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Placebo pp 17-35 | Cite as

Placebo, Nocebo, and Learning Mechanisms

  • Luana CollocaEmail author
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 225)

Abstract

Recent substantial laboratory and theoretical research hints for different learning mechanisms regulating the formation of placebo and nocebo responses. Moreover, psychological and biological variants may play a role as modulators of learning mechanisms underlying placebo and nocebo responses. In this chapter, we present pioneering and recent human and nonhuman research that has impressively increased our knowledge of learning mechanisms in the context of placebo and nocebo effects across different physiological processes and pathological conditions.

Keywords

Conditioning Expectation Verbal suggestion Observational learning Drug-mimic effects Vicarious hypoalgesia 

Notes

Acknowledgments

This research is supported by the Intramural Research Program of the Clinical Center, NIH, the National Center for Complementary and Alternative Medicine (NCCAM), and the National Institute of Mental Health (NIMH).

Conflict of Interest There are no conflicts of interest.

References

  1. Ader R (1987) Conditioned immune responses: adrenocortical influences. Prog Brain Res 72:79–90PubMedCrossRefGoogle Scholar
  2. Ader R, Cohen N (1982) Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus. Science 215:1534–1536PubMedCrossRefGoogle Scholar
  3. Ader R, Grota LJ, Cohen N (1987) Conditioning phenomena and immune function. Ann N Y Acad Sci 496:532–544PubMedCrossRefGoogle Scholar
  4. Ader R, Felten D, Cohen N (1990) Interactions between the brain and the immune system. Annu Rev Pharmacol Toxicol 30:561–602PubMedCrossRefGoogle Scholar
  5. Ader R, Kelly K, Moynihan JA, Grota LJ, Cohen N (1993) Conditioned enhancement of antibody production using antigen as the unconditioned stimulus. Brain Behav Immun 7:334–343PubMedCrossRefGoogle Scholar
  6. Ader R, Cohen N, Felten D (1995) Psychoneuroimmunology: interactions between the nervous system and the immune system. Lancet 345:99–103PubMedCrossRefGoogle Scholar
  7. Ader R, Mercurio MG, Walton J, James D, Davis M, Ojha V, Kimball AB, Fiorentino D (2010) Conditioned pharmacotherapeutic effects: a preliminary study. Psychosom Med 72:192–197PubMedCrossRefPubMedCentralGoogle Scholar
  8. Alvarez-Buylla R, Carrasco-Zanini J (1960) A conditioned reflex which reproduces the hypoglycemic effect of insulin. Acta Physiol Lat Am 10:153–158PubMedGoogle Scholar
  9. Amanzio M, Benedetti F (1999) Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems. J Neurosci 19:484–494PubMedGoogle Scholar
  10. Benedetti F, Amanzio M, Baldi S, Casadio C, Cavallo A, Mancuso M, Ruffini E, Oliaro A, Maggi G (1998) The specific effects of prior opioid exposure on placebo analgesia and placebo respiratory depression. Pain 75:313–319PubMedCrossRefGoogle Scholar
  11. Benedetti F, Amanzio M, Baldi S, Casadio C, Maggi G (1999) Inducing placebo respiratory depressant responses in humans via opioid receptors. Eur J Neurosci 11:625–631PubMedCrossRefGoogle Scholar
  12. 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 23:4315–4323PubMedGoogle Scholar
  13. Benedetti F, Colloca L, Torre E, Lanotte M, Melcarne A, Pesare M, Bergamasco B, Lopiano L (2004) Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus. Nat Neurosci 7:587–588PubMedCrossRefGoogle Scholar
