This review article presents and summarizes up-to-date literature on the clinical manifestations, diagnosis, pathophysiological mechanisms, and treatment options for fibromyalgia patients. First, the most recent diagnostic criteria for fibromyalgia, as put forth by the American College of Rheumatology will be summarized. Clinical features, including chronic widespread pain, hyperalgesia, mood disorders, anxiety, and disturbed sleep patterns will be explored in-depth. The pathogenesis and pathophysiology of fibromyalgia involves alterations in multiple ascending and descending central nervous system pathways, as well as peripheral pathways, leading to heightened pain sensitivity. Risk factors have been studied extensively, and the most recent research focuses on various genetic influences and the contributions of stress and poor sleep. Lastly, the discussion in this article focuses on treatment options for fibromyalgia; some have been mainstay options for many years. Pharmacological agents include tricyclic antidepressants, anti-epileptic drugs, selective serotonin reuptake inhibitors, norepinephrine/serotonin reuptake inhibitors, as well as some investigational agents. The evidence behind non-pharmacologic treatments, including massage therapy, exercise, and acupuncture, are discussed.
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Smith HS, Harris RE, Clauw DJ. Fibromyalgia. In: Benzon HT, Raja SN, Molly RE, Liu SS, Fishman SM, editors. Essentials of pain medicine. 3rd ed. Philadelphia: Elsevier; 2011. p. 345–50.
Choy EHS. The role of sleep in pain and fibromyalgia. Nat Rev Rheumatol. 2015;11:513–20. A review on the role of sleep dysfunction as a cause and consequence of fibromyalgia; it examines how sleep deprivation leads to abnormal pain processing.
Hadler NM. “Fibromyalgia” and the medicalization of misery. J Rheumatol. 2003;30:1668–70.
Inanici F, Yunus MB. History of fibromyalgia: past to present. Curr Pain Headache Rep. 2004;8:369–78.
Theoharides TC, Tsilioni I, Arbetman L, et al. Fibromyalgia syndrome in need of effective treatments. J Pharmacol Exp Ther. 2015;355:255–63.
Diaz-Piedra C, Di Stasi LL, Baldwin CM, Buela-Casal G, Catena A. Sleep disturbances of adult women suffering from fibromyalgia: a systematic review of observational studies. Sleep Med Rev. 2015;21:86–99.
Blanco I, Béritze N, Argüelles M, Cárcaba V, Fernández F, Janciauskiene S, et al. Abnormal overexpression of mastocytes in skin biopsies of fibromyalgia patients. Clin Rheumatol. 2010;29:1403–12.
Wolfe F, Clauw DJ, Fitzcharles MA, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res. 2010;62:600–10. The most recent update on changes to the diagnostic and classification criteria for fibromyalgia, as published by the American College of Rheumatology.
NFRA: Fibromyalgia Pressure Point. Salem (OR): National Fibromyalgia Research Association. http://www.nfra.net/fibromyalgia_pressure_point.php accessed 2016 Jan 18.
Clauw DJ. Fibromyalgia: a clinical review. JAMA. 2014;311:1547–55.
Ferrari R, Russell AS. A questionnaire using the modified 2010 American College of Rheumatology criteria for fibromyalgia: specificity and sensitivity in clinical practice. J Rheumatol. 2013;40:1590–5.
Alciati A, Sgiarovello P, Atzeni F, Sarzi-Puttini P. Psychiatric problems in fibromyalgia: clinical and neurobiological links between mood disorders and fibromyalgia. Reumatismo. 2012;64:268–74.
Goldenberg DL. Differential Diagnosis of fibromyalgia. In: Scher PH (ed). UpToDate. Waltham, MA. 2015. Retrieved from http://www.uptodate.com/contents/differential-diagnosis-of-fibromyalgia?source=search_result&search=differential+diagnosis+of+fibromyalgia&selectedTitle=1%7E142.
Nijs J, Malfliet A, Ickmans K, Baert I, Meeus M. Treatment of central sensitization in patients with ‘unexplained’ chronic pain: an update. Expert Opin Pharmacother. 2014;15:1671–83.
Lorenz J, Grasedyck K, Bromm B. Middle and long latency somatosensory evoked potentials after painful laser stimulation in patients with fibromyalgia syndrome. Electroencephalogr Clin Neurophysiol. 1996;100:165–8.
