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Pain and the context

Nature Reviews Rheumatology volume 10, pages 348–355 (2014)Cite this article

Subjects

Key Points

  • Pain is modulated by a variety of contextual factors

  • Positive contexts, such as those related to placebo administration, have been found to activate a number of endogenous antinociceptive systems

  • Negative contexts, such as those related to nocebo effects, activate endogenous systems that increase pain

  • Contexts with positive meanings might even turn pain into a rewarding experience

  • If therapy has no positive context, so that patients have no expectations of benefit, the effectiveness of treatment is reduced

  • Consultations, diagnostic procedures and treatments are carried out within a context; this context might be a crucial determinant of symptom perception and therapeutic outcome

Abstract

Pain is a sensory and emotional experience that is substantially modulated by psychological, social and contextual factors. Research now indicates that the influence of these factors is even more powerful than expected and involves the therapeutic response to analgesic drugs as well as the pain experience itself, which in some circumstances can even be a form of reward. Different experimental approaches and models, both in the laboratory and in the clinical setting, have been used to better characterize and understand the complex neurobiology of pain modulation. These approaches include placebo analgesia, nocebo hyperalgesia, hidden administration of analgesics, and the manipulation of the pain–reward relationship. Overall, these studies show that different neurochemical systems are activated in different positive and negative contexts. Moreover, pain can activate reward mechanisms when experienced within contexts that have special positive meaning. Because routine medical practice usually takes place in contexts that use different rituals, these neurobiological insights might have profound clinical implications.

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Figure 1: The positive context.
Figure 2: The negative context.
Figure 3: Pain is perceived in different contexts according to special meanings.
Figure 4: Placebo response during pain reduction with remifentanil.

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References

  1. Wiech, K., Ploner, M. & Tracey, I. Neurocognitive aspects of pain perception. Trends Cogn. Sci. 12, 306–313 (2008).

    Article  PubMed  Google Scholar 

  2. Bushnell, M. C., Ceko, M. & Low, L. A. Cognitive and emotional control of pain and its disruption in chronic pain. Nat. Rev. Neurosci. 14, 502–511 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Villemure, C. & Bushnell, M. C. Cognitive modulation of pain: how do attention and emotion influence pain processing? Pain 95, 195–199 (2002).

    PubMed  Google Scholar 

  4. Villemure, C. & Bushnell, M. C. Mood influences supraspinal pain processing separately from attention. J. Neurosci. 29, 705–715 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Wiech, K. & Tracey, I. The influence of negative emotions on pain: behavioral effects and neural mechanisms. Neuroimage 47, 987–994 (2009).

    Article  PubMed  Google Scholar 

  6. Balint, M. The doctor, his patient, and the illness. Lancet 268, 683–688 (1955).

    Article  CAS  PubMed  Google Scholar 

  7. 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 

  8. Benedetti, F. Placebo Effects: Understanding the Mechanisms in Health and Disease, 2nd edn (Oxford University Press, 2008).

    Book  Google Scholar 

  9. 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 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Price, D. D., Finniss, D. G. & Benedetti, F. A comprehensive review of the placebo effect: recent advances and current thought. Annu. Rev. Psychol. 59, 565–590 (2008).

    Article  PubMed  Google Scholar 

  13. Leknes, S. & Tracey, I. A common neurobiology for pain and pleasure. Nat. Rev. Neurosci. 9, 314–320 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. Benedetti, F., Carlino, E. & Pollo, A. Hidden administration of drugs. Clin. Pharmacol. Ther. 90, 651–661 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Benedetti, F., Carlino, E. & Pollo, A. How placebos change the patient's brain. Neuropsychopharmacology 36, 339–354 (2011).