  14. Benedetti F, Lanotte M, Lopiano L, Colloca L (2007a) When words are painful: unraveling the mechanisms of the nocebo effect. Neuroscience 147:260–271PubMedCrossRefGoogle Scholar
  15. Benedetti F, Pollo A, Colloca L (2007b) Opioid-mediated placebo responses boost pain endurance and physical performance: is it doping in sport competitions? J Neurosci 27:11934–11939PubMedCrossRefGoogle Scholar
  16. 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 587:3869–3883PubMedCrossRefPubMedCentralGoogle Scholar
  17. Chung SK, Price DD, Verne GN, Robinson ME (2007) Revelation of a personal placebo response: its effects on mood, attitudes and future placebo responding. Pain 132:281–288PubMedCrossRefPubMedCentralGoogle Scholar
  18. Colloca L, Benedetti F (2006) How prior experience shapes placebo analgesia. Pain 124:126–133PubMedCrossRefGoogle Scholar
  19. Colloca L, Benedetti F (2009) Placebo analgesia induced by social observational learning. Pain 144:28–34PubMedCrossRefGoogle Scholar
  20. Colloca L, Finniss D (2012) Nocebo effects, patient-clinician communication, and therapeutic outcomes. JAMA 307:567–568PubMedCrossRefGoogle Scholar
  21. Colloca L, Miller FG (2011a) Harnessing the placebo effect: the need for translational research. Philos Trans R Soc Lond B Biol Sci 366:1922–1930PubMedCrossRefPubMedCentralGoogle Scholar
  22. Colloca L, Miller FG (2011b) How placebo responses are formed: a learning perspective. Philos Trans R Soc Lond B Biol Sci 366:1859–1869PubMedCrossRefPubMedCentralGoogle Scholar
  23. Colloca L, Miller FG (2011c) The nocebo effect and its relevance for clinical practice. Psychosom Med 73:598–603PubMedCrossRefPubMedCentralGoogle Scholar
  24. Colloca L, Sigaudo M, Benedetti F (2008a) The role of learning in nocebo and placebo effects. Pain 136:211–218PubMedCrossRefGoogle Scholar
  25. Colloca L, Tinazzi M, Recchia S, le Pera D, Fiaschi A, Benedetti F, Valeriani M (2008b) Learning potentiates neurophysiological and behavioral placebo analgesic responses. Pain 139:306–314PubMedCrossRefGoogle Scholar
  26. Colloca L, Petrovic P, Wager TD, Ingvar M, Benedetti F (2010) How the number of learning trials affects placebo and nocebo responses. Pain 151:430–439PubMedCrossRefPubMedCentralGoogle Scholar
  27. Colloca L, Flaten MA, Meissner K (2013a) Placebo and pain: from bench to bedside. Elsevier, OxfordGoogle Scholar
  28. Colloca L, Klinger R, Flor H, Bingel U (2013b) Placebo analgesia: psychological and neurobiological mechanisms. Pain 154:511–514PubMedCrossRefPubMedCentralGoogle Scholar
  29. Engert VP, Franziska P, Miller R, Kirschbaum C, Singer T (2014) Cortisol increase in empathic stress is modulated by social closeness and observation modality. Psychoneuroendocrinology 45:192–201PubMedCrossRefGoogle Scholar
  30. Fiorio M, Recchia S, Corra F, Simonetto S, Garcia-Larrea L, Tinazzi M (2012) Enhancing non-noxious perception: behavioural and neurophysiological correlates of a placebo-like manipulation. Neuroscience 217:96–104PubMedCrossRefGoogle Scholar
  31. Fiorio M, Recchia S, Corra F, Tinazzi M (2014) Behavioural and neurophysiological investigation of the influence of verbal suggestion on tactile perception. Neuroscience 258:332–339PubMedCrossRefGoogle Scholar
  32. Flaten MA, Simonsen T, Olsen H (1999) Drug-related information generates placebo and nocebo responses that modify the drug response. Psychosom Med 61:250–255PubMedCrossRefGoogle Scholar