Fields HL, Basbaum AI, Heinricher MM. Central nervous system mechanisms of pain modulation. In: McMahon SB, Koltzenburg M, editors. Wall and Melzack’s textbook of pain. 5th ed. Philadelphia: Elsevier; 2006. p. 125–42.
Harris RE, Clauw DJ, Scott DJ, McLean SA, Gracely RH, Zubieta JK. Decreased central mu-opioid receptor availability in fibromyalgia. J Neurosci. 2007;27:10000–6.
Baraniuk JN, Whalen G, Cunningham J, et al. Cerebrospinal fluid levels of opioid peptides in fibromyalgia and chronic low back pain. BMC Musculoskelet Disord. 2004;5:48.
Kosek E, Hansson P. Modulatory influence on somatosensory perception from vibration and heterotopic noxious conditioning stimulation (HNCS) in fibromyalgia patients and healthy subjects. Pain. 1997;70:41–51.
Vaerøy H, Helle R, Førre O, Kåss E, Terenius L. Cerebrospinal fluid levels of beta-endorphin in patients with fibromyalgia (fibrositis syndrome). J Rheumatol. 1988;15:1804–6.
Xu XJ, Dalsgaard CJ, Wiesenfeld-Hallin Z. Spinal substance P and N-methyl-d-aspartate receptors are coactivated in the induction of central sensitization of the nociceptive flexor reflex. Neuroscience. 1992;51:641–8.
Bradley LA, Alberts KR, Alarcon GS, et al. Abnormal brain regional cerebral blood flow and cerebrospinal fluid levels of substance P in patients and non-patients with fibromyalgia. Arthritis Rheum. 1996;39:1109.
Littlejohn G. Neurogenic neuroinflammation in fibromyalgia and complex regional pain syndrome. Nat Rev Rheumatol. 2015;11:639–48. A review which introduces the concept of “neurogenic neuroinflammation” as a possible peripheral mechanism in the pathogenesis of fibromyalgia.
Arnold LM, Fan J, Russell IJ, Yunus MB, Khan MA, Kushner I, et al. The fibromyalgia family study: a genome-wide linkage scan study. Arthritis Rheum. 2013;65:1122–8.
Arnold LM, Hudson JI, Hess EV, Ware AE, Fritz DA, Auchenbach MB, et al. Family study of fibromyalgia. Arthritis Rheum. 2004;50:944–52.
Kato K, Sullivan PF, Evengård B, Pedersen NL. Chronic widespread pain and its comorbidities: a population-based study. Arch Intern Med. 2006;166:1649–54.
Vargas-Alarcón G, Fragoso JM, Cruz-Robles D, Vargas A, Martinez A, Lao-Villadóniga JI, et al. Association of adrenergic receptor gene polymorphisms with different fibromyalgia syndrome domains. Arthritis Rheum. 2009;60:2169–73.
Martinez-Lavin M. Biology and therapy of fibromyalgia. Stress, the stress response system, and fibromyalgia. Arthritis Res Ther. 2007;9:216.
Ablin JN, Buskila D. Update on the genetics of fibromyalgia syndrome. Best Pract Res Clin Rheumatol. 2015;29:20–8.
Bozkurt M, Caglayan M, Oktayoglu P, Em S, Batmaz I, Sariyildiz MA, et al. Serum prolidase enzyme activity and oxidative status in patients with fibromyalgia. Redox Rep. 2014;19:148–53.
Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. Lower plasma coenzyme Q10 in depression: a marker for treatment resistance and chronic fatigue in depression and a risk factor to cardiovascular disorder in that illness. Neuroendocrinol Lett. 2009;30:462–9.
Bigatti SM, Hernandez AM, Cronan TA, Rand KL. Sleep disturbances in fibromyalgia syndrome: relationship to pain and depression. Arthritis Rheum. 2008;59:961–7.
Scheuler W, Stinshoff D, Kubicki S. The alpha-sleep pattern. Differentiation from other sleep patterns and effect of hypnotics. Neuropsychobiology. 1983;10:183–9.
Dijk DJ. Regulation and functional correlates of slow wave sleep. J Clin Sleep Med. 2009;5:S6–S15.
