Restricted accessResearch articleFirst published online 2025-7
Differences in Plasma BDNF Levels Between Chronic Primary Musculoskeletal Pain,Fibromyalgia Syndrome,and Asymptomatic Subjects: A Cross-Sectional Study
This cross-sectional study compared plasma brain-derived neurotrophic factor (BDNF) levels among chronic primary musculoskeletal pain patients, chronic widespread pain patients, and asymptomatic controls. The study included 126 participants aged 18–65, divided into three groups of 42 each. Pain intensity was assessed using a Numeric Rating Scale (NRS), and plasma BDNF levels were measured via ELISA. Differences between groups were evaluated using ANOVA with 2000 bootstrap resamples and a bias-corrected and accelerated method. Results showed significantly higher plasma BDNF levels in chronic widespread pain patients (mean difference [MD] = 0.44; 95% CI = 0.28, 0.62; p < .001) compared to controls, and higher than in chronic primary musculoskeletal pain patients (MD = 0.83; 95% CI = 0.64, 1.02; p < .001). Chronic primary musculoskeletal pain patients had lower plasma BDNF levels compared to controls (MD = −0.39; 95% CI = −0.54, −0.24; p < .001). No significant correlations were observed between plasma BDNF levels and clinical variables. These findings suggest the potential of BDNF as a biomarker to differentiate chronic primary pain conditions.
ArnoldL. M.BennettR. M.CroffordL. J.DeanL. E.ClauwD. J.GoldenbergD. L.FitzcharlesM. A.PaivaE. S.StaudR.Sarzi-PuttiniP.BuskilaD.MacfarlaneG. J. (2019). AAPT diagnostic criteria for fibromyalgia. The Journal of Pain, 20(6), 611–628. https://doi.org/10.1016/j.jpain.2018.10.008
2.
AzevedoL. F.Costa-PereiraA.MendonçaL.DiasC. C.Castro-LopesJ. M. (2016). The economic impact of chronic pain: A nationwide population-based cost-of-illness study in Portugal. The European Journal of Health Economics, 17(1), 87–98. https://doi.org/10.1007/s10198-014-0659-4
3.
BaumeisterD.EichW.SaftS.GeiselO.HellwegR.FinnA.SvenssonC. I.TesarzJ. (2019). No evidence for altered plasma NGF and BDNF levels in fibromyalgia patients. Scientific Reports, 9(1), Article 13667. https://doi.org/10.1038/s41598-019-49403-7
4.
BehnoushA. H.KhalajiA.KhanmohammadiS.AlehosseinP.SaeedianB.ShobeiriP.TeixeiraA. L.RezaeiN. (2023). Brain-derived neurotrophic factor in fibromyalgia: A systematic review and meta-analysis of its role as a potential biomarker. PLoS One, 18(12), Article e0296103. https://doi.org/10.1371/journal.pone.0296103
5.
BidariA.Ghavidel-ParsaB.GharibpoorF. (2022). Comparison of the serum brain-derived neurotrophic factor (BDNF) between fibromyalgia and nociceptive pain groups; and effect of duloxetine on the BDNF level. BMC Musculoskeletal Disorders, 23(1), 411. https://doi.org/10.1186/s12891-022-05369-8
6.
BjellandI.DahlA. A.HaugT.NeckelmannD. (nd). The validity of the Hospital Anxiety and Depression Scale. An updated literature review.
CaldeiraM. V.MeloC. V.PereiraD. B.CarvalhoR. F.CarvalhoA. L.DuarteC. B. (2007). BDNF regulates the expression and traffic of NMDA receptors in cultured hippocampal neurons. Molecular and Cellular Neuroscience, 35(2), 208–219. https://doi.org/10.1016/j.mcn.2007.02.019
9.
