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Licensed Unlicensed Requires Authentication Published by De Gruyter March 20, 2019

Detection of systemic inflammation in severely impaired chronic pain patients and effects of a multimodal pain rehabilitation program

Eva-Britt Hysing ORCID logo EMAIL logo , Lena Smith , Måns Thulin , Rolf Karlsten , Kristoffer Bothelius and Torsten Gordh


Background and aims

Recent research indicates a previously unknown low-grade systemic or neurogenic inflammation in groups of chronic pain (CP) patients. Low-grade inflammation may have an important role in symptoms that have previously not been well depicted: widespread pain, tiredness and cognitive dysfunctions frequently seen in severely impaired CP patients. This study aimed to investigate the plasma inflammatory profile in a group of very complex CP patients at baseline and at a 1-year follow-up after participation in a cognitive behavior therapy (CBT)-based multimodal pain rehabilitation program (PRP).


Blood samples were collected from 52 well-characterized CP patients. Age- and sex-matched healthy blood donors served as controls. The samples were analyzed with a multiple Proximal Extension Analysis allowing a simultaneous analysis of 92 inflammation-related proteins consisting mainly of cytokines, chemokines and growth-factors. At follow-up, 1-year after participation in the RPR samples from 28 patients were analyzed. The results were confirmed by a multi-array technology that allows quantitative estimation.


Clear signs of increased inflammatory activity were detected in the CP patients. Accepting a false discovery rate (FDR) of 5%, there were significant differences in 43/92 inflammatory biomarkers compared with the controls. In three biomarkers (CXCL5, SIRT2, AXIN1) the expression levels were elevated more than eight times. One year after the PRP, with the patients serving as their own controls, a significant decrease in overall inflammatory activity was found.


Our results indicate that the most impaired CP patients suffer from low-grade chronic systemic inflammation not described earlier with this level of detail. The results may have implications for a better understanding of the cluster of co-morbid symptoms described as the “sickness-syndrome” and the wide-spread pain seen in this group of patients. The decrease in inflammatory biomarkers noted at the follow-up after participation in the PRP may reflect the positive effects obtained on somatic and psycho-social mechanisms involved in the inflammatory process by a rehabilitation program. Besides the PRP, no major changes in medication or lifestyle factors were implemented during the same period. To our knowledge, this is the first study reporting that a PRP may induce inflammatory-reducing effects. Further studies are needed to verify the objective findings in CP patients and address the question of causality that remains to be solved.


The findings offer a new insight into the complicated biological processes underlying CP. It may have implications for the understanding of symptoms collectively described as the “sickness-syndrome” – frequently seen in this group of patients. The lowering of cytokines after the participation in a PRP indicate a new way to evaluate this treatment; by measuring inflammatory biomarkers.

Funding source: Swedish Research Council

Award Identifier / Grant number: P29797-1

Funding statement: The research project was supported by Uppsala University Hospital, Uppsala University and Uppsala Berzelii Technology Centre for Neurodiagnostics, with financing from the Swedish Governmental Agency for Innovation Systems (VINNOVA) and the Swedish Research Council (grant no. P29797-1).

  1. Authors’ statements

  2. Conflict of interest: The authors state no conflict of interest.

  3. Informed consent: All study participants provided written informed consent.

  4. Ethical improvement: The study was approved by the Regional Ethical Review Board in Uppsala, Sweden (Dnr 2010/182). The study was performed in accordance with the Declaration of Helsinki (1964 and later revisions).


[1] Raffaeli W, Arnaudo E. Pain as a disease: an overview. J Pain Res 2017;10:2003–8.10.2147/JPR.S138864Search in Google Scholar PubMed PubMed Central

[2] Gatchel RJ, Polatin PB, Mayer TG. The dominant role of psychosocial risk factors in the development of chronic low back pain disability. Spine 1995;20:2702–9.10.1097/00007632-199512150-00011Search in Google Scholar PubMed

[3] Pincus T, Burton AK, Vogel S, Field AP. A systematic review of psychological factors as predictors of chronicity/disability in prospective cohorts of low back pain. Spine 2002;27:E109–20.10.1097/00007632-200203010-00017Search in Google Scholar PubMed

