Ted J. Kaptchuk

Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome

Objective To investigate whether placebo effects can experimentally be separated into the response to three components—assessment and observation, a therapeutic ritual (placebo treatment), and a supportive patient-practitioner relationship—and then progressively combined to produce incremental clinical improvement in patients with irritable bowel syndrome. To assess the relative magnitude of these components. Design A six week single blind three arm randomised controlled trial. Setting Academic medical centre. Participants 262 adults (76% women), mean (SD) age 39 (14), diagnosed by Rome II criteria for and with a score of ≥150 on the symptom severity scale. Interventions For three weeks either waiting list (observation), placebo acupuncture alone (“limited”), or placebo acupuncture with a patient-practitioner relationship augmented by warmth, attention, and confidence (“augmented”). At three weeks, half of the patients were randomly assigned to continue in their originally assigned group for an additional three weeks. Main outcome measures Global improvement scale (range 1-7), adequate relief of symptoms, symptom severity score, and quality of life. Results At three weeks, scores on the global improvement scale were 3.8 (SD 1.0) v 4.3 (SD 1.4) v 5.0 (SD 1.3) for waiting list versus “limited” versus “augmented,” respectively (P<0.001 for trend). The proportion of patients reporting adequate relief showed a similar pattern: 28% on waiting list, 44% in limited group, and 62% in augmented group (P<0.001 for trend). The same trend in response existed in symptom severity score (30 (63) v 42 (67) v 82 (89), P<0.001) and quality of life (3.6 (8.1) v 4.1 (9.4) v 9.3 (14.0), P<0.001). All pairwise comparisons between augmented and limited patient-practitioner relationship were significant: global improvement scale (P<0.001), adequate relief of symptoms (P<0.001), symptom severity score (P=0.007), quality of life (P=0.01).Results were similar at six week follow-up. Conclusion Factors contributing to the placebo effect can be progressively combined in a manner resembling a graded dose escalation of component parts. Non-specific effects can produce statistically and clinically significant outcomes and the patient-practitioner relationship is the most robust component. Trial registration Clinical Trials NCT00065403.

Biological, clinical, and ethical advances of placebo effects

For many years, placebos have been defined by their inert content and their use as controls in clinical trials and treatments in clinical practice. Recent research shows that placebo effects are genuine psychobiological events attributable to the overall therapeutic context, and that these effects can be robust in both laboratory and clinical settings. There is also evidence that placebo effects can exist in clinical practice, even if no placebo is given. Further promotion and integration of laboratory and clinical research will allow advances in the ethical use of placebo mechanisms that are inherent in routine clinical care, and encourage the use of treatments that stimulate placebo effects.

Long-Term Trends in the Use of Complementary and Alternative Medical Therapies in the United States

Community surveys done over the past decade have documented that a substantial proportion of Americans use complementary and alternative medical (CAM) therapies (14), which have been defined as interventions neither taught widely in medical schools nor generally available in U.S. hospitals (1). Many managed care organizations have responded to this evidence by providing insurance coverage for some CAM therapies (5). Furthermore, most U.S. medical schools have begun offering courses on CAM therapies (6). These responses imply that CAM therapies are perceived to be a force to be reckoned with for some time to come. Yet, little is known about the likelihood that this will be the case. The prevailing assumption is that CAM therapies were used by a fairly narrow segment of the population until the 1970s, at which time the ideology associated with the youth counterculture led to a rapid dissemination and use of CAM therapies that has persisted through the present (7). However, lack of rigorous trend data from epidemiologic surveys have precluded evaluating this assumption rigorously or projecting the future growth of CAM therapies on the basis of evidence of past trends. In the current report, we present nationally representative trend data of this sort from a prevalence study. The data came from retrospective self-reports of a nationally representative sample of the U.S. general population in a 19971998 telephone survey (4) about age at first use of 20 representative CAM therapies. In our analysis, we studied trends by examining between-cohort differences in rates of initiation of CAM therapy use (8). In the absence of prospective data, which do not exist, our results represent, to our knowledge, the most accurate information currently available on U.S. trends in CAM therapy use over the past half-century. Methods Sample The telephone survey was conducted between November 1997 and February 1998 in a nationally representative household sample. Random-digit dialing was used to select households, and a random-selection method was used to select one respondent 18 years of age or older for interview in each sample household. Eligibility was limited to English speakers without cognitive or physical impairment that would prevent interview completion. The average administration time was 30 minutes. A

Acupuncture: theory, efficacy, and practice.

