This article, in a slightly edited form, first appeared on Pain News Network on April 31, 2019.

Most of us have been prescribed a medicine at some time in our lives, and if we got better, we probably assumed it was because the medication was effective.

However, this may not have been completely true. A positive result following the use of a medication may have little to do with the drug.

If you’re a M*A*S*H fan, you may have seen an episode called “Major Topper.” In that show, Colonel Potter suggests they treat people in pain with a placebo because there is a morphine shortage—and it works. Did that mean their pain wasn’t real?

Placebos Work So Well They Can Fool Researchers

One of the greatest challenges in evaluating the efficacy of medical treatments is to minimize what is known as the placebo effect. The benefit provided by a treatment during clinical trials may appear to be significant. However, the treatment may fail to be approved by the FDA if the benefits for patients who receive a placebo are too similar to those who got active treatment. Drug approval requires that active treatment results differ statistically and are meaningful from placebo results, even though both provide similar improved outcomes when compared to a baseline.

I study drugs for their potential to be abused—what the FDA calls Human Abuse Potential (HAP) study. People who participate in HAP studies must admit they recreationally use the class of drug which is undergoing evaluation, and must report a strong preference for the drug when compared to a placebo. Most people would be surprised to learn that as many as 50% of the subjects who commonly use the class of drug for recreational cannot adequately differentiate between the active drug and the placebo. Even more surprising is that one in five subjects report a much greater preference or “getting high” experience with the placebo than with the active drug.

There are several reasons for this. It could be that they don’t realize researchers know which drug they received and in what order; they are simply hoping to guess correctly because they want to participate in the study. Or the subjects may be anticipating an effect that they want (to get high), and that anticipation creates the effect in the reward center of their brain even without using an active drug.

This effect is not limited to drugs. As a principal investigator in a study, I surgically implanted wires at the base of the occiput (the skull) to stimulate occipital nerves in an attempt to prevent or treat migraine headaches. Although all subjects underwent the operation and were implanted with the wires, only half received active stimulation. The other half were programmed with a sham pattern of stimulation.

When the study was unblinded, we discovered that almost everyone in both groups (active and placebo) derived remarkable, but similar, relief from the therapy. We concluded it was their expectations that an invasive procedure would be therapeutic that provided the positive outcome. Unfortunately, the positive results of both treatment and placebo meant the new procedure could not be approved on the basis of our testing.

Placebos Work Even When People Know About Them

Ted Kaptchuk, a Harvard Medical School professor of medicine, is the director of the Program in Placebo Studies at the Beth Israel Deaconess Medical Center. In a recent episode of the NPR’s “Hidden Brain” podcast, Kaptchuk recounts similar results when testing the placebo effect.

However, his research added a new twist. Kaptchuk wanted to see what would happen if he used “radical honesty” to determine the potential of the placebo effect. Instead of tricking patients into believing they may receive an actual treatment instead of a placebo, Kaptchuk told his subjects they would receive a placebo. In other words, no actual drug would be administered to subjects, and they were all aware of that.

Surprisingly, he found that a placebo could still work. “Hidden Brain” host Shankar Vedantam talked to Linda Bonanno, who participated in Kaptchuk’s study. Bonanno explained that Kaptchuk gave her a placebo to treat her irritable bowel syndrome, and it eased the agonizing pain she had been living with for years. The pain did not return until Kaptchuk stopped “prescribing” the placebo. For Bonanno, what seemed to help the most was the trusting relationship she had with Kaptchuk. The warmth and caring of her health care provider may have been enough to mitigate her pain.

Placebo Relief Doesn’t Mean the Pain Wasn’t Real

As we know, pain isn’t only a physical experience. It is a complex emotional experience that has psychological, social, and spiritual elements. If a doctor’s empathy, warmth, listening, and caring can ease a patient’s pain, that shouldn’t call into question whether the patient’s pain was real. It simply makes the case that a trusting relationship with a health care provider is as important for successful treatment as the medication or procedure itself.

Lynn R. Webster, MD, is a vice president of scientific affairs for PRA Health Sciences and consults with the pharmaceutical industry. He is author of the award-winning book, “The Painful Truth,” and co-producer of the documentary, “It Hurts Until You Die.”

You can find him on Twitter: @LynnRWebsterMD.