Int. J. Pharm. Med. & Bio. Sc. 2013 Kumar Amit et al., 2013 ISSN 2278 – 5221 www.ijpmbs.com Vol. 2, No. 4, October 2013 © 2013 IJPMBS. All Rights Reserved A COMPARATIVE STUDY OF EFFICACY OF TERBINAFINE AND FLUCONAZOLE IN PATIENTS OF TINEA CORPORIS
Isik.zrc-sazu.siCOMPLEMENTARY AND ALTERNATIVE MEDICINE SERIES
Series Editors: David M. Eisenberg, MD, and Ted J. Kaptchuk, OMD
Academia and Clinic The Placebo Effect in Alternative Medicine: Can the Performance of a
Healing Ritual Have Clinical Significance?
Ted J. Kaptchuk, OMD
In alternative medicine, the main question regarding placebo has
Therapeutic patterns that heighten placebo effects are espe-
been whether a given therapy has more than a placebo effect. Just
cially prominent in unconventional healing, and it seems possible
as mainstream medicine ignores the clinical significance of its
that the unique drama of this realm may have "enhanced" pla-
own placebo effect, the placebo effect of unconventional medicine
cebo effects in particular conditions. Ultimately, only prospective
is disregarded except for polemics. This essay looks at the placebo
trials directly comparing the placebo effects of unconventional and
effect of alternative medicine as a distinct entity. This is done by
mainstream medicine can provide reliable evidence to support
reviewing current knowledge about the placebo effect and how it
such claims. Nonetheless, the possibility of enhanced placebo
may pertain to alternative medicine. The term placebo effect is
effects raises complex conundrums. Can an alternative ritual with
taken to mean not only the narrow effect of a dummy intervention
only nonspecific psychosocial effects have more positive health
but also the broad array of nonspecific effects in the patient–
outcomes than a proven, specific conventional treatment? What
physician relationship, including attention; compassionate care;
makes therapy legitimate, positive clinical outcomes or culturally
and the modulation of expectations, anxiety, and self-awareness.
acceptable methods of attainment? Who decides?
Five components of the placebo effect—patient, practitioner,
patient–practitioner interaction, nature of the illness, and treat-
Ann Intern Med. 2002;136:817-825.
ment and setting—are examined.
For the author affiliation and current address, see end of text.
Efficacious therapy, in one biomedical definition, is native medicine and raises the possibility that some
therapy that has positive effects greater than those of types of unconventional medicine may produce placebo an indistinguishable dummy treatment in a randomized, outcomes that are dramatic and, from the patient's per- controlled trial (RCT) (1–3). Such specific efficacy is spective, especially compelling. The term placebo effect is actually a comparative measure: intervention contrasted taken to mean not only the narrow effect of an imitation with placebo. This relative effectiveness, which is esti- intervention but also the broad amalgam of nonspecific mated by statistical testing, is taken to indicate "authen- effects present in any patient–practitioner relationship, ticity." The clinical significance, that is, the outcome including attention; communication of concern; intense measured by using the patient's original condition as a monitoring; diagnostic procedures; labeling of com- baseline, is usually a secondary consideration for deter- plaint; and alterations produced in a patient's expect- mining "legitimate" medical interventions. Any clinical ancy, anxiety, and relationship to the illness. This essay impact due to the placebo, which is deemed to lack asks whether alternative medicine can have an "en- "truthfulness," is even less notable and is valued only as hanced" placebo effect. In some conditions, can any of a comparison baseline for "genuine" effects (3). Specific alternative medicine's particular rituals have a greater effects are by definition superior to nonspecific effects.
impact than the rituals of conventional medicine or than The clinical repercussions of the placebo are tolerated as a proven physiologically active treatment? After all, as necessary nuisance noise but are otherwise considered many of the examples in this essay will demonstrate, inconsequential or treated with contempt (4).
"two interventions may have different effects on patient Given the privileged status of specific effects, it is outcome even though both [are] equivalent to placebo not surprising that the clinical impact of alternative in clinical trials" (6). Dismissing a treatment as "just a medicine's placebo effects are routinely ignored (5). The placebo" may not be enough.
only serious question has been whether alternative med- Alternative medicine may be an especially successful icine has more than a placebo effect. Discarding all pla- placebo-generating health care system. Rather than spe- cebo effects in a single trash basket of "untruthfulness," cific biological consequences, which epidemiologists des- however, diminishes our knowledge of important di- ignate as "fastidious efficacy" (7), alternative medicine mensions of health care. This essay examines the ne- may administer an especially large dose of what anthro- glected clinical significance of the placebo effect in alter- pologists call "performative efficacy" (8). Performative 2002 American College of Physicians–American Society of Internal Medicine 817
Academia and Clinic The Placebo Effect in Alternative Medicine efficacy relies on the power of belief, imagination, sym- with taking placebo and those who do not—are associ- bols, meaning, expectation, persuasion, and self-relation- ated not only with symptom relief but also with con- ship. This essay takes five components of the placebo crete end points, including survival (22–24). Indeed, drama—patient, practitioner, patient–practitioner inter- differences in adherence are associated with differences action, nature of the illness, and treatment and setting— in outcomes that exceed the effects of many pharmaceu- and examines their "placebogenic" potentials in uncon- tical agents (25). Patient preferences for one type of ventional healing practices. Much of the evidence is intervention, especially in participative interventions derived from conventional research and is speculatively (for example, exercise or diet programs), may contribute applied to alternative medicine. Also, it should be noted significantly to outcomes, including increased placebo that most of the placebo research discussed in this essay responses (26 –28).
does not represent an "artifactual" placebo effect ex- In contrast to conventional medicine, with its mea- plainable by natural history or regression to the mean.
sured objectivity, alternative medicine offers a charged Rather, it usually involves comparative experiments with constellation of expectations. Alternative medicine's ro- two different types of placebo or the same placebo de- mantic vision is inhabited by benevolent and intentional livered under different cognitive or emotional circum- forces (for example, the innate intelligence of chiroprac- stances where two distinct placebo outcomes would not tic or the qi of acupuncture) that are unrestrained by the support the idea of placebo effect as only natural history.
laws of normative physics (29). An exaggerated notion Finally, this essay argues mostly in generalities. Obvi- of the possible readily elicits patients' magical anticipa- ously, the placebo effect is likely to be at least as heter- tion. These unconventional concepts do not require ab- ogeneous in alternative medicine as in conventional solute belief "in the sense that their truth value is certi- medicine, but it is hoped that raising these questions fied by logic or argument" but rather requires moderate will encourage further discussion and research.
openness "in the sense that they are taken into the imag-ination and lived with, if only for a time" (30).
