The American Journal of Medicine
Volume 122, Issue 12, Supplement , Pages S44-S55 , December 2009

Further Strategies for Treating Fibromyalgia: The Role of Serotonin and Norepinephrine Reuptake Inhibitors

  • Philip J. Mease, MD

      Affiliations

    • Corresponding Author InformationRequests for reprints should be addressed to Philip J. Mease, MD, Seattle Rheumatology Associates, 1101 Madison Street, Suite 1000, Seattle, Washington 98104

References 

  1. Mease P. Fibromyalgia syndrome: review of clinical presentation, pathogenesis, outcome measures, and treatment. J Rheumatol Suppl. 2005;75:6–21
  2. Yunus MB. Role of central sensitization in symptoms beyond muscle pain, and the evaluation of a patient with widespread pain. Best Pract Res Clin Rheumatol. 2007;21:481–497
  3. Lautenbacher S, Rollman GB, McCain GA. Multi-method assessment of experimental and clinical pain in patients with fibromyalgia. Pain. 1994;59:45–53
  4. Gracely RH, Petzke F, Wolf JM, Clauw DJ. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum. 2002;46:1333–1343
  5. Staud R, Rodriguez ME. Mechanisms of disease: pain in fibromyalgia syndrome. Nat Clin Pract Rheumatol. 2006;2:90–98
  6. Houvenagel E, Forzy G, Leloire O, et al. Cerebrospinal fluid monoamines in primary fibromyalgia [in French]. Rev Rhum Mal Osteoartic. 1990;57:21–23
  7. Russell IJ, Vaerøy H, Javors M, Nyberg F. Cerebrospinal fluid biogenic amine metabolites in fibromyalgia/fibrositis syndrome and rheumatoid arthritis. Arthritis Rheum. 1992;35:550–556
  8. Staud R. Predictors of clinical pain intensity in patients with fibromyalgia syndrome. Curr Pain Headache Rep. 2005;9:316–321
  9. Fields HL, Heinricher MM, Mason P. Neurotransmitters in nociceptive modulatory circuits. Annu Rev Neurosci. 1991;14:219–245
  10. Kranzler JD, Gendreau JF, Rao SG. The psychopharmacology of fibromyalgia: a drug development perspective. Psychopharmacol Bull. 2002;36:165–213
  11. Mochizucki D. Serotonin and noradrenaline reuptake inhibitors in animal models of pain. Hum Psychopharmacol. 2004;19(suppl 1):S15–S19
  12. Arnold LM, Lu Y, Crofford LJ, et al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum. 2004;50:2974–2984
  13. Arnold LM, Rosen A, Pritchett YL, et al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain. 2005;119:5–15
  14. Russell IJ, Mease PJ, Smith TR, et al. Efficacy and safety of duloxetine for treatment of fibromyalgia in patients with or without major depressive disorder: results from a 6-month, randomized, double-blind, placebo-controlled, fixed-dose trial. Pain. 2008;136:432–444
  15. Gendreau RM, Thorn MD, Gendreau JF, et al. Efficacy of milnacipran in patients with fibromyalgia. J Rheumatol. 2005;32:1975–1985
  16. Mease PJ, Clauw DJ, Gendreau RM, et al. The efficacy and safety of milnacipran for treatment of fibromyalgia: a randomized, double-blind, placebo-controlled trial [published correction appears in J Rheumatol 2009;36:661]. J Rheumatol. 2009;36:389–409
  17. Clauw DJ, Mease P, Palmer RH, Gendreau RM, Wang Y. Milnacipran for the treatment of fibromyalgia in adults: a 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial [published correction appears in Clin Ther 2009;31:446]. Clin Ther. 2008;30:1988–2004
  18. Branco JC, Zachrisson O, Perrot S, et al. A European, multicenter, randomized, double-blind, placebo-controlled monotherapy clinical trial of milnacipran in the treatment of fibromyalgia. J Rheumatol. 2009;In press
  19. Clauw DJ. Fibromyalgia: an overview. Am J Med. 2009;122(suppl):S3–S13
  20. Bradley LA. Pathophysiology of fibromyalgia. Am J Med. 2009;122(suppl):S22–S30
  21. Stratz T, Samborski W, Hrycaj P, et al. Serotonin concentration in serum of patients with generalized tendomyopathy (fibromyalgia) and chronic polyarthritis [in German]. Med Klin (Munich). 1993;88:458–462
  22. Yunus MB, Dailey JW, Aldag JC, Masi AT, Jobe PC. Plasma tryptophan and other amino acids in primary fibromyalgia: a controlled study. J Rheumatol. 1992;19:90–94
