The placebo effect: dissolving the expectancy versus conditioning debate.

The authors review the literature on the 2 main models of the placebo effect: expectancy theory and classical conditioning. A path is suggested to dissolving the theoretical impasse that has long plagued this issue. The key is to make a clear distinction between 2 questions: What factors shape placebo effects? and What learning mediates the placebo effect? The reviewed literature suggests that classical conditioning procedures are one shaping factor but that verbal information can also shape placebo effects. The literature also suggests that conditioning procedures and other sources of information sometimes shape conscious expectancies and that these expectancies mediate some placebo effects; however, in other cases conditioning procedures appear to shape placebo effects that are not mediated by conscious cognition.

[1]  R. Bolles Reinforcement, expectancy, and learning. , 1972 .

[2]  I. Kirsch,et al.  Apples, oranges, and placebos: heterogeneity in a meta-analysis of placebo effects. , 2001, Advances in mind-body medicine.

[3]  T. Kaptchuk,et al.  The powerful placebo: doubting the doubters. , 2001, Advances in mind-body medicine.

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

[5]  Fabrizio Benedetti,et al.  Response expectancies in placebo analgesia and their clinical relevance , 2001, Pain.

[6]  I. Kirsch,et al.  Double-blind versus deceptive administration of a placebo. , 1988, Behavioral neuroscience.

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

[8]  Harald Merckelbach,et al.  The placebo effect in pain reduction: The influence of conditioning experiences and response expectancies , 1996, International journal of behavioral medicine.

[9]  Martin E. P. Seligman,et al.  Unpredictable and Uncontrollable Aversive Events , 1971 .

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

[11]  W. Jonas,et al.  Toward a research agenda on placebo. , 2000, Advances in mind-body medicine.

[12]  M. Seligman,et al.  Biological boundaries of learning. , 1972 .

[13]  W. Grings,et al.  Comparison of classical conditioning and relational learning. , 1968, Journal of experimental psychology.

[14]  H. Byerly Explaining and Exploiting Placebo Effects , 2015, Perspectives in biology and medicine.

[15]  S. Ross,et al.  DRUGS AND PLACEBOS: THE EFFECTS OF INSTRUCTIONS UPON PERFORMANCE AND MOOD UNDER AMPHETAMINE SULPHATE AND CHLORAL HYDRATE. , 1964, Journal of abnormal psychology.

[16]  M. Seligman,et al.  Learned helplessness: Theory and evidence. , 1976 .

[17]  S. Mineka,et al.  Fears, phobias, and preparedness: toward an evolved module of fear and fear learning. , 2001, Psychological review.

[18]  M. Dawson Can classical conditioning occur without contingency learning? A review and evaluation of the evidence. , 1973, Psychophysiology.

[19]  I. Kirsch Changing expectations: A key to effective psychotherapy. , 1990 .

[20]  R. Rescorla Associative Changes with a Random CS-US Relationship , 2000, The Quarterly journal of experimental psychology. B, Comparative and physiological psychology.

[21]  N. Spanos,et al.  Hypnotic suggestion and placebo for the treatment of chronic headache in a university volunteer sample , 1993, Cognitive Therapy and Research.

[22]  N. Voudouris,et al.  Conditioned response models of placebo phenomena: further support , 1989, Pain.

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

[24]  J. Kleijnen,et al.  Placebo effect in double-blind clinical trials: a review of interactions with medications , 1994, The Lancet.

[25]  I. Kirsch,et al.  Clinical hypnosis as a nondeceptive placebo: empirically derived techniques. , 1994, The American journal of clinical hypnosis.

[26]  N. H. Spector,et al.  NEUROIMMUNE INTERACTIONS: PROCEEDINGS OF THE SECOND INTERNATIONAL WORKSHOP ON NEUROIMMUNOMODULATION , 1987 .

[27]  S. Siegel,et al.  Evidence from rats that morphine tolerance is a learned response. , 1975, Journal of comparative and physiological psychology.