20 financial incentive for participation was offered. The Beth Israel Deaconess Committee on Clinical Investigations, Boston, Massachusetts, approved the survey methods. Of the initial sample of 9750 telephone numbers, 26% did not work, 17% were not assigned to households, and 9% were unavailable despite six attempted follow-up contacts. Of the remaining households, 481 were ineligible because of language barrier or cognitive or physical incapacity. Of the 4167 total eligible respondents, 1720 (41.3%) completed the interview on initial request. Of a random subsample of 1066 persons who initially declined and were offered an increased stipend (

Placebos without Deception: A Randomized Controlled Trial in Irritable Bowel Syndrome

50), 335 agreed to participate. In all, 2055 interviews were completed. After we extrapolated the conversion rate to all persons who had initially declined and weighted the data for the undersampling of those who participated after initially declining, the weighted overall response rate among eligible respondents was 60%. The data were weighted for three factors: 1) probability of selection within household as well as geographic variation in cooperation (by region of the country and urbanicity [local population density]], 2) nonresponse, and 3) post-stratification for aggregate discrepancies between the sample distributions and Census population distributions on a variety of sociodemographic variables (9, 10). More details on the sample design have been presented elsewhere (4). Age data were missing for 6 respondents; our analyses are limited to the remaining 2049 respondents. Measures The interview was described to respondents as a survey by investigators from Harvard Medical School about the health care practices of Americans. Interviewers made no mention of CAM therapies. The first substantive questions concerned perceived health, functional impairment due to health problems, interactions with physicians, and history of chronic medical conditions. Interviewers then queried respondents about their lifetime and recent use of 20 CAM therapiesacupuncture, aromatherapy, biofeedback, chiropractic care, commercial diet programs, energy healing (for example, laying on of hands), folk remedy, herbal medicine, homeopathy, hypnosis, imagery, lifestyle diet (such as vegetarianism or macrobiotics), massage, megavitamin therapy, naturopathy, osteopathy, relaxation techniques, self-help group, spiritual healing by others, and yoga. Users of each therapy were asked their age at first use as well as details about the conditions for which the therapy was initiated. The final set of questions dealt with sociodemographic issues. Cohorts were aggregated into three subsamples: prebaby boom (respondents 54 years of age at interview, born before 1945); baby boom (34 to 53 years of age at interview, born 19451964); and postbaby boom (18 to 33 years of age at interview, born 19651979). For sociodemographic variables, we used two categories for sex (male or female), four for race/ethnicity (non-Hispanic white, non-Hispanic black, Hispanic, or other), four for education (less than high school, high school graduate, some college, or college graduate), four for U.S. region (northeast, midwest, south, or west), and four for urbanicity (residence in a large city, small city, suburb, town/rural). Statistical Analysis All analyses were performed with weighted data by using SAS statistical software (11). To assess differences in trends among cohorts, the KaplanMeier (12) method was used to generate a graphic representation of the cumulative lifetime prevalences of CAM therapy use according to cohort. The significance of historical changes in lifetime use was estimated by using discrete-time survival analysis (13), a method of survival analysis appropriate for data in which events are recorded only at discrete time points (for example, in yearly increments). Discrete-time survival analysis was operationalized as a logistic regression with person-year as the unit of analysis and first use of CAM therapy as the outcome variable. The predictors of primary interest were a series of dummy variables for decades of historical time, and covariates included sociodemographic and dummy variables adjusted for the baseline hazard rate of each year of a persons life. This model results in an intercept for each time period, and the odds ratios (ORs) can be interpreted as the relative risk for the annual risk for use of alternative therapy. Subsample models were estimated to study sociodemographic variation in trends. Disaggregated models were estimated to study trends in the use of particular CAM therapies. To adjust for the design effects introduced by weighting of the data, the method of jackknife repeated replications (14) was used to estimate standard errors (SEs). For this method, we used user-written macros in SAS statistical software. For this process, 50 random primary sampling units were created with two random half-samples in each unit for a total of 100 random replicates. Jackknife repeated replication is a method that uses simulations of coefficient distributions in subsamples to generate empirical estimates of SEs and significance tests. The ratios of the coefficients to these adjusted SEs are used to compute the 95% CIs of the ORs. Tests for the significance of sets of predictors taken together were computed by using the Wald chi-square test from coefficient variancecovariance matrices based on the jackknife repeated replications simulations. Results Differences in Aggregate Use Trends among Cohorts At the time of interview, 67.6% of all respondents had used at least one CAM therapy at some time in their lives. The Figure presents KaplanMeier age-of-onset curves showing trends in each cohort in the cumulative probabilities of use according to age. Of note are the dramatic differences in use among cohorts. This is seen most clearly by focusing on cumulative probabilities of use for age 33 years, the oldest age represented in all three cohorts. Approximately 3 of every 10 respondents in the prebaby boom cohort used some type of CAM therapy by the age of 33 years compared with 5 of 10 in the baby boom cohort and 7 of 10 in the postbaby boom cohort. Figure. Weighted KaplanMeier estimates of age of first use of any complementary and alternative medical (CAM) therapy among lifetime users according to cohort. Historical Trends in Aggregate Use The aggregate data in the Figure are presented in a different format in the bottom row of Table 1, where the risk ratios are shown from a discrete-time survival model that estimated the effects of historical time in predicting age at first use of CAM therapy among respondents after adjustment for person-year and sociodemographic variables. The contrast category is first use before 1960. Consistent with the pattern in the Figure, the results of the model for the outcome of any therapy show monotonically increasing risk ratios in each decade from the 1960s through the 1990s. Table 1. Trends in Relative Risk for First Use of 20 Specific Complementary and Alternative Medical Therapies, according to Decade Possible demographic subsample differences in time trends were examined by estimating separate subsample models that were identical to the discrete-time survival model for any therapy and by evaluating the statistical significance of differences in trends across subsamples. No statistically significant (0.05 level in two-sided tests) differences in trends were found for sex, race/ethnicity, education level, region of the country, or urbanicity. Trends in the Use of Specific Therapies Table 1 also shows the risk ratios to estimate first use of each of the 20 CAM therapies assessed. All tre