    Article  PubMed  Google Scholar 

  17. Benedetti, F. Placebo and the new physiology of the doctor-patient relationship. Physiol. Rev. 93, 1207–1246 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Colloca, L. & Benedetti, F. Placebos and painkillers: is mind as real as matter? Nat. Rev. Neurosci. 6, 545–552 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  20. Benedetti, F., Amanzio, M., Rosato, R. & Blanchard, C. Nonopioid placebo analgesia is mediated by CB1 cannabinoid receptors. Nat. Med. 17, 1228–1230 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Escobar, W. et al. Metamizol, a non-opioid analgesic, acts via endocannabinoids in the PAG-RVM axis during inflammation in rats. Eur. J. Pain 16, 676–689 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Peciña, M. et al. FAAH selectively influences placebo effects. Mol. Psychiatry. http://dx.doi.org/10.1038/mp.2013.124.

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  25. Benedetti, F., Amanzio, M. & Thoen, W. Disruption of opioid-induced placebo responses by activation of cholecystokinin type-2 receptors. Psychopharmacology (Berl.) 213, 791–797 (2011).

    Article  CAS  Google Scholar 

  26. Guo, J. Y., Wang, J. Y. & Luo, F. Dissection of placebo analgesia in mice: the conditions for activation of opioid and non-opioid systems. J. Psychopharmacol. 24, 1561–1567 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Nolan, T. A., Price, D. D., Caudle, R. M., Murphy, N. P. & Neubert, J. K. Placebo-induced analgesia in an operant pain model in rats. Pain 153, 2009–2016 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Zhang, R. R., Zhang, W. C., Wang, J. Y. & Guo, J. Y. The opioid placebo analgesia is mediated exclusively through μ-opioid receptor in rat. Int. J. Neuropsychopharmacol. 16, 849–856 (2013).

    Article  CAS  PubMed  Google Scholar 

  29. 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 

  30. Zubieta, J. K. et al. Placebo effects mediated by endogenous opioid activity on mu-opioid receptors. J. Neurosci. 25, 7754–7762 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wager, T. D., Scott, D. J. & Zubieta, J. K. Placebo effects on human mu-opioid activity during pain. Proc. Natl Acad. Sci. USA 104, 11056–11061 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Eippert, F. et al. Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron 63, 533–543 (2009).

    Article  CAS  PubMed  Google Scholar 

  33. Eippert, F., Finsterbusch, J., Bingel, U. & Büchel, C. Direct evidence for spinal cord involvement in placebo analgesia. Science 326, 404 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  35. 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 

  36. Wager, T. D., Atlas, L. Y., Leotti, L. A. & Rilling, J. K. Predicting individual differences in placebo analgesia: contributions of brain activity during anticipation and pain experience. J. Neurosci. 31, 439–452 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bingel, U., Lorenz, J., Schoell, E., Weiller, C. & Büchel, C. Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network. Pain 120, 8–15 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Kong, J. et al. Brain activity associated with expectancy-enhanced placebo analgesia as measured by functional magnetic resonance imaging. J. Neurosci. 26, 381–388 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Price, D. D., Craggs, J., Verne, G. N., Perlstein, W. M. & Robinson, M. E. Placebo analgesia is accompanied by large reductions in pain-related brain activity in irritable bowel syndrome patients. Pain 127, 63–72 (2007).

    Article  PubMed  Google Scholar 

  40. Scott, D. J. et al. Individual differences in reward responding explain placebo-induced expectations and effects. Neuron 55, 325–336 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Scott, D. J. et al. Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch. Gen. Psychiatry 65, 220–231 (2008).

    Article  PubMed  Google Scholar 

  42. Zubieta, J. K. & Stohler, C. S. Neurobiological mechanisms of placebo responses. Ann. NY Acad. Sci. 1156, 198–210 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Lui, F. et al. Neural bases of conditioned placebo analgesia. Pain 151, 816–824 (2010).

