The main symptoms of fibromyalgia comprise diffuse pain, disability, depressive symptoms, catastrophizing, sleep disruption and fatigue, associated with dysfunction of the descending pain-modulating system (DPMS).
Objectives:
We aimed to identify patterns of main symptoms of fibromyalgia and neuroplasticity biomarkers (i.e. brain-derived neurotrophic factor (BDNF) and S100B protein) in non-responders to the conditioned pain modulation task (CPM-task) induced by immersion of hand in cold water (0–1°C). Furthermore, we evaluated if these patterns predict responsiveness to CPM-task.
Methods:
This cross-sectional study included 117 women with fibromyalgia ((n = 60) non-responders and (n = 57) responders), with age ranging from 30 to 65 years old. We analysed changes in numerical pain scale (NPS-10) during the CPM-task using a standardized protocol.
Results:
A hierarchical multivariate logistic regression analysis was used to construct a propensity score-adjusted index to identify non-responders compared to responders to CPM-task. The following variables were retained in the models: analgesic use four or more times per week, heat pain threshold (HPT), poor sleep quality, pain catastrophizing, serum levels of BDNF, number of psychiatric diagnoses and the impact of symptoms of fibromyalgia on quality of life. Receiver operator characteristics (ROC) analysis showed non-responders can be discriminated from responders by a composite index of more frequent symptoms of fibromyalgia and neuroplasticity markers (area under the curve (AUC) = 0.83, sensitivity = 100% and specificity = 98%).
Conclusion:
Patterns of fibromyalgia symptoms and neuroplasticity markers may be helpful to predict responsiveness to the CPM-task which might help personalize treatment and thereby contribute to the care of patients with fibromyalgia.
AsmundsonGJNortonPJNortonGR. Beyond pain: the role of fear and avoidance in chronicity. Clin Psychol Rev1999; 19(1): 97–119.
2.
PanWBanksWAFasoldMB, et al. Transport of brain-derived neurotrophic factor across the blood-brain barrier. Neuropharmacology1998; 37(12): 1553–1561.
3.
PodusloJFCurranGL. Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF. Brain Res Mol Brain Res1996; 36(2): 280–286.
4.
CoullJAMBeggsSBoudreauD, et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature2005; 438(7070): 1017–1021.
5.
LatremoliereAWoolfCJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain2009; 10(9): 895–926.
6.
InoueKTsudaM. Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential. Nat Rev Neurosci2018; 19(3): 138–152.
7.
YunusMB. Fibromyalgia and overlapping disorders: the unifying concept of central sensitivity syndromes. Semin Arthritis Rheum2007; 36(6): 339–356.
8.
YunusMB. Central sensitivity syndromes: a new paradigm and group nosology for fibromyalgia and overlapping conditions, and the related issue of disease versus illness. Semin Arthritis Rheum2008; 37(6): 339–352.
9.
CaumoWAntunesLCElkfuryJL, et al. The central sensitization inventory validated and adapted for a Brazilian population: psychometric properties and its relationship with brain-derived neurotrophic factor. J Pain Res2017; 10: 2109–2122.
10.
SteinerJBernsteinHGBielauH, et al. Evidence for a wide extra-astrocytic distribution of S100B in human brain. BMC Neurosci2007; 8: 2.
11.
SchroeterMLAbdul-KhaliqHKrebsM, et al. Serum markers support disease-specific glial pathology in major depression. J Affect Disord2008; 111(2–3): 271–280.
12.
SchroeterMSacherJSteinerJ, et al. Serum S100B represents a new biomarker for mood disorders. Curr Drug Targets2013; 14(11): 1237–1248.
13.
KowianskiPLietzauGCzubaE, et al. BDNF: a key factor with multipotent impact on brain signaling and synaptic plasticity. Cell Mol Neurobiol2018; 38(3): 579–593.
14.
StefaniLCTorresILde SouzaIC, et al. BDNF as an effect modifier for gender effects on pain thresholds in healthy subjects. Neurosci Lett2012; 514(1): 62–66.
15.
YarnitskyDArendt-NielsenLBouhassiraD, et al. Recommendations on terminology and practice of psychophysical DNIC testing. Eur J Pain2010; 14: 339–339.
16.
Le BarsDDickensonAHBessonJM. Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat. Pain1979; 6: 283–304.
17.
BabaYKohaseHOonoY, et al. Effects of dexmedetomidine on conditioned pain modulation in humans. Eur J Pain2012; 16(8): 1137–1147.
18.
TreisterRPudDEisenbergE. The dopamine agonist apomorphine enhances conditioned pain modulation in healthy humans. Neurosci Lett2013; 548: 115–119.
19.
LindstedtFBerrebiJGreayerE, et al. Conditioned pain modulation is associated with common polymorphisms in the serotonin transporter gene. PLoS ONE2011; 6(3): e18252.
20.
LauritoCEBaughmanVLBeckerGL, et al. The effectiveness of oral clonidine as a sedative/anxiolytic and as a drug to blunt the hemodynamic responses to laryngoscopy. J Clin Anesth1991; 3: 186–193.
