Original Report| Volume 15, ISSUE 12, P1282-1293, December 2014

Expectancy-Induced Placebo Analgesia in Children and the Role of Magical Thinking

  • Peter Krummenacher
    Address reprint requests to Peter Krummenacher, PhD, ETH Zurich and University of Zurich, Collegium Helveticum, Schmelzbergstrasse 25, CH-8092 Zurich, Switzerland.
    Department of Psychology, Clinical Psychology and Psychotherapy, University of Basel, Basel, Switzerland

    Collegium Helveticum, University of Zurich and ETH Zurich, Zurich, Switzerland

    brainability LLC, Zurich, Switzerland
    Search for articles by this author
  • Joe Kossowsky
    Department of Psychology, Clinical Psychology and Psychotherapy, University of Basel, Basel, Switzerland

    Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts

    Program in Placebo Studies, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts
    Search for articles by this author
  • Caroline Schwarz
    Department of Psychology, Clinical Psychology and Psychotherapy, University of Basel, Basel, Switzerland
    Search for articles by this author
  • Peter Brugger
    Neuropsychology Unit, Department of Neurology, University Hospital Zurich, Zurich, Switzerland
    Search for articles by this author
  • John M. Kelley
    Program in Placebo Studies, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts

    Psychiatry Department, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts

    Psychology Department, Endicott College, Beverly, Massachusetts
    Search for articles by this author
  • Andrea Meyer
    Department of Psychology, Clinical Psychology and Epidemiology, University of Basel, Switzerland
    Search for articles by this author
  • Jens Gaab
    Department of Psychology, Clinical Psychology and Psychotherapy, University of Basel, Basel, Switzerland
    Search for articles by this author
Published:September 24, 2014DOI:


      • The study documents the first experimental evidence for a substantial expectancy-induced placebo analgesia response in healthy children aged 6 to 9 years.
      • The placebo responses were 5.6 times larger for pain tolerance and 3.6 times larger for pain threshold than those found in adults in a recently published study using a similar heat pain paradigm.
      • Girls were more placebo responsive for pain threshold than boys.
      • Pain perception in boys was modulated by magical thinking and it was differentially so for the left and right forearms.


      Expectations and beliefs shape the experience of pain. This is most evident in context-induced, placebo analgesia, which has recently been shown to interact with the trait of magical thinking (MT) in adults. In children, placebo analgesia and the possible roles that MT and gender might play as modulators of placebo analgesia have remained unexplored. Using a paradigm in which heat pain stimuli were applied to both forearms, we investigated whether MT and gender can influence the magnitude of placebo analgesia in children. Participants were 49 right-handed children (aged 6–9 years) who were randomly assigned—stratified for MT and gender—to either an analgesia-expectation or a control-expectation condition. For both conditions, the placebo was a blue-colored hand disinfectant that was applied to the children's forearms. Independent of MT, the placebo treatment significantly increased both heat pain threshold and tolerance. The threshold placebo effect was more pronounced for girls than boys. In addition, independent of the expectation treatment, low-MT boys showed a lower tolerance increase on the left compared to the right side. Finally, MT specifically modulated tolerance on the right forearm side: Low-MT boys showed an increase, whereas high-MT boys showed a decrease in heat pain tolerance. This study documented a substantial expectation-induced placebo analgesia response in children (girls > boys) and demonstrated MT and gender-dependent laterality effects in pain perception. The findings may help improve individualized pain management for children.