Alternative medicine emphasizes personal responsi- bility, which can facilitate adherence. Indeed, the act of Although the patient is the protagonist in the pla- switching to another medical system and exhibiting cebo drama, research has failed to find consistent pla- preference by action demonstrates an openness to active cebo responders or to identify personality traits or other participation and adherence and possibly enhances it.
qualities of persons who frequently react to placebo (9 – Paying out-of-pocket and other signs of commitment, 11). However, evidence shows that patient expectations such as following daily lifestyle regimens, undoubtedly influence outcomes of both placebo and active treat- marshal adherence effects. The reasons that patients ment. Asthmatic patients who believe that an inert sub- choose alternative medicine may also potentiate a pla- stance is a bronchodilator or a bronchoconstrictor re- cebo response. Patients with chronic diseases often turn spond accordingly (12–14). In a small but classic to unconventional healing after long-term negative con- crossover experiment, healthy volunteers received a pla- ditioning with mainstream medicine (31). In this situa- cebo pill in which a magnet was embedded. In random tion, patients' hope (based on no previous experience order, at different times, they were told that they were with alternative medicine) may provide an opportunity receiving a relaxant, a stimulant, or a placebo. Subse- for "deconditioning" from previous unsuccessful medi- quent gastric motility was significantly consistent with cal experiences.
patients' expectations (15). Patient expectancies also sig-nificantly change or even reverse the actions of manypotent pharmaceutical agents (16 –19).
Adherence to placebo may also be a surrogate The practitioner-healer must expertly play the role marker for a patient's own contribution to the activation of heroic rescuer to facilitate a placebo effect (32). Nu- of the placebo response (20, 21). In RCTs, such "place- merous RCTs have compared optimistic or enthusiastic bo adherence effects"—the post hoc differences ob- physician attitudes toward drug or placebo with neutral served in the placebo arm between those who comply or doubtful physician attitudes. Practitioners have had 818 4 June 2002 Annals of Internal Medicine Volume 136 • Number 11
The Placebo Effect in Alternative Medicine Academia and Clinic significant impact on such clinical conditions as pain cal expectations need to be negotiated and joined in the (33–36), psychiatric illness (37– 41), hypertension (42, patient–physician duet. Many studies indicate that the 43), obesity (44), and perimenopause symptoms (45).
patient–practitioner encounter is a potent factor in Although some studies have shown no effect of physi- health outcomes (54 –56) and that for many non–life- cians' expectations on clinical end points (46 – 48), a threatening illnesses, clear diagnosis, assurance of recov- systematic review of 85 studies found that although ery, opportunity for dialogue, and physician–patient more research is needed, provider-induced "expectancies agreement about the nature of the problem hasten re- are a mechanism for placebo effects, [which have] re- covery or relief (57, 58). One study examined 200 pa- ceived support across a range of clinical areas in a variety tients who presented to general practitioners with symp- of studies" (49). A second review, which used more toms but no abnormal physical signs and in whom no stringent entry criteria, found 25 RCTs that examined definite diagnosis could be made. Patients were ran- the impact of randomly assigning patients with physical domly assigned in a 2 ⫻ 2 design to treatment or no illnesses to different levels of expectancy and emotional treatment and to a positive consultation, in which they support. Although researchers found inconsistent effects received "a firm diagnosis and [were] told confidently and determined that further research was needed, they that [they] would be better in a few days," or a negative also found that "enhancing patients' expectations consultation, in which they were told that their condi- through positive information about the treatment or ill- tion was uncertain. Although provision of treatment ness, while providing support or reassurance, [seemed made no difference, positive interaction produced signif- to] significantly influence health outcomes" (50).
icantly faster recovery (59). A similar experiment in 100 Even in blinded RCTs, practitioner certitude seems patients with acute tonsillitis had analogous results (60).
to influence the magnitude of the placebo effect. In one Consultation in unconventional medicine is more RCT that simultaneously compared two double-blind likely than its mainstream counterpart to produce a pre- RCTs, dental patients in one trial received placebo, nar- cise diagnosis that matches patients' perceptions. In un- cotic analgesics, or narcotic antagonists and those in the conventional medicine, patient experience is never de- other trial received only a placebo or a narcotic antago- valued or brushed aside as unreliable (61). Inevitably, nist. Dentists knew the possible interventions in both since the alternative world is not as constrained by the trials but remained blinded to administration of medi- dichotomy of objectivity and subjectivity, the chiroprac- cation. Pain in placebo recipients was significantly worse tor will find the subluxation, the acupuncturist will de- in the second trial, in which narcotic drugs were not an tect the yin–yang disharmony, and the health food ad- option, than in the first trial (51). An earlier RCT of the vocate will identify the transgression that makes sense of effect of physician expectations on hypertension drugs the patient's life-world. In addition, if a patient is new also found that practitioner belief can transform out- to alternative medicine, an opportunity for exchange is invariably offered, providing the patient with "theoreti- Practitioners of unconventional medicine are less re- cal explanations designed to take the mystery out of strained by scientific objectivity than practitioners of process and problems" (62). When it is considered that conventional medicine. The sensibilities of alternative 40% to 60% of patients may never receive a firm diag- practitioners are therefore often more optimistic and nosis in conventional medicine (63, 64), an alternative positive than those of their mainstream counterparts diagnosis may be a potent form of nonspecific healing (53). The characteristics thought to enhance the placebo that changes the circumstances under which the patient effect (and any active intervention) seem to be fully op- exists (65– 67), including reducing the "dysphoria of un- erational in the offices of alternative medicine.
