Considerable progress has been made in our understanding of the neurobiological mechanisms of the placebo effect, and most of our knowledge originates from the field of pain and analgesia. Today, the placebo effect represents a promising model that could allow us to shed new light on mind–body interactions. The mental events induced by placebo administration can activate mechanisms that are similar to those activated by drugs, which indicates a similarity between psychosocial and pharmacodynamic effects. These new neurobiological advances are already changing our conception of how clinical trials and medical practice must be viewed and conducted.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Musculoskeletal practitioners’ perceptions of contextual factors that may influence chronic low back pain outcomes: a modified Delphi study
Chiropractic & Manual Therapies Open Access 05 April 2023
Scientific Reports Open Access 09 February 2023
Der Schmerz Open Access 13 January 2023
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Balint, M. The doctor, his patient, and the illness. Lancet 1, 683–688 (1955).
Stewart, M. A., McWhinney, I. R. & Buck, C. W. The doctor-patient relationship and its effect upon outcome. J. R. Coll. Gen. Pract. 29, 77–82 (1979).
Thomas, K. B. General practice consultations: is there any point in being positive? BMJ 294, 1200–1202 (1987).
Brody, H. The symbolic power of the modern personal physician: the placebo response under challenge. J. Drug Issues 29, 149–161 (1988).
Di Blasi, Z., Harkness, E., Ernst, E., Georgiou, A. & Kleijnen, J. Influence of context effects on health outcomes: a systematic review. Lancet 357, 757–762 (2001).
Benedetti, F. How the doctor's words affect the patient's brain. Eval. Health Prof. 25, 369–386 (2002).
Moerman, D. E. (ed.) Meaning, Medicine, and the Placebo Effect (Cambridge Univ. Press, Cambridge, Massachusetts, USA, 2002).
Benedetti, F. & Colloca, L. Placebo-induced analgesia: methodology, neurobiology, clinical use, and ethics. Rev. Analgesia 7, 129–143 (2004).
Gracely, R. H., Dubner, R., Deeter, W. R. & Wolskee, P. J. Clinician's expectations influence placebo analgesia. Lancet 1, 43 (1985).
Kirsch, I. & Weixel, L. J. Double-blind versus deceptive administration of a placebo. Behav. Neurosci. 102, 319–323 (1988).
Kirsch, I. (ed.) How Expectancies Shape Experience (American Psychological Association, Washington DC, USA, 1999).
Amanzio, M. & Benedetti, F. Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific sub-systems. J. Neurosci. 19, 484–494 (1999).
Benedetti, F., Arduino, C. & Amanzio, M. Somatotopic activation of opioid systems by target-directed expectations of analgesia. J. Neurosci. 19, 3639–3648 (1999).
Price, D. D. (ed.) Psychological Mechanisms of Pain and Analgesia (IASP, Seattle, Washington, USA, 1999).
Pollo, A. et al. Response expectancies in placebo analgesia and their clinical relevance. Pain 93, 77–84 (2001).
Benedetti, F. et al. Conscious expectation and unconscious conditioning in analgesic, motor, and hormonal placebo/nocebo responses. J. Neurosci. 23, 4315–4323 (2003).
Stewart-Williams, S. & Podd, J. The placebo effect: dissolving the expectancy versus conditioning debate. Psychol. Bull. 130, 324–340 (2004).
Herrnstein, R. J. Placebo effect in the rat. Science 138, 677–678 (1962).
Ader, R. & Cohen, N. Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus. Science 215, 1534–1536 (1982).
Voudouris, N. J., Connie, L. P. & Coleman, G. Conditioned response models of placebo phenomena: further support. Pain 38, 109–116 (1989).
Ader, R. in The Placebo Effect: an Interdisciplinary Exploration (ed. Harrington, A.) 138–165 (Harvard Univ. Press, Cambridge, Massachusetts, USA, 1997).
Siegel, S. in The Science of the Placebo: Toward an Interdisciplinary Research Agenda (eds Guess, H. A., Kleinman, A., Kusek, J. W. & Engel, L. W.) 133–157 (BMJ Books, London, UK, 2002).
Kaptchuk, T. J. Powerful placebo: the dark side of the randomized controlled trial. Lancet 351, 1722–1725 (1998).
Kaptchuk, T. J. The double-blind, randomized, placebo-controlled trial: gold standard or golden calf? J. Clin. Epidemiol. 54, 541–549 (2001).
