Skip to main content
SpringerLink
Log in

Experimental designs and brain mapping approaches for studying the placebo analgesic effect

  • Invited Review
  • Published:
European Journal of Applied Physiology Aims and scope Submit manuscript

Abstract

The placebo effect has intrigued scientists since it was proposed. The debate has now centered on how it works. Significant progress has been made and most of our knowledge about the neurobiological mechanisms comes from the field of pain and analgesia. The appropriateness of the experimental/clinical paradigms is crucial when we want to investigate the mechanisms of the placebo phenomenon. Recently, functional imaging techniques, such as positron emission tomography, magnetic resonance imaging, and electro/magnetoencephalography have also given the opportunity to define the neuroanatomical bases of placebo analgesia. This work systematically reviews the literature that deals with placebo analgesia, emphasizing both the methodological aspects and the neurobiological advances. The understanding of placebo mechanisms is fundamental and necessary to identify ways of accessing and harnessing these mechanisms in clinical practice to the patient’s benefit.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Allan LG, Siegel S (2002) A signal detection theory analysis of the placebo effect. Eval Health Prof 25:410–420

    Article  PubMed  Google Scholar 

  • Bausell RB, Lao L, Bergman S, Lee W-L, Berman BM (2005) Is acupuncture analgesia an expectancy effect? Preliminary evidence based upon participants’ perceived assignments in two placebo controlled trials. Eval Health Prof 28(1):9–26

    Article  PubMed  Google Scholar 

  • Beecher HK (1955) The powerful placebo. JAMA 159:1602–1606

    CAS  Google Scholar 

  • Benedetti F (2002) How the doctor’ s words affect the patient’ s brain. Eval Health Prof 25:369–386

    Article  PubMed  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, Colloca L, Torre E, Lanotte M, Melcarne A, Pesare M, Bergamasco B, Lopiano L (2004) Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus. Nat Neurosci 7:587–588

    Article  PubMed  CAS  Google Scholar 

  • Benedetti F, Colloca L (2004) Placebo-induced analgesia: methodology, neurobiology, clinical use, and ethics. Rev Analg 7:129–143

    Article  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 B, Arduino C, Costa S, Vighetti S, Tarenzi L, Rainero I, Asteggiano G, (2006) Loss of expectation-related mechanisms in Alzheimer’s disease makes analgesic therapies less effective. Pain 121(1–2):133–144

    Article  PubMed  CAS  Google Scholar 

  • Benedetti F (2007a) Placebo and endogenous mechanisms of analgesia. Handb Exp Pharmacol 26(46):12014–12022

    Google Scholar 

  • Benedetti F (2007b) What do you expect from this treatment? Changing our mind about clinical trials. Pain 128(3):193–194

    Article  PubMed  Google Scholar 

  • Bingel U, Lorenz J, Schoell E, Weiller C, Buchel C (2006) Mechanisms of placebo analgesia: rACC recruitment of subcortical antinociceptive network. Pain 120(1–2):8–15

    Article  PubMed  CAS  Google Scholar 

  • Colloca L, Benedetti F (2004) The placebo in clinical studies and in medical practice. In: Price DD, Bushnell C (eds) Mechanisms of psychological modulation of pain: integrating basic science and clinical perspectives. IASP 29, Seattle, pp. 187–205

    Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Colloca L, Lopiano L, Benedetti F, Lanotte M (2005) The placebo response in conditions other than pain. Semi Pain Med 3(1):43–47

    Article  Google Scholar 

  • Colloca L, Benedetti F (2005) Placebos and painkillers: is mind as really as matter? Nat Rev Neurosci 6(7):545–52

    Article  PubMed  CAS  Google Scholar 

  • Craig AD (2002) How do you feel? Inreroception: the sense of physiological condition of the body. Nat Rev Neurosci 3(8):655–666