      The study documents the first experimental evidence for a substantial expectancy-induced placebo analgesia response in healthy children aged 6 to 9 years (girls > boys). Moreover, the effect was substantially higher than the placebo response typically found in adults. The findings may help improve individualized pain management for children.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Abbott K.
        • Fowler-Kerry S.
        The use of a topical refrigerant anesthetic to reduce injection pain in children.
        J Pain Symptom Manage. 1995; 10: 584-590
        • Arts S.E.
        • Abu-Saad H.H.
        • Champion G.D.
        • Crawford M.R.
        • Fisher R.J.
        • Juniper K.H.
        • Ziegler J.B.
        Age-related response to lidocaine-prilocaine (EMLA) emulsion and effect of music distraction on the pain of intravenous cannulation.
        Pediatrics. 1994; 93: 797-801
        • Bauman D.E.
        • Bul P.I.
        [Human inheritability of hypnotizability].
        Genetika. 1981; 17: 352-356
        • Benedetti F.
        Mechanisms of placebo and placebo-related effects across diseases and treatments.
        Annu Rev Pharmacol Toxicol. 2008; 48: 33-60
        • Benedetti F.
        Placebo and the new physiology of the doctor-patient relationship.
        Physiol Rev. 2013; 93: 1207-1246
        • Benedetti F.
        • Arduino C.
        • Costa S.
        • Vighetti S.
        • Tarenzi L.
        • Rainero I.
        • Asteggiano G.
        Loss of expectation-related mechanisms in Alzheimer's disease makes analgesic therapies less effective.
        Pain. 2006; 121: 133-144
        • Benedetti F.
        • Thoen W.
        • Blanchard C.
        • Vighetti S.
        • Arduino C.
        Pain as a reward: Changing the meaning of pain from negative to positive co-activates opioid and cannabinoid systems.
        Pain. 2013; 154: 361-367
        • Bingel U.
        • Wanigasekera V.
        • Wiech K.
        • Ni Mhuircheartaigh R.
        • Lee M.C.
        • Ploner M.
        • Tracey I.
        The effect of treatment expectation on drug efficacy: Imaging the analgesic benefit of the opioid remifentanil.
        Sci Transl Med. 2011; 3: 70ra14
        • Bolton D.
        • Dearsley P.
        • Madronal-Luque R.
        • Baron-Cohen S.
        Magical thinking in childhood and adolescence: Development and relation to obsessive compulsion.
        Br J Dev Psychol. 2002; 20: 479-494
        • Booth J.R.
        • Burman D.D.
        • Meyer J.R.
        • Trommer B.L.
        • Davenport N.D.
        • Parrish T.B.
        • Gitelman D.R.
        • Mesulam M.M.
        Brain-behavior correlation in children depends on the neurocognitive network.
        Hum Brain Mapp. 2004; 23: 99-108
        • Brown T.T.
        • Lugar H.M.
        • Coalson R.S.
        • Miezin F.M.
        • Petersen S.E.
        • Schlaggar B.L.
        Developmental changes in human cerebral functional organization for word generation.
        Cereb Cortex. 2005; 15: 275-290
        • Bruck M.
        • Melnyk L.
        Individual differences in children’s suggestibility: A review and synthesis.
        Appl Cognit Psychol. 2004; 18: 947-996
        • Brugger P.
        Tracking a finer madness.
        Sci Am Mind. 2007; 10: 77-79
        • Brugger P.
        • Mohr C.
        The paranormal mind: How the study of anomalous experiences and beliefs may inform cognitive neuroscience.
        Cortex. 2008; 44: 1291-1298
        • Buck M.
        The placebo response in pediatric clinical trials.
        Pediatr Pharmacol. 2012; 18
        • Casey B.J.
        • Castellanos F.X.
        • Giedd J.N.
        • Marsh W.L.
        • Hamburger S.D.
        • Schubert A.B.
        • Vauss Y.C.
        • Vaituzis A.C.
        • Dickstein D.P.
        • Sarfatti S.E.
