Pavlov’s Pain: the Effect of Classical Conditioning on Pain Perception and its Clinical Implications

  • Libo Zhang
  • Xuejing LuEmail author
  • Yanzhi Bi
  • Li HuEmail author
Psychological and Behavioral Aspects of Headache and Pain (D. Buse, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Psychological and Behavioral Aspects of Headache and Pain


Purpose of Review

It has been known for decades that classical conditioning influences pain perception. However, the precise relationship between conditioning and pain remains unclear. In addition, the clinical implications of their relationship are vastly underappreciated. Thus, we aim to (a) examine how conditioning increases or decreases pain sensitivity, (b) assess how conditioning contributes to the development and maintenance of chronic pain, and (c) explore strategies to utilize conditioning to optimize pain treatment.

Recent Findings

We first review studies regarding how classical conditioning alters pain perception with an emphasis on two phenomena where conditioning increases pain sensitivity (i.e., conditioned hyperalgesia) or decreases it (i.e., conditioned hypoalgesia). Specifically, we critically examine empirical studies about conditioned hyperalgesia and conditioned hypoalgesia, explore reasons why conditioning leads to these two seemingly opposite phenomena, and discuss the neural mechanisms behind them. We then highlight how conditioning contributes to the development and maintenance of chronic pain, and present neuroscientific evidence for maladaptive aversive conditioning in chronic pain patients. Moreover, we propose a framework for understanding how to exploit conditioning to optimize pain treatment, including minimizing conditioned hyperalgesia, maximizing conditioned hypoalgesia, and eliminating excessive fear and overgeneralization in chronic pain.


Classical conditioning profoundly modulates the experience of pain and affects the development and maintenance of chronic pain. The relationship between them has far-reaching clinical implications in pain treatment. Further investigations should tackle crucial issues in previous studies, including the complex relationship between conditioning and explicit expectation, and a lack of relevant clinical studies. Resolving these issues, future research would advance our understanding of the nature of pain, help relieve the suffering of patients, and thus contribute to promoting human flourishing.


Classical conditioning Conditioned hyperalgesia Conditioned hypoalgesia Chronic pain Clinical implications 



We thank Fengrui Zhang for his invaluable help with illustrating figures.

Funding Information

This work was supported by the National Natural Science Foundation of China (No. 31671141, 31701000, 31822025), the Informatization Special Project of Chinese Academy of Sciences (No. XXH13506-306), and the Scientific Foundation Project of Institute of Psychology, Chinese Academy of Sciences (No. Y6CX021008, KLMH2018ZG02).

Compliance with Ethical Standards

Conflict of Interest Statement

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Loeser JD, Treede R-D. The Kyoto protocol of IASP basic pain terminology. Pain. 2008;137:473–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Tabor A, Thacker MA, Moseley GL, Körding KP. Pain: a statistical account. PLoS Comput Biol. 2017;13:e1005142.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Apkarian AV, Baliki MN, Geha PY. Towards a theory of chronic pain. Prog Neurobiol. 2009;87:81–97.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Mazza S, Frot M, Rey AE. A comprehensive literature review of chronic pain and memory. Prog Neuro-Psychopharmacol Biol Psychiatry. 2018;87:183–92.CrossRefGoogle Scholar
  5. 5.
    Rescorla RA. Pavlovian conditioning: it’s not what you think it is. Am Psychol. 1988;43:151–60.PubMedCrossRefGoogle Scholar
  6. 6.
    •• Bräscher A, Witthöft M, Becker S. The underestimated significance of conditioning in placebo hypoalgesia and nocebo hyperalgesia. Pain Res Manag. 2018;2018:1–8. A highly relevant review that discussed how classical conditioning contributed to placebo hypoalgesia and nocebo hyperalgesia independently of explicit expectation. CrossRefGoogle Scholar
  7. 7.
    • Madden VJ, Harvie DS, Parker R, Jensen KB, Vlaeyen JWS, Moseley GL, et al. Can pain or hyperalgesia be a classically conditioned response in humans? A systematic review and meta-analysis. Pain Med. 2016;17:1094–111. A very good systematic review showing that classical conditioning can augment pain perception. PubMedGoogle Scholar
  8. 8.
    Miguez G, Laborda MA, Miller RR. Classical conditioning and pain: conditioned analgesia and hyperalgesia. Acta Psychol (Amst). 2014;145:10–20.CrossRefGoogle Scholar
  9. 9.
    Turk DC, Fernandez E. Cognitive-behavioral management strategies for pain and suffering. Curr Pain Headache Rep. 1997;1:99–106.CrossRefGoogle Scholar
  10. 10.
    Madden VJ, Moseley GL. Do clinicians think that pain can be a classically conditioned response to a non- noxious stimulus? Man Ther. 2016;22:165–73.PubMedCrossRefGoogle Scholar
  11. 11.