Besides diagnosis, the healing encounter also estab- lishes therapeutic goals. Paradoxically, while the alterna- tive diagnosis tends to be precise, treatment aims can be The placebo drama is probably more successful if diverse. Because of such notions as "holistic medicine" the patient and practitioner find each other's beliefs and and "body, mind, spirit," alternative medicine can have actions mutually credible or at least intriguing. Recipro- extremely broad, indeterminate therapeutic targets and 4 June 2002 Annals of Internal Medicine Volume 136 • Number 11 819
Academia and Clinic The Placebo Effect in Alternative Medicine therefore, at least from a cultural view, "in some sense either active or inert ingredients may often yield better re- cannot fail" (69). Such amorphous goals can provide sults than an identical treatment that is not as well known additional maneuvering room for positive progress, or at (96), and devices or elaborate procedures can have greater least incremental change (70). If the patient's symptoms placebo effects than pills (97, 98). Active placebos (placebos do not directly improve, it is likely that something pos- containing medications, such as atropine, that are ineffec- itive will happen and be attributed to the intervention tive for the condition being studied but produce recogniz- (even if the change pertains only to alternative con- able drug-related side effects) seem to provide genuine structs, such as the homeopathic spiritual force or the treatment recognition that leads to heightened placebo ef- acupuncture qi). Taken together, the alternative diagno- fects (99, 100). With good showmanship, a well-designed, sis, prognosis, and treatment aims serve "to regulate totally inert stage prop can offer this kind of "feedback symptom intensity and distress" and "create enough cer- loop" and can produce exaggerated placebo effects.
tainty to diminish the threat of the inchoate while pre- Two RCTs— one of transcutaneous electrical nerve serving enough ambiguity to allow for fresh improvisa- stimulation and one of "placebo electronic machines"— demonstrated that, with good staging, blank machinescan provide feedback sensations. In the first study, all patients reported an electrical sensation after adjustment HE NATURE OF THE ILLNESS
of the dummy apparatus, which was equipped with vi- The placebo effect may benefit from the types of ill- sual and sound feedback (101). In the second trial nesses that alternative medicine commonly treats. Data in- (which used only dummy machines under two different dicate that the overwhelming majority of medical condi- sets of expectations), a significant number of partici- tions treated by unconventional medicine fall into the pants "felt" the nonexistent current, and some even vol- following categories: highly subjective symptoms lacking unteered that the sensation was "just amazing" (102).
identifiable physiologic correlates, chronic conditions with Biomedicine and alternative medicine each have a a fluctuating course often influenced by selective attention, special allure of mystery and exotic power; it would be and affective disorders (2, 72). Not surprisingly, these con- hard to argue that one backdrop consistently provides a ditions are precisely those that researchers believe are espe- superior placebo effect. However, alternative medicine cially susceptible to inordinately strong placebo responses: has the advantage of always having an intervention sce- back and chronic pain (73–75), fatigue (76, 77), arthritis nario. Therapeutic passivity is rarely an option, and (78, 79) headache (80, 81), allergies (82, 83), hypertension practitioners can, at a minimum, offer something that is (in some situations) (84, 85), insomnia (86, 87), asthma likely to have a placebo effect. In some situations, and at (13, 88), chronic digestive disorders (89, 90) depression least for continuous subjective outcomes, an interven- (91, 92), and anxiety (93). Even researchers who question tion presumably has a greater effect than no treatment the existence or significance of a placebo effect—at least in (94, 103). Also, to demonstrate "active" intervention, the narrow sense of the outcome produced by a dummy alternative medicine treatments have unique feedback intervention— concede its impact when outcomes are con- loops that are likely to facilitate, if not heighten, sub- tinuous and subjective (94). Also, persons with self-limiting stantial placebo responses. For example, chiropractic ad- diseases, such as the common cold and sprains and strains, justment often triggers an audible "pop" so that the also frequently use alternative medicine. In these cases, the patient can hear the subluxation being fixed (104), acu- natural course of the disease undoubtedly creates the ap- puncturists propagate a sensation of vital energy cours- pearance of treatment response and enhances the percep- ing through invisible meridians (105), and psychic heal- tion of unconventional medicine's effectiveness.
ers summon tingling vibrations (106).
TREATMENT AND SETTING
Treatment paraphernalia and setting affect the impact DOES ALTERNATIVE MEDICINE HAVE ENHANCED
of a placebo performance. For placebo pills, a regimen of four times per day seems more effective than a regimen of Despite the arguments and speculations already pre- twice per day (95). A "brand-name" therapy that includes sented, there is scant empirical evidence that any partic- 820 4 June 2002 Annals of Internal Medicine Volume 136 • Number 11
The Placebo Effect in Alternative Medicine Academia and Clinic ular type of alternative medicine used for any particular alternative medicine would probably require many such condition has an augmented placebo effect. Even con- cerning the placebo effect in general, the evidence cited Some may dismiss these types of investigation as earlier is often methodologically weak and limited by useless. After all, a placebo is just a placebo. Others small numbers and short follow-up periods. Some social would argue that such avoidance impoverishes and nar- scientists argue that "for the believer in science, medical rows the understanding of what patients receive from care that appears to be scientific would provide a supe- alternative medicine (and, by extension, conventional rior placebo; for the believer . . of whatever other medicine). Even those who doubt the existence or sig- cultural system of meaning and values," alternative med- nificance of a "narrow" placebo effect seem open to the icine may "provide a superior placebo" (107). Perhaps possibility of "broad" placebo effects embedded in the biomedicine's effort to eliminate ritual or placebo inter- psychosocial context of the patient–practitioner relation- ventions itself produces an improved placebo effect.
ship (110, 111).
