It's the thought that counts

Belief in placebos can release natural painkillers in patients

By Dennis O'Brien

Sun reporter

Originally published December 8, 2021

Using brain scans, acupuncture and the nasty stuff that puts the sting in pepper spray, researchers are learning how placebos play out in our brains.

These innocuous medications - long used as decoys in clinical drug trials - aren't supposed to have real chemical effect on the body. But experience over the years has taught doctors that some patients who take placebos experience real relief.

Now brain scans show that when test subjects think a placebo is a real medication or treatment, the expectation of relief can release natural painkillers. That, in turn, can ease the discomfort of ailments from overworked muscles to a stinging hand.

"I think what we've shown is that the effects of placebo are real. It's not false pain relief at all. The body is releasing a chemical that induces pain relief," said Dr. James N. Campbell, professor of neurosurgery and director of the Blaustein Pain Treatment Center at Johns Hopkins Hospital.

Campbell's tools are positron emission tomography (PET) scans and capsaicin - the compound that makes hot peppers hot and puts the sting in pepper spray. His tests show that when someone gets a placebo, a specific region of the brain responds by activating neurotransmitters thought to release morphine-like painkillers.

"The question we asked was, 'Is there a release of morphine that corresponds to this placebo effect?' The remarkable finding was that there is," Campbell said.

In initial tests, researchers applied capsaicin to the left hands of 30 volunteers. They also got injections that doctors described as a soothing medication.

The injections were, in fact, a harmless inactive saline solution, but a thermal device connected to the volunteers' hands reduced skin temperature to about 80 degrees Fahrenheit. That eased the effects of the capsaicin so that volunteers came to associate the injections with reduced pain.

In follow-up tests, volunteers again got capsaicin treatments. Some also got placebo "painkiller" injections, while others got no injections at all. Meanwhile, researchers ran PET scans on subjects while they were given the injections.

PET scans use positron emission tomography to trace the path of a mildly radioactive substance through the body. It's typically used to identify tumors or spot areas of brain function.

The tests showed that when given the placebo injections, volunteers reported less pain from the capsaicin - even though the pepper treatments were the same. More importantly, the scans showed they actually had different reactions in the mid-brain area known as the periaque- ductal gray (PAG).

The PAG released a class of painkillers known as endogenous opioids. Scientists couldn't tell exactly which opioids were released - brain scanning isn't that precise - but Campbell believes they were endorphins, which reduce the sensation of pain.

Campbell reported his results last month at the annual conference of the Society for Neuroscience in Atlanta. He said his goal is maximizing the placebo effect by harnessing the body's ability to reduce pain naturally.

'Cognitive strategies'

That could happen through cognitive therapy, self-hypnosis or focusing on the kind of distraction from pain experienced by someone watching a gripping movie.

"You can't go around all the time in a state of self-hypnosis, but there could be some kind of cognitive strategies developed to control pain," Campbell said.

Skeptics say the benefits attributed to placebos might stem from our ability to heal without treatment or medication. Researchers at the University of Copenhagen in Denmark concluded in 2001 that the benefits attributed to placebos were largely the result of diseases running their course.

Believers in placebos acknowledge that benefits are often hard to nail down - if relief or healing occurs, it's hard to determine how much of it was from the placebo and how much was part of the natural healing process.

But scientists such as Campbell argue that brain scans don't lie - they show that something physical is actually happening in our heads.

They note that placebos in controlled experiments produce the desired effects about 30 percent of the time, and in clinical trials of drugs before they're approved for market, placebos will sometimes be as effective as the tested medication.

"Placebos are an inherent part of manipulation whenever a clinician gives a medication. They work very well at blocking pain. That's why a doctor will always talk up the effects of a medication - it increases the likelihood it will help," said Allan Basbaum, a neuroscientist at the University of California, San Francisco.

Expectation a key

Some experts say placebos are proof of the power of positive thinking.

"A patient who has pain - if you give them a medication and tell them it will reduce the pain, that has a positive effect on the outcome," said Dr. Jon-Kar Zubieta, a psychiatrist who studies the effects of placebos on the brain at the University of Michigan.

Part of Zubieta's research is aimed at figuring out why some people are more susceptible to the placebo effect than others. "There could be a genetic component, but nothing is certain," he said.

Zubieta reported last year in the journal Neuroscience that giving placebos to volunteers who thought they were getting painkillers released natural compounds in several areas of the brain, including the prefrontal cortex and the anterior cingulate. Those areas are believed to control our expectations and how we regulate emotions.

Unfortunately for researchers, the brain has no single pain control center, so pinpointing areas where placebos curb pain is a challenge. "There's an entire system of circuits that become activated, at just the expectation of pain relief," Zubieta said.

Researchers have been studying placebo effects for years. But many placebo studies don't compare the outcomes from a placebo with those of accepted drugs, said Ted Kaptchuk, an assistant professor of medicine at the Harvard Medical School.

Comparisons

"One problem is there's been no controls in a lot of cases," Kaptchuk said. "If I give 100 people with colds a sugar pill and two weeks later the cold symptoms disappear, was that the placebo? A lot of what you see are those kind of reports."

This year, Kaptchuk turned to acupuncture to try to determine whether some placebos are more effective than others.

He divided 270 patients, all with chronic arm pain from repetitive stress syndrome, into two groups. He gave one group either a dose of a pain medication in pill form, or a placebo pill. Members of the other group got either acupuncture or a sham acupuncture treatment involving needlelike sticks that didn't penetrate deeply enough to hit the right pressure points.

Those given sham acupuncture reported a more significant decrease in pain - about 10 percent - than those given a placebo pill, Kaptchuk said. He reported the results Feb. 1 in the British Medical Journal.

One unexpected result: The placebo effect also boosted the volunteers' chances of experiencing adverse reactions when they were warned in advance that unpleasant side effects might occur. In fact, some 30 percent of the patients who got acupuncture - but were told they might experience more pain afterward - actually reported experiencing more pain as a result, Kaptchuk said.

The same percentage of placebo pill takers reported getting drowsy and experiencing dry mouths after they were warned about those side effects, he said.

Kaptchuk is planning future research into the magnitude of placebo effects on patients with a number of conditions, including irritable bowel syndrome, asthma and chronic pain.

"I think there's an intrinsic scientific value in understanding how the body reacts to what's going on in the mind," he said.

Posted 12-18-06