Benedetti, F., Amanzio, M. & Maggi, G. Potentiation of placebo analgesia by proglumide. Lancet 346, 1231 (1995).
Wiertelak, E. P., Maier, S. F. & Watkins, L. R. Cholecystokinin antianalgesia: safety cues abolish morphine analgesia. Science 256, 830–833 (1992).
Wheeler, J. A. & Zurek, H. (eds) Quantum Theory and Measurement (Princeton Univ. Press, New Jersey, USA, 1983).
Reiss, S. Pavlovian conditioning and human fear: an expectancy model. Behav. Ther. 11, 380–396 (1980).
Rescorla, R. A. Pavlovian conditioning: it's not what you think it is. Am. Psychol. 43, 151–160 (1988).
Kirsch, I. Response expectancy as a determinant of experience and behavior. Am. Psychol. 40, 1189–1202 (1985).
Levine, J. D., Gordon, N. C. & Fields, H. L. The mechanisms of placebo analgesia. Lancet 2, 654–657 (1978).
Grevert, P., Albert, L. H. & Goldstein, A. Partial antagonism of placebo analgesia by naloxone. Pain 16, 129–143 (1983).
Levine, J. D. & Gordon, N. C. Influence of the method of drug administration on analgesic response. Nature 312, 755–756 (1984).
Benedetti, F. The opposite effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia. Pain 64, 535–543 (1996).
Gracely, R. H., Dubner, R., Wolskee, P. J. & Deeter, W. R. Placebo and naloxone can alter postsurgical pain by separate mechanisms. Nature 306, 264–265 (1983).
Montgomery, G. H. & Kirsch, I. Mechanism of placebo pain reduction: an empirical investigation. Psychol. Sci. 7, 174–176 (1996).
Price, D. D. et al. An analysis of factors that contribute to the magnitude of the placebo analgesia in a experimental paradigm. Pain 83, 147–156 (1999).
Benedetti, F. Cholecystokinin type A and type B receptors and their modulation of opioid analgesia. News Physiol. Sci. 12, 263–268 (1997).
Lipman, J. J. et al. Peak B endorphin concentration in cerebrospinal fluid: reduced in chronic pain patients and increased during the placebo response. Psychopharmacology 102, 112–116 (1990).
Benedetti, F. et al. The specific effects of prior opioid exposure on placebo analgesia and placebo respiratory depression. Pain 75, 313–319 (1998).
Benedetti, F., Amanzio, M., Baldi, S., Casadio, C. & Maggi, G. Inducing placebo respiratory depressant responses in humans via opioid receptors. Eur. J. Neurosci. 11, 625–631 (1999).
Pollo, A., Rainero, I., Vighetti, S. & Benedetti, F. Placebo analgesia and the heart. Pain 102, 125–133 (2003).
Petrovic, P., Kalso, E., Petersson, K. M. & Ingvar, M. Placebo and opioid analgesia — imaging a shared neuronal network. Science 295, 1737–1740 (2002).
Petrovic, P. Opioid and placebo analgesia share the same network. Sem. Pain. Med. 3, 31–36 (2005).
Fields, H. L. & Price, D. D. in The placebo Effect: an Interdisciplinary Exploration (ed. Harrington, A.) 93–116 (Harvard Univ. Press, Cambridge, Massachusetts, USA, 1997).
Fields, H. L. & Basbaum, A. I. in Textbook of Pain (eds Wall, P. D. & Melzack, R.) 309–329 (Churchill Livingstone, Edinburgh, UK, 1999).
Vogt, B. A., Sikes, R. W. & Vogt, L. J. in Neurobiology of Cingulate Cortex and Limbic Thalamus (eds Vogt, B. A. & Gabriel, M.) 313–344 (Birkhäuser, Boston, Massachusetts, USA, 1993).
Zubieta, J. K. et al. Regional mu opioid receptor regulation of sensory and affective dimension of pain. Science 293, 311–315 (2001).
Zubieta, J. K. et al. COMT val158met genotype affects μ-opioid neurotransmitter responses to a pain stressor. Science 299, 1240–1243 (2003).
Willoch, F. et al. Central pain after pontine infarction is associated with changes in opioid receptor binding: a PET study with 11C-diprenorphine. Am. J. Neuroradiol. 20, 686–690 (1999).
Willoch, F. et al. Central poststroke pain and reduced opioid receptor binding within pain processing circuitries: a [11C]dinorphine PET study. Pain 108, 213–220 (2004).
