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Placebo and Nocebo Effects: An Introduction to Psychological and Biological Mechanisms

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Book cover Placebo

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 225))

Abstract

Placebo and nocebo effects are essential components of medical practice and efficacy research, and can be regarded as a special case of context learning. A fundamental function of the central nervous system is to configure the way in which previous learned context becomes linked to corresponding responses. These responses could be either automatic procedures with little flexibility or highly adaptive procedures modified by associated contexts and consequences. Placebo and nocebo effects may represent a typical example of the combination of the two: conditioning effect, which is an inflexible, instinctual, and automatic response, and cognitive expectancy effect, which is a flexible adaptive response modified by prevailing conscious context. Given the fact that contextual learning originates in the brain, neuroimaging tools have been widely used to study placebo and nocebo effects. In addition, pretest resting state fMRI may be a valuable biomarker to predict placebo responses.

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References

  • Alkire MT, White NS, Hsieh R, Haier RJ (2004) Dissociable brain activation responses to 5-Hz electrical pain stimulation. Anesthesiology 100:939–946

    Article  PubMed  Google Scholar 

  • Amanzio M, Benedetti F (1999) Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems. J Neurosci 19(1):484–494

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Amanzio M, Benedetti F, Porro CA, Palermo S, Cauda F (2013) Activation likelihood estimation meta-analysis of brain correlates of placebo analgesia in human experimental pain. Hum Brain Mapp 34(3):738–752

    PubMed  Google Scholar 

  • Atlas LY, Wager TD (2012) How expectations shape pain. Neurosci Lett 520(2):140–148

    Article  PubMed  CAS  Google Scholar 

  • Atlas LY, Bolger N, Lindquist MA, Wager TD (2010) Brain mediators of predictive cue effects on perceived pain. J Neurosci 30(39):12964–12977

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Atlas LY, Whittington RA, Lindquist MA, Wielgosz J, Sonty N, Wager TD (2012) Dissociable influences of opiates and expectations on pain. J Neurosci 32(23):8053–8064

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Barsky AJ, Saintfort R, Rogers MP, Borus JF (2002) Nonspecific medication side effects and the nocebo phenomenon. JAMA 287(5):622–627

    Article  PubMed  Google Scholar 

  • Benedetti F (2008) Mechanisms of placebo and placebo-related effects across diseases and treatments. Annu Rev Pharmacol Toxicol 48:33–60

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Benedetti F, Pollo A, Lopiano L, Lanotte M, Vighetti S, Rainero I (2003) Conscious expectation and unconscious conditioning in analgesic, motor, and hormonal placebo/nocebo responses. J Neurosci 23:4315–4323

    PubMed  CAS  Google Scholar 

  • Benedetti F, Mayberg HS, Wager TD, Stohler CS, Zubieta JK (2005) Neurobiological mechanisms of the placebo effect. J Neurosci 25(45):10390–10402

    Article  PubMed  CAS  Google Scholar 

  • Benedetti F, Amanzio M, Rosato R, Blanchard C (2011) Non-opioid placebo analgesia is mediated by CB1 cannabinoid receptors. Nat Med 17:1228–1230

    Article  PubMed  CAS  Google Scholar 

  • Bingel U, Wanigasekera V, Wiech K, Mhuircheartaigh RN, Lee MC, Ploner M et al (2011) The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci Transl Med 3(70):70ra14

    Article  PubMed  Google Scholar 

  • Bornhovd K, Quante M, Glauche V, Bromm B, Weiller C, Buchel C (2002) Painful stimuli evoke different stimulus–response functions in the amygdala, prefrontal, insula and somatosensory cortex: a single-trial fMRI study. Brain 125:1326–1336

    Article  PubMed  CAS  Google Scholar 

  • Buchel C, Bornhovd K, Quante M, Glauche V, Bromm B, Weiller C (2002) Dissociable neural responses related to pain intensity, stimulus intensity, and stimulus awareness within the anterior cingulate cortex: a parametric single-trial laser functional magnetic resonance imaging study. J Neurosci 22(3):970–976

    PubMed  CAS  Google Scholar 

  • Cleophas TJ (1995) The importance of placebo effects. JAMA 273:283

    Article  PubMed  CAS  Google Scholar 

  • Coghill RC, Sang CN, Maisog JM, Iadorola MJ (1999) Pain intensity processing within the human brain: a bilateral, distributed mechanism. J Neurophysiol 82:1934–1943

