New Perspectives on the Placebo Effect: Implications for Research and Clinical Practice

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DOI: 10.1089/act.2012.18304 • MARY ANN LIEBERT, INC. • VOL. 18 NO. 3 ALTERNATIVE AND COMPLEMENTARY THERAPIESJUNE 2012

Patient expectations about treatment outcomes have con-ventionally been considered nuisance variables, which has led to placebo-controlled clinical trials becoming the norm in research. A recent study demonstrating that placebo ef-fects can occur even in open-label trials in which subjects are informed that they are being treated with an inert pill is prompting revised thinking about this phenomenon. This ar-ticle reviews conventional and new perspectives on placebos and related effects, placebos’ mechanisms of action, the new field of placebo studies, and implications for research design and clinical practice.

The Standard Placebo-Controlled Research Paradigm

Derived from the Latin word for “I please” (as in medieval prayers reciting “I shall please the Lord”), placebo was defined in the eighteenth century as a remedy used more to please pa-tients than to heal them, and the placebo effect or response became an integral part of the modern medical vocabulary.1 Until the nineteenth century, placebos were mainly what allo-pathic physicians had to offer patients.2 Therefore, the history of medical treatment, until relatively recently, can be charac-terized as a history of the placebo effect. American founding father and scientist Benjamin Franklin (1706–1790) has been credited with conducting the first placebo-controlled experi-ment in testing a woman’s belief that she could be cured with “mesmerized” water.3

In a clinical trial reported in a 1955 article in The Jour-nal of the American Medical Association, the placebo effect was called a powerful methodological tool with a high degree of therapeutic effectiveness (35% in this case).4 However, by the 1970s, the placebo effect had fallen into disfavor as a po-tential treatment despite its high efficacy, according to Her-bert Benson, MD, a pioneer in mind–body medicine who is now an associate professor of medicine at the Mind/Body Medicine Institute of Harvard Medical School, in Boston, Massachusetts.2 The placebo effect has long been considered an extraneous factor to be “neutralized” in randomized, pla-

cebo-controlled clinical trials, which are the gold standard in evidence-based medicine.5

While not as widely known or as frequent as the placebo effect, the nocebo effect, in which negative expectations with respect to a treatment may reduce its effectiveness and produce side-effects, is estimated to affect ~ 25% of participants in clin-ical trials. A systematic review of 100 recent multiple sclerosis (MS) studies found that nocebo responses ranged from 25% in trials involving common MS symptoms (e.g., fatigue and muscle stiffness) to 74% in trials of disease-modifying drugs.6

In a study of a painkiller’s efficacy in healthy volunteers be-ing treated for minor experimentally induced pain, being told that a painkilling drug had been withdrawn when it was not, strongly influenced its therapeutic effectiveness and subjects’ anxiety levels. Brain imaging showed that different areas of the brain were activated in cases of negative expectancy effects (the hippocampus) versus positive expectancy effects (the endog-enous pain-modulatory system).7

A related, understudied effect is placebo-by-proxy, in which responses of patients’ family members and other associates may influence clinical decision-making in either an empowering or harmful manner. For example, parental expectations may in-fluence a clinician to prescribe an unnecessary antibiotic. In research settings, improvement may be rated differently by ob-servers and patients. In a meta-analysis of studies of irritable bowel syndrome (IBS), the pooled placebo response rate for physician-rated improvement was 53%, compared with 37% for patient-rated improvement. Similar mechanisms are be-lieved to underlie placebo and placebo-by-proxy effects.8

A New “Open Label” Placebo Research Paradigm

Research findings in recent years have raised questions about the conceptual, methodological, ethical, and clinical implica-tions of the placebo effect. In a landmark randomized con-trolled trial challenging the conventional wisdom that placebo effects require “intentional ignorance,” researchers compared the effects of open-label placebo with no-treatment for IBS.9 Half of the 80 patients took open-label placebo pills (2 pills

New Perspectives on the Placebo Effect

Sala Horowitz, PhD

Implications for Research and Clinical Practice

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ALTERNATIVE AND COMPLEMENTARY THERAPIES • JUNE 2012

MARY ANN LIEBERT, INC. • VOL. 18 NO. 3

New Perspectives on the Placebo Effect Implications for Research and Clinical Practice

twice daily) presented as “placebo pills made of an inert sub-stance, like sugar pills, that have been shown in clinical stud-ies to produce significant improvement in IBS symptoms through mind–body self-healing processes,” while the controls received no treatment. Both groups were engaged in support-ive patient–provider interactions. At the 11-day midpoint and at the 21-day endpoint, open-label placebos produced signifi-cantly higher mean scores on the IBS Global Improvement Scale. At the end of the 3-week trial, 59% of patients who were given the placebos—which is higher than the typical reported placebo response of 30%–40%—reported relief of symptoms, compared to 35% of the controls, as assessed by primary and secondary outcome measures.

