1932

Abstract

Pharmacological strategies for pain management have primarily focused on dampening ascending neurotransmission and on opioid receptor–mediated therapies. Little is known about the contribution of endogenous descending modulatory systems to clinical pain outcomes and why some patients are mildly affected while others suffer debilitating pain-induced dysfunctions. Placebo effects that arise from patients’ positive expectancies and the underlying endogenous modulatory mechanisms may in part account for the variability in pain experience and severity, adherence to treatment, distinct coping strategies, and chronicity. Expectancy-induced analgesia and placebo effects in general have emerged as useful models to assess individual endogenous pain modulatory systems. Different systems and mechanisms trigger placebo effects that highly impact pain processing, clinical outcomes, and sense of well-being. This review illustrates critical elements of placebo mechanisms that inform the methodology of clinical trials, the discovery of new therapeutic targets, and the advancement of personalized pain management.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-010818-021542
2019-01-06
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/59/1/annurev-pharmtox-010818-021542.html?itemId=/content/journals/10.1146/annurev-pharmtox-010818-021542&mimeType=html&fmt=ahah

Literature Cited

  1. 1.  Colloca L, Benedetti F 2005. Placebos and painkillers: Is mind as real as matter?. Nat. Rev. Neurosci. 6:545–52
    [Google Scholar]
  2. 2.  Colloca L 2018. Neurobiology of the Placebo Effect Volume I–II Cambridge, MA: Elsevier/Academic PressThis two-volume book emphasizes recent findings and new directions in placebo research.
  3. 3.  Ernst E, Resch KL 1995. Concept of true and perceived placebo effects. BMJ 311:551–53
    [Google Scholar]
  4. 4.  Vase L, Amanzio M, Price DD 2015. Nocebo versus placebo: the challenges of trial design in analgesia research. Clin. Pharmacol. Ther. 97:143–50
    [Google Scholar]
  5. 5.  Colloca L 2017. Treatment of pediatric migraine. N. Engl. J. Med. 376:1387–88
    [Google Scholar]
  6. 6.  Colloca L, Lopiano L, Lanotte M, Benedetti F 2004. Overt versus covert treatment for pain, anxiety, and Parkinson's disease. Lancet Neurol 3:679–84
    [Google Scholar]
  7. 7.  Colloca L, Lopiano L, Benedetti F, Lanotte M 2005. The placebo response in conditions other than pain. Semin. Pain Med. 3:43–47
    [Google Scholar]
  8. 8.  Benedetti F 2008. Mechanisms of placebo and placebo-related effects across diseases and treatments. Annu. Rev. Pharmacol. Toxicol. 48:33–60
    [Google Scholar]
  9. 9.  Raicek JE, Stone BH, Kaptchuk TJ 2012. Placebos in 19th century medicine: a quantitative analysis of the BMJ. BMJ 345:e8326
    [Google Scholar]
  10. 10.  Berman A 1972. The Pharmacopoeia Reformata of London (1744) and its anonymous author. Ohio State Med. J. 68:774–75
    [Google Scholar]
  11. 11.  Shapiro AK 1959. The placebo effect in the history of medical treatment: implications for psychiatry. Am. J. Psychiatry 116:298–304
    [Google Scholar]
  12. 12.  Wolff HG, Dubois EF, Cattell M 1946. Conferences on therapy: the use of placebos in therapy. New York State J. Med. 46:1718–27
    [Google Scholar]
  13. 13.  Jefferson T 1905. The Works of Thomas Jefferson, Vol. 10 Correspondence and Papers 1803–1807 PL Ford New York/London: G.P. Putnam's Sons
  14. 14.  Miller FG 2013. The concept and significance of the placebo effect. The Placebo: A Reader FG Miller 1–9 Baltimore, MD: Johns Hopkins Univ. Press
    [Google Scholar]
  15. 15.  Beecher HK 1955. The powerful placebo. J. Am. Med. Assoc. 159:1602–6
    [Google Scholar]
  16. 16.  Levine JD, Gordon NC, Fields HL 1978. The mechanism of placebo analgesia. Lancet 2:654–57Pioneering study that stimulated research in the area of placebo and its underlying endogenous mechanisms.