Sham device v inert pill: randomised controlled trial of two placebo treatments

Acupuncture is an important therapy in East Asian medicine (the traditional medicine of China, Japan, and Korea). Treating headache by placing pins in the hands or treating asthma by placing needles in the feet challenges modern biomedical understanding. Thirty years ago, most physicians considered acupuncture a Chinese equivalent of voodoo. Despite the strangeness of its theory and method, in a very short period, acupuncture has changed from a cultural curiosity to an alternative therapy that, at a minimum, deserves a respectful hearing. This essay reviews the historical and theoretical framework of acupuncture, the scientific evidence for its claims to effectiveness, and its safety profile. The essay also discusses the provision of acupuncture therapy. History The earliest health care in China involved shaman-like rituals to placate spirits or demons (1, 2). At the same time, during the first few centuries BC, when philosophical systems such as Confucianism and Taoism were significantly replacing earlier Chinese supernatural thinking, acupuncture and other associated practices began to supplant antecedent magico-religious healing approaches (3, 4). Chinas emerging philosophies required a new medical system, free of supernatural thought and compatible with naturalistic, human-centered presuppositions. The precise origin of acupuncture techniques is a subject of scholarly debate. A multilinear development toward acupuncture seems likely (2). Early awareness of practical, needle-like therapy that used bamboo or bone needles to open abscesses may have contributed to the development of acupuncture (2). Knowledge of exact body locations (now considered acupuncture points) found in nondecorative tattoos on Stone Age mummies suggest another precursor route (5). The earliest Chinese archeologic textual material points to the existence of methods of heat stimulation (see following discussion) at precise regions of the body (which are clearly related to acupuncture channels) before any needling of acupuncture sites occurred (6). Another possible origin of acupuncture may be the bloodletting described in the earliest acupuncture sources. Bloodletting was originally used for magical healing, but by the time of the early acupuncture literature, it was being used for naturalistic reasons at acupuncture points based on Chinese medicine theory (7). Whatever the exact pathway may have been, by the time East Asian medicine was codified at some time in the first century BC (in a canonical text known as the Inner Classic of the Yellow Emperor), acupuncture was already a signature therapy of Chinese medicine. Basic Theory and Conceptual Framework From the Chinese perspective, acupuncture is necessarily embedded in a complex theoretical framework that provides conceptual and therapeutic directions. Unlike the earliest Chinese healing, which relied on supernatural guidance or altered states of consciousness, classic Chinese medicine relies on ordinary human sensory awareness. Its fundamental assertion, like the kindred philosophical systems of Confucianism and Taoism, is that contemplation and reflection on sensory perceptions and ordinary appearances are sufficient to understand the human condition, including health and illness. This assertion is fundamentally different from the biomedical viewpoint, which gives privileged status to objective technology and quantitative measurement. Ideally, the scientific analysis penetrates beyond the visible life world of the patient, revealing an underlying pathophysiologic disruption, independent from human subjectivity (8). Despite acupunctures claim to be based on ordinary perceptions, it is full of strange concepts that can act as formidable barriers (or attractions) to many Westerners. In fact, the foreign-sounding key words of acupuncturefor example, yin, yang, dampness, wind, fire, dryness, cold, and earthare ordinary images or patterns (some culturally unique) of a persons state of being and behavior. They represent human meteorologic conditions, which are sometimes pathologic and disruptive and sometimes necessary and healthy. They are the fundamental patterns for detecting and synthesizing clinical information. These patterns also create a unique medical thought process. Yin-Yang Yin and yang are the basic root intuitions of China. They are recognizable in images akin to weather. Yin is associated with cold, darkness, being stationary, passiveness, receptivity, tranquility, and quiescence. Yang is associated with heat, light, stimulation, excess, assertiveness, dominance, movement, arousal, and dynamic potential. These complementary opposites are successively intertwined for additional levels of descriptive refinement. A simple example is dampness. It has the yin qualities of cold, wet, soft, and lingering and also the yang qualities of excessiveness, dominance, heaviness, and inexhaustible abundance. Acupuncturists claim that dampness