Antidepressant-induced analgesia in chronic non-malignant pain: a meta-analysis of 39 placebo-controlled studies

&NA; For 39 controlled studies on the analgesic effect of antidepressants, a meta‐analysis was conducted to get an estimation of the effect size, and to obtain a sight on the possible modes of action and the methodology used. The mean size of the analgesic effect was 0.64. It means that the average chronic pain patient who received an antidepressant treatment had less pain than 74% of the chronic pain patients who received a placebo. This quantification, however, is only as good as the studies on which it is based, and it could be differentiated for each of the pain syndromes and antidepressants examined. Real analgesic qualities of antidepressive agents seemed to offer the most plausible and economical explanation for the effect, but the predominant importance of serotonin reuptake blocking was not confirmed. Finally, the meta‐analysis appeared to be fruitful for the generation of new hypotheses, for making some recommendations for future research, and for proposing some provisional guidelines for the clinical use of antidepressants in chronic non‐malignant pain.

[1]  W. Scott The relief of pain with an antidepressant in arthritis. , 1969, The Practitioner.

[2]  P. Thorpe,et al.  THE ROLE OF AN ANTIDEPRESSANT, DIBENZEPIN (NOVERIL), IN THE RELIEF OF PAIN IN CHRONIC ARTHRITIC STATES , 1974, The Medical journal of Australia.

[3]  Philip C. Abrami,et al.  Implementation Problems in Meta-Analysis , 1988 .

[4]  A. Ebbutt,et al.  Tofranil in the treatment of low back pain. , 1976, The Journal of international medical research.

[5]  Gene V. Glass,et al.  The benefits of psychotherapy , 1980 .

[6]  J. Couch,et al.  Amitriptyline in migraine prophylaxis. , 1979, Archives of neurology.

[7]  G. Pasternak,et al.  Analgesic activity of tricyclic antidepressants , 1983, Annals of neurology.

[8]  R. Newman,et al.  Controlled trial of imipramine for chronic low back pain. , 1982, The Journal of family practice.

[9]  H. Merskey,et al.  Amitriptyline versus placebo in post-herpetic neuralgia , 1981, PAIN.

[10]  Robert E. Slavin,et al.  Best-Evidence Synthesis: An Alternative to Meta-Analytic and Traditional Reviews , 1986 .

[11]  B. Blackwell,et al.  The effects of antidepressant drugs on pain relief and mood in the chronically ill. A double-blind study. , 1973, Psychosomatics.

[12]  R. Fogelholm,et al.  Maprotiline in Chronic Tension Headache: a Double‐blind Cross‐over Study , 1985, Headache.

[13]  M. Stöhr,et al.  An open and double-blind cross-over study on the efficacy of clomipramine (Anafranil) in patients with painful mono- and polyneuropathies. , 1982, European Neurology.

[14]  R. Messing,et al.  Serotonin-containing neurons: their possible role in pain and analgesia , 1977, Pain.

[15]  I. Pilowsky,et al.  A controlled study of psychotherapy and amitriptyline used individually and in combination in the treatment of chronic intractable, “psychogenic” pain , 1990, Pain.

[16]  H. Eysenck An exercise in mega-silliness. , 1978 .

[17]  B. Bromm,et al.  Imipramine reduces experimental pain , 1986, Pain.

[18]  S. Dencker,et al.  A Double-Blind Study of Dothiepin Hydrochloride (Prothiaden) and Amitriptyline in Out-Patients with Masked Depression , 1981, The Journal of international medical research.

[19]  H. Fields,et al.  Potentiation of morphine antinociception by monoamine reuptake inhibitors in the rat spinal cord , 1985, Pain.

[20]  A I Basbaum,et al.  Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. , 1984, Annual review of neuroscience.

[21]  Ebbutt Af,et al.  Tofranil in the treatment of low back pain. , 1976 .

[22]  T. Walsh Antidepressants in chronic pain. , 1983, Clinical neuropharmacology.

[23]  G. Glass,et al.  Meta-analysis in social research , 1981 .

[24]  A. Panerai,et al.  A controlled clinical trial on the effectiveness of antide-pressants in central pain , 1987, PAIN.

[25]  R. Voiosu,et al.  Long-Term Controlled Clinical Trial of a New Anti-Inflammatory Drug, Diftalone, in Rheumatoid Arthritis , 1974, The Journal of international medical research.

[26]  M. Strube,et al.  Meta-analysis of non-medical treatments for chronic pain , 1988, Pain.

[27]  Scott Wa The relief of pain with an antidepressant in arthritis. , 1969 .

[28]  Robert E. Slavin,et al.  Meta-Analysis in Education: How Has It Been Used? , 1984 .

[29]  L. von Knorring,et al.  A double-blind randomized study of clomipramine versus maprotiline in patients with idiopathic pain syndromes. , 1988, Neuropsychobiology.

