New Insights into the Pathophysiology and Treatment of Fibromyalgia

Tobias Schmidt-Wilcke, Martin Diers, Tobias Schmidt-Wilcke, Martin Diers

Abstract

Fibromyalgia is characterized by chronic widespread pain and several additional symptoms such as fatigue, cognitive dysfunction, depressive episodes, and anxiety. The underlying pathophysiology of fibromyalgia is still poorly understood, and treatment is often unsatisfactory. Current research provides evidence for altered pain processing in chronic pain patients, and specifically in fibromyalgia patients, possibly based on altered functional connectivity and brain chemistry in brain regions within the pain processing system. Besides discussing evidence from studies applying brain imaging (specifically resting state fMRI (Functional magnetic resonance imaging)), the current review aims at providing an overview of pharmacological and non-pharmacological treatment options. We will also summarize the most important results from recently performed brain imaging studies providing new insights into the potential mechanisms of various therapeutic approaches.

Keywords: chronic pain; fMRI (functional magnetic resonance imaging); fibromyalgia; learning; resting state.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Pre-treatment resting state functional connectivity predicts decrease in pain interference in response to MLN treatment. Displays pre-milnacipran (MLN) treatment connectivity as a predictor for pain response to MLN. Results displayed contain seed-to-target connectivity (seed regions displayed on left) and plots of significant regressions for the MLN treatment arm and corresponding statistics for the placebo treatment period. ACC = anterior cingulate cortex, BPI Int = Brief Pain Inventory interference scores, IC = insular cortex, IPL = inferior parietal lobule, L = left, MLN = milnacipran, PBO = placebo, R = right.

References

    1. Blyth F.M., March L.M., Brnabic A.J.M., Jorm L.R., Williamson M., Cousins M.J. Chronic pain in Australia: A prevalence study. Pain. 2001;89:127–134. doi: 10.1016/S0304-3959(00)00355-9.
    1. Harker J., Reid K.J., Bekkering G.E., Kellen E., Malgorzata M., Riemsma R., Worthy G., Misso K., Kleijnen J. Epidemiology of chronic pain in Denmark and Sweden. Pain Res. Treat. 2012;2012 doi: 10.1155/2012/371248.
    1. Manchikanti L., Singh V., Datta S., Cohen S.P., Hirsch J. A Comprehensive review of epidemiology, scope, and impact of spinal pain. Pain Physician. 2009;12:E35–E70.
    1. Clauw D.J. Fibromyalgia: A clinical review. JAMA. 2014;311:1547–1555. doi: 10.1001/jama.2014.3266.
    1. Brummett C.M., Urquhart A.G., Hassett A.L., Tsodikov A., Hallstrom B.R., Wood N.I., Williams D.A., Clauw D.J. Characteristics of fibromyalgia independently predict poorer long-term analgesic outcomes following total knee and hip arthroplasty. Arthritis Rheumatol. 2015;67:1386–1394. doi: 10.1002/art.39051.
    1. Wolfe F., Ross K., Anderson J., Russell I.J., Hebert L. The Prevalence and Characteristics of Fibromyalgia in the General Population. Arthritis Rheumatol. 1995;38:19–28. doi: 10.1002/art.1780380104.
    1. Assumpção A., Cavalcante A., Capela C., Al E. Prevalence of fibromyalgia in a low socioeconomic status population. BMC Musculoskelet. Disord. 2009;10:64–70. doi: 10.1186/1471-2474-10-64.
    1. Helmick C.G., Felson D.T., Lawrence R.C., Gabriel S., Hirsch R., Kwoh C.K., Liang M.H., Kremers H.M., Mayes M.D., Merkel P.A., et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheumatol. 2008;58:15–25. doi: 10.1002/art.23177.
    1. Lawrence R.C., Felson D.T., Helmick C.G., Arnold L.M., Choi H., Deyo R.A., Gabriel S., Hirsch R., Hochberg M.C., Hunder G.G., et al. National Arthritis Data Workgroup Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: Part II. Arthritis Rheum. 2008;58:26–35. doi: 10.1002/art.23176.