    Moseley GL, Vlaeyen JWS. Beyond nociception: the imprecision hypothesis of chronic pain. Pain. 2015;156:35–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Vlaeyen JWS, Linton SJ. Fear-avoidance and its consequences in chronic musculoskeletal pain: a state of the art. Pain. 2000;85:317–32.PubMedCrossRefGoogle Scholar
  13. 13.
    Peerdeman KJ, van Laarhoven AIM, Keij SM, Vase L, Rovers MM, Peters ML, et al. Relieving patients’ pain with expectation interventions: a meta-analysis. Pain. 2016;157:1179–91.PubMedCrossRefGoogle Scholar
  14. 14.
    Jennings EM, Okine BN, Roche M, Finn DP. Stress-induced hyperalgesia. Prog Neurobiol. 2014;121:1–18.PubMedCrossRefGoogle Scholar
  15. 15.
    Butler RK, Finn DP. Stress-induced analgesia. Prog Neurobiol. 2009;88:184–202.CrossRefPubMedGoogle Scholar
  16. 16.
    Colloca L, Grillon C. Understanding placebo and nocebo responses for pain management. Curr Pain Headache Rep. 2014;18:419.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Colloca L, Benedetti F. How prior experience shapes placebo analgesia. Pain. 2006;124:126–33.PubMedCrossRefGoogle Scholar
  18. 18.
    Colloca L, Sigaudo M, Benedetti F. The role of learning in nocebo and placebo effects. Pain. 2008;136:211–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Wei H, Zhou L, Zhang H, Chen J, Lu X, Hu L. The influence of expectation on nondeceptive placebo and nocebo effects. Pain Res Manag. 2018;2018:8459429.
  20. 20.
    Yeung STA, Colagiuri B, Lovibond PF, Colloca L. Partial reinforcement, extinction, and placebo analgesia. Pain. 2014;155:1110–7.PubMedCentralCrossRefGoogle Scholar
  21. 21.
    Zhang H, Zhou L, Wei H, Lu X, Hu L. The sustained influence of prior experience induced by social observation on placebo and nocebo responses. J Pain Res. 2017;10:2769–80.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Zhou L, Wei H, Zhang H, Li X, Bo C, Wan L, et al. The influence of expectancy level and personal characteristics on placebo effects: psychological underpinnings. Front Psychiatry. 2019;10:20. Scholar
  23. 23.
    Harvie DS, Meulders A, Madden VJ, Hillier SL, Peto DK, Brinkworth R, et al. When touch predicts pain: predictive tactile cues modulate perceived intensity of painful stimulation independent of expectancy. Scand J Pain. 2016;11:11–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Jensen K, Kircher I, Odmalm S, Kaptchuk TJ, Ingvar M. Classical conditioning of analgesic and hyperalgesic pain responses without conscious awareness. Proc Natl Acad Sci. 2015;112:7863–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Madden VJ, Bellan V, Russek LN, Camfferman D, Vlaeyen JWS, Moseley GL. Pain by association? Experimental modulation of human pain thresholds using classical conditioning. J Pain. 2016;17:1105–15.PubMedCrossRefGoogle Scholar
  26. 26.
    Williams AE, Rhudy JL. The influence of conditioned fear on human pain thresholds: does preparedness play a role? J Pain. 2007;8:598–606.PubMedCrossRefGoogle Scholar
  27. 27.
    Egorova N, Park J, Orr SP, Kirsch I, Gollub RL, Kong J. Not seeing or feeling is still believing: conscious and non-conscious pain modulation after direct and observational learning. Sci Rep. 2015;5:16809.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Egorova N, Park J, Kong J. In the face of pain: the choice of visual cues in pain conditioning matters. Eur J Pain. 2017;21:1243–51.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Harvie DS, Sterling M, Smith AD. Do pain-associated contexts increase pain sensitivity? An investigation using virtual reality. Scand J Pain. 2018;18:525–32.PubMedCrossRefGoogle Scholar
  30. 30.
    Icenhour A, Labrenz F, Ritter C, Theysohn N, Forsting M, Bingel U, et al. Learning by experience? Visceral pain-related neural and behavioral responses in a classical conditioning paradigm. Neurogastroenterol Motil. 2017;29:e13026.CrossRefGoogle Scholar
  31. 31.
    Labrenz F, Icenhour A, Schlamann M, Forsting M, Bingel U, Elsenbruch S. From Pavlov to pain: how predictability affects the anticipation and processing of visceral pain in a fear conditioning paradigm. NeuroImage. 2016;130:104–14.PubMedCrossRefGoogle Scholar
  32. 32.
    Madden VJ, Russek LN, Harvie DS, Vlaeyen JWS, Moseley GL. Classical conditioning fails to elicit allodynia in an experimental study with healthy humans. Pain Med. 2016;18:1314–25.Google Scholar
  33. 33.
    Reicherts P, Gerdes ABM, Pauli P, Wieser MJ. Psychological placebo and nocebo effects on pain rely on expectation and previous experience. J Pain. 2016;17:203–14.PubMedCrossRefGoogle Scholar
  34. 34.
