Manipulating the Placebo Response in Experimental Pain by Altering Doctor's Performance Style

Efrat Czerniak, Anat Biegon, Amitai Ziv, Orit Karnieli-Miller, Mark Weiser, Uri Alon, Atay Citron, Efrat Czerniak, Anat Biegon, Amitai Ziv, Orit Karnieli-Miller, Mark Weiser, Uri Alon, Atay Citron

Abstract

Background: Performance is paramount in traditional healing rituals. From a Western perspective, such performative behavior can be understood principally as inducing patients' faith in the performer's supernatural healing powers and effecting positive changes through the same mechanisms attributed to the placebo response, which is defined as improvement of clinical outcome in individuals receiving inactive treatment. Here we examined the possibility of using theatrical performance tools, including stage directions and scripting, to reproducibly manipulate the style and content of a simulated doctor-patient encounter and influence the placebo response in experimental pain.

Methods: A total of 122 healthy volunteers (18-45 years, 76 men) exposed to experimental pain (the cold pressor test) were assessed for pain threshold and tolerance before and after receiving a placebo cream from a "doctor" impersonated by a trained actor. The actor alternated between two distinct scripts and stage directions, i.e., performance styles created by a theater director/playwright, one emulating a standard doctor-patient encounter (scenario A) and the other emphasizing attentiveness and strong suggestion, elements also present in ritual healing (scenario B). The placebo response size was calculated as the %difference in pain threshold and tolerance after exposure relative to baseline. In addition, subjects demonstrating a ≥30% increase in pain threshold or tolerance relative to baseline were defined as responders. Each encounter was videotaped in its entirety.

Results: Inspection of the videotapes confirmed the reproducibility and consistency of the distinct scenarios enacted by the "doctor"-performer. Furthermore, scenario B resulted in a significant increase in pain threshold relative to scenario A. Interestingly, this increase derived from the placebo responder subgroup; as shown by two-way analysis of variance (performance style, F = 4.30; p = 0.040; η(2) = 0.035; style × responder status interaction term, F = 5.21; p = 0.024) followed by post hoc analysis showing a ∼60% increase in pain threshold in responders exposed to scenario B (p = 0.020).

Conclusion: These results support the hypothesis that structured manipulation of physician's verbal and non-verbal performance, designed to build rapport and increase faith in treatment, is feasible and may have a significant beneficial effect on the size of the response to placebo analgesia. They also demonstrate that subjects, who are not susceptible to placebo, are also not susceptible to performance style.

Keywords: doctor–patient interaction; pain; performance style; placebo; placebo analgesia; placebo responder; placebo response; reward expectation.

Figures

FIGURE 1
FIGURE 1
Experimental design. CPT, cold pressor test; A/B, performance scenarios.
FIGURE 2
FIGURE 2
Representative illustrations from scenarios A and B. Top row – scenario A, bottom row – scenario B. Left panels: “doctor” greeting subject. Middle panels: Inspection of the hand. Right panels: Presentation of the medication.
FIGURE 3
FIGURE 3
Performance style and response size in placebo responders and non-responders. Bars represent mean ± SE of % change in CPT threshold of 60 subjects in scenario A: 53 non-responders vs. 7 responders and 62 subjects in scenario B: 51 non-responders and 11 responders. Two-way ANOVA by performance style and responsiveness revealed significant effects of doctor’s performance (F = 4.30; p = 0.040; η2 = 0.035) and responsiveness (F = 134.71; p < 0.001) as well as a significant interaction term (F = 5.21; p = 0.024). ∗p = 0.020, Fisher’s least significant difference post hoc test.

