The Fallible Mind

Emotion, perception, and other tricks of the brain

The Placebo Response: Not in Your Head but in Your Brain

How sugar pills and sham treatments mimic the real thing

* A surgeon cuts the skin over your knee instead of performing arthroscopic surgery, but your knee pain still goes away.

* You swallow a dummy pill that contains nothing but starch, and yet your migraine vanishes as if you had taken an Imitrex.

* A saltwater injection eases your asthma the same amount that puffing on a bronchial inhaler does.

What's going on here? All three of the above are examples of the placebo effect, but how does it work? Rather than having to do with deception and suggestibility-mind over matter as is commonly believed-the placebo response sheds new light on the art of medicine. For a long time the phrase "art of medicine" has referred to ill-defined qualities of skill or aspects of temperament such as warmth, tone of voice, affability, or trustworthiness. Its negative connotation relegated medical art to the background while bringing objectively measurable biology to the front. New research, however, has turned the conventional attitude upside down. The placebo effect is neither mumbo-jumbo nor magic. Rather, it works through your brain.

The name placebo comes from the Latin for "I will please," likening it to a healing salve. Clinical research today defines it as any inert substance used to hide the genuine treatment under study. The "placebo effect" is whatever effect the sugar pill produces. The problem with the standard definition is that it is an oxymoron: a pill cannot logically be inert if it causes an effect. So what is the placebo actually doing?

Let's start with some observations. First, placebos work better for some things rather than others. They won't shrink a tumor, for instance, or reduce a fever but they do affect pain, insomnia, anxiety, asthma, depression, irritable bowels, and stomach ulcers. And far from needing deception in order to work, placebos are effective even when patients are in on their use. Likewise, there is no overlap between people who are hypnotizable and those who respond strongly to placebo, nor do suggestibility scales predict placebo responders. On the contrary there is a profound relationship between placebos and naloxone, a drug that counteracts narcotics by blocking their access to the brain's opiod receptors. Assurances that dummy pills will be effective cause the brain to release pain-killing endorphins from its inbuilt pharmacy. After the demonstration some years back that naloxone prevented this endorphin release and thereby blocked the placebo effect, no one could longer claim that the placebo response was imaginary.

 

Consider a situation in which an identical action produces two different outcomes. We know that different parts of the brain handle different types of signals. Physical signals for touch, pain, and movement are dealt with in their respective areas while other parts handle emotion, anxiety, and expectation. Still others are dedicated to immune interactions, planning, and memory. If, for example, you were to stick a needle in a person's hand you would see activation in parts of the brain that feel the needle, register it as pain, and perhaps reflexively draw the hand away. If the person were anxious or alarmed about the encounter then emotional areas would activate, too.

If, however, before you stuck it in the same spot you called the needle therapy-acupuncture let's say-you would activate the same brain areas as the first time and additionally switch on the endogenous opioids and other inbuilt pain responses. One explanation for the puzzling duality is that the "acupuncture needle" has nothing to do with the relief. The placebo response is instead masking an important phenomenon in the clinical encounter. That phenomenon has to do with the healer's words and the patient's expectations.

This current thinking is especially put forth by Harvard's Ted Kaptchuk, director of its Program in Placebo Studies and Therapeutic Encounters. He calls placebos "surrogate markers" that measure the effect of just caring-the words, gestures, eye contact, attitude, the medical symbols of white coats, diplomas, prescriptions pads, and medical trappings. They are embedded in an elaborate context of ritual procedures that are part of every encounter: waiting, talking, attentive listening, disrobing, the laying on of hands and being examined, and then being treated with pills, talk, or surgery. Ultimately they have to do with the power of imagination, trust, and hope in both parties. In this view, the placebo doesn't do anything. Being in a healing relationship does. Dummy pills, saline injections, and even sham operations bring forward what has previously been hidden in the elaborate context of caring, rituals, and symbols that constitute every doctor-patient relationship.

Emerging evidence suggests that these factors have real biologic effects, on the immune system or the healing of ulcers, for example. More importantly they have an enormous effect on the experience of illness, or how a person feels. The laying on of hands, herbal remedies, and healing rituals go back centuries. The Office of Alternative Medicine at NIH has been trying to understand how cultural beliefs and expectations color the experience of illness and influence how we heal. The sickness ritual begins by going to a practitioner and asking for help, a therapeutic encounter that is learned very early on. We fall down and bring our skinned knee to Mommy who says, "I'll kiss it and make it better." Such a learned conditioned response is possibly humankind's earliest placebo effect. Kissing boo-boos is an important part of who we are.

Expectation is not the sole mechanism behind placebos of course. At the psychological level conditioning, the projection of anxiety, and feeling comfortable play a role. Expectations do not have to be consciously held beliefs, a mind over matter type thing. Rather, they can be shaped by the number of pills we take, the place in which we take them, the optimistic or cautious message that the physician conveys about them, and what the larger culture believes. Our culture believes that higher priced things are valuable. Drug companies know this and accordingly brand their pills. One study in Switzerland showed that generic aspirin works fine for headaches, but that Bayer aspirin worked even better. Color, size, and shape matter too. The larger the tablet, the better the effect. Two pills are better than one. Capsules are more effective than pills, and injections trump either for effectiveness. Then there is the matter of color, colored pills relieving pain better than plain white ones. Blue pills are superior to red in treating insomnia. Anxiety responds best to green capsules. These subtle kinds of meanings all affect treatment outcome. In the same way that meaning attaches to the doctor's authority, language, or the white coat, a ritual smell or taste attached to a drug can ramp the immune system up or down.

In recent years we have linked neurotransmitters besides opiates to placebos. The conventional treatment for Parkinson's disease is dopamine. When Parkinson patients get a saline injection that they think is a new drug, the striatum of the brains releases a significant amount of dopamine that has the same therapeutic effect as an exogenous dose. Marijuana-like cannabinoids and other transmitters likewise participate in placebo responses, while brain regions such as the anterior insula and cingulate gyrus bridge physical sensation and our attitude about it. The brain is the most complex object in the universe. No one size can fit all. The beauty of placebos is the way they illustrate the interaction of imagination and expectation with the biological chemistry of the brain. The more we understand this interaction the more we will be able to translate it into strategies and techniques for relief and well-being.

Richard E. Cytowic, M.D., is a neurologist best known for bringing synesthesia back to mainstream science. His latest book is Wednesday Is Indigo Blue.

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