        • Rapoport J.L.
        Implication of right frontostriatal circuitry in response inhibition and attention-deficit/hyperactivity disorder.
        J Am Acad Child Adolesc Psychiatry. 1997; 36: 374-383
        • Casey B.J.
        • Duhoux S.
        • Malter Cohen M.
        Adolescence: What do transmission, transition, and translation have to do with it?.
        Neuron. 2010; 67: 749-760
        • Casey B.J.
        • Tottenham N.
        • Liston C.
        • Durston S.
        Imaging the developing brain: What have we learned about cognitive development?.
        Trends Cogn Sci. 2005; 9: 104-110
        • Chiron C.
        • Jambaque I.
        • Nabbout R.
        • Lounes R.
        • Syrota A.
        • Dulac O.
        The right brain hemisphere is dominant in human infants.
        Brain. 1997; 120: 1057-1065
        • Coghill R.C.
        • Gilron I.
        • Iadarola M.J.
        Hemispheric lateralization of somatosensory processing.
        J Neurophysiol. 2001; 85: 2602-2612
        • Colloca L.
        • Benedetti F.
        Placebo analgesia induced by social observational learning.
        Pain. 2009; 144: 28-34
        • Colloca L.
        • Klinger R.
        • Flor H.
        • Bingel U.
        Placebo analgesia: Psychological and neurobiological mechanisms.
        Pain. 2013; 154: 511-514
        • Colloca L.
        • Miller F.G.
        How placebo responses are formed: A learning perspective.
        Philos Trans R Soc Lond B Biol Sci. 2011; 366: 1859-1869
        • Colloca L.
        • Sigaudo M.
        • Benedetti F.
        The role of learning in nocebo and placebo effects.
        Pain. 2008; 136: 211-218
        • de la Fuente-Fernandez R.
        • Ruth T.J.
        • Sossi V.
        • Schulzer M.
        • Calne D.B.
        • Stoessl A.J.
        Expectation and dopamine release: Mechanism of the placebo effect in Parkinson's disease.
        Science. 2001; 293: 1164-1166
        • Eckblad M.
        • Chapman L.J.
        Magical ideation as an indicator of schizotypy.
        J Consult Clin Psychol. 1983; 51: 215-225
        • Eippert F.
        • Bingel U.
        • Schoell E.D.
        • Yacubian J.
        • Klinger R.
        • Lorenz J.
        • Buchel C.
        Activation of the opioidergic descending pain control system underlies placebo analgesia.
        Neuron. 2009; 63: 533-543
        • Enck P.
        • Benedetti F.
        • Schedlowski M.
        New insights into the placebo and nocebo responses.
        Neuron. 2008; 59: 195-206
        • Evers S.
        • Marziniak M.
        • Frese A.
        • Gralow I.
        Placebo efficacy in childhood and adolescence migraine: An analysis of double-blind and placebo-controlled studies.
        Cephalalgia. 2009; 29: 436-444
        • Folley B.S.
        • Park S.
        Verbal creativity and schizotypal personality in relation to prefrontal hemispheric laterality: A behavioral and near-infrared optical imaging study.
        Schizophr Res. 2005; 80: 271-282
        • Giedd J.N.
        • Rapoport J.L.
        Structural MRI of pediatric brain development: What have we learned and where are we going?.
        Neuron. 2010; 67: 728-734
        • Gogtay N.
        • Giedd J.N.
        • Lusk L.
        • Hayashi K.M.
        • Greenstein D.
        • Vaituzis A.C.
        • Nugent 3rd, T.F.
        • Herman D.H.
        • Clasen L.S.
        • Toga A.W.
        • Rapoport J.L.
        • Thompson P.M.
        Dynamic mapping of human cortical development during childhood through early adulthood.
        Proc Natl Acad Sci U S A. 2004; 101: 8174-8179
        • Goodenough B.
        • Kampel L.
        • Champion G.D.
        • Laubreaux L.
        • Nicholas M.K.
        • Ziegler J.B.
        • McInerney M.
        An investigation of the placebo effect and age-related factors in the report of needle pain from venipuncture in children.
