Advertisement

Is Chronic Pain a Disease?

  • Jane C. Ballantyne
    Correspondence
    Address reprint requests to Jane C. Ballantyne, MD, FRCA, Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Box 356540, Seattle, WA 98195-6560.
    Affiliations
    Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, Washington
    Search for articles by this author
  • Mark D. Sullivan
    Affiliations
    Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington
    Search for articles by this author

      Abstract

      It was not until the twentieth century that pain was considered a disease. Before that it was managed medically as a symptom. The motivations for declaring chronic pain a disease, whether of the body or of the brain, include increasing its legitimacy as clinical problem and research focus worthy of attention from healthcare and research organizations alike. But 1 problem with disease concepts is that having a disease favors medical solutions and tends to reduce patient participation. We argue that chronic pain, particularly chronic primary pain (recently designated a first tier pain diagnosis in International Diagnostic Codes 11), is a learned state that is not intransigent even if it has biological correlates. Chronic pain is sometimes a symptom, and may sometimes be its own disease. But here we question the value of a disease focus for much of chronic pain for which patient involvement is essential, and which may need a much broader societal approach than is suggested by the disease designation.

      Perspective

      This article examines whether designating chronic pain a disease of the body or brain is helpful or harmful to patients. Can the disease designation help advance treatment, and is it needed to achieve future therapeutic breakthrough? Or does it make patients over-reliant on medical intervention and reduce their engagement in the process of recovery?

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Ashar YK
        • Chang LJ
        • Wager TD.
        Brain mechanisms of the placebo effect: An affective appraisal account.
        Annu Rev Clin Psychol. 2017; 13: 73-98https://doi.org/10.1146/annurev-clinpsy-021815-093015
        • Ashar YK
        • Gordon A
        • Schubiner H
        • Uipi C
        • Knight K
        • Anderson Z
        • Carlisle J
        • Polisky L
        • Geuter S
        • Flood TF
        • Kragel PA
        • Dimidjian S
        • Lumley MA
        • Wager TD.
        Effect of pain reprocessing therapy vs placebo and usual care for patients with chronic back pain: A randomized clinical trial.
        JAMA psychiatry. 2022; 79: 13-23https://doi.org/10.1001/jamapsychiatry.2021.2669
        • Bagley EE IS
        Endogenous opioid peptides in the descending pain modulatory circuit.
        Neuropharmacology. 2020; 15: 108-131https://doi.org/10.1016/j.neuropharm.2020.108131
        • Baliki MN
        • Apkarian AV.
        Nociception, pain, negative moods, and behavior selection.
        Neuron. 2015; 87: 474-491https://doi.org/10.1016/j.neuron.2015.06.005
        • Ballantyne JC
        • Koob GF.
        Allostasis theory in opioid tolerance.
        Pain. 2020; https://doi.org/10.1097/j.pain.0000000000002280
        • Ballantyne JC
        • Sullivan MD
        • Koob GF.
        Refractory dependence on opioid analgesics.
        Pain. 2019; 160: 2655-2660https://doi.org/10.1097/j.pain.0000000000001680
        • Beecher HK.
        Increased stress and effectiveness of placebos and “active” drugs.
        Science. 1960; 132 (Available at:): 91-92
        • Bonica JJ.
        Anesthesiology in the People's Republic of China.
        Anesthesiology. 1974; 40: 175-186https://doi.org/10.1097/00000542-197402000-00016
        • Borsook D.
        Opioidergic tone and pain susceptibility: Interactions between reward systems and opioid receptors.
        Pain. 2017; 158: 185-186https://doi.org/10.1097/j.pain.0000000000000726
        • Borsook D
        • Edwards R
        • Elman I
        • Becerra L
        • Levine J.
        Pain and analgesia: The value of salience circuits.
        Prog Neurobiol. 2013; 104: 93-105https://doi.org/10.1016/j.pneurobio.2013.02.003
        • Bradshaw DH EC
        • Davis P
        • Lipschitz D
        • Dalton P
        • Nakamura Y
        • Chapman CR
        Trends in funding for research on pain: A report on the National Institutes Of Health grant awards over the years 2003 to 2007.
        J Pain. 2008; 9: 1077-1087https://doi.org/10.1016/j.jpain.2008.09.008
        • Burton JL
        • Underwood J.
        Clinical, educational, and epidemiological value of autopsy.
        Lancet. 2007; 369 (Available at:): 1471-1480
        • Cahill CM
        • Cook C
        • Pickens S.
        Migraine and reward system-or is it aversive?.
        Curr Pain Headache Rep. 2014; 18: 410https://doi.org/10.1007/s11916-014-0410-y
        • Case A
        • Deaton A.
        Deaths of despair and the future of capitalism.