21.
HughesJWWatkinsLBlumenthalJA, et al. Depression and anxiety symptoms are related to increased 24-hour urinary norepinephrine excretion among healthy middle-aged women. J Psychosom Res2004; 57(4): 353–358.
22.
Horjales-AraujoEDemontisDLundEK, et al. Polymorphism in serotonin receptor 3B is associated with pain catastrophizing. PLoS ONE2013; 8(11): e78889.
23.
KargKBurmeisterMSheddenK, et al. The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited. Arch Gen Psychiatry2011; 68(5): 444–454.
24.
CaumoWSchmidtAPSchneiderCN, et al. Risk factors for postoperative anxiety in adults. Anaesthesia2001; 56(8): 720–728.
25.
RacineMTousignant-LaflammeYKlodaLA, et al. A systematic literature review of 10 years of research on sex/gender and experimental pain perception – Part 1: are there really differences between women and men. Pain2012; 153(3): 602–618.
26.
Nahman-AverbuchHNirR-RSprecherE, et al. Psychological factors and conditioned pain modulation. Clin J Pain2016; 32: 541–554.
27.
BoyerNDallelRArtolaA, et al. General trigeminospinal central sensitization and impaired descending pain inhibitory controls contribute to migraine progression. Pain2014; 155(7): 1196–1205.
28.
Schmidt-WilckeTClauwDJ. Fibromyalgia: from pathophysiology to therapy. Nat Rev Rheumatol2011; 7: 518–527.
29.
SchestatskyPValls-SoleJCostaJ, et al. Skin autonomic reactivity to thermoalgesic stimuli. Clin Auton Res2007; 17(6): 349–355.
30.
SchestatskyPStefaniLCSanchesPR, et al. Validation of a Brazilian quantitative sensory testing (QST) device for the diagnosis of small fiber neuropathies. Arq Neuropsiquiatr2011; 69(6): 943–948.
31.
BotelhoLMMorales-QuezadaLRoziskyJR, et al. A framework for understanding the relationship between descending pain modulation, motor corticospinal, and neuroplasticity regulation systems in chronic myofascial pain. Front Hum Neurosci2016; 10: 308.
32.
MarquesPBarsante SantosAMMatsutaniLA, et al. Validation of the Brazilian version of the fibromyalgia impact questionnaire (FIQ). Rev Bras Reum2006; 46: 4570.
33.
SehnFFChachamovichEMDPVidorLP, et al. Cross-cultural adaptation and validation of the Brazilian Portuguese version of the pain catastrophizing scale. Pain Med2012; 13(11): 1425–1435.
34.
KerstenPWhitePJTennantA. Is the pain visual analogue scale linear and responsive to change? An exploration using Rasch analysis. PLoS ONE2014; 9(6): e99485.
35.
SullivanMJLBishopSRPivikJ. The pain catastrophizing scale: development and validation. Psychol Assess1995; 7: 524–532.
36.
Gomes-OliveiraMHGorensteinCLotufo NetoF, et al. Validation of the Brazilian Portuguese version of the beck depression inventory-II in a community sample. Braz J Psychiatry2012; 34(4): 389–394.
37.
BertolaziANFagondesSCHoffLS, et al. Validation of the Brazilian Portuguese version of the Pittsburgh sleep quality index. Sleep Med2011; 12(1): 70–75.
38.
AmorimP. Mini international neuropsychiatric interview (MINI): validation of a short structured diagnostic psychiatric interview. Rev Bras Psiquiatr2000; 22: 106–115.
39.
HanleyJAMcNeilBJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology1982; 143: 29–36.
40.
ManuscriptAPlasticityCNLatremoliereA, et al. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain2009; 10: 895–926.
41.
WolfeFWalittB. Culture, science and the changing nature of fibromyalgia. Nat Rev Rheumatol2013; 9(12): 751–755.
42.
CaumoWDeitosACarvalhoS, et al. Motor cortex excitability and BDNF levels in chronic musculoskeletal pain according to structural pathology. Front Hum Neurosci2016; 10: 357.
43.
Spezia AdachiLNQuevedoASde SouzaA, et al. Exogenously induced brain activation regulates neuronal activity by top-down modulation: conceptualized model for electrical brain stimulation. Exp Brain Res2015; 233(5): 1377–1389.
44.
GuoWRobbinsMTWeiF, et al. Supraspinal brain-derived neurotrophic factor signaling: a novel mechanism for descending pain facilitation. J Neurosci2006; 26(1): 126–137.
45.
LaskeCEschweilerG. Brain-derived neurotrophic factor: from nerve growth factor to modulator of brain plasticity in cognitive processes and psychiatric diseases. Nervenari77: 523–537.
46.
MolendijkMLBusBAASpinhovenP, et al. Serum levels of brain-derived neurotrophic factor in major depressive disorder: state-trait issues, clinical features and pharmacological treatment. Mol Psychiatry2011; 16(11): 1088–1095.
47.
