THE PLACEBO EFFECT:Who’s being deceived?

“It has brought me great comfort to know that I could, in some way, help people feel better,” said Leo Sternbach, inventor of the antianxiety drug diazepam. Sternbach certainly did that—in spades. What is only just starting to emerge is just how much Leo Sternbach’s drug depends on people helping themselves to feel better.

From 1969 to 1982, diazepam, marketed as Valium, was the top-selling pharmaceutical in the United States. At the height of its powers, Sternbach’s employer, the pharmaceutical giant Hoffman LaRoche, sold 2.3 billion of the little yellow pills marked with a V. That was in 1978, and the drug had already been part of popular culture for more than a decade; “Mother’s Little
Helper” by the Rolling Stones, released in 1966, is a satire on domestic abuse of Valium. In the same year that song was released, the drug gained a starring role in the cult novel Valley of the Dolls; diazepam “dolls” were the lead characters’ means of getting through the strains of life in New York. Diazepam
is now, according to the World Health Organization, a “core medicine,”
essential for any nation’s pharmaceutical store. The strange thing is, it doesn’t work unless you know you’re taking it.In 2003 a paper in Prevention and Treatment reported that diazepam had no effect on anxiety when it was administered without the patient’s knowledge.
In an extraordinary experiment, researchers in Turin split a group of trial subjects into two. One half were given diazepam by a doctor who told them they were being given a powerful antianxiety drug. The other group were hooked up to an automatic infusion machine and given the same dose of diazepam—but with no one in the room and no way of telling they had received the drug. Two hours later, the people in the first group reported a significant reduction in their levels of anxiety. The second group reported no change. “Anxiety reduction after the open diazepam administration was a placebo effect,” the researchers suggested.
A placebo is a medical procedure that has no medicine in it. A sugar pill, or a spoonful of sugar water, a saline drip—or anything, really. A parade of doctors in white coats coming to your bedside to offer reassurances can be enough to trigger the effect. The power of placebo comes from the deceptive message that comes with it. You are told (or you sense) this procedure or ritual
will have an effect on your body or state of mind, and if you genuinely believe it, taking the pill or the drink, or in some cases just seeing the doctor,
will produce exactly that effect. Witch doctors, shamans, and other purveyors
of the magical arts are known to deal in placebos. When they carry out a sham ritual to cure a paying believer, that cure can work wonders. The same might be said of televangelists. And Western medical doctors, too; research
has shown that white coats and stethoscopes can produce surprisingly
effective placebo effects—as can a good bedside manner. Doctors know that if patients feel they are getting a suitable treatment, the treatment is enormously more effective.
In one sense there’s an easy explanation for all this: the chemistry of the drug is being augmented by chemicals secreted in the brain—the effect of what Fabrizio Benedetti, the leader of the Turin group, calls “the molecules of hope.” The difficult side of the new experimental evidence is that, where we once thought we had a handle on the placebo effect, it is now becoming clear that we don’t.
In medicine, we have long been accustomed to accounting for placebo. Modern scientific medicine was constructed on the notion of the randomized
double-blind, placebo-controlled trial, where drugs have to perform better than a dummy pill or inert saline injection. Now, though, things aren’t so clear. Some analyses of the data suggest that the placebo effect is largely a myth. What’s more, the medical system was set up assuming not only the existence
of placebo but also that its effects can be separated out from the chemistry of the drugs being tested. It seems that assumption was false, and the edifice of the pharmaceutical trial may have to be dismantled. No wonder
a recent National Institutes of Health conference declared placebo research
an “urgent priority.”
Benjamin Franklin, the father of rational, “evidence-based” medicine, must be turning in his grave. In 1785 Franklin headed a commission to investigate
the claims of “animal magnetism.” The Austrian physician Franz Anton Mesmer had entranced (hence mesmerized) Paris with his claims that magnets and glasses of water could be used to healing effect. Louis XVI wanted to know whether these claims stood up, and some of the greatest scientists
in Europe were commissioned to find out the truth. Their tests were the first scientific inquiries to use blindfolds that prevented the subjects from biasing the results—the original “blinded” trials really were just that. The commission’s report came out in 1785. Any healing effect is “really due to the power of the imagination,” it said.