        Pain. 1997; 72: 383-391
        • Grob A.
        • Meyer C.S.
        • Hagmann-von Arx P.
        Intelligence and Development Scales (IDS).
        Hans Huber, Bern2009
        • Hedl J.J.
        • Papay J.P.
        The factor structure of the State-Trait Anxiety Inventory for Children: Kindergarten through the fourth grades.
        Pers Indiv Differ. 1982; 3: 439-446
        • Hicks C.L.
        • von Baeyer C.L.
        • Spafford P.A.
        • van Korlaar I.
        • Goodenough B.
        The Faces Pain Scale-Revised: Toward a common metric in pediatric pain measurement.
        Pain. 2001; 93: 173-183
        • Jensen K.B.
        • Kaptchuk T.J.
        • Kirsch I.
        • Raicek J.
        • Lindstrom K.M.
        • Berna C.
        • Gollub R.L.
        • Ingvar M.
        • Kong J.
        Nonconscious activation of placebo and nocebo pain responses.
        Proc Natl Acad Sci U S A. 2012; 109: 15959-15964
        • Kaptchuk T.J.
        • Kelley J.M.
        • Conboy L.A.
        • Davis R.B.
        • Kerr C.E.
        • Jacobson E.E.
        • Kirsch I.
        • Schyner R.N.
        • Nam B.H.
        • Nguyen L.T.
        • Park M.
        • Rivers A.L.
        • McManus C.
        • Kokkotou E.
        • Drossman D.A.
        • Goldman P.
        • Lembo A.J.
        Components of placebo effect: Randomised controlled trial in patients with irritable bowel syndrome.
        BMJ. 2008; 336: 999-1003
        • Kelley J.M.
        • Lembo A.J.
        • Ablon J.S.
        • Villanueva J.J.
        • Conboy L.A.
        • Levy R.
        • Marci C.D.
        • Kerr C.E.
        • Kirsch I.
        • Jacobson E.E.
        • Riess H.
        • Kaptchuk T.J.
        Patient and practitioner influences on the placebo effect in irritable bowel syndrome.
        Psychosom Med. 2009; 71: 789-797
        • Kirsch I.
        • Sapirstein G.
        Listening to Prozac but hearing placebo: A meta-analysis of antidepressant medication.
        Prev Treatment. 1998; 1: 2a
        • Klemenz C.
        • Regard M.
        • Brugger P.
        • Emch O.
        Laterality of pain: Modulation by placebo and participants' paranormal belief.
        Cogn Behav Neurol. 2009; 22: 186-189
        • Kossowsky J.
        • Donado C.
        • Berde C.B.
        Immediate rescue designs in pediatric analgesic trials: A systematic review and meta-analysis.
        Anesthesiology. 2014 Sep 12; (
        • Krummenacher P.
        • Candia V.
        • Folkers G.
        • Schedlowski M.
        • Schönbächler G.
        Prefrontal cortex modulates placebo analgesia.
        Pain. 2010; 148: 368-374
        • Krummenacher P.
        • Mohr C.
        • Haker H.
        • Brugger P.
        Dopamine, paranormal belief, and the detection of meaningful stimuli.
        J Cogn Neurosci. 2010; 22: 1670-1681
        • Kut E.
        • Schaffner N.
        • Wittwer A.
        • Candia V.
        • Brockmann M.
        • Storck C.
        • Folkers G.
        Changes in self-perceived role identity modulate pain perception.
        Pain. 2007; 131: 191-201
        • Leonhard D.
        • Brugger P.
        Creative, paranormal, and delusional thought: A consequence of right hemisphere semantic activation?.
        Neuropsychiatry Neuropsychol Behav Neurol. 1998; 11: 177-183
        • Lewis D.W.
        • Kellstein D.
        • Dahl G.
        • Burke B.
        • Frank L.M.
        • Toor S.
        • Northam R.S.
        • White L.W.
        • Lawson L.
        Children's ibuprofen suspension for the acute treatment of pediatric migraine.
        Headache. 2002; 42: 780-786
        • Lidstone S.C.
        • Schulzer M.
        • Dinelle K.
        • Mak E.
        • Sossi V.
        • Ruth T.J.
        • de la Fuente-Fernandez R.
