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Review

Drug discovery and development for fibromyalgia using practical biomarkers throughout the process from relevant animal models to patients

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Pages 539-549 | Received 31 Jan 2023, Accepted 06 Apr 2023, Published online: 13 Apr 2023

References

  • Salaffi F, Di Carlo M, Farah S, et al. Diagnosis of fibromyalgia: comparison of the 2011/2016 ACR and AAPT criteria and validation of the modified Fibromyalgia Assessment Status. Rheumatology (Oxford). 2020 Oct 1;59(10):3042–3049. DOI:10.1093/rheumatology/keaa061
  • Wolfe F, Clauw DJ, Fitzcharles MA, et al. Revisions to the 2010/2011 fibromyalgia diagnostic criteria. Semin Arthritis Rheum. 2016 Dec;46(3):319–329.
  • Clauw DJ. Fibromyalgia: a clinical review. JAMA. 2014 Apr 16;311(15):1547–1555.
  • D’Onghia M, Ciaffi J, Ruscitti P, et al. The economic burden of fibromyalgia: a systematic literature review. Semin Arthritis Rheum. 2022 Oct;56:152060.
  • Calandre EP, Rico-Villademoros F, Slim M. An update on pharmacotherapy for the treatment of fibromyalgia. Expert Opin Pharmacother. 2015 Jun;16(9):1347–1368.
  • Doebl S, Macfarlane GJ, Hollick RJ. “No one wants to look after the fibro patient”. Understanding models, and patient perspectives, of care for fibromyalgia: reviews of current evidence. Pain. 2020 Aug;161(8):1716–1725.
  • Ben-Ami Shor D, Weitzman D, Dahan S, et al. Adherence and persistence with drug therapy among fibromyalgia patients: data from a large health maintenance organization. J Rheumatol. 2017 Oct;44(10):1499–1506.
  • Briley M. Drugs to treat fibromyalgia - the transatlantic difference. Curr Opin Invest Drugs. 2010 Jan;11(1):16–18.
  • Ghavidel-Parsa B, Bidari A, Amir Maafi A, et al. The iceberg nature of fibromyalgia burden: the clinical and economic aspects. Korean J Pain. 2015 Jul;28(3):169–176.
  • Bhusal S, Diomampo S, Magrey MN. Clinical utility, safety, and efficacy of pregabalin in the treatment of fibromyalgia. Drug Healthc Patient Saf. 2016;8:13–23.
  • Häuser W, Walitt B, Fitzcharles MA, et al. Review of pharmacological therapies in fibromyalgia syndrome. Arthritis Res Ther. 2014 Jan 17;16(1):201. DOI:10.1186/ar4441
  • Curia G, Biagini G, Perucca E, et al. Lacosamide: a new approach to target voltage-gated sodium currents in epileptic disorders. CNS Drugs. 2009;23(7):555–568. DOI:10.2165/00023210-200923070-00002
  • Hearn L, Derry S, Moore RA. Lacosamide for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2012 Feb 15;2012(2):Cd009318.
  • Bourke SL, Schlag AK, O’Sullivan SE, et al. Cannabinoids and the endocannabinoid system in fibromyalgia: a review of preclinical and clinical research. Pharmacol Ther. 2022 Dec;240:108216.
  • Nagakura Y. The need for fundamental reforms in the pain research field to develop innovative drugs. Expert Opin Drug Discov. 2017 Jan;12(1):39–46.
  • Kissin I. Scientometrics of drug discovery efforts: pain-related molecular targets. Drug Des Devel Ther. 2015;9:3393–3404.
  • Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011 Mar;152(3 Suppl):S2–s15.
  • Ablin K, Clauw DJ. From fibrositis to functional somatic syndromes to a bell-shaped curve of pain and sensory sensitivity: evolution of a clinical construct. Rheum Dis Clin North Am. 2009 May;35(2):233–251.
  • Chinn S, Caldwell W, Gritsenko K. Fibromyalgia pathogenesis and treatment options update. Curr Pain Headache Rep. 2016 Apr;20(4):25.
  • Ramaswamy S, Wodehouse T. Conditioned pain modulation-A comprehensive review. Neurophysiol Clin. 2021 Jun;51(3):197–208.
  • O’Brien AT, Deitos A, Triñanes Pego Y, et al. Defective endogenous pain modulation in fibromyalgia: a meta-analysis of temporal summation and conditioned pain modulation paradigms. J Pain. 2018 Aug;19(8):819–836.