        Princeton University Press, 2020 (ISBN: 9780691190785)
        • Case A
        • Deaton A.
        Rising morbidity and mortality in midlife among white non-Hispanic Americans in the 21st century.
        Proc Natl Acad Sci U S A. 2015; 112: 15078-15083https://doi.org/10.1073/pnas.1518393112
        • Castro DC OC
        • Zhang ET
        • Pedersen CE
        • Piantadosi SC
        • Rossi MA
        • Hunker AC
        • Guglin A
        • Morón JA
        • Zweifel LS
        • Stuber GD
        • Bruchas MR.
        An endogenous opioid circuit determines state-dependent reward consumption.
        Nature. 2021; 598: 646-651https://doi.org/10.1038/s41586-021-04013-0
        • Chaijale NN
        • Curtis AL
        • Wood SK
        • Zhang XY
        • Bhatnagar S
        • Reyes BA
        • Van Bockstaele EJ
        • Valentino RJ.
        Social stress engages opioid regulation of locus coeruleus norepinephrine neurons and induces a state of cellular and physical opiate dependence.
        Neuropsychopharmacology. 2013; 38: 1833-1843https://doi.org/10.1038/npp.2013.117
        • Clauw DJ.
        Fibromyalgia: A clinical review.
        Jama. 2014; 311: 1547-1555https://doi.org/10.1001/jama.2014.3266
        • Clauw DJ
        • D'Arcy Y
        • Gebke K
        • Semel D
        • Pauer L
        • Jones KD
        Normalizing fibromyalgia as a chronic illness.
        Postgrad Med. 2018; 130: 9-18https://doi.org/10.1080/00325481.2018.1411743
        • Clauw DJ
        • Essex MN
        • Pitman V
        • Jones KD.
        Reframing chronic pain as a disease, not a symptom: Rationale and implications for pain management.
        Postgrad Med. 2019; 131: 185-198https://doi.org/10.1080/00325481.2019.1574403
        • Coenen VA
        • Schlaepfer TE
        • Maedler B
        • Panksepp J.
        Cross-species affective functions of the medial forebrain bundle-implications for the treatment of affective pain and depression in humans.
        Neurosci Biobehav Rev. 2011; 35: 1971-1981https://doi.org/10.1016/j.neubiorev.2010.12.009
        • Creamer MR WT
        • Babb S
        Tobacco product use and cessation indicators among adults — United States, 2018.
        MMWR Morb Mortal Wkly Rep. 2019; 68
        • Davis KD
        • Kucyi A
        • Moayedi M.
        The pain switch: An "ouch" detector.
        Pain. 2015; 156: 2164-2166https://doi.org/10.1097/j.pain.0000000000000303
        • De Ruddere L
        • Bosmans M
        • Crombez G
        • Goubert L.
        Patients are socially excluded when their pain has no medical explanation.
        J Pain. 2016; 17: 1028-1035https://doi.org/10.1016/j.jpain.2016.06.005
        • DiSabato DJ
        • Quan N
        • Godbout JP.
        Neuroinflammation: The devil is in the details.
        J Neurochem. 2016; 139: 136-153https://doi.org/10.1111/jnc.13607
        • Edwards MJ.
        Functional neurological disorder: Lighting the way to a new paradigm for medicine.
        Brain. 2021; 144: 3279-3282https://doi.org/10.1093/brain/awab358
        • Eippert F
        • Tracey I.
        Pain and the PAG: Learning from painful mistakes.
        Nat Neurosci. 2014; 17: 1438-1439https://doi.org/10.1038/nn.3844
        • Eisenberger NI
        • Lieberman MD
        • Williams KD.
        Does rejection hurt? An FMRI study of social exclusion.
        Science. 2003; 302 (Available at:): 290-292
        • Elman I
        • Borsook D.
        Common brain mechanisms of chronic pain and addiction.
        Neuron. 2016; 89: 11-36https://doi.org/10.1016/j.neuron.2015.11.027
        • Evdokimov D
        • Frank J
        • Klitsch A
        • Unterecker S
        • Warrings B
        • Serra J
        • Papagianni A
        • Saffer N
        • Meyer Zu Altenschildesche C
        • Kampik D
        • Malik RA
        • Sommer C
        • Uceyler N
        Reduction of skin innervation is associated with a severe fibromyalgia phenotype.
        Ann Neurol. 2019; 86: 504-516https://doi.org/10.1002/ana.25565
        • Fareed A
        • Eilender P
        • Haber M
        • Bremner J
        • Whitfield N
        • Drexler K.
        Comorbid posttraumatic stress disorder and opiate addiction: A literature review.
        J Addict Dis. 2013; 32: 168-179https://doi.org/10.1080/10550887.2013.795467
        • Fields HL.