Moldofsky H, Scarisbrick P. Induction of neurasthenic musculoskeletal pain syndrome by selective sleep stage deprivation. Psychosom Med. 1976;38:35–44.
McBeth J, Lacey RJ, Wilkie R. Predictors of new-onset widespread pain in older adults: results from a population-based prospective cohort study in the UK. Arthritis Rheum. 2014;66:757–67.
Jesus CAS, Feder D, Peres MFP. The role of vitamin D in pathophysiology and treatment of fibromyalgia. Curr Pain Headache Rep. 2013;17:355–61.
Costantini A, Pala MI, Tundo S, Matteucci P. High-dose thiamine improves the symptoms of fibromyalgia. BMJ Case Rep. 2013. doi:10.1136/bcr-2013-009019.
Regland B, Forsmark S, Halaouate L, Matousek M, Peilot B, Zachrisson O, et al. Response to vitamin B12 and folic acid in myalgic encephalomyelitis and fibromyalgia. PLoS ONE. 2015;10(4), e0124648. doi:10.1371/journal.pone.0124648.
Sakarya ST, Akyol Y, Bedir A, Canturk F. The relationship between serum antioxidant vitamins, magnesium levels, and clinical parameters in patients with primary fibromyalgia syndrome. Clin Rheumatol. 2011;30:1039–43.
Halpern R, Shah SN, Cappelleri JC, Masters ET, Clair A. Evaluating guideline-recommended pain medication use among patients with newly diagnosed fibromyalgia. Pain Pract. 2015. doi:10.1111/papr.12364.
Calandre EP, Rico-Villademoros F, Slim M. An update on pharmacotherapy for the treatment of fibromyalgia. Expert Opin Pharmacother. 2015;16:1347–68. An updated review of current evidence for and against pharmacological treatment options for fibromyalgia.
Goldenberg D, Mayskiy M, Mossey C, Ruthazer R, Schid C. A randomized, double-blind crossover trial of fluoxetine and Amitriptyline in the treatment of fibromyalgia. Arthritis Rheum. 1996;39:1852–9.
Häuser W, Petzke F, Üçeyler N, Sommer C. Comparative efficacy and acceptability of Amitriptyline, duloxetine and milnacipran in fibromyalgia syndrome: a systematic review with meta-analysis. Rheumatology. 2011;50:532–43.
Arnold LM, Clauw D, Wang F, et al. Flexible dosed duloxetine in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled trial. J Rheumatol. 2010;37:2578–86.
Häuser W, Urrútia G, Tort S, Üçeyler N, Walitt B. Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome. Cochrane Database Syst Rev. 2013;2013(1), CD010292. doi:10.1002/14651858.CD010292.
Cording M, Derry S, Phillips T, Moore RA, Wiffen PJ. Milnacipran for pain in fibromyalgia in adults. Cochrane Database Syst Rev. 2015;10, CD008244. doi:10.1002/14651858.CD008244.pub3.
Arnold LM, Hess EV, Hudson JI, et al. A randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia. Am J Med. 2002;112:191–7.
Walitt B, Urrútia G, Nishishinya MB, Cantrell SE, Häuser W. Selective serotonin reuptake inhibitors for fibromyalgia syndrome. Cochrane Database Syst Rev. 2015;2015(6), CD011735. doi:10.1002/14651858.CD011735. A meta-analysis of all the most recent literature and evidence for the efficacy of different serotonin reuptake inhibitors used towards the treatment of fibromyalgia.
Späth M, Stratz T, Neeck G, et al. Efficacy and tolerability of intravenous tropisetron in the treatment of fibromyalgia. Scand J Rheumatol. 2004;33:267–27.
Skrabek RQ, Galimova L, Ethans K, et al. Nabilone for the treatment of pain in fibromyalgia. J Pain. 2008;9:164–73.
Ware MA, Fitzcharles MA, Joseph L, et al. The effects of nabilone on sleep in fibromyalgia: results of a randomized controlled trial. Anesth Analg. 2010;110:604–10.
Staud R. Sodium oxybate for the treatment of fibromyalgia. Expert Opin Pharmacother. 2011;12:1789–98.