is easy to recognize and that it applies to psychological, ecological, and even moral as well as corporeal phenomena (9). Some damp signs point to imbalance, or bad weather, for example, weeping eczema, edema, slippery pulse, heaviness in digestion, indecision, clinging, or being helpful to others at the expense of oneself. Some dampness is an essential component of a healthy state of being, for example, smooth skin, normal secretions and excretions, being imperturbable when threatened, generosity, and patience. In addition to a general synthesis, yin and yang and their climatic subcategories are used to interpret specific subregions of a persons health. These subregions can be different from a persons general meteorologic pattern and can create overlapping domains of yin and yang (for example, yins within yangs) that are as complex as multiple, intersecting circles. Both for the overview pattern and for the subregions, no single sign is conclusive; the overall context defines the parts. Heaviness in digestion or generosity might be wind if it appeared in a different configuration of signs. Unlike western medicine, in which signs and symptoms are used analytically to isolate an underlying mechanism, East Asian medicine seeks to discern a qualitative image in the overall gestalt or regions of a persons signs and behaviors. Whereas biomedicine aspires toward the scientific and dimensionally measurable quantitative, East Asian medicine emphasizes a human-centered approach of artistic impressions and sensitivities (10). If Chinese medicine resembles anything in the West, it would be the prescientific but rational Greek humoral medical system, which also perceived health status in such images of weather as phlegmatic (cold-moist) and choleric (hot-dry) (11). Qi In traditional acupuncture, the connection between such diverse phenomena as edema and generosity is explained by qi (pronounced chee). Qi is the linkage in the cosmos that, like the Greek notion of pneuma, takes myriad forms. The concept of qi has little scientific cogency, but for the Chinese, it provides a rationale for explaining change and linking phenomena. This rationale unites objective and subjective phenomena and locates disorders in the broadest context of a persons life (12). Whether qi is some kind of real quantitative energy in the western sense (akin to 19th century vitalist life-force notions [13]) or a metaphoric way of depicting and experiencing interconnection is not a serious intellectual issue in classic Asian thought (14). In addition, the target of treatment in Chinese medicine is the state of disharmony, any imbalance in yin-yang and its connecting qi. It is not an abstract diagnosis or truth existing independent of the patient. A Chinese diagnosis can be compared to a practical weather report to guide the practitioners response to the overall configuration of a patients life. Acupuncture Therapeutics Imbalances in yin-yang and qi need to be dynamically harmonized. Acupuncture is used to shift a persons unique climate. It can moisten, dry, cool, warm, augment, deplete, redirect, reorganize, unblock, stabilize, raise, or lower a persons weather patterns. Fine needles are inserted into precisely defined, specific points on the body to correct disruptions in harmony. Heat stimulation, a technique known as moxibustion, which burns the herb Artemisia vulgaris near the acupuncture point, is sometimes used (especially to warm or move the qi). Hand pressure (acupressure) is also sometimes applied. Classic theory recognizes about 365 points, said to be located on 14 main channels (or meridians) connecting the body in a weblike interconnecting matrix. These channels are not detectable by ordinary scientific methods (15). Additional acupuncture points (both on and off the channel) have been added through the millennia, and the total universe of points has increased to at least 2000 (16). In practice, however, the repertoire of a typical acupuncturist may be only 150 points. Traditionally, each acupuncture point has defined therapeutic actions; some points treat an entire yin-yang emblematic configuration, whereas others affect local symptoms. Between 5 and 15 needles are used in a typical treatment, with the point combinations varying during a course of sessions. China, Japan, and Korea have each developed a distinct version of acupuncture. Thousands of years of history, interpretation, and innovation have produced multiple approaches (17). Specialized acupuncture has also been developed for the ears, scalp, and hands (18). Western nations have developed their own traditions, and one can begin to speak of French (19), British (20), and even American styles of acupuncture (21). Biomedically trained physicians have developed acupuncture variants that reject the metaphysical explanations and the necessity for mystical rituals (22). Their approach emphasizes using acupuncture points based on western understanding of myofascial trigger points, the nervous system, or recent scienti