        Understanding how opioids contribute to reward and analgesia.
        Reg Anesth Pain Med. 2007; 32: 242-246https://doi.org/10.1016/j.rapm.2007.01.001
        • Fisher CE.
        It’s misleading to call addiction a disease.
        https://www.nytimes.com/2022/01/15/opinion/addiction-disease.html. New York Times, 2022 (Available at:)
        • Fitzcharles MA CS
        • Clauw DJ
        • Littlejohn G
        • Usui C
        • Häuser W
        Nociplastic pain: Towards an understanding of prevalent pain conditions.
        Lancet. 2021; 397: 2098-2110https://doi.org/10.1016/S0140-6736(21)00392-5
        • Foley KM IC
        Analgesic drug therapy in cancer pain: Principles and practice.
        Med Clin North Am. 1987; 71: 207-232https://doi.org/10.1016/s0025-7125(16)30866-5
        • Foucault M.
        The Birth of the Clinic: An Archeology of Medical Perception.
        Vintage Books, New York, NY1973
        • Gatchel RJ
        • McGeary DD
        • McGeary CA
        • Lippe B.
        Interdisciplinary chronic pain management: Past, present, and future.
        Am Psychol. 2014; 69: 119-130https://doi.org/10.1037/a0035514
        • Gosselin RD
        • Suter MR
        • Ji RR
        • Decosterd I.
        Glial cells and chronic pain.
        Neuroscientist. 2010; 16: 519-531https://doi.org/10.1177/1073858409360822
        • Gracely RH
        • Ambrose KR.
        Neuroimaging of fibromyalgia.
        Best Pract Res Clin Rheumatol. 2011; 25: 271-284https://doi.org/10.1016/j.berh.2011.02.003
        • Grayston R
        • Czanner G
        • Elhadd K
        • Goebel A
        • Frank B
        • Uceyler N
        • Malik RA
        • Alam U.
        A systematic review and meta-analysis of the prevalence of small fiber pathology in fibromyalgia: Implications for a new paradigm in fibromyalgia etiopathogenesis.
        Semin Arthritis Rheum. 2019; 48: 933-940https://doi.org/10.1016/j.semarthrit.2018.08.003
        • Hardy JD
        • Wolff HG
        • Goodell H.
        Experimental evidence on the nature of cutaneous hyperalgesia.
        J Clin Invest. 1950; 29: 115-140https://doi.org/10.1172/JCI102227
        • Hashmi JA
        • Baliki MN
        • Huang L
        • Baria AT
        • Torbey S
        • Hermann KM
        • Schnitzer TJ
        • Apkarian AV.
        Shape shifting pain: Chronification of back pain shifts brain representation from nociceptive to emotional circuits.
        Brain. 2013; 136: 2751-2768https://doi.org/10.1093/brain/awt211
        • Hughes J
        • Smith TW
        • Kosterlitz HW
        • Fothergill LA
        • Morgan BA
        • Morris HR.
        Identification of two related pentapeptides from the brain with potent opiate agonist activity.
        Nature. 1975; 258: 577-580
        • Iannetti GD
        • Mouraux A.
        From the neuromatrix to the pain matrix (and back).
        Exp Brain Res. 2010; 205: 1-12https://doi.org/10.1007/s00221-010-2340-1
      1. IASP. Available at: https://wwwiasp-painorg/resources/terminology/#central-sensitization Accessed December 9, 2021.

        • Imbierowicz K
        • Egle UT.
        Childhood adversities in patients with fibromyalgia and somatoform pain disorder.
        Eur J Pain. 2003; 7: 113-119https://doi.org/10.1016/S1090-3801(02)00072-1
        • Jackson JL
        • Kroenke K.
        Managing somatization: Medically unexplained should not mean medically ignored.
        J Gen Intern Med. 2006; 21 (Available at): 797-799
        • Jacobsen LK
        • Southwick SM
        • Kosten TR.
        Substance use disorders in patients with posttraumatic stress disorder: A review of the literature.
        Am J Psychiatry. 2001; 158: 1184-1190https://doi.org/10.1176/appi.ajp.158.8.1184
        • Ji RR
        • Berta T
        • Nedergaard M.
        Glia and pain: Is chronic pain a gliopathy?.
        Pain. 2013; 154: S10-S28https://doi.org/10.1016/j.pain.2013.06.022
        • Ji RR
        • Nackley A
        • Huh Y
        • Terrando N
        • Maixner W.
        Neuroinflammation and central sensitization in chronic and widespread pain.
        Anesthesiology. 2018; 129: 343-366https://doi.org/10.1097/ALN.0000000000002130
        • Kaptchuk TJ
        • Hemond CC
        • Miller FG.