CardinalT. M.AntunesL. C.BrietzkeA. P.ParizottiC. S.CarvalhoF.De SouzaA.da Silva TorresI. L.FregniF.CaumoW. (2019). Differential neuroplastic changes in fibromyalgia and depression indexed by up-regulation of motor cortex inhibition and disinhibition of the descending pain system: An exploratory study. Frontiers in Human Neuroscience, 13, 138. https://doi.org/10.3389/fnhum.2019.00138
10.
CaumoW.DeitosA.CarvalhoS.LeiteJ.CarvalhoF.Dussán-SarriaJ. A.Lopes TarragóM. d. G.SouzaA.TorresI. L. d. S.FregniF. (2016). Motor cortex excitability and BDNF levels in chronic musculoskeletal pain according to structural pathology. Frontiers in Human Neuroscience, 10, 357. https://doi.org/10.3389/fnhum.2016.00357
11.
ChenZ.-Y.BathK.McewenB.HempsteadB.LeeF. (nd). Impact of genetic variant BDNF (Val66Met) on brain structure and function.
12.
ChinnS.CaldwellW.GritsenkoK. (2016). Fibromyalgia pathogenesis and treatment options update. Current Pain and Headache Reports, 20(4), 1–10. https://doi.org/10.1007/s11916-016-0556-x
13.
CookR.WeisbergS.WeisbergD. (1982). Residuals and influence in regression. Chapman & Hall.
14.
CorreiaA. S.CardosoA.ValeN. (2023). BDNF unveiled: Exploring its role in major depression disorder serotonergic imbalance and associated stress conditions. Pharmaceutics, 15(8), 2081. https://doi.org/10.3390/pharmaceutics15082081
Da Silveira AlvesC. F.CaumoW.SilvestriJ. M.ZorteaM.Dos SantosV. S.CardosoD. F.RegnerA.De SouzaA. H.SimonD. (2020). Pain catastrophizing is associated with the Val66Met polymorphism of the brain-derived neurotrophic factor in fibromyalgia. Advances in Rheumatology, 60(1), 39. https://doi.org/10.1186/s42358-020-00141-9
17.
DeitosA.Dussán-SarriaJ. A.SouzaA. d.MedeirosL.TarragôM. d. G.SehnF.ChassotM.ZanetteS.SchwertnerA.FregniF.TorresI. L. S.CaumoW. (2015). Clinical value of serum neuroplasticity mediators in identifying the central sensitivity syndrome in patients with chronic pain with and without structural pathology. The Clinical Journal of Pain, 31(11), 959–967. https://doi.org/10.1097/AJP.0000000000000194
18.
DimmekD. J.KorallusC.BuynyS.ChristophG.LichtinghagenR.JacobsR.NugrahaB. (2021). Brain-derived neurotrophic factor and immune cells in osteoarthritis, chronic low back pain, and chronic widespread pain patients: Association with anxiety and depression. Medicina (Lithuania), 57(4), 327. https://doi.org/10.3390/medicina57040327
19.
DobsonK. G.MustardC.CarnideN.FurlanA.SmithP. M. (2022). Impact of persistent pain symptoms on work absence, health status and employment 18 months following disabling work-related injury or illness. Occupational and Environmental Medicine, 79(10), 697–705. https://doi.org/10.1136/oemed-2022-108383
20.
DomschkeK.LawfordB.LajeG.BergerK.YoungR.MorrisP.DeckertJ.AroltV.McMahonF. J.BauneB. T. (2010). Brain-derived neurotrophic factor (BDNF) gene: No major impact on antidepressant treatment response. International Journal of Neuropsychopharmacology, 13(1), 93–101. https://doi.org/10.1017/S1461145709000030
EfronB.TibshiraniR. J. (1994). An introduction to the bootstrap (p. 456). Chapman and Hall/CRC.
23.
Ferrer-PeñaR.Gil-MartínezA.Pardo-MonteroJ.Jiménez-PenickV.Gallego-IzquierdoT.La ToucheR. (2016). Adaptation and validation of the Spanish version of the graded chronic pain scale. Reumatología Clínica, 12(3), 130–138. https://doi.org/10.1016/j.reuma.2015.07.004
24.