    [Google Scholar]
  17. 17.  Eippert F, Finsterbusch J, Bingel U, Buchel C 2009. Direct evidence for spinal cord involvement in placebo analgesia. Science 326:404
    [Google Scholar]
  18. 18.  Eippert F, Bingel U, Schoell ED, Yacubian J, Klinger R et al. 2009. Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron 63:533–43Naloxone and functional magnetic resonance imaging illustrate the brain areas involved in placebo-induced analgesia.
    [Google Scholar]
  19. 19.  Benedetti F 1996. The opposite effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia. Pain 64:535–43
    [Google Scholar]
  20. 20.  Amanzio M, Benedetti F 1999. Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems. J. Neurosci. 19:484–94Demonstration of the differential role of the opioid system for verbally induced and conditioned placebo effects.
    [Google Scholar]
  21. 21.  Wager TD, Scott DJ, Zubieta JK 2007. Placebo effects on human μ-opioid activity during pain. PNAS 104:11056–61
    [Google Scholar]
  22. 22.  Zubieta JK, Bueller JA, Jackson LR, Scott DJ, Xu Y et al. 2005. Placebo effects mediated by endogenous opioid activity on μ-opioid receptors. J. Neurosci. 25:7754–62This was the first in vivo brain imaging demonstration of the involvement of endogenous opioids.
    [Google Scholar]
  23. 23.  Benedetti F, Pollo A, Colloca L 2007. Opioid-mediated placebo responses boost pain endurance and physical performance: Is it doping in sport competitions?. J. Neurosci. 27:11934–39
    [Google Scholar]
  24. 24.  Oroszi G, Goldman D 2004. Alcoholism: genes and mechanisms. Pharmacogenomics 5:1037–48
    [Google Scholar]
  25. 25.  Stoeber M, Jullie D, Lobingier BT, Laeremans T, Steyaert J et al. 2018. A genetically encoded biosensor reveals location bias of opioid drug action. Neuron 98:5963–76.e5Opioid drugs produce a pattern of activation that differs from the modulation driven by opioids that are naturally released.
    [Google Scholar]
  26. 26.  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. 29:4882–87
    [Google Scholar]
  27. 27.  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 65:220–31
    [Google Scholar]
  28. 28.  Skyt I, Moslemi K, Baastrup C, Grosen K, Benedetti F et al. 2017. Dopaminergic tone does not influence pain levels during placebo interventions in patients with chronic neuropathic pain. Pain 159:2261–72
    [Google Scholar]
  29. 29.  Wrobel N, Wiech K, Forkmann K, Ritter C, Bingel U 2014. Haloperidol blocks dorsal striatum activity but not analgesia in a placebo paradigm. Cortex 57:60–73
    [Google Scholar]
  30. 30.  Jarcho JM, Feier NA, Labus JS, Naliboff B, Smith SR et al. 2016. Placebo analgesia: self-report measures and preliminary evidence of cortical dopamine release associated with placebo response. Neuroimage Clin 10:107–14
    [Google Scholar]
  31. 31.  Benedetti F, Colloca L, Torre E, Lanotte M, Melcarne A et al. 2004. Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus. Nat. Neurosci. 7:587–88
    [Google Scholar]
  32. 32.  Benedetti F, Lanotte M, Colloca L, Ducati A, Zibetti M, Lopiano L 2009. Electrophysiological properties of thalamic, subthalamic and nigral neurons during the anti-parkinsonian placebo response. J. Physiol. 587:3869–83
    [Google Scholar]
  33. 33.  Mercado R, Constantoyannis C, Mandat T, Kumar A, Schulzer M et al. 2006. Expectation and the placebo effect in Parkinson's disease patients with subthalamic nucleus deep brain stimulation. Mov. Disord. 21:1457–61
    [Google Scholar]
  34. 34.  Lidstone SC, Schulzer M, Dinelle K, Mak E, Sossi V et al. 2010. Effects of expectation on placebo-induced dopamine release in Parkinson disease. Arch. Gen. Psychiatry 67:857–65
    [Google Scholar]
  35. 35.  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 293:1164–66
    [Google Scholar]
  36. 36.  Colloca L, Pine DS, Ernst M, Miller FG, Grillon C 2016. Vasopressin boosts placebo analgesic effects in women: a randomized trial. Biol. Psychiatry 79:794–802This study provided the first evidence that the nanopeptide vasopressin increases placebo effects in women.
    [Google Scholar]
  37. 37.  Kessner S, Sprenger C, Wrobel N, Wiech K, Bingel U 2013. Effect of oxytocin on placebo analgesia: a randomized study. JAMA 310:1733–35This study provided the first evidence that the nanopeptide oxytocin increases placebo effects in men.
