Placebo analgesia induced by verbal suggestion in the context of experimentally induced fear and anxiety

Autoři: Karolina Świder aff001;  Przemysław Bąbel aff002;  Eligiusz Wronka aff003;  Clementina M. van Rijn aff001;  Joukje M. Oosterman aff001
Působiště autorů: Donders Institute for Brain, Cognition & Behaviour, Radboud University, Nijmegen, The Netherlands aff001;  Institute of Psychology, Pain Research Group, Jagiellonian University, Kraków, Poland aff002;  Institute of Psychology, Jagiellonian University, Kraków, Poland aff003
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pone.0222805


The role of state anxiety and state fear in placebo effects is still to be determined. We aimed to investigate the effect of fear of movement-related pain (FMRP) and contextual pain related anxiety (CPRA) on the magnitude of placebo analgesia induced by verbal suggestion. Fifty-six female participants completed a modified voluntary joystick movement paradigm (VJMP) where half participated in a predictable pain condition (PC), in which one of the joystick movements is always followed by pain and the other movement is never followed by pain, and half in an unpredictable pain condition (UC), in which pain was delivered unpredictably. By varying the level of pain predictability, FMRP and CPRA were induced in PC and UC respectively. Colour stimuli were presented at the beginning of each trail. Half of the participants were verbally informed that the green or red colour indicated less painful stimuli (experimental groups), the other half did not receive any suggestion (control groups). We measured self-reported pain intensity, expectancy of pain intensity (PC only), pain related fear and anxiety (eyeblink startle response and self-ratings) and avoidance behaviour (movement-onset latency and duration). The results indicate that the placebo effect was successfully induced in both experimental conditions. In the PC, the placebo effect was predicted by expectancy. Despite the fact that FMRP and CPRA were successfully induced, no difference was found in the magnitude of the placebo effect between PC and UC. Concluding, we did not find a divergent effect of fear and anxiety on placebo analgesia.

Klíčová slova:

Anxiety – Conditioned response – Emotions – Eye movements – Fear – Reaction time – Analgesia – Pain sensation


1. Vase L, Robinson ME, Verne GN, Price DD. Increased placebo analgesia over time in irritable bowel syndrome (IBS) patients is associated with desire and expectation but not endogenous opioid mechanisms. Pain. 2005;115: 338–347. doi: 10.1016/j.pain.2005.03.014 15911161

2. Vase L, Robinson ME, Verne GN, Price DD. The contributions of suggestion, desire, and expectation to placebo effects in irritable bowel syndrome patients: An empirical investigation. Pain. 2003;105: 17–25. doi: 10.1016/s0304-3959(03)00073-3 14499416

3. Lyby PS, Forsberg JT, Åsli O, Flaten MA. Induced fear reduces the effectiveness of a placebo intervention on pain. Pain. 2012;153: 1114–1121. doi: 10.1016/j.pain.2012.02.042 22464696

4. de Jong PJ, van Baast R, Arntz A, Merckelbach H. The Placebo Effect in Pain Reduction: The Influence of Conditioning Experiences and Response Expectancies. Int J Behav Med. 1996;3: 14–29. doi: 10.1207/s15327558ijbm0301_2 16250764

5. Evans F. The placebo control of pain: a paradigm for investigating non–specific effects in psychotherapy. In: Brady J, Mendels J, Reiger W, Orne M, editors. Psychiatry: Areas of Promise and Advancement. New York: Plenum Press; 1977. pp. 249–271.

6. McGlashan TH, Evans FJ, Orne MT. The Nature of Hypnotic Analgesia and Placebo Response to Experimental. Pain. 1969;31: 227–246.

7. Noyes R, Roth M, Burrows GD. The assessment of state and trait anxiety. In: Noyes R Jr, Roth M BG, editor. Handbook of Anxiety, Vol2:Etiological Factors and Associated Disturbances Elsevier Science Publishers. Amsterdam: Elsevier; 1988. pp. 31–51.

