Current Pain and Headache Reports

, Volume 7, Issue 1, pp 24–33 | Cite as

Antidepressants for chronic neuropathic pain

  • Lori Reisner


Tricyclic antidepressants have been used to manage pain for several decades, and are superior treatments for some patients suffering from neuropathic pain. Unfortunately, older antidepressants have dose-limiting side effects that can lead to drug intolerance. The most common are anticholinergic side effects, although some patients experience sexual dysfunction. Cognitive impairment, sedation, and orthostatic hypotension also are relatively common. Taking an overdose of tricyclic antidepressants can be lethal in overdose. Several weeks of therapy may be required before antinociception occurs, but tricyclic antidepressants in optimal doses appear to be the most effective treatment for neuropathic pain; this is supported by systematic reviews comparing them with other agents. Newer medications such as atypical antidepressants and anticonvulsants may be overtaking older antidepressants, but they should not be overlooked as important options for the management of pain.


Neuropathic Pain Imipramine Amitriptyline Venlafaxine Bupropion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Krishnan KR, France RD: Antidepressants in chronic pain syndromes. Am Fam Physician 1989, 4:233–237.Google Scholar
  2. 2.
    Lee R, Spencer PS: Antidepressants and pain: a review of the pharmacologic data supporting the use of certain tricyclics in chronic pain. J Int Med Res 1977, 5(suppl 1):146–156.PubMedGoogle Scholar
  3. 3.
    Feinmann C: Pain relief by antidepressants: possible modes of action. Pain 1985, 23:1–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Yokogawa F, Kiuchi Y, Ishikawa Y, et al.: An investigation of monoamine receptors involved in antinociceptive effects of antidepressants. Anesth Analg 2002, 95:163–168.PubMedCrossRefGoogle Scholar
  5. 5.
    Gray AM, Pache DM, Sewell RD: Do alpha2-adrenoceptors play an integral role in the antinociceptive mechanism of action of antidepressant compounds? Eur J Pharmacol 1999, 378:161–168.PubMedCrossRefGoogle Scholar
  6. 6.
    Schmauss C, Hammond DL, Ochi JW, Yaksh TL: Pharmacologic antagonism of the antinociceptive effects of serotonin in the rat spinal cord. Eur J Pharmacol 1983, 90:349–357.PubMedCrossRefGoogle Scholar
  7. 7.
    Max MB, Lynch SA, Muir J, et al.: Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 1992, 326:1250–1256.PubMedCrossRefGoogle Scholar
  8. 8.
    Turkington RW: Depression masquerading as diabetic neuropathy. JAMA 1980, 243:1147–1150.PubMedCrossRefGoogle Scholar
  9. 9.
    Max MB, Culnane M, Schafer SC, et al.: Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology 1987, 37:589–596.PubMedGoogle Scholar
  10. 10.
    McQuay HJ, Carroll D, Glynn CJ: Low-dose amitriptyline in the treatment of chronic pain. Anaesthesia 1992, 47:646–652.PubMedCrossRefGoogle Scholar
  11. 11.
    Kiefel JM, Cooper ML, Bodnar RJ: Serotonin receptor subtype antagonists in the medial ventral medulla inhibit mesencephalic opiate analgesia. Brain Res 1992, 597:331–338.PubMedCrossRefGoogle Scholar
  12. 12.
    Steinman JL, Carlton SM, Haber B, Willis WD: Differential effects of p-chlorophenylalanine on indolamines in brainstem nuclei and spinal cord of rats I: biochemical and behavioral analysis. Brain Res 1987, 426:297–309.PubMedCrossRefGoogle Scholar
  13. 13.
    Messing RB, Lytle LD: Serotonin-containing neurons: their possible role in pain and analgesia. Pain 1977, 4:1–21.PubMedCrossRefGoogle Scholar
  14. 14.
