The Placebo Effect: Studies Reveal How Fake Medicine Actually Reduces Pain

A team of researchers smears a cream said to contain a powerful anesthetic on the skin of your forearm. Then, in their mad-scientist way, they apply an electric heating pad that can be dialed up to painfully hot levels.

Imagine being pleasantly surprised to find that the cream works — the heat seems quite bearable. The researchers even run a brain scan to document just how well this cream works.

But picture your dismay at learning that the cream was actually inert and contained no anesthetic. Nada.

Guileless lab rat that you are, you have been punked. By a placebo.

Scenes like this are playing out in U.S. and European laboratories as neuroscientists try to figure out how our brains can be tricked by sham treatments into producing potent pain-blocking effects that rival (and may sometimes enhance) the effects of real drugs.

The details of the emerging picture are still being sketched in, but it seems that our expectations — whether shaped through conditioning or a simple verbal instruction — can trigger our native pain-control networks, some of which extend from higher cognitive regions deep into the brain stem and spinal cord.

In recent papers published in Science and Neuron, a team of scientists led by Falk Eippert and Ulrike Bingel at University Medical Center Hamburg-Eppendorf in Germany explored how placebos activate the brain's "descending pain control system," which involves structures in the brain stem. It's a complex process that relies on opioids — naturally produced substances that chemically resemble opium and block the transmission of pain signals.

The scientists induced the placebo effect in their 48 test subjects by falsely telling them they were applying a cream containing lidocaine, a topical anesthetic. But some subjects also received naloxone, a drug that blocks the effects of opioids (the rest got an inert injection of saline solution).

Next, the scientists studied their subjects' brains with a functional magnetic resonance imaging scanner and asked them to subjectively rate the pain intensity.

The subjects who received naloxone (which blocked opioid activity in the dorsolateral prefrontal cortex and midbrain structures like the rostral anterior cingulate cortex, amygdala, hypothalamus, the periaqueductal gray and the rostral ventromedial medulla) saw markedly lower pain relief than those who had received saline, the team reported.

"Until now it was believed that placebo was just a psychological phenomenon that has no neurobiological basis, but that's really not the case," Eippert said. He noted that naloxone did not completely erase the pain-relief effect, suggesting that placebo treatment may also engage other less-studied brain networks.

The placebo effect is probably at work even when proven opiates are administered for pain relief, Eippert said. Experiments have shown that patients experience some pain relief when they are given opiates without their knowledge, which is no surprise. "However, when you give this drug and tell the patient, the pain relief is going to be much, much stronger," he said. "The interesting thing is if you give naloxone at the same time, then this additional effect of telling the patient is completely canceled. There's a placebo component in treatment as well."

Tor Wager, an associate professor of psychology at Columbia University, has shown that placebos are associated with increased activity in the brain's frontal cortex, which sends projections deep into the brain stem, where physiological responses to emotional events are regulated.

Wager hailed Eippert's study for conclusively showing the role of opioids in placebo pain control and for showing how much of the effect happens in the spinal cord.