    Flor H, Birbaumer N, Schulz R, Grüsser SM, Mucha RF. Pavlovian conditioning of opioid and nonopioid pain inhibitory mechanisms in humans. Eur J Pain. 2002;6:395–402.PubMedCrossRefGoogle Scholar
  35. 35.
    Flor H, Grosser SM. Conditioned stress-induced analgesia in humans. Eur J Pain. 1999;3:317–24.PubMedCrossRefGoogle Scholar
  36. 36.
    Schafer SM, Colloca L, Wager TD. Conditioned placebo analgesia persists when subjects know they are receiving a placebo. J Pain. 2015;16:412–20.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Lui F, Colloca L, Duzzi D, Anchisi D, Benedetti F, Porro CA. Neural bases of conditioned placebo analgesia. Pain. 2010;151:816–24.PubMedCrossRefGoogle Scholar
  38. 38.
    Valentini E, Martini M, Lee M, Aglioti SM, Iannetti G. Seeing facial expressions enhances placebo analgesia. Pain. 2014;155:666–73.PubMedCrossRefGoogle Scholar
  39. 39.
    Carlino E, Torta D, Piedimonte A, Frisaldi E, Vighetti S, Benedetti F. Role of explicit verbal information in conditioned analgesia. Eur J Pain. 2015;19:546–53.PubMedCrossRefGoogle Scholar
  40. 40.
    Flaten MA, Bjørkedal E, Lyby PS, Figenschau Y, Aslaksen PM. Failure to find a conditioned placebo analgesic response. Front Psychol. 2018;9:1198.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Rhudy JL, Güereca YM, Kuhn BL, Palit S, Flaten MA. The influence of placebo analgesia manipulations on pain report, the nociceptive flexion reflex, and autonomic responses to pain. J Pain. 2018;00:1–18.Google Scholar
  42. 42.
    Rhudy JL, Meagher MW. Fear and anxiety: divergent effects on human pain thresholds. Pain. 2000;84:65–75.PubMedCrossRefGoogle Scholar
  43. 43.
    Colloca L, Petrovic P, Wager TD, Ingvar M, Benedetti F. How the number of learning trials affects placebo and nocebo responses. Pain. 2010;151:430–9.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Jensen K, Kaptchuk T, Kirsch I, Raicek J, Lindstrom K, Berna C, et al. Nonconscious activation of placebo and nocebo pain responses. Proc Natl Acad Sci. 2012;109:15959–64.PubMedCrossRefGoogle Scholar
  45. 45.
    Rhudy JL, Williams AE, McCabe KM, Russell JL, Maynard LJ. Emotional control of nociceptive reactions (ECON): do affective valence and arousal play a role? Pain. 2008;136:250–61.PubMedCrossRefGoogle Scholar
  46. 46.
    Absi MA, Rokke PD. Can anxiety help us tolerate pain? Pain. 1991;46:43–51.PubMedCrossRefGoogle Scholar
  47. 47.
    Finn DP, Beckett SRG, Richardson D, Kendall DA, Marsden CA, Chapman V. Evidence for differential modulation of conditioned aversion and fear-conditioned analgesia by CB1 receptors. Eur J Neurosci. 2004;20:848–52.PubMedCrossRefGoogle Scholar
  48. 48.
    Ploghaus A, Narain C, Beckmann CF, Clare S, Bantick S, Wise R, et al. Exacerbation of pain by anxiety is associated with activity in a hippocampal network. J Neurosci. 2001;21:9896–903.PubMedCrossRefGoogle Scholar
  49. 49.
    Rhudy JL, Grimes JS, Meagher MW. Fear-induced hypoalgesia in humans: effects on low intensity thermal stimulation and finger temperature. J Pain. 2004;5:458–68.PubMedCrossRefGoogle Scholar
  50. 50.
    Colloca L, Benedetti F. Nocebo hyperalgesia: how anxiety is turned into pain. Curr Opin Anaesthesiol. 2007;20:435–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Benedetti F, Amanzio M, Casadio C, Oliaro A, Maggi G. Blockade of nocebo hyperalgesia by the cholecystokinin antagonist proglumide. Pain. 1997;71:135–40.PubMedCrossRefGoogle Scholar
  52. 52.
    Benedetti F, Amanzio M, Vighetti S, Asteggiano G. The biochemical and neuroendocrine bases of the hyperalgesic nocebo effect. J Neurosci. 2006;26:12014–22.PubMedCrossRefGoogle Scholar
  53. 53.
    Davis M. The role of the amygdala in fear and anxiety. Annu Rev Neurosci. 1992;15:353–75.CrossRefPubMedGoogle Scholar
  54. 54.
    Paulus MP, Stein MB. An insular view of anxiety. Biol Psychiatry. 2006;60:383–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Jensen K, Kaptchuk T, Chen X, Kirsch I, Ingvar M, Gollub R, et al. A neural mechanism for nonconscious activation of conditioned placebo and nocebo responses. Cereb Cortex. 2015;25:3903–10.PubMedCrossRefGoogle Scholar
  56. 56.