  33. Galef BG Jr, Durlach PJ (1993) Absence of blocking, overshadowing, and latent inhibition in social enhancement of food preferences. Anim Learn Behav 21:214–220CrossRefGoogle Scholar
  34. Giang DW, Goodman AD, Schiffer RB, Mattson DH, Petrie M, Cohen N, Ader R (1996) Conditioning of cyclophosphamide-induced leukopenia in humans. J Neuropsychiatry Clin Neurosci 8:194–201PubMedGoogle Scholar
  35. Goebel MU, Trebst AE, Steiner J, Xie YF, Exton MS, Frede S, Canbay AE, Michel MC, Heemann U, Schedlowski M (2002) Behavioral conditioning of immunosuppression is possible in humans. FASEB J 16:1869–1873PubMedCrossRefGoogle Scholar
  36. 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 24:1561–1567PubMedCrossRefGoogle Scholar
  37. Guo JY, Yuan XY, Sui F, Zhang WC, Wang JY, Luo F, Luo J (2011) Placebo analgesia affects the behavioral despair tests and hormonal secretions in mice. Psychopharmacology (Berl) 217:83–90CrossRefGoogle Scholar
  38. Herrnstein RJ (1962) Placebo effect in the rat. Science 138:677–678PubMedCrossRefGoogle Scholar
  39. Hrobjartsson A, Kaptchuk TJ, Miller FG (2011) Placebo effect studies are susceptible to response bias and to other types of biases. J Clin Epidemiol 64:1223–1229PubMedCrossRefPubMedCentralGoogle Scholar
  40. 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(7):914–922PubMedCrossRefGoogle Scholar
  41. Kessner S, Wiech K, Forkmann K, Ploner M, Bingel U (2013) The effect of treatment history on therapeutic outcome: an experimental approach. JAMA Int Med 1–2Google Scholar
  42. Kirsch I (1985) Response expectancy as a determinant of experience and behavior. Am Psychol 40:1189–1202CrossRefGoogle Scholar
  43. Kirsch I, Weixel LJ (1988) Double-blind versus deceptive administration of a placebo. Behav Neurosci 102:319–323PubMedCrossRefGoogle Scholar
  44. Lanzetta JT, Orr SP (1980) Influence of facial expressions on the classical conditioning of fear. J Pers Soc Psychol 39:1081–1087PubMedCrossRefGoogle Scholar
  45. Levy R, Dostrovsky JO, Lang AE, Sime E, Hutchison WD, Lozano AM (2001) Effects of apomorphine on subthalamic nucleus and globus pallidus internus neurons in patients with Parkinson’s disease. J Neurophysiol 86:249–260PubMedGoogle Scholar
  46. Luparello TJ, Leist N, Lourie CH, Sweet P (1970) The interaction of psychologic stimuli and pharmacologic agents on airway reactivity in asthmatic subjects. Psychosom Med 32:509–513PubMedCrossRefGoogle Scholar
  47. Mazzoni G, Foan L, Hyland ME, Kirsch I (2010) The effects of observation and gender on psychogenic symptoms. Health Psychol 29:181–185PubMedCrossRefGoogle Scholar
  48. Olness K, Ader R (1992) Conditioning as an adjunct in the pharmacotherapy of lupus erythematosus. J Dev Behav Pediatr 13:124–125PubMedCrossRefGoogle Scholar
  49. Pacheco-Lopez G, Riether C, Doenlen R, Engler H, Niemi MB, Engler A, Kavelaars A, Heijnen CJ, Schedlowski M (2009) Calcineurin inhibition in splenocytes induced by pavlovian conditioning. FASEB J 23:1161–1167PubMedCrossRefGoogle Scholar
  50. Pavlov IP (1927) Conditioned reflexes: an investigation of the physiological activity of the cerebral cortex. Oxford University Press, LondonGoogle Scholar
  51. Price DD, Milling LS, Kirsch I, Duff A, Montgomery GH, Nicholls SS (1999) An analysis of factors that contribute to the magnitude of placebo analgesia in an experimental paradigm. Pain 83:147–156PubMedCrossRefGoogle Scholar