        • Phillips A.G.
        • Stoessl A.J.
        Effects of expectation on placebo-induced dopamine release in Parkinson disease.
        Arch Gen Psychiatry. 2010; 67: 857-865
        • Lu Q.
        • Zeltzer L.K.
        • Tsao J.C.
        • Kim S.C.
        • Turk N.
        • Naliboff B.D.
        Heart rate mediation of sex differences in pain tolerance in children.
        Pain. 2005; 118: 185-193
        • Luna B.
        • Thulborn K.R.
        • Munoz D.P.
        • Merriam E.P.
        • Garver K.E.
        • Minshew N.J.
        • Keshavan M.S.
        • Genovese C.R.
        • Eddy W.F.
        • Sweeney J.A.
        Maturation of widely distributed brain function subserves cognitive development.
        Neuroimage. 2001; 13: 786-793
        • McGrath P.A.
        • Seifert C.E.
        • Speechley K.N.
        • Booth J.C.
        • Stitt L.
        • Gibson M.C.
        A new analogue scale for assessing children's pain: An initial validation study.
        Pain. 1996; 64: 435-443
        • Meier P.M.
        • Berde C.B.
        • DiCanzio J.
        • Zurakowski D.
        • Sethna N.F.
        Quantitative assessment of cutaneous thermal and vibration sensation and thermal pain detection thresholds in healthy children and adolescents.
        Muscle Nerve. 2001; 24: 1339-1345
        • Messerschmidt R.
        The suggestibility of boys and girls between the ages of six and sixteen years.
        Pedagogical Semin J Genet Psychol. 1933; 43: 422-437
        • Mohr C.
        • Bracha H.S.
        • Brugger P.
        Magical ideation modulates spatial behavior.
        J Neuropsychiatry Clin Neurosci. 2003; 15: 168-174
        • Mohr C.
        • Krummenacher P.
        • Landis T.
        • Sandor P.S.
        • Fathi M.
        • Brugger P.
        Psychometric schizotypy modulates levodopa effects on lateralized lexical decision performance.
        J Psychiatr Res. 2005; 39: 241-250
        • Morgan A.H.
        • Ernest R.H.
        Age differences in susceptibility to hypnosis.
        Int J Clin Exp Hypn. 1973; 21: 78-85
        • Oldfield R.C.
        The assessment and analysis of handedness: The Edinburgh inventory.
        Neuropsychologia. 1971; 9: 97-113
        • Page R.A.
        • Green J.P.
        An update on age, hypnotic suggestibility, and gender: A brief report.
        Am J Clin Hypn. 2007; 49: 283-287
        • Papay J.P.
        • Spielberger C.D.
        Assessment of anxiety and achievement in kindergarten and first- and second-grade children.
        J Abnorm Child Psychol. 1986; 14: 279-286
        • Parellada M.
        • Moreno C.
        • Moreno M.
        • Espliego A.
        • de Portugal E.
        • Arango C.
        Placebo effect in child and adolescent psychiatric trials.
        Eur Neuropsychopharmacol. 2012; 22: 787-799
        • 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
        • Piaget J.P.
        The Child’s Conception of the World.
        Routledge & Kegan Paul, London1929
        • Pizzagalli D.
        • Lehmann D.
        • Gianotti L.
        • Koenig T.
        • Tanaka H.
        • Wackermann J.
        • Brugger P.
        Brain electric correlates of strong belief in paranormal phenomena: Intracerebral EEG source and regional Omega complexity analyses.
        Psychiatry Res. 2000; 100: 139-154
        • Price D.D.
        • Finniss D.G.
        • Benedetti F.
        A comprehensive review of the placebo effect: Recent advances and current thought.
        Annu Rev Psychol. 2008; 59: 565-590
        • Schaffner N.
        • Folkers G.
        • Kappeli S.
        • Musholt M.
        • Hofbauer G.F.
        • Candia V.
        A new tool for real-time pain assessment in experimental and clinical environments.
        PLoS One. 2012; 7: e51014
        • Schweinhardt P.
        • Seminowicz D.A.
