Pain in the Blood? Envisioning Mechanism-Based Diagnoses and Biomarkers in Clinical Pain Medicine

Emmanuel Bäckryd, Emmanuel Bäckryd

Abstract

Chronic pain is highly prevalent, and pain medicine lacks objective biomarkers to guide diagnosis and choice of treatment. The current U.S. "opioid epidemic" is a reminder of the paucity of effective and safe treatment options. Traditional pain diagnoses according to the International Classification of Diseases are often unspecific, and analgesics are often prescribed on a trial-and-error basis. In contrast to this current state of affairs, the vision of future mechanism-based diagnoses of chronic pain conditions is presented in this non-technical paper, focusing on the need for biomarkers and the theoretical complexity of the task. Pain is and will remain a subjective experience, and as such is not objectively measurable. Therefore, the concept of "noci-marker" is presented as an alternative to "pain biomarker", the goal being to find objective, measurable correlates of the pathophysiological processes involved in different chronic pain conditions. This vision entails a call for more translational pain research in order to bridge the gap between clinical pain medicine and preclinical science.

Keywords: biomarker; biopsychosocial; diagnosis; neuropathic; nociception; nociceptive; pain.

References

    1. Minde J. Norrbottnian Congenital Insensitivity to Pain. Acta Orthop. Suppl. 2006;77:2–32. doi: 10.1080/17453670610045911.
    1. Craig A.D. A new view of pain as a homeostatic emotion. Trends Neurosci. 2003;26:303–307. doi: 10.1016/S0166-2236(03)00123-1.
    1. Turk D.C., Wilson H.D., Cahana A. Treatment of chronic non-cancer pain. Lancet. 2011;377:2226–2235. doi: 10.1016/S0140-6736(11)60402-9.
    1. Brodal P. The Central Nervous System: Structure and Function. Oxford University Press; New York, NY, USA: 2010. Pain; pp. 204–214.
    1. Wu C.L., Raja S.N. Treatment of acute postoperative pain. Lancet. 2011;377:2215–2225. doi: 10.1016/S0140-6736(11)60245-6.
    1. Portenoy R.K. Treatment of cancer pain. Lancet. 2011;377:2236–2247. doi: 10.1016/S0140-6736(11)60236-5.
    1. Niv D., Devor M. Chronic pain as a disease in its own right. Pain Pract. 2004;4:179–181. doi: 10.1111/j.1533-2500.2004.04301.x.
    1. Dickinson B.D., Head C.A., Gitlow S., Osbahr A.J., III Maldynia: Pathophysiology and management of neuropathic and maladaptive pain—A report of the ama council on science and public health. Pain Med. 2010;11:1635–1653. doi: 10.1111/j.1526-4637.2010.00986.x.
    1. Grace P.M., Hutchinson M.R., Maier S.F., Watkins L.R. Pathological pain and the neuroimmune interface. Nat. Rev. Immunol. 2014;14:217–231. doi: 10.1038/nri3621.
    1. Breivik H., Collett B., Ventafridda V., Cohen R., Gallacher D. Survey of chronic pain in europe: Prevalence, impact on daily life, and treatment. Eur. J. Pain. 2006;10:287–333. doi: 10.1016/j.ejpain.2005.06.009.
    1. Goldberg D.S., McGee S.J. Pain as a global public health priority. BMC Public Health. 2011;11:770. doi: 10.1186/1471-2458-11-770.
    1. Manchikanti L., Helm S., II, Fellows B., Janata J.W., Pampati V., Grider J.S., Boswell M.V. Opioid epidemic in the United States. Pain Physician. 2012;15:ES9–ES38.
    1. Centers for Disease Control CDC grand rounds: Prescription drug overdoses—A U.S. Epidemic. Morb. Mortal. Wkly. Rep. 2012;61:10–13.
    1. Biomarkers Definitions Working Group Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clin. Pharmacol. Ther. 2001;69:89–95.
    1. Borsook D., Becerra L., Hargreaves R. Biomarkers for chronic pain and analgesia. Part 1: The need, reality, challenges, and solutions. Discov. Med. 2011;11:197–207.
    1. Arendt-Nielsen L., Nielsen T.A., Gazerani P. Translational pain biomarkers in the early development of new neurotherapeutics for pain management. Expert Rev. Neurother. 2014;14:241–254. doi: 10.1586/14737175.2014.884925.
    1. Van Wijk G., Veldhuijzen D.S. Perspective on diffuse noxious inhibitory controls as a model of endogenous pain modulation in clinical pain syndromes. J. Pain. 2010;11:408–419. doi: 10.1016/j.jpain.2009.10.009.