    [Google Scholar]
  38. 38.  Kogan A, Saslow LR, Impett EA, Oveis C, Keltner D, Rodrigues Saturn S 2011. Thin-slicing study of the oxytocin receptor (OXTR) gene and the evaluation and expression of the prosocial disposition. PNAS 108:19189–92
    [Google Scholar]
  39. 39.  Donaldson ZR, Young LJ 2008. Oxytocin, vasopressin, and the neurogenetics of sociality. Science 322:900–4
    [Google Scholar]
  40. 40.  Bielsky IF, Hu SB, Young LJ 2005. Sexual dimorphism in the vasopressin system: lack of an altered behavioral phenotype in female V1a receptor knockout mice. Behav. Brain Res. 164:132–36
    [Google Scholar]
  41. 41.  Ebstein RP, Israel S, Lerer E, Uzefovsky F, Shalev I et al. 2009. Arginine vasopressin and oxytocin modulate human social behavior. Ann. N. Y. Acad. Sci. 1167:87–102
    [Google Scholar]
  42. 42.  Heinrichs M, Domes G 2008. Neuropeptides and social behaviour: effects of oxytocin and vasopressin in humans. Prog. Brain Res. 170:337–50
    [Google Scholar]
  43. 43.  Heinrichs M, von Dawans B, Domes G 2009. Oxytocin, vasopressin, and human social behavior. Front. Neuroendocrinol. 30:548–57
    [Google Scholar]
  44. 44.  Young LJ, Wang Z 2004. The neurobiology of pair bonding. Nat. Neurosci. 7:1048–54
    [Google Scholar]
  45. 45.  Feng C, Hackett PD, DeMarco AC, Chen X, Stair S et al. 2015. Oxytocin and vasopressin effects on the neural response to social cooperation are modulated by sex in humans. Brain Imaging Behav 9:754–64
    [Google Scholar]
  46. 46.  Thompson R, Gupta S, Miller K, Mills S, Orr S 2004. The effects of vasopressin on human facial responses related to social communication. Psychoneuroendocrinology 29:35–48
    [Google Scholar]
  47. 47.  Thompson RR, George K, Walton JC, Orr SP, Benson J 2006. Sex-specific influences of vasopressin on human social communication. PNAS 103:7889–94
    [Google Scholar]
  48. 48.  Born J, Lange T, Kern W, McGregor GP, Bickel U, Fehm HL 2002. Sniffing neuropeptides: a transnasal approach to the human brain. Nat. Neurosci. 5:514–16
    [Google Scholar]
  49. 49.  Meissner K, Bingel U, Colloca L, Wager TD, Watson A, Flaten MA 2011. The placebo effect: advances from different methodological approaches. J. Neurosci. 31:16117–24
    [Google Scholar]
  50. 50.  Goodson JL, Thompson RR 2010. Nonapeptide mechanisms of social cognition, behavior and species-specific social systems. Curr. Opin. Neurobiol. 20:784–94
    [Google Scholar]
  51. 51.  Ferris CF, Melloni RH Jr., Koppel G, Perry KW, Fuller RW, Delville Y 1997. Vasopressin/serotonin interactions in the anterior hypothalamus control aggressive behavior in golden hamsters. J. Neurosci. 17:4331–40
    [Google Scholar]
  52. 52.  Gobrogge KL, Liu Y, Young LJ, Wang Z 2009. Anterior hypothalamic vasopressin regulates pair-bonding and drug-induced aggression in a monogamous rodent. PNAS 106:19144–49
    [Google Scholar]
  53. 53.  Freeman SM, Walum H, Inoue K, Smith AL, Goodman MM et al. 2014. Neuroanatomical distribution of oxytocin and vasopressin 1a receptors in the socially monogamous coppery titi monkey (Callicebus cupreus). Neuroscience 273:12–23
    [Google Scholar]
  54. 54.  Moerman DE, Jonas WB 2002. Deconstructing the placebo effect and finding the meaning response. Ann. Intern. Med. 136:471–76
    [Google Scholar]
  55. 55.  Colloca L, Klinger R, Flor H, Bingel U 2013. Placebo analgesia: psychological and neurobiological mechanisms. Pain 154:511–14
    [Google Scholar]
  56. 56.  Colloca L, Miller FG 2011. How placebo responses are formed: a learning perspective. Philos. Trans. R. Soc. Lond. B Biol. Sci. 366:1859–69
    [Google Scholar]
  57. 57.  Colloca L, Flaten MA, Meissner K, eds. 2013. Placebo and Pain: From Bench to Bedside Oxford, UK: Elsevier
  58. 58.  Colloca L, Petrovic P, Wager TD, Ingvar M, Benedetti F 2010. How the number of learning trials affects placebo and nocebo responses. Pain 151:430–39
    [Google Scholar]
  59. 59.  Colloca L, Benedetti F 2006. How prior experience shapes placebo analgesia. Pain 124:126–33
    [Google Scholar]
  60. 60.  Au Yeung ST, Colagiuri B, Lovibond PF, Colloca L 2014. Partial reinforcement, extinction, and placebo analgesia. Pain 155:1110–17This study demonstrated that partial reinforcement prevents extinction of placebo analgesic effects over time.
