Pre-Exposure, But Not Overshadowing, Inhibits Nocebo Hyperalgesia

Published:February 23, 2021DOI:


      • Nocebo hyperalgesia can be established via conditioning.
      • Pre-exposing individuals to treatment cues inhibits conditioned nocebo hyperalgesia.
      • Overshadowing with audio-visual cues did not reduce conditioned nocebo hyperalgesia.
      • Pre-exposure may be an effective method of reducing nocebo hyperalgesia clinically.


      Nocebo hyperalgesia is a pervasive problem that significantly adds to the burden of pain. Conditioning is a key mechanism of nocebo hyperalgesia and recent evidence indicates that, once established, nocebo hyperalgesia is resistant to extinction. This means that preventive strategies are critical. We therefore tested whether two novel strategies – overshadowing (Experiment 1) and pre-exposure (Experiment 2) – could inhibit conditioned nocebo hyperalgesia. Overshadowing involves introducing additional cues during conditioning that should compete with and overshadow learning about the target nocebo cue. Pre-exposure involves pre-exposing the target nocebo cue in the absence of pain, which should diminish its ability to become associated with pain later. In both studies, healthy volunteers (N = 141) received exposure to a series of electrocutaneous pain stimuli with and without a sham electrode ‘activated’, which they were led to believe was a genuine hyperalgesic treatment. Nocebo conditioning was achieved by pairing sham activation with high pain prior to testing at equivalent pain intensity. In both studies, standard nocebo conditioning led to clear nocebo hyperalgesia relative to natural history controls. In Experiment 1, there was no evidence that overshadowing attenuated nocebo hyperalgesia. Importantly, however, Experiment 2 found that pre-exposure successfully attenuated nocebo hyperalgesia with post hoc analysis suggesting that this effect was dose-dependent. These findings provide novel evidence that pre-exposure, but not overshadowing, could be a cheap and effective way for mitigating the substantial harm caused by conditioned nocebo hyperalgesia in clinical settings.


      Nocebo hyperalgesia causes substantial patient burden with few preventive options available. Our study found novel evidence that pre-exposing treatment cues without pain, but not overshadowing them with other cues, has the capacity to inhibit conditioned nocebo hyperalgesia. Pre-exposure may therefore be an effective preventive strategy to combat nocebo hyperalgesia.

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        • Aslaksen PM
        • Åsli O
        • Øvervoll M
        • Bjørkedal E
        Nocebo hyperalgesia and the startle response.
        Neuroscience. 2016; 339: 599-607
        • Au Yeung ST
        • Colagiuri B
        • Lovibond PF
        • Colloca L
        Partial reinforcement, extinction, and placebo analgesia.
        Pain. 2014; : 1110-1117
        • Benedetti F
        • Frisaldi E
        • Barbiani D
        • Camerone E
        • Shaibani A
        Nocebo and the contribution of psychosocial factors to the generation of pain.
        J Neural Transm (Vienna). 2020; 127: 687-696
        • Bergh I
        • Sjöström B
        • Odén A
        • Steen B
        An application of pain rating scales in geriatric patients.
        Aging Clin Exp Res. 2000; 12: 380-387
        • Björkstrand P-Å
        Effects of conditioned stimulus pre-exposure on human electrodermal conditioning to fear-relevant and fear-irrelevant stimuli.
        Biol Psychol. 1990; 30: 35-50
        • Blackwelder WC
        Proving the null hypothesis" in clinical trials.
        Control Clin Trials. 1982; 3: 345-353
        • Blasini M
        • Corsi N
        • Klinger R
        • Colloca L
        Nocebo and pain: An overview of the psychoneurobiological mechanisms.
        Pain reports. 2017; 2: e585
        • Bouton ME
        Learning and Behavior: A Contemporary Synthesis.
        Sinauer Associates, Sunderland, MA2007
        • Caplandies FC
        • Colagiuri B
        • Helfer SG
        • Geers AL
        Effect type but not attribute framing alters nocebo headaches in an experimental paradigm.
        Psychol Conscious: Theory Res Pract. 2017; 4: 259-273
        • Colagiuri B
        • Quinn VF
        Autonomic arousal as a mechanism of the persistence of nocebo hyperalgesia.
        J Pain. 2018; 19: 476-486
        • Colagiuri B
        • Quinn VF
        • Colloca L
        NoceboHyperalgesia, partial reinforcement, and extinction.
        J Pain. 2015; 16: 995-1004
        • Colloca L
        • Petrovic P
        • Wager TD
        • Ingvar M
        • Benedetti F
        How the number of learning trials affects placebo and nocebo responses.
        Pain. 2010; 151: 430-439
        • Colloca L
        • Sigaudo M
        • Benedetti F
        The role of learning in nocebo and placebo effects.
        Pain. 2008; 136: 211-218
        • De la Casa LG
        • Lubow RE
        An empirical analysis of the super-latent inhibition effect.
        Anim Learn Behav. 2002; 30: 112-120
        • Devlin EJ
        • Denson LA
        • Whitford HS
        Cancer treatment side effects: A meta-analysis of the relationship between response expectancies and experience.
        J Pain Symptom Manage. 2017; 54 (.e2): 245-258
        • Domjan M
        The Principles of Learning and Behavior: Active Learning Edition.
        5th Edition ed. Thomson Wadsworth, Belmont, CA2006
        • Fletcher C
        • Wilson C
        • Hutchinson AD
        • Grunfeld EA
        The relationship between anticipated response and subsequent experience of cancer treatment-related side effects: a meta-analysis comparing effects before and after treatment exposure.
        Cancer Treat Rev. 2018; 68: 86-93
        • Forrest DRL
        • Mather M
        • Harris JA
        Unmasking latent inhibition in humans.
        Q J Exp Psychol. 2016; 71: 380-395
        • Gallistel CR
        The importance of proving the null.
        Psychol Rev. 2009; 116: 439-453
        • Garcia J
        • Koelling RA
        Relation of cue to consequence in avoidance learning.
        Psychon Sci. 1966; 4: 123-124
        • Geers AL
        • Close S
        • Caplandies FC
        • Vogel CL
        • Murray AB
        • Pertiwi Y
        • Handley IM
        • Vase L
        Testing a positive-affect induction to reduce verbally induced nocebo hyperalgesia in an experimental pain paradigm.
        Pain. 2019; 160
      1. Geers, AL, Faasse, K, Guevarra, DA, Clemens, KS, Helfer, SG, and Colagiuri, B, Affect and emotions in placebo and nocebo effects: What do we know so far? Soc Pers Psychol Compass 15:e12575, DOI: 10.1111/spc3.12575