    1. Chang L. Altered glutamatergic metabolism and activated glia: Biomarkers for neuropathic pain? Pain. 2013;154:181–182. doi: 10.1016/j.pain.2012.11.001.
    1. Cruccu G., Truini A. Tools for assessing neuropathic pain. PLoS Med. 2009;6:e1000045. doi: 10.1371/journal.pmed.1000045.
    1. Kleggetveit I.P., Namer B., Schmidt R., Helas T., Ruckel M., Orstavik K., Schmelz M., Jorum E. High spontaneous activity of c-nociceptors in painful polyneuropathy. Pain. 2012;153:2040–2047. doi: 10.1016/j.pain.2012.05.017.
    1. Peterson M., Svardsudd K., Appel L., Engler H., Aarnio M., Gordh T., Langstrom B., Sorensen J. Pet-scan shows peripherally increased neurokinin 1 receptor availability in chronic tennis elbow: Visualizing neurogenic inflammation? PLoS One. 2013;8:e75859. doi: 10.1371/journal.pone.0075859.
    1. Serra J. Microneurography: Towards a biomarker of spontaneous pain. Pain. 2012;153:1989–1990. doi: 10.1016/j.pain.2012.07.008.
    1. Stephenson D.T., Arneric S.P. Neuroimaging of pain: Advances and future prospects. J. Pain. 2008;9:567–579. doi: 10.1016/j.jpain.2008.02.008.
    1. Arendt-Nielsen L., Eskehave T.N., Egsgaard L.L., Petersen K.K., Graven-Nielsen T., Hoeck H.C., Simonsen O., Siebuhr A.S., Karsdal M., Bay-Jensen A.C. Association between experimental pain biomarkers and serologic markers in patients with different degrees of painful knee osteoarthritis. Arthritis Rheumatol. 2014;66:3317–3326.
    1. Kalso E. Biomarkers for pain. Pain. 2004;107:199–201. doi: 10.1016/j.pain.2003.12.009.
    1. Backryd E. Pain and consciousness mocks philosophers and scientists. Lakartidningen. 2012;109:1039–1040.
    1. Backryd E., Ghafouri B., Larsson B., Gerdle B. Do low levels of beta-endorphin in the cerebrospinal fluid indicate defective top-down inhibition in patients with chronic neuropathic pain? A cross-sectional, comparative study. Pain Med. 2014;15:111–119. doi: 10.1111/pme.12248.
    1. Chalmers D.J. The puzzle of conscious experience. Sci. Am. 1995;273:80–86. doi: 10.1038/scientificamerican1295-80.
    1. Baumgartner U. Nociceptive system: Nociceptors, fiber types, spinal pathways, and projection areas. Schmerz. 2010;24:105–113. doi: 10.1007/s00482-010-0904-4.
    1. Woolf C.J. Pain: Moving from symptom control toward mechanism-specific pharmacologic management. Ann. Intern. Med. 2004;140:441–451. doi: 10.7326/0003-4819-140-1-200401060-00009.
    1. Merskey H. The taxonomy of pain. Med. Clin. North Am. 2007;91:13–20. doi: 10.1016/j.mcna.2006.10.009.
    1. Loeser J.D., Treede R.D. The Kyoto protocol of IASP basic pain terminology. Pain. 2008;137:473–477. doi: 10.1016/j.pain.2008.04.025.
    1. Jensen T.S., Baron R., Haanpaa M., Kalso E., Loeser J.D., Rice A.S., Treede R.D. A new definition of neuropathic pain. Pain. 2011;152:2204–2205. doi: 10.1016/j.pain.2011.06.017.
    1. Stålnacke B., Bäckryd E., Roeck Hansen E., Novo M., Gerdle B. Smärtanalys och Diagnossättning vid Kroniska Smärtor Inom Specialiserad Smärtvård—Rapport 2014:3. [(accessed on 20 December 2014)]. (in Swedish) Available online: .
    1. Woolf C.J. Evidence for a central component of post-injury pain hypersensitivity. Nature. 1983;306:686–688. doi: 10.1038/306686a0.
    1. Woolf C.J. Central sensitization: Implications for the diagnosis and treatment of pain. Pain. 2011;152:S2–S15. doi: 10.1016/j.pain.2010.09.030.
    1. Brodal P. The Central Nervous System: Structure and Function. Oxford University Press; New York, NY, USA: 2010. Neurotransmitters and their receptors; pp. 53–71.
