Abstract
The biopsychosocial model claims that illness is generated by biological, psychological, and social factors. The nocebo response, particularly nocebo hyperalgesia, is an excellent model and approach to understand these effects and their psychophysiological underpinnings, as nocebos are made of negative psychological and social factors, such as negative expectations and social interactions. There is today experimental evidence that nocebos can create symptoms and illness from nothing, in particular pain, whereby a combination of biological, psychological and social factors interact with each other in the generation of the global painful experience. Several biochemical pathways have been identified, e.g. cholecystokinin and cyclooxygenase, and the activation of these mechanisms has been specifically investigated in the field of pain, analgesia and hyperalgesia. The study of placebo and nocebo oxygen at high-altitude has been crucial to unravel these mechanisms, as reduction of oxygen pressure (hypoxia) leads to headache pain. Indeed, the investigation of oxygen-related conditions, such as hypoxia, represents today an excellent approach to understand how nocebos can contribute to generate illness and pain. In this review we discuss old and new findings that help us better understand the interplay between biology and psychology.
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Ader R, Cohen N (1975) Behaviorally conditioned immunosuppression. Psychosom Med 37(4):333–340
Amanzio M, Corazzini LL, Vase L, Benedetti F (2009) A systematic review of adverse events in placebo groups of anti-migraine clinical trials. Pain 146(3):261–269. https://doi.org/10.1016/j.pain.2009.07.010
Andre J, Zeau B, Pohl M, Cesselin F, Benoliel JJ, Becker C (2005) Involvement of cholecystokininergic systems in anxiety-induced hyperalgesia in male rats: behavioral and biochemical studies. J Neurosci 25(35):7896–7904. https://doi.org/10.1523/JNEUROSCI.0743-05.2005
Bąbel P (2019) Classical conditioning as a distinct mechanism of placebo effects. Front Psychiatry 10:449. https://doi.org/10.3389/fpsyt.2019.00449
Barbiani D, Camerone E, Benedetti F (2018) What is the relative contribution of biological and psychosocial factors to the generation of hypoxia headache? Can J Pain 2(1):160–168. https://doi.org/10.1080/24740527.2018.1478224
Barsky AJ, Saintfort R, Rogers MP, Borus JF (2002) Nonspecific medication side effects and the nocebo phenomenon. JAMA 287(5):622–627. https://doi.org/10.1001/jama.287.5.622
Benedetti F (1997) Cholecystokinin type A and type B receptors and their modulation of opioid analgesia. Physiology 12(6):263–268. https://doi.org/10.1152/physiologyonline.1997.12.6.263
Benedetti F (2008a) Mechanisms of placebo and placebo-related effects across diseases and treatments. Annu Rev Pharmacol Toxicol 48:33–60
Benedetti F (2008b) Placebo effects: understanding the mechanisms in health and disease. Oxford University Press, Oxford
Benedetti F (2013) Placebo and the new physiology of the doctor–patient relationship. Physiol Rev 93(3):1207–1246. https://doi.org/10.1152/physrev.00043.2012
Benedetti F (2014) Placebo effects: from the neurobiological paradigm to translational implications. Neuron 84(3):623–637. https://doi.org/10.1016/j.neuron.2014.10.023
Benedetti F, Amanzio M (1997) The neurobiology of placebo analgesia: from endogenous opioids to cholecystokinin. Prog Neurobiol 52(2):109–125. https://doi.org/10.1016/S0301-0082(97)00006-3
Benedetti F, Colloca L (2003) Placebo-induced analgesia: methodology, neurobiology, clinical use, and ethics. Rev Analg 7(2):129–143. https://doi.org/10.3727/000000003783992955