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

[29]  Irving Kirsch,et al.  Specifying nonspecifics: Psychological mechanisms of placebo effects. , 1997 .

[30]  M. Seligman On the generality of the laws of learning , 1970 .

[31]  The role of conditioning in the placebo response: a comment on Voudouris et al., PAIN, 43 (1990) 121—128 , 1993, Pain.

[32]  Irving Kirsch,et al.  The placebo effect as a conditioned response: Failures of the “litmus test” , 1991, Behavioral and Brain Sciences.

[33]  H. Brody,et al.  Placebo and health--II. Three perspectives on the placebo response: expectancy, conditioning, and meaning. , 2000, Advances in mind-body medicine.

[34]  I. Kirsch The logical consequences of the common-factor definition of the term placebo.. , 1985 .

[35]  S. Ross,et al.  Further Support for a Placebo Effect in the Rat , 1963 .

[36]  J. Falk Physiology and Behavior. , 1973 .

[37]  J. Werry,et al.  The effectiveness of psychotherapy. , 1993, Journal of the American Academy of Child and Adolescent Psychiatry.

[38]  David R Shanks,et al.  Autonomic and eyeblink conditioning are closely related to contingency awareness: reply to Wiens and Ohman (2002) and Manns et al. (2002). , 2002, Journal of experimental psychology. Animal behavior processes.

[39]  John Garcia,et al.  Relation of cue to consequence in avoidance learning , 1966 .

[40]  N. H. Spector,et al.  Influence of Conditioned Natural Immunity on Tumor Growth a , 1987, Annals of the New York Academy of Sciences.

[41]  J K ADAMS,et al.  Laboratory studies of behavior without awareness. , 1957, Psychological bulletin.

[42]  F. Benedetti,et al.  THE NEUROBIOLOGY OF PLACEBO ANALGESIA: FROM ENDOGENOUS OPIOIDS TO CHOLECYSTOKININ , 1997, Progress in Neurobiology.

[43]  R. Rescorla Probability of shock in the presence and absence of CS in fear conditioning. , 1968, Journal of comparative and physiological psychology.

[44]  H. Kiene,et al.  The powerful placebo effect: fact or fiction? , 1997, Journal of clinical epidemiology.

[45]  W. Wilkins Psychotherapy: the powerful placebo. , 1984, Journal of consulting and clinical psychology.

[46]  T. Luparello,et al.  The Interaction of Psychologic Stimuli and Pharmacologic Agents on Airway Reactivity in Asthmatic Subjects , 1970, Psychosomatic medicine.

[47]  L. Kamin Predictability, surprise, attention, and conditioning , 1967 .

[48]  S. Siegel Pavlovian conditioning and heroin overdose: Reports by overdose victims , 1984 .

[49]  Anne Harrington,et al.  The Placebo Effect: An Interdisciplinary Exploration , 1999 .

[50]  Mark P. Jensen,et al.  Motivation and expectancy factors in symptom perception: a laboratory study of the placebo effect. , 1991, Psychosomatic medicine.

[51]  R. Ader,et al.  Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus. , 1982, Science.

[52]  P. Salmon,et al.  Reduction of post-operative swelling by a placebo effect. , 1988, Journal of psychosomatic research.

[53]  D. Levis,et al.  The S-S Construct of Expectancy Versus the S-R Construct of Fear: Which Motivates the Acquisition of Avoidance Behavior? , 2003, The Journal of general psychology.

[54]  K. Zener The significance of behavior accompanying conditioned salivary secretion for theories of the conditioned response. , 1937 .

[55]  M. Fillmore,et al.  The expected drug and its expected effect interact to determine placebo responses to alcohol and caffeine , 1994, Psychopharmacology.

[56]  B. Campbell,et al.  Punishment and aversive behavior , 1969 .

[57]  C. Staats,et al.  Attitudes established by classical conditioning. , 1958, Journal of abnormal psychology.