    PubMed  CAS  Google Scholar 

  • Davis CE (2002) Regression to the mean or placebo effect? In: Guess HA, Kleinman A, Kusek JW, Engel LW (eds) The science of the placebo: toward an interdisciplinary research agenda. BMJ Books, London, pp. 158–166

    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  Google Scholar 

  • Epps J, Monk C, Savage S, Marlatt GA (1998) Improving credibility of instruction in the balanced placebo design: a misattribution manipulation. Addict Behav 23:426–35

    Article  Google Scholar 

  • Fields HL, Levine JD (1984) Placebo analgesia-a role for endorphins. Trends Neurosci 7:271–273

    Article  CAS  Google Scholar 

  • Fields HL, Basbaum AI (1994) Central nervous system mechanism of pain modulation. In: Wall PD, Melzack R (eds) Textbook of pain. Churchill Livingstone, New York, pp. 243–257

    Google Scholar 

  • Fields HL, Price DD (1997) Towards a neurobiology of placebo analgesia. In: Harrington A (eds) The placebo effect: an interdisciplinary exploration. Harvard University Press, Cambridge, pp. 93–116

    Google Scholar 

  • Fields HL (2004) State-dependent opioid control of pain. Nat Rev Neurosci 5(7):565–75

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Goebel MU, Trebst AE, Steiner J, Xie YF, Exton MS, Frede S, Canbay AE, Michel MC, Heemann U, Schedlowki M (2002) Behavioral conditioning of immunosuppression is possible in humans. FASEB J 16(14):1869–1873

    Article  PubMed  CAS  Google Scholar 

  • Heeg MJ, Deutsch KF, Deutsch E (1997) The placebo effect. Eur J Nucl Med 24(11):1433–1440

    Article  PubMed  CAS  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 

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

    Article  PubMed  Google Scholar 

  • Hróbjartsson A, Gøtzsche PC (2006) Unsubstantiated claims of large effects of placebo on pain. Serious errors in meta-analysis of placebo analgesia mechanism studies. J Clin Epidemiol 59(4):336–338

    Article  PubMed  Google Scholar 

  • Jones AK, Watabe H, Cunningham VJ, Jones T (2004) Cerebral decreases in opioid receptor binding in patients with central neuropathic pain measured by [11C] diprenorphine binding and PET. Eur J Pain 8:479–485

    Article  PubMed  CAS  Google Scholar 

  • Jones AK, Cunningham VJ, Ha-Kawa S, Fujiwara T, Luthra SK, Silva S, Derbyshire S, Jones T (1994) Changes in central opioid receptor binding in relation to inflammation and pain in patients with rheumatoid arthritis. Br J Rheumatol 33:909–16

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Kienle GS, Kiene H (1996) Placebo effect and placebo concept: a critical methodological and conceptual analysis of reports on the magnitude of the placebo effect. Altern Ther Health Med 2(6):39–54

    PubMed  CAS  Google Scholar 

  • Kienle GS, Kiene H (1997) The powerful placebo effect: fact or fiction? J Clin Epidemiol 50(12):1311–1318

    Article  PubMed  CAS  Google Scholar 

  • Kirsch I, Weixel LJ (1988) Double-blind versus deceptive administration of a placebo. Behav Neurosci 102(2):319–323

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Koyama T, McHaffie JG, Laurienti PJ, Coghill RC (2005) The subjective experience of pain: where expectations became reality. Proc Natl Acad Sci USA 102(36):12950–12955

    Article  PubMed  CAS  Google Scholar 

  • Leuchter AF, Cook IA, Witte EA, Morgan M, Abrams M (2002) Changes in brain function of depressed subjects during treatment with placebo. Am J Psychiatry 159:122–129

    Article  PubMed  Google Scholar 

  • Leuchter AF, Morgan M, Cook IA, Dunkin J, Abrams M, Witte EA (2004) Pretreatment neurophysiological and clinical characteristics of placebo responders in treatment trials for major depression. Psychopharmacoloy 177(1–2):15–22