    PubMed  CAS  Google Scholar 

  • Colloca L, Tinazzi M, Recchia S, Le Pera D, Fiaschi A, Benedetti F et al (2008) Learning potentiates neurophysiological and behavioral placebo analgesic responses. Pain 139(2):306–314

    Article  PubMed  Google Scholar 

  • Custers R, Aarts H (2010) The unconscious will: how the pursuit of goals operates outside of conscious awareness. Science 329(5987):47–50

    Article  PubMed  CAS  Google Scholar 

  • de la Fuente-Fernandez R, Schulzer M, Stoessl AJ (2002) The placebo effect in neurological disorders. Lancet Neurol 1:85–91

    Article  PubMed  Google Scholar 

  • de la Fuente-Fernandez R, Ruth TJ, Sossi V, Schulzer M, Calne DB, Stoessl AJ (2001) Expectation and dopamine release: mechanism of the placebo effect in Parkinson’s disease. Science 293:1164–1166

    Article  PubMed  Google Scholar 

  • Eippert F, Bingel U, Schoell ED, Yacubian J, Klinger R, Lorenz J et al (2009) Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron 63(4):533–543

    Article  PubMed  CAS  Google Scholar 

  • Enck P, Benedetti F, Schedlowski M (2008) New insights into the placebo and nocebo responses. Neuron 59(2):195–206

    Article  PubMed  CAS  Google Scholar 

  • Fields H (2004) State-dependent opioid control of pain. Nat Rev Neurosci 5(7):565–575

    Article  PubMed  CAS  Google Scholar 

  • Finniss DG, Kaptchuk TJ, Miller F, Benedetti F (2010) Biological, clinical, and ethical advances of placebo effects. Lancet 375(9715):686–695

    Article  PubMed  PubMed Central  Google Scholar 

  • Hashmi JA, Baria AT, Baliki MN, Huang L, Schnitzer TJ, Apkarian AV (2012) Brain networks predicting placebo analgesia in a clinical trial for chronic back pain. Pain 153(12):2393–2402. doi:10.1016/j.pain.2012.08.008

    Article  PubMed  PubMed Central  Google Scholar 

  • Hashmi JA, Kong J, Spaeth R, Khan S, Kaptchuk TJ, Gollub RG (2014) Functional network architecture predicts psychologically mediated analgesia related to treatment in chronic knee pain patients. J Neurosci 34(11):3924–3936

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Hoffman GA, Harrington A, Fields HL (2005) Pain and the placebo: what we have learned. Perspect Biol Med 48(2):248–265

    Article  PubMed  Google Scholar 

  • Honey GD, Corlett PR, Absalom AR, Lee M, Pomarol-Clotet E, Murray GK et al (2008) Individual differences in psychotic effects of ketamine are predicted by brain function measured under placebo. J Neurosci 28(25):6295–6303. doi:10.1523/JNEUROSCI.0910-08.2008

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Hrobjartsson A, Gotzsche PC (2001) Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med 344(21):1594–1602

    Article  PubMed  CAS  Google Scholar 

  • Jensen KB, Kaptchuk TJ, Kirsch I, Raicek J, Lindstrom KM, Berna C, Gollub RL, Ingvar M, Kong J (2012) Nonconscious activation of placebo and nocebo pain responses. Proc Natl Acad Sci USA 109(39):15959–15964

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kaptchuk TJ (2002) The placebo effect in alternative medicine: can the performance of a healing ritual have clinical significance? Ann Intern Med 136(11):817–825

    Article  PubMed  Google Scholar 

  • Kirsch I (1999) How expectancies shape experience. American Psychological Association, Washington, DC

    Book  Google Scholar 

  • Kirsch I (2000) Are drug and placebo effects in depression additive? Biol Psychiatry 47(8):733–735

    Article  PubMed  CAS  Google Scholar 

  • Kleijnen J, de Craen AJ, van Everdingen J, Krol L (1994) Placebo effect in double-blind clinical trials: a review of interactions with medications. Lancet 344(8933):1347–1349