GalánS.RoyR.SoléE.RacineM.de la VegaR.JensenM. P.MiróJ. (2019). Committed action, disability and perceived health in individuals with fibromyalgia. Behavioral Medicine, 45(1), 62–69. https://doi.org/10.1080/08964289.2018.1467370
25.
Galvez-SánchezC. M.Del PasoG. A. R. (2020). Diagnostic criteria for fibromyalgia: Critical review and future perspectives. Journal of Clinical Medicine, 9(4), 1219. https://doi.org/10.3390/jcm9041219
26.
Galvez-SánchezC. M.DuschekS.Reyes Del PasoG. A. (2019). Psychological impact of fibromyalgia: Current perspectives. Psychology Research and Behavior Management, 12, 117–127. https://doi.org/10.2147/PRBM.S178240
27.
Galvez-SánchezC. M.Reyes del PasoG. A.DuschekS. (2018). Cognitive impairments in Fibromyalgia syndrome: Associations with positive and negative affect, alexithymia, pain catastrophizing and self-esteem. Frontiers in Psychology, 12, 117–127. https://doi.org/10.3389/fpsyg.2018.00377
GejlA. K.EnevoldC.BuggeA.AndersenM. S.NielsenC. H.AndersenL. B. (2019). Associations between serum and plasma brain-derived neurotrophic factor and influence of storage time and centrifugation strategy. Scientific Reports, 9(1), 9655. https://doi.org/10.1038/s41598-019-45976-5
30.
HaasL.PortelaL. V. C.BöhmerA. E.OsesJ. P.LaraD. R. (2010). Increased plasma levels of brain derived neurotrophic factor (BDNF) in patients with fibromyalgia. Neurochemical Research, 35(5), 830–834. https://doi.org/10.1007/s11064-010-0129-z
31.
HjermstadM. J.FayersP. M.HaugenD. F.CaraceniA.HanksG. W.LogeJ. H.FainsingerR.AassN.KaasaS.European Palliative Care Research Collaborative EPCRC. (2011). Studies comparing numerical rating scales, verbal rating scales, and visual analogue scales for assessment of pain intensity in adults: A systematic literature review. Journal of Pain and Symptom Management, 41(6), 1073–1093. https://doi.org/10.1016/j.jpainsymman.2010.08.016
32.
IssaG.WilsonC.TerryA. V.PillaiA. (2010). An inverse relationship between cortisol and BDNF levels in schizophrenia: Data from human postmortem and animal studies. Neurobiology of Disease, 39(3), 327–333. https://doi.org/10.1016/j.nbd.2010.04.017
33.
JablochkovaA.BäckrydE.KosekE.MannerkorpiK.ErnbergM.GerdleB.GhafouriB. (2019). Unaltered low nerve growth factor and high brain-derived neurotrophic factor levels in plasma from patients with fibromyalgia after a 15-week progressive resistance exercise. Journal of Rehabilitation Medicine, 51(10), 779–787. https://doi.org/10.2340/16501977-2593
34.
JacobyR.BarskyK. G.PoratT.HarelS.MillerT. H.GoldzweigG. (2021). Individual stress response patterns: Preliminary findings and possible implications. PLoS One, 16(8), e0255889. https://doi.org/10.1371/journal.pone.0255889
35.
KarosK.WilliamsA. C. d. C.MeuldersA.VlaeyenJ. W. S. (2018). Pain as a threat to the social self: A motivational account. Pain, 159(9), 1690–1695. https://doi.org/10.1097/j.pain.0000000000001257
36.
KleimanR. J.TianN.KrizajD.HwangT. N.CopenhagenD. R.ReichardtL. F.Reichardt BDNF-L. F. (2000). BDNF-induced potentiation of spontaneous twitching in innervated myocytes requires calcium release from intracellular stores. https://www.jn.physiology.org/
37.