    1. Arnold L.M., Hudson J.I., Hess E.V., Ware A.E., Fritz D.A., Auchenbach M.B., Starck L.O., Keck P.E. Family Study of Fibromyalgia. Arthritis Rheumatol. 2004;50:944–952. doi: 10.1002/art.20042.
    1. Diatchenko L., Nackley A.G., Slade G.D., Fillingim R.B., Maixner W. Idiopathic pain disorders–pathways of vulnerability. Pain. 2006;123:226–230. doi: 10.1016/j.pain.2006.04.015.
    1. Papageorgiou A.C., Silman A.J., Macfarlane G.J. Chronic widespread pain in the population: A seven year follow up study. Ann. Rheum. Dis. 2002;61:1071–1074. doi: 10.1136/ard.61.12.1071.
    1. McBeth J., Macfarlane G.J., Benjamin S., Morris S., Silman A.J., Beth J.M.C. The association between tender points, psychological distress, and adverse childhood experiences: A community-based study. Arthritis Rheum. 1999;42:1397–1404. doi: 10.1002/1529-0131(199907)42:7<1397::AID-ANR13>;2-7.
    1. Gracely R.H., Petzke F., Wolf J.M., Clauw D.J. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum. 2002;46:1333–1343. doi: 10.1002/art.10225.
    1. Giesecke T., Gracely R., Grant M.A., Nachemson A., Petzke F., Williams D., Clauw D. Evidence of augmented central pain processing in idiopathich chronic low back pain. Arthritis Rheum. 2004;50:613–623. doi: 10.1002/art.20063.
    1. Cook D.B., Lange G., Ciccone D.S., Liu W.C., Steffener J., Natelson B.H. Functional imaging of pain in patients with primary fibromyalgia. J. Rheumatol. 2004;31:364–378.
    1. Jensen K.B., Loitoile R., Kosek E., Petzke F., Carville S., Fransson P., Marcus H., Williams S.C.R., Choy E., Mainguy Y., et al. Patients with fibromyalgia display less functional connectivity in the brain’s pain inhibitory network. Mol. Pain. 2012;8:32. doi: 10.1186/1744-8069-8-32.
    1. Harte S.E., Ichesco E., Hampson J.P., Peltier S.J., Schmidt-Wilcke T., Clauw D.J., Harris R.E. Pharmacologic attenuation of cross-modal sensory augmentation within the chronic pain insula. Pain. 2016;157:1933. doi: 10.1097/j.pain.0000000000000593.
    1. Napadow V., LaCount L., Park K., As-Sanie S., Clauw D.J., Harris R.E. Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity. Arthritis Rheum. 2010;62:2545–2555. doi: 10.1002/art.27497.
    1. Ichesco E., Schmidt-Wilcke T., Bhavsar R., Clauw D.J., Peltier S.J., Kim J., Napadow V., Hampson J.P., Kairys A.E., Williams D.A., et al. Altered resting state connectivity of the insular cortex in individuals with fibromyalgia. J. Pain. 2014;15:815–826.e1. doi: 10.1016/j.jpain.2014.04.007.
    1. Tracey I. Nociceptive processing in the human brain. Curr. Opin. Neurobiol. 2005;15:478–487. doi: 10.1016/j.conb.2005.06.010.
    1. Kim J., Loggia M.L., Cahalan C.M., Harris R.E., Beissner F., Garcia R.G., Kim H., Barbieri R., Wasan A.D., Edwards R.R., et al. The somatosensory link in fibromyalgia: Functional connectivity of the primary somatosensory cortex is altered by sustained pain and is associated with clinical/autonomic dysfunction. Arthritis Rheumatol. 2015;67:1395–1405. doi: 10.1002/art.39043.
    1. Napadow V., Harris R.E. What has functional connectivity and chemical neuroimaging in fibromyalgia taught us about the mechanisms and management of “centralized” pain? Arthritis Res. Ther. 2014;16:425. doi: 10.1186/s13075-014-0425-0.