        Placebos in chronic pain: Evidence, theory, ethics, and use in clinical practice.
        BMJ. 2020; 370: m1668https://doi.org/10.1136/bmj.m1668
        • Kendler KS
        • Hettema JM
        • Butera F
        • Gardner CO
        • Prescott CA.
        Life event dimensions of loss, humiliation, entrapment, and danger in the prediction of onsets of major depression and generalized anxiety.
        Arch Gen Psychiatry. 2003; 60: 789-796https://doi.org/10.1001/archpsyc.60.8.789
        • Khan F AB
        Rehabilitation in multiple sclerosis: A systematic review of systematic reviews.
        Arch Phys Med Rehabil. 2017; 98: 353-367https://doi.org/10.1016/j.apmr.2016.04.016
        • Kleckner IR
        • Zhang J
        • Touroutoglou A
        • Chanes L
        • Xia C
        • Simmons WK
        • Quigley KS
        • Dickerson BC
        • Barrett LF.
        Evidence for a large-scale brain system supporting allostasis and interoception in humans.
        Nat Hum Behav. 2017; 1https://doi.org/10.1038/s41562-017-0069
        • Kroenke K.
        Patients presenting with somatic complaints: Epidemiology, psychiatric comorbidity and management.
        Int J Methods Psychiatr Res. 2003; 12: 34-43
        • Kucyi A
        • Davis KD.
        The neural code for pain: From single-cell electrophysiology to the dynamic pain connectome.
        Neuroscientist. 2016; 23: 397-414https://doi.org/10.1177/1073858416667716
        • Kutch JJ
        • Ichesco E
        • Hampson JP
        • Labus JS
        • Farmer MA
        • Martucci KT
        • Ness TJ
        • Deutsch G
        • Apkarian AV
        • Mackey SC
        • Klumpp DJ
        • Schaeffer AJ
        • Rodriguez LV
        • Kreder KJ
        • Buchwald D
        • Andriole GL
        • Lai HH
        • Mullins C
        • Kusek JW
        • Landis JR
        • Mayer EA
        • Clemens JQ
        • Clauw DJ
        • Harris RE
        • Network MR.
        Brain signature and functional impact of centralized pain: A multidisciplinary approach to the study of chronic pelvic pain (MAPP) network study.
        Pain. 2017; https://doi.org/10.1097/j.pain.0000000000001001
        • Landa A
        • Peterson BS
        • Fallon BA.
        Somatoform pain: A developmental theory and translational research review.
        Psychosom Med. 2012; 74: 717-727https://doi.org/10.1097/PSY.0b013e3182688e8b
        • Latremoliere A
        • Woolf CJ.
        Central sensitization: A generator of pain hypersensitivity by central neural plasticity.
        J Pain. 2009; 10: 895-926https://doi.org/10.1016/j.jpain.2009.06.012
        • Le Bars D
        • Chitour D
        • Kraus E
        • Clot AM
        • Dickenson AH
        • Besson JM
        The effect of systemic morphine upon diffuse noxious inhibitory controls (DNIC) in the rat: Evidence for a lifting of certain descending inhibitory controls of dorsal horn convergent neurones.
        Brain Res. 1981; 215: 257-274https://doi.org/10.1016/0006-8993(81)90506-0
        • Legrain V
        • Iannetti GD
        • Plaghki L
        • Mouraux A.
        The pain matrix reloaded: A salience detection system for the body.
        Prog Neurobiol. 2011; 93: 111-124https://doi.org/10.1016/j.pneurobio.2010.10.005
        • Lewis M.
        Brain change in addiction as learning, not disease.
        N Engl J Med. 2018; 379: 1551-1560https://doi.org/10.1056/NEJMra1602872
        • Loggia ML
        • Chonde DB
        • Akeju O
        • Arabasz G
        • Catana C
        • Edwards RR
        • Hill E
        • Hsu S
        • Izquierdo-Garcia D
        • Ji RR
        • Riley M
        • Wasan AD
        • Zurcher NR
        • Albrecht DS
        • Vangel MG
        • Rosen BR
        • Napadow V
        • Hooker JM
        Evidence for brain glial activation in chronic pain patients.
        Brain. 2015; 138: 604-615https://doi.org/10.1093/brain/awu377
        • Lopez-Quintero C HD
        • de Los Cobos JP
        Probability and predictors of remission from life-time nicotine, alcohol, cannabis or cocaine dependence: Results from the national epidemiologic survey on alcohol and related conditions.
        Addiction. 2011; 106: 657-669
        • MacFarlane GJ TE
        • Papageorgiou AC
        • Schollum J
        • Croft PR
        • Silman AJ
        The natural history of chronic pain in the community: A better prognosis than in the clinic?.
