Stronger than drugs

Brain scans afterwards revealed that levels of dopamine were higher in every case. But what the participants didn’t know was that none of them had taken levodopa – all had been given the placebo. Despite that, the sugar pill – or perhaps the expectation of a result – had caused chemical changes in their brains.1

The power of the placebo is recognized by medicine as a way to test the real effects of a drug over and above our thoughts or expectations. The trick is to not tell the participant whether he’s been given a drug or a placebo in what is called a ‘double-blind placebo-controlled’ trial, the gold standard of medical studies.

But something strange has been happening with the placebo effect over the past 20 years – it’s been getting stronger. In fact, it’s been getting so strong that it’s matching, and sometimes surpassing, the effects of painkillers, and it’s stopping the development of new drugs in its tracks.

Several major new drugs have fallen at the last hurdle when tested against the placebo response, and it may cost a drug company upwards of £1 billion in research and development for a product that has to be scrapped.

Researchers at McGill University in Montreal discovered the phenomenon of the rising placebo effect when they looked back at 80 trials testing painkillers to treat pain from nerve damage carried out between 1990 and 2013. There was a steady increase in the placebo response, but drug responses remained stable, over those years until, in the most recent studies, people reported a 30 per cent decrease in pain whether given a drug or a placebo.2

There was one curious factor in all of this: the phenomenon happened only in American trials, whereas no similar increase in placebo effect was seen in European or Asian trials. Lead researcher Jeffrey Mogil is mystified, but surmises it could be because American trials are now longer and bigger, so participants’ expectations were higher. But if so, wouldn’t there be a similar increase in the effectiveness of drugs as well? Mogil accepts the point – and other studies that have demonstrated that morphine is 50 per cent less effective if patients don’t know they’re getting it just muddy the water further.
“You’d have to be a hard-ass or a hold-out not to believe in the efficacy of the placebo,” says Mogil, but quite what is going on remains a mystery.

That’s the thing about the placebo effect: the more you look, the stranger it becomes. Ted Kaptchuk, professor of medicine at Harvard Medical School, has been studying the placebo effect for years, but he still can’t really explain what’s happening, and he’s looked every which way at the phenomenon.
In one study, he even tried to fool the participants. He gathered together 66 migraine sufferers, and during an attack, each was handed one of three envelopes that described the contents as being the painkiller Maxalt (rizatriptan), a placebo, or either Maxalt or a placebo for a ‘double-blind’ effect.

On top of that, sometimes the description was accurate, but sometimes it was false. But it didn’t seem to make any difference: pain relief was similar whether the painkiller or the placebo was taken. Pain relief was less effective when participants knew it was a placebo, but it still had some effect. But it didn’t seem to work the other way round: when the drug was mislabelled as placebo, it stopped working.3

Other researchers have come up with similar results: even when participants knew they were taking a placebo, it still worked. But, say researchers from the University of Colorado, it doesn’t happen immediately. In their experiment, they found that the placebo effect kicked in only after four sessions.

On each occasion, a heating element was placed on the forearm of each participant and the area was then ‘treated’ with a cooling gel that was, in fact, Vaseline with some blue colouring added. But it was only during the fourth session that the participants said they could feel relief, even though they knew what was being applied to the skin wouldn’t work.4

So how is it that a placebo can match the healing effects of a powerful painkiller or salve? Scientists reckon a placebo pill affects the same pain pathways targeted by drugs. PET (positron emission tomography) and MRI (magnetic resonance imaging) scans have shown that pain-reducing responses are accompanied by reduced neural activity in pain-processing areas of the brain and spinal cord even when someone has taken a placebo. In other words, thoughts and expectations are activating the same pain-reducing processes as the drugs do.

But it isn’t just pain that can be reduced by placebo. The effect has worked across a range of conditions, including Parkinson’s disease, depression and even psychotic episodes. Psychosis is recognized as a severe mental-health problem in which the sufferer loses touch with reality – and yet the condition has been reversed with a sugar pill.

So something more must be going on. The University of Colorado researchers reckoned the four sessions were essential for building a belief in the power of the treatment, coupled with the ritual of applying the ointment, which allowed the brain to respond as if it were a
‘real event’.
Kaptchuk agrees. Medical ritual seems to trump our awareness that we’re taking a placebo. He proved the point when he gave either a useless sugar pill or nothing at all to a group of 80 IBS (irritable bowel syndrome) sufferers. Those given a placebo were told that’s what they were taking, even down to handing them a container with the word ‘Placebo’ plastered across it. Yet, within three weeks, 59 per cent of those given the placebo reported significant improvement in their symptoms compared with just 39 per cent who weren’t given anything.5

To put this result in perspective, a pooled analysis of studies of the IBS drug alosetron found that 51 per cent of sufferers reported “adequate” improvement in their symptoms.6
In other words, Kaptchuk’s well-advertised placebo outperformed a seemingly effective drug. And why? Kaptchuk believes it has something to do with the ritual of handing out medication in a medical setting.5

Essentially, it’s all to do with the drama of medicine, he reckons. That can include all the medical paraphernalia, pills, symbols and interactions with the doctor. “All those things merge, triggering brain mechanisms of expectation and potentially contributing to a placebo effect,” he says.7
Damien Finniss at the University of Sydney agrees that the effect involves many different factors. But he reckons you don’t have to hand out a placebo to have a placebo effect; it’s part and parcel of routine clinical care.

Doctors have known this for years. The German Medical Association reports that placebo prescriptions are “booming” and that “half of German doctors” are prescribing them regularly.8 Similar behaviour can be seen in Canada, where 20 per cent of psychiatrists and non-psychiatrists say they’ve prescribed a placebo. Also, among psychiatrists, 60 per cent describe placebos as genuinely helpful and of therapeutic value.9

The problem could be related to the way experiments are set up in the first place. It isn’t a case of placebo or drug, argues Mogil, because they are interchangeable. The placebo effect is rising because it’s cancelling out the effects of drugs by using the sam
e neural pathways the drugs are targeting. Expectation and anticipation are everything, and the placebo is merely a device that ‘allows’ the painkilling process to begin.

If Mogil and Kaptchuk are right, this is bad news indeed for the drugs industry. Instead of spending billions of dollars on painkillers, antidepressants, anti-Parkinson drugs and antipsychotics, we just need to take a sugar pill and let the brain do the rest. When it comes to healing, perhaps it really is the thought that counts.
Bryan Hubbard

One of the earliest tests of the placebo effect was in 1799 when physician John Haygarth tested a strange medical device called ‘Perkin’s tractor’ on a group of patients suffering from rheumatic pain. The tractor comprised a pair of metal rods that the inventor said would “suck” disease from the body. The rods were supposedly made of special alloys that had healing effects.

But when Haygarth substituted wood for the metal rods, four of the five sufferers still said they experienced pain relief. A similar response was achieved the following day when he used the metal rods again. “Such is the wonderful force of the imagination,” said Haygarth afterwards.