8. Sylvers P, Lilienfeld SO, LaPrairie JL. Differences between trait fear and trait anxiety: Implications for psychopathology. Clin Psychol Rev. 2011;31: 122–137. doi: 10.1016/j.cpr.2010.08.004 20817337

9. Rachman S. Anxiety. Anxiety. 2nd ed. Hove: Psychology Press; 2004. pp. 1–7.

10. Rhudy JL, Meagher MW. Fear and anxiety: divergent effects on human pain thresholds. Pain. 2000;84: 65–75. doi: 10.1016/s0304-3959(99)00183-9 10601674

11. Meulders A, Vansteenwegen D, Vlaeyen JWS. Women, but not men, report increasingly more pain during repeated (un)predictable painful electrocutaneous stimulation: Evidence for mediation by fear of pain. Pain. 2012;153: 1030–41. doi: 10.1016/j.pain.2012.02.005 22401700

12. 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: 2460–2469. doi: 10.1016/j.pain.2011.05.015 21723664

13. Meulders A, Vlaeyen JWS. Reduction of fear of movement-related pain and pain-related anxiety: An associative learning approach using a voluntary movement paradigm. Pain. 2012;153: 1504–1513. doi: 10.1016/j.pain.2012.04.013 22617631

14. Meulders A, Meulders M, Vlaeyen JWS. Positive affect protects against deficient safety learning during extinction of fear of movement-related pain in healthy individuals scoring relatively high on trait anxiety. J Pain. Elsevier Ltd; 2014;15: 632–644. doi: 10.1016/j.jpain.2014.02.009 24650796

15. Perusini JN, Fanselow MS. Neurobehavioral perspectives on the distinction between fear and anxiety. Learn Mem. 2015;22: 417–25. doi: 10.1101/lm.039180.115 26286652

16. Colloca L, Benedetti F. Placebo analgesia induced by social observational learning. Pain. 2009;144: 28–34. doi: 10.1016/j.pain.2009.01.033 19278785

17. Amanzio M, Benedetti F. Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems. J Neurosci. 1999;19: 484–494. doi: 10.1523/JNEUROSCI.19-01-00484.1999 9870976

18. Aslaksen PM, Flaten MA. The roles of physiological and subjective stress in the effectiveness of a placebo on experimentally induced pain. Psychosom Med. 2008;70: 811–8. doi: 10.1097/PSY.0b013e31818105ed 18725424

19. Voudouris NJ, Peck CL, Coleman G. Conditioned placebo responses. J Pers Soc Psychol. 1985;48: 47. doi: 10.1037//0022-3514.48.1.47 3981392

20. Montgomery GH, Kirsch I. Classical conditioning and the placebo effect. Pain. 1997;72: 107–113. doi: 10.1016/s0304-3959(97)00016-x 9272794

21. Świder K, Babel P. The effect of the type and colour of placebo stimuli on placebo effects induced by observational learning. PLoS One. 2016;11. doi: 10.1371/journal.pone.0158363 27362552

22. Świder K, Bąbel P. The effect of the sex of a model on nocebo hyperalgesia induced by social observational learning. Pain. 2013;154: 1312–7. doi: 10.1016/j.pain.2013.04.001 23725779

23. Colloca L, Miller FG. How placebo responses are formed: a learning perspective. Philos Trans R Soc B Biol Sci. 2011;366: 1859–1869. doi: 10.1098/rstb.2010.0398 21576143

24. Kirsch I. Response Expectancy as a Determinant of Experience and Behavior. Am Psychol. 1985;40: 1189–1202. doi: 10.1037/0003-066X.40.11.1189

25. Kirsch I, Kong J, Sadler P, Spaeth R, Cook A, Kaptchuk TJ, et al. Expectancy and conditioning in placebo analgesia: separate or connected processes? Psychol Conscious Theory, Res Pract. 2014;1: 51.

