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What’s in a Sugar Pill? Maybe More Than You Think

Image: Migraine brain

The migraine brain is more excitable than the healthy brain. This example illustrates abnormal activation (in red, on the right) in the thalamus (green areas on left in the middle of the brain) in migraine subjects. Rami Burstein / Harvard Medical School

Doctors trying to use psychology to boost the power of migraine medication have made a startling discovery about how attitude can affect pain. They found that people felt relief from placebos — sugar pills — even when they knew they were taking placebos.

While a real pain drug always worked better than placebo, the researchers also found a kind of “reverse-placebo” effect. If patients thought they were getting a placebo, the real drug didn’t work as well as it should have, the report in the journal Science Translational Medicine.

Doctors have known about the placebo effect for thousands of years. It’s how snake oil salesmen have thrived and it causes so much chaos in testing new drugs that regulators require new drug developers to test products against sugar pills or sham treatments.

But while the study showed the placebo effect is real, it also showed something puzzling. Placebo effect can reduce the effectiveness of a real drug, but it doesn’t seem to boost it, the team at Beth Israel Deaconess Hospital and Harvard Medical School in Boston found.

And it works even if the patients are told not to expect it to. Patients given a pill and told it was a placebo still felt some relief.

“When you tell a patient, ‘I am giving you a sugar pill’ and yet it helps him, it’s not what we expect,” said Harvard’s Dr. Rami Burstein.

Burstein wasn’t looking to study the placebo effect. “I was interested in seeing if there was any way I could boost the effectiveness of the drug I was giving patients,” he told NBC News.

“The motivation was to figure out whether there was something in the information we give the patients that could actually made the drug more effective.”

Burstein and his colleague Ted Kaptchuk were working with migraine patients using a drug called Maxalt, known generically as rizatriptan. It’s very effective, but patients often need multiple doses to get complete pain relief and Burstein wanted to see if there was a way to improve the effects.

They tested 66 chronic migraine patients, giving them envelopes of pills labeled either “Maxalt” or “placebo." The patients were told the Maxalt had been found effective in reducing pain and they were told the placebos were sugar pills that would do nothing. They were instructed to take the pills the next time they felt a migraine coming on and told to take them in a certain order, regardless of what the label said.

But they mixed the pills up. Sometimes the pill in a “Maxalt” envelope really was Maxalt, and sometimes it was a placebo. And sometimes the pills in the “placebo” envelope were really Maxalt. “What we did not tell them was when we switched the pill,” Burstein said.

If patients took a “Maxalt” pill and it really was Maxalt, it worked the best, Burstein says. About 25 percent of the patients who took Maxalt had no pain at some point, compared to 6.6 percent of those who took placebo. When Maxalt was mislabeled as placebo, 15 percent of patients said their pain was gone. When a placebo was labeled as Maxalt, 7.7 percent said their pain went away.

Patients also reported how much their pain was relieved, on a scale of 1 to 10. “The typical decrease in pain score was 47.6 percent for Maxalt treatment versus 20.7 percent for placebo treatment,” the researchers wrote. “Even when placebo treatment was labeled accurately and openly described as placebo, pain scores typically decreased by 14.5 percent, ” they added.

“We can reduce the effectiveness of the drug but we cannot increase it,” Burstein said.

This wasn’t what Burstein was hoping for, but it does shed light on how the mind can help control pain. Burstein compares it to when an injured person trying to escape a killer can temporarily shut out the pain.It’s also important news for doctors, who need to explain clearly why they think a drug will help a patient.

“Doctors don’t necessarily have to tell the patient the drug they are taking is the best thing since sliced bread,” Burstein said. But saying little or nothing about the drug might hurt how well it works.

One thing Burstein is clear about – the study does not mean that migraine is somehow imagined or exaggerated.

“The study does not mean that migraine is all in your head,” he said. “The reason placebo works is that the brain has the ability to turn off pain signals.” Some people can do this better than others, and Burstein is trying to understand why.

More than 10 percent of adults get migraine, the World Health Organization says.

They’re caused by abnormal brain activity – something Burstein has spent decades documenting. Electrical and chemical signals cascade along the nerves, affecting blood flow in the brain and surrounding areas. Patients experience pain, but also other effects such as nausea, vertigo, sensitivity to light and sound, and visual effects such as “aura” and flickering or flashing lights.

Migraine is notoriously difficult to treat.

Many drugs are used to treat migraines, from simple painkillers such as naproxen or ibuprofen to seizure medications such as topiramate and migraine-specific drugs called triptans, ergots and isometheptene.