The power of the placebo effect

[Guest guest]

The power of the placebo effect

* 20 August 2008

* NewScientist.com news service

*

IT SEEMED like a good idea until I saw the electrodes. Dr Luana

Colloca's white coat offered scant reassurance. " Do you mind receiving

a series of electric shocks? " she asked.

I

could hardly say no - after all, this was why I was here. Colloca's

colleague, Fabrizio Benedetti of the University of Turin in Italy, had

invited me to come and experience their placebo research first hand.

Colloca strapped an electrode to my forearm and sat me in a reclining

chair in front of a computer screen. " Try to relax, " she said.

First,

we established my pain scale by determining the mildest current I could

feel, and the maximum amount I could bear. Then Colloca told me that,

before I got another shock, a red or a green light would appear on the

computer screen.

A

green light meant I would receive a mild shock. A red light meant the

shock would be more severe, like the jolt you get from an electric

fence. All I had to do was rate the pain on a scale of 1 to 10, mild to

severe.

Conditioned

After

15 minutes - and what seemed like hundreds of shocks - the experiment

ended with a series of mild shocks. Or so I thought, until Colloca told

me that the last series of shocks were all severe.

I

had felt the electric fence jolts as a series of gentle taps on the arm

because my brain had been conditioned to anticipate low pain whenever

it saw a green light - an example of the placebo effect.

Benedetti

watched the procedure with a smile on his face. He was not sure his

team could induce a placebo response in me if I knew I was about to be

deceived. As it turns out, I succumbed, hook, line and sinker.

Such

is the power of placebo. This was once thought to be a simple affair,

involving little more than the power of positive thinking. Make people

believe they are receiving good medical care - with anything from a

sugar pill to a kindly manner - and in many cases they begin to feel

better without any further medical intervention.

However,

Benedetti and others are now claiming that the true nature of placebo

is far more complex. The placebo effect, it turns out, can lead us on a

merry dance. Drug trials, Benedetti says, are particularly problematic.

" An ineffective drug can be better than a placebo in a standard trial, "

says Benedetti.

Taken aback

The

opposite can also be true, as Ted Kaptchuk of Harvard Medical School in

Boston points out. " Often, an active drug is not better than placebo in

a standard trial, even when we can be confident that the active drug

does work, " he says.

Some

researchers are so taken aback by the results of their studies that

they are calling for the very term " placebo " to be scrapped. Others

suggest the latest findings undermine the very foundations of

evidence-based medicine. " Placebo is ruining the credibility of

medicine, " Benedetti says.

“The findings threaten the very credibility of modern medicineâ€

How

did it come to this? After all, the foundation of evidence-based

medicine, the clinical trial, is meant to rule out the placebo effect.

If

you're testing a drug such as a new painkiller, it's supposed to work

like this. First, you recruit the test subjects. Then you randomly

assign each person to one of two groups to ensure both groups are

alike. One group gets the painkiller, the other gets a dummy treatment.

Then, you might think, all you have to do is compare the two groups.

Trials on trial

It's

not that simple, though, because this is where the placebo problem

kicks in. If people getting an experimental painkiller expect it to

work, it will work to some extent - just as seeing a green light

reduced the pain I felt when shocked. If the control group know they're

getting a dummy pill whereas the other group know they're getting the

" real " drug, the experimental painkiller might appear to work better

than the dummy when in fact the difference between the groups is

entirely due to the placebo effect.

So

it's crucial not to tell the subjects what they are getting. Those

running the trial should not know either, so they cannot give anything

away, creating the gold standard of clinical trials, the double-blind

randomised controlled trial. This does not eliminate the placebo

effect, but should make it equal in both groups. According to

conventional wisdom, in a double-blind trial any " extra " effect in the

group given the real drug must be entirely down to the drug's physical

effect.

Benedetti,

however, has shown this is not necessarily true. His early work in this

area involved an existing painkiller called a CCK-antagonist. First, he

performed a standard double-blind randomised controlled trial. As you

would expect, the CCK-antagonist performed better than the placebo.

Standard interpretation: the CCK-antagonist is an effective painkiller.

Mind boggling

Now comes the mind-boggling part. When Benedetti gave the same drug to

volunteers without telling them what he was doing, it had no effect.

