The placebo effect grows (but only in the US)

Medication was administered to a patient participating in an Alzheimer’s study at Brigham and Women’s Hospital earlier this year. The medicine was either Solanezumab or a placebo.Jessica Rinaldi/Globe Staff/file 2015

The placebo effect is a little like love — we know for sure it exists, but it's hard to pin down. We don't actually know, in scientific terms, why you can tell a patient he's getting medicine, then give him a sugar pill, and he'll feel better all the same.

If the existence of the placebo effect is a mystery, new research on pain medication poses an even greater riddle. Not only is the placebo effect real, it seems to be growing exclusively in the United States.

The study was published in the journal Pain in August and analyzed 84 clinical trials of pain medicines conducted between 1990 and 2013. These trials each featured a placebo-control, which is used to try and isolate the beneficial effects of the drugs apart from any psychological effects. The authors found that two decades ago real drugs were 27 percent more effective at reducing pain than placebos, while by 2013 they were only 9 percent more effective. Even more startling, the placebo-gap seemed to be shrinking only in the United States.

"This [geographic] effect was staring us in the face and it was huge. It was very true in US trials and there was nothing at all changing in non-US trials," says Jeffrey Mogil, a neuroscientist at McGill University and coauthor of the paper.

That the placebo effect is real is largely accepted among scientists. Studies have shown, for example, that morphine is 50 percent less effective at reducing pain if patients don't know they're receiving the drug. In the face of this kind of evidence, and other studies showing that placebo response counts for a major part of the effectiveness of many powerful drugs, Mogil says, "You'd have to be a hard-ass or a hold-out not to believe in its efficacy."

Understanding how the placebo effect occurs is more of a work in progress. It's only in the last decade that researchers have begun to identify a genetic basis for the effect and the neuropathways along which it operates — putting some hard science on a previously mystical phenomenon.

"The brain is a prediction machine and when it has predictions that pain is going to get better, it will release chemicals that will turn down the pain," explains Ted Kaptchuk, professor at Harvard Medical School and director of the Program in Placebo Studies and Therapeutic Encounter at Beth Israel Deaconess Medical Center.

Apart from how the placebo effect works, there's the question of why it seems to be growing. Previous studies have found that the placebo effect has increased over time in clinical trials of antidepressant and antipsychotic medications. This newest paper is one of the first to identify the same effect in pain medication — and its suggestion that this is taking place in the United States, but not elsewhere, is entirely novel.

Mogil says there are a number of things that could be going on. One theory, which he doesn't subscribe to, is that direct-to-consumer pharmaceutical advertising has increased expectations for what prescription drugs can achieve. These advertisements are only legal in two countries in the world — the United States and New Zealand — and could prime patients to perceive big effects even when they're unknowingly taking a placebo pill.

A second theory relates the increasing placebo effect to the growing length of clinical trials, which have become more extensive in recent years in response to tougher Food and Drug Administration mandates. The longer trials are motivated in part by a desire to more rigorously separate placebo effects from real effects, but they could be having the unintended consequence of increasing the placebo effect itself.

"The longer a trial is, the bigger a trial is, the bigger the placebo response," Mogil says. "In mind what this suggests is that big and long trials are probably expensive trials. They might have giveaways to people in them, and people come to realize they're in a big, expensive trial. That increases the placebo effect."

Kaptchuk thinks that Mogil's study raises important questions, but says "the evidence isn't completely convincing to me" that the placebo response really is growing. To settle that question, he says (and Mogil agrees), it would be necessary to conduct new experiments rather than relying on retrospective analysis as the current paper does.

Whatever the explanation, changes in the placebo effect have big implications for the kinds of drugs that ultimately make their way to patients. Drugs are typically evaluated based on their benefit over placebo response. That is, measure a drug's effect, subtract the amount of placebo response, and you're left with its efficacy. This is known as an "additive" way of thinking about drug effects and this new study implies it may not be correct. This is because while Mogil and his coauthors found the placebo effect increasing over time, they didn't find that the overall performance of pain drugs had increased over time — which is what you'd expect if the placebo response were growing and you assumed that, at the very least, pain drugs weren't getting worse.

What this suggests is that to some extent, the placebo effect might cancel out some of the effects of pain drugs rather than adding to them. And it would cancel out those effects by occupying the same neuropathways that the drugs were seeking to use to relieve pain.

"The relationship between the placebo effect and drug effect is not additive, it's interactive," speculates Mogil. "Placebo uses the same biological pathways as analgesics, so expecting them to be additive is possibly not correct."