[4] Hoogendoorn WE, van Poppel MN, Bongers PM, Koes BW, Bouter LM. Systematic review of psychosocial factors at work and private life as risk factors for back pain. Spine 2000;25:2114–25.10.1097/00007632-200008150-00017Search in Google Scholar PubMed

[5] McKillop AB, Carroll LJ, Jones CA, Battie MC. The relation of social support and depression in patients with chronic low back pain. Disabil Rehabil 2017;39:1482–8.10.1080/09638288.2016.1202335Search in Google Scholar PubMed

[6] Hancock MJ, Maher CG, Laslett M, Hay E, Koes B. Discussion paper: what happened to the ‘bio’ in the bio-psycho-social model of low back pain? Eur Spine J 2011;20:2105–10.10.1007/s00586-011-1886-3Search in Google Scholar PubMed PubMed Central

[7] Arendt-Nielsen L, Morlion B, Perrot S, Dahan A, Dickenson A, Kress HG, Wells C, Bouhassira D, Mohr Drewes A. Assessment and manifestation of central sensitisation across different chronic pain conditions. Eur J Pain 2018;22:216–41.10.1002/ejp.1140Search in Google Scholar PubMed

[8] Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain 2011;152(3 Suppl):S2–15.10.1016/j.pain.2010.09.030Search in Google Scholar PubMed PubMed Central

[9] Karshikoff B, Jensen KB, Kosek E, Kalpouzos G, Soop A, Ingvar M, Olgart Hoglund C, Lekander M, Axelsson J. Why sickness hurts: a central mechanism for pain induced by peripheral inflammation. Brain Behav Immun 2016;57:38–46.10.1016/j.bbi.2016.04.001Search in Google Scholar PubMed

[10] Walker AK, Kavelaars A, Heijnen CJ, Dantzer R. Neuroinflammation and comorbidity of pain and depression. Pharmacol Rev 2014;66:80–101.10.1124/pr.113.008144Search in Google Scholar PubMed PubMed Central

[11] Backryd E, Tanum L, Lind AL, Larsson A, Gordh T. 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;10:515–25.10.2147/JPR.S128508Search in Google Scholar PubMed PubMed Central

[12] Kadetoff D, Lampa J, Westman M, Andersson M, Kosek E. Evidence of central inflammation in fibromyalgia-increased cerebrospinal fluid interleukin-8 levels. J Neuroimmunol 2012;242:33–8.10.1016/j.jneuroim.2011.10.013Search in Google Scholar PubMed

[13] Gerdle B, Ghafouri B, Ghafouri N, Backryd E, Gordh T. Signs of ongoing inflammation in female patients with chronic widespread pain: a multivariate, explorative, cross-sectional study of blood samples. Medicine 2017;96:e6130.10.1097/MD.0000000000006130Search in Google Scholar PubMed PubMed Central

[14] Uceyler N, Rogausch JP, Toyka KV, Sommer C. Differential expression of cytokines in painful and painless neuropathies. Neurology 2007;69:42–9.10.1212/01.wnl.0000265062.92340.a5Search in Google Scholar PubMed

[15] Uceyler N, Hauser W, Sommer C. Systematic review with meta-analysis: cytokines in fibromyalgia syndrome. BMC Musculoskelet Disord 2011;12:245.10.1186/1471-2474-12-245Search in Google Scholar PubMed PubMed Central

[16] Watkins LR, Maier SF. Immune regulation of central nervous system functions: from sickness responses to pathological pain. J Intern Med 2005;257:139–55.10.1111/j.1365-2796.2004.01443.xSearch in Google Scholar PubMed

[17] Pedersen LM, Schistad E, Jacobsen LM, Roe C, Gjerstad J. Serum levels of the pro-inflammatory interleukins 6 (IL-6) and -8 (IL-8) in patients with lumbar radicular pain due to disc herniation: a 12-month prospective study. Brain Behav Immun 2015;46:132–6.10.1016/j.bbi.2015.01.008Search in Google Scholar PubMed