    Sindrup SH, Jensen TS: Efficacy of pharmacologic treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 1999, 83:389–400. Provides excellent mechanistic background.PubMedCrossRefGoogle Scholar
  15. 15.
    Bowsher D: The effects of pre-emptive treatment of postherpetic neuralgia with amitriptyline: a randomized, doubleblind, placebo-controlled trial. J Pain Symptom Manage 1997, 13:327–331.PubMedCrossRefGoogle Scholar
  16. 16.
    Terron JA: Is the 5-HT(7) receptor involved in the pathogenesis and prophylactic treatment of migraine? Eur J Pharmacol 2002, 439:1–11.PubMedCrossRefGoogle Scholar
  17. 17.
    de Felipe MC, De Ceballos ML, Gil C, Fuentes JA: Chronic antidepressant treatment increases enkephalin levels in n. accumbens and striatum of the rat. Eur J Pharmacol 1985, 112:119–122.PubMedCrossRefGoogle Scholar
  18. 18.
    Gray AM, Spencer PS, Sewell RD: The involvement of the opioidergic system in the antinociceptive mechanism of action of antidepressant compounds. Br J Pharmacol 1998, 124:669–674.PubMedCrossRefGoogle Scholar
  19. 19.
    Schreiber S, Backer MM, Pick CG: The antinociceptive effect of venlafaxine in mice is mediated through opioid and adrenergic mechanisms. Neurosci Lett 1999, 273:85–88.PubMedCrossRefGoogle Scholar
  20. 20.
    Schreiber S, Bleich A, Pick CG: Venlafaxine and mirtazapine: different mechanisms of antidepressant action, common opioid-mediated antinociceptive effects: a possible opioid involvement in severe depression? J Mol Neurosci 2002, 18:143–149. Provides evidence that newer antidepressants exert pain-relieving benefits through a unique mechanism of action.PubMedCrossRefGoogle Scholar
  21. 21.
    Schreiber S, Backer MM, Herman I, et al.: The antinociceptive effect of trazodone in mice is mediated through both μ-opioid and serotonergic mechanisms. Behav Brain Res 2000, 114:51–56.PubMedCrossRefGoogle Scholar
  22. 22.
    Schreiber S, Backer MM, Yanai J, Pick CG: The antinociceptive effect of fluvoxamine. Eur Neuropsychopharmacol 1996, 6:281–284.PubMedCrossRefGoogle Scholar
  23. 23.
    Post C, Gordh T Jr, Jansson I, et al.: Interactions between spinal noradrenergic and cholinergic mechanism of anti-nociception [abstract]. Pain 1987, 66(suppl 4):S408.CrossRefGoogle Scholar
  24. 24.
    Bhargava VK, Saha L: Cholinergic mechanism in imipramine and morphine antinociception. Boll Chim Farm 2001, 140:201–204.PubMedGoogle Scholar
  25. 25.
    Bryson HM, Wilde MI: Amitriptyline: a review of its pharmacologic properties and therapeutic use in chronic pain states. Drugs Aging 1996, 8:459–476.PubMedGoogle Scholar
  26. 26.
    Bielefeldt K, Ozaki N, Whiteis C, Gebhart GF: Amitriptyline inhibits voltage-sensitive sodium currents in rat gastric sensory neurons. Dig Dis Sci 2002, 47:959–966.PubMedCrossRefGoogle Scholar
  27. 27.
    Gerner P, Mujtaba M, Sinnott CJ, Wang GK: Amitriptyline versus bupivacaine in rat sciatic nerve blockade. Anesthesiology 2001, 94:661–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Brau ME, Dreimann M, Olschewski A, et al.: Effect of drugs used for neuropathic pain management on tetrodotoxinresistant Na(+) currents in rat sensory neurons. Anesthesiology 2001, 94:137–144.PubMedCrossRefGoogle Scholar
  29. 29.
    Pancrazio JJ, Kamatchi GL, Roscoe AK, Lynch C: Inhibition of neuronal Na+ channels by antidepressant drugs. J Pharmacol Exp Ther 1998, 284:208–214.PubMedGoogle Scholar
  30. 30.
    Ulugol A, Karadag HC, Tamer M, et al.: Involvement of adenosine in the anti-allodynic effect of amitriptyline in streptozotocin-induced diabetic rats. Neurosci Lett 2002, 328:129–132.PubMedCrossRefGoogle Scholar
  31. 31.
    Bailey DN: Percutaneous absorption of tricyclic antidepressants: amitriptyline, nortriptyline, imipramine, and desipramine. J Anal Toxicol 1990, 14:217–218.PubMedGoogle Scholar