StefaniLCLeiteFMda GraçaL, et al. BDNF and Serum S100B levels according the spectrum of structural pathology in chronic pain patients. Neurosci Lett2019; 706: 105–109.
48.
ZanetteSADussan-SarriaJASouzaA, et al. Higher serum S100B and BDNF levels are correlated with a lower pressure-pain threshold in fibromyalgia. Mol Pain2014; 10: 46.
49.
StreitburgerDPArelinKKratzschJ, et al. Validating serum S100B and neuron-specific enolase as biomarkers for the human brain – a combined serum, gene expression and MRI study. PLoS ONE2012; 7(8): e43284.
50.
PolyakovaMSanderCArelinK, et al. First evidence for glial pathology in late life minor depression: S100B is increased in males with minor depression. Front Cell Neurosci2015; 9: 406.
51.
SchreiberKLLoggiaMLKimJ, et al. Painful after-sensations in fibromyalgia are linked to catastrophizing and differences in brain response in the medial temporal lobe. J Pain2017; 18(7): 855–867.
52.
de HeerEWVriezekolkJEvan der Feltz-CornelisCM. Poor illness perceptions are a risk factor for depressive and anxious symptomatology in fibromyalgia syndrome: a longitudinal cohort study. Front Psychiat2017; 8: 217.
53.
LawsonK. Emerging pharmacological strategies for the treatment of fibromyalgia Emerging pharmacological strategies for the treatment of fibromyalgia. World J Pharmacol2017; 6: 1–10.
54.
EdwardsRRGraceEPetersonS, et al. Sleep continuity and architecture: associations with pain-inhibitory processes in patients with temporomandibular joint disorder. Eur J Pain2009; 13(10): 1043–1047.
55.
LeeYCLuBEdwardsRR, et al. The role of sleep problems in central pain processing in rheumatoid arthritis. Arthritis Rheum2013; 65(1): 59–68.
56.
KeskindagBKaraazizM. The association between pain and sleep in fibromyalgia. Saudi Med J2017; 38: 465–475.
57.
MillanMJ. Descending control of pain. Prog Neurobiol2002; 66: 355–474.
58.
IsaacSOBerridgeCW. Wake-promoting actions of dopamine D1 and D2 receptor stimulation. J Pharmacol Exp Ther2003; 307(1): 386–394.
59.
LuJJhouTCSaperCB. Identification of wake-active dopaminergic neurons in the ventral periaqueductal gray matter. J Neurosci2006; 26(1): 193–202.
60.
SuzukiRRyghLJDickensonAH. Bad news from the brain: descending 5-HT pathways that control spinal pain processing. Trends Pharmacol Sci2004; 25(12): 613–617.
61.
WillerJCBouhassiraDLe BarsD. Bases neurophysiologiques du phénomène de contre-irritation: les contrôles inhibiteurs diffus induits par stimulations nociceptives. Neurophysiol Clin Neurophysiol1999; 29: 379–400.
62.
SastreJPBudaCKitahamaK, et al. Importance of the ventrolateral region of the periaqueductal gray and adjacent tegmentum in the control of paradoxical sleep as studied by muscimol microinjections in the cat. Neuroscience1996; 74(2): 415–426.
63.
JensenKBKosekEPetzkeF, et al. Evidence of dysfunctional pain inhibition in Fibromyalgia reflected in rACC during provoked pain. Pain2009; 144(1–2): 95–100.
64.
SprengerCBingelUBuchelC. Treating pain with pain: supraspinal mechanisms of endogenous analgesia elicited by heterotopic noxious conditioning stimulation. Pain2011; 152(2): 428–439.
65.
GracelyRHGeisserMEGieseckeT, et al. Pain catastrophizing and neural responses to pain among persons with fibromyalgia. Brain2004; 127(Pt4): 835–843.
66.
PicheMBouinMArsenaultM, et al. Decreased pain inhibition in irritable bowel syndrome depends on altered descending modulation and higher-order brain processes. Neuroscience2011; 195: 166–175.
67.
Nahman-AverbuchHMartucciKTGranovskyY, et al. Distinct brain mechanisms support spatial vs temporal filtering of nociceptive information. Pain2014; 155(12): 2491–2501.
68.
LeonardMTChatkoffDKGallawayM. Association between pain catastrophizing, spouse responses to pain, and blood pressure in chronic pain patients: a pathway to potential comorbidity. Int J Behav Med2013; 20(4): 590–598.
69.
ChalayePDevoizeLLafrenayeS, et al. Cardiovascular influences on conditioned pain modulation. Pain2013; 154(8): 1377–1382.
70.
ChalayePLafrenayeSGoffauxP, et al. The role of cardiovascular activity in fibromyalgia and conditioned pain modulation. Pain2014; 155(6): 1064–1069.
MogilJS. Sex-based divergence of mechanisms underlying pain and pain inhibition. Curr Opin Behav Sci2018; 23: 113–117.
73.
GrashornWSprengerCForkmannK, et al. Age-dependent decline of endogenous pain control: exploring the effect of expectation and depression. PLoS ONE2013; 8(9): e75629.