    [Google Scholar]
  61. 61.  Kessner S, Wiech K, Forkmann K, Ploner M, Bingel U 2013. The effect of treatment history on therapeutic outcome: an experimental approach. JAMA Intern. Med. 173:1468–69Positive and negative prior therapeutic experiences shape not only behavioral but also brain responses.
    [Google Scholar]
  62. 62.  Lui F, Colloca L, Duzzi D, Anchisi D, Benedetti F, Porro CA 2010. Neural bases of conditioned placebo analgesia. Pain 151:816–24
    [Google Scholar]
  63. 63.  Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL et al. 2004. Placebo-induced changes in fMRI in the anticipation and experience of pain. Science 303:1162–67
    [Google Scholar]
  64. 64.  Colloca L 2017. Nocebo effects can make you feel pain. Science 358:44
    [Google Scholar]
  65. 65.  Colloca L, Sigaudo M, Benedetti F 2008. The role of learning in nocebo and placebo effects. Pain 136:211–18
    [Google Scholar]
  66. 66.  Schenk LA, Krimmel SR, Colloca L 2017. Observe to get pain relief: current evidence and potential mechanisms of socially learned pain modulation. Pain 158:2077–81
    [Google Scholar]
  67. 67.  Colloca L, Benedetti F 2009. Placebo analgesia induced by social observational learning. Pain 144:28–34First demonstration that observing a therapeutic outcome in others elicits placebo effects.
    [Google Scholar]
  68. 68.  Hunter T, Siess F, Colloca L 2014. Socially induced placebo analgesia: a comparison of a pre-recorded versus live face-to-face observation. Eur. J. Pain 18:914–22
    [Google Scholar]
  69. 69.  Bootzin RR, Caspi O 2002. Explanatory mechanisms for placebo effects: cognition, personality and social learning. The Science of the Placebo: Toward an Interdisciplinary Research Agenda HA Guess, A Kleinman, JW Kusek, LW Engel 108–32 London: BMJ Books
    [Google Scholar]
  70. 70.  Kirsch I 1985. Response expectancy as a determinant of experience and behavior. Am. Psychol. 40:1189–202
    [Google Scholar]
  71. 71.  Wickramasekera I 1980. A conditioned response model of the placebo effect predictions from the model. Biofeedback Self Regul 5:5–18
    [Google Scholar]
  72. 72.  Colloca L 2014. Placebo, nocebo, and learning mechanisms. Handb. Exp. Pharmacol. 225:17–35
    [Google Scholar]
  73. 73.  Di Blasi Z, Harkness E, Ernst E, Georgiou A, Kleijnen J 2001. Influence of context effects on health outcomes: a systematic review. Lancet 357:757–62
    [Google Scholar]
  74. 74.  Kruschke JK 2006. Locally Bayesian learning with applications to retrospective revaluation and highlighting. Psychol. Rev. 113:677–99
    [Google Scholar]
  75. 75.  Schenk LA, Sprenger C, Onat S, Colloca L, Buchel C 2017. Suppression of striatal prediction errors by the prefrontal cortex in placebo hypoalgesia. J. Neurosci. 37:9715–23
    [Google Scholar]
  76. 76.  Wiech K 2016. Deconstructing the sensation of pain: the influence of cognitive processes on pain perception. Science 354:584–87
    [Google Scholar]
  77. 77.  Colloca L, Miller FG 2011. Role of expectations in health. Curr. Opin. Psychiatry 24:149–55
    [Google Scholar]
  78. 78.  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. 23:4315–23
    [Google Scholar]
  79. 79.  Gil M 2010. Reward expectations in honeybees. Commun. Integr. Biol. 3:95–100
    [Google Scholar]
  80. 80.  Ader R, Cohen N 1982. Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus. Science 215:1534–36
    [Google Scholar]
  81. 81.  Herrnstein RJ 1962. Placebo effect in the rat. Science 138:677–78
    [Google Scholar]
  82. 82.  Keller AA, Akintola T, Colloca L 2018. Placebo analgesia in rodents: current and future research. See Reference 2 1–15