    Article  PubMed  CAS  Google Scholar 

  • Kong J, Gollub RL, Rosman IS, Webb JM, Vangel MG, Kirsch I et al (2006a) Brain activity associated with expectancy-enhanced placebo analgesia as measured by functional magnetic resonance imaging. J Neurosci 26(2):381–388

    Article  PubMed  CAS  Google Scholar 

  • Kong J, White NS, Kwong KK, Vangel MG, Rosman IS, Gracely RH et al (2006b) Using fMRI to dissociate sensory encoding from cognitive evaluation of heat pain intensity. Hum Brain Mapp 27(8):715–721

    Article  PubMed  Google Scholar 

  • Kong J, Kaptchuk TJ, Polich G, Kirsch I, Gollub RL (2007) Placebo analgesia: findings from brain imaging studies and emerging hypotheses. Rev Neurosci 18(3–4):173–190

    PubMed  Google Scholar 

  • Kong J, Gollub RL, Polich G, Kirsch I, Laviolette P, Vangel M et al (2008) A functional magnetic resonance imaging study on the neural mechanisms of hyperalgesic nocebo effect. J Neurosci 28(49):13354–13362

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kong J, Kaptachuk TJ, Polich G, Kirsch IV, Angel M, Zyloney C et al (2009a) Expectancy and treatment interactions: a dissociation between acupuncture analgesia and expectancy evoked placebo analgesia. Neuroimage 45:940–949, PMID: 19159691

    Article  PubMed  PubMed Central  Google Scholar 

  • Kong J, Kaptchuk TJ, Polich G, Kirsch I, Vangel M, Zyloney C et al (2009b) An fMRI study on the interaction and dissociation between expectation of pain relief and acupuncture treatment. Neuroimage 47(3):1066–1076, PMID: 19501656

    Article  PubMed  PubMed Central  Google Scholar 

  • Kong J, Loggia ML, Zyloney C, Tu P, Laviolette P, Gollub RL (2010a) Exploring the brain in pain: activations, deactivations and their relation. Pain 148:257–267, PMID: 20005043

    Article  PubMed  PubMed Central  Google Scholar 

  • Kong J, Tu PC, Zyloney C, Su TP (2010b) Intrinsic functional connectivity of the periaqueductal gray, a resting fMRI study. Behav Brain Res 211(2):215–219

    Article  PubMed  PubMed Central  Google Scholar 

  • Kong J, Jensen K, Loiotile R, Cheetham A, Wey HY, Tan T et al (2013a) Functional connectivity of frontoparietal network predicts cognitive modulation of pain. Pain 154(3):459–467

    Article  PubMed  PubMed Central  Google Scholar 

  • Kong J, Spaeth R, Cook A, Kirsch I, Claggett B, Vangel M et al (2013b) Are all placebo effects equal? Placebo pills, sham acupuncture, cue conditioning and their association. PLoS ONE 8(7):e67485. doi:10.1371/journal.pone.0067485

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Leknes S, Lee M, Berna C, Andersson J, Tracey I (2011) Relief as a reward: hedonic and neural responses to safety from pain. PLoS ONE 6(4):e17870

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Lewis CM, Baldassarre A, Committeri G, Romani GL, Corbetta M (2009) Learning sculpts the spontaneous activity of the resting human brain. Proc Natl Acad Sci USA 106(41):17558–17563

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Mayberg HS, Silva JA, Brannan SK, Tekell JL, Mahurin RK, McGinnis S et al (2002) The functional neuroanatomy of the placebo effect. Am J Psychiatry 159(5):728–737

    Article  PubMed  Google Scholar 

  • Mesulam MM (1998) From sensation to cognition. Brain 121:1013–1052

    Article  PubMed  Google Scholar 

  • Miller FG, Kaptchuk TJ (2008) The power of context: reconceptualizing the placebo effect. J R Soc Med 101(5):222–225

    Article  PubMed  PubMed Central  Google Scholar 

  • Miller FG, Colloca L, Kaptchuk TJ (2009) The placebo effect: illness and interpersonal healing. Perspect Biol Med 52(4):518–539

    Article  PubMed  PubMed Central  Google Scholar 

  • Pessiglione M, Petrovic P, Daunizeau J, Palminteri S, Dolan RJ, Frith CD (2008) Subliminal instrumental conditioning demonstrated in the human brain. Neuron 59(4):561–567