  • Cagnie B, Coppieters I, Denecker S, et al. Central sensitization in fibromyalgia? A systematic review on structural and functional brain MRI. Semin Arthritis Rheum. 2014 Aug;44(1):68–75.
  • Napadow V, Harris RE. What has functional connectivity and chemical neuroimaging in fibromyalgia taught us about the mechanisms and management of ‘centralized’ pain? Arthritis Res Ther. 2014;16(5):425.
  • Napadow V, LaCount L, Park K, et al. Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity. Arthritis Rheum. 2010 Aug;62(8):2545–2555.
  • Ichesco E, Schmidt-Wilcke T, Bhavsar R, et al. Altered resting state connectivity of the insular cortex in individuals with fibromyalgia. J Pain. 2014 Aug;15(8):815–826.e1.
  • Assavarittirong C, Samborski W, Grygiel-Górniak B. Oxidative stress in fibromyalgia: from pathology to treatment. Oxid Med Cell Longev. 2022;2022:1582432.
  • La Rubia M, Rus A, Molina F, et al. Is fibromyalgia-related oxidative stress implicated in the decline of physical and mental health status? Clin Exp Rheumatol. 2013 Nov;31(6 Suppl 79):S121–7.
  • Cordero MD, Moreno-Fernández AM, deMiguel M, et al. Coenzyme Q10 distribution in blood is altered in patients with fibromyalgia. Clin Biochem. 2009 May;42(7–8):732–735.
  • Cordero MD, De Miguel M, Moreno Fernández AM, et al. Mitochondrial dysfunction and mitophagy activation in blood mononuclear cells of fibromyalgia patients: implications in the pathogenesis of the disease. Arthritis Res Ther. 2010;12(1):R17. DOI:10.1186/ar2918
  • Sánchez-Domínguez B, Bullón P, Román-Malo L, et al. Oxidative stress, mitochondrial dysfunction and, inflammation common events in skin of patients with Fibromyalgia. Mitochondrion. 2015 Mar;21:69–75.
  • Meeus M, Nijs J, Hermans L, et al. The role of mitochondrial dysfunctions due to oxidative and nitrosative stress in the chronic pain or chronic fatigue syndromes and fibromyalgia patients: peripheral and central mechanisms as therapeutic targets? Expert Opin Ther Targets. 2013 Sep;17(9):1081–1089.
  • Fitzcharles MA, Perrot S, Häuser W. Comorbid fibromyalgia: a qualitative review of prevalence and importance. Eur J Pain. 2018 Oct;22(9):1565–1576.
  • Puntillo F, Giglio M, Paladini A, et al. Pathophysiology of musculoskeletal pain: a narrative review. Ther Adv Musculoskelet Dis. 2021 ;13:1759720x21995067.
  • O’Mahony LF, Srivastava A, Mehta P, et al. Is fibromyalgia associated with a unique cytokine profile? A systematic review and meta-analysis. Rheumatology (Oxford). 2021 Jun 18;60(6):2602–2614. DOI:10.1093/rheumatology/keab146.
  • Kumbhare D, Hassan S, Diep D, et al. Potential role of blood biomarkers in patients with fibromyalgia: a systematic review with meta-analysis. Pain. 2022 Jul 1;163(7):1232–1253. DOI:10.1097/j.pain.0000000000002510
  • Andrés-Rodríguez L, Borràs X, Feliu-Soler A, et al. Peripheral immune aberrations in fibromyalgia: a systematic review, meta-analysis and meta-regression. Brain Behav Immun. 2020 Jul;87:881–889.
  • Ohgidani M, Kato TA, Hosoi M, et al. Fibromyalgia and microglial TNF-α: translational research using human blood induced microglia-like cells. Sci Rep. 2017 Sep 19;7(1):11882. DOI:10.1038/s41598-017-11506-4
  • Merriwether EN, Agalave NM, Dailey DL, et al. IL-5 mediates monocyte phenotype and pain outcomes in fibromyalgia. Pain. 2021 May 1;162(5):1468–1482. DOI:10.1097/j.pain.0000000000002089
  • Meester I, Rivera-Silva GF, González-Salazar F. Immune system sex differences may bridge the gap between sex and gender in fibromyalgia. Front Neurosci. 2019;13:1414.
  • Ernberg M, Christidis N, Ghafouri B, et al. Plasma cytokine levels in fibromyalgia and their response to 15 weeks of progressive resistance exercise or relaxation therapy. Mediators Inflamm. 2018 ;2018:3985154.
  • Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001 Mar;69(3):89–95. DOI:10.1067/mcp.2001.113989.
  • Califf RM. Biomarker definitions and their applications. Exp Biol Med (Maywood). 2018 Feb;243(3):213–221.
  • The effect of intensive diabetes therapy on the development and progression of neuropathy. The diabetes control and complications trial research group. Ann Intern Med. 1995 Apr 15;122(8):561–568. DOI:10.7326/0003-4819-122-8-199504150-00001
  • Twomey JD, Brahme NN, Zhang B. Drug-biomarker co-development in oncology - 20 years and counting. Drug Resist Updat. 2017 Jan;30:48–62.
  • Sarzi-Puttini P, Giorgi V, Atzeni F, et al. Fibromyalgia position paper. Clin Exp Rheumatol. 2021 May;39(Suppl 130(3)):186–193.
  • Singh L, Kaur A, Bhatti MS, et al. Possible molecular mediators involved and mechanistic insight into fibromyalgia and associated co-morbidities. Neurochem Res. 2019 Jul;44(7):1517–1532.
  • Davis KD, Aghaeepour N, Ahn AH, et al. Discovery and validation of biomarkers to aid the development of safe and effective pain therapeutics: challenges and opportunities. Nat Rev Neurol. 2020 Jul;16(7):381–400.
  • Clauw DJ, Arnold LM, McCarberg BH. The science of fibromyalgia. Mayo Clin Proc. 2011 Sep;86(9):907–911.
  • Siracusa R, Paola RD, Cuzzocrea S, et al. Fibromyalgia: pathogenesis, mechanisms, diagnosis and treatment options update. Int J Mol Sci. 2021 Apr 9;22(8):3891. DOI:10.3390/ijms22083891
  • Russell IJ, Vaeroy H, Javors M, et al. Cerebrospinal fluid biogenic amine metabolites in fibromyalgia/fibrositis syndrome and rheumatoid arthritis. Arthritis Rheum. 1992 May;35(5):550–556.
  • Harris RE, Sundgren PC, Craig AD, et al. Elevated insular glutamate in fibromyalgia is associated with experimental pain. Arthritis Rheum. 2009 Oct;60(10):3146–3152.
  • Foerster BR, Petrou M, Edden RA, et al. Reduced insular γ-aminobutyric acid in fibromyalgia. Arthritis Rheum. 2012 Feb;64(2):579–583.
  • Foerster BR, Nascimento TD, DeBoer M, et al. Excitatory and inhibitory brain metabolites as targets of motor cortex transcranial direct current stimulation therapy and predictors of its efficacy in fibromyalgia. Arthritis & Rheumatology. 2015 Feb;67(2):576–581.
  • Egerton A. The potential of (1)H-MRS in CNS drug development. Psychopharmacol (Berl). 2021 May;238(5):1241–1254.
  • Quesada C, Kostenko A, Ho I, et al. Human surrogate models of central sensitization: a critical review and practical guide. Eur J Pain. 2021 Aug;25(7):1389–1428.
  • Rolke R, Baron R, Maier C, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain. 2006 Aug;123(3):231–243.
  • Weaver KR, Griffioen MA, Klinedinst NJ, et al. Quantitative sensory testing across chronic pain conditions and use in special populations. Front Pain Res (Lausanne). 2021 ;2:779068.
  • Demant DT, Lund K, Vollert J, et al. The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: a randomised, double-blind, placebo-controlled phenotype-stratified study. Pain. 2014 Nov;155(11):2263–2273.
  • van de Donk T, Niesters M, Kowal MA, et al. An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia. Pain. 2019 Apr;160(4):860–869.
  • Oaks Z, Stage A, Middleton B, et al. Clinical utility of the cold pressor test: evaluation of pain patients, treatment of opioid-induced hyperalgesia and fibromyalgia with low dose naltrexone. Discov Med. 2018 Nov;26(144):197–206.
  • Castelo-Branco L, Cardenas-Rojas A, Rebello-Sanchez I, et al. Temporal summation in fibromyalgia patients: comparing phasic and tonic paradigms. Front Pain Res (Lausanne). 2022;3:881543.
  • Arendt-Nielsen L, Morlion B, Perrot S, et al. Assessment and manifestation of central sensitisation across different chronic pain conditions. Eur J Pain. 2018 Feb;22(2):216–241.
