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Placebos and painkillers: is mind as real as matter?

Abstract

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.

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Figure 1: An emerging uncertainty principle imposes limitations on our understanding of the effects of a therapeutic agent.
Figure 2: Putative cascade of biochemical events in the brain after placebo administration.
Figure 3: Summary of brain imaging studies showing the different brain regions that are involved in placebo analgesia.
Figure 4: Examples of two clinical trials that used the open–hidden paradigm, revealing an ineffective and an effective treatment.

References

  1. Balint, M. The doctor, his patient, and the illness. Lancet 1, 683–688 (1955).

    Article  Google Scholar 

  2. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Thomas, K. B. General practice consultations: is there any point in being positive? BMJ 294, 1200–1202 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Brody, H. The symbolic power of the modern personal physician: the placebo response under challenge. J. Drug Issues 29, 149–161 (1988).

    Article  Google Scholar 

  5. 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).

    Article  CAS  PubMed  Google Scholar 

  6. Benedetti, F. How the doctor's words affect the patient's brain. Eval. Health Prof. 25, 369–386 (2002).

    Article  PubMed  Google Scholar 

  7. Moerman, D. E. (ed.) Meaning, Medicine, and the Placebo Effect (Cambridge Univ. Press, Cambridge, Massachusetts, USA, 2002).

    Book  Google Scholar 

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

    Article  Google Scholar 

  9. Gracely, R. H., Dubner, R., Deeter, W. R. & Wolskee, P. J. Clinician's expectations influence placebo analgesia. Lancet 1, 43 (1985).

    Article  CAS  PubMed  Google Scholar 

  10. Kirsch, I. & Weixel, L. J. Double-blind versus deceptive administration of a placebo. Behav. Neurosci. 102, 319–323 (1988).

    Article  CAS  PubMed  Google Scholar 

  11. Kirsch, I. (ed.) How Expectancies Shape Experience (American Psychological Association, Washington DC, USA, 1999).

    Book  Google Scholar 

  12. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Benedetti, F., Arduino, C. & Amanzio, M. Somatotopic activation of opioid systems by target-directed expectations of analgesia. J. Neurosci. 19, 3639–3648 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Price, D. D. (ed.) Psychological Mechanisms of Pain and Analgesia (IASP, Seattle, Washington, USA, 1999).

    Google Scholar 

  15. Pollo, A. et al. Response expectancies in placebo analgesia and their clinical relevance. Pain 93, 77–84 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Benedetti, F. et al. Conscious expectation and unconscious conditioning in analgesic, motor, and hormonal placebo/nocebo responses. J. Neurosci. 23, 4315–4323 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Stewart-Williams, S. & Podd, J. The placebo effect: dissolving the expectancy versus conditioning debate. Psychol. Bull. 130, 324–340 (2004).

    Article  PubMed  Google Scholar 

  18. Herrnstein, R. J. Placebo effect in the rat. Science 138, 677–678 (1962).

    Article  CAS  PubMed  Google Scholar 

  19. Ader, R. & Cohen, N. Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus. Science 215, 1534–1536 (1982).

    Article  CAS  PubMed  Google Scholar 

  20. Voudouris, N. J., Connie, L. P. & Coleman, G. Conditioned response models of placebo phenomena: further support. Pain 38, 109–116 (1989).

    Article  CAS  PubMed  Google Scholar 

  21. Ader, R. in The Placebo Effect: an Interdisciplinary Exploration (ed. Harrington, A.) 138–165 (Harvard Univ. Press, Cambridge, Massachusetts, USA, 1997).

    Google Scholar 

  22. 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).

    Google Scholar 

  23. Kaptchuk, T. J. Powerful placebo: the dark side of the randomized controlled trial. Lancet 351, 1722–1725 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Kaptchuk, T. J. The double-blind, randomized, placebo-controlled trial: gold standard or golden calf? J. Clin. Epidemiol. 54, 541–549 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Benedetti, F., Amanzio, M. & Maggi, G. Potentiation of placebo analgesia by proglumide. Lancet 346, 1231 (1995).

    Article  CAS  PubMed  Google Scholar 

  26. Wiertelak, E. P., Maier, S. F. & Watkins, L. R. Cholecystokinin antianalgesia: safety cues abolish morphine analgesia. Science 256, 830–833 (1992).