    Article  PubMed  Google Scholar 

  44. Meissner, K. et al. The placebo effect: advances from different methodological approaches. J. Neurosci. 31, 16117–16124 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hashmi, J. A. et al. Brain networks predicting placebo analgesia in a clinical trial for chronic back pain. Pain 153, 2393–2402 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Wells, R. E. & Kaptchuk, T. J. To tell the truth, the whole truth, may do patients harm: the problem of the nocebo effect for informed consent. Am. J. Bioeth. 12, 22–29 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Holloway, R. G., Gramling, R. & Kelly, A. G. Estimating and communicating prognosis in advanced neurologic disease. Neurology 80, 764–772 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Oftedal, G., Straume, A., Johnsson, A. & Stovner, L. J. Mobile phone headache: a double blind, sham-controlled provocation study. Cephalalgia 27, 447–455 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Amanzio, M., Corazzini, L. L., Vase, L. & Benedetti, F. A systematic review of adverse events in placebo groups of anti-migraine clinical trials. Pain 146, 261–269 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Benedetti, F., Amanzio, M., Casadio, C., Oliaro, A. & Maggi, G. Blockade of nocebo hyperalgesia by the cholecystokinin antagonist proglumide. Pain 71, 135–140 (1997).

    Article  CAS  PubMed  Google Scholar 

  51. Benedetti, F., Amanzio, M., Vighetti, S. & Asteggiano, G. The biochemical and neuroendocrine bases of the hyperalgesic nocebo effect. J. Neurosci. 26, 12014–12022 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Andre, J. et al. Involvement of cholecystokininergic systems in anxiety-induced hyperalgesia in male rats: behavioral and biochemical studies. J. Neurosci. 25, 7896–7904 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sawamoto, N. et al. 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, 7438–7445 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Koyama, T., McHaffie, J. G., Laurienti, P. J. & Coghill, R. C. The subjective experience of pain: where expectations become reality. Proc. Natl Acad. Sci. USA 102, 12950–12955 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Keltner, J. R. et al. Isolating the modulatory effect of expectation on pain transmission: a functional magnetic resonance imaging study. J. Neurosci. 26, 4437–4443 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Willer, J. C. & Albe-Fessard, D. Electrophysiological evidence for a release of endogenous opiates in stress-induced' analgesia' in man. Brain Res. 198, 419–426 (1980).

    Article  CAS  PubMed  Google Scholar 

  57. Terman, G. W., Morgan, M. J. & Liebeskind, J. C. Opioid and non-opioid stress analgesia from cold water swim: importance of stress severity. Brain Res. 372, 167–171 (1986).

    Article  CAS  PubMed  Google Scholar 

  58. Flor & Grüsser . Conditioned stress-induced analgesia in humans. Eur. J. Pain 3, 317–324 (1999).

    Article  CAS  PubMed  Google Scholar 

  59. Colloca, L. & Benedetti, F. Nocebo hyperalgesia: how anxiety is turned into pain. Curr. Opin. Anaesthesiol. 20, 435–439 (2007).

    Article  PubMed  Google Scholar 

  60. Koyama, T., Tanaka, Y. Z. & Mikami, A. Nociceptive neurons in the macaque anterior cingulate activate during anticipation of pain. Neuroreport 9, 2663–2667 (1998).

    Article  CAS  PubMed  Google Scholar 

  61. Price, D. D. Psychological and neural mechanisms of the affective dimension of pain. Science 288, 1769–1772 (2000).

    Article  CAS  PubMed  Google Scholar 

  62. Dannecker, E. A., Price, D. D. & Robinson, M. E. An examination of the relationships among recalled, expected, and actual intensity and unpleasantness of delayed onset muscle pain. J. Pain 4, 74–81 (2003).

    Article  PubMed  Google Scholar 

  63. Chua, P., Krams, M., Toni, I., Passingham, R. & Dolan, R. A functional anatomy of anticipatory anxiety. NeuroImage 9, 563–571 (1999).

    Article  CAS  PubMed  Google Scholar 

  64. Hsieh, J. C., Stone-Elander, S. & Ingvar, M. Anticipatory coping of pain expressed in the human anterior cingulate cortex: a positron emission tomography study. Neurosci. Lett. 262, 61–64 (1999).

