Deconstructing the Placebo Effect and Finding the Meaning Response

[The cure for the headache] was a kind of leaf, which required to be accompanied by a charm, and if a person would repeat the charm at the same time that he used the cure, he would be made whole; but that without the charm the leaf would be of no avail. Socrates, according to Plato (1) There is a renewed interest in placebos and the placebo effecton their reality, their ethics, their place in medicine, or not, both in and out of the clinic and academy. The U.S. National Institutes of Health recently sponsored a large conference called Science of the Placebo (2). At least five serious books on the subject (3-7) plus a book of poetry (8) and a novel (9)each titled Placebo Effecthave been published since 1997. In the past 10 years, the National Library of Medicine has annually listed an average of 3972 scholarly papers with the keywords placebo, placebos, or placebo effect, with a low of 3362 papers in 1992 and a high of 4814 in 2000. During the fall of 2000, a discussion of the effect of new drag free suits, which might give an edge to Olympic swimmers, appeared in US News and World Report: [S]wimming officials aren't convinced this is anything more than the placebo effect. Swimmers excel because they think they've got an edge (10). One widely reported study, which concluded that placebos were powerless (11), or represented the Wizard of Oz (12), occasioned a blizzard of criticism (13-26) and some support (27). It's in the papers (28, 29). It's in the air. Yet the most recent serious attempt to try logically to define the placebo effect failed utterly (30). Given the ways people have gone about it, this seems unsurprising. Arthur K. Shapiro, MD, who spent much of his career as a psychiatrist studying the placebo effect, recently wrote: A placebo is a substance or procedure that is objectively without specific activity for the condition being treated The placebo effect is the therapeutic effect produced by a placebo. (31) If we replace the word placebo in the second sentence with its definition from the first, we get: The placebo effect is the therapeutic effect produced by [things] objectively without specific activity for the condition being treated. This makes no sense whatsoever. Indeed, it flies in the face of the obvious. The one thing of which we can be absolutely certain is that placebos do not cause placebo effects. Placebos are inert and don't cause anything. Moreover, people frequently expand the concept of the placebo effect very broadly to include just about every conceivable sort of beneficial biological, social, or human interaction that doesn't involve some drug well-known to the pharmacopoeia. A narrower form of this expansion includes identifying natural history or regression to the mean (as we might observe them in a randomized, controlled trial) as part of the placebo effect. But natural history and regression occur not only in the control group. Nothing in the theory of regression to the mean (31) hints that when people are selected for being extreme on some measure (blood pressure or cholesterol, for example), they are immune to regression if they receive active treatment. Such recipients are as likely (or unlikely) to move toward homeostasis as are control group patients. So, regression to the mean is in no meaningful way a placebo effect. Ernst and Resch (32) took an important step in trying to clarify this situation by differentiating the true from the perceived placebo effect. But true placebo effect hasn't really caught on as a viable concept. The concept of the placebo effect has been expanded much more broadly than this. Some attribute the effects of various alternative medical systems, such as homeopathy (33) or chiropractic (34), to the placebo effect. Others have described studies that show the positive effects of enhanced communication, such as Egbert's (35), as the placebo response without the placebo (7). No wonder things are confusing. Meaning and Medicine We suggest thinking about this issue in a new way. A group of medical students was asked to participate in a study of two new drugs, one a tranquilizer and the other a stimulant [36]. Each student was given a packet containing either one or two blue or red tablets; the tablets were inert. The students' responses to a questionnaire indicated that 1) the red tablets acted as stimulants while the blue ones acted as depressants and 2) two tablets had more effect than one. The students were not responding to the inertness of the tablets. Moreover, these responses cannot be easily accounted for by natural history, regression to the mean, or physician enthusiasm [presumably the experimenters were as enthusiastic about the reds as the blues]. Instead, they can be explained by the meanings in the experiment: 1) Red means up, hot, danger, while blue means down, cool, quiet and 2) two means more than one. These effects of color (37-40) and number (41, 42) have been widely replicated. In a British