  23. Wolfe F, Russell IJ, Vipraio G, Ross K, Anderson J. Serotonin levels, pain threshold, and fibromyalgia symptoms in the general population. J Rheumatol. 1997;24:555–559
  24. Rao SG, Gendreau JF, Kranzler JD. Understanding the fibromyalgia syndrome. Psychopharmacol Bull. 2007;40:24–67
  25. Owens MJ, Nemeroff CB. Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem. 1994;40:288–295
  26. Offenbaecher M, Bondy B, de Jonge S, et al. Possible association of fibromyalgia with a polymorphism in the serotonin transporter gene regulatory region. Arthritis Rheum. 1999;42:2482–2488
  27. Gursoy S. Absence of association of the serotonin transporter gene polymorphism with the mentally healthy subset of fibromyalgia patients. Clin Rheumatol. 2002;21:194–197
  28. Jones CK, Eastwood BJ, Need AB, Shannon HE. Analgesic effects of serotonergic, noradrenergic or dual reuptake inhibitors in the carrageenan test in rats: evidence for synergism between serotonergic and noradrenergic reuptake inhibition. Neuropharmacology. 2006;51:1172–1180
  29. Fishbain D. Evidence-based data on pain relief with antidepressants. Ann Med. 2000;32:305–316
  30. Arnold LM, Keck PE, Welge JA. Antidepressant treatment of fibromyalgia: a meta-analysis and review. Psychosomatics. 2000;41:104–113
  31. Owens MJ, Morgan WN, Plott SJ, Nemeroff CB. Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther. 1997;283:1305–1322
  32. Vaishnavi SN, Nemeroff CB, Plott SJ, Rao SG, Kranzler J, Owens MJ. Milnacipran: a comparative analysis of human monoamine uptake and transporter binding affinity. Biol Psychiatry. 2004;55:320–322
  33. Owens MJ, Knight DL, Nemeroff CB. Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry. 2001;50:345–350
  34. Savella [package insert]. St. Louis, MO: Forest Pharmaceuticals, Inc; 2009;
  35. Puozzo C, Panconi E, Deprez D. Pharmacology and pharmacokinetics of milnacipran. Int Clin Psychopharmacol. 2002;17(suppl 1):S25–S35
  36. O'Malley PG, Balden E, Tomkins G, Santoro J, Kroenke K, Jackson JL. Treatment of fibromyalgia with antidepressants: a meta-analysis. J Gen Intern Med. 2000;15:659–666
  37. 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
  38. Lynch ME. Antidepressants as analgesics: a review of randomized controlled trials. J Psychiatry Neurosci. 2001;26:30–36
  39. Jung AC, Staiger T, Sullivan M. The efficacy of selective serotonin reuptake inhibitors for the management of chronic pain. J Gen Intern Med. 1997;12:384–389
  40. Tofferi JK, Jackson JL, O'Malley PG. Treatment of fibromyalgia with cyclobenzaprine: a meta-analysis. Arthritis Rheum. 2004;51:9–13
  41. Häuser W, Bernardy K, Uceyler N, Sommer C. Treatment of fibromyalgia syndrome with antidepressants: a meta-analysis. JAMA. 2009;301:198–209
  42. Staud R. Treatment of fibromyalgia and its symptoms. Expert Opin Pharmacother. 2007;8:1629–1642
  43. Beliles K, Stoudemire A. Psychopharmacologic treatment of depression in the medically ill. Psychosomatics. 1998;39:S2–S19
  44. Goldenberg DL. Pharmacological treatment of fibromyalgia and other chronic musculoskeletal pain. Best Pract Res Clin Rheumatol. 2007;21:499–511
  45. Arnold LM. Duloxetine and other antidepressants in the treatment of patients with fibromyalgia. Pain Med. 2007;8:S63–S74
  46. Harvey AT, Rudolph RL, Preskorn SH. Evidence of the dual mechanisms of action of venlafaxine. Arch Gen Psychiatry. 2000;57:503–509
  47. Sayar K, Aksu G, Ak I, Tosun M. Venlafaxine treatment of fibromyalgia. Ann Pharmacother. 2003;37:1561–1565
  48. Dwight MM, Arnold LM, O'Brien H, Metzger R, Morris-Park E, Keck PE. An open clinical trial of venlafaxine treatment of fibromyalgia. Psychosomatics. 1998;39:14–17
  49. Zijlstra TR, Barendregt PJ, van de Laar MAF. Venlafaxine in fibromyalgia: results of a randomized, placebo-controlled, double-blind trial [abstract]. Arthritis Rheum. 2002;46(suppl):S105
  50. Cymbalta [package insert]. Indianapolis, IN: Eli Lilly and Company; 2008;
  51. Chappell AS, Bradley LA, Wiltse C, Detke MJ, D'Souza DN, Spaeth M. A six-month double-blind, placebo-controlled, randomized trial of duloxetine for the treatment of fibromyalgia. Int J Gen Med. 2008;1:91–102
