The Chemical Contrails of the Placebo
Studies are finding that the pain relief induced by placebos may come from releasing the body's own chemical pain relievers.
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.
"These are new insights," Wager said. "It's surprising that you could get a signal in a spinal cord … much less influence it with a placebo treatment."
The placebo effect has long vexed drug companies conducting expensive drug trials, Wager said. Scientists have had a hard time accepting the validity of placebo effects "because we think of psychological things as not real, and we think of drugs as being physical," he said. "The truth is, thoughts and feelings — particularly strong emotional states — are physiological and neurochemical events in your brain."
Wager is curious about what physiological changes occur in the brain when an expectation is created. Expectations involve making a prediction about the future that draws on the memory of past experience and is related to the self, he said.
A key area of interest is the ventral medial prefrontal cortex, the region that is activated when people make judgments about how things relate to them, as opposed to others.
"This is the only area of the cortex — in monkeys and rats, at least — that sends projections all the way back down to the brain stem nuclei that control the spinal cord," Wager said. "They control the autonomic nervous system. It's a major source of projections to essentially the brain's stress system in the hypothalamus and the brain's pain control system. It's the right area to be seeing increased opioid release with placebo."
Meanwhile, Swiss neuroscientist Peter Krummenacher and his colleagues report in a forthcoming study in the journal Pain that the use of repetitive transcranial magnetic stimulation (or rTMS) to temporarily disable the left and right dorsolateral prefrontal cortex "completely blocked" placebo-based pain relief.
They subjected their 40 male subjects to rTMS — which induces an electric current in the brain — on both sides of the head and achieved identical results. The researchers noted that the dorsolateral prefrontal cortex plays a major role in higher cognition, working memory and general attention. If the placebo response disappears when that region is temporarily disabled, they wrote, it might be "a consequence of a transiently disrupted cognitive representation of pain analgesia and the result of redirected attention away from pain."
All this new research could help pharmaceutical companies better understand the role that placebos play in the efficacy of their treatments — an urgent need, Columbia's Tor Wager said, since clinical trials that can cost as much as $100 million often founder on placebo effects.
"What these studies do is help to understand what the neurobiological principles are," Wager said. "It can lead to ideas and treatments that we hadn't thought of because we understand the neurobiological principles."
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