[58]  R. Overton,et al.  A comparison of fixed-effects and mixed (random-effects) models for meta-analysis tests of moderator , 1998 .

[59]  R. Solomon,et al.  Discriminative classical conditioning in dogs paralyzed by curare can later control discriminative avoidance responses in the normal state. , 1962, Psychological review.

[60]  T. Kaptchuk,et al.  Do medical devices have enhanced placebo effects? , 2000, Journal of clinical epidemiology.

[61]  M. Frankenhaeuser,et al.  PSYCHOPHYSIOLOGICAL REACTIONS TO TWO DIFFERENT PLACEBO TREATMENTS , 1963 .

[62]  A. Black,et al.  Aversive conditioning and learning , 1971 .

[63]  R. Herrnstein Placebo Effect in the Rat , 1962, Science.

[64]  Nicholas J. Voudouris,et al.  The role of conditioning and verbal expectancy in the placebo response , 1990, Pain.

[65]  J. M. Olson,et al.  An expectancy-attribution model of the effects of placebos. , 1981, Psychological review.

[66]  R. Sysko,et al.  Placebo response in studies of major depression: variable, substantial, and growing. , 2002, JAMA.

[67]  N. Mackintosh,et al.  Conditioning And Associative Learning , 1983 .

[68]  D. Newlin Placebo responding in the same direction as alcohol in women. , 1989, Alcoholism, clinical and experimental research.

[69]  R. Rescorla A theory of pavlovian conditioning: The effectiveness of reinforcement and non-reinforcement , 1972 .

[70]  R. Ader,et al.  The Influence of Conditioning on Immune Responses , 1991 .

[71]  A. Grünbaum,et al.  The placebo concept. , 1981, Behaviour research and therapy.

[72]  L. Kamin Attention-like processes in classical conditioning , 1967 .

[73]  D. Whitteridge Lectures on Conditioned Reflexes , 1942, Nature.

[74]  J. Kihlstrom THE SEDUCTIONS OF MATERIALISM AND THE PLEASURES OF DUALISM , 2002 .

[75]  I. Kirsch,et al.  Listening to Prozac but Hearing Placebo: A Meta-Analysis of Antidepressant Medication , 1998 .

[76]  Conditioned compensatory responses elicited by environmental signals for cyclophosphamide-induced suppression of antibody production in mice , 1988, Psychobiology.

[77]  D. Buss Evolutionary Psychology -- The New Science of the Mind , 1998 .

[78]  C. Peck,et al.  Implications of placebo theory for clinical research and practice in pain management , 1991, Theoretical medicine.

[79]  F. O. Bastos,et al.  [Behaviorism]. , 1953, Gazeta medica portuguesa.

[80]  F. W. Irwin Purposive Behavior in Animals and Men , 1932, The Psychological Clinic.

[81]  J. Tijssen,et al.  Placebo effect in the acute treatment of migraine: subcutaneous placebos are better than oral placebos , 2000, Journal of Neurology.

[82]  Stefan Wiens,et al.  Unawareness is more than a chance event: comment on Lovibond and Shanks (2002). , 2002, Journal of experimental psychology. Animal behavior processes.

[83]  Irving Kirsch,et al.  Response expectancy as a determinant of experience and behavior. , 1985 .

[84]  F. Baeyens,et al.  Awareness inflated, evaluative conditioning underestimated , 1994, Behavioral and Brain Sciences.

[85]  R Ader,et al.  Behaviorally Conditioned Immunosuppression , 1974, Psychosomatic medicine.

[86]  Vilfredo De Pascalis,et al.  The contribution of suggestibility and expectation to placebo analgesia phenomenon in an experimental setting , 2002, Pain.

[87]  E. R. Mcfadden,et al.  Influences of Suggestion on Airway Reactivity in Asthmatic Subjects , 1968, Psychosomatic medicine.

[88]  H. Brody,et al.  A challenge to core beliefs. , 2001, Advances in mind-body medicine.