  83. 83.  Krank MD, Hinson RE, Siegel S 1981. Conditional hyperalgesia is elicited by environmental signals of morphine. Behav. Neural Biol. 32:148–57
    [Google Scholar]
  84. 84.  Valone JM, Randall CK, Kraemer PJ, Bardo MT 1998. Olfactory cues and morphine-induced conditioned analgesia in rats. Pharmacol. Biochem. Behav. 60:115–18
    [Google Scholar]
  85. 85.  Bardo MT, Valone JM 1994. Morphine-conditioned analgesia using a taste cue: dissociation of taste aversion and analgesia. Psychopharmacology 114:269–74
    [Google Scholar]
  86. 86.  Bryant CD, Roberts KW, Culbertson CS, Le A, Evans CJ, Fanselow MS 2009. Pavlovian conditioning of multiple opioid-like responses in mice. Drug Alcohol Depend 103:74–83
    [Google Scholar]
  87. 87.  Guo JY, Wang JY, Luo F 2010. Dissection of placebo analgesia in mice: the conditions for activation of opioid and non-opioid systems. J. Psychopharmacol. 24:1561–67
    [Google Scholar]
  88. 88.  Guo JY, Yuan XY, Sui F, Zhang WC, Wang JY et al. 2011. Placebo analgesia affects the behavioral despair tests and hormonal secretions in mice. Psychopharmacology 217:83–90
    [Google Scholar]
  89. 89.  Zhang RR, Zhang WC, Wang JY, Guo JY 2013. The opioid placebo analgesia is mediated exclusively through μ-opioid receptor in rat. Int. J. Neuropsychopharmacol. 16:849–56
    [Google Scholar]
  90. 90.  Lee IS, Lee B, Park HJ, Olausson H, Enck P, Chae Y 2015. A new animal model of placebo analgesia: involvement of the dopaminergic system in reward learning. Sci. Rep. 5:17140
    [Google Scholar]
  91. 91.  Schedlowski M, Pacheco-Lopez G 2010. The learned immune response: Pavlov and beyond. Brain Behav. Immun. 24:176–85
    [Google Scholar]
  92. 92.  Bermudez-Rattoni F 2004. Molecular mechanisms of taste-recognition memory. Nat. Rev. Neurosci. 5:209–17
    [Google Scholar]
  93. 93.  Ader R 2003. Conditioned immunomodulation: research needs and directions. Brain Behav. Immun. 17:Suppl. 1S51–57
    [Google Scholar]
  94. 94.  Ader R, Cohen N 1975. Behaviorally conditioned immunosuppression. Psychosom. Med. 37:333–40
    [Google Scholar]
  95. 95.  Pacheco-Lopez G, Riether C, Doenlen R, Engler H, Niemi MB et al. 2009. Calcineurin inhibition in splenocytes induced by pavlovian conditioning. FASEB J 23:1161–67
    [Google Scholar]
  96. 96.  Hadamitzky M, Sondermann W, Benson S, Schedlowski M 2018. Placebo effects in the immune system. Int. Rev. Neurobiol. 138:39–59
    [Google Scholar]
  97. 97.  Colloca L, Enck P, DeGrazia D 2016. Relieving pain using dose-extending placebos: a scoping review. Pain 157:1590–98
    [Google Scholar]
  98. 98.  Ader R, Mercurio MG, Walton J, James D, Davis M et al. 2010. Conditioned pharmacotherapeutic effects: a preliminary study. Psychosom. Med. 72:192–97
    [Google Scholar]
  99. 99.  Perlis M, Grandner M, Zee J, Bremer E, Whinnery J et al. 2015. Durability of treatment response to zolpidem with three different maintenance regimens: a preliminary study. Sleep Med 16:1160–68
    [Google Scholar]
  100. 100.  Sandler AD, Bodfish JW 2008. Open-label use of placebos in the treatment of ADHD: a pilot study. Child Care Health Dev 34:104–10
    [Google Scholar]
  101. 101.  Goebel MU, Meykadeh N, Kou W, Schedlowski M, Hengge UR 2008. Behavioral conditioning of antihistamine effects in patients with allergic rhinitis. Psychother. Psychosom. 77:227–34
    [Google Scholar]
  102. 102.  Kirchhof J, Petrakova L, Brinkhoff A, Benson S, Schmidt J et al. 2018. Learned immunosuppressive placebo responses in renal transplant patients. PNAS 115:4223–27
    [Google Scholar]
