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Not All Placebos Are Born Equal

From New Scientist (December 11, 2010)

Some drugs may make it to market purely because they have noticeable side effects

Are we wasting billions on worthless drugs because the complex placebo effect is undermining clinical trials?

PLACEBO comes from the Latin for "I shall please". And for people suffering from conditions such as Parkinson's disease, asthma, irritable bowel syndrome, arthritis and depression, placebos are very pleasing. After all, wouldn’t everyone want a treatment?- be it sugar pill "drug" or sham acupuncture?- that made them feel better without producing the side effects associated with active medications? Some side effects in patient information leaflets are scary indeed.

Placebos are, however, less good news for clinical researchers, drug developers and the like, who need to be able to disentangle the physical actions of "real" interventions from the effects produced by the power of suggestion. One of the biggest disease groups caught up in the complexities of the placebo is mental illness. This affects nearly 20 per cent of us at some stage in our lives and fuels a $19-billion drugs industry.

I have spent the past few years making waves with papers and books about placebos and their role in the development and action of psychiatric drugs. After extracting reams of unpublished drug trial data from the major pharmaceutical companies (via the US Food and Drug Administration, and freedom of information legislation), I have come up with a bold-sounding theory: the placebo effect may account for all of the benefits of antidepressants.

Proving this will be extremely difficult, since big pharma naturally has a vested interest in drugs working as stated, so I’m going to come at the problem from a variety of directions. One is to use more effective placebos in double-blind clinical trials. Another is to give cheap, simple questionnaires to drug-trial participants.

First let’s look at how placebos are used in clinical trials. Before a new drug is approved for marketing, it has to be tested for safety and efficacy. The gold standard for establishing efficacy is the randomised clinical trial (RCT), in which patients with a particular disorder are randomly assigned to receive either the active drug or a placebo?- a dummy pill with no active ingredients. The medication is approved only if its effect in treating the disease is reliably superior to that of a placebo.

A critical aspect of the RCT is that it should be double blind, meaning that neither doctor nor patient knows whether the patient is receiving drug or placebo. Blinding is important because of the need to control for the effect of expectancy - the belief that one is receiving treatment - since it seems that a person’s belief that they will get better is often enough to make them feel better. The current thinking by most doctors is that if patients know they have been given a placebo, the placebo effect would disappear; conversely, patients would show an especially large placebo effect if they were certain they had been given the drug being trialled.

The double-blind RCT is supposed to control for these responses, so we know that any differences are due to the chemical effects of the medication on the patient’s disorder. The question is whether RCTs are up to the job of keeping patients blind.

Studying clinical trials of antidepressants shows they are not. Many patients and their doctors are able to work out whether the patient has been given the real antidepressant or the placebo. In one of the few clinical trials in which patients were asked to guess what group they were in, 78 per cent were able to do so accurately. The doctors were even better: their accuracy rate was a whopping 87 per cent. If patients and doctors "break blind", then differences between drug and placebo in clinical trials may be illusions.

So how are patients and doctors breaking blind? One big possibility is that patients on the real drug are tipped off by the side effects produced. Researchers at Syracuse University in New York state reported a correlation of 0.85 between patients’ reports of side effects and the amount of improvement they experienced. A perfect correlation would be 1.00, so 0.85 is huge. I call it the "enhanced placebo" effect: where patients notice side effects, realise that they have been given the real drug and therefore feel an improvement.

The problem of breaking blind on the basis of side effects may not be limited to antidepressants, but we just don’t know how widespread it is because patients are rarely asked to guess what they have been given in clinical trials. But the few studies there have been show they are often able to do so accurately.

I need to inject a word of caution: please don’t get me wrong, I am sure most prescription drugs are more effective than placebos. But when the differences between drug and placebo are small, and the drugs produce easily noticeable side effects, it is possible that there may be no real drug effect. We may be fooling ourselves with clinical trial methods that don’t do what they are supposed to - and wasting billions on worthless medications.

What can we do? There are some research designs aimed at getting around the problem of breaking blind. One of them involves using an "active" placebo, a real drug that does not affect the condition being studied but which produces real side effects. For example, atropine has been used in a few clinical trials of antidepressants. Atropine is used in the treatment of many conditions, including irritable bowel syndrome, peptic ulcers, and to control symptoms of Parkinson’s disease. It is not an antidepressant, but it has some of the same side effects, including a dry mouth, insomnia, headaches and drowsiness.

Of the nine antidepressant trials in which atropine was used as an active placebo, researchers in two reported that the drug being tested showed significant benefits. In the other seven, no significant difference was found. Unfortunately, these studies were done decades ago on the first generation of antidepressants. The newer drugs have only been compared with inert placebos that do not produce side effects?- at least not because of their chemical composition. Placebos can produce side effects psychologically, though these are generally much fewer than those induced by active drugs.

Active placebos might seem like a major alteration of clinical trial methods, but the change is less radical than it seems. Placebos are necessarily composed of some substance, and as Beatrice Golomb at the University of California, San Diego, School of Medicine recently pointed out, no substance is truly inert. When Golomb researched the placebos used in clinical trials, she discovered that the ingredients were usually not disclosed.

Where they were revealed, she found that sometimes they were substances capable of distorting the clinical trial results. In one study, lactose was used as a placebo to test a weight-promoting drug for cancer patients. The problem is that lactose intolerance is common in cancer patients. So the lactose in the placebo might have induced gastrointestinal problems that enhanced weight loss and made the drug look better than it was.

My active-placebo proposal is that the ingredients of placebos be chosen to mimic the side effects of the drug being tested and, as Golomb recommended, they should be disclosed when clinical trials are published.

Active placebos alone may not be enough to solve the problem of breaking blind, however. In the atropine trials, the real drugs produced more side effects than the active placebo, and patients were more accurate in guessing the drug they were on than would be predicted by chance. So there could be spurious side effects even when active placebos are used. Still, given the substantial sums being spent on medications that might not have real benefits but produce unwanted side effects, funding studies with active placebos might be money well spent?- at least for patients and taxpayers.

Meanwhile, there is one easy thing we can do: assess the level to which patients are breaking blind in antidepressant trials that use ordinary placebos. All we have to do is ask patients to guess if they have been given the real drug or the placebo?- it would cost next to nothing. Why not make it a requirement for licensing new drugs? And by finding out how many clinical trials involve patients breaking blind, we could end up making a strong case for clinical trials using active placebos. n


Irving Kirsch is an emeritus professor of psychology at the University of Hull, UK. His latest book is The Emperor’s New Drugs, published by Bodley Head last year. He has recently been part of a team researching placebos without deception, with the results due out soon in PLoS One


Posted: December 2010