Search tips
Search criteria 


Logo of jpnSubmit a ManuscriptEmail AlertsAbout JPNJournal of Psychiatry and Neuroscience
J Psychiatry Neurosci. 2001 January; 26(1): 30–36.
PMCID: PMC1408040

Antidepressants as analgesics: a review of randomized controlled trials.


This review provides an overview of 59 randomized placebo-controlled trials that examined the analgesic effect of antidepressants. To summarize, there is significant evidence that the tricyclic group of antidepressants is analgesic and that trazodone is not; the data regarding selective serotonin reuptake inhibitors are conflicting. To date, there are no randomized controlled trials examining the potential analgesic action of nefazodone or venlafaxine, but on the basis of initial clinical reports and its structural similarity to other analgesics, venlafaxine shows promise as an analgesic.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.1M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Magni G. The use of antidepressants in the treatment of chronic pain. A review of the current evidence. Drugs. 1991 Nov;42(5):730–748. [PubMed]
  • Onghena P, Van Houdenhove B. Antidepressant-induced analgesia in chronic non-malignant pain: a meta-analysis of 39 placebo-controlled studies. Pain. 1992 May;49(2):205–219. [PubMed]
  • McQuay HJ, Tramèr M, Nye BA, Carroll D, Wiffen PJ, Moore RA. A systematic review of antidepressants in neuropathic pain. Pain. 1996 Dec;68(2-3):217–227. [PubMed]
  • LANCE JW, CURRAN DA. TREATMENT OF CHRONIC TENSION HEADACHE. Lancet. 1964 Jun 6;1(7345):1236–1239. [PubMed]
  • Evans W, Gensler F, Blackwell B, Galbrecht C. The effects of antidepressant drugs on pain relief and mood in the chronically ill. A double-blind study. Psychosomatics. 1973 Jul-Aug;14(4):214–219. [PubMed]
  • Gomersall JD, Stuart A. Amitriptyline in migraine prophylaxis. Changes in pattern of attacks during a controlled clinical trial. J Neurol Neurosurg Psychiatry. 1973 Aug;36(4):684–690. [PMC free article] [PubMed]
  • Okasha A, Ghaleb HA, Sadek A. A double blind trial for the clinical management of psychogenic headache. Br J Psychiatry. 1973 Feb;122(567):181–183. [PubMed]
  • Jenkins DG, Ebbutt AF, Evans CD. Tofranil in the treatment of low back pain. J Int Med Res. 1976;4(2 Suppl):28–40. [PubMed]
  • Couch JR, Hassanein RS. Amitriptyline in migraine prophylaxis. Arch Neurol. 1979 Nov;36(11):695–699. [PubMed]
  • Mørland TJ, Storli OV, Mogstad TE. Doxepin in the prophylactic treatment of mixed 'vascular' and tension headache. Headache. 1979 Nov;19(7):382–383. [PubMed]
  • Alcoff J, Jones E, Rust P, Newman R. Controlled trial of imipramine for chronic low back pain. J Fam Pract. 1982 May;14(5):841–846. [PubMed]
  • Hameroff SR, Cork RC, Scherer K, Crago BR, Neuman C, Womble JR, Davis TP. Doxepin effects on chronic pain, depression and plasma opioids. J Clin Psychiatry. 1982 Aug;43(8 Pt 2):22–27. [PubMed]
  • Pilowsky I, Hallett EC, Bassett DL, Thomas PG, Penhall RK. A controlled study of amitriptyline in the treatment of chronic pain. Pain. 1982 Oct;14(2):169–179. [PubMed]
  • Sjaastad O. So-called "tension headache"--the response to a 5-HT uptake inhibitor: femoxetine. Cephalalgia. 1983 Mar;3(1):53–60. [PubMed]
  • Watson CP, Evans RJ, Reed K, Merskey H, Goldsmith L, Warsh J. Amitriptyline versus placebo in postherpetic neuralgia. Neurology. 1982 Jun;32(6):671–673. [PubMed]