Two examples from RCTs may help readers con- cretely envision an enhanced placebo effect. In a four-arm crossover RCT involving 44 patients with chronic WHAT IS LEGITIMATE HEALING?
cervical osteoarthritis of more than 6 months' duration, Besides clinical and scientific value, the question of acupuncture, sham acupuncture, and diazepam were all enhanced placebo effects raises complex ethical ques- equivalent and were superior to a placebo pill (108). In tions concerning what is "legitimate" healing. What this study, the outcome of the ritual of acupuncture should determine appropriate healing, a patient's im- (real and sham acupuncture were not different) equaled provement from his or her own baseline (clinical signif- the outcome of an effective drug. In a second RCT, icance) or relative improvement compared with a pla- which studied spinal manipulation, 256 patients with cebo (fastidious efficacy)? As one philosopher of nonspecific back and neck disorders were randomly as- medicine has asked, are results less important than signed to receive manual therapy (the Dutch equivalent method (3)? Both performative and fastidious efficacy of chiropractic), physical therapy, placebo-device ther- can be measured. Which measurement represents uni- apy with a "detuned" ultrasonography machine and versal science? Which measurement embodies cultural "detuned" short-wave diathermy that emitted sounds judgment on what is "correct" healing? Are the concerns and lights, or treatment from a general practitioner of the physician identical to those of the patient? Is (109). Six weeks of manual therapy and physical therapy denying patients with nonspecific back pain treatment were equally and significantly better than the sham ma- with a sham machine an ethical judgment or a scientific chine, which significantly outperformed the general judgment? Should a patient with chronic neck pain who practitioner. It cannot be determined whether the man- cannot take diazepam because of unacceptable side ef- ual and physical therapies had specific treatment effects fects be denied acupuncture that may have an "en- or simply yielded better placebo effects than the inani- hanced placebo effect" because such an effect is "bogus"? mate gadget. Nonetheless, in this experiment, treatment Who should decide? with a sham machine surpassed treatment from a com- Patients' attitudes toward placebo interventions (es- petent physician for relief of low back pain.
pecially enhanced interventions) probably differ from To more rigorously test these possible relative non- physicians' attitudes (112). This distinction is probably specific effects, my colleagues and I are performing a most evident in surgery, another field in which a height- National Institutes of Health–funded RCT that ran- ened placebo effect is possible (97, 113), as illustrated by domly assigns patients with chronic pain to one of two two RCTs that tested implantation of fetal dopaminer- parallel run-in phases. Before entering two subsequent gic cells for Parkinson disease. Patients with Parkinson RCTs, one run-in group receives a conventional-appear- disease seem to have a robust placebo response (114, ing placebo pill and the other receives an alternative 115); the biochemical substrate of this response in rela- medicine sham procedure; the main goal of the run-in tion to the release of dopamine in the striatum has re- phases is to detect differing placebo effects (97). Any cently been shown on positron emission tomography confident assertion about a placebo effect enhanced by (116). At the conclusion of one of the two RCTs, 4 June 2002 Annals of Internal Medicine Volume 136 • Number 11 821
Academia and Clinic The Placebo Effect in Alternative Medicine patients were unblinded, and half were told they had received sham surgery that had performed the same as 1. Temple RJ. When are clinical trials of a given agent vs. placebo no longer
real surgery. In the early reports from this study, both appropriate or feasible? Control Clin Trials. 1997;18:613-20. [PMID: 9408723]
2. Kaptchuk TJ, Edwards RA, Eisenberg DM. Complementary medicine: effi-
groups experienced significant clinical improvement.
cacy beyond the placebo effect. In: Ernst E, ed. Complementary Medicine: (The subsequent full report, which included long-term An Objective Appraisal. Oxford: Butterworth-Heinemann; 1996.
data, reported a less durable placebo effect .) When 3. Sullivan MD. Placebo controls and epistemic control in orthodox medicine.
patients who had received the sham surgery were told J Med Philos. 1993;18:213-31. [PMID: 8315363] that they could not receive the real but now "discredit- 4. wan Weel C. Examination of context of medicine. Lancet. 2001;357:733-4.
ed" surgery, as they had been promised in the informed 5. Kaptchuk TJ. Powerful placebo: the dark side of the randomised controlled
consent form, 70% were disappointed or "outraged" be- trial. Lancet. 1998;351:1722-5. [PMID: 9734904] cause of the dramatic benefits they had already received 6. Vickers AJ, de Craen AJ. Why use placebos in clinical trials? A narrative review
from sham surgery (118 –120). They wanted the "real" of the methodological literature. J Clin Epidemiol. 2000;53:157-61. [PMID:10729687] procedure even if it was equivalent to the sham. Of 7. Feinstein AR. Clinical Epidemiology. Philadelphia: WB Saunders; 1985.
interest, the second RCT, which also found no differ- 8. Tambiah SJ. Magic, Science, Religion, and the Scope of Rationality. Cam-
ence between active and imitation surgery, demon- bridge, United Kingdom: Cambridge Univ Pr; 1990.
strated a stable and significant placebo effect after 18 9. Shapiro AK, Shapiro E. The Powerful Placebo: From Ancient Priest to Mod-
months (121). For many patients, performative efficacy ern Physician. Baltimore: Johns Hopkins Univ Pr; 1997.
may be more critical than fastidious efficacy. Obviously, 10. Wolf S, Doering CR, Clark ML, Hagans JA. Chance distribution and the
placebo "reactor." J Lab Clin Med. 1957;49:837-41.
this illustration is not meant to advocate ritualistic sur- 11. Liberman RP. The elusive placebo reactor. Neuropsychopharmacology.
gery. Rather, it is meant to highlight the complex rela- tionship among clinical, scientific, and ethical judg- 12. Luparello TJ, Leist N, Lourie CH, Sweet P. The interaction of psychologic
stimuli and pharmacologic agents on airway reactivity in asthmatic subjects.
Psychosom Med. 1970;32:509-13. [PMID: 4097491]
13. Butler C, Steptoe A. Placebo responses: an experimental study of psycho-
physiological processes in asthmatic volunteers. Br J Clin Psychol. 1986;25(Pt 3):173-83. [PMID: 3768575] Alternative medicine may be composed of healing 14. Sodergren SC, Hyland ME. Expectancy and asthma. In: Kirsch I, ed. How
rituals that have especially potent performative efficacy.