        • Granger KT
        • Moran PM
        • Buckley MG
        • Haselgrove M
        Enhanced latent inhibition in high schizotypy individuals.
        Pers Indiv Diff. 2016; 91: 31-39
        • Haefeli M
        • Elfering A
        Pain assessment.
        Eur Spine J. 2006; 15: S17-S24
        • Haesen K
        • Beckers T
        • Baeyens F
        • Vervliet B
        One-trial overshadowing: Evidence for fast specific fear learning in humans.
        Behav Res Ther. 2017; 90: 16-24
        • 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: 1227-1238
        • Hamm A
        • Vaitl D
        • Lang P
        Fear conditioning, meaning, and belongingness: A selective association analysis.
        J Abnorm Psychol. 1989; 98: 395-406
        • Holmes NM
        • Harris JA
        Latent Inhibition.
        in: Mitchell C.J. Le Pelley M.E. Attention and Associative Learning: from Brain to Behaviour. Oxford University Press, Oxford2010: 99-130
        • Howell DC
        Statistical Methods for Psychology.
        7th ed. Wadsworth Cengage, Belmont, USA2010
        • Jensen KB
        • Kaptchuk TJ
        • Kirsch I
        • Raicek J
        • Lindstrom KM
        • Berna C
        • Gollub RL
        • Ingvar M
        • Kong J
        Nonconscious activation of placebo and nocebo pain responses.
        PNAS. 2012; 109: 15959-15964
        • Klosterhalfen S
        • Kellermann S
        • Stockhorst U
        • Wolf J
        • Kirschbaum C
        • Hall G
        • Enck P
        Latent inhibition of rotation chair-induced nausea in healthy male and female volunteers.
        Psychosom Med. 2005; 67: 335-340
        • Kwok DWS
        • Harris JA
        • Boakes RA
        Timing of interfering events in one-trial serial overshadowing of a taste aversion.
        Learn Behav. 2017; 45: 124-134
        • Lovibond PF
        • Lovibond SH
        The structure of negative emotional states: Comparison of the depression anxiety stress scales (DASS) with the beck depression and anxiety inventories.
        Behav Res Ther. 1995; 33: 335-343
        • Lubow RE
        Latent inhibition.
        Psychol Bull. 1973; 79: 398-407
        • Lubow RE
        • Moore AU
        Latent inhibition: The effect of nonreinforced pre-exposure to the conditional stimulus.
        J Comp Physiol Psychol. 1959; 52: 415-419
        • Mackintosh NJ
        An analysis of overshadowing and blocking.
        Q J Exp Psychol. 1971; 23: 118-125
        • Mackintosh NJ
        Overshadowing and Stimulus Intensity.
        Psychonomic Society, US1976: 186-192
        • Mackintosh NJ
        • Reese B
        One-trial overshadowing.
        Q J Exp Psychol. 1979; 31: 519-526
        • Manaï M
        • van Middendorp H
        • Veldhuijzen DS
        • Huizinga TWJ
        • Evers AWM
        How to prevent, minimize, or extinguish nocebo effects in pain: A narrative review on mechanisms, predictors, and interventions.
        Pain Rep. 2019; 4
        • Morey RD
        • Rouder JN
        • Jamil T
        • Urbanek K
        • Ly A
        BayesFactor: Computation of Bayes Factors for Common Designs.
        2018 (This is a statistical programme, the version number is: 0.9.12-4.2)
        • Pavlov IP
        Oxford University Press, London1927
        • Peter M
        • Vlaar AP
        • Taal E
        • Gheith RE
        • Rasker JJ
        • Ayman K
        • van de Laar MA