  • Pheasant H, Bursk A, Goldfarb J, Azen SP, Weiss JN, Borelli L. Amitriptyline and chronic low-back pain. A randomized double-blind crossover study. Spine (Phila Pa 1976) 1983 Jul-Aug;8(5):552–557. [PubMed]
  • Hameroff SR, Weiss JL, Lerman JC, Cork RC, Watts KS, Crago BR, Neuman CP, Womble JR, Davis TP. Doxepin's effects on chronic pain and depression: a controlled study. J Clin Psychiatry. 1984 Mar;45(3 Pt 2):47–53. [PubMed]
  • Kvinesdal B, Molin J, Frøland A, Gram LF. Imipramine treatment of painful diabetic neuropathy. JAMA. 1984 Apr 6;251(13):1727–1730. [PubMed]
  • Carette S, McCain GA, Bell DA, Fam AG. Evaluation of amitriptyline in primary fibrositis. A double-blind, placebo-controlled study. Arthritis Rheum. 1986 May;29(5):655–659. [PubMed]
  • Goldenberg DL, Felson DT, Dinerman H. A randomized, controlled trial of amitriptyline and naproxen in the treatment of patients with fibromyalgia. Arthritis Rheum. 1986 Nov;29(11):1371–1377. [PubMed]
  • Macfarlane JG, Jalali S, Grace EM. Trimipramine in rheumatoid arthritis: a randomized double-blind trial in relieving pain and joint tenderness. Curr Med Res Opin. 1986;10(2):89–93. [PubMed]
  • Sharav Y, Singer E, Schmidt E, Dionne RA, Dubner R. The analgesic effect of amitriptyline on chronic facial pain. Pain. 1987 Nov;31(2):199–209. [PubMed]
  • Max MB, Culnane M, Schafer SC, Gracely RH, Walther DJ, Smoller B, Dubner R. Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology. 1987 Apr;37(4):589–596. [PubMed]
  • Frank RG, Beck NC, Parker JC, Kashani JH, Elliott TR, Haut AE, Smith E, Atwood C, Brownlee-Duffeck M, Kay DR. Depression in rheumatoid arthritis. J Rheumatol. 1988 Jun;15(6):920–925. [PubMed]
  • Max MB, Schafer SC, Culnane M, Smoller B, Dubner R, Gracely RH. Amitriptyline, but not lorazepam, relieves postherpetic neuralgia. Neurology. 1988 Sep;38(9):1427–1432. [PubMed]
  • Leijon G, Boivie J. Central post-stroke pain--a controlled trial of amitriptyline and carbamazepine. Pain. 1989 Jan;36(1):27–36. [PubMed]
  • Loldrup D, Langemark M, Hansen HJ, Olesen J, Bech P. Clomipramine and mianserin in chronic idiopathic pain syndrome. A placebo controlled study. Psychopharmacology (Berl) 1989;99(1):1–7. [PubMed]
  • Pilowsky I, Barrow CG. A controlled study of psychotherapy and amitriptyline used individually and in combination in the treatment of chronic intractable, 'psychogenic' pain. Pain. 1990 Jan;40(1):3–19. [PubMed]
  • Panerai AE, Monza G, Movilia P, Bianchi M, Francucci BM, Tiengo M. A randomized, within-patient, cross-over, placebo-controlled trial on the efficacy and tolerability of the tricyclic antidepressants chlorimipramine and nortriptyline in central pain. Acta Neurol Scand. 1990 Jul;82(1):34–38. [PubMed]
  • Max MB, Kishore-Kumar R, Schafer SC, Meister B, Gracely RH, Smoller B, Dubner R. Efficacy of desipramine in painful diabetic neuropathy: a placebo-controlled trial. Pain. 1991 Apr;45(1):3–2. [PubMed]
  • Sindrup SH, Ejlertsen B, Frøland A, Sindrup EH, Brøsen K, Gram LF. Imipramine treatment in diabetic neuropathy: relief of subjective symptoms without changes in peripheral and autonomic nerve function. Eur J Clin Pharmacol. 1989;37(2):151–153. [PubMed]