    Article  CAS  PubMed  Google Scholar 

  27. Wheeler, J. A. & Zurek, H. (eds) Quantum Theory and Measurement (Princeton Univ. Press, New Jersey, USA, 1983).

    Book  Google Scholar 

  28. Reiss, S. Pavlovian conditioning and human fear: an expectancy model. Behav. Ther. 11, 380–396 (1980).

    Article  Google Scholar 

  29. Rescorla, R. A. Pavlovian conditioning: it's not what you think it is. Am. Psychol. 43, 151–160 (1988).

    Article  CAS  PubMed  Google Scholar 

  30. Kirsch, I. Response expectancy as a determinant of experience and behavior. Am. Psychol. 40, 1189–1202 (1985).

    Article  Google Scholar 

  31. Levine, J. D., Gordon, N. C. & Fields, H. L. The mechanisms of placebo analgesia. Lancet 2, 654–657 (1978).

    Article  CAS  PubMed  Google Scholar 

  32. Grevert, P., Albert, L. H. & Goldstein, A. Partial antagonism of placebo analgesia by naloxone. Pain 16, 129–143 (1983).

    Article  CAS  PubMed  Google Scholar 

  33. Levine, J. D. & Gordon, N. C. Influence of the method of drug administration on analgesic response. Nature 312, 755–756 (1984).

    Article  CAS  PubMed  Google Scholar 

  34. Benedetti, F. The opposite effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia. Pain 64, 535–543 (1996).

    Article  CAS  PubMed  Google Scholar 

  35. 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).

    Article  CAS  PubMed  Google Scholar 

  36. Montgomery, G. H. & Kirsch, I. Mechanism of placebo pain reduction: an empirical investigation. Psychol. Sci. 7, 174–176 (1996).

    Article  Google Scholar 

  37. 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).

    Article  CAS  PubMed  Google Scholar 

  38. Benedetti, F. Cholecystokinin type A and type B receptors and their modulation of opioid analgesia. News Physiol. Sci. 12, 263–268 (1997).

    CAS  Google Scholar 

  39. 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).

    Article  CAS  PubMed  Google Scholar 

  40. Benedetti, F. et al. The specific effects of prior opioid exposure on placebo analgesia and placebo respiratory depression. Pain 75, 313–319 (1998).

    Article  CAS  PubMed  Google Scholar 

  41. 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).

    Article  CAS  PubMed  Google Scholar 

  42. Pollo, A., Rainero, I., Vighetti, S. & Benedetti, F. Placebo analgesia and the heart. Pain 102, 125–133 (2003).

    Article  PubMed  Google Scholar 

  43. Petrovic, P., Kalso, E., Petersson, K. M. & Ingvar, M. Placebo and opioid analgesia — imaging a shared neuronal network. Science 295, 1737–1740 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Petrovic, P. Opioid and placebo analgesia share the same network. Sem. Pain. Med. 3, 31–36 (2005).

    Article  Google Scholar 

  45. 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).

    Google Scholar 

  46. Fields, H. L. & Basbaum, A. I. in Textbook of Pain (eds Wall, P. D. & Melzack, R.) 309–329 (Churchill Livingstone, Edinburgh, UK, 1999).

    Google Scholar 

  47. 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).

    Book  Google Scholar 

  48. Zubieta, J. K. et al. Regional mu opioid receptor regulation of sensory and affective dimension of pain. Science 293, 311–315 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Zubieta, J. K. et al. COMT val158met genotype affects μ-opioid neurotransmitter responses to a pain stressor. Science 299, 1240–1243 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 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).

    Article  CAS  PubMed  Google Scholar 

  52. Wager, T. D. et al. Placebo-induced changes in fMRI in the anticipation and experience of pain. Science 303, 1162–1167 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Lieberman, M. D. et al. The neural correlates of placebo effects: a disruption account. Neuroimage 22, 447–455 (2004).

    Article  PubMed  Google Scholar 

  54. Wager, T. D. The neural basis of placebo effects in anticipation and pain. Sem. Pain Med. 3, 22–30 (2005).

    Article  Google Scholar 

  55. 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).

    Article  PubMed  Google Scholar 

  56. 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).

    Article  CAS  PubMed  Google Scholar 

  57. 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).

    Article  CAS  PubMed  Google Scholar 

  58. 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).

  59. Colloca, L., Lopiano, L., Benedetti, F. & Lanotte, M. The placebo response in conditions other than pain. Sem. Pain Med. 3, 43–47 (2005).

    Article  Google Scholar 

  60. Giang, D. W. et al. Conditioning of cyclophosphamide-induced leukopenia in humans. J. Neuropsychiatry Clin. Neurosci. 8, 194–201 (1996).

    Article  CAS  PubMed  Google Scholar 

  61. Goebel, M. U. et al. Behavioral conditioning of immunosuppression is possible in humans. FASEB J. 16, 1869–1873 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Ader, R. Conditioned immunomodulation: research needs and directions. Brain Behav. Immun. 17, S51–S57 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. 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).