26. Stewart-Williams S, Podd J. The Placebo Effect: Dissolving the Expectancy Versus Conditioning Debate. Psychol Bull. 2004;130: 324–340. doi: 10.1037/0033-2909.130.2.324 14979775

27. Price DD, Milling LS, Kirsch I, Duff A, Montgomery GH, Nicholls SS. An analysis of factors that contribute to the magnitude of placebo analgesia in an experimental paradigm. Pain. 1999;83: 147–156. doi: 10.1016/s0304-3959(99)00081-0 10534585

28. Schmid J, Bingel U, Ritter C, Benson S, Schedlowski M, Gramsch C, et al. Neural underpinnings of nocebo hyperalgesia in visceral pain: A fMRI study in healthy volunteers. Neuroimage. 2015;120: 114–122. doi: 10.1016/j.neuroimage.2015.06.060 26123378

29. Freeman S, Yu R, Egorova N, Chen X, Kirsch I, Claggett B, et al. Distinct neural representations of placebo and nocebo effects. Neuroimage. 2015;112: 197–207. doi: 10.1016/j.neuroimage.2015.03.015 25776211

30. Bąbel P, Bajcar EA, Adamczyk W, Kicman P, Lisińska N, Świder K, et al. Classical conditioning without verbal suggestions elicits placebo analgesia and nocebo hyperalgesia. PLoS One. 2017;12: 1–12. doi: 10.1371/journal.pone.0181856 28750001

31. Bąbel P, Adamczyk W, Świder K, Bajcar EA, Kicman P, Lisińska N. How Classical Conditioning Shapes Placebo Analgesia: Hidden versus Open Conditioning. Pain Med. 2018;19: 1156–1169. doi: 10.1093/pm/pnx177 29016984

32. Colagiuri B, Quinn VF, Colloca L. Nocebo Hyperalgesia, Partial Reinforcement, and Extinction. J Pain. 2015;16: 995–1004. doi: 10.1016/j.jpain.2015.06.012 26168876

33. Blumenthal TD, Cuthbert BN, Filion DL, Hackley S, Lipp O V, Boxtel AVAN. Committee report: Guidelines for human startle eyeblink electromyographic studies. Psychophysiology. 2005;42: 1–15. doi: 10.1111/j.1469-8986.2005.00271.x 15720576

34. Meulders A, Vlaeyen JWS. Mere Intention to Perform Painful Movements Elicits Fear of Movement-Related Pain: An Experimental Study on Fear Acquisition Beyond Actual Movements. J Pain. Elsevier Ltd; 2013;14: 412–423. doi: 10.1016/j.jpain.2012.12.014 23453562

35. Lachaud CM, Renaud O. A tutorial for analyzing human reaction times: How to filter data, manage missing values, and choose a statistical model. Appl Psycholinguist. 2011;32: 389–416. doi: 10.1017/S0142716410000457

36. Hubbard CS, Ornitz E, Gaspar JX, Smith S, Amin J, Labus JS, et al. Modulation of nociceptive and acoustic startle responses to an unpredictable threat in men and women. Pain. 2011;152: 1632–1640. doi: 10.1016/j.pain.2011.03.001 21477924

37. Oka S, Chapman CR, Kim B, Shimizu O, Noma N, Takeichi O, et al. Predictability of Painful Stimulation Modulates Subjective and Physiological Responses. J Pain. 2010;11: 239–246. doi: 10.1016/j.jpain.2009.07.009 19853519

38. Petrovic P, Dietrich T, Fransson P, Andersson J, Carlsson K, Ingvar M. Placebo in emotional processing—Induced expectations of anxiety relief activate a generalized modulatory network. Neuron. 2005;46: 957–969. doi: 10.1016/j.neuron.2005.05.023 15953423

39. Wager TD. Placebo-Induced Changes in fMRI in the Anticipation and Experience of Pain. Science (80-). 2004;303: 1162–1167. doi: 10.1126/science.1093065 14976306

40. Bąbel P. Psychologiczne mechanizmy negatywnego działania placebo. Analiza empiryczna [Psychological mechanisms of negative placebo action. An empirical analysis]. Stud Psychol. 2008;46: 13–14.