  • Sindrup SH, Gram LF, Skjold T, Frøland A, Beck-Nielsen H. Concentration-response relationship in imipramine treatment of diabetic neuropathy symptoms. Clin Pharmacol Ther. 1990 Apr;47(4):509–515. [PubMed]
  • Kishore-Kumar R, Max MB, Schafer SC, Gaughan AM, Smoller B, Gracely RH, Dubner R. Desipramine relieves postherpetic neuralgia. Clin Pharmacol Ther. 1990 Mar;47(3):305–312. [PubMed]
  • Sindrup SH, Bjerre U, Dejgaard A, Brøsen K, Aaes-Jørgensen T, Gram LF. The selective serotonin reuptake inhibitor citalopram relieves the symptoms of diabetic neuropathy. Clin Pharmacol Ther. 1992 Nov;52(5):547–552. [PubMed]
  • Sindrup SH, Gram LF, Brøsen K, Eshøj O, Mogensen EF. The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain. 1990 Aug;42(2):135–144. [PubMed]
  • Reisby N, Gram LF, Bech P, Nagy A, Petersen GO, Ortmann J, Ibsen I, Dencker SJ, Jacobsen O, Krautwald O, et al. Imipramine: clinical effects and pharmacokinetic variability. Psychopharmacology (Berl) 1977 Nov 15;54(3):263–272. [PubMed]
  • McQuay HJ, Carroll D, Glynn CJ. Dose-response for analgesic effect of amitriptyline in chronic pain. Anaesthesia. 1993 Apr;48(4):281–285. [PubMed]
  • Zitman FG, Linssen AC, Edelbroek PM, Van Kempen GM. Does addition of low-dose flupentixol enhance the analgetic effects of low-dose amitriptyline in somatoform pain disorder? Pain. 1991 Oct;47(1):25–30. [PubMed]
  • Bowsher D. The effects of pre-emptive treatment of postherpetic neuralgia with amitriptyline: a randomized, double-blind, placebo-controlled trial. J Pain Symptom Manage. 1997 Jun;13(6):327–331. [PubMed]
  • Gordon NC, Heller PH, Levine JD. Enhancement of pentazocine analgesia by clonidine. Pain. 1992 Feb;48(2):167–169. [PubMed]
  • Levine JD, Gordon NC, Smith R, McBryde R. Desipramine enhances opiate postoperative analgesia. Pain. 1986 Oct;27(1):45–49. [PubMed]
  • Bendtsen L, Jensen R, Olesen J. A non-selective (amitriptyline), but not a selective (citalopram), serotonin reuptake inhibitor is effective in the prophylactic treatment of chronic tension-type headache. J Neurol Neurosurg Psychiatry. 1996 Sep;61(3):285–290. [PMC free article] [PubMed]
  • Zeeberg I, Orholm M, Nielsen JD, Honore PL, Larsen JJ. Femoxetine in the prophylaxis of migraine--a randomised comparison with placebo. Acta Neurol Scand. 1981 Dec;64(6):452–459. [PubMed]
  • Orholm M, Honoré PF, Zeeberg I. A randomized general practice group-comparative study of femoxetine and placebo in the prophylaxis of migraine. Acta Neurol Scand. 1986 Sep;74(3):235–239. [PubMed]
  • Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med. 1992 May 7;326(19):1250–1256. [PubMed]
  • Wolfe F, Cathey MA, Hawley DJ. A double-blind placebo controlled trial of fluoxetine in fibromyalgia. Scand J Rheumatol. 1994;23(5):255–259. [PubMed]
  • Goldenberg D, Mayskiy M, Mossey C, Ruthazer R, Schmid C. A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia. Arthritis Rheum. 1996 Nov;39(11):1852–1859. [PubMed]
  • Nørregaard J, Volkmann H, Danneskiold-Samsøe B. A randomized controlled trial of citalopram in the treatment of fibromyalgia. Pain. 1995 Jun;61(3):445–449. [PubMed]
  • Johansson F, von Knorring L. A double-blind controlled study of seratonin uptake inhibitor (Zimelidine) versus placebo in chronic pain patients. Pain. 1979 Aug;7(1):69–78. [PubMed]