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Petrovic P, Dietrich T, Fransson P, Andersson J, Carlsson K, Ingvar M (2005) Placebo in emotional processing–induced expectations of anxiety relief activate a generalized modulatory network. Neuron 46(6):957–969

    Article  PubMed  CAS  Google Scholar 

  • Price DD, Craggs J, Verne GN, Perlstein WM, Robinson ME (2007) Placebo analgesia is accompanied by large reductions in pain-related brain activity in irritable bowel syndrome patients. Pain 127(1–2):63–72

    Article  PubMed  Google Scholar 

  • Schenk LA, Sprenger C, Geuter S, Buchel C (2014) Expectation requires treatment to boost pain relief: an fMRI study. Pain 155(1):150–157. doi:10.1016/j.pain.2013.09.024

    Article  PubMed  Google Scholar 

  • Schweinhardt P, Seminowicz DA, Jaeger E, Duncan GH, Bushnell MC (2009) The anatomy of the mesolimbic reward system: a link between personality and the placebo analgesic response. J Neurosci 29(15):4882–4887. doi:10.1523/jneurosci.5634-08.2009

    Article  PubMed  CAS  Google Scholar 

  • Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK (2007) Individual differences in reward responding explain placebo-induced expectations and effects. Neuron 55(2):325–336

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Tedeschi JT, Schlenker BR, Bonoma TV (1971) Cognitive dissonance: private ratiocination or public spectacle? Am Psychol 26:685–695

    Article  Google Scholar 

  • Tracey I (2010) Getting the pain you expect: mechanisms of placebo, nocebo and reappraisal effects in humans. Nat Med 16(11):1277–1283

    Article  PubMed  CAS  Google Scholar 

  • Volkow ND, Wang GJ, Ma Y, Fowler JS, Zhu W, Maynard L et al (2003) Expectation enhances the regional brain metabolic and the reinforcing effects of stimulants in cocaine abusers. J Neurosci 23(36):11461–11468

    PubMed  CAS  Google Scholar 

  • Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ et al (2004) Placebo-induced changes in FMRI in the anticipation and experience of pain. Science 303:1162–1167

    Article  PubMed  CAS  Google Scholar 

  • Wager TD, Scott DJ, Zubieta JK (2007) Placebo effects on human mu-opioid activity during pain. Proc Natl Acad Sci USA 104(26):11056–11061

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Wager TD, Atlas LY, Leotti LA, Rilling JK (2011) Predicting individual differences in placebo analgesia: contributions of brain activity during anticipation and pain experience. J Neurosci 31(2):439–452

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Yu R, Gollub RL, Vangel M, Kaptchuk T, Smoller JW, Kong J (2014) Placebo analgesia and reward processing: integrating genetics, personality, and intrinsic brain activity. Hum Brain Mapp. doi:10.1002/hbm.22496

    Google Scholar 

  • Zubieta JK, Bueller JA, Jackson LR, Scott DJ, Xu Y, Koeppe RA et al (2005) Placebo effects mediated by endogenous opioid activity on mu-opioid receptors. J Neurosci 25(34):7754–7762

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Psychiatry Department, Massachusetts General Hospital, Harvard Medical School, Building 120, 2nd street, Suite 101C, Charlestown, MA, 02129, USA

    Jian Kong

  2. Department of Neuroscience, University of Turin Medical School, National Institute of Neuroscience, Turin, Italy

    Fabrizio Benedetti

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  1. Jian Kong
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  2. Fabrizio Benedetti
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Correspondence to Jian Kong .

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Editors and Affiliations

  1. Neuroscience Department and National Institute of Neuroscience Labs, University of Turin Medical School, Turin, Italy

    Fabrizio Benedetti

  2. Department of Psychosomatic Medicine, University Hospitals Tuebingen, Tuebingen, Germany

    Paul Enck

  3. Neuroscience Department and National Institute of Neuroscience Labs, University of Turin Medical School, Turin, Italy

    Elisa Frisaldi

  4. Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, Essen, Germany

    Manfred Schedlowski

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Kong, J., Benedetti, F. (2014). Placebo and Nocebo Effects: An Introduction to Psychological and Biological Mechanisms. In: Benedetti, F., Enck, P., Frisaldi, E., Schedlowski, M. (eds) Placebo. Handbook of Experimental Pharmacology, vol 225. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-44519-8_1

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