" If it were a real painkiller, we should expect no difference compared

to the routine overt administration, " he says. " What we found is that

the covert CCK-antagonist was completely ineffective in relieving pain. "

“If you don't know you have been given the painkiller, it has no effectâ€

Benedetti's

team has since shown that the combination of a patient's expectation

and the administration of the CCK-antagonist stimulates the production

of natural painkilling endorphins. It has been known since 1978 that

the placebo effect alone can relieve pain in this way. What Benedetti

has uncovered, however, is a far more complex interaction between a

drug and the placebo effect. His work suggests the CCK-antagonist is

not actually a painkiller in the conventional sense, more of a " placebo

amplifier " - and the same might be true of many other drugs.

" We

can never be sure about the real action of a drug, " says Benedetti.

" The very act of administering a drug activates a complex cascade of

biochemical events in the patient's brain. " A drug may interact with

these expectation-activated molecules, confounding the interpretation

of results.

This

could be true of some rather famous - and profitable - substances.

Benedetti has found that diazepam, for instance, doesn't reduce anxiety

in patients after an operation unless they know they are taking it. The

placebo effect is required in order for it to be effective. It's not

yet clear if this is also true of diazepam's other effects.

Great expectations

Even

with drugs that do have direct effects independently of patients'

expectations, the strength of these effects can be influenced by

expectation. If you don't tell people that they are getting an

injection of morphine, you have to inject at least 12 milligrams to get

a painkilling effect, whereas if you tell them, far lower doses can

make a difference.

Such

findings prove that we need to change the way trials are done,

Benedetti says. He thinks this is true of all placebo-controlled

trials, not just those involving conditions in which placebos can have

a strong effect, such as on pain.

The

alternatives include Benedetti's hidden treatment approach, where

participants are not always told when they are getting a drug, and the

" balanced placebo design " , in which you tell some people they got the

drug when they actually got the placebo and vice versa.

These

approaches are a great way of teasing apart true drug effects from

placebo, says lin of the US National Institutes of Health.

The problem is the degree of deception involved. " There is no way we're

going to be able to do clinical trials that involve deceiving patients

about what they are getting. I don't see that as a useable method, " he

says.

Informed consent

Colloca

disagrees. With hidden treatments, a patient might not know when the

drug infusion starts and ends, but they know that a drug will be given.

Therefore, she argues, there is full informed consent.

For

Kaptchuk, the issue is not just teasing apart drug effects from

placebo; it's the very notion that only treatments that are better than

placebo have any value. " It's never enough to just test against

placebo, " he says.

In a study published in April, his team compared three " treatments " for

irritable

bowel syndrome. One group got sham acupuncture and lots of attention.

The second group also got sham acupuncture, but no attention. A third

group of patients just got left on a " waiting list " .

Patients

in both sham acupuncture groups did better than those kept on the fake

waiting list. However, the group who had felt listened to and consulted

about their symptoms, feelings and treatments reported an improvement

that was equivalent to the " positive " trial results for drugs commonly

used to treat irritable bowel syndrome - drugs that are supposed to

have been proved better than placebo. Does this finding mean the drugs

should not have been approved, even though patients are better off with

either drugs or placebo than no treatment at all?

Word of mouth

This

study shows how a placebo can be boosted by combining factors that

contribute to its effect. And all sorts of factors can be involved.

Even word of mouth can help, Colloca says, such as learning that a

treatment has worked for others.

Conditioning

through repetition, as in the process I went through, is another

important factor. " Many trials use the repeated administration of

drugs, thus triggering learning mechanisms that lead to increased

placebo responsiveness, " Benedetti says.

This

is yet another reason to change clinical trials, he argues. It could

explain, for instance, why the placebo effect appears to be growing

stronger in clinical trials, causing problems for drug companies

attempting to prove their products are better than placebo.

Harnessing the power

The

issue isn't just about disentangling the effect of a placebo from that

of a drug. It's also about harnessing its power. For instance, Colloca

thinks the conditioning effect could be exploited to reduce doses of painkilling

drugs with potentially dangerous side effects.