    Reicherts P, Wiemer J, Gerdes ABM, Schulz SM, Pauli P, Wieser MJ. Anxious anticipation and pain: the influence of instructed vs conditioned threat on pain. Soc Cogn Affect Neurosci. 2017;12:544–54.PubMedCrossRefGoogle Scholar
  57. 57.
    Izquierdo I, Furini CRG, Myskiw JC. Fear memory. Physiol Rev. 2016;96:695–750.CrossRefPubMedGoogle Scholar
  58. 58.
    Maren S. Neurobiology of Pavlovian fear conditioning. Annu Rev Neurosci. 2001;24:897–931.CrossRefPubMedGoogle Scholar
  59. 59.
    Kong J, Gollub RL, Polich G, Kirsch I, LaViolette P, Vangel M, et al. A functional magnetic resonance imaging study on the neural mechanisms of hyperalgesic nocebo effect. J Neurosci. 2008;28:13354–62.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Atlas LY, Wager TD. How expectations shape pain. Neurosci Lett. 2012;520:140–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Lau BK, Vaughan CW. Descending modulation of pain: the GABA disinhibition hypothesis of analgesia. Curr Opin Neurobiol. 2014;29:159–64.CrossRefPubMedGoogle Scholar
  62. 62.
    Rea K, Olango WM, Harhen B, Kerr DM, Galligan R, Fitzgerald S, et al. Evidence for a role of GABAergic and glutamatergic signalling in the basolateral amygdala in endocannabinoid-mediated fear-conditioned analgesia in rats. Pain. 2013;154:576–85.PubMedCrossRefGoogle Scholar
  63. 63.
    Chance WT, White AC, Krynock GM, Rosecrans JA. Autoanalgesia: behaviorally activated antinociception. Eur J Pharmacol. 1977;44:283–4.PubMedCrossRefGoogle Scholar
  64. 64.
    Chance WT, White AC, Krynock GM, Rosecrans JA. Conditional fear-induced antinociception and decreased binding of [3H]N-Leu-enkephalin to rat brain. Brain Res. 1978;141:371–4.PubMedCrossRefGoogle Scholar
  65. 65.
    Davis HD, Hendersen RW. Effects of conditioned fear on responsiveness to pain: long-term retention and reversibility by naloxone. Behav Neurosci. 1985;99:277–89.PubMedCrossRefGoogle Scholar
  66. 66.
    Lee HJ, Choi J-S, Brown TH, Kim JJ. Amygdalar NMDA receptors are critical for the expression of multiple conditioned fear responses. J Neurosci. 2001;21:4116–24.PubMedCrossRefGoogle Scholar
  67. 67.
    Helmstetter FJ. Stress-induced hypoalgesia and defensive freezing are attenuated by application of diazepam to the amygdala. Pharmacol Biochem Behav. 1993;44:433–8.CrossRefPubMedGoogle Scholar
  68. 68.
    Harris JA, Westbrook RF. Effects of benzodiazepine microinjection into the amygdala or periaqueductal gray on the expression of conditioned fear and hypoalgesia in rats. Behav Neurosci. 1995;109:295–304.PubMedCrossRefGoogle Scholar
  69. 69.
    Harris JA, Westbrook RF. Midazolam impairs the acquisition of conditioned analgesia if rats are tested with an acute but not a chronic noxious stimulus. Brain Res Bull. 1996;39:227–33.PubMedCrossRefGoogle Scholar
  70. 70.
    De Felice M, Ossipov MH. Cortical and subcortical modulation of pain. Pain Manag. 2016;6:111–20.PubMedCrossRefGoogle Scholar
  71. 71.
    Ossipov MH, Morimura K, Porreca F. Descending pain modulation and chronification of pain. Curr Opin Support Palliat Care. 2014;8:143–51.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Bingel U, Lorenz J, Schoell E, Weiller C, Büchel C. Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network. Pain. 2006;120:8–15.PubMedCrossRefGoogle Scholar
  73. 73.
    Eippert F, Bingel U, Schoell ED, Yacubian J, Klinger R, Lorenz J, et al. Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron. 2009;63:533–43.PubMedCrossRefGoogle Scholar
  74. 74.
    Krummenacher P, Candia V, Folkers G, Schedlowski M, Schönbächler G. Prefrontal cortex modulates placebo analgesia. Pain. 2010;148:368–74.PubMedCrossRefGoogle Scholar
  75. 75.
    Watson A, El-Deredy W, Iannetti GD, Lloyd D, Tracey I, Vogt BA, et al. Placebo conditioning and placebo analgesia modulate a common brain network during pain anticipation and perception. Pain. 2009;145:24–30.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Fox RJ, Sorenson CA. Bilateral lesions of the amygdala attenuate analgesia induced by diverse environmental challenges. Brain Res. 1994;648:215–21.PubMedCrossRefGoogle Scholar
  77. 77.