[89]  I. Kirsch,et al.  Classical conditioning and the placebo effect , 1997, PAIN.

[90]  Jacob Cohen Statistical Power Analysis for the Behavioral Sciences , 1969, The SAGE Encyclopedia of Research Design.

[91]  Irving Kirsch,et al.  Do double-blind studies with informed consent yield externally valid results? , 1993, Psychopharmacology.

[92]  S. Rachman The conditioning theory of fear-acquisition: a critical examination. , 1977, Behaviour research and therapy.

[93]  F. Benedetti,et al.  The specific effects of prior opioid exposure on placebo analgesia and placebo respiratory depression , 1998, Pain.

[94]  Steven Jay Lynn,et al.  The role of cognition in classical and operant conditioning. , 2004, Journal of clinical psychology.

[95]  M. Flaten Information about drug effects modify arousal: An investigation of the placebo response , 1998 .

[96]  R. R. Miller,et al.  What's elementary about associative learning? , 1997, Annual review of psychology.

[97]  D. Shanks,et al.  Characteristics of dissociable human learning systems , 1994, Behavioral and Brain Sciences.

[98]  G. Schwartz,et al.  Placebo Theory, Research , and Mechanisms , 1985 .

[99]  R. Ader,et al.  Conditioning as an adjunct in the pharmacotherapy of lupus erythematosus. , 1992, Journal of developmental and behavioral pediatrics : JDBP.

[100]  J. Tijssen,et al.  Placebo effect in the treatment of duodenal ulcer. , 1999, British journal of clinical pharmacology.

[101]  A. Perlini,et al.  Hypnosis, suggestion, and placebo in the reduction of experimental pain. , 1989, Journal of abnormal psychology.

[102]  G. Razran,et al.  The observable unconscious and the inferable conscious in current Soviet psychophysiology: interoceptive conditioning, semantic conditioning, and the orienting reflex. , 1961, Psychological review.

[103]  K. Berridge Measuring hedonic impact in animals and infants: microstructure of affective taste reactivity patterns , 2000, Neuroscience & Biobehavioral Reviews.

[104]  D. Price,et al.  An analysis of factors that contribute to the magnitude of placebo analgesia in an experimental paradigm , 1999, PAIN.

[105]  J. Critelli,et al.  The placebo. Conceptual analysis of a construct in transition. , 1984, The American psychologist.

[106]  A. Catania The aware pigeon , 1994, Behavioral and Brain Sciences.

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

[108]  Ian Wickramasekera PhD A conditioned response model of the placebo effect , 1980, Biofeedback and self-regulation.

[109]  A. Bergin,et al.  Handbook of psychotherapy and behavior change, 4th ed. , 1994 .

[110]  I. Kirsch How expectancies shape experience. , 1999 .

[111]  N. Voudouris,et al.  Conditioned placebo responses. , 1985, Journal of personality and social psychology.

[112]  A. Hrõbjartsson,et al.  Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. , 2001, The New England journal of medicine.

[113]  Windy Dryden,et al.  Handbook of Psychotherapy and Behavior Change , 1987, Journal of Cognitive Psychotherapy.

[114]  F. Benedetti,et al.  Inducing placebo respiratory depressant responses in humans via opioid receptors , 1999, The European journal of neuroscience.

[115]  Larry R Squire,et al.  Standard delay eyeblink classical conditioning is independent of awareness. , 2002, Journal of experimental psychology. Animal behavior processes.

[116]  T. Roszman,et al.  Some parameters of conditioned immunosuppression: Species difference and CS-US delay , 1986, Physiology & Behavior.

[117]  R A Deyo,et al.  The importance of placebo effects in pain treatment and research. , 1994, JAMA.

[118]  I. Kirsch The placebo effect and the cognitive-behavioral revolution , 1978, Cognitive Therapy and Research.

[119]  D. Shanks,et al.  The role of awareness in Pavlovian conditioning: empirical evidence and theoretical implications. , 2002, Journal of experimental psychology. Animal behavior processes.