        J Rheumatol. 1996; 23: 1617-1620
        • Malterud K AA
        Medically unexplained symptoms: Are we making progress?.
        Br J Gen Pract. 2019; 69: 164-165https://doi.org/10.3399/bjgp19X701885
        • Massaly N
        • Ream A
        • Hipolito L
        • Wilson-Poe A
        • Walker B
        • Bruchas M
        • Moron-Concepcion J.
        (323) Kappa opioid receptors in the nucleus accumbens mediate pain-induced decrease in motivated behavior.
        J Pain. 2016; 17: S56https://doi.org/10.1016/j.jpain.2016.01.230
        • McEwen BS.
        Allostasis and allostatic load: Implications for neuropsychopharmacology.
        Neuropsychopharmacology. 2000; 22: 108-124https://doi.org/10.1016/S0893-133X(99)00129-3
        • McMahon SB
        • Malcangio M.
        Current challenges in glia-pain biology.
        Neuron. 2009; 64: 46-54https://doi.org/10.1016/j.neuron.2009.09.033
        • Melzack R
        • Wall PD.
        Pain mechanisms: A new theory.
        Science. 1965; 150 (Available at:): 971-979
        • Mendieta D
        • De la Cruz-Aguilera DL
        • Barrera-Villalpando MI
        • Becerril-Villanueva E
        • Arreola R
        • Hernandez-Ferreira E
        • Perez-Tapia SM
        • Perez-Sanchez G
        • Garces-Alvarez ME
        • Aguirre-Cruz L
        • Velasco-Velazquez MA
        • Pavon L.
        IL-8 and IL-6 primarily mediate the inflammatory response in fibromyalgia patients.
        J Neuroimmunol. 2016; 290: 22-25https://doi.org/10.1016/j.jneuroim.2015.11.011
        • Meulders A.
        Fear in the context of pain: Lessons learned from 100 years of fear conditioning research.
        Behav Res Ther. 2020; 131103635https://doi.org/10.1016/j.brat.2020.103635
        • Mitka M.CT
        MRI scans offer new tools for autopsy.
        Jama. 2007; 298 (Available at:): 392-393
        • Mol KA SA
        • Rahel BM
        • Meeder JG
        • Janssen L
        • Doevendans PA
        • Cramer MJ
        Non-cardiac chest pain: Prognosis and secondary healthcare utilisation.
        Open Heart. 2018; 5e000859https://doi.org/10.1136/openhrt-2018-000859
        • Moseley GL
        • Butler DS.
        Fifteen years of explaining pain: The past, present, and future.
        J Pain. 2015; 16: 807-813https://doi.org/10.1016/j.jpain.2015.05.005
        • 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: 425https://doi.org/10.1186/s13075-014-0425-0
        • Nation KM
        • De Felice M
        • Hernandez PI
        • Dodick DW
        • Neugebauer V
        • Navratilova E
        • Porreca F.
        Lateralized kappa opioid receptor signaling from the amygdala central nucleus promotes stress-induced functional pain.
        Pain. 2018; 159: 919-928https://doi.org/10.1097/j.pain.0000000000001167
        • Navratilova E
        • Atcherley CW
        • Porreca F.
        Brain circuits encoding reward from pain relief.
        Trends Neurosci. 2015; 38: 741-750https://doi.org/10.1016/j.tins.2015.09.003
        • Navratilova E
        • Nation K
        • Remeniuk B
        • Neugebauer V
        • Bannister K
        • Dickenson AH
        • Porreca F.
        Selective modulation of tonic aversive qualities of neuropathic pain by morphine in the central nucleus of the amygdala requires endogenous opioid signaling in the anterior cingulate cortex.
        Pain. 2020; 161: 609-618https://doi.org/10.1097/j.pain.0000000000001748
        • Neugebauer V
        • Mazzitelli M
        • Cragg B
        • Ji G
        • Navratilova E
        • Porreca F
        Amygdala, neuropeptides, and chronic pain-related affective behaviors.
        Neuropharmacology. 2020; 170108052https://doi.org/10.1016/j.neuropharm.2020.108052
        • NICE
        Chronic pain (primary and secondary) in over 16s: assessment of all chronic pain and management of chronic primary pain.
        2021
        • Nicholas M
        • Vlaeyen JWS
        • Rief W
        • Barke A
        • Aziz Q
        • Benoliel R
        • Cohen M
        • Evers S
        • Giamberardino MA
        • Goebel A
        • Korwisi B
        • Perrot S
        • Svensson P
        • Wang SJ
        • Treede RD
        Pain ITftCoC. The IASP classification of chronic pain for ICD-11: Chronic primary pain.
        Pain. 2019; 160: 28-37https://doi.org/10.1097/j.pain.0000000000001390
        • Panksepp J
        • Herman B
        • Conner R
        • Bishop P
        • Scott JP.