The

problem with trying to exploit the placebo effect, says , is that

the term means very different things to different people. Many doctors

don't believe placebo has any effect other than to placate those

demanding some kind of treatment. " People say it's noise, or nothing,

or something just to please the patient, " says.

Those

involved with clinical trials, by contrast, tend to overestimate the

power of placebo. Consider the way trials are carried out. If the

people in the control group - the ones who get the placebo - get

better, it's almost always attributed to the placebo effect. But in

fact, there are many other reasons why those in the control group can

improve. Many conditions get better all by themselves given enough

time, for instance. To distinguish between the apparent effect of a

placebo and its actual effect, you have to compare a placebo treatment

with no treatment at all, as in the irritable bowel study.

Contextual healing

In

an article published earlier this year, and Kaptchuk argue that

the very notion of placebo has became so laden with baggage that it

should be ditched. Instead, they suggest that doctors and researchers

should think in terms of " contextual healing " - the aspect of healing

that is produced, activated or enhanced by the context of the clinical

encounter, rather than by the specific treatment given.

Whatever

you call it, trying to harness the placebo effect raises tricky ethical

issues: can doctors exploit it without lying to patients? Maybe. If my

shocking experience is anything to go by, knowing you are getting a

placebo does not necessarily stop it working.

" It's

a complicated issue, but one that deserves a lot more attention, "

says. " Finding ethically appropriate ways to tap the use of

placebo in clinical practice is where the field needs to be moving. "

Doctors,

however, are not hanging around waiting for the results of rigorous

studies that show whether or not placebos can be used effectively and

ethically for specific conditions. Surveys suggest around half of

doctors regularly prescribe a placebo and that a substantial minority

do so not just to get patients out of the consulting room but because

they believe placebos produce objective benefits.

Disservice

Are

they doing their patients a disservice? In 2001 Asbjorn Hróbjartsson of

the Nordic Cochrane Institute in Stockholm, Sweden, did a meta-analysis

of 130 clinical trials that compared the placebo group with a

no-treatment group, to reveal the " true " placebo effect. The studies

involved around 7500 patients suffering from about 40 different

conditions ranging from alcohol dependence to Parkinson's disease. The

meta-analysis concluded that, overall, placebos have no significant

effects. Two years later the team published a follow-up study with data

from 11,737 patients, and Hróbjartsson will publish another in the next

few months. " The results are similar again, " he says. Placebos are

overrated and largely ineffective, Hróbjartsson concludes, and doctors

should stop using them.

However,

if you consider only studies whose outcomes are measured by patients'

reports, such as how much pain they feel, placebos do appear to have a

small but significant effect, he says. In other words, the placebo

effect can make you feel better - even if you aren't actually better.

Does

this mean it's not a real effect? Was I deluded when I reported feeling

severe shocks as mild ones? " What does 'real' mean in this situation? "

responds Hróbjartsson. " My concern is not so much whether effects of

placebo are real or not, but whether there is evidence for clinically

relevant effects. "

Giving

patients plenty of TLC is where placebo intervention should end, he

thinks. " Most of us working in the field think that's just another way

of saying 'be a good doctor'. "

Measurable effects

Colloca

and Benedetti think there is scope for doing much better than that. " We

already know that placebos don't work everywhere, therefore the small

magnitude of the placebo effect in that meta-analysis is not surprising

at all, " Benedetti says. " It is as if you wanted to test the effects of

morphine in gut disorders, pain, heart diseases, marital discord,

depression and such like. If you average the effects of morphine across

all these conditions, the outcome would be that overall morphine is

ineffective. "

The

other reason not to take the meta-analyses too seriously is the

evidence that placebo can have measurable biochemical effects. The

release of painkilling endorphins, for instance, has been confirmed by

showing that drugs which block endorphins also block the placebo effect

on pain, and by brain scans that " light up " endorphins. Placebos have

also been shown to trigger the release of dopamine in people with

Parkinson's disease. In 2004, Benedetti demonstrated that, after

conditioning, individual neurons in the brains of Parkinson's patients

respond to a salt solution in the same way as they do to a genuine drug

designed to relieve tremors.

When it comes to the placebo effect, it seems, nothing is simple. We still have

a lot to learn about this elusive phenomenon.

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