  52. Arnold LM, Pritchett YL, D'Souza DN, Kajdasz DK, Iyengar S, Wernicke JF. Duloxetine for the treatment of fibromyalgia in women: pooled results from two randomized, placebo-controlled clinical trials. J Womens Health. 2007;16:1145–1156
  53. Wise TN, Perahia DG, Pangallo BA, Losin WG, Wiltse CG. Effects of the antidepressant duloxetine on body weight: analyses of 10 clinical studies. Prim Care Companion J Clin Psychiatry. 2006;8:269–278
  54. Study of Milnacipran for the Treatment of Fibromyalgia. [ClinicalTrials.gov Website.] http://clinicaltrials.gov/ct2/show/NCT00314249Accessed March 20, 2009
  55. Mease PJ. Milnacipran: a new treatment option for fibromyalgia. Practical Pain Management. 2009; May;52–57
  56. Dionne RA, Bartoshuk L, Mogil J, Witter J. Individual responder analyses for pain: does one pain scale fit all?. Trends Pharmacol Sci. 2005;26:125–130
  57. Stahl SM, Grady MM, Moret C, Briley M. SNRIs: their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants. CNS Spectr. 2005;10:732–747
  58. Goldenberg DL, Clauw DJ, Palmer RH, Mease P, Chen W, Gendreau RM. Durability of therapeutic response to milnacipran treatment for fibromyalgia (Results of a randomized, double-blind, monotherapy 6-month extension study). Pain Med. 2009;In press
  59. Pae CU, Masand PS, Ajwani N, Lee C, Patkar AA. Guidelines on the irritable bowel syndrome: mechanisms and practical management. Gut. 2007;56:1770–1798
  60. Pae CU, Masand PS, Ajwani N, Lee C, Patkar AA. Irritable bowel syndrome in psychiatric perspectives: a comprehensive review. Int J Clin Pract. 2007;61:1708–1718
  61. Drossman DA, Toner BB, Whitehead WE, et al. Cognitive-behavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders. Gastroenterology. 2003;125:19–31
  62. Abdul-Baki H, El Zahabi LMN, El Hajj II, et al. A randomized double-blind placebo-controlled trial of imipramine in patients with irritable bowel syndrome [abstract]. Am J Gastroenterol. 2006;101:S479
  63. Quartero AO, Meineche-Schmidt V, Muris J, Rubin G, de Wit N. Bulking agents, antispasmodic and antidepressant medication for the treatment of irritable bowel syndrome. Cochrane Database Syst Rev. 2005;(2):CD003460
  64. Jackson JL, O'Malley PG, Kroenke K. Antidepressants and cognitive-behavioral therapy for symptom syndromes. CNS Spectr. 2006;11:212–222
  65. Saad RJ, Chey WD. Recent developments in the therapy of irritable bowel syndrome. Expert Opin Investig Drugs. 2008;17:117–130
  66. Comparison of Psychological and Pharmacological Treatments of Pain Due to TMD. [ClinicalTrials.gov Website.] http://clinicaltrials.gov/ct2/show/NCT00066937Accessed March 20, 2009
  67. Goodnick PJ. Treatment of chronic fatigue syndrome with venlafaxine. Am J Psychiatry. 1996;153:294
  68. Toyofuku A, Miyako H. A case of temporo-mandibular disorder with fibromyalgia treated with the antidepressant, milnacipran. Hum Psychopharmacol. 2004;19:357–358
  69. Rosenhagen MC, Schmidt U, Ebinger M, Nickel T, Uhr M. Successful treatment of chronic fatigue syndrome with duloxetine and trijodthyronine--a case study. J Clin Psychopharmacol. 2008;28:105–107
  70. Double-blind Trial of Duloxetine in Chronic Fatigue Syndrome. [ClinicalTrials.gov Website.] http://clinicaltrials.gov/ct2/show/NCT00375973Accessed March 20, 2009
  71. An Open-Label Trial of Duloxetine for the Treatment of Irritable Bowel Syndrome. [ClinicalTrials.gov Website.] http://clinicaltrials.gov/ct2/show/NCT00401258Accessed March 20, 2009
  72. Krell HV, Leuchter AF, Cook IA, Abrams M. Evaluation of reboxetine, a noradrenergic antidepressant, for the treatment of fibromyalgia and chronic low back pain. Psychosomatics. 2005;46:379–384

 Statement of author disclosure: Please see the Author Disclosures section at the end of this article.

PII: S0002-9343(09)00827-4

doi: 10.1016/j.amjmed.2009.09.010

The American Journal of Medicine
Volume 122, Issue 12, Supplement , Pages S44-S55 , December 2009

Article Tools

* Image Usage & Resolution