    1. Linton S.J., Götestam K.G. Controlling pain reports through operant conditioning: A laboratory demonstration. Percept. Mot. Skills. 1985;60:427–437. doi: 10.2466/pms.1985.60.2.427.
    1. Fordyce W.E. Behavioral Concepts in Chronic Pain and Illness. Mosby; St. Louis, MO, USA: 1976.
    1. Flor H., Knost B., Birbaumer N. The role of operant conditioning in chronic pain: An experimental investigation. Pain. 2002;95:111–118. doi: 10.1016/S0304-3959(01)00385-2.
    1. Knost B., Flor H., Birbaumer N., Schugens M.M. Learned maintenance of pain: Muscle tension reduces central nervous system processing of painful stimulation in chronic and subchronic pain patients. Psychophysiology. 1999;36:755–764. doi: 10.1111/1469-8986.3660755.
    1. Elert J., Kendall S.A., Larsson B., Mansson B., Gerdle B. Chronic pain and difficulty in relaxing postural muscles in patients with fibromyalgia and chronic whiplash associated disorders. J. Rheumatol. 2001;28:1361–1368.
    1. Hölzl R., Kleinbohl D., Huse E. Implicit operant learning of pain sensitization. Pain. 2005;115:12–20.
    1. Becker S., Kleinbo D., Klossika I., Ho R. Operant conditioning of enhanced pain sensitivity by heat—Pain titration. Pain. 2008;140:104–114. doi: 10.1016/j.pain.2008.07.018.
    1. Becker S., Kleinböhl D., Baus D., Hölzl R. Operant learning of perceptual sensitization and habituation is impaired in fibromyalgia patients with and without irritable bowel syndrome. Pain. 2011;152:1408–1417. doi: 10.1016/j.pain.2011.02.027.
    1. Schneider C., Palomba D., Flor H. Pavlovian conditioning of muscular responses in chronic pain patients: Central and peripheral correlates. Pain. 2004;112:239–247. doi: 10.1016/j.pain.2004.08.025.
    1. Jenewein J., Moergeli H., Sprott H., Honegger D., Brunner L., Ettlin D., Grillon C., Bloch K., Brügger M., Schwegler K., et al. Fear-learning deficits in subjects with fibromyalgia syndrome? Eur. J. Pain UK. 2013;17:1374–1384. doi: 10.1002/j.1532-2149.2013.00300.x.
    1. Guyatt G., Oxman A.D., Akl E.A., Kunz R., Vist G., Brozek J., Norris S., Falck-Ytter Y., Glasziou P., Debeer H., et al. GRADE guidelines: 1. Introduction—GRADE evidence profiles and summary of findings tables. J. Clin. Epidemiol. 2011;64:383–394. doi: 10.1016/j.jclinepi.2010.04.026.
    1. Macfarlane G.J., Kronisch C., Dean L.E., Atzeni F., Häuser W., Fluß E., Choy E., Kosek E., Amris K., Branco J., et al. EULAR revised recommendations for the management of fibromyalgia. Ann. Rheum. Dis. 2017;76:318–328. doi: 10.1136/annrheumdis-2016-209724.
    1. Arnold L.M., Keck P.E., Welge J.A. Antidepressant treatment of fibromyalgia. A meta-analysis and review. Psychosomatics. 2000;41:104–113. doi: 10.1176/appi.psy.41.2.104.
    1. Hauser W., Bernardy K., Uceyler N., Sommer C., Häuser W., Bernardy K., Uçeyler N., Sommer C. Treatment of Fibromyalgia Syndrome with Antidepressants: A Meta-analysis. JAMA J. Am. Med. Assoc. 2009;301:198–209. doi: 10.1001/jama.2008.944.
    1. Rico-Villademoros F., Slim M., Calandre E.P. Amitriptyline for the treatment of fibromyalgia: A comprehensive review. Expert Rev. Neurother. 2015;15:1123–1150. doi: 10.1586/14737175.2015.1091726.