KumbhareD.HassanS.DiepD.DuarteF.HungJ.DamodaraS.WestD.SelvaganapathyP. (2022). Potential role of blood biomarkers in patients with fibromyalgia: A systematic review with meta-analysis. Pain, 163(7), 1232–1253. https://doi.org/10.1097/j.pain.0000000000002510
38.
LaskeC.StranskyE.EschweilerG. W.KleinR.WittorfA.LeyheT.RichartzE.KöhlerN.BartelsM.BuchkremerG.SchottK. (2007). Increased BDNF serum concentration in fibromyalgia with or without depression or antidepressants. Journal of Psychiatric Research, 41(7), 600–605. https://doi.org/10.1016/j.jpsychires.2006.02.007
39.
LiG.PeskindE. R.MillardS. P.ChiP.SokalI.YuC. E.BekrisL. M.RaskindM. A.GalaskoD. R.MontineT. J. (2009). Cerebrospinal fluid concentration of brain-derived neurotrophic factor and cognitive function in non-demented subjects. PLoS One, 4(5), Article e5424. https://doi.org/10.1371/journal.pone.0005424
40.
LiR.LiJ.LiuY.LiD.ChuL.ZhangJ.LuoX.ZhangY. (2023). Serum BDNF levels are involved in the diagnosis and treatment response in patients with PD. Journal of Affective Disorders, 327, 31–37. https://doi.org/10.1016/j.jad.2023.01.107
41.
LiS.CaiJ.FengZ. B.JinZ. R.LiuB. H.ZhaoH. Y.JingH. B.WeiT. J.YangG. N.LiuL. Y.CuiY. J.XingG. G. (2017). BDNF contributes to spinal long-term potentiation and mechanical hypersensitivity via fyn-mediated phosphorylation of NMDA receptor GluN2B subunit at tyrosine 1472 in rats following spinal nerve ligation. Neurochemical Research, 42(10), 2712–2729. https://doi.org/10.1007/s11064-017-2274-0
42.
LiangF.-Q.AllenG.EarnestD. (2000). Role of brain-derived neurotrophic factor in the circadian regulation of the suprachiasmatic pacemaker by light.
43.
LiuX.-G.ZhouL.-J. (2014). Long-term potentiation at spinal C-fiber synapses: A target for pathological pain. Current Pharmaceutical Design, 21(7), 895–905. https://doi.org/10.2174/1381612820666141027115949
44.
MandelmanS. D.GrigorenkoE. L. (2012). BDNF Val66Met and cognition: All, none, or some? A meta-analysis of the genetic association. Genes, Brain and Behavior, 11(2), 127–136. https://doi.org/10.1111/j.1601-183X.2011.00738.x
45.
MartinD. G.WienerC. D.de FreitasC. X.CostaJ. L.RombaldiA. J.OsesJ. P. (2018). Levels of brain-derived neurotrophic factor in patients with fibromyalgia and chronic low back pain: Results of an aquatic physical therapy protocol. Facets, 3(1), 12–21. https://doi.org/10.1139/facets-2017-0016
46.
MerighiA. (2021). Cross talk of BDNF and GDNF in spinal substantia gelatinosa (Lamina II): Focus on circuitry. Advances in Experimental Medicine and Biology, 1331, 215–229. https://doi.org/10.1007/978-3-030-74046-7_14
NicholasM.VlaeyenJ. W. S.RiefW.BarkeA.AzizQ.BenolielR.CohenM.EversS.GiamberardinoM. A.GoebelA.KorwisiB.PerrotS.SvenssonP.WangS. J.TreedeR. D.IASP Taskforce for the Classification of Chronic Pain. (2019). The IASP classification of chronic pain for ICD-11: Chronic primary pain. Pain, 160(1), 28–37. https://doi.org/10.1097/j.pain.0000000000001390
NugrahaB.KorallusC.GutenbrunnerC. (2013). Serum level of brain-derived neurotrophic factor in fibromyalgia syndrome correlates with depression but not anxiety. Neurochemistry International, 62(3), 281–286. https://doi.org/10.1016/j.neuint.2013.01.001
51.
