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Take the pill the pleasant doctor gives you // Feel better, just as you thought you would // Suffer the side effects she warned you about // Confuse trial results because your sugar pill works just as well as the genuine article.

The Placebo Problem

By Rachael Moeller Gorman // Illustrations by Leigh Wells // Summer 2006
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People were crying,” recalls Ted Kaptchuk. “They said they were drowsy all the time and wanted to cut their dosage in half. Two weeks into the study, nearly 30% of the subjects were experiencing adverse effects.” Yet most patients’ pain also subsided—strangely so, because no one in Kaptchuk’s clinical trial had received “real” treatment.

Kaptchuk, an assistant professor of medicine at Harvard Medical School’s Osher Institute, had devised the pain-relief study to compare two placebos—an inert pill and sham acupuncture—and the outcome, reported in the British Medical Journal in February 2006, was remarkable: Both placebos reduced patient pain, though to differing degrees. (People who thought they were receiving acupuncture—but in fact were being “treated” with sham needles that retracted into a hollow shaft—experienced greater relief over six weeks than did those taking inactive pills.) What’s more, subjects in the two groups suffered entirely different side effects, depending on what they were told during informed consent at the beginning of the trial. People receiving the sham acupuncture had been warned of the potential side effects of real acupuncture, such as redness or swelling, while subjects getting the placebo pills heard about the drowsiness and dry mouth that may bother patients taking amitriptyline, a pain medication. Those were the side effects subjects from each group reported.

These surprising results come from the latest of several recent studies that are changing the way science understands placebos. While it has long been known that taking a sugar pill may produce a measurable physiological effect, the new research reveals more about what actually goes on in the body and how variable the impact can be. The placebo effect is visible on brain scans, showing activity in areas involved in the response to pain; it disappears when a drug is given covertly, presumably because subjects don’t expect any benefit. Moreover, as Kaptchuk’s study shows, the magnitude of the placebo effect depends strongly on the circumstances of treatment—a new, unexpected finding. Patients taking pills at home alone responded quite differently than did those getting acupuncture in clinical settings surrounded by concerned caregivers.

Still, curious as they are, these findings might be nothing more than medical oddities if not for the huge role of the placebo group in modern medicine. Randomized double-blind placebo-controlled trials (RCTs), the biggest and best medical research studies science has to offer, sort out the effectiveness of new drugs and treatments by comparing people on real regimens with those in placebo groups (as long as patients are healthy enough to forgo treatment or no good treatment exists). Subjects randomly assigned to a placebo group go through a trial experience identical to that of those getting actual treatment, except that for the placebo group the active ingredient in a pill or the key action in a treatment has been left out. Neither subjects nor doctors know their group assignment—hence, double-blind—and so such trials are supposed to reveal what really works and what doesn’t.

Establishing causal links between treatments and clinical results is crucial, particularly in evaluating drugs being considered for U.S. Food and Drug Administration (FDA) approval. In passing judgment on new treatments—at a cost, factoring in countless failures, of about $800 million per drug—the FDA requires a series of human trials, the last and most important of which is an RCT involving hundreds or even thousands of subjects.

For decades, scientists have assumed that subjects receiving placebos formed a reliable control group, a static baseline against which a treatment’s safety and efficacy could be gauged. But what if, as the latest research suggests, the placebo effect is not only powerful but also inconsistent? What if some drugs actually work through the same brain pathways as does the placebo effect? Will RCTs have to be redesigned to take this new understanding into account? And will the placebo, medical wallflower no more, have to be factored into treatment plans and drug designs? If, for example, a compassionate physician can heighten the positive effects of a placebo, doesn’t that argue for paying greater attention to how care is delivered?

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1. “Sham Device v Inert Pill: Randomised Controlled Trial of Two Placebo Treatments,” by Ted J. Kaptchuk et al., British Medical Journal, Feb. 18, 2006. Kaptchuk’s study which found that the placebo effect not only exists but also that its magnitude differs depending on the type of placebo given and that each placebo produces unique side effects.

2. “Powerful Placebo: The Dark Side of the Randomised Controlled Trial,” by Ted J. Kaptchuk, The Lancet, June 6, 1998. A thought-provoking history of the placebo and its tumultuous relationship with randomized controlled trials.

3. Science of the Placebo: Toward an Interdisciplinary Research Agenda, edited by Harry Guess, Arthur Kleinman, John Kusek and Linda Engel [Blackwell BMJ Books, 2002]. An exciting series of articles on the biological, cultural and ethical aspects of the placebo effect by researchers in various fields that resulted from a groundbreaking National Institutes of Health conference in 2000.

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