Interestingly, 1785 was also the year the term placebo appeared for the first time in a medical dictionary. It was the expanded second edition of George Motherby’s New Medical Dictionary, and the word, to Motherby, meant “a common place method or medicine.” Though that is not particularly
damning at first glance, it was most likely a negative label, meaning the medicine was trivial, or unimpressive, because the word already had a negative
connotation. Placebo, which means “I will please,” had come to signify insincerity, flattery, and profiteering since medieval times, when greedy churchmen would take mourners’ money to sing Psalm 116 at funerals. The psalm begins, Placebo Domino in regione vivorum (I will please the Lord in the land of the living). By 1811, that negative connotation was well established;
Robert Hooper published his New Medical Dictionary with an entry for placebo that read: “an epithet given to any medicine adapted more to please than benefit the patient.” Little did the clinicians of Hooper’s day know that a placebo might benefit patients just as much as it pleased them.
As often happens, that knowledge had been gained and lost before. Itwas certainly known to the ancient Greeks. In 380 BCE Plato wrote Charmides, in which the Thracian king Zamolxis tells Socrates that the great error of the physicians of his day was the separation of the soul from the body. Despite doctors’ best efforts, curing the body is impossible without flattering the mind, Zamolxis says.
If the head and body are to be well, you must begin by curing the soul; that is the first thing. And the cure, my dear youth, has to be effected by the use of certain charms, and these charms are fair words; and by them temperance is implanted in the soul, and where temperance is, there health is speedily imparted, not only to the head, but to the whole body.
Plato was right; words are powerful. If you communicate that you are doing something—if you utter what the French psychiatrist Patrick Lemoine calls the incantation—it can work wonders.
An example of an incantation, drawn from Lemoine’s experience, might be, “I’m going to prescribe you some magnesium that will treat your anxiety.”
Magnesium isn’t a licensed cure for anxiety, but magnesium deficiency produces symptoms similar to anxiety; in a bizarre nod to the principles of vaccination, European clinicians often prescribe magnesium for anxiety, Lemoine says. And not only are his patients satisfied; they get better—and relapse if the treatment is interrupted. Nearly 250 years into the era of evidence-based medicine, the incantation is still a powerful force.
A 1954 paper in the Lancet declared that the placebo effect is only useful in treating “some unintelligent or inadequate patients”; that seems almost laughable now. According to Ann Helm of the Oregon Health Sciences University,
somewhere between 35 and 45 percent of all medical prescriptions are placebos. That estimate was made in 1985. In 2003 a survey of nearly eight hundred Danish clinicians, published in Evaluation and the Health Professions, found that almost half prescribed a placebo ten or more times per year. A 2004 study of Israeli doctors, published in the British Medical Journal, determined that 60 percent had prescribed placebos, more than half of them doing it once a month or more. Of the Israeli doctors who prescribed placebos, 94 percent said they found them to be an effective means of treatment.
These are not pure placebos. The doctor can’t send you to a pharmacy to get a sugar pill; after all, you might read the prescription, breaking the spell. No, doctors routinely prescribe medications that have a tiny bit of something useful in them—but its licensed use is not to treat what is ailing
you.
Despite being so commonplace, it is a practice that splits the medical community. It is seen by some as unethical—dangerous, even. And not only is it practicing deception on a patient; it also forces other medical professionals
to act as accomplices to the placebo-prescribing physician. After all, what do you do with your prescription? You take it along to the pharmacist. Your pharmacist then—willingly or reluctantly—tends to play along. An article
in the Journal of the American Pharmaceutical Association even provides a script for their role. Realizing that a doctor has prescribed a placebo, the pharmacist should deliver the medication with these words: “Generally, a larger dose is used for most patients, but your doctor believes that you’ll benefit from this dose.” The pharmacist might then advise you of some possible
side effects. Or not.
If this shocks you, you can be comforted by the fact that no one is out to fleece you. Neither your doctor nor your pharmacist is getting away with some scam. They are simply doing what they can for your health. They know that you have faith in their abilities; otherwise you wouldn’t have come for the consultation. And their abilities include the knowledge that placebos work—though no one knows exactly why. You have faith in your doctor, and that faith can make you well. The nature of placebo simply means that they have to practice a tiny little deception to help it happen. Is that wrong? There is no consensus on the answer to that question.