study, 835 women who regularly used analgesics for headache were randomly assigned to one of four groups (43). One group received aspirin labeled with a widely advertised brand name (one of the most popular analgesics in the United Kingdom that had been widely available for many years and supported by extensive advertising). The other groups received the same aspirin in a plain package, placebo marked with the same widely advertised brand name, or unmarked placebo. In this study, branded aspirin worked better than unbranded aspirin, which worked better than branded placebo, which worked better than unbranded placebo. Among 435 headaches reported by branded placebo users, 64% were reported as improved 1 hour after pill administration compared with only 45% of the 410 headaches reported as improved among the unbranded placebo users. Aspirin relieves headaches, but so does the knowledge that the pills you are taking are good ones. In a study of the benefits of aerobic exercise, two groups participated in a 10-week exercise program. One group was told that the exercise would enhance their aerobic capacity, while the other group was told that the exercise would enhance aerobic capacity and psychological well-being. Both groups improved their aerobic capacity, but only the second group improved in psychological well-being (actually self-esteem). The researchers called this strong evidence that exercise may enhance psychological well-being via a strong placebo effect (44). In the red versus blue pill study, we can correctly (if not very helpfully) classify the responses of the students as placebo effects because they did indeed receive inert tablets; it seems clear, however, that they responded not to the pills but to their colors. In the second study, the presence of the brand name enhanced the effect of both the inert and the active drug. It doesn't seem reasonable to classify the brand name effect as a placebo effect because no placebos are necessarily involved. Meanwhile, calling the consequences of authoritative instruction to the exercisers a placebo effect could come only from someone who believes that words do not affect the world, someone who has never been told I love you or who has never read the reviews of a rejected grant proposal. It seems reasonable to label all these effects (except, of course, of the aspirin and the exercise) as meaning responses, a term that seeks, among other things, to recall Dr. Herbert Benson's relaxation response (45). Ironically, although placebos clearly cannot do anything themselves, their meaning can. We define the meaning response as the physiologic or psychological effects of meaning in the origins or treatment of illness; meaning responses elicited after the use of inert or sham treatment can be called the placebo effect when they are desirable and the nocebo effect (46) when they are undesirable. This is obviously a complex notion with several terms that would be challenging to unpack (desirable, effect, meaning, treatment, illness)an exercise that cannot be carried out here. Note that this definition excludes several elements that are usually included in our understanding of the placebo effect, such as natural history, regression, experimenter or subject bias, and error in measurement or reporting. Note as well that the definition is not phrased in terms of nonspecific effects; although many elements of the meaning response or placebo effect may seem nonspecific, they are often quite specific in principle after they are understood. Meaning Permeates Medical Treatment Insofar as medicine is meaningful, it can affect patients, and it can affect the outcome of treatment (47-49). Most elements of medicine are meaningful, even if practitioners do not intend them to be so. The physician's costume (the white coat with stethoscope hanging out of the pocket) (50), manner (enthusiastic or not), style (therapeutic or experimental), and language (51) are all meaningful and can be shown to affect the outcome; indeed, we argue that both diagnosis (52) and prognosis (53) can be important forms of treatment. Many studies can be cited to document aspects of the therapeutic quality of the practitioner's manner (54). In one, a strong message of the effect of a drug (an inert capsule) substantially reduced the patients' report of the pain of mandibular block injection compared with the pain after a weak message. Patients who received the weak message reported less pain than a group that received no placebos and no message at all (55). In another study, 200 patients with symptoms but no abnormal physical signs were randomly assigned to a positive or a negative consultation. In a survey of patients 2 weeks later, 64% of patients in the positive consultation group said they were all better, while only 39% of those who had negative consultations thought they were better (56). Although there is strong evidence for such physician effects, little evidence shows that patient effects are very important. A mass of research in the 1