Expectancies Shape Experience. Washington, DC: American Psychological Assoc; Therapeutic characteristics that may enhance placebo ef- 1999.
15. Sternbach RA. The effects of instructional sets on autonomic responsivity.
fects seem especially prominent in unconventional heal- ing. Although more research into this question is neces- 16. Kaptchuk TJ. The double-blind, randomized, placebo-controlled trial. Gold
sary before any such assertion can be made with standard or golden calf? J Clin Epidemiol. 2001;54:541-9. [PMID: 11377113] confidence, an enhanced placebo effect raises complex 17. Mitchell SH, Laurent CL, de Wit H. Interaction of expectancy and the
questions about what is legitimate therapy, and who de- pharmacological effects of d-amphetamine: subjective effects and self-administra-tion. Psychopharmacology (Berl). 1996;125:371-8. [PMID: 8826542] 18. Flaten MG, Simonsen T, Olsen H. Drug-related information generates
placebo and nocebo responses that modify the drug response. Psychosom Med.
From Harvard Medical School, Boston, Massachusetts.
1999;61:250-5. [PMID: 10204979]
19. Dworkin SF, Chen AC, Schubert MM, Clark DW. Cognitive modification
Acknowledgment: The author thanks Robb Scholten, June Cobb, Pat
of pain: information with N2O. Pain. 1984;19:339-51. [PMID: 6483450] Wilkinson, John C. Wilson, Maria Van Rompay, and Marcia Rich for 20. Horwitz RI, Horwitz SM. Adherence to treatment and health outcomes.
editorial and research assistance.
Arch Intern Med. 1993;153:1863-8. [PMID: 8250647]
21. Czajkowski SM, Chesney MA. Adherence and the placebo effect. In: Shu-
maker SA, Schron EB, Ockene JK, eds. The Handbook of Health Behavior
Grant Support: In part by the National Institutes of Health
Change. New York: Springer; 1990.
(1R01AT00402-01, U24 AR43441, and 1R21AT00553), the John E.
22. Influence of adherence to treatment and response of cholesterol on mortality Fetzer Institute, the Waletzky Charitable Trust, the Friends of Beth in the coronary drug project. N Engl J Med. 1980;303:1038-41. [PMID: Israel Deaconess Medical Center, and American Specialty Health Plan.
23. Horwitz RI, Viscoli CM, Berkman L, Donaldson RM, Horwitz SM,
Requests for Single Reprints: Ted J. Kaptchuk, OMD, Beth Israel
Murray CJ, et al. Treatment adherence and risk of death after a myocardial
Deaconess Medical Center, Harvard Medical School, 330 Brookline Av- infarction. Lancet. 1990;336:542-5. [PMID: 1975045] enue, Boston, MA 02215.
24. Gallagher EJ, Viscoli CM, Horwitz RI. The relationship of treatment
822 4 June 2002 Annals of Internal Medicine Volume 136 • Number 11
The Placebo Effect in Alternative Medicine Academia and Clinic adherence to the risk of death after myocardial infarction in women. JAMA.
sic effect of tramadol in chronic pain patients: a 2 ⫻ 2 factorial, randomised, 1993;270:742-4. [PMID: 8336377] placebo-controlled, double-blind trial. In: Placebos and Placebo Effects in Clini- 25. Mattocks KM, Horwitz RI. Placebos, active control groups, and the unpre-
cal Trials [Dissertation]. Amsterdam: Univ of Amsterdam; 1998.
dictability paradox. Biol Psychiatry. 2000;47:693-8. [PMID: 10773175] 47. Cooper WD, Currie WJ, Vandenburg MJ. The influence of physicians'
26. Wennberg JE. What is outcomes research? In: Gelijns AC, ed. Modern
instructions on the outcome of antihypertensive therapy. Br J Clin Pract. 1983; Methods of Clinical Investigation. Washington, DC: National Academy Pr; 37:99-103. [PMID: 6882631] 48. Kincheloe JE, Mealiea WL Jr, Mattison GD, Seib K. Psychophysical mea-
27. McPherson K, Britton AR, Wennberg JE. Are randomized controlled trials
surement on pain perception after administration of a topical anesthetic. Quin- controlled? Patient preferences and unblind trials. J R Soc Med. 1997;90:652-6.
tessence Int. 1991;22:311-5. [PMID: 1891606] 49. Crow R, Gage H, Hampson S, Hart J, Kimber A, Thomas H. The role of
28. Brewin CR, Bradley C. Patient preferences and randomised clinical trials.
expectancies in the placebo effect and their use in the delivery of health care: a BMJ. 1989;299:313-5. [PMID: 2504416] systematic review. Health Technol Assess. 1999;3:1-96. [PMID: 10448203] 29. Kaptchuk TJ. History of vitalism. In: Micozzi MS, ed. Fundamentals of
50. Di Blasi Z, Harkness E, Ernst E, Georgiou A, Kleijnen J. Influence of
Complementary and Alternative Medicine. New York: Churchill Livingstone; context effects on health outcomes: a systematic review. Lancet. 2001;357:757- 62. [PMID: 11253970] 30. Kirmayer LJ. Healing and the invention of metaphor: the effectiveness of
51. Gracely RH, Dubner R, Deeter WR, Wolskee PJ. Clinicians' expectations
symbols revisited. Cult Med Psychiatry. 1993;17:161-95. [PMID: 7693395] influence placebo analgesia [Letter]. Lancet. 1985;1:43. [PMID: 2856960] 31. Zollman C, Vickers A. ABC of complementary medicine. Complementary
52. Shapiro AP, Myer T, Reiser MF, Ferris EB. Comparison of blood pressure
medicine and the patient. BMJ. 1999;319:1486-9. [PMID: 10582937] response to Veriloid and to the doctor. Psychosom Med. 1954;16:478-88.