    1. Salter M.W. Dorsal horn plasticity and neuron-microgila interactions. In: Tracey I., editor. Pain 2012 Refresher Courses, 14ht World Congress on Pain. IASP Press; Seattle, WA, USA: 2012. pp. 15–25.
    1. Hansson P. Translational aspects of central sensitization induced by primary afferent activity: What it is and what it is not. Pain. 2014;155:1932–1934. doi: 10.1016/j.pain.2014.07.016.
    1. Clauw D.J. Fibromyalgia: A clinical review. JAMA. 2014;311:1547–1555. doi: 10.1001/jama.2014.3266.
    1. Staud R. Abnormal endogenous pain modulation is a shared characteristic of many chronic pain conditions. Expert Rev. Neurother. 2012;12:577–585. doi: 10.1586/ern.12.41.
    1. Gatchel R.J., Peng Y.B., Peters M.L., Fuchs P.N., Turk D.C. The biopsychosocial approach to chronic pain: Scientific advances and future directions. Psychol. Bull. 2007;133:581. doi: 10.1037/0033-2909.133.4.581.
    1. Borrell-Carrio F., Suchman A.L., Epstein R.M. The biopsychosocial model 25 years later: Principles, practice, and scientific inquiry. Ann. Fam. Med. 2004;2:576–582. doi: 10.1370/afm.245.
    1. Engel G.L. The need for a new medical model: A challenge for biomedicine. Science. 1977;196:129–136. doi: 10.1126/science.847460.
    1. Melzack R. From the gate to the neuromatrix. Pain. 1999;6:S121–S126. doi: 10.1016/S0304-3959(99)00145-1.
    1. Vlaeyen J.W., Linton S.J. Fear-avoidance model of chronic musculoskeletal pain: 12 years on. Pain. 2012;153:1144–1147. doi: 10.1016/j.pain.2011.12.009.
    1. Linton S.J., Bergbom S. Understanding the link between depression and pain. Scand. J. Pain. 2011;2:47–54. doi: 10.1016/j.sjpain.2011.01.005.
    1. Wise T.N., Fishbain D.A., Holder-Perkins V. Painful physical symptoms in depression: A clinical challenge. Pain Med. 2007;8(Suppl. 2):S75–S82. doi: 10.1111/j.1526-4637.2007.00352.x.
    1. Melzack R., Wall P.D. Pain mechanisms: A new theory. Science. 1965;150:971–979. doi: 10.1126/science.150.3699.971.
    1. Ossipov M.H., Dussor G.O., Porreca F. Central modulation of pain. J. Clin. Investig. 2010;120:3779–3787. doi: 10.1172/JCI43766.
    1. Mao J. Translational pain research: Achievements and challenges. J. Pain. 2009;10:1001–1011. doi: 10.1016/j.jpain.2009.06.002.
    1. Linnman C. New pieces for the substance p puzzle. Pain. 2013;154:966–967. doi: 10.1016/j.pain.2013.04.020.
    1. Ahmedzai S.H. Personalized medicine—One size fits one: Tailoring pain therapy to individuals’ needs. J. Pain Palliat. Care Pharmacother. 2013;27:83–85. doi: 10.3109/15360288.2012.760706.
    1. Roche S., Gabelle A., Lehmann S. Clinical proteomics of the cerebrospinal fluid: Towards the discovery of new biomarkers. Proteomics Clin. Appl. 2008;2:428–436. doi: 10.1002/prca.200780040.
    1. Blennow K., Zetterberg H., Fagan A.M. Fluid biomarkers in Alzheimer disease. Cold Spring Harb. Perspect. Med. 2012;2:a006221. doi: 10.1101/cshperspect.a006221.
    1. Cortese I., Calabresi P.A. Inflammatory and demyelinating disorders. In: Irani D.N., editor. Cerebrospinal Fluid in Clinical Practice. Saunders; Philadelphia, PA, USA: 2009. pp. 209–223.
    1. Romeo M.J., Espina V., Lowenthal M., Espina B.H., Petricoin E.F., 3rd, Liotta L.A. CSF proteome: A protein repository for potential biomarker identification. Expert Rev. Proteomics. 2005;2:57–70. doi: 10.1586/14789450.2.1.57.
    1. Mannes A.J., Martin B.M., Yang H.Y., Keller J.M., Lewin S., Gaiser R.R., Iadarola M.J. Cystatin C as a cerebrospinal fluid biomarker for pain in humans. Pain. 2003;102:251–256. doi: 10.1016/S0304-3959(02)00403-7.