    Helmstetter FJ. The amygdala is essential for the expression of conditional hypoalgesia. Behav Neurosci. 1992;106:518–28.CrossRefPubMedGoogle Scholar
  78. 78.
    Watkins LR, Wiertelak EP, Maier SF. The amygdala is necessary for the expression of conditioned but not unconditioned analgesia. Behav Neurosci. 1993;107:402–5.PubMedCrossRefGoogle Scholar
  79. 79.
    Merskey H. Bogduk N, Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms. 2nd ed. Seattle, WA: IASP Press; 1994.Google Scholar
  80. 80.
    Gentry W, Bernal G. Chronic pain. In: Williams G, Gentry W, editors. Behav approaches medical treatment. Cambridge: Ballinger; 1977. p. 173–82.Google Scholar
  81. 81.
    Klinger R, Matter N, Kothe R, Dahme B, Hofmann UG, Krug F. Unconditioned and conditioned muscular responses in patients with chronic back pain and chronic tension-type headaches and in healthy controls. Pain. 2010;150:66–74.PubMedCrossRefGoogle Scholar
  82. 82.
    Schneider C, Palomba D, Flor H. Pavlovian conditioning of muscular responses in chronic pain patients: central and peripheral correlates. Pain. 2004;112:239–47.PubMedCrossRefGoogle Scholar
  83. 83.
    Lethem J, Slade PD, Troup JDG, Bentley G. Outline of a fear-avoidance model of exaggerated pain perception—I. Behav Res Ther. 1983;21:401–8.PubMedCrossRefGoogle Scholar
  84. 84.
    Vlaeyen JWS, Linton SJ. Fear-avoidance model of chronic musculoskeletal pain: 12 years on. Pain. 2012;153:1144–7.PubMedCrossRefGoogle Scholar
  85. 85.
    George SZ, Dannecker EA, Robinson ME. Fear of pain, not pain catastrophizing, predicts acute pain intensity, but neither factor predicts tolerance or blood pressure reactivity: an experimental investigation in pain- free individuals. Eur J Pain. 2006;10:457–65.PubMedCrossRefGoogle Scholar
  86. 86.
    Smeets RJEM, Vlaeyen JWS, Kester ADM, Knottnerus JA. Reduction of pain catastrophizing mediates the outcome of both physical and cognitive-behavioral treatment in chronic low back pain. J Pain. 2006;7:261–71.PubMedCrossRefGoogle Scholar
  87. 87.
    Turner JA, Jensen MP, Warms CA, Cardenas DD. Catastrophizing is associated with pain intensity, psychological distress, and pain-related disability among individuals with chronic pain after spinal cord injury. Pain. 2002;98:127–34.PubMedCrossRefGoogle Scholar
  88. 88.
    Turk DC, Wilson HD. Fear of pain as a prognostic factor in chronic pain: conceptual models, assessment, and treatment implications. Curr Pain Headache Rep. 2010;14:88–95.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Harvie DS, Moseley GL, Hillier SL, Meulders A. Classical conditioning differences associated with chronic pain: a systematic review. J Pain. 2017;18:889–98.PubMedCrossRefGoogle Scholar
  90. 90.
    Flor H, Birbaumer N, Roberts LE, Feige B, Lutzenberger W, Hermann C, et al. Slow potentials, event-related potentials, “gamma-band” activity, and motor responses during aversive conditioning in humans. Exp Brain Res. 1996;112:298–312.PubMedCrossRefGoogle Scholar
  91. 91.
    Icenhour A, Langhorst J, Benson S, Schlamann M, Hampel S, Engler H, et al. Neural circuitry of abdominal pain-related fear learning and reinstatement in irritable bowel syndrome. Neurogastroenterol Motil. 2015;27:114–27.PubMedCrossRefGoogle Scholar
  92. 92.
    Claassen J, Labrenz F, Ernst TM, Icenhour A, Langhorst J, Forsting M, et al. Altered cerebellar activity in visceral pain-related fear conditioning in irritable bowel syndrome. Cerebellum. 2017;16:508–17.PubMedCrossRefGoogle Scholar
  93. 93.
    Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2163–96.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Thomas BL, Cutler M, Novak C. A modified counterconditioning procedure prevents the renewal of conditioned fear in rats. Learn Motiv. 2012;43:24–34.CrossRefGoogle Scholar
  95. 95.
    Meulders A, Karsdorp PA, Claes N, Vlaeyen JWS. Comparing counterconditioning and extinction as methods to reduce fear of movement-related pain. J Pain. 2015;16:1353–65.PubMedCrossRefGoogle Scholar
  96. 96.
    Meulders A, Vansteenwegen D, Vlaeyen JWS. The acquisition of fear of movement-related pain and associative learning: a novel pain-relevant human fear conditioning paradigm. Pain. 2011;152:2460–9.PubMedCrossRefGoogle Scholar
  97. 97.