Russel IJ, Holman AJ, Swick TJ, et al. S Sodium oxybate reduces pain, fatigue, and sleep disturbance and improves functionality in fibromyalgia: results from a 14-week, randomized, double-blind, placebo-controlled study. Pain. 2011;152:1007–17.
Arnold LM, Goldenberg D, Stanford S, et al. Gabapentin in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled, multicenter trial. Arthritis Rheum. 2007;56:1336–44.
Crofford LJ, Mease PJ, Simpson SL. Fibromyalgia relapse evaluation and efficacy for durability of meaningful relief (FREEDOM): a 6-month, double-blind, placebo controlled trial with pregabalin. Pain. 2008;136:419–31. A promising, long-term placebo-controlled trial demonstrating how pregabalin improves multiple dimensions of fibromyalgia, including pain, sleep, fatigue, and quality of life.
Üçeyler N, Sommer C, Walitt B, Häuser W. Anticonvulsants for fibromyalgia. Cochrane Database Syst Rev. 2013;2013(10), CD010782. doi:10.1002/14651858.CD010782. A meta-analysis of various anticonvulsant agents for use towards fibromyalgia symptoms.
White HD, Robin TD. A novel use of testosterone to treat central sensitization of chronic pain in fibromyalgia patients. Int Immunopharmacol. 2015;27:244–8.
Busch AJ, Webber SC, Richards RS, Bidonde J, Schachter CL, Schafer LA, et al. Resistance exercise training for fibromyalgia. Cochrane Database Syst Rev. 2013;2013(12), CD010884. doi:10.1002/14651858.CD010884.
Busch AJ, Barber KA, Overend TJ, Peloso PMJ, Schachter CL. Exercise for treating fibromyalgia syndrome. Cochrane Database Syst Rev. 2007;2007(4), CD003786. doi:10.1002/14651858.CD003786.pub2.
Bidonde J, Busch AJ, Webber SC, Schachter CL, Danyliw A, Overend TJ, et al. Aquatic exercise training for fibromyalgia. Cochrane Database Syst Rev. 2014;2014(10), CD011336. doi:10.1002/14651858.CD011336.
Sawynok J, Lynch M. Qigong and fibromyalgia: randomized controlled trials and beyond. Evid Based Complement Alternat Med. 2014;2014, 379715. doi:10.1155/2014/379715.
Raman G, Mudedla S, Wang C. How effective is Tai Chi mind-body therapy for fibromyalgia: a systematic review and meta-analysis. J Altern Complement Med. 2014;20:A66–6.
Li Y-h, Wang F-y, Feng C-q, Yang X-f, Sun Y-h. Massage therapy for fibromyalgia: a systematic review and meta-analysis of randomized controlled trials. PLoS ONE. 2014;9, e89304.
Yuan SLK, Matsutani LA, Marques AP. Effectiveness of different styles of massage therapy in fibromyalgia: a systematic review and meta-analysis. Man Ther. 2015;20:257–64.
Deare JC, Zheng Z, Xue CCL, Liu JP, Shang J, Scott SW, et al. Acupuncture for treating fibromyalgia. Cochrane Database Syst Rev. 2013;2013(5), CD007070. doi:10.1002/14651858.CD007070.pub2. A meta-analysis demonstrating the efficacy of acupuncture.
Stival RS, Cavalheiro PR, Stasiak CE, Galdino DT, Hoekstra BE, Schafranski MD. Acupuncture in fibromyalgia: a randomized, controlled study addressing the immediate pain response. Rev Bras Reumatol. 2014;54:431–6.
Lin JG, Hsieh CL, Lin YW. Analgesic effect of electroacupuncture in a mouse fibromyalgia model: roles of TRPV1, TRPV4, and pERK. PLoS ONE. 2015;10(6), e0128037.
Conflict of Interest
Steven Chinn, William Caldwell, and Karina Gritsenko declare that they have no conflict of interest.
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This article does not contain any studies with human or animal subjects performed by any of the authors.
This article is part of the Topical Collection on Other Pain
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Chinn, S., Caldwell, W. & Gritsenko, K. Fibromyalgia Pathogenesis and Treatment Options Update. Curr Pain Headache Rep 20, 25 (2016). https://doi.org/10.1007/s11916-016-0556-x