References

    1. Achterberg J. (1985). Imagery in healing: Shamanism and Modern Science. Boston, MA: New Science Library, 113–142, 161–190.
    1. Anderson C., Horne J. A. (2008). Placebo response to caffeine improves reaction time performance in sleepy people. Hum. Psychopharmacol. 23 333–336. 10.1002/hup.931
    1. Bartels D. J., van Laarhoven A. I., van de Kerkhof P. C., Evers A. W. (2016). Placebo and nocebo effects on itch: effects, mechanisms, and predictors. Eur. J. Pain 20 8–13. 10.1002/ejp.750
    1. Benedetti F. (2009). Placebo Effects: Understanding the Mechanisms in Health and Disease. New York, NY: Oxford University Press.
    1. Berridge K. C., Robinson T. E. (1998). What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res. Brain Res. Rev. 28 309–369. 10.1016/S0165-0173(98)00019-8
    1. Cappelleri J. C., Bushmakin A. G., Zlateva G., Sadosky A. (2009). Pain responder analysis: use of area under the curve to enhance interpretation of clinical trial results. Pain Pract. 9 348–353. 10.1111/j.1533-2500.2009.00293.x
    1. Cardinal R. N., Parkinson J. A., Hall J., Everitt B. J. (2002). Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex. Neurosci. Biobehav. Rev. 26 321–352. 10.1016/S0149-7634(02)00007-6
    1. Charon R., Hermann N., Devlin M. J. (2016). Close reading and creative writing in clinical education: teaching attention, representation, and affiliation. Acad. Med. 91 345–350. 10.1097/ACM.0000000000000827
    1. Cohen J. D. (1988). Statistical Power Analysis for the Behavioral Sciences Mahwah, NJ: Lawrence Erlbaum.
    1. Czerniak E., Davidson M. (2012). Placebo, a historical perspective. Eur. Neuropsychopharmacol. 22 770–774. 10.1016/j.euroneuro.2012.04.003
    1. Darragh M., Chang J. W., Booth R. J., Consedine N. S. (2015). The placebo effect in inflammatory skin reactions: the influence of verbal suggestion on itch and weal size. J. Psychosom. Res. 78 489–494. 10.1016/j.jpsychores.2015.01.011
    1. de la Fuente-Fernandez R. (2009). The placebo-reward hypothesis: dopamine and the placebo effect. Parkinsonism. Relat. Disord. 15(Suppl. 3), S72–S74. 10.1016/S1353-8020(09)70785-0
    1. de la Fuente-Fernandez R., Ruth T. J., Sossi V., Schulzer M., Calne D. B., Stoessl A. J. (2001). Expectation and dopamine release: mechanism of the placebo effect in Parkinson’s disease. Science 293 1164–1166. 10.1126/science.1060937
    1. de la Fuente-Fernandez R., Stoessl A. J. (2002). The biochemical bases for reward. Implications for the placebo effect. Eval. Health Prof. 25 387–398. 10.1177/0163278702238052
    1. Doehring A., Kusener N., Fluhr K., Neddermeyer T. J., Schneider G., Lotsch J. (2011). Effect sizes in experimental pain produced by gender, genetic variants and sensitization procedures. PLoS ONE 6:e17724 10.1371/journal.pone.0017724
    1. Dzau V. J., Pizzo P. A. (2014). Relieving pain in america: insights from an institute of medicine committee. JAMA 312 1507–1508. 10.1001/jama.2014.12986
    1. Eliade M. (1964). Shamanism: Archaic Techniques of Ecstasy. Princeton, NJ: Princeton University Press.
    1. Goffman E. (1959). The Presentation of Self in Everyday Life. New York, NY: Random House.
    1. Hall K. T., Lembo A. J., Kirsch I., Ziogas D. C., Douaiher J., Jensen K. B., et al. (2012). Catechol-O-methyltransferase val158met polymorphism predicts placebo effect in irritable bowel syndrome. PLoS ONE 7:e48135 10.1371/journal.pone.0048135
    1. Hashmi J. A., Kong J., Spaeth R., Khan S., Kaptchuk T. J., Gollub R. L. (2014). Functional network architecture predicts psychologically mediated analgesia related to treatment in chronic knee pain patients. J. Neurosci. 34 3924–3936. 10.1523/JNEUROSCI.3155-13.2014
    1. Hilsden R. J., Verhoef M. J. (1999). Complementary therapies: evaluating their effectiveness in cancer. Patient Educ. Couns. 38 101–108. 10.1016/S0738-3991(99)00057-9
    1. Hines E. A., Brown G. E. (1936). Cold pressor test for measuring the reactibility of blood pressure. Am. Heart J. 11 1–9. 10.1016/S0002-8703(36)90370-8
    1. Kalivas P. W., Churchill L., Romanides A. (1999). Involvement of the pallidal-thalamocortical circuit in adaptive behavior. Ann. N. Y. Acad. Sci. 877 64–70. 10.1111/j.1749-6632.1999.tb09261.x