  103. 103.  Belcher AM, Ferre S, Martinez PE, Colloca L 2018. Role of placebo effects in pain and neuropsychiatric disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry 87:Pt. B298–306
    [Google Scholar]
  104. 104.  Chou R, Turner JA, Devine EB, Hansen RN, Sullivan SD et al. 2015. The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann. Intern. Med. 162:276–86
    [Google Scholar]
  105. 105.  Kaplovitch E, Gomes T, Camacho X, Dhalla IA, Mamdani MM, Juurlink DN 2015. Sex differences in dose escalation and overdose death during chronic opioid therapy: a population-based cohort study. PLOS ONE 10:e0134550
    [Google Scholar]
  106. 106.  Brummett CM, Waljee JF, Goesling J, Moser S, Lin P et al. 2017. New persistent opioid use after minor and major surgical procedures in US adults. JAMA Surg 152:e170504
    [Google Scholar]
  107. 107.  Park LC, Covi L 1965. Nonblind placebo trial: an exploration of neurotic patient's responses to placebo when its inert content is disclosed. Arch. Gen. Psychiatry 12:36–45
    [Google Scholar]
  108. 108.  Kaptchuk TJ, Friedlander E, Kelley JM, Sanchez MN, Kokkotou E et al. 2010. Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PLOS ONE 5:e15591
    [Google Scholar]
  109. 109.  Carvalho C, Caetano JM, Cunha L, Rebouta P, Kaptchuk TJ, Kirsch I 2016. Open-label placebo treatment in chronic low back pain: a randomized controlled trial. Pain 157:2766–72Chronic low-back pain patients showed long-lasting pain reduction when pills were labeled as placebos.
    [Google Scholar]
  110. 110.  Kelley JM, Kaptchuk TJ, Cusin C, Lipkin S, Fava M 2012. Open-label placebo for major depressive disorder: a pilot randomized controlled trial. Psychother. Psychosom. 81:312–14
    [Google Scholar]
  111. 111.  Schaefer M, Harke R, Denke C 2016. Open-label placebos improve symptoms in allergic rhinitis: a randomized controlled trial. Psychother. Psychosom. 85:373–74
    [Google Scholar]
  112. 112.  Hoenemeyer TW, Kaptchuk TJ, Mehta TS, Fontaine KR 2018. Open-label placebo treatment for cancer-related fatigue: a randomized-controlled clinical trial. Sci. Rep. 8:2784
    [Google Scholar]
  113. 113.  Locher C, Nascimento AF, Kirsch I, Kossowsky J, Meyer A, Gaab J 2017. Is the rationale more important than deception? A randomized controlled trial of open-label placebo analgesia. Pain 158:2320–28
    [Google Scholar]
  114. 114.  Schafer SM, Colloca L, Wager TD 2015. Conditioned placebo analgesia persists when subjects know they are receiving a placebo. J. Pain 16:412–20
    [Google Scholar]
  115. 115.  Colloca L, Howick J 2018. Placebos without deception: outcomes, mechanisms, and ethics. Int. Rev. Neurobiol. 138:219–40
    [Google Scholar]
  116. 116.  Fava M, Evins AE, Dorer DJ, Schoenfeld DA 2003. The problem of the placebo response in clinical trials for psychiatric disorders: culprits, possible remedies, and a novel study design approach. Psychother. Psychosom. 72:115–27
    [Google Scholar]
  117. 117.  Staud R, Price DD 2008. Role of placebo factors in clinical trials with special focus on enrichment designs. Pain 139:479–80
    [Google Scholar]
  118. 118.  Simmons K, Ortiz R, Kossowsky J, Krummenacher P, Grillon C et al. 2014. Pain and placebo in pediatrics: a comprehensive review of laboratory and clinical findings. Pain 155:2229–35
    [Google Scholar]
  119. 119.  Gramling R, Epstein R 2011. Optimism amid serious disease: clinical panacea or ethical conundrum? Comment on “Recovery expectations and long-term prognosis of patients with coronary heart disease. .” Arch. Intern. Med. 171:935–36
    [Google Scholar]
  120. 120.  Barefoot JC, Brummett BH, Williams RB, Siegler IC, Helms MJ et al. 2011. Recovery expectations and long-term prognosis of patients with coronary heart disease. Arch. Intern. Med. 171:929–35