Benedetti F, Dogue S (2015) Different placebos, different mechanisms, different outcomes: lessons for clinical trials. PLoS One 10(11):e0140967
Benedetti F, Amanzio M, Casadio C, Oliaro A, Maggi G (1997) Blockade of nocebo hyperalgesia by the cholecystokinin antagonist proglumide. Pain 71(2):135–140
Benedetti F, Maggi G, Lopiano L, Lanotte M, Rainero I, Vighetti S, Pollo A (2003) Open versus hidden medical treatments: the patient’s knowledge about a therapy affects the therapy outcome. Prev Treat 6(1):1a. https://doi.org/10.1037/1522-3736.6.1.61a
Benedetti F, Amanzio M, Vighetti S, Asteggiano G (2006) The biochemical and neuroendocrine bases of the hyperalgesic nocebo effect. J Neurosci 26(46):12014–12022. https://doi.org/10.1523/JNEUROSCI.2947-06.2006
Benedetti F, Lanotte M, Lopiano L, Colloca L (2007) When words are painful: unraveling the mechanisms of the nocebo effect. Neuroscience 147(2):260–271. https://doi.org/10.1016/j.neuroscience.2007.02.020
Benedetti F, Durando J, Vighetti S (2014) Nocebo and placebo modulation of hypobaric hypoxia headache involves the cyclooxygenase-prostaglandins pathway. Pain 155(5):921–928. https://doi.org/10.1016/j.pain.2014.01.016
Benedetti F, Durando J, Giudetti L, Pampallona A, Vighetti S (2015) High-altitude headache: the effects of real vs sham oxygen administration. Pain 156(11):2326–2336. https://doi.org/10.1097/j.pain.0000000000000288
Benedetti F, Barbiani D, Camerone E (2018) Critical life functions: can placebo replace oxygen? Int Rev Neurobiol 138:201–218. https://doi.org/10.1016/bs.irn.2018.01.009(Academic Press)
Bräscher AK, Witthöft M, Becker S (2018) The underestimated significance of conditioning in placebo hypoalgesia and nocebo hyperalgesia. Pain Res Manag 2018:6841985. https://doi.org/10.1155/2018/6841985
Chua P, Krams M, Toni I, Passingham R, Dolan R (1999) A functional anatomy of anticipatory anxiety. Neuroimage 9(6):563–571. https://doi.org/10.1006/nimg.1999.0407
Colloca L, Benedetti F (2007) Nocebo hyperalgesia: how anxiety is turned into pain. Curr Opin Anesthesio 20(5):435–439. https://doi.org/10.1097/ACO.0b013e3282b972fb
Colloca L, Lopiano L, Lanotte M, Benedetti F (2004) Overt versus covert treatment for pain, anxiety, and Parkinson’s disease. Lancet Neurol 3(11):679–684. https://doi.org/10.1016/S1474-4422(04)00908-1
Colloca L, Sigaudo M, Benedetti F (2008) The role of learning in nocebo and placebo effects. Pain 136(1–2):211–218. https://doi.org/10.1016/j.pain.2008.02.006
Dannecker EA, Price DD, Robinson ME (2003) An examination of the relationships among recalled, expected, and actual intensity and unpleasantness of delayed onset muscle pain. J Pain 4(2):74–81. https://doi.org/10.1054/jpai.2003.7
Dworkin SF, Chen AC, LeResche L, Clark DW (1983) Cognitive reversal of expected nitrous oxide analgesia for acute pain. Anesth Analg 62(12):1073–1077
Elenkov IJ, Chrousos GP (1999) Stress hormones, Th1/Th2 patterns, pro/anti-inflammatory cytokines and susceptibility to disease. Trends Endocrin Met 10(9):359–368. https://doi.org/10.1016/S1043-2760(99)00188-5
Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES (2000) The sympathetic nerve—an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev 52(4):595–638
Elsenbruch S, Schmid J, Bäsler M, Cesko E, Schedlowski M, Benson S (2012) How positive and negative expectations shape the experience of visceral pain: an experimental pilot study in healthy women. Neurogastroenterol Motil 24(10):914-e460. https://doi.org/10.1111/j.1365-2982.2012.01950.x