    1. Anderberg U.M., Marteinsdottir I., von Knorring L. Citalopram in patients with fibromyalgia—A randomized, double-blind, placebo-controlled study. Eur. J. Pain. 2000;4:27–35. doi: 10.1053/eujp.1999.0148.
    1. Norregaard J., Volkmann H., Danneskiold-Samsoe B. A randomized controlled trial of citalopram in the treatment of fibromyalgia. Pain. 1995;61:445–449. doi: 10.1016/0304-3959(94)00218-4.
    1. Arnold L.M., Clauw D.J., Wohlreich M.M., Wang F., Ahl J., Gaynor P.J., Chappell A.S. Efficacy of duloxetine in patients with fibromyalgia: Pooled analysis of 4 placebo-controlled clinical trials. Prim Care Companion J. Clin. Psychiatry. 2009;11:237–244. doi: 10.4088/PCC.08m00680.
    1. Vitton O., Gendreau M., Gendreau J., Kranzler J., Rao S.G. A double-blind placebo-controlled trial of milnacipran in the treatment of fibromyalgia. Hum. Psychopharmacol. Clin. Exp. 2004;19:S27–S35. doi: 10.1002/hup.622.
    1. Collins S.L., Moore R.A., McQuay H.J., Wiffen P. Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: A quantitative systematic review. J. Pain Symptom Manag. 2000;20:449–458. doi: 10.1016/S0885-3924(00)00218-9.
    1. Straube S., Derry S., Moore R.A., McQuay H.J. Pregabalin in fibromyalgia: Meta-analysis of efficacy and safety from company clinical trial reports. Rheumatology. 2010;49:706–715. doi: 10.1093/rheumatology/kep432.
    1. Hauser W., Bernardy K., Uceyler N., Sommer C. Treatment of fibromyalgia syndrome with gabapentin and pregabalin—A meta-analysis of randomized controlled trials. Pain. 2009;145:69–81. doi: 10.1016/j.pain.2009.05.014.
    1. Schmidt-Wilcke T., Clauw D.J. Pharmacotherapy in fibromyalgia (FM)—Implications for the underlying pathophysiology. Pharmacol. Ther. 2010;127:283–294. doi: 10.1016/j.pharmthera.2010.03.002.
    1. Schmidt-Wilcke T., Clauw D.J. Fibromyalgia: From pathophysiology to therapy. Nat. Rev. Rheumatol. 2011;7:518–527. doi: 10.1038/nrrheum.2011.98.
    1. Jensen K.B., Petzke F., Carville S., Choy E., Fransson P., Gracely R.H., Vitton O., Marcus H., Williams S.C.R., Ingvar M., et al. Segregating the cerebral mechanisms of antidepressants and placebo in fibromyalgia. J. Pain. 2014;15:1328–1337. doi: 10.1016/j.jpain.2014.09.011.
    1. Schmidt-Wilcke T., Ichesco E., Hampson J.P., Kairys A., Peltier S., Harte S., Clauw D.J., Harris R.E. Resting state connectivity correlates with drug and placebo response in fibromyalgia patients. Neuroimage Clin. 2014;6:252–261. doi: 10.1016/j.nicl.2014.09.007.
    1. Harris R.E., Napadow V., Huggins J.P., Pauer L., Kim J., Hampson J., Sundgren P.C., Foerster B., Petrou M., Schmidt-Wilcke T., Clauw D.J. Pregabalin rectifies aberrant brain chemistry, connectivity, and functional response in chronic pain patients. Anesthesiology. 2013;119:1453–1464. doi: 10.1097/ALN.0000000000000017.
    1. Thieme K., Gromnica-Ihle E., Flor H. Operant Behavioral Treatment of Fibromyalgia: A Controlled Study. Arthritis Rheum. Arthritis Care Res. 2003;49:314–320. doi: 10.1002/art.11124.