[18] Backryd E, Lind AL, Thulin M, Larsson A, Gerdle B, Gordh T. High levels of cerebrospinal fluid chemokines point to the presence of neuroinflammation in peripheral neuropathic pain: a cross-sectional study of 2 cohorts of patients compared with healthy controls. Pain 2017;158:2487–95.10.1097/j.pain.0000000000001061Search in Google Scholar PubMed PubMed Central

[19] Moen A, Lind AL, Thulin M, Kamali-Moghaddam M, Roe C, Gjerstad J, Gordh T. Inflammatory serum protein profiling of patients with lumbar radicular pain one year after disc herniation. Int J Inflam 2016;2016:3874964.10.1155/2016/3874964Search in Google Scholar PubMed PubMed Central

[20] Hysing EB, Smith L, Thulin M, Karlsten R, Butler S, GordhT. Identifying characteristics of the most severely impaired chronic pain patients treated at a specialized inpatient pain clinic. Scand J Pain 2017;17:178–85.10.1016/j.sjpain.2017.09.008Search in Google Scholar PubMed

[21] Lasselin J, Treadway MT, Lacourt TE, Soop A, Olsson MJ, Karshikoff B, Paues-Goranson S, Axelsson J, Dantzer R, Lekander M. Lipopolysaccharide alters motivated behavior in a monetary reward task: a randomized trial. Neuropsychopharmacology 2017;42:801–10.10.1038/npp.2016.191Search in Google Scholar PubMed PubMed Central

[22] Larsson A, Carlsson L, Gordh T, Lind AL, Thulin M, Kamali-Moghaddam M. The effects of age and gender on plasma levels of 63 cytokines. J Immunol Methods 2015;425:58–61.10.1016/j.jim.2015.06.009Search in Google Scholar PubMed

[23] Assarsson E, Lundberg M, Holmquist G, Bjorkesten J, Thorsen SB, Ekman D, Eriksson A, Rennel Dickens E, Ohlsson S, Edfeldt G, Andersson AC, Lindstedt P, Stenvang J, Gullberg M, Fredriksson S. Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability. PLoS One 2014;9:e95192.10.1371/journal.pone.0095192Search in Google Scholar PubMed PubMed Central

[24] Dabitao D, Margolick JB, Lopez J, Bream JH. Multiplex measurement of proinflammatory cytokines in human serum: comparison of the Meso Scale Discovery electrochemiluminescence assay and the Cytometric Bead Array. J Immunol Methods 2011;372:71–7.10.1016/j.jim.2011.06.033Search in Google Scholar PubMed PubMed Central

[25] Stehlík M, Střelec L, Thulin M. On robust testing for normality in chemometrics. Chemom Intell Lab Syst 2014;130:98–108.10.1016/j.chemolab.2013.10.010Search in Google Scholar

[26] Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B (Methodol) 1995;57:289–300.10.1111/j.2517-6161.1995.tb02031.xSearch in Google Scholar

[27] Johnson RA, Wichern DW. Applied multivariate statistical analysis. Upper Saddle River, NJ: Pearson Prentice Hall, 2007.Search in Google Scholar

[28] Adams F. The Sydenham Society. The genuine works of Hippocrates. London: Sydenham Society, William Wood & co, 1849.Search in Google Scholar

[29] McCusker RH, Kelley KW. Immune-neural connections: how the immune system’s response to infectious agents influences behavior. J Exp Biol 2013;216(Pt 1):84–98.10.1242/jeb.073411Search in Google Scholar PubMed PubMed Central

[30] Slavich GM, Irwin MR. From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychol Bull 2014;140:774–815.10.1037/a0035302Search in Google Scholar PubMed PubMed Central

[31] Eisenberger NI. The neural bases of social pain: evidence for shared representations with physical pain. Psychosom Med 2012;74:126–35.10.1097/PSY.0b013e3182464dd1Search in Google Scholar PubMed PubMed Central

[32] Irwin MR, Cole SW. Reciprocal regulation of the neural and innate immune systems. Nat Rev Immunol 2011;11:625–32.10.1038/nri3042Search in Google Scholar PubMed PubMed Central