Enck P, Benedetti F, Schedlowski M (2008) New insights into the placebo and nocebo responses. Neuron 59(2):195–206. https://doi.org/10.1016/j.neuron.2008.06.030
Engel GL (1977) The need for a new medical model: a challenge for biomedicine. Science 96(4286):129–136. https://doi.org/10.1126/science.847460
Finniss DG, Kaptchuk TJ, Miller F, Benedetti F (2010) Biological, clinical, and ethical advances of placebo effects. Lancet 375(9715):686–695. https://doi.org/10.1016/S0140-6736(09)61706-2
Flaten MA, Simonsen T, Olsen H (1999) Drug-related information generates placebo and nocebo responses that modify the drug response. Psychosom Med 61(2):250–255
Flor H, Grösser SM (1999) Conditioned stress-induced analgesia in humans. Eur J Pain 3(4):317–324. https://doi.org/10.1053/eujp.1999.0137
Geuter S, Büchel C (2013) Facilitation of pain in the human spinal cord by nocebo treatment. J Neurosci 33(34):13784–13790. https://doi.org/10.1523/JNEUROSCI.2191-13.2013
Häuser W, Bartram C, Bartram-Wunn E, Tölle T (2012) Adverse events attributable to nocebo in randomized controlled drug trials in fibromyalgia syndrome and painful diabetic peripheral neuropathy: systematic review. Clin J Pain 28(5):437–451. https://doi.org/10.1097/AJP.0b013e3182321ad8
Hebb AL, Poulin JF, Roach SP, Zacharko RM, Drolet G (2005) Cholecystokinin and endogenous opioid peptides: interactive influence on pain, cognition, and emotion. Prog Neuropsychopharmacol Biol Psychiatry 29(8):1225–1238. https://doi.org/10.1016/j.pnpbp.2005.08.008
Heinricher MM, Neubert MJ (2004) Neural basis for the hyperalgesic action of cholecystokinin in the rostral ventromedial medulla. J Neurophysiol 92(4):1982–1989. https://doi.org/10.1152/jn.00411.2004
Heinricher MM, McGaraughty S, Grandy DK (1997) Circuitry underlying antiopioid actions of orphanin FQ in the rostral ventromedial medulla. J Neurophysiol 78(6):3351–3358. https://doi.org/10.1152/jn.2001.85.1.280
Holloway RG, Gramling R, Kelly AG (2013) Estimating and communicating prognosis in advanced neurologic disease. Neurology 80(8):764–772. https://doi.org/10.1212/WNL.0b013e318282509c
Hsieh JC, Stone-Elander S, Ingvar M (1999) Anticipatory coping of pain expressed in the human anterior cingulate cortex: a positron emission tomography study. Neurosci Lett 262(1):61–64. https://doi.org/10.1016/s0304-3940(99)00060-9
Katafuchi T, Ichijo T, Take S, Hori T (1993) Hypothalamic modulation of splenic natural killer cell activity in rats. J Physiol 471(1):209–221. https://doi.org/10.1113/jphysiol.1993.sp019898
Katafuchi R, Oh Y, Hori K, Komota T, Yanase T, Ikeda K, Omura T, Fujimi S (1994) An important role of glomerular segmental lesions on progression of IgA nephropathy: a multivariate analysis. Clin Nephrol 41(4):191–198
Keltner JR, Furst A, Fan C, Redfern R, Inglis B, Fields HL (2006) Isolating the modulatory effect of expectation on pain transmission: a functional magnetic resonance imaging study. J Neurosci 26(16):4437–4443. https://doi.org/10.1523/JNEUROSCI.4463-05.2006
Kong J, Gollub RL, Polich G, Kirsch I, LaViolette P, Vangel M, Rosen B, Kaptchuk TJ (2008) A functional magnetic resonance imaging study on the neural mechanisms of hyperalgesic nocebo effect. J Neurosci 28(49):13354–13362. https://doi.org/10.1523/JNEUROSCI.2944-08.2008
Koyama T, Tanaka YZ, Mikami A (1998) Nociceptive neurons in the macaque anterior cingulate activate during anticipation of pain. Neuro Report 9(11):2663–2667. https://doi.org/10.1097/00001756-199808030-00044
Koyama T, McHaffie JG, Laurienti PJ, Coghill RC (2005) The subjective experience of pain: where expectations become reality. Proc Natl Acad Sci USA 102(36):12950–12955. https://doi.org/10.1073/pnas.0408576102