    Article  CAS  PubMed  Google Scholar 

  65. Ploghaus, A. et al. Dissociating pain from its anticipation in the human brain. Science 284, 1979–1981 (1999).

    Article  CAS  PubMed  Google Scholar 

  66. Porro, C. A. et al. Does anticipation of pain affect cortical nociceptive systems? J. Neurosci. 22, 3206–3214 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Porro, C. A., Cettolo, V., Francescato, M. P. & Baraldi, P. Functional activity mapping of the mesial hemispheric wall during anticipation of pain. NeuroImage 19, 1738–1747 (2003).

    Article  PubMed  Google Scholar 

  68. Lorenz, J. et al. Cortical correlates of false expectations during pain intensity judgments—a possible manifestation of placebo/nocebo cognitions. Brain Behav. Immun. 19, 283–295 (2005).

    Article  PubMed  Google Scholar 

  69. Kong, J. et al. A functional magnetic resonance imaging study on the neural mechanisms of hyperalgesic nocebo effect. J. Neurosci. 28, 13354–13362 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Geuter, S. & Büchel, C. Facilitation of pain in the human spinal cord by nocebo treatment. J. Neurosci. 33, 13784–13790 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Coan, J. A., Schaefer, H. S. & Davidson, R. J. Lending a hand. Social regulation of the neural response to threat. Psychol. Sci. 17, 1032–1039 (2006).

    Article  PubMed  Google Scholar 

  72. Montoya, P., Larbig, W., Braun, C., Preissl, H. & Birbaumer, N. Influence of social support and emotional context on pain processing and magnetic brain responses in fibromyalgia. Arthritis Rheum. 50, 4035–4044 (2004).

    Article  PubMed  Google Scholar 

  73. Ferrell, B. R. & Dean, G. The meaning of cancer pain. Semin. Oncol. Nurs. 11, 17–22 (1995).

    Article  CAS  PubMed  Google Scholar 

  74. Smith, W. B., Gracely, R. H. & Safer, M. A. The meaning of pain: cancer patients' rating and recall of pain intensity and affect. Pain 78, 123–129 (1998).

    Article  CAS  PubMed  Google Scholar 

  75. Cormie, P. J., Nairn, M. & Welsh, J. Guideline Development Group. Control of pain in adults with cancer: summary of SIGN guidelines. BMJ http://dx.doi.org/10.1136/bmj.a2154.

  76. Henderson, S. W. The unnatural nature of pain. JAMA 283, 117 (2000).

    Article  CAS  PubMed  Google Scholar 

  77. Whitman, S. M. Pain and suffering as viewed by the Hindu religion. Pain 8, 607–613 (2007).

    Article  Google Scholar 

  78. Koffman, J., Morgan, M., Edmonds, P., Speck, P. & Higginson, I. J. Cultural meanings of pain: a qualitative study of Black Carribean and White British patients with advanced cancer. Palliat. Med. 22, 350–359 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Benedetti, F., Thoen, W., Blanchard, C., Vighetti, S. & Arduino, C. Pain as a reward: changing the meaning of pain from negative to positive co-activates opioid and cannabinoid systems. Pain 154, 361–367 (2013).

    Article  PubMed  Google Scholar 

  80. Leknes, S. et al. The importance of context: when relative relief renders pain pleasant. Pain 154, 402–410 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Fields, H. L. Understanding how opioids contribute to reward and analgesia. Reg. Anesth. Pain Med. 32, 242–246 (2007).

    Article  CAS  PubMed  Google Scholar 

  82. Borsook, D. et al. Reward-aversion circuitry in analgesia and pain: implications for psychiatric disorders. Eur. J. Pain 11, 7–20 (2007).

    Article  PubMed  Google Scholar 

  83. Kut, E. et al. Pleasure-related analgesia activates opioid-insensitive circuits. J. Neurosci. 31, 4148–4153 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Cota, D., Tschöp, M. H., Horvath, T. L. & Levine, A. S. Cannabinoids, opioids and eating behavior: the molecular face of hedonism? Brain Res. Rev. 51, 85–107 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Desroches, J. & Beaulieu, P. Opioids and cannabinoids interactions: involvement in pain management. Curr. Drug Targets. 11, 462–473 (2010).