        • Jaeger E.
        • Duncan G.H.
        • Bushnell M.C.
        The anatomy of the mesolimbic reward system: A link between personality and the placebo analgesic response.
        J Neurosci. 2009; 29: 4882-4887
        • Scott D.J.
        • Stohler C.S.
        • Egnatuk C.M.
        • Wang H.
        • Koeppe R.A.
        • Zubieta J.K.
        Individual differences in reward responding explain placebo-induced expectations and effects.
        Neuron. 2007; 55: 325-336
        • Scott D.J.
        • Stohler C.S.
        • Egnatuk C.M.
        • Wang H.
        • Koeppe R.A.
        • Zubieta J.K.
        Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses.
        Arch Gen Psychiatry. 2008; 65: 220-231
        • Simmons K.
        • Ortiz R.
        • Kossowsky J.
        • Krummenacher P.
        • Grillon C.
        • Pine D.
        • Colloca L.
        Pain and placebo in pediatrics: A comprehensive review of laboratory and clinical findings.
        Pain. 2014; ( [Epub ahead of print])
        • Spielberger C.D.
        STAIC. Preliminary Manual for the State-Trait Anxiety Inventory for Children.
        Consulting Psychologists Press, Palo Alto, CA1973
        • Stein N.
        • Sprenger C.
        • Scholz J.
        • Wiech K.
        • Bingel U.
        White matter integrity of the descending pain modulatory system is associated with interindividual differences in placebo analgesia.
        Pain. 2012; 153: 2210-2217
        • Stewart-Williams S.
        • Podd J.
        The placebo effect: Dissolving the expectancy versus conditioning debate.
        Psychol Bull. 2004; 130: 324-340
        • Symonds L.L.
        • Gordon N.S.
        • Bixby J.C.
        • Mande M.M.
        Right-lateralized pain processing in the human cortex: An FMRI study.
        J Neurophysiol. 2006; 95: 3823-3830
        • Tomlinson D.
        • von Baeyer C.L.
        • Stinson J.N.
        • Sung L.
        A systematic review of faces scales for the self-report of pain intensity in children.
        Pediatrics. 2010; 126: e1168-1198
        • Trapanotto M.
        • Pozziani G.
        • Perissinotto E.
        • Barbieri S.
        • Zacchello F.
        • Benini F.
        The cold pressor test for the pediatric population: Refinement of procedures, development of norms, and study of psychological variables.
        J Pediatr Psychol. 2009; 34: 749-759
        • Vase L.
        • Riley 3rd, J.L.
        • Price D.D.
        A comparison of placebo effects in clinical analgesic trials versus studies of placebo analgesia.
        Pain. 2002; 99: 443-452
        • Wager T.D.
        • Atlas L.Y.
        • Leotti L.A.
        • Rilling J.K.
        Predicting individual differences in placebo analgesia: Contributions of brain activity during anticipation and pain experience.
        J Neurosci. 2011; 31: 439-452
        • Wager T.D.
        • Rilling J.K.
        • Smith E.E.
        • Sokolik A.
        • Casey K.L.
        • Davidson R.J.
        • Kosslyn S.M.
        • Rose R.M.
        • Cohen J.D.
        Placebo-induced changes in FMRI in the anticipation and experience of pain.
        Science. 2004; 303: 1162-1167
        • Weimer K.
        • Gulewitsch M.D.
        • Schlarb A.A.
        • Schwille-Kiuntke J.
        • Klosterhalfen S.
        • Enck P.
        Placebo effects in children: A review.
        Pediatr Res. 2013; 74: 96-102
        • Wollgarten-Hadamek I.
        • Hohmeister J.
        • Zohsel K.
        • Flor H.
        • Hermann C.
        Do school-aged children with burn injuries during infancy show stress-induced activation of pain inhibitory mechanisms?.
        Eur J Pain. 2011; 15: 423.e1-423.e10
        • Zusne L.
        • Jones W.H.
        Anomalistic Psychology: A Study of Magical Thinking.
        2nd ed. Erlbaum, Hillsdale1989