A manifesto for the next revolution in nocebo and placebo studies

“When he had asked me if I knew the cure for headache, I somehow contrived to answer that I knew.

Then what is it? he asked.

So I told him that the thing itself was a certain leaf, but there was a charm to go with the remedy; and if one uttered the charm at the moment of its application, the remedy made one perfectly well; but without the charm there was no efficacy in the leaf.”
—Plato, Charmides

“Three factors are of major importance in the suffering of badly wounded men [during World War II]: pain; mental distress; and thirst. Therapy has been almost entirely directed to pain, and this usually limited to the administration of morphine in large dosage.”
—Henry Knowles Beecher, “The Relief of Suffering”

Cenobo and Bocepal

Insomnia is a serious chronic disease that affects many people. Treatment often involves sedatives, which have side effects ranging from dependence to overdose and death. A pharmaceutical company called Panycom developed a new drug called Cenobo to treat insomnia. Small trials suggested it worked better than existing sedatives and did not appear to be addictive. Panycom invested in a larger trial with over a thousand patients. The National Institutes of Health sponsored another large trial, also with a thousand patients. But before the trials were finished, it became clear that Cenobo caused harms ranging from headaches to nausea in half of the people in the trial. There were also seven reports of serious amnesia. The amnesia was rare, and it couldn’t be established whether Cenobo caused the amnesia or whether it would have happened anyway. Yet, because Cenobo seemed likely to play a role in the serious amnesia, Panycom compensated a number of those who suffered from it an undisclosed amount believed to be between 20 million and 30 million dollars in total. Panycom pulled Cenobo from the market and stopped making it.

Luckily for Panycom, the Cenobo disaster didn’t sink them because another drug they developed called Bocepal (for treating migraines) fared much better. Migraines are terrible, common, and often treated with drugs that can have serious side effects, including dependence. Like Cenobo, Bocepal showed early promise, so both Panycom and the National Institutes of Health sponsored large trials. Bocepal was a huge success. Not only was it cheap and effective for treating migraines, but the trials also found that the side effects of Bocepal were positive: it reduced other chronic and acute pain, mild depression, and mild anxiety by a small amount. At some of the medical centers that were part of the trial, more dramatic benefits were observed, including people completely coming off their strong pain and depression medications. The dramatic benefits were rare and could have occurred even without the drugs, but some people swore by Bocepal, and it became a blockbuster drug for treating migraines.

Then something strange happened. Some doctors still believed that Cenobo was an excellent treatment for insomnia. Not believing the reports of the serious side effects, they thought Cenobo was the best option for some of their patients. They were able to obtain Cenobo from a rogue pharmaceutical manufacturer in a developing country. When they gave Cenobo to patients, the doctors mentioned the possible harms but emphasized that in their experience, Cenobo was a sound treatment and that the benefits outweighed any harms.

A different set of doctors didn’t believe that Bocepal was any good. They said that it couldn’t work as well as it appeared to and that the fact it did so many things at once was suspicious. Instead of Bocepal, they prescribed more expensive and more potentially harmful treatments like diclofenac, which causes heart attacks in some people. When their patients asked them about Bocepal, these doctors said that Bocepal was okay but not nearly as strong as diclofenac.

Clearly, the doctors who prescribed Cenobo, and the doctors who didn’t prescribe Bocepal were acting unethically. Cenobo was harmful, and withholding Bocepal prevented benefits. In ethics-speak, causing harm violates the doctors’ duty of non-maleficence (to do no harm), while avoiding likely benefit violates the duty of beneficence (to help whenever they can).

As you may have suspected, “Bocepal” is an anagram of the word “placebo,” and “Cenobo” is an anagram of the word “nocebo.” Like Cenobo, nocebos are harmful, and like Bocepal, placebos are beneficial for many people. It follows that not prescribing placebos and allowing nocebo effects to thrive is unethical. This conclusion is an oversimplification because it ignores other relevant issues including (a) whether placebos require deception, (b) whether we can generate placebo effects without placebos, and (c) whether it is possible to avoid nocebo effects. These issues will be examined rigorously in the remainder of this book.

It is useful for the reader to keep the examples of Cenobo and Bocepal in mind. placebos are an ethical requirement and that nocebos need to be avoided more rigorously, things need to change. Currently, some well-known doctors consider placebos to be unethical. Asbjørn Hróbjartsson, who is the director of Cochrane Denmark (formerly the Nordic Cochrane Centre) wrote a paper titled “Clinical Placebo Interventions Are Unethical, Unnecessary, and Unprofessional.” Alain Braillon, a physician and an expert on public health, says that a placebo is “far from benign: it is disease-mongering.” In parallel, nocebo effects appear to be widespread. About half of the people in clinical trials who take placebos to report at least one negative side effect (a nocebo effect), and it appears that many of them can be avoided.

Jeremy Howick is a philosopher of science and clinical epidemiologist. He is the author of The Power of Placebos: How the Science of Placebos and Nocebos Can Improve Health Care.