[30]  J. D. Gomersall,et al.  Amitriptyline in migraine prophylaxis , 1973, Journal of neurology, neurosurgery, and psychiatry.

[31]  R. Marshall The pharmacology of mianserin--an update. , 1983, British journal of clinical pharmacology.

[32]  Ronald Melzack,et al.  Pain Measurement and Assessment , 1983 .

[33]  C. Watson,et al.  Therapeutic window for amitriptyline analgesia. , 1984, Canadian Medical Association journal.

[34]  F. Gómez-Pérez,et al.  Nortriptyline and fluphenazine in the symptomatic treatment of diabetic neuropathy. A double-blind cross-over study , 1985, Pain.

[35]  Y. Sharav,et al.  The analgesic effect of amitriptyline on chronic facial pain , 1987, Pain.

[36]  S. Hameroff,et al.  Doxepin effects on chronic pain, depression and plasma opioids. , 1982, The Journal of clinical psychiatry.

[37]  H. Meltzer,et al.  Psychopharmacology : the third generation of progress , 1987 .

[38]  F. Johansson,et al.  A double-blind controlled study of a serotonin uptake inhibitor (Zimelidine) versus placebo in chronic pain patients , 1979, Pain.

[39]  T. Morland,et al.  Doxepin in the Prophylactic Treatment of Mixed ‘Vascular’ and Tension Headache , 1979, Headache.

[40]  W. Dick,et al.  Imipramine and rheumatoid factor. , 1976, The Journal of international medical research.

[41]  Gwenn W. Gröndal,et al.  Meta-analytic procedures for social research , 1993 .

[42]  E. Ellinwood,et al.  Therapeutic effects of antidepressants in chronic pain. , 1984, General hospital psychiatry.

[43]  S. Diamond,et al.  CHRONIC TENSION HEADACHE‐TREATED WITH AMITRIPTYLINE‐A DOUBLE‐BLIND STUDY , 1971, Headache.

[44]  A. Eschalier,et al.  Activities of five antidepressants in a behavioral pain test in rats. , 1983, Life sciences.

[45]  D. Blumer,et al.  Systematic treatment of chronic pain with antidepressants. , 1980, Henry Ford Hospital medical journal.

[46]  J. Besson,et al.  Reduction of arthritis and pain behaviour following chronic administration of amitriptyline or imipramine in rats with adjuvant-induced arthritis , 1985, Pain.

[47]  H. Merskey,et al.  Amitriptyline versus placebo in post-herpetic neuralgia , 1981, Pain.

[48]  H. Merskey,et al.  Classification of chronic pain. Descriptions of chronic pain syndromes and definitions of pain terms. Prepared by the International Association for the Study of Pain, Subcommittee on Taxonomy. , 1994, Pain. Supplement.

[49]  A. Agnoli,et al.  Migraine and the Noradrenergic Control of Vasomotricity: A Study With Alpha‐2 Stimulant and Alpha‐2 Blocker Drugs , 1985, Headache.

[50]  J. Schwartz,et al.  Histamine receptors in brain as targets for tricyclic antidepressants , 1981 .

[51]  C Peter N Watson,et al.  A comparative trial of amitriptyline and zimelidine in post-herpetic neuralgia , 1985, Pain.

[52]  R. Kocher Use of psychotropic drugs for the treatment of chronic severe pains. , 1979, International rehabilitation medicine.

[53]  S. Azen,et al.  Amitriptyline and Chronic Low-Back Pain: A Randomized Double-Blind Crossover Study , 1983, Spine.

[54]  D. Blumer,et al.  Second-year follow-up study on systematic treatment of chronic pain with antidepressants. , 1981, Henry Ford Hospital medical journal.

[55]  Amitriptyline, but not lorazepam, relieves postherpetic neuralgia , 1988, Neurology.

[56]  R. W. Turkington Depression Masquerading as Diabetic Neuropathy , 1980, JAMA.

[57]  D. Blumer,et al.  Chronic Pain as a Variant of Depressive Disease The Pain‐Prone Disorder , 1982, The Journal of nervous and mental disease.

[58]  Robert E. Slavin,et al.  Best-Evidence Synthesis: Why Less Is More , 1987 .

[59]  C. Feinmann,et al.  Psychogenic facial pain: presentation and treatment. , 1983, Journal of psychosomatic research.

[60]  P. Spencer,et al.  Antidepressants and pain: a review of the pharmacological data supporting the use of certain tricyclics in chronic pain. , 1977, The Journal of international medical research.

[61]  G. A. Mccain,et al.  Evaluation of amitriptyline in primary fibrositis. A double-blind, placebo-controlled study. , 1986, Arthritis and rheumatism.

[62]  E. Grace,et al.  Trimipramine in rheumatoid arthritis: a randomized double-blind trial in relieving pain and joint tenderness. , 1986, Current medical research and opinion.