    1. Kaptchuk T. J. (2002). The placebo effect in alternative medicine: can the performance of a healing ritual have clinical significance? Ann. Intern. Med. 136 817–825. 10.7326/0003-4819-136-11-200206040-00011
    1. Kaptchuk T. J., Kelley J. M., Conboy L. A., Davis R. B., Kerr C. E., Jacobson E. E., et al. (2008). Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ 336 999–1003. 10.1136/bmj.39524.439618.25
    1. Kelley J. M., Lembo A. J., Ablon J. S., Villanueva J. J., Conboy L. A., Levy R., et al. (2009). Patient and practitioner influences on the placebo effect in irritable bowel syndrome. Psychosom. Med. 71 789–797. 10.1097/PSY.0b013e3181acee12
    1. Kemp A. S., Schooler N. R., Kalali A. H., Alphs L., Anand R., Awad G., et al. (2010). What is causing the reduced drug-placebo difference in recent schizophrenia clinical trials and what can be done about it? Schizophr. Bull. 36 504–509. 10.1093/schbul/sbn110
    1. Kendall L. (1996). “Initiating performance: the story of Chini, a Korean shaman,” in The Performance of Healing, eds Browning B., Laderman C., Roseman M. (Abingdon: Rotledge; ), 17–58.
    1. Kienle G. S., Kiene H. (1997). The powerful placebo effect: fact or fiction? J. Clin. Epidemiol. 50 1311–1318. 10.1016/S0895-4356(97)00203-5
    1. Kirby E. T. (1975). Ur Drama: The Origins of Theatre. Ur Drama: The Origins of Theatre. New York, NY: New York University Press.
    1. Kowalczyk W. J., Evans S. M., Bisaga A. M., Sullivan M. A., Comer S. D. (2006). Sex differences and hormonal influences on response to cold pressor pain in humans. J. Pain 7 151–160. 10.1016/j.jpain.2005.10.004
    1. Lakoff A. (2002). The mousetrap: managing the placebo effect in antidepressant trials. Mol. Interv. 2 72–76. 10.1124/mi.2.2.72
    1. Lee D.-H. (1990). Korean Shamans: Role Playing Through Trance Possession. In By Means of Performance: Intercultural Studies of Theatre and Ritual, eds Schechner R., Appel W. (Cambridge: Cambridge University Press; ), 149–166. 10.1017/CBO9780511607806.011
    1. Leuchter A. F., McCracken J. T., Hunter A. M., Cook I. A., Alpert J. E. (2009). Monoamine oxidase a and catechol-o-methyltransferase functional polymorphisms and the placebo response in major depressive disorder. J. Clin. Psychopharmacol. 29 372–377. 10.1097/JCP.0b013e3181ac4aaf
    1. Lovallo W. (1975). The cold pressor test and autonomic function: a review and integration. Psychophysiology 12 268–282. 10.1111/j.1469-8986.1975.tb01289.x
    1. Meissner K., Fassler M., Rucker G., Kleijnen J., Hrobjartsson A., Schneider A., et al. (2013). Differential effectiveness of placebo treatments: a systematic review of migraine prophylaxis. JAMA Intern. Med. 173 1941–1951. 10.1001/jamainternmed.2013.10391
    1. Moerman D. (2002). Meaning, Medicine and the Placebo Effect. Cambridge, UK: Cambridge University Press.
    1. Moffitt Cook P. (1997). Shaman, Jhankri & Néle: Music Healers Of Indigenous Cultures. Roslyn, NY: Ellipsis Arts.
    1. Mogenson G. J., Yang C. R. (1991). The contribution of basal forebrain to limbic-motor integration and the mediation of motivation to action. Adv. Exp. Med. Biol. 295 267–290. 10.1007/978-1-4757-0145-6_14
    1. Montgomery S. A. (1999). The failure of placebo-controlled studies. ECNP Consensus Meeting, September 13, 1997, Vienna. European College of Neuropsychopharmacology. Eur. Neuropsychopharmacol. 9 271–276. 10.1016/S0924-977X(98)00050-9
    1. Muthen B., Brown H. C. (2009). Estimating drug effects in the presence of placebo response: causal inference using growth mixture modeling. Stat. Med. 28 3363–3385. 10.1002/sim.3721
    1. Pecina M., Love T., Stohler C. S., Goldman D., Zubieta J. K. (2015). Effects of the Mu opioid receptor polymorphism (OPRM1 A118G) on pain regulation, placebo effects and associated personality trait measures. Neuropsychopharmacol. 40 957–965. 10.1038/npp.2014.272
    1. Pergolizzi J., Boger R. H., Budd K., Dahan A., Erdine S., Hans G., et al. (2008). Opioids and the management of chronic severe pain in the elderly: consensus statement of an international expert panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone). Pain Pract. 8 287–313. 10.1111/j.1533-2500.2008.00204.x
    1. Raia F., Deng M. (2014). Relational Medicine: Personalizing Modern Healthcare: the Practice of High-tech Medicine as a Relational Act. Singapore: World Scientific.
