Sunday, August 3, 2003

Sweet relief: The placebo

First appeared in the Boston Globe.

Researchers at Harvard Medical School are putting the lowly placebo to the test. Can it establish itself as a legitimate remedy?

By Harvey Blume

IN THE 1960s, Saturday Review editor Norman Cousins, paralyzed by a degenerative disease that seemed well on the way to killing him, took batches of vitamin C, laughed his head off watching Marx Brothers movies, and experienced complete remission. Cousins gave total credit for his recovery to what he called the “doctor who resides within”-the placebo effect. 

The mysteries of the placebo-how it works, and whether it works at all-have haunted mainstream medicine for decades. Can an inert substance or a mere change of attitude sometimes do more for patients than “real medicine”? Now, with the advent of powerful brain-imaging techniQues, and prompted in part by the fact that Americans spend millions of dollars each year on alternative medicine, the medical establishment is demanding answers to these Questions.

As it happens, Harvard Medical School is in the forefront of providing them. Since 1997, a group of researchers have been meeting under the auspices of the school’s Osher Institute to analyze the placebo. These researchers, who range from senior biomedical scientists to a Tai Chi master, recognize that this is make-or-break time for the placebo effect, the moment when it will either prove it has something of value to teach mainstream medicine or fade back into the shadows.

The term “placebo,” Latin for “I shall be pleasing,” is the first word of the Roman Catholic hymn traditionally sung in the Vespers for the Dead. Since the 1970s, the placebo has been identified with the inert substances-the sham or “dummy” interventions-that genuine, or “verum,” treatments must outperform in clinical trials in order to win Food and Drug Administration approval. Today, however, the National Institutes for Health (NIH) and its component agency, the National Center for Complementary and Alternative Medicine, are funding clinical trials that push placebos to center stage, and subJect them to the kind of scrutiny once reserved for active drugs. The Harvard group completed the first of its NIH-funded trials in June, and will publish the results in the fall. Another maJor long-term study will be launched shortly.

Placebos have a long connection with Harvard. It was, after all, Dr. Harry Beecher, a Harvard-trained surgeon, who gave placebos their place in modern medicine. When Beecher, who served with the Army during its assault on Anzio during World War II, ran out of morphine for severely wounded GIs, he found that normal saline could fill in as a pain-killer-provided the soldiers were told by trusted members of the staff that they were getting morphine. Back at Harvard Medical School, where he held America’s first endowed chair in anesthesiology, Beecher continued to probe the healing properties of placebos, summing up his conclusions in his landmark 1955 paper, “The Powerful Placebo.” Beecher argued that inert substances often outperform supposedly “potent pharmacologic” agents, and he maintained that approximately one-third of all patients respond to placebos, and not only with regard to pain.

Debunkers, however, have long maintained that reports of placebo power are nothing more than medicine’s version of UFO sightings-a hash of rumor, gullibility, and misunderstood natural phenomena. In a much-noted article in The New England Journal of Medicine two years ago, the Danish researchers AsbJorn HrobJartsson and Peter C. Gotzsche argued that placebo effects are inconseQuential. After scrutinizing 114 clinical trials, they found “little evidence” of placebo effectiveness, and “no justification for the use of placebos” in clinical settings.

The article prompted ongoing statistical mud-wrestling, but one of the Danes’ points is already changing the way medical research is conducted. As currently designed, clinical trials overlook a fundamental truth about illness-namely, that sometimes people do simply get better on their own. Because clinical trials generally lack a no-treatment arm, they provide no way to gauge how many recoveries should be chalked up to what is known, in research parlance, as “the natural history of disease.”

But Drs. HrobJartsson and Gotzsche had, in fact, surveyed a far-flung collection of trials that contained groups receiving neither active substances nor placebos. These trials proved, to their satisfaction, that people who got various sorts of placebos fared no better than the people who didn’t get so much as a sugar pill or a pat on the head.

The finding has hardly fazed the Harvard group. Ted Kaptchuk, the group’s founder and an assistant professor at the Osher Institute, believes HrobJartsson and Gotzsche’s paper has set the stage for an “era of research that dispenses with myth and can focus on science.”

Kaptchuk’s group certainly brings a diverse set of credentials to the task. Kaptchuk himself is trained in traditional Chinese medicine, and is the author of “The Web That Has No Weaver,” a standard text in that field. In addition to a professor emeritus of clinical pharmacology at Harvard Medical School, the group boasts a Tai Chi master with years of experience as a research biologist, and an instructor in Harvard’s department of social medicine who came to the group after a brush with cancer. In 1995, Cathy Kerr was diagnosed with “a rare cancer of the immune system thought to have a very negative prognosis,” she says. Kerr believes that her studies with a teacher of Chinese Qigong, a meditative discipline similar to Tai Chi, have helped her defy the odds and hold the disease in check. “My Qigong experience convinced me that something was missing from biomedical accounts of cancer,” she says, “and I began to look for ways in which I might be able to pursue work on the topic full time.”