  • Gourlay GK, Cherry DA, Cousins MJ, Love BL, Graham JR, McLachlan MO. A controlled study of a serotonin reuptake blocker, zimelidine, in the treatment of chronic pain. Pain. 1986 Apr;25(1):35–52. [PubMed]
  • Rani PU, Naidu MU, Prasad VB, Rao TR, Shobha JC. An evaluation of antidepressants in rheumatic pain conditions. Anesth Analg. 1996 Aug;83(2):371–375. [PubMed]
  • Engel CC, Jr, Walker EA, Engel AL, Bullis J, Armstrong A. A randomized, double-blind crossover trial of sertraline in women with chronic pelvic pain. J Psychosom Res. 1998 Feb;44(2):203–207. [PubMed]
  • Atkinson JH, Slater MA, Wahlgren DR, Williams RA, Zisook S, Pruitt SD, Epping-Jordan JE, Patterson TL, Grant I, Abramson I, et al. Effects of noradrenergic and serotonergic antidepressants on chronic low back pain intensity. Pain. 1999 Nov;83(2):137–145. [PubMed]
  • Gordon NC, Heller PH, Gear RW, Levine JD. Interactions between fluoxetine and opiate analgesia for postoperative dental pain. Pain. 1994 Jul;58(1):85–88. [PubMed]
  • Dirksen R, Van Luijtelaar EL, Van Rijn CM. Selective serotonin reuptake inhibitors may enhance responses to noxious stimulation. Pharmacol Biochem Behav. 1998 Jul;60(3):719–725. [PubMed]
  • Davidoff G, Guarracini M, Roth E, Sliwa J, Yarkony G. Trazodone hydrochloride in the treatment of dysesthetic pain in traumatic myelopathy: a randomized, double-blind, placebo-controlled study. Pain. 1987 May;29(2):151–161. [PubMed]
  • Battistella PA, Ruffilli R, Cernetti R, Pettenazzo A, Baldin L, Bertoli S, Zacchello F. A placebo-controlled crossover trial using trazodone in pediatric migraine. Headache. 1993 Jan;33(1):36–39. [PubMed]
  • Goodkin K, Gullion CM, Agras WS. A randomized, double-blind, placebo-controlled trial of trazodone hydrochloride in chronic low back pain syndrome. J Clin Psychopharmacol. 1990 Aug;10(4):269–278. [PubMed]
  • Ventafridda V, Caraceni A, Saita L, Bonezzi C, De Conno F, Guarise G, Ramella G, Silvani V, Tamburini M, Toscani F. Trazodone for deafferentation pain. Comparison with amitriptyline. Psychopharmacology (Berl) 1988;95 (Suppl):S44–S49. [PubMed]
  • Lascelles RG. Atypical facial pain and depression. Br J Psychiatry. 1966 Jul;112(488):651–659. [PubMed]
  • Galer BS. Neuropathic pain of peripheral origin: advances in pharmacologic treatment. Neurology. 1995 Dec;45(12 Suppl 9):S17–S36. [PubMed]
  • Markowitz JS, Patrick KS. Venlafaxine-tramadol similarities. Med Hypotheses. 1998 Aug;51(2):167–168. [PubMed]
  • Dwight MM, Arnold LM, O'Brien H, Metzger R, Morris-Park E, Keck PE., Jr An open clinical trial of venlafaxine treatment of fibromyalgia. Psychosomatics. 1998 Jan-Feb;39(1):14–17. [PubMed]
  • Taylor K, Rowbotham MC. Venlafaxine hydrochloride and chronic pain. West J Med. 1996 Sep;165(3):147–148. [PMC free article] [PubMed]
  • Songer DA, Schulte H. Venlafaxine for the treatment of chronic pain. Am J Psychiatry. 1996 May;153(5):737–737. [PubMed]
  • Lang E, Hord AH, Denson D. Venlafaxine hydrochloride (Effexor) relieves thermal hyperalgesia in rats with an experimental mononeuropathy. Pain. 1996 Nov;68(1):151–155. [PubMed]
  • Nascimento ED. Profilaxia da migrânea. Estudo aberto com a venlafaxina em 42 pacientes. Arq Neuropsiquiatr. 1998 Dec;56(4):744–746. [PubMed]

Articles from Journal of Psychiatry & Neuroscience : JPN are provided here courtesy of Canadian Medical Association