OsmanA.BarriosF. X.KopperB. A.HauptmannW.JonesJ.O'NeillE. (1997). Factor structure, reliability, and validity of the pain catastrophizing scale. Journal of Behavioral Medicine, 20(6), 589–605. https://doi.org/10.1023/a:1025570508954
52.
ParkH.PooM. M. (2012). Neurotrophin regulation of neural circuit development and function. Nature Reviews Neuroscience, 14(1), 7–23. https://doi.org/10.1038/nrn3379
53.
ParkerR. S.LewisG. N.RiceD. A.McnairP. J. (2016). Is motor cortical excitability altered in people with chronic pain? A systematic review and meta-analysis. Brain Stimulation, 9(4), 488–500. https://doi.org/10.1016/j.brs.2016.03.020
54.
PhillipsC. (2017). Brain-derived neurotrophic factor, depression, and physical activity: Making the neuroplastic connection. Neural Plasticity, 2017(8), Article 7260130. https://doi.org/10.1155/2017/7260130
55.
PintoA. M.LuísM.GeenenR.PalavraF.LumleyM. A.AblinJ. N.AmrisK.BrancoJ.BuskilaD.CastelhanoJ.Castelo-BrancoM.CroffordL. J.FitzcharlesM.-A.HäuserW.KosekE.MeaseP. J.MarquesT. R.JacobsJ. W. G.CastilhoP.da SilvaJ. A. P. (2023). Neurophysiological and psychosocial mechanisms of fibromyalgia: A comprehensive review and call for an integrative model. Neuroscience & Biobehavioral Reviews, 151(1), Article 105235. https://doi.org/10.1016/j.neubiorev.2023.105235
56.
RanzolinA.DuarteA. L. B. P.BredemeierM.da Costa NetoC. A.AscoliB. M.Wollenhaupt-AguiarB.KapczinskiF.XavierR. M. (2016). Evaluation of cytokines, oxidative stress markers and brain-derived neurotrophic factor in patients with fibromyalgia - A controlled cross-sectional study. Cytokine, 84, 25–28. https://doi.org/10.1016/j.cyto.2016.05.011
57.
RenK.DubnerR. (2007). Pain facilitation and activity-dependent plasticity in pain modulatory circuitry: Role of BDNF-TrkB signaling and NMDA receptors. Molecular Neurobiology, 35(3), 224–235. https://doi.org/10.1007/s12035-007-0028-8
58.
SáK. N.MoreiraL.BaptistaA. F.YengL. T.TeixeiraM. J.GalhardoniR.De AndradeD. C. (2019). Prevalence of chronic pain in developing countries: Systematic review and meta-analysis. Pain Reports, 4(6), Article e779. https://doi.org/10.1097/PR9.0000000000000779
59.
SaarelainenT.HendolinP.LucasG.KoponenE.SairanenM.MacdonaldE.AgermanK.HaapasaloA.NawaH.AloyzR.ErnforsP.CastrénE. (2002). Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects.
60.
SarchielliP.ManciniM. L.FloridiA.CoppolaF.RossiC.NardiK.AcciarresiM.PiniL. A.CalabresiP. (2007). Increased levels of neurotrophins are not specific for chronic migraine: Evidence from primary fibromyalgia syndrome. The Journal of Pain, 8(9), 737–745. https://doi.org/10.1016/j.jpain.2007.05.002
61.
SeoJ.KimS. H.KimY. T.SongH. jinLeeJ. junKimS. H.HanS. W.NamE. J.KimS. K.LeeH. J.LeeS. J.ChangY. (2012). Working memory impairment in fibromyalgia patients associated with altered frontoparietal memory network. PLoS One, 7(6), Article e37808. https://doi.org/10.1371/journal.pone.0037808
62.
ShenZ.ZhuJ.YuanY.RenL.QianM.LinM.CaiM.ZhangZ.ShenX. (2019). The roles of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in predicting treatment remission in a Chinese Han population with generalized anxiety disorder. Psychiatry Research, 271, 319–324. https://doi.org/10.1016/j.psychres.2018.08.111
63.