    Article  CAS  Google Scholar 

  • Linde K, Witt CM, Streng A, Weidenhammer W, Wangpfeil S, Brinkhaus B, Willich SN, Melchart D (2007) The impact of patient expectations on outcomes in four randomized controlled trials of acupuncture in patients with chronic pain. Pain 128(3):264–271

    Article  PubMed  Google Scholar 

  • Lieberman MD, Jarcho JM, Berman S, Naliboff BD, Suyenobu BY, Mandelkern M, Mayer EA (2004) The neural correlates of placebo effects: a disruption account. Neuroimage 22:447–455

    Article  PubMed  Google Scholar 

  • Luparello TJ, Leist N, Lourie CH, Sweet P (1970) The interaction of psychologic stimuli and pharmacologic agents on airway reactivity in asthmatic subjects. Psychosom Med 32(5):509–513

    PubMed  CAS  Google Scholar 

  • McRae C, Cherin E, Yamazaki G, Diem G, Vo AH, Russell D, et al. (2004) Effects of perceived treatment on quality of life and medical outcomes in a double-blind placebo surgery trial. Arch Gen Psychiatry 61:412–420

    Article  PubMed  Google Scholar 

  • Marlatt GA, Demming B, Reid JB (1973) Loss of control drinking in alcoholics: an experimental analogue. J Abnorm Psychol 81:223–241

    Article  Google Scholar 

  • Matre D, Casey KL, Knardahl S (2006) Placebo-induced changes in spinal cord pain processing. J Neurosci 26(2):559–563

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Mitchell SH, Laurent CL, de Wit H (1996) Interaction of expectancy and the pharmacological effects of d-amphetamine: subjective effects and self-administration. Psychopharmacology 125:371–378

    Article  PubMed  CAS  Google Scholar 

  • Pacheco-Lopez G, Engler H, Niemi MB, Schedlowski M (2006) Expectations and associations that heal: immunomodulatory placebo effects and its neurobiology. Brain Behav Immun 20(5):430–446

    Article  PubMed  Google Scholar 

  • Petrovic P, Kalso E, Petersson KM, Ingvar M (2002) Placebo and opioid analgesia—imaging a shared neuronal network. Science 295(5560):1737–1740

    Article  PubMed  CAS  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 46:957–969

    Article  PubMed  CAS  Google Scholar 

  • Pollo A, Amanzio M, Arslanian A, Casadio C, Maggi G, Benedetti F (2001) Response expectancies in placebo analgesia and their clinical relevance. Pain 93(1):77–84

    Article  PubMed  CAS  Google Scholar 

  • Porro CA, Lui F (2007) Pain anticipation in the cingulate gyrus. In: Vogt BA (Ed.) Cingulate neurobiology and disease, vol. 1, Infrastructure, diagnosis, treatment. Oxford University Press, Oxford

  • Price DD (1999) Psychological mechanisms of pain and analgesia. IASP Press, Seattle

  • Price DD, Craggs J, Nicholas Verne G, 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 

  • Rainville P, Duncan GH (2006) Functional brain imaging of placebo analgesia: methodological challenges and recommendations. Pain 121(3):177–180

    Article  PubMed  Google Scholar 

  • Rohsenow DJ, Bachorowski J (1984) Effects of alcohol and expectancies on verbal aggression in men and women. J Abnorm Psychol 93:418–432

    Article  PubMed  CAS  Google Scholar 

  • Ross S, Krugman AD, Lyerly SB, Clyde DJ (1962) Drugs and placebos: a model design. Psychol Rep 10:383–392

    Article  Google Scholar 

  • Seminowicz DA (2006) Believe in your placebo. J Neurosci 26(17):4453–4454

    Article  PubMed  CAS  Google Scholar 

  • Shapiro AK, Morris LA (1977) Placebos in psychiatric therapy. Curr Psychiatr Ther 17:157–163