[63]  M. Cousins,et al.  A controlled study of a serotonin reuptake blocker, zimelidine, in the treatment of chronic pain , 1986, Pain.

[64]  O. Sjaastad So-Called “Tension Headache” — The Response to a 5-HT Uptake Inhibitor: Femoxetine , 1983, Cephalalgia : an international journal of headache.

[65]  Jacob Cohen Statistical Power Analysis for the Behavioral Sciences , 1969, The SAGE Encyclopedia of Research Design.

[66]  Michael A. McDaniel,et al.  Guidelines for Conducting and Reporting Meta-Analyses , 1989 .

[67]  Aronoff Gm,et al.  Doxepin as an adjunct in the treatment of chronic pain. , 1982 .

[68]  A. Okasha,et al.  A Double Blind Trial for the Clinical Management of Psychogenic Headache , 1973, British Journal of Psychiatry.

[69]  R. Penhall,et al.  A controlled study of amitriptyline in the treatment of chronic pain , 1982, Pain.

[70]  G. Leijon,et al.  Central post-stroke pain — a controlled trial of amitriptyline and carbamazepine , 1989, Pain.

[71]  K. Shin,et al.  Tumours of the central nervous system: an epidemiologic survey. , 1984, Canadian Medical Association journal.

[72]  G. Magni On the relationship between chronic pain and depression when there is no organic lesion , 1987, PAIN®.

[73]  J. Lance,et al.  TREATMENT OF CHRONIC TENSION HEADACHE. , 1964, Lancet.

[74]  Walsh Td Antidepressants in chronic pain. , 1983 .

[75]  Changes in endorphins and 5-hydroxyindoleacetic acid in cerebrospinal fluid as a result of treatment with a serotonin reuptake inhibitor (zimelidine) in chronic pain patients , 1980, Psychiatry Research.

[76]  Gregg B. Jackson,et al.  Methods for Integrative Reviews , 1980 .

[77]  R. Lascelles Atypical Facial Pain and Depression , 1966, British Journal of Psychiatry.

[78]  R. Rosenthal Combining results of independent studies. , 1978 .

[79]  D. Felson,et al.  A randomized, controlled trial of amitriptyline and naproxen in the treatment of patients with fibromyalgia. , 1986, Arthritis and rheumatism.

[80]  E. Roth,et al.  Trazodone hydrochloride in the treatment of dysesthetic pain in traumatic myelopathy: a randomized, double-blind, placebo-controlled study , 1987, Pain.

[81]  S. Hameroff,et al.  Doxepin's effects on chronic pain and depression: a controlled study. , 1984, The Journal of clinical psychiatry.

[82]  S. Gershon Chronic pain: hypothesized mechanism and rationale for treatment. , 1986, Neuropsychobiology.

[83]  A. Fro̸land,et al.  Imipramine treatment of painful diabetic neuropathy. , 1984, JAMA.

[84]  R. Rosenthal Meta-analytic procedures for social research , 1984 .

[85]  B. Guiraud-Chaumeil,et al.  Measurement of plasma levels of clomipramine in the treatment of chronic pain. , 1985, Clinical neuropharmacology.

[86]  R. Carasso,et al.  Clomipramine and amitriptyline in the treatment of severe pain. , 1979, The International journal of neuroscience.

[87]  R. Melzack The McGill Pain Questionnaire: Major properties and scoring methods , 1975, PAIN.

[88]  C. Feinmann Pain relief by antidepressants: Possible modes of action , 1985, Pain.

[89]  D. Blumer,et al.  “Chronic Pain as a Variant of Depressive Disease”: A Rejoinder , 1984, The Journal of nervous and mental disease.

[90]  A. Coppen,et al.  Mianserin in the prophylaxis of migraine: a double‐blind study , 1985, Acta psychiatrica Scandinavica. Supplementum.

[91]  S. Diamond Psychogenic headaches with mixed anxiety and depression. , 1975, IMJ. Illinois medical journal.

[92]  D. Bakan,et al.  The test of significance in psychological research. , 1966, Psychological bulletin.

[93]  N. Beck,et al.  Antidepressant analgesia in rheumatoid arthritis. , 1988, The Journal of rheumatology.

[94]  P. Lindsay,et al.  The depression-pain syndrome and its response to antidepressants. , 1981, Psychosomatics.

[95]  R. Sternbach Pain Patients: Traits and Treatments , 1974 .

[96]  M. L. Smith,et al.  Meta-analysis of psychotherapy outcome studies. , 1977, The American psychologist.

[97]  J. Seldrup,et al.  A comparative trial of clomipramine and placebo as adjunctive therapy in arthralgia. , 1980, The Journal of international medical research.

[98]  M. Gringras A clinical trial of Tofranil in rheumatic pain in general practice. , 1976, The Journal of international medical research.