SiracusaR.PaolaR. D.CuzzocreaS.ImpellizzeriD. (2021). Fibromyalgia: Pathogenesis, mechanisms, diagnosis and treatment options update. International Journal of Molecular Sciences, 22(8), 3891. https://doi.org/10.3390/ijms22083891
StefaniL. C.LeiteF. M.da Graça L TarragóM.ZanetteS. A.de SouzaA.CastroS. M.CaumoW.CaumoW. (2019). BDNF and serum S100B levels according the spectrum of structural pathology in chronic pain patients. Neuroscience Letters, 706, 105–109. https://doi.org/10.1016/j.neulet.2019.05.021
66.
SulimanS.HemmingsS. M.SeedatS. (2013). Brain-Derived Neurotrophic Factor (BDNF) protein levels in anxiety disorders: Systematic review and meta-regression analysis. Frontiers in Integrative Neuroscience, 7(7), 55. https://doi.org/10.3389/fnint.2013.00055
67.
TaflkonE. O.AydemirO.DeveciA.TaneliF.SelçukiD.CerrahogluL.DanaciE. A. (2008). Serum brain-derived neurotrophic factor levels in pain syndromes: A comparative study with major depression. Klinik Psikofarmakoloji Bülteni, 18(4), 259–265. https://www.psikofarmakoloji.org/
68.
TengH. W.TaniJ.ChangT. S.ChenH. J.LinY. C.LinC. S. Y.SungJ. Y. (2021). Altered sensory nerve excitability in fibromyalgia. Journal of the Formosan Medical Association, 120(8), 1611–1619. https://doi.org/10.1016/j.jfma.2021.02.003
69.
Terminology. (2021). International association for the study of pain (IASP). International Association for the Study of Pain.
70.
ThanhN. X.TanguayR. L.ManhasK. J. P.Kania-RichmondA.KashubaS.GeyerT.PereiraJ. X.WasylakT. (2022). Economic burden of chronic pain in Alberta, Canada. PLoS One, 17(8), Article e0272638. https://doi.org/10.1371/journal.pone.0272638
71.
TreedeR. D.RiefW.BarkeA.AzizQ.BennettM. I.BenolielR.CohenM.EversS.FinnerupN. B.FirstM. B.GiamberardinoM. A.KaasaS.KosekE.Lavand’hommeP.NicholasM.PerrotS.ScholzJ.SchugS.SmithB. H.WangS. J. (2015). A classification of chronic pain for ICD-11. Pain, 156(6), 1003–1007. https://doi.org/10.1097/j.pain.0000000000000160
72.
WrightD. B.LondonK.FieldA. P. (2011). Using bootstrap estimation and the plug-in principle for clinical psychology data. Journal of Experimental Psychopathology, 2(2), 252–270. https://doi.org/10.5127/jep.013611
73.
XiongH. Y.HendrixJ.SchabrunS.WynsA.CampenhoutJ. V.NijsJ.PolliA. (2024). The role of the brain-derived neurotrophic factor in chronic pain: Links to central sensitization and neuroinflammation. Biomolecules, 14(1), 71. https://doi.org/10.3390/biom14010071
ZhouL. J.YangT.WeiX.LiuY.XinW. J.ChenY.PangR. P.ZangY.LiY. Y.LiuX. G. (2011). Brain-derived neurotrophic factor contributes to spinal long-term potentiation and mechanical hypersensitivity by activation of spinal microglia in rat. Brain, Behavior, and Immunity, 25(2), 322–334. https://doi.org/10.1016/j.bbi.2010.09.025
77.
ZouY.ZhangY.TuM.YeY.LiM.RanR.ZouZ. (2024). Brain-derived neurotrophic factor levels across psychiatric disorders: A systemic review and network meta-analysis. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 131(1), Article 110954. https://doi.org/10.1016/j.pnpbp.2024.110954
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