    PubMed  CAS  Google Scholar 

  • Sutton SR (1991) Great expectations: some suggestions for applying the balanced placebo design to nicotine and smoking. Br J Addict 86(5):659–662

    Article  PubMed  CAS  Google Scholar 

  • Tracey I (2005) The neural matrix of pain processing and placebo analgesia: evidence from functional imaging. Headache Currents 2(6):123–126

    Article  Google Scholar 

  • Vase L, Riley JL 3rd, Price DD (2002) A comparison of placebo effects in clinical analgesic trials versus studies of placebo analgesia. Pain 99(3):443–452

    Article  PubMed  Google Scholar 

  • Volkow ND, Wang GJ, Ma Y, Fowler JS, Zhu W, Maynard L, Telang F, Vaska P, Ding YS, Wong C, Swanson JM (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 

  • Volkow ND, Wang GJ, Ma Y, Fowler JS, Wong C, Jayne M, Telang F, Swanson JM (2006) Effects of expectation on the brain metabolic responses to methylphenidate and to its placebo in non-drug abusing subjects. Neuroimage 32:1782–1792

    Article  PubMed  Google Scholar 

  • Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ, Kosslyn SM, Rose RM, Cohen JD (2004) Placebo-induced changes in FMRI in the anticipation and experience of pain. Science 303(5661):1162–1167

    Article  PubMed  CAS  Google Scholar 

  • Wager TD, Matre D, Casey KL (2006) Placebo effects in laser-evoked pain potentials. Brain Behav Immun 20(3):219–230

    Article  PubMed  Google Scholar 

  • Wall PD (1992) The placebo effect: an unpopular topic. Pain 51(1):1–3

    Article  PubMed  CAS  Google Scholar 

  • Watson A, Deredy W, Vogt BA, Jones AK (2007) Placebo analgesia is not due to compliance or habituation: EEG and behavioural evidence. Neuroreport 28(8):771–775

    Article  Google Scholar 

  • Willoch F, Tolle TR, Wester HJ, Munz F, Petzold A, Schwaiger M, Conrad B, Bartenstein P (1999) Central pain after pontine infarction is associated with changes in opioid receptor binding: a PET study with 11 C-diprenorphine. AJNR Am J Neuroradiol 20(4):686–690

    PubMed  CAS  Google Scholar 

  • Willoch F, Schindler F, Wester HJ, Empl M, Straube A, Schwaiger M, Conrad B, Tolle TR (2004) Central poststroke pain and reduced opioid receptor binding within pain processing circuitries: a [11C]diprenorphine PET study. Pain 108(3):213–220

    Article  PubMed  CAS  Google Scholar 

  • Wilson GT, Niaura RS, Adler JL (1985) Alcohol: selective attention and sexual arousal in men. J Stud Alcohol 46:107–115

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Zubieta JK, Yau WY, Scott DJ, Stolher CS (2006) Belief or need? Accounting for individual variations in the neurochemistry of the placebo effect. Brain Behav Immun 20:15–26

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from Istituto San Paolo di Torino and Regione Piemonte.

Author information

Authors and Affiliations

  1. Department of Neuroscience, University of Turin Medical School and National Institute of Neuroscience, Corso Raffaello 30, 10125, Turin, Italy

    Luana Colloca & Fabrizio Benedetti

  2. Department of Biomedical Sciences, University of Modena and Reggio Emilia Medical School, Modena, Italy

    Carlo Adolfo Porro

Authors
  1. Luana Colloca
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fabrizio Benedetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carlo Adolfo Porro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luana Colloca.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Colloca, L., Benedetti, F. & Porro, C.A. Experimental designs and brain mapping approaches for studying the placebo analgesic effect. Eur J Appl Physiol 102, 371–380 (2008). https://doi.org/10.1007/s00421-007-0593-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00421-007-0593-6

Keywords

Search

Navigation