significant reduction in chronic, musculoskeletal pain. However, in this meta-analysis, TCAs were not associated with significant improvements in functional capacity (21).
• Cancer related pain: amitriptyline has been shown to reduce neuropathic pain from breast cancer, but it is limited by its anticholinergic side effect profile (22). Nortriptyline is commonly substituted for amitriptyline for cancer-related neuropathic pain; however, less is known about its effectiveness. An oral doxepin rinse may reduce cancer-treatment-related mucositis pain (23,24). See Fast Fact #450.

Prescribing pearls

• Amitriptyline: start at 10 mg at bedtime and titrate weekly to effect as tolerated; maximum dose of 150 mg daily. Avoid in older patients due to anticholinergic side effects.
• Nortriptyline: start at 10 mg/day, increase the dose weekly in 10 to 25 mg increments based on response and tolerability; maximum dose of 75 to 150 mg daily.
• Desipramine: start at 25 mg/day, dose can be increased to up to 200 mg/day over a few weeks.
• Imipramine: initial dose 50 mg orally at bedtime, titrate up to 150 mg/day (25).
• Doxepin: 25 mg of a 5 mg/mL aqueous suspension containing 0.1% alcohol and sorbitol rinse for one minute then spit every 4 hours as needed can reduce mucositis pain from radiation therapy (23,24).
• In patients >65 years of age: the maximum dose for secondary amines is half the usual maximal dose. Again, tertiary amines are relatively contraindicated in this patient population.
• The risk of serious toxicity increases in all age groups with dose.
• The therapeutic effect of TCAs for pain usually occurs within six weeks and at lower doses than is typical when TCAs are prescribed for depression.
• As a class, commonly prescribed TCAs (amitriptyline, desipramine, nortriptyline, doxepin) are inexpensive (e.g., $5-15 for a monthly supply).

Adverse effects & contraindications     Anticholinergic adverse effects include dry mouth, orthostatic hypotension, constipation, delirium, and urinary retention (26). These side effects can be reduced by starting with low doses at bedtime and titrating the dose slowly.TCAs are relatively contraindicated in patients with severe cardiac disease, due to increased intraventricular and AV node conduction and QT interval prolongation (24). Caution must be taken when co-prescribed with other serotonergic medications (e.g., SSRIs) due to a risk for serotonin syndrome (27).

Summary   There is a moderate level of evidence that TCAs provide pain relief for many common neuropathic pain conditions. Concern for anticholinergic adverse effects limit its use. For younger patients with chronic neuropathic pain and/or concomitant depression or insomnia, TCAs can be considered.

References

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17. Carette J, Bell MJ, et al.  Comparison of amitriptyline, cyclobenzaprine, and placebo in the treatment of fibromyalgia: a randomized, double-blind clinical trial. Arhtritis Rheum. 1994; 3732-40.
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20. Salerno SM, Browning R, Jackson JL. The effect of antidepressant treatment on chronic back pain: a meta-analysis. Arch Intern Med. 2002; 162:19-24.
21. Kalso E, Tasmuth T, Neuvonen PJ. Amitripyline effectively relieves neuropathic pain following treatment of breast cancer. Pain. 1996; 64(2):293-302.
22. Epstein JB, Epstein JD, et al.  Doxepin rinse for management of mucositis pain in patients with cancer: one week follow-up of topical therapy. Spl Care Dent. 2008; 28(2):73-77.
23. Leenstra JL, Miller RC, Qin R, et al.  Doxepin rinse versus placebo in the treatment of acute oral mucositis in patients receiving head and neck cancer radiotherapy with or without chemotherapy: a phase III, randomized, double-blind trial. J Clin Oncol. 2014; 32(15):1571-1577
24. Sindrup SH, Bach FW, Madsen C, et al. Venlafaxine versus imipramine in painful polyneuropathy: a randomized, controlled trial. Neurology. 2003; 60(8):1284-1289.
25. Arana, GW, Rosenbaum, JF. Antidepressant drugs. In: Handbook of Psychiatric Drug Therapy, 4th ed. Lippincott Williams & Wilkins, Philadelphia 2000. p.53.
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Disclosures: The authors have not disclosed any relevant conflicts of interest.

Authors’ Affiliations: The Medical College of Wisconsin, Milwaukee, WI (SM); University of Virginia Medical Center, Charlottesville, VA (JT).
Version History: originally edited by Drew A Rosielle MD; first electronically published in February 2024.
Editor’s Note: This Fast Fact was initially submitted by Kang Choi DO. Subsequent to its first submission the editors regretfully lost contact with Dr Choi and have been unable to re-establish contact with him as of the time of publication of this Fast Fact. In 2023-2024 Drs Sean Marks and Jennifer Turpen took the original draft, did additional literature review and extensive re-writing of the Fast Fact to ready it for publication. The current authorial ordering is a good faith estimation of the amount of work contributed to this Fast Fact.
–Drew Rosielle MD, Associate Editor of Fast Facts and Concepts, February 5, 2024.