  52. Reiss R (1980) Pavlovian conditioning and human fear: an expectancy model. Behav Ther 11:380–396CrossRefGoogle Scholar
  53. Rescorla RA (1988a) Behavioral studies of Pavlovian conditioning. Annu Rev Neurosci 11:329–352PubMedCrossRefGoogle Scholar
  54. Rescorla RA (1988b) Pavlovian conditioning. It’s not what you think it is. Am Psychol 43:151–160PubMedCrossRefGoogle Scholar
  55. Rodriguez-Raecke R, Doganci B, Breimhorst M, Stankewitz A, Buchel C, Birklein F, May A (2010) Insular cortex activity is associated with effects of negative expectation on nociceptive long-term habituation. J Neurosci 30:11363–11368PubMedCrossRefGoogle Scholar
  56. Sandler AD, Bodfish JW (2008) Open-label use of placebos in the treatment of ADHD: a pilot study. Child Care Health Dev 34:104–110PubMedCrossRefGoogle Scholar
  57. Sandler A, Glesne C, Geller G (2008) Children’s and parents’ perspectives on open-label use of placebos in the treatment of ADHD. Child Care Health Dev 34:111–120PubMedGoogle Scholar
  58. Sandler AD, Glesne CE, Bodfish JW (2010) Conditioned placebo dose reduction: a new treatment in attention-deficit hyperactivity disorder? J Dev Behav Pediatr 31:369–375PubMedCrossRefPubMedCentralGoogle Scholar
  59. Siegel S, Baptista MA, Kim JA, Mcdonald RV, Eise-Kelly L (2000) Pavlovian psychopharmacology: the associative basis of tolerance. Exp Clin Psychopharmacol 8:276–293PubMedCrossRefGoogle Scholar
  60. Stefani A, Bassi A, Mazzone P, Pierantozzi M, Gattoni G, Altibrandi MG, Giacomini P, Peppe A, Bernardi G, Stanzione P (2002) Subdyskinetic apomorphine responses in globus pallidus and subthalamus of parkinsonian patients: lack of clear evidence for the ‘indirect pathway’. Clin Neurophysiol 113:91–100PubMedCrossRefGoogle Scholar
  61. Subkov AAZ, Zilov GN (1937) The role of conditioned reflex adaption in the origin of hyperergic reactions. Bull Biol Med Exp 4:294–296Google Scholar
  62. Swider K, Babel P (2013) The effect of the sex of a model on nocebo hyperalgesia induced by social observational learning. Pain 154:1312–1317PubMedCrossRefGoogle Scholar
  63. Vogtle E, Barke A, Kroner-Herwig B (2013) Nocebo hyperalgesia induced by social observational learning. Pain 154:1427–1433PubMedCrossRefGoogle Scholar
  64. Voudouris NJ, Peck CL, Coleman G (1990) The role of conditioning and verbal expectancy in the placebo response. Pain 43:121–128PubMedCrossRefGoogle Scholar
  65. Wager TD, Matre D, Casey KL (2006) Placebo effects in laser-evoked pain potentials. Brain Behav Immun 20:219–230PubMedCrossRefPubMedCentralGoogle Scholar
  66. Woods SC, Makous W, Hutton RA (1969) Temporal parameters of conditioned hypoglycemia. J Comp Physiol Psychol 69:301–307PubMedCrossRefGoogle Scholar
  67. Zhang RR, Zhang WC, Wang JY, Guo JY (2013) The opioid placebo analgesia is mediated exclusively through mu-opioid receptor in rat. Int J Neuropsychopharmacol 16:849–856PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.National Institute of Mental Health (NIMH), National Institutes of Health (NIH)BethesdaUSA
  2. 2.National Center for Complementary and Alternative Medicine (NCCAM), National Institutes of Health (NIH)BethesdaUSA
  3. 3.Department of BioethicsClinical Center, National Institutes of HealthBethesdaUSA

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