        The biology of social attachments: Opiates alleviate separation distress.
        Biol Psychiatry. 1978; 13: 607-618
        • Pearce E
        • Wlodarski R
        • Machin A
        • Dunbar RIM.
        Variation in the beta-endorphin, oxytocin, and dopamine receptor genes is associated with different dimensions of human sociality.
        Proc Natl Acad Sci U S A. 2017; 114: 5300-5305https://doi.org/10.1073/pnas.1700712114
        • Pert CB
        • Snyder SH.
        Opiate receptor: Demonstration in nervous tissue.
        Science. 1973; 179: 1011-1014
        • Peters A
        • McEwen BS.
        Introduction for the allostatic load special issue.
        Physiol Behav. 2012; 106: 1-4https://doi.org/10.1016/j.physbeh.2011.12.019
        • Peyron R
        • Laurent B
        • Garcia-Larrea L.
        Functional imaging of brain responses to pain. A review and meta-analysis (2000).
        Neurophysiol Clin. 2000; 30 (Available at:): 263-288
        • Porreca F
        • Navratilova E.
        Reward, motivation, and emotion of pain and its relief.
        Pain. 2017; 158: S43-S49https://doi.org/10.1097/j.pain.0000000000000798
        • Health Porter D.
        Civilization, and the State: A History of Public Health from Ancient to Modern Times.
        Routledge, New York, NY1999
        • Porter R.
        The Greatest Benefit to Mankind: A Medical History of Humanity (The Norton History of Science).
        W. W. Norton, New York1999
        • Ramsay DS
        • Woods SC
        • Kaiyala KJ.
        Drug-induced regulatory overcompensation has motivational consequences: Implications for homeostatic and allostatic models of drug addiction.
        Temperature (Austin). 2014; 1: 248-256https://doi.org/10.4161/23328940.2014.944802
        • Ren K
        • Dubner R.
        Interactions between the immune and nervous systems in pain.
        Nat Med. 2010; 16: 1267-1276https://doi.org/10.1038/nm.2234
        • Rhodes LA
        • McPhillips-Tangum CA
        • Markham C
        • Klenk R.
        The power of the visible: The meaning of diagnostic tests in chronic back pain.
        Soc Sci Med. 1999; 48 (Available at:): 1189-1203
        • Ribeiro SC
        • Kennedy SE
        • Smith YR
        • Stohler CS
        • Zubieta JK.
        Interface of physical and emotional stress regulation through the endogenous opioid system and mu-opioid receptors.
        Progress Neuro-Psychopharmacol Biolog Psychiat. 2005; 29: 1264-1280https://doi.org/10.1016/j.pnpbp.2005.08.011
        • Schaefer CP AE
        • Udall M
        • Masters ET
        • Mann RM
        • Daniel SR
        • McElroy HJ
        • Cappelleri JC
        • Clair AG
        • Hopps M
        • Staud R
        • Mease P
        • Silverman SL
        Fibromyalgia outcomes over time: Results from a prospective observational study in the United States.
        Open Rheumatol J. 2016; 30: 109-121https://doi.org/10.2174/1874312901610010109
        • Schrepf A
        • Harper DE
        • Harte SE
        • Wang H
        • Ichesco E
        • Hampson JP
        • Zubieta JK
        • Clauw DJ
        • Harris RE.
        Endogenous opioidergic dysregulation of pain in fibromyalgia: A PET and fMRI study.
        Pain. 2016; 157: 2217-2225https://doi.org/10.1097/j.pain.0000000000000633
        • Schulkin J.
        Social allostasis: Anticipatory regulation of the internal milieu.
        Front Evol Neurosci. 2011; 2: 111https://doi.org/10.3389/fnevo.2010.00111
        • Scully JL.
        What is a disease?.
        EMBO Rep. 2004; 5: 650-653https://doi.org/10.1038/sj.embor.7400195
        • Seymour B.
        Pain: A precision signal for reinforcement learning and control.
        Neuron. 2019; 101: 1029-1041https://doi.org/10.1016/j.neuron.2019.01.055
        • Slade GD
        • Conrad MS
        • Diatchenko L
        • Rashid NU
        • Zhong S
        • Smith S
        • Rhodes J
        • Medvedev A
        • Makarov S
        • Maixner W
        • Nackley AG.
        Cytokine biomarkers and chronic pain: Association of genes, transcription, and circulating proteins with temporomandibular disorders and widespread palpation tenderness.
        Pain. 2011; 152: 2802-2812https://doi.org/10.1016/j.pain.2011.09.005
        • Sluka KA
        • Clauw DJ.
        Neurobiology of fibromyalgia and chronic widespread pain.
