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#211 Pain getting on your nerves? Tricyclic antidepressants for neuropathic pain

What are the benefits and harms of using tricyclic antidepressants (TCAs) for neuropathic pain?

Compared to placeboTCAs may provide 30% reduction in pain for an additional 1 in 4-6 people with neuropathic painwith 1 in 5 experiencing an adverse event and 1 in 11 stopping medication because of side effectsOverall, evidence is limited by inconsistent outcome reporting in small studies of short duration.  

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  • Systematic review of 10 Randomized Control Trials (RCTs) of amitriptyline involving 588 patients with predominantly diabetic neuropathy (DN) or post herpetic neuralgia (PHN), followed 3-52 weeks:1 
    • At least moderate (30%) pain relief: 64% versus 32%, Number Needed to Treat (NNT)=4. 
    • Desipramine and imipramine similar. 
  • Systematic Review (four amitriptyline RCTs, 384 patients with DN, PHN, mixed neuropathy, followed 4-9 weeks):2  
    • Inconsistently defined pain relief (examples ³50% pain reduction or patient-reported moderate pain relief)39versus 20%, NNT=6.  
    • At least one adverse effect (six RCTs, 519 patients):  
      • 55% versus 36%; Number Needed to Harm (NNH)=5. 
        • Common adverse effects include sedation, dry mouth, vertigo.3,4  
    • Withdrawal due to adverse effects (three RCTs, 303 patients):  
      • 16% versus 7%NNH=11. 
  • Other systematic reviews did not provide meta-analyses.5-7 Individual study highlights: 
    • 30% pain reduction: 40% nortriptyline versus 37% placebo; patient-reported ‘a lot’ of pain relief: desipramine 17-31% versus 4-8% placebo; patient-reported ‘good’ pain relief: imipramine 23% versus 5% placebo. 
  • Limitations:  
    • Inconsistent outcome reporting.  
    • Small study sizes and short duration (may overestimate treatment effect). 
    • Largest systematic review did not report adverse effects. 
    • No adverse effectanalysis at varying doses despite wide dose ranges (10-150 mg).5 
    • Some crossover designs did not use washout period. 
  • Guidelines8,9 recommend TCAs as a first-line agent for treating neuropathic pain.  
  • Other treatments for neuropathic pain have similar benefit (NNT of 5-8): 
    • Gabapentin, pregabalinserotonin-noradrenaline reuptake inhibitors, tramadol, and opioids.10 
    • Desipramine and nortriptyline11 may be better tolerated than imipramine and amitriptyline, particularly in geriatrics.12 
  • TCAs cost ~$25-75 for 90 days (25 mg). Others:13-14 
    • ~$60 duloxetine, ~$65 gabapentin, ~$110 pregabalin.13  

Aidlee Craft May 27, 2024

Price differential is important for those with drug coverage

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  • Danielle Perry RN
  • Joey Ton PharmD
  • Michael R Kolber BSc MD CCFP MSc

1. Saarto T, Wiffen PJ. Cochrane Database Syst Rev. 2007;(4):CD005454.

2. Moore RA, Derry S, Aldington D, et al. Cochrane Database Syst Rev. 2015; (7):CD008242.

3. Vrethem M, Boivie J, Arnqvist H, et al. Clin J Pain. 1997 Dec; 13(4):313-23.

4. Biesbroeck R, Bril V, Hollander P, et al. Adv Ther. 1995 Mar-Apr; 12(2):111-20.

5. Hearn L, Derry S, Phillips T, et al. Cochrane Database Syst Rev. 2014; (5):CD010769.

6. Hearn L, Moore RA, Derry S, et al. Cochrane Database Syst Rev. 2014; (9):CD011003.

7. Derry S, Wiffen PJ, Aldington D, et al. Cochrane Database Syst Rev. 2015; (1):CD011209.

8. Moulin DE, Boulanger A, Clark AJ, et al. Pain Res Manag. 2014; 19(6):328-335.

9. Attal N, Cruccu G, Baron R, et al. Eur J Neurol. 2010 Sep; 17(9):1113-e88.

10. Finnerup N, Attal N, Haroutounian S, et al. Lancet Neurol. 2015 Feb; 14(2):162-73.

11. Watson P, Vernich L, Chipman M, et al. Neurology. 1998 Oct; 51(4):1166-71.

12. CPS [Internet]. Ottawa (ON): Canadian Pharmacists Association; c2018 [updated 2016 December; cited 2018 03 20]. Tricyclic Antidepressants [product monograph] Available from: or

13. Nickonchuk T, Lee J, Kolber M, et al. Available from: Last accessed: February 15, 2018.

14. Alberta Health. Interactive drug benefit list. Available from: Last accessed: February 22, 2018.

Authors do not have any conflicts of interest to declare.

Les auteurs n’ont aucun conflit d’intérêts à déclarer.