    1. Thieme K., Flor H., Turk D.C. Psychological pain treatment in fibromyalgia syndrome: Efficacy of operant behavioural and cognitive behavioural treatments. Arthritis Res. Ther. 2006;8:R121. doi: 10.1186/ar2010.
    1. Diers M., Yilmaz P., Rance M., Thieme K., Gracely R.H., Rolko C., Schley M.T., Kiessling U., Wang H., Flor H. Treatment-related changes in brain activation in patients with fibromyalgia syndrome. Exp. Brain Res. 2012;218:619–628. doi: 10.1007/s00221-012-3055-2.
    1. Hassett A.L., Williams D.A. Non-pharmacological treatment of chronic widespread musculoskeletal pain. Best Pract. Res. Clin. Rheumatol. 2011;25:299–309. doi: 10.1016/j.berh.2011.01.005.
    1. Hoffman B.M., Papas R.K., Chatkoff D.K., Kerns R.D. Meta-analysis of psychological interventions for chronic low back pain. Health Psychol. 2007;26:1–9. doi: 10.1037/0278-6133.26.1.1.
    1. Jensen K.B., Kosek E., Wicksell R., Kemani M., Olsson G., Merle J.V., Kadetoff D., Ingvar M. Cognitive Behavioral Therapy increases pain-evoked activation of the prefrontal cortex in patients with fibromyalgeia. Pain. 2012;153:1495–1503. doi: 10.1016/j.pain.2012.04.010.
    1. Lazaridou A., Kim J., Cahalan C.M., Loggia M.L., Franceschelli O., Berna C., Schur P., Napadow V., Edwards R.R. Effects of Cognitive-behavioral Therapy (CBT) on Brain Connectivity Supporting Catastrophizing in Fibromyalgia. Clin. J. Pain. 2017;33:215–221. doi: 10.1097/AJP.0000000000000422.
    1. Flor H. Current Topics in Pain, Proceedings of the 12th World Congress Pain, Glasgow, UK, 17–22 August 2008. IASP Press; Seattle, WA, USA: 2009. Extinction of pain memories: Importance for the treatment of chronic pain; pp. 221–244.
    1. Thieme K., Gracely R.H. Are psychological treatments effective for fibromyalgia pain? Curr. Rheumatol. Rep. 2009;11:443–450. doi: 10.1007/s11926-009-0065-6.
    1. Thieme K., Turk D.C. Cognitive-behavioral and operant-behavioral therapy for people with fibromyalgia. Reumatismo. 2012;64:275–285. doi: 10.4081/reumatismo.2012.275.
    1. Ang D.C., Jensen M.P., Steiner J.L., Hilligoss J., Gracely R.H., Saha C. Combining cognitive-behavioral therapy and milnacipran for fibromyalgia: A feasibility randomized-controlled trial. Clin. J. Pain. 2013;29:747–754. doi: 10.1097/AJP.0b013e31827a784e.
    1. Ressler K.J., Rothbaum B.O., Tannenbaum L., Anderson P. Cognitive Enhancers as Adjuncts to Psychotherapy. Arch. Gen. Psychiatry. 2004;61:1136–1144. doi: 10.1001/archpsyc.61.11.1136.
    1. Hofmann S.G., Meuret A.E., Smits J.A.J., Simon N.M., Pollack M.H., Eisenmenger K., Shiekh M., Otto M.W. Augmentation of Exposure Therapy with d-Cycloserine for Social Anxiety Disorder. Arch. Gen. Psychiatry. 2006;63:11–14. doi: 10.1001/archpsyc.63.3.298.
    1. Marsicano G., Wotjak C.T., Azad S.C., Bisogno T., Rammes G., Cascio M.G., Hermann H., Tang J., Hofmann C., Zieglgänsberger W., et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature. 2002;418:530–534. doi: 10.1038/nature00839.
    1. Wotjak C.T. Role of endogenous cannabinoids in cognition and emotionality. Mini Rev. Med. Chem. 2005;5:659–670. doi: 10.2174/1389557054368763.

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