  32. 32.
    Esser MJ, Chase T, Allen GV, Sawynok J: Chronic administration of amitriptyline and caffeine in a rat model of neuropathic pain: multiple interactions. Eur J Pharmacol 2001, 430:211–218.PubMedCrossRefGoogle Scholar
  33. 33.
    Heughan CE, Allen GV, Chase TD, Sawynok J: Peripheral amitriptyline suppresses formalin-induced Fos expression in the rat spinal cord. Anesth Analg 2002, 94:427–431.PubMedCrossRefGoogle Scholar
  34. 34.
    Kiefer G, Fischer W, Feuerstein TJ: Effects of amitriptyline, amitriptylinoxide, doxepine and clozapine on N-methyl-D-aspartate-evoked release of [3H]-acetylcholine in rat caudatoputamen. Arzneimittelforschung 1999, 49:820–823.PubMedGoogle Scholar
  35. 35.
    Eisenach JC, Gebhart GF: Intrathecal amitriptyline acts as an N-methyl-D-aspartate receptor antagonist in the presence of inflammatory hyperalgesia in rats. Anesthesiology 1995, 83:1046–1054.PubMedCrossRefGoogle Scholar
  36. 36.
    Cai Z, McCaslin PP: Amitriptyline, desipramine, cyproheptadine and carbamazepine, in concentrations used therapeutically, reduce kainate- and N-methyl-D-aspartate-induced intracellular Ca2+ levels in neuronal culture. Eur J Pharmacol 1992, 219:53–57.PubMedCrossRefGoogle Scholar
  37. 37.
    McCaslin PP, Yu XZ, Ho IK, Smith TG: Amitriptyline prevents N-methyl-D-aspartate (NMDA)-induced toxicity, does not prevent NMDA-induced elevations of extracellular glutamate, but augments kainate-induced elevations of glutamate. J Neurochem 1992, 59:401–405.PubMedCrossRefGoogle Scholar
  38. 38.
    Ghelardini C, Galeotti N, Bartolini A: Amitriptyline and clomipramine activate Gi-protein signaling pathway in the induction of analgesia. Naunyn Schmiedebergs Arch Pharmacol 2002, 365:1–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Bartholoma P, Erlandsson N, Kaufmann K, et al.: Neuronal cell death induced by antidepressants: lack of correlation with Egr-1, NF-kappa B, and extracellular signal-regulated protein kinase activation. Biochem Pharmacol 2002, 63:1507–1516.PubMedCrossRefGoogle Scholar
  40. 40.
    Sawynok J, Esser MJ, Reid AR: Antidepressants as analgesics: an overview of central and peripheral mechanisms of action. J Psychiatry Neurosci 2001, 26:21–29. An updated overview of antidepressants.PubMedGoogle Scholar
  41. 41.
    Joss JD: Tricyclic antidepressant use in diabetic neuropathy. Ann Pharmacother 1999, 33:996–1000. Review of the most common neuropathic pain complaints.PubMedCrossRefGoogle Scholar
  42. 42.
    Jensen PG, Larson JR: Management of painful diabetic neuropathy. Drugs Aging 2001, 18:737–49. Emphasis on managing elder patients with special therapeutic considerations.PubMedCrossRefGoogle Scholar
  43. 43.
    Sindrup SH, Brosen K, Gran LF: The mechanism of action of antidepressants in pain treatment: controlled cross-over studies in diabetic neuropathy. Clin Neuropharmacol 1993, 15(suppl 1):380A-381A.Google Scholar
  44. 44.
    Vrethem M, Boivie J, Arnqvist H, et al.: A comparison a amitriptyline and maprotiline in the treatment of painful polyneuropathy in diabetics and nondiabetics. Clin J Pain 1997, 13:313–323.PubMedCrossRefGoogle Scholar
  45. 45.
    Biesbroeck R, Bril V, Hollander P, et al.: A double-blind comparison of topical capsaicin and oral amitriptyline in painful diabetic neuropathy. Adv Ther 1995, 12:111–120.PubMedGoogle Scholar
  46. 46.
    Satterthwaite JR: Acute herpes zoster: diagnosis and treatment. Pain Manage 1990, 3:17–28.Google Scholar
  47. 47.
    Portenoy RK, Duma C, Foley KM: Acute herpetic and postherpetic neuralgia: clinical review and current management. Ann Neurol 1986, 20:651–664.PubMedCrossRefGoogle Scholar