32. Shapiro AK. Iatroplacebogenics. International Pharmacopsychiatry. 1969;2:
53. Kaptchuk TJ, Eisenberg DM. The persuasive appeal of alternative medicine.
Ann Intern Med. 1998;129:1061-5. [PMID: 9867762] 33. Gryll SL, Katahn M. Situational factors contributing to the placebos effect.
54. Stewart MA. Effective physician-patient communication and health out-
Psychopharmacology (Berl). 1978;57:253-61. [PMID: 97705] .
comes: a review. CMAJ. 1995;152:1423-33. [PMID: 7728691] 34. Hashish I, Hai HK, Harvey W, Feinmann C, Harris M. Reduction of
55. Ong LM, de Haes JC, Hoos AM, Lammes FB. Doctor-patient communi-
postoperative pain and swelling by ultrasound treatment: a placebo effect. Pain.
cation: a review of the literature. Soc Sci Med. 1995;40:903-18. [PMID: 1988;33:303-11. [PMID: 3419838] 35. Ho KH, Hashish I, Salmon P, Freeman R, Harvey W. Reduction of post-
56. Kaplan SH, Greenfield S, Ware JE Jr. Assessing the effects of physician-
operative swelling by a placebo effect. J Psychosom Res. 1988;32:197-205.
patient interactions on the outcomes of chronic disease. Med Care. 1989;27: S110-27. [PMID: 2646486] 36. Bergmann JF, Chassany O, Gandiol J, Deblois P, Kanis JA, Segrestaa JM,
57. Finkler K, Correa M. Factors influencing patient perceived recovery in Mex-
et al. A randomised clinical trial of the effect of informed consent on the analgesic
ico. Soc Sci Med. 1996;42:199-207. [PMID: 8928029] activity of placebo and naproxen in cancer pain. Clin Trials Metaanal. 1994;29: 58. Bass MJ, Buck C, Turner L, Dickie G, Pratt G, Robinson HC. The
41-7. [PMID: 10150184] physician's actions and the outcome of illness in family practice. J Fam Pract.
37. Uhlenhuth EH, Rickels K, Fisher S, Park LC, Lipman RS, Mock J. Drug,
1986;23:43-7. [PMID: 3723083] doctor's verbal attitude and clinic setting in the symptomatic response to phar- 59. Thomas KB. General practice consultations: is there any point in being
macotherapy. Psychopharmacologia. 1966;9:392-418. [PMID: 4872909] positive? Br Med J (Clin Res Ed). 1987;294:1200-2. [PMID: 3109581] 38. Fisher S, Cole JO, Rickels K, Uhlenhuth EH. Drug-set interaction: the
60. Olsson B, Olsson B, Tibblin G. Effect of patients' expectations on recovery
effect of expectations on drug response in outpatients. Neuropsychopharmacol- from acute tonsillitis. Fam Pract. 1989;6:188-92. [PMID: 2792618] ogy. 1964;3:149-56.
61. Hahn RA. "Treat the patient, not the lab:" internal medicine and the concept
39. Wheatley D. Influence of doctors' and patients' attitudes in the treatment of
of ‘person'. Cult Med Psychiatry. 1982;6:219-36. [PMID: 7172711] neurotic illness. Lancet. 1967;2:1133-5. [PMID: 4168567] 62. Oths K. Communication in a chiropractic clinic: how a D.C. treats his
40. Rabkin JG, McGrath PJ, Quitkin FM, Tricamo E, Stewart JW, Klein DF.
patients. Cult Med Psychiatry. 1994;18:83-113. [PMID: 8082319] Effects of pill-giving on maintenance of placebo response in patients with chronic 63. Thomas KB. The placebo in general practice. Lancet. 1994;344:1066-7.
mild depression. Am J Psychiatry. 1990;147:1622-6. [PMID: 2244639] 41. Affleck DC, Eaton MT, Mansfield E. The action of a medication and the
64. Adler HM, Hammett VB. The doctor-patient relationship revisited. An
physician's expectations. Nebr State Med J. 1966;51:331-4. [PMID: 4227004] analysis of the placebo effect. Ann Intern Med. 1973;78:595-8. [PMID: 42. Agras WS, Horne M, Taylor CB. Expectation and the blood-pressure-
lowering effects of relaxation. Psychosom Med. 1982;44:389-95. [PMID: 6755527] 65. Sox HC Jr, Margulies I, Sox CH. Psychologically mediated effects of diag-
43. Amigo I, Cuesta V, Ferna´ndez A, Gonza´lez A. The effect of verbal instruc-
nostic tests. Ann Intern Med. 1981;95:680-5. [PMID: 7305144] tions on blood pressure measurement. J Hypertens. 1993;11:293-6. [PMID: 66. Adler HM. The history of the present illness as treatment: who's listening,
and why does it matter? J Am Board Fam Pract. 1997;10:28-35. [PMID: 44. Freund J, Krupp G, Goodenough D, Preston LW. The doctor-patient
relationship and drug effect. Clin Pharmacol Ther. 1972;13:172-80. [PMID: 67. Brody H, Waters DB. Diagnosis is treatment. J Fam Pract. 1980;10:445-9.
45. Wied GI. U
¨ ber die Bedeutung der Suggestion in der Therapie klimak- 68. Novack DH. Therapeutic aspects of the clinical encounter. J Gen Intern
terischer Ausfallerscheinungen. Arztliche Wochenschrift. 1953;8:623-5.
Med. 1987;2:346-55. [PMID: 3309210] 46. de Craen AJM. Impact of experimentally induced expectancy on the analge-
69. Csordas TJ. The rhetoric of transformation in ritual healing. Cult Med
4 June 2002 Annals of Internal Medicine Volume 136 • Number 11 823
Academia and Clinic The Placebo Effect in Alternative Medicine Psychiatry. 1983;7:333-75. [PMID: 6661923] cation of the placebo response in ulcerative colitis. Gastroenterology. 1997;112: 70. Csordas TJ. Elements of charismatic persuasion and healing. Med Anthropol
1854-8. [PMID: 9178676] Q. 1988;2:121-42.