    Vervliet B, Craske MG, Hermans D. Fear extinction and relapse: state of the art. Annu Rev Clin Psychol. 2013;9:215–48.CrossRefPubMedGoogle Scholar
  98. 98.
    Gramsch C, Kattoor J, Icenhour A, Forsting M, Schedlowski M, Gizewski ER, et al. Learning pain-related fear: neural mechanisms mediating rapid differential conditioning, extinction and reinstatement processes in human visceral pain. Neurobiol Learn Mem. 2014;116:36–45.PubMedCrossRefGoogle Scholar
  99. 99.
    Icenhour A, Kattoor J, Benson S, Boekstegers A, Schlamann M, Merz CJ, et al. Neural circuitry underlying effects of context on human pain-related fear extinction in a renewal paradigm. Hum Brain Mapp. 2015;36:3179–93.PubMedCrossRefGoogle Scholar
  100. 100.
    Kattoor J, Gizewski ER, Kotsis V, Benson S, Gramsch C, Theysohn N, et al. Fear conditioning in an abdominal pain model: neural responses during associative learning and extinction in healthy subjects. PLoS One. 2013;8:e51149.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Maeda Y, Kan S, Fujino Y, Shibata M. Verbal instruction can induce extinction of fear of movement-related pain. J Pain. 2018;19:1063–73.PubMedCrossRefGoogle Scholar
  102. 102.
    Hermans D, Craske MG, Mineka S, Lovibond PF. Extinction in human fear conditioning. Biol Psychiatry. 2006;60:361–8.CrossRefPubMedGoogle Scholar
  103. 103.
    Monfils M-H, Cowansage KK, Klann E, LeDoux JE. Extinction-reconsolidation boundaries: key to persistent attenuation of fear memories. Science. 2009;324:951–5.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Lee JLC, Nader K, Schiller D. An update on memory reconsolidation updating. Trends Cogn Sci. 2017;21:531–45.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Nader K. Reconsolidation and the dynamic nature of memory. Cold Spring Harb Perspect Biol. 2015;7:a021782.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Kindt M, Soeter M, Vervliet B. Beyond extinction: erasing human fear responses and preventing the return of fear. Nat Neurosci. 2009;12:256–8.CrossRefPubMedGoogle Scholar
  107. 107.
    Chan JCK, LaPaglia JA. Impairing existing declarative memory in humans by disrupting reconsolidation. Proc Natl Acad Sci. 2013;110:9309–13.PubMedCrossRefGoogle Scholar
  108. 108.
    Escosteguy-Neto JC, Varela P, Correa-Neto NF, Coelho LS, Onaivi ES, Santos-Junior JG. Reconsolidation and update of morphine-associated contextual memory in mice. Neurobiol Learn Mem. 2016;130:194–201.PubMedCrossRefGoogle Scholar
  109. 109.
    Nader K, Schafe GE, Le Doux JE. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature. 2000;406:722–6.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Schiller D, Monfils M-H, Raio CM, Johnson DC, LeDoux JE, Phelps EA. Preventing the return of fear in humans using reconsolidation update mechanisms. Nature. 2010;463:49–53.CrossRefPubMedGoogle Scholar
  111. 111.
    Steinfurth ECK, Kanen JW, Raio CM, Clem RL, Huganir RL, Phelps EA. Young and old Pavlovian fear memories can be modified with extinction training during reconsolidation in humans. Learn Mem. 2014;21:338–41.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Xue Y, Luo Y, Wu P, Shi H, Xue L, Chen C, et al. A memory retrieval-extinction procedure to prevent drug craving and relapse. Science. 2012;336:241–5.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Agren T. Human reconsolidation: a reactivation and update. Brain Res Bull. 2014;105:70–82.CrossRefPubMedGoogle Scholar
  114. 114.
    Colagiuri B, Quinn VF. Autonomic arousal as a mechanism of the persistence of nocebo hyperalgesia. J Pain. 2018;19:476–86.PubMedCrossRefGoogle Scholar
  115. 115.
    Colagiuri B, Quinn VF, Colloca L. Nocebo hyperalgesia, partial reinforcement, and extinction. J Pain. 2015;16:995–1004.PubMedCrossRefGoogle Scholar
  116. 116.
    • Quinn VF, Colagiuri B. Using learning strategies to inhibit the nocebo effect. Colloca L, editor. Int Rev Neurobiol. Cambridge, MA: Academic Press; 2018. p. 307–27. A very good review discussing how to exploit learning strategies to inhibit the nocebo effect.
  117. 117.
    Lubow RE. Latent inhibition. Psychol Bull. 1973;79:398–407.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Klosterhalfen S, Kellermann S, Stockhorst U, Wolf J, Kirschbaum C, Hall G, et al. Latent inhibition of rotation chair-induced nausea in healthy male and female volunteers. Psychosom Med. 2005;67:335–40.PubMedCrossRefGoogle Scholar
  119. 119.
