The Placebo Effect: Advances from Different Methodological Approaches

There is accumulating evidence from different methodological approaches that the placebo effect is a neurobiological phenomenon. Behavioral, psychophysiological, and neuroimaging results have largely contributed to accepting the placebo response as real. A major aspect of recent and future advances in placebo research is to demonstrate linkages between behavior, brain, and bodily responses. This article provides an overview of the processes involved in the formation of placebo responses by combining research findings from behavioral, psychophysiological, and neuroimaging methods. The integration of these different methodological approaches is a key objective, motivating our scientific pursuits toward a placebo research that can inform and guide important future scientific knowledge.

[1]  Irene Tracey,et al.  Getting the pain you expect: mechanisms of placebo, nocebo and reappraisal effects in humans , 2010, Nature Medicine.

[2]  Stein Knardahl,et al.  Placebo-Induced Changes in Spinal Cord Pain Processing , 2006, The Journal of Neuroscience.

[3]  M. Flaten,et al.  Effects of caffeine, caffeine-associated stimuli, and caffeine-related information on physiological and psychological arousal , 2001, Psychopharmacology.

[4]  A A M Wilde,et al.  It's Not What You Think , 2017 .

[5]  L. Colloca,et al.  Harnessing the placebo effect: the need for translational research , 2011, Philosophical Transactions of the Royal Society B: Biological Sciences.

[6]  Luana Colloca,et al.  Overt versus covert treatment for pain, anxiety, and Parkinson's disease , 2004, The Lancet Neurology.

[7]  D. Price,et al.  The contributions of suggestion, desire, and expectation to placebo effects in irritable bowel syndrome patients An empirical investigation , 2003, Pain.

[8]  Donald D. Price,et al.  Increased placebo analgesia over time in irritable bowel syndrome (IBS) patients is associated with desire and expectation but not endogenous opioid mechanisms , 2005, Pain.

[9]  R. Davidson,et al.  The integration of negative affect, pain and cognitive control in the cingulate cortex , 2011, Nature Reviews Neuroscience.

[10]  Pierre Rainville,et al.  Descending analgesia – When the spine echoes what the brain expects , 2007, PAIN.

[11]  M. Flaten,et al.  The Roles of Physiological and Subjective Stress in the Effectiveness of a Placebo on Experimentally Induced Pain , 2008, Psychosomatic medicine.

[12]  C. Büchel,et al.  Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network , 2006, Pain.

[13]  C. Büchel,et al.  Activation of the Opioidergic Descending Pain Control System Underlies Placebo Analgesia , 2009, Neuron.

[14]  R. Dampney,et al.  The Integrative Action of the Autonomic Nervous System Neurobiology of Homeostasis , 2008 .

[15]  F. Benedetti,et al.  Neuropharmacological Dissection of Placebo Analgesia: Expectation-Activated Opioid Systems versus Conditioning-Activated Specific Subsystems , 1999, The Journal of Neuroscience.

[16]  N. Bolger,et al.  Brain Mediators of Predictive Cue Effects on Perceived Pain , 2010, The Journal of Neuroscience.

[17]  Anthony K. P. Jones,et al.  Placebo analgesia as a case of a cognitive style driven by prior expectation , 2010, Brain Research.

[18]  C. Porro,et al.  Neural bases of conditioned placebo analgesia , 2010, PAIN®.

[19]  S. M. Vambheim,et al.  Gender Differences in Placebo Analgesia: Event-Related Potentials and Emotional Modulation , 2011, Psychosomatic medicine.

[20]  F. Benedetti,et al.  The role of learning in nocebo and placebo effects , 2008, PAIN.

[21]  H. Fields,et al.  Role of pain in placebo analgesia. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Gian Domenico Iannetti,et al.  Placebo conditioning and placebo analgesia modulate a common brain network during pain anticipation and perception , 2009, PAIN®.

[23]  M. Magnin,et al.  On the importance of placebo timing in rTMS studies for pain relief , 2011, PAIN.

[24]  Thomas E. Nichols,et al.  Placebo Effects Mediated by Endogenous Opioid Activity on μ-Opioid Receptors , 2005, The Journal of Neuroscience.

[25]  M. Flaten Drug effects: agonistic and antagonistic processes. , 2009, Scandinavian journal of psychology.

[26]  Tor D Wager,et al.  Predicting Individual Differences in Placebo Analgesia: Contributions of Brain Activity during Anticipation and Pain Experience , 2011, The Journal of Neuroscience.

[27]  Luana Colloca,et al.  Placebos and painkillers: is mind as real as matter? , 2005, Nature Reviews Neuroscience.

[28]  W. Jänig Integrative Action of the Autonomic Nervous System: Neurobiology of Homeostasis , 2006 .

[29]  R. Poldrack Can cognitive processes be inferred from neuroimaging data? , 2006, Trends in Cognitive Sciences.

