Patients in the placebo arthroscopy group were given anaesthetics and a small incision was made in their knees, but there was no arthroscope, no repairing of damaged cartilage, and no cleaning out of loose fragments of bone.

To keep the patients ignorant about which group they were in, the doctors and nurses talked through a real procedure even if they were performing the placebo procedure.

The fake surgery worked as well as the “real” surgery. A review of over 50 placebo-controlled surgery trials found that placebo surgery was as good as the real surgery in more than half the trials.

Honest placebos

A placebo can work even if a patient does not believe it is a “real” treatment.

In the first of the studies of open-label placebos (placebos that patients know are placebos) I know of, two Baltimore doctors by the names of Lee Park and Uno Covi gave open-label placebos to 15 neurotic patients. They presented the placebo pills to the patients and said: “Many people with your kind of condition have been helped by what are sometimes called sugar pills and we feel that a so-called sugar pill may help you, too.”

The patients took the placebos, and many of them got better after having the placebo – even though they knew it was a placebo. However, the patients were neurotic and a bit paranoid so they didn’t believe the doctors. After the placebo made them better, they thought the doctors had lied and actually given them the real drug.

More recently, several higher-quality studies confirm that open-label placebos can work. These “honest” placebos may work because patients have a conditioned response to an encounter with their doctor. Just like an arachnophobe’s body can react negatively to a spider even if they know it’s not poisonous, someone can react positively to treatment from a doctor even if they know the doctor is giving them a sugar pill.

The history of learning how placebos work

An early study investigating the inner pharmacology of placebo mechanisms is Jon Levine and Newton Gordon’s 1978 study of 51 patients who had impacted molars extracted. All 51 patients had received a painkiller called mepivacaine for the surgical procedure. Then, at three and four hours after the surgery, the patients were given either morphine, a placebo or naloxone. The patients didn’t know which one they had received.

Naloxone is an opioid antagonist, which means that it stops drugs such as morphine and endorphins from producing their effects. It literally blocks the cell receptors, so it stops morphine (or endorphins) from docking onto those receptors. It’s used to treat morphine overdose.

The researchers found that naloxone blocked the painkilling effect of placebos. This shows that placebos cause the release of painkilling endorphins. Since then, many experiments have confirmed these results. Hundreds of others have shown that placebo treatments affect the brain and body in several ways.

The main mechanisms by which placebos are believed to work are expectancy and conditioning.

In a comprehensive study published in 1999 of conditioning and expectancy mechanisms, Martina Amanzio and Fabrizio Benedetti divided 229 participants into 12 groups. The groups were given a variety of drugs, were conditioned in a number of ways and were given different messages (to induce high or low expectancy). The study found that placebo effects were caused by both expectancy and conditioning.

Despite the progress, some researchers argue – and I agree – that there is something mysterious about how placebos work. In a personal communication, Dan Moerman, a medical anthropologist and ethnobotanist, explained it better than I can:

We know from all the MRI people that it’s easy enough to see what happens inside to the amygdala, or whatever other bit might be involved, but what moved the amygdala, well, that takes some work.

History of placebo ethics

The accepted view in clinical practice is that placebos are not ethical because they require deception. This view has not yet fully accounted for the evidence that we don’t need deception for placebos to work.

The history of the ethics of placebo controls is more complex. Now that we have many effective treatments, we can compare new treatments with proven therapies. Why would a patient agree to enrol in a trial comparing a new treatment with a placebo when they could enrol in a trial of a new treatment compared with a proven one?

Doctors who take part in such trials may be violating their ethical duty to help and avoid harm. The World Medical Association initially banned placebo-controlled trials where a proven therapy was available. Yet in 2010, they reversed this position and said we sometimes needed placebo-controlled trials, even if there is a proven therapy. They claimed there were “scientific” reasons for doing this.

These so-called scientific reasons have been presented using obscure (to most people) concepts such as “assay sensitivity” and “absolute effect size”. In plain English, they boil down to two (mistaken) claims:

1. They say we can only trust placebo controls. This was true in the past. Historically, treatments like bloodletting and cocaine were used to treat a number of ailments yet were often harmful. Say we’d done a trial comparing bloodletting with cocaine for anxiety, and it turned out bloodletting was better than cocaine. We couldn’t infer that bloodletting was effective: it could have been worse than a placebo or doing nothing. In these historical cases, it would have been better to compare those treatments against a placebo. But now, we have effective treatments that can be used as benchmarks. So if a new drug came along for treating anxiety, we could compare it with the proven effective treatment. If the new treatment proved to be at least as good as the old one, we could say it is effective.

2. They say only placebo controls provide a constant baseline. This is based on the mistaken view that placebo treatments are “inert” and therefore have constant, invariable effects. This, too, is mistaken. In a systematic review of placebo pills in ulcer trials, the placebo response ranged from 0% (not having any effect) to 100% (complete cure).

As the arguments supporting placebo-controlled trials are being questioned, there is now a movement urging the World Medical Association needs to do another U-turn, back to its original position.

Whither placebo?

For centuries, the word “placebo” was closely linked to deception and pleasing people. Recent studies of open-label placebos show that they need not be deceptive to work. Contrariwise, studies of placebos show that they are not inert or invariable and the basis for the current World Medical Association position has been undermined. The recent history of placebos seems to pave the way for more placebo treatments in clinical practice and fewer in clinical trials.

I acknowledge the James Lind Library, the writing of Ted Kaptchuk, Jeffrey Aronson, and the mentorship of Dan Moerman.

Jeremy Howick, Director of the Oxford Empathy Programme, University of Oxford

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Image: "Headache Pills" by sacks08 is licensed under CC BY 2.0