Pursuing the placebo effect: What exactly is it?
■ The use of placebo has been associated by patients with trickery or losing out, but some researchers are looking for something about it that can be harnessed to heal.
The placebo-controlled trial long has been the standard-bearer that provides the comparison point by which a medical intervention, particularly a drug, can be deemed to work or not.
Increasingly, though, researchers are considering the value of placebo on an entirely different level, asking whether something can be learned from the fact that beneficial effects are sometimes seen in subjects taking dummy pills and if this occurrence can somehow be translated into improved medical care.
"The placebo response is important -- not because we're going to treat people with placebo, because that would be unethical -- but if we can find out what it is about placebos that helps people get better, we can try to apply it more broadly," said Andrew Leuchter, MD, professor and vice chair of the Dept. of Psychiatry at the Neuropsychiatric Institute at the University of California, Los Angeles. He has published several papers documenting differences between the brains of patients with depression who respond to placebo and those who don't.
The National Institutes of Health is funding several studies related to the placebo effect, including Dr. Leuchter's, but the agency is asking questions beyond simply how and why it happens. The NIH also is funding studies to divine ways physicians can actually use this phenomenon in practice. The NIH's National Center for Complementary and Alternative Medicine is leading the charge in this research, although most of the other institutes have some interest, too.
One investigation, for instance, funded by NCCAM and the National Heart, Lung, and Blood Institute, will examine whether Food and Drug Administration-approved asthma drugs can be more effective if prescribed with information beyond the usual disease education. In this case, the study group also will hear positive statements from a physician or other health care professional about how the drugs have helped other patients and probably will benefit them, too. The control group will receive only pamphlets with asthma information.
Meanwhile, other projects are exploring whether patients can be conditioned to respond to a placebo as if they were receiving an active drug by interspersing dummy pills with medication.
"The theory is that a placebo that is given after the active medication has a greater effect than the placebo that's given before the active medication," said Thomas Pickering, MD, PhD, principal investigator on the study using this method to treat borderline hypertension. "If it works, you could give people holidays from the active medication. This would reduce the cost, and it might also reduce the side effects. It has important possibilities," added Dr. Pickering, who is also director of the behavioral cardiovascular health and hypertension program at Columbia University College of Physicians and Surgeons in New York.
The increasing interest in this area is the result of decades of anecdotal reports of patients getting better after receiving placebo. Over the years, several studies even have noted that patients with some medical conditions start to experience an improvement in symptoms just by reaching for medication or by approaching the door of a doctor's office.
Most recently, a study presented at last month's American Heart Assn. annual scientific sessions in New Orleans found that heart failure patients participating in a large international clinical trial who took all of their pills, whether in the placebo or active arm, had lower rates of death and hospitalization than those who weren't as conscientious. The rates for those taking placebo were not as good as those taking the actual drug, but were still extremely close.
"There's still an advantage to being on active therapy," said Bradi Granger, RN, PhD, lead author of the study and director of nursing research in the Duke University Heart Center in Durham, N.C. "But the fact that you can do almost as well on a sugar pill is a reason for us to figure out why."
The phenomenon is often attributed to the power of expectation. In other words, if a patient thinks he or she will get well, then it is more likely that he or she will.
"We have a very difficult time appreciating the importance of trust and expectation and all the things that go with the placebo effect and integrating it into our overall understanding of therapeutics," said James Goodwin, MD, the George and Cynthia Mitchell distinguished chair in Geriatric Medicine at the University of Texas Medical Branch at Galveston, who has studied the use of placebo in medical practice. "Any research that brings this powerful effect into something that scientific medicine can better appreciate is good."
Concern and curiosity
Many physicians are watching these studies carefully, with concern and curiosity.
On one hand, in many ways the study of the placebo response is an attempt to give value to old-fashioned doctoring, which is at the core of primary care medicine -- steps such as listening, acting kind, giving words of encouragement and, in the case of the AHA study, convincing patients to take their medicine. The medication, real or otherwise, and the act of pill-taking is but one part of the experience.