The study’s lead author Ted Kaptchuk, BA—with a diplo-ma in Traditional Chinese Medicine, an associate professor of medicine at Harvard Medical School in Boston, Massachusetts, and director of Harvard’s Program in Placebo Studies & the Therapeutic Encounter (see Resources)—concluded that it may be appropriate in the case of some disorders for clinicians to suggest that patients try an inexpensive, safe placebo accompa-nied by wait-and-watch monitoring. Regarding this “placebos without deception” study, Mr. Kaptchuk commented:

The conventional wisdom is you need to make [patients] think they are taking a drug, you have to use deception and lies. . . .Our results suggest that the placebo response is not necessarily neutralized when placebos are admin-istered openly. Thus our study points to a potential novel strategy that might allow the ethical use of placebos con-sistent with evidence-based medicine.

This proof-of-principle pilot study was funded in part by the National Center for Complementary and Alternative Medi-cine (NCCAM) of the National Institutes of Health.9

Other Placebo-Effect Issues

Mr. Kaptchuk has also found that not all placebos admin-istered with informed consent are the same. In a study of two placebo treatments for persistent arm pain in 270 patients, acupuncture with a sham acupuncture needle twice a week for 6 weeks had a greater effect on perceived pain reduction than an inert pill taken once a day for 8 weeks.10 Placebos can also be administered in a manner analogous to dose-dependent pharmaceuticals (e.g., varying the quality of time the clinician spends with a patient).11 Some researchers have wondered whether placebo-controlled studies are actually comparing one treatment effect to another, namely, that of the placebo.12

A New Interdisciplinary Field of Study

The emerging field of placebo studies represents this new paradigm. Research at the Program in Placebo Studies (PiPS), the world’s first interdisciplinary center dedicated to the study

of the placebo effect, encompasses studies in clinical areas; neuroscience, genetics, and molecular biology; the social sci-ences; and bioethics and humanities. This Harvard Medical School center, hosted at Beth Israel Deaconess Medical Cen-ter in Boston, Massachusetts, has published the following statement:

Just as research-based scientific research drives the prog-ress of medical therapy, so too evidence-based research is needed to guide and enhance the art of medicine. . . .Only recently have researchers redefined it [the placebo effect] as the key to understanding the healing that arises from medical ritual, the context of treatment, the patient–provider relationship and the power of imagination, hope and expectation.13

Irving Kirsch, PhD, the associate director of the PiPS cen-ter (and professor emeritus of psychology at University of Hull, in the United Kingdom, and at the University of Con-necticut, in Storrs), addressed a plenary session of a meeting with a presentation entitled “Placebo Therapy as an Ethical Alternative.” The meeting was the Integrative Medicine & Health Congress, which was held in Portland, Oregon, May 15–18, 2012.14 Dr. Kirsch is one of the coauthors of the “placebos without deception” study by Kaptchuk et al. on IBS discussed above,9 and Dr. Kirsch has also studied the placebo response in relation to asthma, chronic pain, and depression.

From a meta-analysis of the efficacy of new-generation an-tidepressant medications, Dr. Kirsch found that, when unpub-lished clinical trial data (which pharmaceutical companies had submitted to the U.S. Food and Drug Administration in the drug-licensing process) were included, there was little clini-cally significant difference between drugs and placebos. Fur-thermore, even the relatively small drug effects might have re-ally been placebo effects as well, because many patients in these supposedly double-blinded clinical trials could tell if they had been given an actual drug because of its side-effects. Dr. Kirsch concluded that the weak association between initial depression severity and antidepressant effectiveness was attributable to decreased responsiveness to a placebo, rather than to increased responsiveness to medication.15