    1. Eisenach J.C., Thomas J.A., Rauck R.L., Curry R., Li X. Cystatin C in cerebrospinal fluid is not a diagnostic test for pain in humans. Pain. 2004;107:207–212. doi: 10.1016/j.pain.2003.09.007.
    1. Perlson E., Medzihradszky K.F., Darula Z., Munno D.W., Syed N.I., Burlingame A.L., Fainzilber M. Differential proteomics reveals multiple components in retrogradely transported axoplasm after nerve injury. Mol. Cell. Proteomics. 2004;3:510–520. doi: 10.1074/mcp.M400004-MCP200.
    1. Capelle H.H., Weigel R., Schmelz M., Krauss J.K. Neurotrophins in the cerebrospinal fluid of patient cohorts with neuropathic pain, nociceptive pain, or normal pressure hydrocephalus. Clin. J. Pain. 2009;25:729–733. doi: 10.1097/AJP.0b013e3181a776e4.
    1. Lundborg C., Hahn-Zoric M., Biber B., Hansson E. Glial cell line-derived neurotrophic factor is increased in cerebrospinal fluid but decreased in blood during long-term pain. J. Neuroimmunol. 2010;220:108–113. doi: 10.1016/j.jneuroim.2010.01.007.
    1. Brooks H., Elton C.D., Smart D., Rowbotham D.J., McKnight A.T., Lambert D.G. Identification of nociceptin in human cerebrospinal fluid: Comparison of levels in pain and non-pain states. Pain. 1998;78:71–73. doi: 10.1016/S0304-3959(98)00130-4.
    1. Raffaeli W., Samolsky Dekel B.G., Landuzzi D., Caminiti A., Righetti D., Balestri M., Montanari F., Romualdi P., Candeletti S. Nociceptin levels in the cerebrospinal fluid of chronic pain patients with or without intrathecal administration of morphine. J. Pain Symptom Manag. 2006;32:372–377. doi: 10.1016/j.jpainsymman.2006.05.013.
    1. Almay B.G., Johansson F., Von Knorring L., Terenius L., Wahlstrom A. Endorphins in chronic pain. I. Differences in CSF endorphin levels between organic and psychogenic pain syndromes. Pain. 1978;5:153–162. doi: 10.1016/0304-3959(78)90037-4.
    1. Vaeroy H., Helle R., Forre O., Kass E., Terenius L. Cerebrospinal fluid levels of beta-endorphin in patients with fibromyalgia (fibrositis syndrome) J. Rheumatol. 1988;15:1804–1806.
    1. Almay B.G., Johansson F., Von Knorring L., Le Greves P., Terenius L. Substance P in CSF of patients with chronic pain syndromes. Pain. 1988;33:3–9. doi: 10.1016/0304-3959(88)90197-2.
    1. Vaeroy H., Helle R., Forre O., Kass E., Terenius L. Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: New features for diagnosis. Pain. 1988;32:21–26. doi: 10.1016/0304-3959(88)90019-X.
    1. Russell I.J., Orr M.D., Littman B., Vipraio G.A., Alboukrek D., Michalek J.E., Lopez Y., MacKillip F. Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome. Arthritis Rheum. 1994;37:1593–1601. doi: 10.1002/art.1780371106.
    1. Mischak H., Apweiler R., Banks R.E., Conaway M., Coon J., Dominiczak A., Ehrich J.H., Fliser D., Girolami M., Hermjakob H., et al. Clinical proteomics: A need to define the field and to begin to set adequate standards. Proteomics Clin. Appl. 2007;1:148–156. doi: 10.1002/prca.200600771.
    1. Biesecker L.G. Hypothesis-generating research and predictive medicine. Genome Res. 2013;23:1051–1053. doi: 10.1101/gr.157826.113.
    1. Wheelock A.M., Wheelock C.E. Trials and tribulations of ‘omics data analysis: Assessing quality of simca-based multivariate models using examples from pulmonary medicine. Mol. Biosyst. 2013;9:2589–2596. doi: 10.1039/c3mb70194h.
    1. Eriksson L., Byrne T., Johansson E., Trygg J., Vikström C. Multi- and Megavariate Data Analysis: Basic Principles and Applications. 3rd ed. MKS Umetrics AB; Malmö, Sweden: 2013.
    1. Wold S., Sjöström M., Eriksson L. PLS-regression: A basic tool of chemometrics. Chemom. Intell. Lab. Syst. 2001;58:109–130. doi: 10.1016/S0169-7439(01)00155-1.