[30]  F. Benedetti,et al.  Opioid-Mediated Placebo Responses Boost Pain Endurance and Physical Performance: Is It Doping in Sport Competitions? , 2007, The Journal of Neuroscience.

[31]  K. Meissner The placebo effect and the autonomic nervous system: evidence for an intimate relationship , 2011, Philosophical Transactions of the Royal Society B: Biological Sciences.

[32]  J. Zakrzewska,et al.  Wall and Melzack's textbook of pain , 2006 .

[33]  Stephanie L. Fowler,et al.  Dispositional optimism predicts placebo analgesia. , 2010, The journal of pain : official journal of the American Pain Society.

[34]  M. Flaten,et al.  Interaction between expectancies and drug effects: an experimental investigation of placebo analgesia with caffeine as an active placebo , 2011, Psychopharmacology.

[35]  F. Benedetti,et al.  Nocebo hyperalgesia: how anxiety is turned into pain , 2007, Current opinion in anaesthesiology.

[36]  M. Flaten,et al.  Placebo and Nocebo Responses, Cortisol, and Circulating Beta-Endorphin , 2003, Psychosomatic medicine.

[37]  F. Benedetti,et al.  How prior experience shapes placebo analgesia , 2006, Pain.

[38]  Fabrizio Benedetti,et al.  The Biochemical and Neuroendocrine Bases of the Hyperalgesic Nocebo Effect , 2006, The Journal of Neuroscience.

[39]  Gian Domenico Iannetti,et al.  A multisensory investigation of the functional significance of the “pain matrix” , 2011, NeuroImage.

[40]  Wilfrid Jänig The Integrative Action of the Autonomic Nervous System: Introduction , 2006 .

[41]  P. Petrovic,et al.  How the number of learning trials affects placebo and nocebo responses , 2010, PAIN®.

[42]  Tor D. Wager,et al.  The new field of Brain–Body Medicine: What have we learned and where are we headed? , 2009, NeuroImage.

[43]  J. Zubieta,et al.  Placebo effects on human μ-opioid activity during pain , 2007, Proceedings of the National Academy of Sciences.

[44]  Jason G. Craggs,et al.  Placebo analgesia is accompanied by large reductions in pain-related brain activity in irritable bowel syndrome patients , 2007, Pain.

[45]  S. B. Fisher,et al.  The Effect of a Placebo on the Perception of Painful Radiant Heat Stimuli , 1972, Psychosomatic medicine.

[46]  W. Clark Sensory-decision theory analysis of the placebo effect on the criterion for pain and thermal sensitivity. , 1969, Journal of abnormal psychology.

[47]  Luana Colloca,et al.  Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus , 2004, Nature Neuroscience.

[48]  K. Meissner,et al.  Organ-specificity of placebo effects on blood pressure , 2011, Autonomic Neuroscience.

[49]  A. Canbay,et al.  Behavioral conditioning of immunosuppression is possible in humans , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[50]  U. Mitzdorf,et al.  Evidence for placebo effects on physical but not on biochemical outcome parameters: a review of clinical trials , 2007, BMC medicine.

[51]  D. Schadendorf,et al.  Behavioural conditioning as the mediator of placebo responses in the immune system , 2011, Philosophical Transactions of the Royal Society B: Biological Sciences.

[52]  E. Benarroch The central autonomic network: functional organization, dysfunction, and perspective. , 1993, Mayo Clinic proceedings.

[53]  H. Fields,et al.  MECHANISM OF PLACEBO ANALGESIA , 1978, The Lancet.

[54]  Terry D. Blumenthal,et al.  Caffeine-associated stimuli elicit conditioned responses: an experimental model of the placebo effect , 1999, Psychopharmacology.

[55]  I. Kirsch,et al.  Mechanisms of Placebo Pain Reduction: An Empirical Investigation , 1996 .

[56]  Lisa Feldman Barrett,et al.  Functional grouping and cortical–subcortical interactions in emotion: A meta-analysis of neuroimaging studies , 2008, NeuroImage.

[57]  M. Vangel,et al.  Brain Activity Associated with Expectancy-Enhanced Placebo Analgesia as Measured by Functional Magnetic Resonance Imaging , 2006, The Journal of Neuroscience.

[58]  J. Lorenz,et al.  Somatotopy of placebo analgesia is independent of spatial attention , 2011, Journal of pain research.

[59]  Reynold A Panettieri,et al.  Placebo response in asthma: a robust and objective phenomenon. , 2007, The Journal of allergy and clinical immunology.

[60]  Andrew L. Geers,et al.  Reconsidering the role of personality in placebo effects: dispositional optimism, situational expectations, and the placebo response. , 2005, Journal of psychosomatic research.

[61]  Domenica Le Pera,et al.  Learning potentiates neurophysiological and behavioral placebo analgesic responses , 2008, PAIN.