No one typifies the group’s eclectic approach and its dexterity more than Kaptchuk himself. As Kaptchuk has pointed out freQuently in essays and lectures, placebos both affirm and negate conventional ideas about biomedicine. On the one hand, placebos used in clinical trials help confer legitimacy on our pharmacopoeia by providing a baseline against which to measure a drug’s effectiveness. At the same time, many researchers and practitioners regard the placebo as a code word for everything Western medicine doesn’t understand about healing, everything millions of Americans get more of from an acupuncturist or an herbalist than they do from an MD.

After doing substantial historical and theoretical research on the multiple meanings of placebos, Kaptchuk, who is in his mid-50s, let himself be lured by the subJect into doing real science. “I kept writing all these articles,” he said. “At some point it became clear I should test my hypotheses, and I had to learn how. I became a scientist almost by accident.”

In addition to analyzing past clinical studies and designing their own, the group regularly discusses and dissects some of what might be called the accumulating folklore of the placebo. Take, for example, the tale of internal mammary ligation, a form of heart surgery now known to have been based on bogus assumptions about the body’s circulatory system. Before being discredited, however, internal mammary ligation led to a 90 percent reduction of angina pain in one clinical trial-the same rate of improvement, incidentally, that resulted from the placebo surgery used in that trial.

And then there’s the placebo’s evil twin, the nocebo effect. After all, if an inert substance plus positive spin can have medical benefits, why shouldn’t an inert substance plus negative spin induce distress? It has been reported, for example, that all 13 recruits to one Japanese clinical trial broke out in a rash when informed that the innocuous leaves being rubbed on their arms were poison ivy. Score that one for the nocebo.

The Harvard group’s new $2.1 million study is one of the first of a wave of NIH-sponsored trials explicitly designed to address HrobJartsson and Gotzsche’s anti-placebo critiQue. It has a no-treatment arm in addition to two placebo arms and one verum arm. (Recruits who are randomized into the no-treatment arm can, if they like, be treated for free after the study ends with the verum under investigation.)

The no-treatment arm is not this trial’s only innovation. Another goal is, as Kerr puts it, “to crack open the black box of clinical trials.” Throughout the study, patients will confer with practitioners about what it’s like to receive medical treatment in the unusual setting of a clinical trial. Kerr and others in the group suspect that medical ritual influences clinical outcomes. In the “interaction between the practitioner and the patient,” Kerr told me, “there are particular ways of talking and listening that may drive therapeutic change.” By controlling the practitioner’s approach to patients, she will be able to test this hypothesis.

Details of this study-it concerns a chronic condition-are still being ironed out, and cannot be made public at this time. More can be said about the clinical trial completed last June that involved 270 people who suffer from repetitive stress inJury (RSI), including carpal tunnel syndrome and tendinitis. That study has two verum arms (acupuncture and the drug Amitriptyline) and two placebo arms (sham acupuncture and a placebo pill).

In sham acupuncture, the needles are retracted back into their casing, never piercing the skin. Nevertheless sham acupuncture involves more patient/practitioner contact, more medical ritual, than merely swallowing a pill. If one of the placebos outperforms the other, that may yield information about the impact of ritual on healing. It would also suggest that there is something going on with placebo effects that cannot be ascribed to the natural history of disease.

Results of this study will be published in the fall, but preliminary reports confirm the placebo’s power to generate paradox. According to Harvard Medical School’s Dr. Rose Goldman, a co-principal investigator in the RSI study, some recruits Quit early on because they blamed dry mouth, sleeplessness, and other side effects on the pills they were getting. It turned out they were getting placebo pills. Joseph Kay, an acupuncturist, saw exactly the opposite sort of reaction. Out of the 50-odd people he treated, the most dramatic results involved positive responses to placebo needling. One long-term sufferer from RSI, for example, felt all better after four applications of sham needles, and “wondered if she should continue with the study, because she was cured.”

Is the placebo effect a medical UFO? Or does it have implications for healing that Western medicine has ignored for too long? It’s too soon to say. One event sure to probe these Questions to the depth is scheduled for Harvard Medical School this October. That’s when Ted Kaptchuk has arranged for Dr. HrobJartsson to deliver a lecture and participate in what Kaptchuk diplomatically predicts will be a “lively and friendly debate.”

Harvey Blume has written on art and culture for The New York Times, The American Prospect, and Wired.

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