41. Kirsch I. Response expectancy theory and application: A decennial review. Appl Prev Psychol. 1997;6: 69–79. doi: 10.1016/S0962-1849(05)80012-5

42. Miller FG, Colloca L. Semiotics and the placebo effect. Perspect Biol Med. 2010;53: 509–516. doi: 10.1353/pbm.2010.0004 21037405

43. Büchel C, Geuter S, Sprenger C, Eippert F. Placebo analgesia: A predictive coding perspective. Neuron. 2014;81: 1223–1239. doi: 10.1016/j.neuron.2014.02.042 24656247

44. Tracey I. Getting the pain you expect: mechanisms of placebo, nocebo and reappraisal effects in humans. Nat Am. 2010;16: 1277–1283.

45. Wager TD, Atlas LY, Lindquist MA, Roy M, Woo C-W, Kross E. An fMRI-Based Neurologic Signature of Physical Pain. N Engl J Med. 2013;368: 1388–1397. doi: 10.1056/NEJMoa1204471 23574118

46. 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: 533–543. doi: 10.1016/j.neuron.2009.07.014 19709634

47. Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK. Individual Differences in Reward Responding Explain Placebo-Induced Expectations and Effects. Neuron. 2007;55: 325–336. doi: 10.1016/j.neuron.2007.06.028 17640532

48. Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta J-K. Placebo and Nocebo Effects Are Defined by Opposite Opioid and Dopaminergic Responses. Arch Gen Psychiatry. 2008;65: 220. doi: 10.1001/archgenpsychiatry.2007.34 18250260

49. Piedimonte A, Guerra G, Vighetti S, Carlino E. Measuring expectation of pain: Contingent negative variation in placebo and nocebo effects. Eur J Pain (United Kingdom). 2017;21: 874–885. doi: 10.1002/ejp.990 28106308

50. Olsson A, Phelps EA. Social learning of fear. Nature Neuroscience. 2007. pp. 1095–1102. doi: 10.1038/nn1968 17726475

51. Helsen K, Goubert L, Peters ML, Vlaeyen JWS. Observational learning and pain-related fear: An experimental study with colored cold pressor tasks. J Pain. 2011;12: 1230–1239. doi: 10.1016/j.jpain.2011.07.002 22019133

52. Walker DL, Toufexis DJ, Davis M. Role of the bed nucleus of the stria terminalis versus the amygdala in fear, stress, and anxiety. Eur J Pharmacol. 2003;463: 199–216. doi: 10.1016/s0014-2999(03)01282-2 12600711

53. Grillon C. Models and mechanisms of anxiety: Evidence from startle studies. Psychopharmacology (Berl). 2008;199: 421–437. doi: 10.1007/s00213-007-1019-1 18058089

54. Crombez G, Vlaeyen JW, Heuts PH, Lysens R. Pain-related fear is more disabling than pain itself: evidence on the role of pain-related fear in chronic back pain disability. Pain. 1999;80: 329–39. doi: 10.1016/s0304-3959(98)00229-2 10204746

55. Buer N, Linton SJ. Fear-avoidance beliefs and catastrophizing: Occurrence and risk factor in back pain and ADL in the general population. Pain. 2002. pp. 485–491. doi: 10.1016/s0304-3959(02)00265-8 12406524

56. McCracken LM, Samuel VM. The role of avoidance, pacing, and other activity patterns in chronic pain. Pain. 2007;130: 119–125. doi: 10.1016/j.pain.2006.11.016 17240065

Článok vyšiel v časopise


2019 Číslo 9

Najčítanejšie v tomto čísle

Tejto téme sa ďalej venujú…


Zvýšte si kvalifikáciu online z pohodlia domova

Faktory ovlivňující léčbu levotyroxinem
nový kurz

Kurz originály vs. generika

Autori: MUDr. Petr Výborný, CSc., FEBO

Autori: MUDr. Jiří Horažďovský, Ph.D

Klinická farmakokinetika betablokátorů

Všetky kurzy
Zabudnuté heslo

Nemáte účet?  Registrujte sa

Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.


Nemáte účet?  Registrujte sa