    Article  CAS  PubMed  Google Scholar 

  64. Benedetti, F. et al. Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus. Nature Neurosci. 7, 587–588 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. de la Fuente-Fernandez, R. & Stoessl, A. J. The biochemical bases for reward. Eval. Health Prof. 25, 387–398 (2002).

    Article  PubMed  Google Scholar 

  66. 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).

    Article  PubMed  Google Scholar 

  67. Lidstone, S., de la Fuente-Fernandez, R. & Stoessl, A. J. The placebo response as a reward mechanism. Sem. Pain Med. 3, 37–42 (2005).

    Article  Google Scholar 

  68. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Finniss, D. G. & Benedetti, F. Mechanisms of the placebo response and their impact on clinical trials and clinical practice. Pain 114, 3–6 (2005).

    Article  PubMed  Google Scholar 

  70. Price, D. D. Assessing placebo effects without placebo groups: an untapped possibility? Pain 90, 201–203 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. 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).

  72. World Medical Association. Declaration of Helsinki. Amended by the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000. JAMA 284, 3043–3045 (2000).

  73. 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).

    Article  PubMed  Google Scholar 

  74. Stoessl, A. J. & de la Fuente-Fernandez, R. Willing oneself better on placebo—effective in its own right. Lancet 364, 227–228 (2004).

    Article  PubMed  Google Scholar 

  75. 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).

    Article  PubMed  Google Scholar 

  76. Benedetti, F. The importance of considering the effects of perceived group assignment in placebo-controlled trials. Eval. Health Prof. 28, 5–6 (2005).

    Article  PubMed  Google Scholar 

  77. Mayberg, H. S. et al. The functional neuroanatomy of the placebo effect. Am. J. Psychiatry 159, 728–737 (2002).

    Article  PubMed  Google Scholar 

  78. 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).

    Article  PubMed  Google Scholar 

  79. Leuchter, A. F. et al. Pretreatment neurophysiological and clinical characteristics of placebo responders in treatment trials for major depression. Psychopharmacology 177, 15–22 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Benedetti, F., Rainero, I. & Pollo, A. New insights into placebo analgesia. Curr. Opin. Anaesthesiol. 16, 515–519 (2003).

    Article  PubMed  Google Scholar 

  81. 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).

    Google Scholar 

  82. Fields, H. L. & Levine, J. D. Placebo analgesia — a role for endorphins? Trends Neurosci. 7, 271–273 (1984).

    Article  CAS  Google Scholar 

  83. Ernst, E. & Resch, K. L. Concept of true and perceived placebo effects. BMJ 311, 551–553 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 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).

    Google Scholar 

  85. Allan, L. G. & Siegel, S. A signal detection theory analysis of the placebo effect. Eval. Health Prof. 25, 410–420 (2002).

    Article  PubMed  Google Scholar 

  86. 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).

    Google Scholar 

  87. Hróbjartsoon, A. & Gotzsche, P. C. Is the placebo power-less? N. Engl. J. Med. 344, 1594–1602 (2001).

    Article  Google Scholar 

  88. 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).

    Article  PubMed  Google Scholar 

  89. Bok, S. The ethics of giving placebos. Sci. Am. 231, 17–23 (1974).

    Article  CAS  PubMed  Google Scholar 

  90. 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).

    Google Scholar 

  91. Hahn, R. A. in Placebo: Theory, Research, and Mechanisms (eds White, L., Tursky, B. & Schwartz, G. E.) 167–195 (Guilford, New York, USA, 1985).

    Google Scholar 

  92. Benedetti, F., Amanzio, M., Casadio, C., Oliaro, A. & Maggi, G. Blockade of nocebo hyperalgesia by the cholecystokinin antagonist proglumide. Pain 70, 135–140 (1997).

    Article  Google Scholar 

  93. 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).

    Article  CAS  PubMed  Google Scholar 

  94. Barsky, A. J., Saintfort, R., Rogers, M. P. & Borus, J. F. Nonspecific medication side effects and the nocebo phenomenon. JAMA 287, 622–627 (2002).

    Article  PubMed  Google Scholar 

  95. Halgren, E. Mental phenomena induced by stimulation in the limbic system. Hum. Neurobiol. 1, 251–260 (1982).

    CAS  PubMed  Google Scholar 

  96. 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).

    Article  PubMed  Google Scholar 

  97. Price, D. D. New facts and improved ethical guidelines for placebo analgesia. J. Pain 6, 213–214 (2005).

    Article  PubMed  Google Scholar 

  98. Sullivan, M. et al. APS position statement on the use of placebos in pain management. J. Pain 6, 215–217 (2005).

    Article  PubMed  Google Scholar 

  99. Martin, J. H. Neuroanatomy: Text and Atlas 2nd edn (Appleton & Lange, Stamford, Connecticut, 1996).

    Google Scholar 

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Acknowledgements

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).

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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

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