  • Fernandes C, Pidal-Miranda M, Samartin-Veiga N, et al. Conditioned pain modulation as a biomarker of chronic pain: a systematic review of its concurrent validity. Pain. 2019 Dec;160(12):2679–2690.
  • Albrecht DS, MacKie PJ, Kareken DA, et al. Differential dopamine function in fibromyalgia. Brain Imaging Behav. 2016 Sep;10(3):829–839.
  • Napadow V, Kim J, Clauw DJ, et al. Decreased intrinsic brain connectivity is associated with reduced clinical pain in fibromyalgia. Arthritis Rheum. 2012 Jul;64(7):2398–2403.
  • Ricci M, Cimini A, Grivet Fojaja MR, et al. Novel approaches in molecular imaging and neuroimaging of fibromyalgia. Int J Mol Sci. 2022 Dec 8;23(24):15519.
  • Shukla V, Kumar DS, Ali MA, et al. Nitric oxide, lipid peroxidation products, and antioxidants in primary fibromyalgia and correlation with disease severity. J Med Biochem. 2020 Jan 23;39(2):165–170.
  • Cordero MD, Cano-García FJ, Alcocer-Gómez E, et al. Oxidative stress correlates with headache symptoms in fibromyalgia: coenzyme Q₁₀ effect on clinical improvement. PLoS ONE. 2012;7(4):e35677.
  • Sawaddiruk P, Apaijai N, Paiboonworachat S, et al. Coenzyme Q10 supplementation alleviates pain in pregabalin-treated fibromyalgia patients via reducing brain activity and mitochondrial dysfunction. Free Radic Res. 2019 Aug;53(8):901–909.
  • Fernández-Araque A, Verde Z, Torres-Ortega C, et al. Effects of antioxidants on pain perception in patients with fibromyalgia-a systematic review. J Clin Med. 2022 Apr 27;11(9):2462.
  • Bäckryd E, Tanum L, Lind AL, et al. Evidence of both systemic inflammation and neuroinflammation in fibromyalgia patients, as assessed by a multiplex protein panel applied to the cerebrospinal fluid and to plasma. J Pain Res. 2017;10:515–525.
  • Hsu WH, Han DS, Ku WC, et al. Metabolomic and proteomic characterization of sng and pain phenotypes in fibromyalgia. Eur J Pain. 2022 Feb;26(2):445–462.
  • Mendieta D, De la Cruz-Aguilera DL, Barrera-Villalpando MI, et al. IL-8 and IL-6 primarily mediate the inflammatory response in fibromyalgia patients. J Neuroimmunol. 2016 Jan 15;290:22–25.
  • Fineschi S, Klar J, Gustafsson KA, et al. Inflammation and interferon signatures in peripheral b-lymphocytes and sera of individuals with fibromyalgia. Front Immunol. 2022;13:874490.
  • Salm DC, Belmonte LAO, Emer AA, et al. Aquatic exercise and Far Infrared (FIR) modulates pain and blood cytokines in fibromyalgia patients: a double-blind, randomized, placebo-controlled pilot study. J Neuroimmunol. 2019 Dec 15;337:577077.
  • Sluka KA, Kalra A, Moore SA. Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia. Muscle Nerve. 2001 Jan;24(1):37–46.
  • Nagakura Y, Oe T, Aoki T, et al. Biogenic amine depletion causes chronic muscular pain and tactile allodynia accompanied by depression: a putative animal model of fibromyalgia. Pain. 2009 Nov;146(1–2):26–33.
  • Nishiyori M, Ueda H. Prolonged gabapentin analgesia in an experimental mouse model of fibromyalgia. Mol Pain. 2008 Nov 6;4:52.
  • Brum ES, Becker G, Fialho MFP, et al. Animal models of fibromyalgia: what is the best choice? Pharmacol Ther. 2022 Feb;230:107959.
  • Skyba DA, Lisi TL, Sluka KA. Excitatory amino acid concentrations increase in the spinal cord dorsal horn after repeated intramuscular injection of acidic saline. Pain. 2005 Dec 15;119(1–3):142–149.
  • Nagakura Y, Miwa M, Yoshida M, et al. Spontaneous pain-associated facial expression and efficacy of clinically used drugs in the reserpine-induced rat model of fibromyalgia. Eur J Pharmacol. 2019 Dec 1;864:172716.
  • Abd-Ellatief RB, Mohamed HK, Kotb HI. Reactive astrogliosis in an experimental model of fibromyalgia: effect of dexmedetomidine. Cells Tissues Organs. 2018;205(2):105–119.