91. Brown WA, Johnson MF, Chen MG. Clinical features of depressed patients
71. Kirmayer LJ. Improvisation and authority in illness meaning. Cult Med
who do and do not improve with placebo. Psychiatry Res. 1992;41:203-14.
Psychiatry. 1994;18:183-214. [PMID: 7924400] 72. Eisenberg DM, Davis RB, Ettner SL, Appel S, Wilkey S, Van Rompay M,
92. Kirsch I, Sapirstein G. Listening to Prozac but hearing placebo: a meta-
et al. Trends in alternative medicine use in the United States, 1990-1997: results
analysis of antidepressant medications. In: Kirsch I, ed. How Expectancies Shape of a follow-up national survey. JAMA. 1998;280:1569-75. [PMID: 9820257] Experience. Washington, DC: American Psychological Assoc; 1999.
73. Turner JA, Deyo RA, Loeser JD, Von Korff M, Fordyce WE. The impor-
93. Rosenberg NK, Mellergård M, Rosenberg R, Beck P, Ottosson JO. Char-
tance of placebo effects in pain treatment and research. JAMA. 1994;271:1609- acteristics of panic disorder patients responding to placebo. Acta Psychiatr Scand 14. [PMID: 7880221] Suppl. 1991;365:33-8. [PMID: 1862732] 74. Wall PD. Pain and the placebo response. In: Bock G, Marsh J, eds. Exper-
94. Hro´bjartsson A, Gøtzsche PC. Is the placebo powerless? An analysis of
imental and Theoretical Studies of Consciousness. Ciba Foundation Symposium clinical trials comparing placebo with no treatment. N Engl J Med. 2001;344: 174. New York: J Wiley; 1993.
1594-602. [PMID: 11372012] 75. McQuay H, Carroll D, Moore A. Variation in the placebo effect in random-
95. de Craen AJ, Moerman DE, Heisterkamp SH, Tytgat GN, Tijssen JG,
ised controlled trials of analgesics: all is as blind as it seems. Pain. 1996;64:331-5.
Kleijnen J. Placebo effect in the treatment of duodenal ulcer. Br J Clin Pharma-
col. 1999;48:853-60. [PMID: 10594490] 76. Lasagna L, Laties VG, Dohan JL. Further studies on the "pharmacology" of
96. Branthwaite A, Cooper P. Analgesic effects of branding in treatment of
placebo administration. J Clin Invest. 1958;37:533-7.
headaches. Br Med J (Clin Res Ed). 1981;282:1576-8. [PMID: 6786566] 77. Brodeur DW. The effects of stimulant and tranquilizer placebos on healthy
97. Kaptchuk TJ, Goldman P, Stone DA, Stason WB. Do medical devices have
subjects in a real-life situation. Psychopharmacologia. 1965;7:444-52. [PMID: enhanced placebo effects? J Clin Epidemiol. 2000;53:786-92. [PMID: 78. Morison RA, Woodmansey A, Young AJ. Placebo responses in an arthritis
98. de Craen AJ, Tijssen JG, de Gans J, Kleijnen J. Placebo effect in the acute
trial. Ann Rheum Dis. 1961;20:178-85.
treatment of migraine: subcutaneous placebos are better than oral placebos.
79. Pillemer SR, Fowler SE, Tilley BC, Alarco´n GS, Heyse SP, Trentham DE,
J Neurol. 2000;247:183-8. [PMID: 10787112] et al . Meaningful improvement criteria sets in a rheumatoid arthritis clinical trial.
99. Moncrieff J, Wessely S, Hardy R. Meta-analysis of trials comparing antide-
MIRA Trial Group. Minocycline in Rheumatoid Arthritis. Arthritis Rheum.
pressants with active placebos. Br J Psychiatry. 1998;172:227-31. [PMID: 1997;40:419-25. [PMID: 9082927] 80. Couch JR Jr. Placebo effect and clinical trials in migraine therapy. Neuroepi-
100. Fisher S, Greenberg RP. How sound is the double-blind design for evalu-
demiology. 1987;6:178-85. [PMID: 3317098] ating psychotropic drugs? J Nerv Ment Dis. 1993;181:345-50. [PMID: 81. Diener HC, Dowson AJ, Ferrari M, Nappi G, Tfelt-Hansen P. Unbalanced
randomization influences placebo response: scientific versus ethical issues around 101. Marchand S, Charest J, Li J, Chenard JR, Lavignolle B, Laurencelle L. Is
the use of placebo in migraine trials. Cephalalgia. 1999;19:699-700. [PMID: TENS purely a placebo effect? A controlled study on chronic low back pain. Pain.
1993;54:99-106. [PMID: 8378107] 82. Kagan G, Dabrowicki E, Huddlestone L, Kapur TR, Wolstencroft P. A
102. Schwitzgebel RK, Traugott M. Initial note on the placebo effect of ma-
double blind trial of terfenadine and placebo in hay fever using a substitution chines. Behav Sci. 1968;13:267-73. [PMID: 5663895] technique for non-responders. J Int Med Res. 1980;8:404-7. [PMID: 6108264] 103. Ernst E, Resch KL. Concept of true and perceived placebo effects. BMJ.
83. D'Souza MF, Emanuel MB, Gregg J, Charlton J, Goldschmidt J. A method
1995;311:551-3. [PMID: 7663213] for evaluating therapy for hay fever. A comparison of four treatments. Clin Al- 104. Kaptchuk TJ, Eisenberg DM. Chiropractic: origins, controversies, and
lergy. 1983;13:329-35. [PMID: 6411382] contributions. Arch Intern Med. 1998;158:2215-24. [PMID: 9818801] 84. Preston RA, Materson BJ, Reda DJ, Williams DW. Placebo-associated
105. Kaptchuk TJ. The Web That Has No Weaver: Understanding Chinese
blood pressure response and adverse effects in the treatment of hypertension: Medicine. Chicago: Contemporary; 2000.
observations from a Department of Veterans Affairs Cooperative Study. Arch 106. McGuire MB. Ritual Healing in Suburban America. New Brunswick, NJ:
Intern Med. 2000;160:1449-54. [PMID: 10826457] Rutgers Univ Pr; 1988.