placebo effect turns into something like medicine’s equivalent
of dark energy: a repeatable, measurable phenomenon that could still turn out to be an illusion. A broad analysis of the best clinical data says itmight not exist—at least not in significant amounts. But even with full knowledge of what was going on, I found myself powerless to resist the placebo effect. It is not simply about deception, a sugar pill being perceived as an efficacious cure. We can create it with mind tricks, brain implants, or chemical cocktails, and we can see it working on brain scans. Though there is scientific evidence that the placebo effect is a myth, or that we have misled
ourselves about what is going on, there is perhaps more evidence pointing
the other way.
Clinical studies show you can cut morphine use by half—over the long term—if you just make sure the patient knows you’re giving it. Telling patients
they are being injected with a painkiller—while injecting them with saline—is as effective as injecting 6–8 mg of morphine. Studies at the U.S. National Institutes of Health found that cocaine abusers in a recovery clinic can get by on half doses too—as long as they know they’re getting something.
Expectation is a powerful thing.
In fact, we’re back at diazepam. On its own—administered covertly— it does nothing. It’s about diazepam plus the expectation chemicals that anticipation of a dose produces; the expectation chemicals are quite good by themselves, but with diazepam added to the mix, you’re really in for a treat.
These expectation chemicals have a dark side too, though. Benedetti and Colloca have already started to put warnings out that placebo research could be exploited for questionable purposes. We are only wading in the shallows of the science of placebo, and it’s already clear that this, like genetics, could be a murky pond. “There are...potentially negative outcomes of placebo research,” they wrote in a Nature Reviews article in 2005. “If future research leads to a full understanding of the mechanisms of suggestibility of the human
mind, an ethical debate will then be required.”

That is especially true in light of the nocebo effect, where deliberately inducing anxiety can make pain worse. Benedetti is one of the few people who have been able to study this phenomenon; if researching placebo poses an ethical dilemma for doctors, nocebo doubles it.
Nocebo means “I shall harm.” In a nocebo study, the harmless medicine is delivered with a phrase such as, “This really will make you feel much worse.” It could prove an extremely valuable tool, and Benedetti is already using his nocebo experience to overcome the limitations of current painkillers, but what kind of ethics committee gives approval to a scheme designed to make patients more uncomfortable through lying to them? None. Which is why Benedetti has to rely on paid volunteers who are willing
to suffer. It started in 1997, when he and his colleagues were testing the idea that anxiety makes pain worse. They injected a group of patients who were recovering
from painful surgery with proglumide, a chemical that blocks the action of cholecystokinin (CCK), a neurotransmitter chemical associated with anxiety. When they gave these patients an inert pill and told them it would make them feel worse, it simply didn’t. It was impossible to induce the nocebo effect when CCK was blocked.
It was a good result, but scientifically lacking—there was no control group that didn’t get the CCK-blocking proglumide and thus did feel the additional
discomfort that anxiety can bring. Unfortunately (for Benedetti, if not for the patients), there was no ethical approval for a control group.
It took Benedetti nearly ten years to get approval and volunteers for a follow-up study. At the end of 2006 his team published a paper showing that we—or rather our neurotransmitters—can turn anxiety into pain. The volunteers
underwent a routine involving a tourniquet, some injections, and a verbal warning that their pain would increase while Benedetti’s team took blood samples and asked them how they rated their pain. The blood samples
gave the researchers what they were looking for: proof that proglumide stops us from turning chemical signals of anxiety into exaggerated pain. Proglumide is the only CCK blocker licensed for human use, but it is not particularly effective. When researchers manage to develop something better,
they will have a drug that can be mixed with narcotics to alleviate physiological
and psychological pain simultaneously. Though nocebo seems somewhat dark—one can imagine it being exploited to produce extra anxiety
and thus pain in interrogations, for example—at least it has positive applications
too.



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