Wager, T. D. et al. Placebo-induced changes in fMRI in the anticipation and experience of pain. Science 303, 1162–1167 (2004).
Lieberman, M. D. et al. The neural correlates of placebo effects: a disruption account. Neuroimage 22, 447–455 (2004).
Wager, T. D. The neural basis of placebo effects in anticipation and pain. Sem. Pain Med. 3, 22–30 (2005).
Colloca, L., Lopiano, L., Lanotte, M. & Benedetti, F. Overt versus covert treatment for pain, anxiety and Parkinson's disease. Lancet Neurol. 3, 679–684 (2004).
Levine, J. D., Gordon, N. C., Smith, R. & Fields, H. L. Analgesic responses to morphine and placebo in individuals with postoperative pain. Pain 10, 379–389 (1981).
Amanzio, M., Pollo, A., Maggi, G. & Benedetti, F. Response variability to analgesics: a role for non-specific activation of endogenous opioids. Pain 90, 205–215 (2001).
Benedetti, F. et al. Open versus hidden medical treatments: the patient's knowledge about a therapy affects the therapy outcome. Prev. Treatment 6, [online] <http://journals.apa.org/prevention/volume6/toc-jun-03.html> (2003).
Colloca, L., Lopiano, L., Benedetti, F. & Lanotte, M. The placebo response in conditions other than pain. Sem. Pain Med. 3, 43–47 (2005).
Giang, D. W. et al. Conditioning of cyclophosphamide-induced leukopenia in humans. J. Neuropsychiatry Clin. Neurosci. 8, 194–201 (1996).
Goebel, M. U. et al. Behavioral conditioning of immunosuppression is possible in humans. FASEB J. 16, 1869–1873 (2002).
Ader, R. Conditioned immunomodulation: research needs and directions. Brain Behav. Immun. 17, S51–S57 (2003).
de la Fuente-Fernandez, R. et al. Expectation and dopamine release: mechanism of the placebo effect in Parkinson's disease. Science 293, 1164–1166 (2001).
Benedetti, F. et al. Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus. Nature Neurosci. 7, 587–588 (2004).
de la Fuente-Fernandez, R. & Stoessl, A. J. The biochemical bases for reward. Eval. Health Prof. 25, 387–398 (2002).
de la Fuente-Fernandez, R., Schulzer, M. & Stoessl, A. J. Placebo mechanisms and reward circuitry: clues from Parkinson's disease. Biol. Psychiatry 56, 67–71 (2004).
Lidstone, S., de la Fuente-Fernandez, R. & Stoessl, A. J. The placebo response as a reward mechanism. Sem. Pain Med. 3, 37–42 (2005).
Volkow, N. D. et al. Expectation enhances the regional brain metabolic and the reinforcing effects of stimulants in cocaine abusers. J. Neurosci. 23, 11461–11468 (2003).
Finniss, D. G. & Benedetti, F. Mechanisms of the placebo response and their impact on clinical trials and clinical practice. Pain 114, 3–6 (2005).
Price, D. D. Assessing placebo effects without placebo groups: an untapped possibility? Pain 90, 201–203 (2001).
Kirsch, I. Hidden administration as ethical alternative to the balanced placebo design. Prev. Treatment 6, [online] <http://journals.apa.org/prevention/volume6/toc-jun-03.html> (2003).
World Medical Association. Declaration of Helsinki. Amended by the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000. JAMA 284, 3043–3045 (2000).
McRae, C. et al. Effects of perceived treatment on quality of life and medical outcomes in a double-blind placebo surgery trial. Arch. Gen. Psychiatry 61, 412–420 (2004).
Stoessl, A. J. & de la Fuente-Fernandez, R. Willing oneself better on placebo—effective in its own right. Lancet 364, 227–228 (2004).
Bausell, R. B., Lao, L., Bergman, S., Lee, W. -L. & Berman, B. M. Is acupuncture analgesia an expectancy effect? Preliminary evidence based upon participants' perceived assignments in two placebo controlled trials. Eval. Health Prof. 28, 9–26 (2005).
Benedetti, F. The importance of considering the effects of perceived group assignment in placebo-controlled trials. Eval. Health Prof. 28, 5–6 (2005).
Mayberg, H. S. et al. The functional neuroanatomy of the placebo effect. Am. J. Psychiatry 159, 728–737 (2002).
Leuchter, A. F., Cook, I. A., Witte, E. A., Morgan, M. & Abrams, M. Changes in brain function of depressed subjects during treatment with placebo. Am. J. Psychiatry 159, 122–129 (2002).