Brain Activity Associated with Expectancy-Enhanced Placebo Analgesia as Measured by Functional Magnetic Resonance Imaging

Background Placebo treatment can significantly influence subjective symptoms. However, it is widely believed that response to placebo requires concealment or deception. We tested whether open-label placebo (non-deceptive and non-concealed administration) is superior to a no-treatment control with matched patient-provider interactions in the treatment of irritable bowel syndrome (IBS). Methods Two-group, randomized, controlled three week trial (August 2009-April 2010) conducted at a single academic center, involving 80 primarily female (70%) patients, mean age 47±18 with IBS diagnosed by Rome III criteria and with a score ≥150 on the IBS Symptom Severity Scale (IBS-SSS). Patients were randomized to either open-label placebo pills presented as “placebo pills made of an inert substance, like sugar pills, that have been shown in clinical studies to produce significant improvement in IBS symptoms through mind-body self-healing processes” or no-treatment controls with the same quality of interaction with providers. The primary outcome was IBS Global Improvement Scale (IBS-GIS). Secondary measures were IBS Symptom Severity Scale (IBS-SSS), IBS Adequate Relief (IBS-AR) and IBS Quality of Life (IBS-QoL). Findings Open-label placebo produced significantly higher mean (±SD) global improvement scores (IBS-GIS) at both 11-day midpoint (5.2±1.0 vs. 4.0±1.1, p<.001) and at 21-day endpoint (5.0±1.5 vs. 3.9±1.3, p = .002). Significant results were also observed at both time points for reduced symptom severity (IBS-SSS, p = .008 and p = .03) and adequate relief (IBS-AR, p = .02 and p = .03); and a trend favoring open-label placebo was observed for quality of life (IBS-QoL) at the 21-day endpoint (p = .08). Conclusion Placebos administered without deception may be an effective treatment for IBS. Further research is warranted in IBS, and perhaps other conditions, to elucidate whether physicians can benefit patients using placebos consistent with informed consent. Trial Registration ClinicalTrials.gov NCT01010191