  48. 48.
    Loeser JD: Postherpetic neuralgia: a review of pathophysiology and treatment. Presented at the Annual Meeting of the American Pain Society. Washington, DC; November 8, 1986.Google Scholar
  49. 49.
    Watson CPN, Evans RJ: A comparative trial of amitriptyline and zimeldine in postherpetic neuralgia. Pain 1985, 23:3887–3894.CrossRefGoogle Scholar
  50. 50.
    Watson CP, Chipman M, Reed K, et al.: Amitriptyline versus maprotiline in postherpetic neuralgia: a randomized, double-blind, crossover trial. Pain 1992, 48:29–36.PubMedCrossRefGoogle Scholar
  51. 51.
    Kanazi GE, Johnson RW, Dworkin RH: Treatment of postherpetic neuralgia: an update. Drugs 2000, 59:1113–1126.PubMedCrossRefGoogle Scholar
  52. 52.
    Watson CP, Vernich L, Chipman M, Reed K: Nortriptyline versus amitriptyline in postherpetic neuralgia: a randomized trial. Neurology 1998, 51:1166–1171.PubMedGoogle Scholar
  53. 53.
    Cardenas DD, Warms CA, Turner JA, et al.: Efficacy of amitriptyline for relief of pain in spinal cord injury: results of a randomized controlled trial. Pain 2002, 96:365–373.PubMedCrossRefGoogle Scholar
  54. 54.
    Rho RH, Brewer RP, Lamer TJ, Wilson PR: Complex regional pain syndrome. Mayo Clin Proc 2002, 77:174–180.PubMedGoogle Scholar
  55. 55.
    Sindrup SH, Gram LF, Brøsen K, et al.: The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy syndromes. Pain 1990, 42:135–145.PubMedCrossRefGoogle Scholar
  56. 56.
    Sumpton JE, Moulin DE: Treatment of neuropathic pain with venlafaxine. Ann Pharmacother 2001, 35:557–559. A look at a newer non-tricyclic antidepressant that may share common mechanistic properties with its predecessors.PubMedCrossRefGoogle Scholar
  57. 57.
    Enggaard TP, Klitgaard NA, Gram LF, et al.: Specific effect of venlafaxine on single and repetitive experimental painful stimuli in humans. Clin Pharmacol Ther 2001, 69:245–251.PubMedCrossRefGoogle Scholar
  58. 58.
    Lang E, Hord AH, Denson D: Venlafaxine hydrochloride (Effexor) relieves thermal hyperalgesia in rats with an experimental mononeuropathy. Pain 1996, 68:151–155.PubMedCrossRefGoogle Scholar
  59. 59.
    Semenchuk MR, Sherman S, Davis B: Double-blind, randomized trial of bupropion SR for the treatment of neuropathic pain. Neurology 2001, 57:1583–1588.PubMedGoogle Scholar
  60. 60.
    Mattia C, Paoletti F, Coluzzi F, Boanelli A: New antidepressants in the treatment of neuropathic pain: a review. Minerva Anestesiol 2002, 68:105–114. Offers a thorough overview of the newer atypical agents in managing painful neuropathies.PubMedGoogle Scholar
  61. 61.
    Kapur S, Mieczkowski T, Mann J: Antidepressant medications and the relative risk of suicide attempt and suicide. JAMA 1992, 268:3441–3345.PubMedCrossRefGoogle Scholar
  62. 62.
    Magi G: The use of antidepressants in the treatment of chronic pain. Drugs 1991, 42:730–748.CrossRefGoogle Scholar
  63. 63.
    Collins SL, Moore RA, McQuay HJ, Wiffen P: Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. J Pain Symptom Manage 2000, 20:449–458. Provides evidenced-based support for the use of antidepressants in the most common types of neuropathic pain.PubMedCrossRefGoogle Scholar
  64. 64.
    Heughan CE, Sawynok J: The interaction between gabapentin and amitriptyline in the rat formalin test after systemic administration. Anesth Analg 2002, 94:975–980.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2003

Authors and Affiliations

  • Lori Reisner
    • 1
  1. 1.Department of Clinical PharmacyUniversity of California, San FranciscoSan FranciscoUSA

Personalised recommendations