85. Suchman AL, Ader R. Classic conditioning and placebo effects in crossover
107. Riley JN. Western medicine's attempt to become more scientific: examples
studies. Clin Pharmacol Ther. 1992;52:372-7. [PMID: 1424409] from the United States and Thailand . Soc Sci Med. 1977;11:549-60. [PMID: 86. Storms MD, Nisbett RE. Insomnia and the attribution process. J Pers Soc
Psychol. 1970;16:319-28. [PMID: 5479134] 108. Thomas M, Eriksson SV, Lundeberg T. A comparative study of diazepam
87. Bootzin RR, Herman CP, Nicassio P. The power of suggestion: another
and acupuncture in patients with osteoarthritis pain: a placebo controlled study.
examination of misattribution and insomnia. J Pers Soc Psychol. 1976;34:673-9.
Am J Chin Med. 1991;19:95-100. [PMID: 1816730] 109. Koes BW, Bouter LM, van Mameren H, Essers AH, Verstegen GM,
88. Godfrey S, Silverman M. Demonstration by placebo response in asthma by
Hofhuizen DM, et al. The effectiveness of manual therapy, physiotherapy, and
means of exercise testing. J Psychosom Res. 1973;17:293-7. [PMID: 4206466] treatment by the general practitioner for nonspecific back and neck complaints.
89. Moerman DE. Cultural variations in the placebo effect: ulcers, anxiety, and
A randomized clinical trial. Spine. 1992;17:28-35. [PMID: 1531552] blood pressure. Med Anthropol Q. 2000;14:51-72. [PMID: 10812563] 110. Hro´bjartsson A, Gøtzsche PC. Is the placebo powerless? [Letter] N Engl
90. Ilnyckyj A, Shanahan F, Anton PA, Cheang M, Bernstein CN. Quantifi-
J Med. 2001;345:1278-9.
824 4 June 2002 Annals of Internal Medicine Volume 136 • Number 11
The Placebo Effect in Alternative Medicine Academia and Clinic 111. Hro´bjartsson A, Gøtzsche PC. Core belief in powerful effects of placebo
Parkinson's disease. Science. 2001;293:1164-6. [PMID: 11498597] interventions is in conflict with no evidence of important effects in a large sys- 117. Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, et al.
tematic review. Advances in Mind-Body Medicine. 2001;17:312-8.
Transplantation of embryonic dopamine neurons for severe Parkinson's disease.
112. Lyno¨e N, Mattsson B, Sandlund M. The attitudes of patients and physi-
N Engl J Med. 2001;344:710-9. [PMID: 11236774] cians towards placebo treatment—a comparative study. Soc Sci Med. 1993;36: 118. Husten L. Fetal-cell-implantation trial yields mixed results. Lancet. 1999;
767-74. [PMID: 8480221] 113. Johnson AG. Surgery as a placebo. Lancet. 1994;344:1140-2. [PMID:
119. Macklin R. The ethical problems with sham surgery in clinical research.
N Engl J Med. 1999;341:992-6. [PMID: 10498498] 114. Shetty N, Friedman JH, Kieburtz K, Marshall FJ, Oakes D. The placebo
120. Johannes L. Sham surgery is used to test effectiveness of novel operations.
response in Parkinson's disease. Parkinson Study Group. Clin Neuropharmacol.
Wall Street Journal. 1998;11 December:A1, A8.
1999;22:207-12. [PMID: 10442249] 121. Watts RL, Freeman RA, Hauser RA, Bakay SA, Ellias AJ, Stoessl AJ, et al.
115. Goetz CG, Leurgans S, Raman R, Stebbins GT. Objective changes in
A double-blind, randomized, controlled, multicenter clinical trial of the safety motor function during placebo treatment in PD. Neurology. 2000;54:710-4.
and efficacy of stereotaxic intrastriatal implantation of fetal porcine ventral mes- encephalic tissue (NeurocellTM-PD) vs. imitation surgery in patients with Parkin- 116. de la Fuente-Ferna´ndez R, Ruth TJ, Sossi V, Schulzer M, Calne DB,
son's disease (PD) [Abstract]. Parkinsonism and Related Disorders. 2001;7 Stoessl AJ. Expectation and dopamine release: mechanism of the placebo effect in
Sometimes we no longer know what is true for us, in which direction our ownintegrity lies . . Reclaiming ourselves usually means coming to recognize and acceptthat we have in us both sides of everything. We are capable of fear and courage,generosity and selfishness, vulnerability and strength. These things do not canceleach other out but offer us a full range of power and response to life. Life is ascomplex as we are.
One of the blessings of growing older is the discovery that many of the things I oncebelieved to be my shortcomings have turned out in the long run to be my strengths,and other things of which I was unduly proud have revealed themselves in the endto be among my shortcomings . . What a blessing it is to outlive yourself-judgments and harvest your failures.
Rachel Naomi Remen, MDKitchen Table Wisdom: Stories That HealNew York: Riverhead Books; 1996:35-8 Submitted by:George Ho Jr., MDEast Carolina University School of MedicineGreenville, NC 27858 Submissions from readers are welcomed. If the quotation is published, the sender's name will beacknowledged. Please include a complete citation (along with page number on which the quotation wasfound), as done for any reference.–The Editor 4 June 2002 Annals of Internal Medicine Volume 136 • Number 11 825
J. Mol. Biol. (2006) 361, 140–152 Xenobiotic Reductase A in the Degradation of Quinolineby Pseudomonas putida 86: PhysiologicalFunction, Structure and Mechanism of8-Hydroxycoumarin Reduction Julia J. Griese1 †, Roman P. Jakob1 †, Stephan Schwarzinger2and Holger Dobbek1⁎ A continuous evolutionary pressure of the biotic and abiotic world has led to the development of a diversity of microbial pathways to degrade and