[33] Rousselle A, Qadri F, Leukel L, Yilmaz R, Fontaine JF, Sihn G, Bader M, Ahluwalia A, Duchene J. CXCL5 limits macrophage foam cell formation in atherosclerosis. J Clin Invest 2013;123:1343–7.10.1172/JCI66580Search in Google Scholar PubMed PubMed Central

[34] Dawes JM, Calvo M, Perkins JR, Paterson KJ, Kiesewetter H, Hobbs C, Kaan TK, Orengo C, Bennett DL, McMahon SB. CXCL5 mediates UVB irradiation-induced pain. Sci Transl Med 2011;3:90ra60.10.1126/scitranslmed.3002193Search in Google Scholar PubMed PubMed Central

[35] Noutsou M, Duarte AMS, Anvarian Z, Didenko T, Minde DP, Kuper I, de Ridder I, Oikonomou C, Friedler A, Boelens R, Rüdiger SGD, Maurice MM. Critical scaffolding regions of the tumor suppressor Axin1 are natively unfolded. J Mol Biol 2011;405:773–86.10.1016/j.jmb.2010.11.013Search in Google Scholar PubMed

[36] Salminen A, Kaarniranta K. NF-kappaB signaling in the aging process. J Clin Immunol 2009;29:397–405.10.1007/s10875-009-9296-6Search in Google Scholar PubMed

[37] Donmez G, Outeiro TF. SIRT1 and SIRT2: emerging targets in neurodegeneration. EMBO Mol Med 2013;5:344–52.10.1002/emmm.201302451Search in Google Scholar PubMed PubMed Central

[38] Ojeda SR, Ma YJ, Rage F. The transforming growth factor alpha gene family is involved in the neuroendocrine control of mammalian puberty. 1997/10/10 ed1997 Sep. 355-8 p.10.1038/ in Google Scholar PubMed

[39] Bowen MA, Patel DD, Li X, Modrell B, Malacko AR, Wang WC, Marquardt H, Neubauer M, Pesando JM, Francke U. Cloning, mapping, and characterization of activated leukocyte-cell adhesion molecule (ALCAM), a CD6 ligand. J Exp Med 1995;181:2213–20.10.1084/jem.181.6.2213Search in Google Scholar PubMed PubMed Central

[40] Nolan KF, Greaves DR, Waldmann H. The human interleukin 18 gene IL18 maps to 11q22.2-q22.3, closely linked to the DRD2 gene locus and distinct from mapped IDDM loci. Genomics 1998;51:161–3.10.1006/geno.1998.5336Search in Google Scholar PubMed

[41] Tanaka M, Miyajima A. Oncostatin M. A multifunctional cytokine. Rev Physiol Biochem Pharmacol 2003;149:39–52.10.1007/s10254-003-0013-1Search in Google Scholar PubMed

[42] Dantzer R, O’Connor JC, Lawson MA, Kelley KW. Inflammation-associated depression: from serotonin to kynurenine. Psychoneuroendocrinology 2011;36:426–36.10.1016/j.psyneuen.2010.09.012Search in Google Scholar PubMed PubMed Central

[43] Dantzer R, Heijnen CJ, Kavelaars A, Laye S, Capuron L. The neuroimmune basis of fatigue. Trends Neurosci 2014;37:39–46.10.1016/j.tins.2013.10.003Search in Google Scholar PubMed PubMed Central

[44] Mullington JM, Simpson NS, Meier-Ewert HK, Haack M. Sleep loss and inflammation. Best Pract Res Clin Endocrinol Metab 2010;24:775–84.10.1016/j.beem.2010.08.014Search in Google Scholar PubMed PubMed Central

[45] Cutolo M, Straub RH. Stress as a risk factor in the pathogenesis of rheumatoid arthritis. Neuroimmunomodulation 2006;13:277–82.10.1159/000104855Search in Google Scholar PubMed

[46] Kivimaki M, Kawachi I. Work stress as a risk factor for cardiovascular disease. Curr Cardiol Rep 2015;17:630.10.1007/s11886-015-0630-8Search in Google Scholar PubMed PubMed Central

[47] Bower JE, Crosswell AD, Slavich GM. Childhood adversity and cumulative life stress: risk factors for cancer-related fatigue. Clin Psychol Sci 2014;2:108–15.10.1177/2167702613496243Search in Google Scholar PubMed PubMed Central