        The validity and reliability of the graphic rating scale and verbal rating scale for measuring pain across cultures: A study in Egyptian and Dutch women with rheumatoid arthritis.
        Clin J Pain. 2006; 22: 827-830
        • Petersen GL
        • Finnerup NB
        • Colloca L
        • Amanzio M
        • Price DD
        • Jensen TS
        • Vase L
        The magnitude of nocebo effects in pain: A meta-analysis.
        Pain. 2014; 155
        • Ploghaus A
        • Narain C
        • Beckmann CF
        • Clare S
        • Bantick S
        • Wise R
        • Matthews PM
        • Rawlins JN
        • Tracey I
        Exacerbation of pain by anxiety is associated with activity in a hippocampal network.
        J Neurosci. 2001; 21: 9896-9903
        • Quinn VF
        • Colagiuri B
        Using learning strategies to inhibit the nocebo effect.
        Int Rev Neurobiol. 2018; 138: 307-327
        • Quinn VF
        • Livesey EJ
        • Colagiuri B
        Latent inhibition reduces nocebo nausea, even without deception.
        Ann Behav Med. 2017; 51: 432-441
        • Rodriguez-Raecke R
        • Doganci B
        • Breimhorst M
        • Stankewitz A
        • Büchel C
        • Birklein F
        • May A
        Insular cortex activity is associated with effects of negative expectation on nociceptive long-term habituation.
        J Neurosci. 2010; 30: 11363-11368
        • Sohl SJ
        • Schnur JB
        • Montgomery GH
        A meta-analysis of the relationship between response expectancies and cancer treatment-related side effects.
        J Pain Symptom Manage. 2009; 38: 775-784
        • 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: 2651-2664
        • Stockhorst U
        • Wiener JA
        • Klosterhalfen S
        • Klosterhalfen W
        • Aul C
        • Steingruber H-J
        Effects of overshadowing on conditioned nausea in cancer patients: An experimental study.
        Physiol Behav. 1998; 64: 743-753
        • Taddio A
        • Shah V
        • Gilbert-MacLeod C
        • Katz J
        Conditioning and hyperalgesia in newborns exposed to repeated heel lances.
        JAMA. 2002; 288: 857-861
        • Tang B
        • Geers A
        • Barnes K
        • Colagiuri B
        Instrumental control enhances placebo analgesia.
        J Pain. 2019; 20: 1486-1497
        • Tang NK
        • Salkovskis PM
        • Hodges A
        • Wright KJ
        • Hanna M
        • Hester J
        Effects of mood on pain responses and pain tolerance: An experimental study in chronic back pain patients.
        Pain. 2008; 138: 392-401
        • Team R
        RStudio: Integrated Development for R.
        RStudio PBC, Boston, MA2020
        • Tesler MD
        • Savedra MC
        • Holzemer WL
        • Wilkie DJ
        • Ward JA
        • Paul SM
        The word-graphic rating scale as a measure of children's and adolescents' pain intensity.
        Res Nurs Health. 1991; 14: 361-371
        • Thomaidou MA
        • Veldhuijzen DS
        • Peerdeman KJ
        • Wiebing NZS
        • Blythe JS
        • Evers AWM
        Learning mechanisms in nocebo hyperalgesia: The role of conditioning and extinction processes.
        Pain. 2020; 161
        • 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: 2769-2780
        • Zhang L
        • Lu X
        • Bi Y
        • Hu L
        Pavlov's pain: The effect of classical conditioning on pain perception and its clinical implications.
        Curr Pain Headache Rep. 2019; 23: 1-12