According to Dr. Kirsch: “The biggest barrier to the use of placebos in clinical practice is the almost universal percep-tion [that], for a placebo to be effective, it must be adminis-tered deceptively.”16 To get around expectations preventing placebo responses in cases in which subjects are openly in-formed of placebo use, he recommends pairing placebos with a convincing rationale as was the case in the “placebos with-out deception” study of IBS.9 He stated: “Be careful to make the rationale convincing and to establish a good therapeutic relationship, including sufficient time and careful listening to the patient’s concerns. These are likely to be crucial to ob-taining the kinds of effects we have seen.” Dr. Kirsch said that certain conditions, such as IBS, pain, and depression, may be more responsive to placebos, and, even in those conditions,

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placebo responses depend on factors, including mode of administration, informa-tion about size of expected effects, probability of get-ting placebo, and quality of the therapeutic relationship. From lessons he has learned to date about the placebo effect, Dr. Kirsch stated that he believes “we may be on the cusp of a new era in which treatments aimed at harnessing and exploiting the placebo effect ethically and without deception can be developed, tested, and

implemented as an adjunct—and sometimes even as an alter-native—to drug treatment.”16

Mechanisms of Action

Results from behavioral, psychophysiologic, and neuroimag-ing methodologies have contributed to the acceptance of the placebo effect as a real neurobiologic phenomenon relevant to healing processes and well-being.17 Among the most-accepted theories of how placebos work are those focusing on classical conditioning in social and cognitive learning (of the process of being treated by a health practitioner), and response expecta-tions and reward effects (concerning a practitioner’s suggestion that a particular treatment may be beneficial).18 The placebo

effect can also be attributed in part to the Hawthorne effect, a concept first studied in industrial psychology that showed that worker productivity increased as a result of the extra attention paid to them by researchers.19

As a result of the picture that has emerged of the multifacto-rial nature of placebos, some researchers think that it is more accurate to refer to many placebo effects, involving different mechanisms, systems, conditions, and interventions, rather than a single effect.20 Recent research tools have uncovered biochemical, anatomical, physiologic, and cellular mechanisms of the placebo effect.

Productive models for understanding placebo effects have been gained from studies of pain analgesia and Parkinson’s dis-ease (PD), in which the neuronal circuits involved in placebo re-

sponsiveness have been identified as being similar to the mech-anisms of, and effects induced by, drugs. From pain-analgesia studies, a neural network, comprised of opioidergic (concerning endogenous opioids), dopaminergic (the dopamine neurotrans-mitter), and cholecystokinergic (gastrointestinal-tract hormonal peptide) effects, has been found to be involved. It has also been found that, if prefrontal brain functioning is impaired, as in Al-zheimer’s disease, placebo responses are attenuated or lacking.21

As up to 50% of patients with PD, pain syndromes, and de-pression have positive placebo responses, it has been suggested that there is an expectation component. For example, objective improvements in PD correlate with dopaminergic pathways that mediate rewards. This explains why diseases that lack cor-tically based regulation may be less placebo-responsive.22

Research suggests that biomedical pharmacologic and pro-cedural interventions involve significant ritual dimensions. Ritual theory states that healing rituals—whether by tradi-tional or allopathic healers—create susceptibility to the influ-ences of culturally sanctioned authoritative figures. Fusing a patient’s narrative into a broader cultural mythos promotes modulations of symptoms through neurobiologic mechanisms as well as changes in affect, self-awareness, and self-appraisal of behavioral capacities.23 One can say that words and rituals are psychosocial stimuli that can alter brain functioning.

As in hypnosis, some patients are more responsive to such effects than others; some evidence posits that there is a genetic basis for differences in placebo responsiveness.21 In a study testing a model of placebo effects, 117 patients with MS were exposed daily to either an active or sham pulsing electromag-netic generator. Patients who scored higher on the personality trait of absorption and who were more confident that the sham device was the active one, accounted for 80% of the placebo responders.24 According to Dr. Kirsch, personality correlates of the placebo effect have been established only within the context of an enhanced therapeutic relationship.

In a functional magnetic resonance imaging study of pain stimulation in healthy subjects (N = 36), responders’ anticipa-tion of receiving placebo analgesia was associated with re-duced activation of certain brain regions (the dorsolateral and

Ethical Considerations for Using Placebos in Clinical Practice*

• Apatient’sinformedconsentisrequiredfortheadminis-tration of a placebo to not compromise the patient–physi-cian relationship, but the physician need not identify this placebo administration specifically or the precise timing of its use.