        Neuroscience. 2016; 338: 114-129https://doi.org/10.1016/j.neuroscience.2016.06.006
        • Smith HS
        • Harris R
        • Clauw D.
        Fibromyalgia: An afferent processing disorder leading to a complex pain generalized syndrome.
        Pain Physician. 2011; 14 (Available at:): E217-E245
        • Staud R
        • Weyl EE
        • Bartley E
        • Price DD
        • Robinson ME.
        Analgesic and anti-hyperalgesic effects of muscle injections with lidocaine or saline in patients with fibromyalgia syndrome.
        Eur J Pain. 2014; 18: 803-812https://doi.org/10.1002/j.1532-2149.2013.00422.x
        • Sterling P
        • Eyer J.
        Allostasis: A new paradigm to explain arousal pathology.
        in: Fisher S Reason J Handbook of Life Stress. Cognition and Health John Wiley, Chichester1988: 629-649
        • Sturgill J
        • McGee E
        • Menzies V.
        Unique cytokine signature in the plasma of patients with fibromyalgia.
        J Immunol Res. 2014; 2014938576https://doi.org/10.1155/2014/938576
        • Sullivan M.
        Psychogenic pain: Old and new.
        in: Corns J Routledge Handbook on the Philosophy of Pain. Routledge, London2017
        • Sullivan M
        • Ballantyne JC.
        The right to pain relief: Its origins in end-of-life care and extension to chronic pain care.
        Clin J Pain. 2021; 38: 58-63
        • Sullivan MD
        • Vowles KE.
        Patient action: As means and end for chronic pain care.
        Pain. 2017; 158: 1405-1407https://doi.org/10.1097/j.pain.0000000000000921
        • Taylor AM
        • Becker S
        • Schweinhardt P
        • Cahill C.
        Mesolimbic dopamine signaling in acute and chronic pain: Implications for motivation, analgesia, and addiction.
        Pain. 2016; 157: 1194-1198https://doi.org/10.1097/j.pain.0000000000000494
        • Tracey I.
        Getting the pain you expect: Mechanisms of placebo, nocebo and reappraisal effects in humans.
        Nat Med. 2010; 16: 1277-1283https://doi.org/10.1038/nm.2229
        • Tracey I.
        A vulnerability to chronic pain and its interrelationship with resistance to analgesia.
        Brain. 2016; 139: 1869-1872https://doi.org/10.1093/brain/aww147
        • Tracey I
        • Bushnell MC.
        How neuroimaging studies have challenged us to rethink: Is chronic pain a disease?.
        J Pain. 2009; 10: 1113-1120https://doi.org/10.1016/j.jpain.2009.09.001
        • Treede RD
        • Rief W
        • Barke A
        • Aziz Q
        • Bennett MI
        • Benoliel R
        • Cohen M
        • Evers S
        • Finnerup NB
        • First MB
        • Giamberardino MA
        • Kaasa S
        • Korwisi B
        • Kosek E
        • Lavand'homme P
        • Nicholas M
        • Perrot S
        • Scholz J
        • Schug S
        • Smith BH
        • Svensson P
        • Vlaeyen JWS
        • Wang SJ.
        Chronic pain as a symptom or a disease: The IASP classification of chronic pain for the international classification of diseases (ICD-11).
        Pain. 2019; 160: 19-27https://doi.org/10.1097/j.pain.0000000000001384
        • Trouvin AP
        • Perrot S.
        New concepts of pain.
        Best Pract Res Clin Rheumatol. 2019; 33101415https://doi.org/10.1016/j.berh.2019.04.007
        • Tsuda M
        • Inoue K
        • Salter MW.
        Neuropathic pain and spinal microglia: A big problem from molecules in "small" glia.
        Trends Neurosci. 2005; 28: 101-107https://doi.org/10.1016/j.tins.2004.12.002
        • Turk DC.
        Clinical effectiveness and cost-effectiveness of treatments for patients with chronic pain.
        Clin J Pain. 2002; 18: 355-365
        • Uceyler N
        • Zeller D
        • Kahn AK
        • Kewenig S
        • Kittel-Schneider S
        • Schmid A
        • Casanova-Molla J
        • Reiners K
        • Sommer C.
        Small fibre pathology in patients with fibromyalgia syndrome.
        Brain. 2013; 136: 1857-1867https://doi.org/10.1093/brain/awt053
        • Valentino RJ
        • Van Bockstaele E
        Endogenous opioids: The downside of opposing stress.
        Neurobiol Stress. 2015; 1: 23-32https://doi.org/10.1016/j.ynstr.2014.09.006
        • Veerbeek JM vWE
        • van Peppen R
        • van der Wees PJ
        • Hendriks E
        • Rietberg M
        • Kwakkel G.