    1. Norden B., Broberg P., Lindberg C., Plymoth A. Analysis and understanding of high-dimensionality data by means of multivariate data analysis. Chem. Biodivers. 2005;2:1487–1494. doi: 10.1002/cbdv.200590120.
    1. Mazzara S. Application of multivariate data analysis for the classification of two dimensional gel images in neuroproteomics. J. Proteomics Bioinform. 2011;4:016–021. doi: 10.4172/jpb.1000162.
    1. Niederberger E., Geisslinger G. Proteomics in neuropathic pain research. Anesthesiology. 2008;108:314–323. doi: 10.1097/01.anes.0000299838.13368.6e.
    1. Perkins J.R., Lees J., Antunes-Martins A., Diboun I., McMahon S.B., Bennett D.L., Orengo C. Painnetworks: A web-based resource for the visualisation of pain-related genes in the context of their network associations. Pain. 2013;154:2586.e1–2586.e12. doi: 10.1016/j.pain.2013.09.003.
    1. Pedersen B.K. Muscles and their myokines. J. Exp. Biol. 2011;214:337–346. doi: 10.1242/jeb.048074.
    1. Kiguchi N., Kobayashi Y., Kishioka S. Chemokines and cytokines in neuroinflammation leading to neuropathic pain. Curr. Opin. Pharmacol. 2012;12:55–61. doi: 10.1016/j.coph.2011.10.007.
    1. Schistad E.I., Espeland A., Pedersen L.M., Sandvik L., Gjerstad J., Roe C. Association between baseline IL-6 and 1-year recovery in lumbar radicular pain. Eur. J. Pain. 2014;18:1394–1401. doi: 10.1002/j.1532-2149.2014.502.x.
    1. Kraychete D.C., Sakata R.K., Issy A.M., Bacellar O., Jesus R.S., Carvalho E.M. Proinflammatory cytokines in patients with neuropathic pain treated with tramadol. Braz. J. Anestesiol. 2009;59:297–303. doi: 10.1590/S0034-70942009000300004.
    1. Zhu S.M., Liu Y.M., An E.D., Chen Q.L. Influence of systemic immune and cytokine responses during the acute phase of zoster on the development of postherpetic neuralgia. J. Zhejiang Univ. Sci. B. 2009;10:625–630. doi: 10.1631/jzus.B0920049.
    1. Backonja M.M., Coe C.L., Muller D.A., Schell K. Altered cytokine levels in the blood and cerebrospinal fluid of chronic pain patients. J. Neuroimmunol. 2008;195:157–163. doi: 10.1016/j.jneuroim.2008.01.005.
    1. Brisby H., Olmarker K., Larsson K., Nutu M., Rydevik B. Proinflammatory cytokines in cerebrospinal fluid and serum in patients with disc herniation and sciatica. Eur. Spine J. 2002;11:62–66. doi: 10.1007/s005860100306.
    1. Ludwig J., Binder A., Steinmann J., Wasner G., Baron R. Cytokine expression in serum and cerebrospinal fluid in non-inflammatory polyneuropathies. J. Neurol. Neurosurg. Psychiatry. 2008;79:1268–1273. doi: 10.1136/jnnp.2007.134528.
    1. Austin P.J., Moalem-Taylor G. The neuro-immune balance in neuropathic pain: Involvement of inflammatory immune cells, immune-like glial cells and cytokines. J. Neuroimmunol. 2010;229:26–50. doi: 10.1016/j.jneuroim.2010.08.013.
    1. Sowa G.A., Perera S., Bechara B., Agarwal V., Boardman J., Huang W., Camacho-Soto A., Vo N., Kang J., Weiner D. Associations between serum biomarkers and pain and pain-related function in older adults with low back pain: A pilot study. J. Am. Geriatr. Soc. 2014;62:2047–2055. doi: 10.1111/jgs.13102.
    1. Uceyler N., Hauser W., Sommer C. Systematic review with meta-analysis: Cytokines in fibromyalgia syndrome. BMC Musculoskelet. Disord. 2011;12:245. doi: 10.1186/1471-2474-12-245.
    1. Reynolds W.J., Chiu B., Inman R.D. Plasma substance p levels in fibrositis. J. Rheumatol. 1988;15:1802–1803.
    1. Lewis G.N., Heales L., Rice D.A., Rome K., McNair P.J. Reliability of the conditioned pain modulation paradigm to assess endogenous inhibitory pain pathways. Pain Res. Manag. 2012;17:98–102.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