• Aphysicianshouldenlistthepatient’scooperationbyex-plaining that evaluating the effects of different medications, including the placebo, can lead to a better understanding of thepatient’smedicalcondition.

• Aplaceboisnottobegiventoservetheconvenienceofthepractitioner (as in the case of a difficult patient) rather than forthepatient’sbenefit.

*Adapted from ref. 32.

Irving Kirsch, PhD, Program in Placebo Studies & the Therapeu-tic Encounter, Harvard Medical School.

Recent research tools have uncovered biochemical,

anatomical, physiologic, and cellular mechanisms of the placebo effect.

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ventrolateral prefrontal cortices, somatosensory cortex, and thalamus), and during pain, with decreased activity in the so-matosensory cortex, posterior cingulate cortex, and thalamus, than in nonresponders.25

In some clinical trials, patients have reported benefits that were the result of placebo effects despite no confirming physiologic changes. For example, in a double-blinded, randomized crossover pilot study of 46 patients with asthma, the interventions of an active albuterol inhaler, a placebo albuterol inhaler, and sham acu-puncture were judged by patients to provide significantly greater relief than the no-intervention control (21%) in that trial. The ac-tual and placebo interventions provided equal subjective improve-ments of 45%–50%, even though an objective measure, maximum forced expiratory volume in one second (FEV1), showed improved lung function of 20% only for subjects who received the active albuterol inhaler. While the researchers concluded that placebo effects can be clinically meaningful, the researchers also caution that patient self-reports can be unreliable.26

Placebo effects that result from contextual psychosocial fac-tors (e.g., the health practitioner’s “bedside manner,” patient characteristics, culturally conditioned expectations, previous experience), can also exist in clinical practice even if no placebo is administered actively.27

Research Implications

A recent update of an earlier meta-analysis examined the outcomes of placebo interventions in 202 randomized clinical trials that included placebo and no-treatment groups for 60 conditions, and found little evidence of statistically significant effects when the results of placebo interventions were pooled

for trials involving 3 or more studies for pain, nausea, depres-sion, and smoking. However, a subset of 28 studies with the ex-plicit purpose of studying the placebo effect showed a greater effect, particularly with respect to pain and nausea. Wide varia-tions in outcomes were attributed to different research designs, sample sizes, nature of the placebos (devices versus pills), and how patients were informed about placebo usage.28

In addition to being more ethical, clinical trials with open-label placebos may narrow such variability of outcomes by leading to more standardized study designs. The challenge re-mains of translational “bench-to-bedside” research that trans-fers knowledge and interpretations from clinical trials into daily patient care.29

Clinical Use and Implications

Outside of clinical trials, the use of placebos remains con-troversial. A recent national survey (funded in part by the NCCAM) of U.S. internists and rheumatologists—doctors who commonly treat debilitating chronic conditions—found that only a small number of the 679 respondents reported surreptitious use of “pure” (inert) placebos. However, approxi-mately half of these specialists regularly recommended medi-cations that they considered to be nonspecific for treating a pa-tient’s condition but that would have been possibly beneficial; these included over-the-counter analgesics (41%), vitamins (38%), sedatives (13%), or antibiotics (13%). Prescribing anti-biotics when not medically necessary was of particular concern to the study authors.30

A systematic review of 22 empirical studies of placebos used in clinical practice in 12 countries likewise found that the use of “pure” placebos, such as sugar pills or saline injections, varied greatly, but was rare compared to the use of active or “impure” placebos. Definitions of what constitutes placebo treatments and attitudes toward them varied widely.31

While placebo effects that involve deception in clinical settings may be beneficial, undisclosed placebo use violates the principles of respect for patient autonomy and informed consent, and “may undermine trust, compromise the pa-tient–physician relationship, and result in medical harm to the patient.”32

Guidelines for Harnessing Placebo Effects Without Deception*

• Providepatientorstudysubjectwithanaccuratedescrip-tion of what is known about placebo effects.

• Provideencouragementtosuspenddisbelief.

• Provideinstructionsthatfosterpositivebutrealistic expectations.

• Providedirectionstoadheretothemedicalritualofpill-taking or other treatment intervention.

*Adapted from ref. 9.