Leuchter, A. F. et al. Pretreatment neurophysiological and clinical characteristics of placebo responders in treatment trials for major depression. Psychopharmacology 177, 15–22 (2004).
Benedetti, F., Rainero, I. & Pollo, A. New insights into placebo analgesia. Curr. Opin. Anaesthesiol. 16, 515–519 (2003).
Pollo, A. & Benedetti, F. in Psychological Methods of Pain Control: Basic Science and Clinical Perspectives (eds Price, D. D. & Bushnell, M. C.) 171–186 (IASP, Seattle, Washington, USA, 2004).
Fields, H. L. & Levine, J. D. Placebo analgesia — a role for endorphins? Trends Neurosci. 7, 271–273 (1984).
Ernst, E. & Resch, K. L. Concept of true and perceived placebo effects. BMJ 311, 551–553 (1995).
Davis, C. E. in The Science of the Placebo: Toward an Interdisciplinary Research Agenda (eds Guess, H. A., Kleinman, A., Kusek, J. W. & Engel, L. W.) 158–166 (BMJ Books, London, UK, 2002).
Allan, L. G. & Siegel, S. A signal detection theory analysis of the placebo effect. Eval. Health Prof. 25, 410–420 (2002).
Colloca, L. & Benedetti, F. in Psychological Methods of Pain Control: Basic Science and Clinical Perspectives (eds Price, D. D. & Bushnell, M. C.) 187–205 (IASP, Seattle, Washington, USA, 2004).
Hróbjartsoon, A. & Gotzsche, P. C. Is the placebo power-less? N. Engl. J. Med. 344, 1594–1602 (2001).
Vase, L., Riley, J. L. & Price, D. D. A comparison of placebo effects in clinical analgesic trials versus studies of placebo analgesia. Pain 99, 443–452 (2002).
Bok, S. The ethics of giving placebos. Sci. Am. 231, 17–23 (1974).
Bok, S. in The Science of the Placebo: Toward an Interdisciplinary Research Agenda (eds Guess, H. A., Kleinman, A., Kusek, J. W. & Engel, L. W.) 63–73 (BMJ Books, London, UK, 2002).
Hahn, R. A. in Placebo: Theory, Research, and Mechanisms (eds White, L., Tursky, B. & Schwartz, G. E.) 167–195 (Guilford, New York, USA, 1985).
Benedetti, F., Amanzio, M., Casadio, C., Oliaro, A. & Maggi, G. Blockade of nocebo hyperalgesia by the cholecystokinin antagonist proglumide. Pain 70, 135–140 (1997).
Flaten, M. A., Simonsen, T. & Olsen, H. Drug-related information generates placebo and nocebo responses that modify the drug response. Psychosom. Med. 61, 250–255 (1999).
Barsky, A. J., Saintfort, R., Rogers, M. P. & Borus, J. F. Nonspecific medication side effects and the nocebo phenomenon. JAMA 287, 622–627 (2002).
Halgren, E. Mental phenomena induced by stimulation in the limbic system. Hum. Neurobiol. 1, 251–260 (1982).
Benedetti, F. et al. Autonomic and emotional responses to open and hidden stimulations of the human subthalamic region. Brain Res. Bull. 63, 203–211 (2004).
Price, D. D. New facts and improved ethical guidelines for placebo analgesia. J. Pain 6, 213–214 (2005).
Sullivan, M. et al. APS position statement on the use of placebos in pain management. J. Pain 6, 215–217 (2005).
Martin, J. H. Neuroanatomy: Text and Atlas 2nd edn (Appleton & Lange, Stamford, Connecticut, 1996).
This work was supported by grants from the 'Neuroscience' project of the National Research Council, from the 'Alzheimer's disease' project of the Italian Ministry of Health, and from the Italian Ministry of University and Research (FIRB).
The authors declare no competing financial interests.
About this article
Cite this article
Colloca, L., Benedetti, F. Placebos and painkillers: is mind as real as matter?. Nat Rev Neurosci 6, 545–552 (2005). https://doi.org/10.1038/nrn1705
This article is cited by
Musculoskeletal practitioners’ perceptions of contextual factors that may influence chronic low back pain outcomes: a modified Delphi study
Chiropractic & Manual Therapies (2023)
Nature Reviews Rheumatology (2023)
Scientific Reports (2023)
Der Schmerz (2023)
Cognitive Processing (2021)