Acupuncture De Qi, from Qualitative History to Quantitative Measurement

Abstract Objective To investigate whether a sham device (a validated sham acupuncture needle) has a greater placebo effect than an inert pill in patients with persistent arm pain. Design A single blind randomised controlled trial created from the two week placebo run-in periods for two nested trials that compared acupuncture and amitriptyline with their respective placebo controls. Comparison of participants who remained on placebo continued beyond the run-in period to the end of the study. Setting Academic medical centre. Participants 270 adults with arm pain due to repetitive use that had lasted at least three months despite treatment and who scored ≥3 on a 10 point pain scale. Interventions Acupuncture with sham device twice a week for six weeks or placebo pill once a day for eight weeks. Main outcomemeasures Arm pain measured on a 10 point pain scale. Secondary outcomes were symptoms measured by the Levine symptom severity scale, function measured by Pranskys upper extremity function scale, and grip strength. Results Pain decreased during the two week placebo run-in period in both the sham device and placebo pill groups, but changes were not different between the groups (−0.14, 95% confidence interval −0.52 to 0.25, P = 0.49). Changes in severity scores for arm symptoms and grip strength were similar between groups, but arm function improved more in the placebo pill group (2.0, 0.06 to 3.92, P = 0.04). Longitudinal regression analyses that followed participants throughout the treatment period showed significantly greater downward slopes per week on the 10 point arm pain scale in the sham device group than in the placebo pill group (−0.33 (−0.40 to −0.26) v −0.15 (−0.21 to −0.09), P = 0.0001) and on the symptom severity scale (−0.07 (−0.09 to −0.05) v −0.05 (−0.06 to −0.03), P = 0.02). Differences were not significant, however, on the function scale or for grip strength. Reported adverse effects were different in the two groups. Conclusions The sham device had greater effects than the placebo pill on self reported pain and severity of symptoms over the entire course of treatment but not during the two week placebo run in. Placebo effects seem to be malleable and depend on the behaviours embedded in medical rituals.

The placebo effect in irritable bowel syndrome trials: a meta-analysis1

In this study, a well established expectancy manipulation model was combined with a novel placebo intervention, a validated sham acupuncture needle, to investigate the brain network involved in placebo analgesia. Sixteen subjects completed the experiment. We found that after placebo acupuncture treatment, subjective pain rating reduction (pre minus post) on the placebo-treated side was significantly greater than on the control side. When we calculated the contrast that subtracts the functional magnetic resonance imaging (fMRI) signal difference between post-treatment and pretreatment during pain application on placebo side from the same difference on control side [e.g., placebo (post – pre) – control (post – pre)], significant differences were observed in the bilateral rostral anterior cingulate cortex (rACC), lateral prefrontal cortex, right anterior insula, supramarginal gyrus, and left inferior parietal lobule. The simple regression (correlation) analysis between each subjects fMRI signal difference of post-treatment and pretreatment difference on placebo and control side and the corresponding subjective pain rating difference showed that significant negative correlation was observed in the bilateral lateral/orbital prefrontal cortex, rACC, cerebellum, right fusiform, parahippocampus, and pons. These results are different from a previous study that found decreased activity in pain-sensitive regions such as the thalamus, insula, and ACC when comparing the response to noxious stimuli applied to control and placebo cream-treated areas of the skin. Our results suggest that placebo analgesia may be configured through multiple brain pathways and mechanisms.

Prescribing “Placebo Treatments”: Results of National Survey of US Internists and Rheumatologists

De qi is an important traditional acupuncture term used to describe the connection between acupuncture needles and the energy pathways of the body. The concept is discussed in the earliest Chinese medical texts, but details of de qi phenomenon, which may include the acupuncturists and/or the patients experiences, were only fully described in the recent hundred years. In this paper, we will trace de qi historically as an evolving concept, and review the literature assessing acupuncture needle sensations, and the relationship between acupuncture-induced de qi and therapeutic effect. Thereafter, we will introduce the MGH Acupuncture Sensation Scale (MASS), a rubric designed to measure sensations evoked by acupuncture stimulation as perceived by the patient alone, and discuss some alternative statistical methods for analyzing the results of this questionnaire. We believe widespread use of this scale, or others like it, and investigations of the correlations between de qi and therapeutic effect will lead to greater precision in acupuncture research and enhance our understanding of acupuncture treatment.