ResourcesProgram

Program in Placebo Studies & the Therapeutic Encounter (PiPS) Harvard Medical School—Hosted at Beth Israel Deaconess Medical Center 330 Brookline Avenue Boston, MA 02215 Phone: (617) 945-7827 E-mail: [email protected] Website: http://programinplacebostudies.org

PiPSistheworld’sfirstinterdisciplinarycenterforplaceboresearch. At the Harvard-wide PiPS center programs across disciplines and campuses, researchers, clinicians, scholars, and students study the placebo effect, its role in the patient–practitioner relationship and the healing process, and the underlying mechanisms of action, to understand and reaffirm the humanistic dimensions of health care.

Online video

The Science of the Placebo Effect By Luana Colloca, MD, PhD May 9, 2011 http://videocast.nih.gov/summary.asp?live=10192

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Because of the negative connotations attached to the placebo effect, Dr. Benson and a colleague have suggested that “remem-bered wellness” should replace the term.33 Whatever it is called,

Beth Darnall, PhD—a pain psychologist, researcher, and assis-tant professor of anesthesiology and perioperative medicine at the Oregon Health & Science University in Portland—urges health practitioners to maximize the placebo effect in their pa-tients: “The most underutilized area of science and medicine is placebo. It used to be associated with weakness. I associate it with power. It perfectly exemplifies the power of the brain.”34

Other researchers have stated: “It is time we stop consider-ing perceptions, feelings, and human interactions in health care as variables that need to be controlled in the pursuit of medical science but include and study these as critically meaningful mediators and moderators of therapeutic out-comes in clinical trials, and daily care.”35 Likewise, Luana Colloca, MD, PhD—a research fellow at the NCCAM and at the department of bioethics at the National Institutes of Health in Bethesda, MD (See Resources for her online video)—says that “consideration of nocebo effects in the context of patient–clinician communication and disclosure in routine practice may be a component of a given therapy and improving outcomes.”36

Conclusion

Studies have confirmed that the placebo effect, rather than being a nuisance variable in research, is a measurable, albeit complex, phenomenon with physiologic correlates that have clinical relevance and is worthy of interdisciplin-ary scientific study it its own right.

In response to ethical concerns raised regarding the norm of using undisclosed placebos in clinical trials and practice, researchers have recently shown open-label placebos to be a viable alternative to standard placebos. Further investi-gation is warranted to identify the conditions and patients most responsive to placebo effects, and ways to stimulate positive mind–body effects and integrate them with other treatment modalities ethically within the multifaceted con-text of the patient–health practitioner relationship. n