[62]  M. Frot,et al.  Brain generators of laser-evoked potentials: from dipoles to functional significance , 2003, Neurophysiologie Clinique/Clinical Neurophysiology.

[63]  J. Rhudy,et al.  Emotional control of nociceptive reactions (ECON): Do affective valence and arousal play a role? , 2008, PAIN.

[64]  M. Flaten,et al.  The relation of emotions to placebo responses , 2011, Philosophical Transactions of the Royal Society B: Biological Sciences.

[65]  A. Steptoe,et al.  Placebo responses: an experimental study of psychophysiological processes in asthmatic volunteers. , 1986, The British journal of clinical psychology.

[66]  Fabrizio Benedetti,et al.  Loss of expectation-related mechanisms in Alzheimer’s disease makes analgesic therapies less effective , 2006, Pain.

[67]  K. Wiech,et al.  The Effect of Treatment Expectation on Drug Efficacy: Imaging the Analgesic Benefit of the Opioid Remifentanil , 2011, Science Translational Medicine.

[68]  L. Allan,et al.  A Signal Detection Theory Analysis of the Placebo Effect , 2002, Evaluation & the health professions.

[69]  Clark Wc Sensory-decision theory analysis of the placebo effect on the criterion for pain and thermal sensitivity. , 1969 .

[70]  E. Israel,et al.  Active albuterol or placebo, sham acupuncture, or no intervention in asthma. , 2011, The New England journal of medicine.

[71]  R. Treede,et al.  Human brain mechanisms of pain perception and regulation in health and disease , 2005, European journal of pain.

[72]  A. Finset,et al.  Cognitive and emotional factors in placebo analgesia. , 2006, Journal of psychosomatic research.

[73]  Wael El-Deredy,et al.  Cognitive changes as a result of a single exposure to placebo , 2010, Neuropsychologia.

[74]  S. Siegel Learning and the wisdom of the body , 2008, Learning & behavior.

[75]  P. Petrovic,et al.  Placebo and Opioid Analgesia-- Imaging a Shared Neuronal Network , 2002, Science.

[76]  S. Morrison Differential control of sympathetic outflow. , 2001, American journal of physiology. Regulatory, integrative and comparative physiology.

[77]  J. Zubieta,et al.  Neurobiological Mechanisms of the Placebo Effect , 2005, The Journal of Neuroscience.

[78]  M. Flaten,et al.  Is fear of pain related to placebo analgesia? , 2010, Journal of psychosomatic research.

[79]  M. Flaten,et al.  Drug-related information generates placebo and nocebo responses that modify the drug response. , 1999, Psychosomatic medicine.

[80]  K. Meissner Effects of placebo interventions on gastric motility and general autonomic activity. , 2009, Journal of psychosomatic research.

[81]  J. Maisog,et al.  Pain intensity processing within the human brain: a bilateral, distributed mechanism. , 1999, Journal of neurophysiology.

[82]  L. Colloca,et al.  How placebo responses are formed: a learning perspective , 2011, Philosophical Transactions of the Royal Society B: Biological Sciences.

[83]  Robert A Koeppe,et al.  Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. , 2008, Archives of general psychiatry.

[84]  Edward E. Smith,et al.  Placebo-Induced Changes in fMRI in the Anticipation and Experience of Pain , 2004, Science.

[85]  H. Engler,et al.  Calcineurin inhibition in splenocytes induced by pavlovian conditioning , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[86]  Christian Büchel,et al.  Direct Evidence for Spinal Cord Involvement in Placebo Analgesia , 2009, Science.

[87]  F. Benedetti,et al.  Placebo analgesia induced by social observational learning , 2009, PAIN®.

[88]  P. Lehrer,et al.  The effects of suggestion and emotional arousal on pulmonary function in asthma: a review and a hypothesis regarding vagal mediation. , 1992, Psychosomatic medicine.

[89]  M. Flaten,et al.  Variability in placebo analgesia and the role of fear of pain—an ERP study , 2011, PAIN®.

[90]  V. Candia,et al.  Prefrontal cortex modulates placebo analgesia , 2010, PAIN®.

[91]  On the survival of the altruistic trait in medicine: is there a link with the placebo effect? , 2005, Journal of clinical epidemiology.

[92]  F. Benedetti,et al.  Somatotopic Activation of Opioid Systems by Target-Directed Expectations of Analgesia , 1999, The Journal of Neuroscience.

[93]  R. Rescorla Pavlovian conditioning. It's not what you think it is. , 1988, The American psychologist.

[94]  M. Posner,et al.  Cognitive and emotional influences in anterior cingulate cortex , 2000, Trends in Cognitive Sciences.

[95]  Brent L. Hughes,et al.  Prefrontal-Subcortical Pathways Mediating Successful Emotion Regulation , 2008, Neuron.