  • Sutton BC, Opp MR. Acute increases in intramuscular inflammatory cytokines are necessary for the development of mechanical hypersensitivity in a mouse model of musculoskeletal sensitization. Brain Behav Immun. 2015 Feb;44:213–220.
  • Lenert ME, Szabo-Pardi TA, Burton MDD. Regulatory T-cells and IL-5 mediate pain outcomes in a preclinical model chronic muscle pain. Mol Pain. 2022 Jun;17:17448069221110691.
  • Leung A, Gregory NS, Allen LH, et al. Regular physical activity prevents chronic pain by altering resident muscle macrophage phenotype and increasing interleukin-10 in mice. Pain. 2016 Jan;157(1):70–79.
  • Gong WY, Abdelhamid RE, Carvalho CS, et al. Resident macrophages in muscle contribute to development of hyperalgesia in a mouse model of noninflammatory muscle pain. J Pain. 2016 Oct;17(10):1081–1094.
  • Arora V, Kuhad A, Tiwari V, et al. Curcumin ameliorates reserpine-induced pain-depression dyad: behavioural, biochemical, neurochemical and molecular evidences. Psychoneuroendocrinology. 2011 Nov;36(10):1570–1581.
  • Fusco R, Siracusa R, D’Amico R, et al. Melatonin plus folic acid treatment ameliorates reserpine-induced fibromyalgia: an evaluation of pain, oxidative stress, and inflammation. Antioxidants (Basel). 2019 Dec 6;8(12):628.
  • Kaur A, Singh L, Singh N, et al. Ameliorative effect of imperatorin in chemically induced fibromyalgia: role of NMDA/NFkB mediated downstream signaling. Biochem Pharmacol. 2019 Aug;166:56–69.
  • De la Luz-Cuellar YE, Rodríguez-Palma EJ, Franco-Enzástiga Ú, et al. Blockade of spinal α(5)-GABA(A) receptors differentially reduces reserpine-induced fibromyalgia-type pain in female rats. Eur J Pharmacol. 2019 Sep 5;858:172443.
  • Taguchi T, Katanosaka K, Yasui M, et al. Peripheral and spinal mechanisms of nociception in a rat reserpine-induced pain model. Pain. 2015 Mar;156(3):415–427.
  • Zhao J, Shi W, Lu Y, et al. Alterations of monoamine neurotransmitters, HPA-axis hormones, and inflammation cytokines in reserpine-induced hyperalgesia and depression comorbidity rat model. BMC Psychiatry. 2022 Jun 22;22(1):419.
  • Singh L, Kaur A, Garg S, et al. Protective effect of esculetin, natural coumarin in mice model of fibromyalgia: targeting pro-inflammatory cytokines and MAO-A. Neurochem Res. 2020 Oct;45(10):2364–2374.
  • Favero G, Trapletti V, Bonomini F, et al. Oral supplementation of melatonin protects against fibromyalgia-related skeletal muscle alterations in reserpine-induced myalgia rats. Int J Mol Sci. 2017 Jun 29;18(7):1389.
  • Akagi T, Matsumura Y, Yasui M, et al. Interferon regulatory factor 8 expressed in microglia contributes to tactile allodynia induced by repeated cold stress in rodents. J Pharmacol Sci. 2014;126(2):172–176.
  • Montserrat-de la Paz S, García-Giménez MD, Ángel-Martín M, et al. Validation and additional support for an experimental animal model of fibromyalgia. Mod Rheumatol. 2015 Jan;25(1):116–122.
  • Montserrat-de la Paz S, Garcia-Gimenez MD, Quilez AM, et al. Ginger rhizome enhances the anti-inflammatory and anti-nociceptive effects of paracetamol in an experimental mouse model of fibromyalgia. Inflammopharmacology. 2018 Aug;26(4):1093–1101.
  • Bonaterra GA, Then H, Oezel L, et al. Morphological alterations in gastrocnemius and soleus muscles in male and female mice in a fibromyalgia model. PLoS ONE. 2016;11(3):e0151116.
  • Littlejohn G, Guymer E. Neurogenic inflammation in fibromyalgia. Semin Immunopathol. 2018 May;40(3):291–300.
  • Wakatsuki K, TU Y, Matsubara T, et al. Peripheral nociceptive mechanisms in an experimental rat model of fibromyalgia induced by repeated cold stress. Neurosci Res. 2021 Jan;162:22–30.

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