"In the 20th century, we became enamored with all these brand new discoveries and all these miracle drugs," said Howard Brody, MD, PhD, professor of family medicine and philosophy at Michigan State University College of Human Medicine in East Lansing and co-author of The Placebo Response. "We sort of, for a while, said that we could put that bedside manner on the shelf. Now, we're waking up to realize that we need both. Good doctoring and good care of the patient requires that we be very good scientists and not neglect the human side of medicine."
On the other hand, though, experts recognize that if these studies do work out, anything learned will be challenging to integrate into modern medicine, because the lessons likely will involve aspects of care that take a lot of time but for which actions are harder to measure than the number of prescriptions a doctor writes.
"If you're trying to package the placebo effect, what are you trying to package? Time? Enthusiasm? Encouragement? Optimism?" asked B. Timothy Walsh, MD, professor of psychiatry at Columbia University. He published a paper in the April 10, 2002, Journal of the American Medical Association concluding that, as people's beliefs in the effectiveness of antidepressants increased, so did the benefit received by subjects taking dummy pills in the placebo-controlled trials of these drugs.
Many doctors are also cautious. Some suggest that the physician enthusiasm involved in some of these trials actually could engender greater patient compliance and that this factor is what might lead to better outcomes.
"I hope they're going to carefully measure adherence, because if a patient thinks it's going to work, they might take it more," said Robert Keeley, MD, MSPH, a family physician and visiting scholar at Stanford University in California. "It might not be the placebo effect that they're measuring."
It is also one thing to be positive about a drug's possible benefits, but many physicians worry about overselling a drug's benefits or feeling the need to lie to a patient to get the desired result.
"It's a difficult balance to achieve between creating a reasonable sense of optimism and unrealistic expectations," said Jeffrey T. Berger, MD, an internist and director of medical ethics at Winthrop University Hospital in Mineola, N.Y.
Those involved in the research, however, are specifically in search of ways to get the most out of it without resorting to deception. And there is some evidence that lying is unnecessary. Several studies often cited by placebo-response devotees have found that morphine is more effective for pain if the patient knows it is being administered. This scenario suggests that knowledge could be enough to elicit the placebo response.
"Enthusiasm helps. Physician attitude helps," said Daniel Moerman, PhD, author of the medical anthropology textbook, Meaning, Medicine and 'Placebo Effect' and professor of anthropology at the University of Michigan, Dearborn, "And just your presence helps."
But it is the negative baggage associated with the word "placebo" that leads those most in favor of it to advocate for different terminology, such as "remembered wellness" or "meaning response." Those working in this area also say achieving a beneficial response in a patient is more than just prescribing a pill, whether it is active medication or otherwise. It is also about the art of medicine: the act of visiting a place associated with receiving help, talking to someone who patients believe can make them well and taking action that they believe will improve their health.
"The term placebo effect is in many ways an outmoded term and is misleading," Dr. Leuchter said. "Some of the things that we think go into the placebo effect are simply kind and compassionate interaction between a physician and a patient."
But no matter what it's called, there are some who doubt the placebo effect even exists. For example, in the May 24, 2001, New England Journal of Medicine, a Danish research team published a systematic review concluding that the placebo effect was limited in its scope and that there was no justification for its use beyond the trial setting. An accompanying editorial suggested that the placebo effect actually could be the result of the natural progress of the disease and the fact that some patients get better on their own.
"The basic problem is that the patient who has had a bad day with cancer or emphysema or a headache does not need a placebo to feel better the next day," wrote John C. Bailar III, MD, PhD, scholar in residence at the National Academies in Washington, D.C.
Many researchers agreed in part with the NEJM study, which found that it was effective only for some conditions -- particularly those involving pain -- which is consistent with other findings. But overall, most disagree that it does not have a place in medicine or that it does not have a wider range.
"Every time we're dealing with conscious patients, there's some piece of placebo effect going on along with whatever else we do," Dr. Brody said. "And I have a duty as a physician to be as attentive to the placebo component of my visit as with any other piece of that visit."