    1. Rogers W., Hutchison K., Skea Z. C., Campbell M. K. (2014). Strengthening the ethical assessment of placebo-controlled surgical trials: three proposals. BMC Med Ethics 15:78 10.1186/1472-6939-15-78
    1. Ross R., Gray C. M., Gill J. M. (2015). Effects of an injected placebo on endurance running performance. Med. Sci. Sports Exerc. 47 1672–1681. 10.1249/MSS.0000000000000584
    1. Rutherford B. R., Pott E., Tandler J. M., Wall M. M., Roose S. P., Lieberman J. A. (2014). Placebo response in antipsychotic clinical trials: a meta-analysis. JAMA Psychiatry 71 1409–1421. 10.1001/jamapsychiatry.2014.1319
    1. Salamone J. D., Correa M., Mingote S. M., Weber S. M. (2005). Beyond the reward hypothesis: alternative functions of nucleus accumbens dopamine. Curr. Opin. Pharmacol. 5 34–41. 10.1016/j.coph.2004.09.004
    1. Schechner R. (1985). Between Theatre and Anthropology. Philadelphia, PA: University of Pennsylvania Press.
    1. Scott D. J., Stohler C. S., Egnatuk C. M., Wang H., Koeppe R. A., Zubieta J. K. (2007). Individual differences in reward responding explain placebo-induced expectations and effects. Neuron 55 325–336. 10.1016/j.neuron.2007.06.028
    1. Shapiro A. K., Shapiro E. (1997). The Powerful Placebo: From Ancient Priest To Modern Physician. Baltimore, MD: Johns Hopkins University Press.
    1. Sinha B., Dubey D. K. (2015). Sex difference in the effect of whole body heating on cardiovascular functions. Indian J. Physiol. Pharmacol. 59 136–147.
    1. Stein D. J., Baldwin D. S., Dolberg O. T., Despiegel N., Bandelow B. (2006). Which factors predict placebo response in anxiety disorders and major depression? An analysis of placebo-controlled studies of escitalopram. J. Clin. Psychiatry 67 1741–1746. 10.4088/JCP.v67n1111
    1. Sun W. H., Fei F. C. (2014). “Social performance studies: A New PS School with Chinese Characteristics,” in Performance Studies in Motion: International Perspectives and Practices in the Twenty-First Century, eds Citron A., Aronson-Lehavi S., Zerbib D. (London: Bloomsbury Methuen Drama; ).
    1. Tamura R. N., Huang X. (2007). An examination of the efficiency of the sequential parallel design in psychiatric clinical trials. Clin. Trials 4 309–317. 10.1177/1740774507081217
    1. Treister R., Pud D., Ebstein R. P., Eisenberg E. (2013). Dopamine transporter genotype dependent effects of apomorphine on cold pain tolerance in healthy volunteers. PLoS ONE 8:e63808 10.1371/journal.pone.0063808
    1. Turner V. (1982). Acting in Everyday Life and Every Day Life in Acting. From Ritual to Theatre: The Human Seriousness of Play. New York, NY: Performing Arts Journal Publications, 102–123.
    1. Vitebsky P. (1995). The Shaman: Voyages of the Soul Trance, Ecstasy and Healing from Siberia to the Amazon. Boston, NY: Little, Brown and Company.
    1. Waber R. L., Shiv B., Carmon Z., Ariely D. (2008). Commercial features of placebo and therapeutic efficacy. JAMA 299 1016–1017. 10.1001/jama.299.9.1016
    1. Walsh B. T., Seidman S. N., Sysko R., Gould M. (2002). Placebo response in studies of major depression: variable, substantial, and growing. JAMA 287 1840–1847. 10.1001/jama.287.14.1840
    1. Wasan A. D., Kong J., Pham L. D., Kaptchuk T. J., Edwards R., Gollub R. L. (2010). The impact of placebo, psychopathology, and expectations on the response to acupuncture needling in patients with chronic low back pain. J. Pain 11 555–563. 10.1016/j.jpain.2009.09.013
    1. Watson K. (2011). Perspective: Serious play: teaching medical skills with improvisational theater techniques. Acad. Med. 86 1260–1265. 10.1097/ACM.0b013e31822cf858
    1. Weimer K., Colloca L., Enck P. (2015). Age and sex as moderators of the placebo response - an evaluation of systematic reviews and meta-analyses across medicine. Gerontology 61 97–108. 10.1159/000365248
    1. Winkelman M. (2000). Shamanism: The Neural Ecology of Consciousness and Healing. Wesport CT: Bergin & Garvey.
    1. Ziv A., Erez D., Munz Y., Vardi A., Barsuk D., Levine I., et al. (2006). The Israel center for medical simulation: a paradigm for cultural change in medical education. Acad. Med. 81 1091–1097. 10.1097/01.ACM.0000246756.55626.1b

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