    Quinn VF, Livesey EJ, Colagiuri B. Latent inhibition reduces nocebo nausea, even without deception. Ann Behav Med. 2017;51:432–41.PubMedCrossRefGoogle Scholar
  120. 120.
    Hall G, Stockhorst U, Enck P, Klosterhalfen S. Overshadowing and latent inhibition in nausea-based context conditioning in humans: theoretical and practical implications. Q J Exp Psychol. 2016;69:1227–38.CrossRefGoogle Scholar
  121. 121.
    Stockhorst U, Hall G, Enck P, Klosterhalfen S. Effects of overshadowing on conditioned and unconditioned nausea in a rotation paradigm with humans. Exp Brain Res. 2014;232:2651–64.PubMedCrossRefGoogle Scholar
  122. 122.
    Stockhorst U, Wiener JA, Klosterhalfen S, Klosterhalfen W, Aul C, Steingrüber H-J. Effects of overshadowing on conditioned nausea in cancer patients: an experimental study. Physiol Behav. 1998;64:743–53.PubMedCrossRefGoogle Scholar
  123. 123.
    Jenkins WO, Stanley JC. Partial reinforcement: a review and critique. Psychol Bull. 1950;47:193–234.PubMedCrossRefGoogle Scholar
  124. 124.
    Coccoz V, Maldonado H, Delorenzi A. The enhancement of reconsolidation with a naturalistic mild stressor improves the expression of a declarative memory in humans. Neuroscience. 2011;185:61–72.PubMedCrossRefGoogle Scholar
  125. 125.
    Coccoz V, Sandoval AV, Stehberg J, Delorenzi A. The temporal dynamics of enhancing a human declarative memory during reconsolidation. Neuroscience. 2013;246:397–408.PubMedCrossRefGoogle Scholar
  126. 126.
    Vlaeyen JWS, de Jong J, Sieben J, Crombez G. Graded exposure in vivo for pain-related fear. Psychol Approaches Pain Manag Pract Handb. 2nd ed. New York: The Guilford Press; 2002. p. 210–33.Google Scholar
  127. 127.
    Boersma K, Linton S, Overmeer T, Jansson M, Vlaeyen JWS, de Jong J. Lowering fear-avoidance and enhancing function through exposure in vivo: a multiple baseline study across six patients with back pain. Pain. 2004;108:8–16.PubMedCrossRefGoogle Scholar
  128. 128.
    Flink IK, Nicholas MK, Boersma K, Linton SJ. Reducing the threat value of chronic pain: a preliminary replicated single-case study of interoceptive exposure versus distraction in six individuals with chronic back pain. Behav Res Ther. 2009;47:721–8.PubMedCrossRefGoogle Scholar
  129. 129.
    de Jong JR, Vlaeyen JWS, Onghena P, Goossens MEJB, Geilen M, Mulder H. Fear of movement/(re)injury in chronic low back pain: education or exposure in vivo as mediator to fear reduction? Clin J Pain. 2005;21:9–17.PubMedCrossRefGoogle Scholar
  130. 130.
    Leeuw M, Goossens MEJB, van Breukelen GJP, de Jong JR, Heuts PHTG, Smeets RJEM, et al. Exposure in vivo versus operant graded activity in chronic low back pain patients: results of a randomized controlled trial. Pain. 2008;138:192–207.PubMedCrossRefGoogle Scholar
  131. 131.
    Vlaeyen JWS, de Jong J, Geilen M, Heuts PHTG, van Breukelen G. Graded exposure in vivo in the treatment of pain-related fear: a replicated single-case experimental design in four patients with chronic low back pain. Behav Res Ther. 2001;39:151–66.PubMedCrossRefGoogle Scholar
  132. 132.
    Woods MP, Asmundson GJG. Evaluating the efficacy of graded in vivo exposure for the treatment of fear in patients with chronic back pain: a randomized controlled clinical trial. Pain. 2008;136:271–80.PubMedCrossRefGoogle Scholar
  133. 133.
    de Jong JR, Vlaeyen JWS, Onghena P, Cuypers C, den Hollander M, Ruijgrok J. Reduction of pain-related fear in complex regional pain syndrome type I: the application of graded exposure in vivo. Pain. 2005;116:264–75.PubMedCrossRefGoogle Scholar
  134. 134.
    de Jong JR, Vlaeyen JWS, van Eijsden M, Loo C, Onghena P. Reduction of pain-related fear and increased function and participation in work-related upper extremity pain (WRUEP): effects of exposure in vivo. Pain. 2012;153:2109–18.PubMedCrossRefGoogle Scholar
  135. 135.
    Linton SJ, Boersma K, Jansson M, Overmeer T, Lindblom K, Vlaeyen JWS. A randomized controlled trial of exposure in vivo for patients with spinal pain reporting fear of work-related activities. Eur J Pain. 2012;12:722–30.CrossRefGoogle Scholar
  136. 136.
    Flor H. The functional organization of the brain in chronic pain. Prog Brain Res. 2000;129:313–22.PubMedCrossRefGoogle Scholar
  137. 137.