Leeuw M, Goossens ME, Linton SJ, Crombez G, Boersma K, Vlaeyen JW (2007) The fear-avoidance model of musculoskeletal pain: current state of scientific evidence. J Behav Med 30(1):77–94. https://doi.org/10.1007/s10865-006-9085-0
Lorenz J, Hauck M, Paur RC, Nakamura Y, Zimmermann R, Bromm B, Engel AK (2005) Cortical correlates of false expectations during pain intensity judgments—a possible manifestation of placebo/nocebo cognitions. Brain Behav Immun 19(4):283–295. https://doi.org/10.1016/j.bbi.2005.03.010
Manchikanti L, Pampati V, Damron K (2005) The role of placebo and nocebo effects of perioperative administration of sedatives and opioids in interventional pain management. Pain Phys 8(4):349
Mitchell JM, Lowe D, Fields HL (1998) The contribution of the rostral ventromedial medulla to the antinociceptive effects of systemic morphine in restrained and unrestrained rats. Neuroscience 87(1):123–133. https://doi.org/10.1016/s0306-4522(98)00119-5
Mitsikostas DD, Mantonakis LI, Chalarakis NG (2011) Nocebo is the enemy, not placebo. A meta-analysis of reported side effects after placebo treatment in headaches. Cephalalgia 31(5):550–561. https://doi.org/10.1177/0333102410391485
Mitsikostas DD, Chalarakis NG, Mantonakis LI, Delicha EM, Sfikakis PP (2012) Nocebo in fibromyalgia: meta-analysis of placebo-controlled clinical trials and implications for practice. Eur J Neurol 19(5):672–680. https://doi.org/10.1111/j.1468-1331.2011.03528.x
Oftedal G, Straume A, Johnsson A, Stovner LJ (2007) Mobile phone headache: a double blind, sham-controlled provocation study. Cephalalgia 27(5):447–455. https://doi.org/10.1111/j.1468-2982.2007.01336.x
Okamoto S, Ibaraki K, Hayashi S, Saito M (1996) Ventromedial hypothalamus suppresses splenic lymphocyte activity through sympathetic innervation. Brain Res 739(1–2):308–313. https://doi.org/10.1016/S0006-8993(96)00840-2
Papadopoulos D, Mitsikostas DD (2012) A meta-analytic approach to estimating nocebo effects in neuropathic pain trials. J Neurol 259(3):436–447. https://doi.org/10.1007/s00415-011-6197-4
Pavlov VA, Tracey KJ (2005) The cholinergic anti-inflammatory pathway. Brain Behav Immun 19(6):493–499. https://doi.org/10.1016/j.bbi.2005.03.015
Ploghaus A, Tracey I, Gati JS, Clare S, Menon RS, Matthews PM, Rawlins JNP (1999) Dissociating pain from its anticipation in the human brain. Science 284(5422):1979–1981. https://doi.org/10.1126/science.284.5422.1979
Porro CA, Baraldi P, Pagnoni G, Serafini M, Facchin P, Maieron M, Nichelli P (2002) Does anticipation of pain affect cortical nociceptive systems? J Neurosci 22(8):3206–3214. https://doi.org/10.1523/JNEUROSCI.22-08-03206.2002
Porro CA, Cettolo V, Francescato MP, Baraldi P (2003) Functional activity mapping of the mesial hemispheric wall during anticipation of pain. Neuroimage 19(4):1738–1747. https://doi.org/10.1016/S1053-8119(03)00184-8
Price DD, Mayer DJ, Mao J, Caruso FS (2000) NMDA-receptor antagonists and opioid receptor interactions as related to analgesia and tolerance. J Pain Symp Manag 19(1):7–11. https://doi.org/10.1016/S0885-3924(99)00121-9
Price DD, Finniss DG, Benedetti F (2008) A comprehensive review of the placebo effect: recent advances and current thought. Annu Rev Psychol 59:565–590. https://doi.org/10.1146/annurev.psych.59.113006.095941
Sanderson C, Hardy J, Spruyt O, Currow DC (2013) Placebo and nocebo effects in randomized controlled trials: the implications for research and practice. J Pain Symptom Manag 46(5):722–730. https://doi.org/10.1016/j.jpainsymman.2012.12.005