[48] Sibille KT, Steingrimsdottir OA, Fillingim RB, Stubhaug A, Schirmer H, Chen H, McEwen BS, Nielsen CS. Investigating the burden of chronic pain: an inflammatory and metabolic composite. Pain Res Manag 2016;2016:7657329.10.1155/2016/7657329Search in Google Scholar PubMed PubMed Central

[49] Danese A, Moffitt TE, Pariante CM, Ambler A, Poulton R, Caspi A. Elevated inflammation levels in depressed adults with a history of childhood maltreatment. Arch Gen Psychiatry 2008;65:409–15.10.1001/archpsyc.65.4.409Search in Google Scholar PubMed PubMed Central

[50] Danese A, Pariante CM, Caspi A, Taylor A, Poulton R. Childhood maltreatment predicts adult inflammation in a life-course study. Proc Natl Acad Sci USA 2007;104:1319–24.10.1073/pnas.0610362104Search in Google Scholar PubMed PubMed Central

[51] Quinn K, Boone L, Scheidell JD, Mateu-Gelabert P, McGorray SP, Beharie N, Cottler LB, Khan MR. The relationships of childhood trauma and adulthood prescription pain reliever misuse and injection drug use. Drug Alcohol Depend 2016;169:190–8.10.1016/j.drugalcdep.2016.09.021Search in Google Scholar PubMed PubMed Central

[52] Tesarz J, Eich W, Treede RD, Gerhardt A. Altered pressure pain thresholds and increased wind-up in adult patients with chronic back pain with a history of childhood maltreatment: a quantitative sensory testing study. Pain 2016;157:1799–809.10.1097/j.pain.0000000000000586Search in Google Scholar PubMed

[53] Poli-Neto OB, Tawasha KAS, Romao A, Hisano MK, Moriyama A, Candido-Dos-Reis FJ, Rosa ESJC, Nogueira AA. History of childhood maltreatment and symptoms of anxiety and depression in women with chronic pelvic pain. J Psychosom Obstet Gynaecol 2018;39:83–9.10.1080/0167482X.2017.1306515Search in Google Scholar PubMed

[54] Burke NN, Finn DP, McGuire BE, Roche M. Psychological stress in early life as a predisposing factor for the development of chronic pain: clinical and preclinical evidence and neurobiological mechanisms. J Neurosci Res 2017;95:1257–70.10.1002/jnr.23802Search in Google Scholar PubMed

[55] Persson E, Lexell J, Eklund M, Rivano-Fischer M. Positive effects of a musculoskeletal pain rehabilitation program regardless of pain duration or diagnosis. PM R 2012;4:355–66.10.1016/j.pmrj.2011.11.007Search in Google Scholar PubMed

[56] Black DS, Slavich GM. Mindfulness meditation and the immune system: a systematic review of randomized controlled trials. Ann N Y Acad Sci 2016;1373:13–24.10.1111/nyas.12998Search in Google Scholar PubMed PubMed Central

[57] Sharif K, Watad A, Bragazzi NL, Lichtbroun M, Amital H, Shoenfeld Y. Physical activity and autoimmune diseases: get moving and manage the disease. Autoimmun Rev 2018;17:53–72.10.1016/j.autrev.2017.11.010Search in Google Scholar PubMed

[58] Paolucci EM, Loukov D, Bowdish DME, Heisz JJ. Exercise reduces depression and inflammation but intensity matters. Biol Psychol 2018;133:79–84.10.1016/j.biopsycho.2018.01.015Search in Google Scholar PubMed

[59] Pearson MJ, Mungovan SF, Smart NA. Effect of aerobic and resistance training on inflammatory markers in heart failure patients: systematic review and meta-analysis. Heart Fail Rev 2018;23:209–23.10.1007/s10741-018-9677-0Search in Google Scholar PubMed

Received: 2018-11-20
Revised: 2019-01-30
Accepted: 2019-02-03
Published Online: 2019-03-20
Published in Print: 2019-04-24

©2019 Scandinavian Association for the Study of Pain. Published by Walter de Gruyter GmbH, Berlin/Boston. All rights reserved.

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