The Mysterious Power of Placebos

Even if people know they are taking inactive medicine, they often get better.

If a headache goes away after a person takes a pill thinking it will zap the pain — even though the so-called medicine contains an inert substance — it’s likely due to the placebo effect. This well-known beneficial health outcome results when someone expects a sham drug, injection, or other therapy to be effective. At least, that’s been the long accepted explanation of how placebos work.

However, researchers are learning the placebo response may be far more complicated and more mysterious than previously thought.

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When drugs are tested to see how well they work and whether they produce side effects, research volunteers taking the medications are typically pitted against a control group of research subjects taking placebos. Double blind studies, in which neither research subjects nor researchers know who is taking the active drug and who is receiving the inert version, are the gold standard of pharmaceutical trials and are supposed to eliminate any placebo effect tainting the findings.

But in recent years, as drug studies have grown larger and longer, something surprising has been revealed about placebos. Placebos can work whether or not people know they are taking bogus medication. And sometimes sham treatments work almost as well as the real drugs being tested.

McGill University scientists analyzed 84 clinical studies of drugs for pain relief and found the amount of pain relief reported by research subjects given placebos has increased steadily in recent years. In fact, studies of drugs versus sham pain pills for nerve pain revealed those taking the inert pills typically experienced a significant 30 percent decrease in pain, according to the analysis published in the journal Pain. Similar increases in the placebo response have previously been observed in clinical trials of antidepressants and antipsychotic drugs, too, among research volunteers given sham pills for their mental illness.

“The data suggest that longer and larger trials are associated with bigger placebo responses,” said Jeffrey Mogil, PhD, professor of pain studies at McGill University, who headed the analysis. “This, in turn, tends to result in the failure of those trials — since it makes it harder for pharmaceutical companies to prove that the drug being tested is more effective than treatment with a placebo.”

Research by Ted Kaptchuk, MD, director of the Program in Placebo Studies and the Therapeutic Encounter at Harvard University and Beth Israel Deaconess Medical Center, has revealed the surprising power of the placebo response, even when people are told they are taking fake medication.

A study headed by Kaptchuk, published in the journal PLOS ONE, involved 80 patients with irritable bowel syndrome, a painful condition which affects about 15 percent of Americans and can be difficult to treat.

One group of the research subjects served as controls and received no treatment. Another group was given fake medication that was clearly labeled “placebo pills,” and they were specifically told the medication was worthless and inert. However, those in the placebo group were informed patients do experience benefit from placebos sometimes.

The result of the study was dramatic and surprising. Those knowingly taking the placebos reported twice as much improvement in symptoms, including relief from bloating, painful cramps, and diarrhea, than the untreated patients in the control group. “Some of the patients came back and asked for more (fake) pills,” Kaptchuk noted.

Kaptchuk has conducted similar studies with people suffering from depression and migraine and, in every case, placebos produced significant benefits.

“The role of placebos and their impact on human health is bigger than many of us realize,” said Edward Partridge, MD, the director of the University of Alabama at Birmingham (UAB) Comprehensive Cancer Center. “I think Kaptchuk is really onto something important, and it will move into mainstream medicine.”

Teri Hoenemeyer, director of education and supportive services at the Comprehensive Cancer Center and a doctoral student in health behavior at UAB, is working on a study to find out if the placebo response can help cancer survivors suffering from fatigue. “People who have survived cancer often experience a penetrating fatigue that seems to go on indefinitely,” said Kevin Fontaine, PhD, chair of the of UAB health behavior department. “It really compromises the quality of their lives, and currently there are no effective treatments.”

Kaptchuk, who holds an adjunct faculty appointment at UAB, is acting as a consultant on the seven-week trial for cancer survivors who have completed treatments for at least six months and are experiencing cancer-related fatigue. Like Kaptchuk’s previous studies, this one will involve “open label” placebos — meaning the research volunteers will be aware they are taking fake pills.

The UAB research team will document any improvement in the fatigue in research subjects who take the placebos compared to those who don’t take the fake medicine. They will also analyze saliva samples from the study participants to see if they can find evidence of possible genetic biomarkers that could indicate whether some people have a genetic predisposition to respond well to placebos.

If they score and find placebo-positive biomarkers, it could help pharmaceutical drug research by weeding out potential research subjects who are more likely to have a positive response to whatever they are given — drug or placebo.

Kaptchuk and UAB researchers are also trying to figure out exactly how placebos work. “We believe there’s some element of classical conditioning going on,” Fontaine said. “Throughout your life, you take a pill and you see an effect. You take an aspirin, for instance, and it takes away your headache. There’s an association there in your mind, and the idea is that the ritual of taking pills may actually produce a beneficial effect.”

It turns out that placebos don’t seem to work in people who have Alzheimer’s disease. That could be a clue about the part of the brain involved with the placebo response. The prefrontal cortex, which is associated with thinking, behavior, and emotions, is impaired in Alzheimer’s, and people with the condition may be unable to develop expectations when they take a pill, according to Fontaine.