Sawamoto N, Honda M, Okada T, Hanakawa T, Kanda M, Fukuyama H, Konishi J, Shibasaki H (2000) Expectation of pain enhances responses to nonpainful somatosensory stimulation in the anterior cingulate cortex and parietal operculum/posterior insula: an event-related functional magnetic resonance imaging study. J Neurosci 20(19):7438–7445
Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK (2008) Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch Gen Psychiatry 65(2):220–231. https://doi.org/10.1001/archgenpsychiatry.2007.34
Shaibani A, Frisaldi E, Benedetti F (2017) Placebo response in pain, fatigue, and performance: possible implications for neuromuscular disorders. Muscle Nerve 56(3):358–367. https://doi.org/10.1002/mus.25635
Solomon GF, Moos RH (1964) Emotions, immunity, and disease: A speculative theoretical integration. Arch Gen Psychiatry 11(6):657–674. https://doi.org/10.1001/archpsyc.1964.01720300087011
Sternberg EM (1997a) Emotions and disease: from balance of humors to balance of molecules. Nature Med 3:264–267
Sternberg EM (1997b) Neural-immune interactions in health and disease. J Clin Inv 100:2641–2647
Svedman P, Ingvar M, Gordh T (2005) “Anxiebo”, placebo, and postoperative pain. BMC Anesthesiol 5(1):9. https://doi.org/10.1186/1471-2253-5-9
Świder K, Bąbel P (2013) The effect of the sex of a model on nocebo hyperalgesia induced by social observational learning. Pain 154(8):1312–1317. https://doi.org/10.1016/j.pain.2013.04.001
Terman GW, Morgan MJ, Liebeskind JC (1986) Opioid and non-opioid stress analgesia from cold-water swim: importance of stress severity. Brain Res 372(1):167–171. https://doi.org/10.1016/0006-8993(86)91472-1
Tracey KJ (2002) The inflammatory reflex. Nature 420(6917):853. https://doi.org/10.1038/nature01321
Van Den Broeke EN, Geene N, Van Rijn CM, Wilder-Smith OHG, Oosterman J (2014) Negative expectations facilitate mechanical hyperalgesia after high-frequency electrical stimulation of human skin. Eur J Pain 18(1):86–91. https://doi.org/10.1002/j.1532-2149.2013.00342.x
Varelmann D, Pancaro C, Cappiello EC, Camann WR (2010) Nocebo-induced hyperalgesia during local anesthetic injection. Anesth Analg 110(3):868–870. https://doi.org/10.1213/ANE.0b013e3181cc5727
Vlaeyen JW, Linton SJ (2000) Fear-avoidance and its consequences in chronic musculoskeletal pain: a state of the art. Pain 85(3):317–332
Vögtle E, Barke A, Kröner-Herwig B (2013) Nocebo hyperalgesia induced by social observational learning. Pain 154(8):1427–1433. https://doi.org/10.1016/j.pain.2013.04.041
Wells RE, Kaptchuk TJ (2012) To tell the truth, the whole truth, may do patients harm: the problem of the nocebo effect for informed consent. Am J Bioeth 12(3):22–29. https://doi.org/10.1080/15265161.2011.652798
Willer JC, Albe-Fessard D (1980) Electrophysiological evidence for a release of endogenous opiates in stress-induced’analgesia’ in man. Brain Res 198(2):419–426. https://doi.org/10.1016/0006-8993(80)90755-6
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This work was supported by the Innovative Clinical Training, Trials & Healthcare Worldwide Initiative to Fabrizio Benedetti, and by the Nerve & Muscle Center of Texas at Houston to Aziz Shaibani.
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Benedetti, F., Frisaldi, E., Barbiani, D. et al. Nocebo and the contribution of psychosocial factors to the generation of pain. J Neural Transm 127, 687–696 (2020). https://doi.org/10.1007/s00702-019-02104-x
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DOI: https://doi.org/10.1007/s00702-019-02104-x