    Article  CAS  PubMed  Google Scholar 

  87. Fattore, L. et al. Cannabinoids and reward: interactions with the opioid system. Crit. Rev. Neurobiol. 16, 147–158 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Maldonado, R. & Valverde, O. Participation of the opioid system in cannabinoid-induced antinociception and emotional-like responses. Eur. Neuropsychopharmacol. 13, 401–410 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Manzanares, J. et al. Pharmacological and biochemical interactions between opioids and cannabinoids. Trends Pharmacol. Sci. 20, 287–294 (1999).

    Article  CAS  PubMed  Google Scholar 

  90. 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 

  91. 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 

  92. 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 

  93. Benedetti, F. et al. Open versus hidden medical treatments: the patient's knowledge about a therapy affects the therapy outcome. Prevention & Treatment 6, (2003) 10.1037/1522–3736.6.1.61a.

  94. 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 

  95. Benedetti, F., Carlino, E. & Pollo, A. Hidden administration of drugs. Clin. Pharmacol. Ther. 90, 651–661 (2011).

    Article  CAS  PubMed  Google Scholar 

  96. Bingel, U. et al. The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci. Trans. Med. 3, 70ra14 (2011).

    Article  CAS  Google Scholar 

  97. Atlas, L. Y. et al. Dissociable effects of opiates and expectations on pain. J. Neurosci. 32, 8053–8064 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Benedetti, F. et al. Loss of expectation-related mechanisms in Alzheimer's disease makes analgesic therapies less effective. Pain 121, 133–144 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Stein, N., Sprenger, C., Scholz, J., Wiech, K. & Bingel, U. White matter integrity of the descending pain modulatory system is associated with interindividual differences in placebo analgesia. Pain 153, 2210–2217 (2012).

    Article  PubMed  Google Scholar 

  100. Häuser, W., Bartram-Wunn, E., Bartram, C., Reinecke, H. & Tölle, T. Systematic review: Placebo response in drug trials of fibromyalgia syndrome and painful peripheral diabetic neuropathy-magnitude and patient-related predictors. Pain 152, 1709–1717 (2011).

    Article  PubMed  Google Scholar 

  101. Häuser, W., Bartram, C., Bartram-Wunn, E. & Tölle, T. Adverse events attributable to nocebo in randomized controlled drug trials in fibromyalgia syndrome and painful diabetic peripheral neuropathy: systematic review. Clin. J. Pain 28, 437–451 (2012).

    Article  PubMed  Google Scholar 

  102. Häuser, W., Sarzi-Puttini, P., Tölle, T. & Wolfe, F. Placebo and nocebo responses in randomised controlled trials of drugs applying for approval for fibromyalgia syndrome treatment: systematic review and meta-analysis. Clin. Exp. Rheumatol. 30 (Suppl. 74), 78–87 (2012).

    PubMed  Google Scholar 

  103. Findley, T. The placebo and the physician. Med. Clin. North Am. 37, 1821–1826 (1953).

    Article  Google Scholar 

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Acknowledgements

This work was supported by Compagnia di San Paolo, Carlo Molo Foundation, and Volkswagen Foundation.

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

    Elisa Carlino, Elisa Frisaldi & Fabrizio Benedetti

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  1. Elisa Carlino
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  2. Elisa Frisaldi
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  3. Fabrizio Benedetti
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E.C. and E.F. planned, discussed and wrote the review. F.B. planned, discussed and wrote the review, and supervised the work.

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Correspondence to Fabrizio Benedetti.

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The authors declare no competing financial interests.

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Carlino, E., Frisaldi, E. & Benedetti, F. Pain and the context. Nat Rev Rheumatol 10, 348–355 (2014). https://doi.org/10.1038/nrrheum.2014.17

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