When new drugs are put on the market, clinical trials determine whether they perform better than inactive pills known as "placebos". Research shows that over the last 25 years the difference in effectiveness between real drugs and these fake ones has narrowed - but more in the US than elsewhere. Are Americans really more susceptible to placebo effects, or is something else going on?
If you were a sick Londoner in the late 18th Century several treatment options were open to you. By no means the cheapest of these was to go along to a little shop on Leicester Square, hand over five guineas and receive a pair of pointy metal rods that would suck the disease from your body.
These instruments were called Perkins Tractors, after their American inventor Elisha Perkins, who claimed George Washington as a customer. They worked, it was said, because they were made of special alloys.
But in 1799 the renowned physician John Haygarth decided to test whether they really worked, and at the same time perform a scientific examination of "that faculty of the mind, that is denominated the Imagination". He organised a trial at a hospital in which five people suffering chronic rheumatism were treated with replica wooden tractors. "All five patients, except one, assured us that their pain was relieved," he reported. "One felt his knee warmer, and he could walk much better, as he shewed us with great satisfaction. One was easier for nine hours, and till he went to bed, when the pain returned. One had a tingling sensation for two hours."
When the "real" metal tractors were used on the second day, they had much the same effect as the fake ones. "Such is the wonderful force of the Imagination!" mused Haygarth.
The phenomenon of patients feeling better simply because they believe a treatment will help them has come to be known as the placebo effect (find out why at the bottom of the page). It comes into play most often when people are experiencing pain, fatigue, depression and nausea. Scans of patients taking a placebo show their brains switching on parts that can help control stress and pain.
When new drugs are being trialled in the US, the Food and Drug Administration (FDA) demands that the researchers factor in the placebo effect. They do this by engaging in controlled trials in which some participants are given the real drug and some are given a placebo - participants are generally not told whether their treatment contains the drug being tested or not.
The drug's effectiveness is then determined by subtracting the placebo response - the extent to which patients in the placebo group get better - from the drug response. Before allowing a drug to go on the market, the FDA demands that it has been shown to outperform a placebo by a significant margin.
It seems, though, that this is happening less and less, because the placebo response has been steadily strengthening. Tests reveal that some well-known drugs for depression and anxiety would struggle to pass their clinical trials if they were re-tested in 2015.
This trend has become a huge concern for the pharmaceutical industry. A slew of drugs have flopped at these final clinical trials, by which time drugs companies have typically spent more than $1bn in research and development.
No-one knows why the placebo response is rising but a fascinating new study in the journal Pain might help experts pin it down.
Drawing on data from 80 trials for drugs to treat neuropathic pain, the researchers led by Dr Jeffrey Mogil at McGill University in Montreal found that the trend was being driven by studies conducted in the US. Americans seem to be getting better merely by taking part in studies these days, regardless of whether they have been given real drugs or not.
Why? What could it be about Americans that might make them particularly susceptible to the placebo effect?
Top of the list of possibilities is that in the US, unlike every other country in the world except New Zealand, direct-to-consumer advertising of drugs is permitted. The placebo effect is strongly linked to patient expectations, and maybe all those adverts showing virile middle-aged men shooting hoops on a basketball court have had a drip-drip effect on the minds of patients taking drugs, even as part of a trial.
Mogil jokes that he and his co-writers disagree vehemently about the causes of the effect they have uncovered. His own favourite hypothesis does not relate to advertising but the fact that US trials have become larger and tend to go on longer than non-US trials.
Drug companies were probably hoping that larger, more ambitious trials would be better at showing the real effect of drugs, Mogil thinks, but in fact the big budgets may have made things worse, he suggests.
A well-funded trial would be reflected in lots of small ways that might come together to increase patients' confidence that they were engaged in a clinically beneficial process. Just adding a snazzy logo to a research trial could make people feel more optimistic.
Mogil believes that US companies are more likely than others to use contract research organisations (CROs) to conduct trials (though since the companies don't have to declare this, it is hard to know for sure). It may be that the staff who work at these service organisations are friendlier than the busy researchers who conduct academic trials. That in itself could make people feel better.
"There's been a push to gather data, not have missing data," says Dr John Farrar, a neurologist and epidemiologist at the University of Pennsylvania. "So a lot more attention has been paid to patients, there's a lot more contact with patients to make sure they fill out the forms in the right way, and a general increase in knowledge about the potential activity of the drug - talking about the science of it, how it might work etc. And one can assume that all of that leads to potentially a higher expectation in patients."
But Farrar adds that the profit motive of CROs might also be driving them to recruit people who shouldn't really be in the trial in the first place. A physician looking for participants may encourage them to classify their symptoms as more severe than they really are so that they become eligible to take part.
"The other thing is there has been a growth of what we would call 'professional patients' - patients who enrol in clinical trials because they find they can make money off that," says Farrar.
In both those scenarios, after being admitted to a trial the patients may start to give a truer account of their symptoms, which may get chalked up as a positive placebo response.
Farrar advocates changing the design of trials in order to reduce the placebo effect. This includes things like:
- more stringent controls on patient recruitment
- being less specific about eligibility criteria, so that it's harder for people to claim they are eligible when they are not
- adding a third group to the controlled trial set-up, which takes an existing drug that is known to work - if both that group and the group given the new drug fail to beat the placebo, researchers know that their trial design is flawed
There is also a drive to lower, through discussions with patients, their expectations of taking part in a trial. What is the best way to do that? "We tell them the truth," says Dr Nathaniel Katz, the president of Analgesic Solutions, a consultancy that helps drug companies avoid trial failures.
"Telling the truth" means reminding patients that they are part of a trial for a drug that may not work, and which they may not even be given. "Even if it works," Katz says, "it only works for about a third to a half of patients - that's as good as it gets these days."
His company also trains trial researchers to avoid "inappropriately optimistic body language" like putting an arm around the patient, shaking their hand or looking them in the eye. "These are all the things that enhance expectations," says Katz.
Find out more
But he adds that if you lower patient expectations too far you will certainly minimise the placebo effect, but you are also likely to lower the effect of the drug being tested.
This was demonstrated in an experiment last year by Ted Kaptchuk at Harvard Medical School. He gave some migraine sufferers either the drug Maxalt or a placebo. But both those cohorts were divided into three further groups. The groups were given their drugs in envelopes with one of three labels: "Maxalt", "Placebo" or "Maxalt or placebo".
"When we gave them the placebo and the envelope said Maxalt, it had a good positive response," Kaptchuk told the BBC. "When we gave them Maxalt and told them it was a placebo, the response was no different, meaning that by just changing the word on the envelopes we could make the placebo as effective as the medication."
The challenge, in Kaptchuk's view, is to find a way of translating the remarkable power of the placebo into everyday clinical practice. While researchers in drug trials are keen to minimise patient expectations, maybe doctors outside the lab owe it to their patients to boost them as much as possible, harnessing John Haygarth's "wonderful force of the imagination".
"Doctors, every time they prescribe a medication - shall they say, 'This is going to help you, this will be really good because of trials'?" asked Kaptchuk. "Or shall they say, 'Shall we try and see if it works?'"
Placebo - the origin of the word, if you please
- Placebo is Latin for "I will please"
- It comes from the Psalm 116:9 of the Bible - "placebo Domino in regione vivorum" or "I will please the Lord in the land of the living"
- It was the first response of mourners to a priest's recitation at a funeral
- Hired mourners and people who came to a funeral to get free food and drink came to be known as "placebos"
- They were seen as insincere, their feelings not authentic
Ted Kaptchuk spoke to Health Check on the BBC World Service.
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