    [Google Scholar]
  121. 121.  Auer CJ, Glombiewski JA, Doering BK, Winkler A, Laferton JA et al. 2016. Patients' expectations predict surgery outcomes: a meta-analysis. Int. J. Behav. Med. 23:49–62
    [Google Scholar]
  122. 122.  Vase L, Robinson ME, Verne GN, Price DD 2003. The contributions of suggestion, desire, and expectation to placebo effects in irritable bowel syndrome patients. An empirical investigation. Pain 105:17–25
    [Google Scholar]
  123. 123.  Devilly GJ, Borkovec TD 2000. Psychometric properties of the credibility/expectancy questionnaire. J. Behav. Ther. Exp. Psychiatry 31:73–86
    [Google Scholar]
  124. 124.  Wechsler ME, Kelley JM, Boyd IO, Dutile S, Marigowda G et al. 2011. Active albuterol or placebo, sham acupuncture, or no intervention in asthma. N. Engl. J. Med. 365:119–26
    [Google Scholar]
  125. 125.  Pecina M, Stohler CS, Zubieta JK 2013. Role of μ-opioid system in the formation of memory of placebo responses. Mol. Psychiatry 18:135–37
    [Google Scholar]
  126. 126.  Schenk LA, Sprenger C, Geuter S, Buchel C 2014. Expectation requires treatment to boost pain relief: an fMRI study. Pain 155:150–57
    [Google Scholar]
  127. 127.  Morton DL, Watson A, El-Deredy W, Jones AK 2009. Reproducibility of placebo analgesia: effect of dispositional optimism. Pain 146:194–98
    [Google Scholar]
  128. 128.  Vase L, Vollert J, Finnerup NB, Miao X, Atkinson G et al. 2015. Predictors of the placebo analgesia response in randomized controlled trials of chronic pain: a meta-analysis of the individual data from nine industrially sponsored trials. Pain 156:1795–802
    [Google Scholar]
  129. 129.  Dolgin E 2010. Fluctuating baseline pain implicated in failure of clinical trials. Nat. Med. 16:1053
    [Google Scholar]
  130. 130.  Bartfai T, Lees GV 2011. Pharma TARP: a troubled asset relief program for novel, abandoned projects in the pharmaceutical industry. ScientificWorldJournal 11:454–57
    [Google Scholar]
  131. 131.  Katz J, Finnerup NB, Dworkin RH 2008. Clinical trial outcome in neuropathic pain: relationship to study characteristics. Neurology 70:263–72
    [Google Scholar]
  132. 132.  Vase L, Petersen GL, Lund K 2014. Placebo effects in idiopathic and neuropathic pain conditions. Handb. Exp. Pharmacol. 225:121–36
    [Google Scholar]
  133. 133.  Petersen GL, Finnerup NB, Grosen K, Pilegaard HK, Tracey I et al. 2014. Expectations and positive emotional feelings accompany reductions in ongoing and evoked neuropathic pain following placebo interventions. Pain 155:2687–98
    [Google Scholar]
  134. 134.  Petersen GL, Finnerup NB, Norskov KN, Grosen K, Pilegaard HK et al. 2012. Placebo manipulations reduce hyperalgesia in neuropathic pain. Pain 153:1292–300
    [Google Scholar]
  135. 135.  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 153:2393–402
    [Google Scholar]
  136. 136.  Tetreault P, Mansour A, Vachon-Presseau E, Schnitzer TJ, Apkarian AV, Baliki MN 2016. Brain connectivity predicts placebo response across chronic pain clinical trials. PLOS Biol 14:e1002570
    [Google Scholar]
  137. 137.  Kong J, Wang Z, Leiser J, Minicucci D, Edwards R et al. 2018. Enhancing treatment of osteoarthritis knee pain by boosting expectancy: a functional neuroimaging study. Neuroimage Clin 18:325–34
    [Google Scholar]
  138. 138.  Kaptchuk TJ, Kelley JM, Conboy LA, Davis RB, Kerr CE et al. 2008. Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ 336:999–1003
    [Google Scholar]