    Kuner R, Flor H. Structural plasticity and reorganisation in chronic pain. Nat Rev Neurosci. 2017;18:20–30.CrossRefGoogle Scholar
  138. 138.
    Moseley GL, Flor H. Targeting cortical representations in the treatment of chronic pain: a review. Neurorehabil Neural Repair. 2012;26:646–52.PubMedCrossRefGoogle Scholar
  139. 139.
    Flor H, Denke C, Schaefer M, Grüsser S. Effect of sensory discrimination training on cortical reorganisation and phantom limb pain. Lancet. 2001;357:1763–4.PubMedCrossRefGoogle Scholar
  140. 140.
    Wakolbinger R, Diers M, Hruby LA, Sturma A, Aszmann OC. Home-based tactile discrimination training reduces phantom limb pain. Pain Pract. 2018;18:709–15.PubMedCrossRefGoogle Scholar
  141. 141.
    Barker KL, Elliott CJ, Sackley CM, Fairbank JC. Treatment of chronic back pain by sensory discrimination training. A phase I RCT of a novel device (FairMed) vs. TENS. BMC Musculoskelet Disord. 2008;9:97.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Trapp W, Weinberger M, Erk S, Fuchs B, Mueller M, Gallhofer B, et al. A brief intervention utilising visual feedback reduces pain and enhances tactile acuity in CLBP patients. J Back Musculoskelet Rehabil. 2015;28:651–60.PubMedCrossRefGoogle Scholar
  143. 143.
    Wand BM, Abbaszadeh S, Smith AJ, Catley MJ, Moseley GL. Acupuncture applied as a sensory discrimination training tool decreases movement-related pain in patients with chronic low back pain more than acupuncture alone: a randomised cross-over experiment. Br J Sports Med. 2013;47:1085–9.PubMedCrossRefGoogle Scholar
  144. 144.
    Moseley GL, Wiech K. The effect of tactile discrimination training is enhanced when patients watch the reflected image of their unaffected limb during training. Pain. 2009;144:314–9.PubMedCrossRefGoogle Scholar
  145. 145.
    Moseley GL, Zalucki NM, Wiech K. Tactile discrimination, but not tactile stimulation alone, reduces chronic limb pain. Pain. 2008;137:600–8.PubMedCrossRefGoogle Scholar
  146. 146.
    Pleger B, Tegenthoff M, Ragert P, Förster A-F, Dinse HR, Schwenkreis P, et al. Sensorimotor returning in complex regional pain syndrome parallels pain reduction. Ann Neurol. 2005;57:425–9.CrossRefPubMedGoogle Scholar
  147. 147.
    Schmid AC, Schwarz A, Gustin SM, Greenspan JD, Hummel FC, Birbaumer N. Pain reduction due to novel sensory-motor training in complex regional pain syndrome I – a pilot study. Scand J Pain. 2017;15:30–7.PubMedCrossRefGoogle Scholar
  148. 148.
    Nir RR, Yarnitsky D, Honigman L, Granot M. Cognitive manipulation targeted at decreasing the conditioning pain perception reduces the efficacy of conditioned pain modulation. Pain. 2012;153:170–6.PubMedCrossRefGoogle Scholar
  149. 149.
    Fazio RH, Olson MA. Implicit measures in social cognition research: their meaning and use. Annu Rev Psychol. 2003;54:297–327.PubMedCrossRefGoogle Scholar
  150. 150.
    Gawronski B, Hofmann W, Wilbur CJ. Are “implicit” attitudes unconscious? Conscious Cogn. 2006;15:485–99.PubMedCrossRefGoogle Scholar
  151. 151.
    Melnikoff DE, Bargh JA. The mythical number two. Trends Cogn Sci. 2018;22:280–93.PubMedCrossRefGoogle Scholar
  152. 152.
    Carew TJ, Hawkins RD, Kandel ER. Differential classical conditioning of a defensive withdrawal reflex in Aplysia californica. Science. 1983;219:397–400.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Berntson GG, Tuber DS, Ronca AE, Bachman DS. The decerebrate human: associative learning. Exp Neurol. 1983;81:77–88.PubMedCrossRefGoogle Scholar
  154. 154.
    Grau JW, Salinas JA, Illich PA, Meagher MW. Associative learning and memory for an antinociceptive response in the spinalized rat. Behav Neurosci. 1990;104:489–94.PubMedCrossRefGoogle Scholar
  155. 155.
    Treede R-D, Rief W, Barke A, Aziz Q, Bennett MI, Benoliel R, et al. A classification of chronic pain for ICD- 11. Pain. 2015;156:1003–7.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.CAS Key Laboratory of Mental HealthInstitute of Psychology Chinese Academy of SciencesBeijingChina
  2. 2.Department of PsychologyUniversity of Chinese Academy of SciencesBeijingChina
  3. 3.Department of Pain Management, The State Key Clinical Specialty in Pain MedicineThe Second Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina

Personalised recommendations