References

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3. Suter WN. Introduction to Educational Research: A Critical Thinking Ap-proach, 2nd ed. Los Angeles: Sage, 2012.4. Beecher HK. The powerful placebo. JAMA 1955;159:1602–1606.5. Macedo A, Farré M, Baños JE. Placebo effect and placebos: What are we talking about? Some conceptual and historical considerations. Eur J Clin Pharmacol 2003;59:337–342. 6. Bowling AC. Placebos and Nocebos—Techniques to Optimize MS Man-agement? [Healthy Living column]. Online document at: http://findarticles.com/p/articles/mi_7402/is_2_4/ai_n57071338/ Accessed February 12, 2012.7. Bingel U, Wanigasekera V, Wiech K, et al. The effect of treatment expecta-tion on drug efficacy: Imaging the analgesic benefit of the opioid remifentanil. Sci Transl Med 2011;3:70ra14.8. Grelotti DJ, Kaptchuk TJ. Placebo by proxy. BMJ 2011;343:d4345. 9. Kaptchuk TJ, Friedlander E, Kelley JM, et al. Placebos without decep-tion: A randomized controlled trial in irritable bowel syndrome. PloS One 2010;5:e15591. 10. Kaptchuk TJ, Stason WB, Davis RB, et al. Sham device v inert pill: Ran-domised controlled trial of two placebo treatments. BMJ 2006;332:391–397.11. Kaptchuk TJ, Kelley JM, Conboy LA, et al. Components of placebo effect: Randomised controlled trial in patients with irritable bowel syndrome. BMJ 2008;336:999–1003.12. Williams KA, Harden N. Managing the placebo effect: Enhancing the signal-to-noise ratio. Current Pain Headache Rep 2011;15:35–38.13. Program in Placebo Studies & the Therapeutic Encounter. Research. Online document at: http://programinplacebostudies.org/research/ Accessed January 16, 2012.14. Integrative Medicine & Health Congress. Plenary Sessions, May 15 –18 [information posted in advance of meeting]. Online document at: http://im consortium-congress2012.org/speakers.html Accessed January 16, 2012.15. Kirsch I, Deacon BJ, Huedo-Medina TB, et al. Initial severity and anti-depressant benefits: A meta-analysis of data submitted to the Food and Drug Administration. PLoS One 2008;5:e45. 16. Kirsch I. Preface. Philos Trans R Soc Lond B Biol Sci 2011;366:1781–1782.17. Meissner K, Bingel U, Colloca L, et al. The placebo effect: Advances from different methodological approaches. J Neurosci 2011;31:16117–16124.18. National Center for Complementary and Alternative Medicine. Poten-tial Roles of the Placebo Effect in Health Care. Online document at: http://nccam.nih.gov/research/results/spotlight/051711.htm Accessed January 19, 2012.19. McCarney R, Warner J, Iliffe S, et al. The Hawthorne effect: A randomised, controlled trial. BMC Med Res Methodol 2007;7:30.20. Carlino E, Pollo A, Benedetti F. Placebo analgesia and beyond: A melting pot of concepts and ideas for neuroscience. Curr Opin Anaethesiol 2011;24: 540–544.21. Benedetti F, Carlino E, Pollo A. How placebos change the patient’s brain. Neuropharmacology 2011;36:339–354.22. Diederich MD, Goetz CG. The placebo treatments in neurosciences: New insights from clinical and neuroimaging studies. Neurology 2008;71:677–684.23. Kaptchuk TJ. Placebo studies and ritual theory: A comparative analysis of Navajo, acupuncture and biomedical healing. Philos Trans R Soc Lond B Biol Sci 2011;366:1849–1858.24. Owens JE, Menard M. The quantification of placebo effects within a gen-eral model of health care outcomes. J Altern Complement Med 2011;17:817–821.25. Elsenbruch S, Kotsis V, Benson S, et al. Neural mechanisms mediating the effects of expectation in visceral placebo analgesia: An fMRI study in healthy placebo responders and non-responders. Pain 2012;153:382–390.26. Wechsler ME, Kelley JM, Boyd IO, et al. Active albuterol or placebo, sham acupuncture, or no intervention in asthma. N Engl J Med 2011;365:119–126.

“The most underutilized area of science and medicine is placebo.”

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27. Finniss DG, Kaptchuk TJ, Miller F, Benedetti F. Biological, clinical, and ethical advances of placebo effects. Lancet 2010;375:686–695.28. Hróbjartsson A, Gøtzsche PC. Placebo interventions for all clinical condi-tions. Cochrane Database Syst Rev 2010;1:CD003974.29. Meissner K, Kohls N, Colloca L. Introduction to placebo effects in medi-cine: Mechanisms and clinical implications. Philos Trans R Soc Lond B Biol Sci 2011;366:1783–1789.30. Tilburt JC, Emanual EJ, Kaptchuk TJ, et al. Prescribing “placebo treat-ments:” Results of a national survey of US internists and rheumatologists. BMJ 2008;337:a1938.31. Fässler M, Meissner K, Schneider A, Linde K. Frequency and circum-stances of placebo use in clinical practice—a systematic review of empirical studies. BMC Med 2010;8:15. 32. American Medical Association. AMA Code of Medical Ethics: Opin-ion 8.083-Placebo Use in Clinical Practice. Report issued June 2007.

Online document at: www.ama-assn.org/ama/pub/physician-resources/medical-ethics/code-medical-ethics/opinion8083.page Accessed January 20, 2012.33. Benson H, Friedman R. Harnessing the power of the placebo effect and renaming it “remembered wellness.” Ann Rev Med 1996;47:193–199.34. Korn P. The pain is all in your head (and researchers say that’s OK). Port-land Tribune, August 11, 2011:1–2.35. Di Blasi Z, Reilly D. Placebos in medicine: Medical paradoxes need dis-tentangling. BMJ 2005;330:45.36. Colloca L, Finniss D. Nocebo effects, patient–clinician communication, and therapeutic outcomes. JAMA 2012;307:567–568.

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New Perspectives on the Placebo Effect: Implications for Research and Clinical Practice