  139. 139.  Vase L, Robinson ME, Verne GN, Price DD 2005. Increased placebo analgesia over time in irritable bowel syndrome (IBS) patients is associated with desire and expectation but not endogenous opioid mechanisms. Pain 115:338–47
    [Google Scholar]
  140. 140.  Kosek E, Rosen A, Carville S, Choy E, Gracely RH et al. 2017. Lower placebo responses after long-term exposure to fibromyalgia pain. J. Pain 18:7835–43
    [Google Scholar]
  141. 141.  Kam-Hansen S, Jakubowski M, Kelley JM, Kirsch I, Hoaglin DC et al. 2014. Altered placebo and drug labeling changes the outcome of episodic migraine attacks. Sci. Transl. Med. 6:218ra5
    [Google Scholar]
  142. 142.  Vase L, Petersen GL, Riley JL 3rd, Price DD 2009. Factors contributing to large analgesic effects in placebo mechanism studies conducted between 2002 and 2007. Pain 145:36–44
    [Google Scholar]
  143. 143.  Waber RL, Shiv B, Carmon Z, Ariely D 2008. Commercial features of placebo and therapeutic efficacy. JAMA 299:1016–17
    [Google Scholar]
  144. 144.  Faasse K, Martin LR, Grey A, Gamble G, Petrie KJ 2016. Impact of brand or generic labeling on medication effectiveness and side effects. Health Psychol 35:187–90
    [Google Scholar]
  145. 145.  Meissner K, Fassler M, Rucker G, Kleijnen J, Hrobjartsson A et al. 2013. Differential effectiveness of placebo treatments: a systematic review of migraine prophylaxis. JAMA Intern. Med. 173:1941–51
    [Google Scholar]
  146. 146.  Mathie RT, Ramparsad N, Legg LA, Clausen J, Moss S et al. 2017. Randomised, double-blind, placebo-controlled trials of non-individualised homeopathic treatment: systematic review and meta-analysis. Syst. Rev. 6:63
    [Google Scholar]
  147. 147.  Vickers AJ, Cronin AM, Maschino AC, Lewith G, MacPherson H et al. 2012. Acupuncture for chronic pain: individual patient data meta-analysis. Arch. Intern. Med. 172:1444–53
    [Google Scholar]
  148. 148.  Hammami MM, Al-Gaai EA, Alvi S, Hammami MB 2010. Interaction between drug and placebo effects: a cross-over balanced placebo design trial. Trials 11:110
    [Google Scholar]
  149. 149.  Hammami MM, Hammami S, Al-Swayeh R, Al-Gaai E, Farah FA, De Padua SJ 2016. Drug*placebo interaction effect may bias clinical trials interpretation: hybrid balanced placebo and randomized placebo-controlled design. BMC Med. Res. Methodol. 16:166
    [Google Scholar]
  150. 150.  Bingel U, Wanigasekera V, Wiech K, Ni Mhuircheartaigh R, Lee MC et al. 2011. The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci. Transl. Med. 3:70ra14
    [Google Scholar]
  151. 151.  Linde K, Witt CM, Streng A, Weidenhammer W, Wagenpfeil S et al. 2007. The impact of patient expectations on outcomes in four randomized controlled trials of acupuncture in patients with chronic pain. Pain 128:264–71
    [Google Scholar]
  152. 152.  Colloca L, Miller FG 2011. The nocebo effect and its relevance for clinical practice. Psychosom. Med. 73:598–603
    [Google Scholar]
  153. 153.  Egbert LD, Battit GE, Welch CE, Bartlett MK 1964. Reduction of postoperative pain by encouragement and instruction of patients. a study of doctor-patient rapport. N. Engl. J. Med. 270:825–27
    [Google Scholar]
  154. 154.  Zunhammer M, Bingel U, Wager TD 2018. Placebo effects on the neurologic pain signature: a meta-analysis of individual participant functional magnetic resonance imaging data. JAMA Neurol 75:111321–30
    [Google Scholar]
  155. 155.  Wager TD, Atlas LY 2015. The neuroscience of placebo effects: connecting context, learning and health. Nat. Rev. Neurosci. 16:7403–18
    [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-010818-021542
Loading
/content/journals/10.1146/annurev-pharmtox-010818-021542
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error