        What is the evidence for physical therapy poststroke? A systematic review and meta-analysis.
        PLoS One. 2014; 9: e87987https://doi.org/10.1371/journal.pone.0087987
        • Viceconti A
        • Geri T
        • De Luca S
        • Maselli F
        • Rossettini G
        • Sulli A
        • Schenone A
        • Testa M.
        Neuropathic pain and symptoms of potential small-fiber neuropathy in fibromyalgic patients: A national on-line survey.
        Joint Bone Spine. 2021; 88105153https://doi.org/10.1016/j.jbspin.2021.105153
        • Vijayakumar N
        • Cheng TW
        • Pfeifer JH.
        Neural correlates of social exclusion across ages: A coordinate-based meta-analysis of functional MRI studies.
        Neuroimage. 2017; 153: 359-368https://doi.org/10.1016/j.neuroimage.2017.02.050
        • Vlaeyen JWS
        • Crombez G.
        Behavioral conceptualization and treatment of chronic pain.
        Annu Rev Clin Psychol. 2020; 16: 187-212https://doi.org/10.1146/annurev-clinpsy-050718-095744
        • Wager TD
        • Atlas LY
        • Lindquist MA
        • Roy M
        • Woo CW
        • Kross E.
        An fMRI-based neurologic signature of physical pain.
        N Engl J Med. 2013; 368: 1388-1397https://doi.org/10.1056/NEJMoa1204471
        • Wager TD
        • Scott DJ
        • Zubieta JK.
        Placebo effects on human mu-opioid activity during pain.
        Proc Natl Acad Sci U S A. 2007; 104: 11056-11061https://doi.org/10.1073/pnas.0702413104
        • Watkins LR
        • Milligan ED
        • Maier SF.
        Glial activation: A driving force for pathological pain.
        Trends Neurosci. 2001; 24: 450-455https://doi.org/10.1016/s0166-2236(00)01854-3
        • Werner A
        • Malterud K.
        It is hard work behaving as a credible patient: Encounters between women with chronic pain and their doctors.
        Soc Sci Med. 2003; 57 (Available at:): 1409-1419
        • White JM.
        Pleasure into pain: The consequences of long-term opioid use.
        Addict Behav. 2004; 29: 1311-1324https://doi.org/10.1016/j.addbeh.2004.06.007
        • Wilder-Smith CH
        • Robert-Yap J.
        Abnormal endogenous pain modulation and somatic and visceral hypersensitivity in female patients with irritable bowel syndrome.
        World J Gastroenterol. 2007; 13: 3699-3704https://doi.org/10.3748/wjg.v13.i27.3699
        • Wolfe F
        • Clauw DJ
        • Fitzcharles MA
        • Goldenberg DL
        • Katz RS
        • Mease P
        • Russell AS
        • Russell IJ
        • Winfield JB
        • Yunus MB.
        The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity.
        Arthritis Care Res (Hoboken). 2010; 62: 600-610https://doi.org/10.1002/acr.20140
        • Wood PB.
        Role of central dopamine in pain and analgesia.
        Expert Rev Neurother. 2008; 8: 781-797https://doi.org/10.1586/14737175.8.5.781
        • Woolf CJ.
        Evidence for a central component of postinjury pain hypersensitivity.
        Nature. 1983; 308: 686-688
        • Woolf CJ.
        Central sensitization: Implications for the diagnosis and treatment of pain.
        Pain. 2011; 152: S2-15https://doi.org/10.1016/j.pain.2010.09.030
        • Woolf CJ.
        What to call the amplification of nociceptive signals in the central nervous system that contribute to widespread pain?.
        Pain. 2014; 155: 1911-1912https://doi.org/10.1016/j.pain.2014.07.021
        • Yarnitsky D.
        Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): Its relevance for acute and chronic pain states.
        Curr Opin Anaesthesiol. 2010; 23: 611-615https://doi.org/10.1097/ACO.0b013e32833c348b
        • Yunus MB.
        Editorial review: An update on central sensitivity syndromes and the issues of nosology and psychobiology.
        Curr Rheumatol Rev. 2015; 11: 70-85https://doi.org/10.2174/157339711102150702112236
        • Zubieta JK
        • Smith YR
        • Bueller JA
        • Xu Y
        • Kilbourn MR
        • Jewett DM
        • Meyer CR
        • Koeppe RA
        • Stohler CS.
        Regional mu opioid receptor regulation of sensory and affective dimensions of pain.
        Science. 2001; 293: 311-315https://doi.org/10.1126/science.1060952
        • Zubieta JK
        • Stohler CS.
        Neurobiological mechanisms of placebo responses.
        Ann N Y Acad Sci. 2009; 1156: 198-210https://doi.org/10.1111/j.1749-6632.2009.04424.x