Side effects are WORSE if you think the drug is expensive

People experience both the good and bad effects of a drug more intensely when they think it’s expensive, a new study shows.  

Research published in Science demonstrates that the perceived cost of a drug can amplify the ‘nocebo effect’ which is the experience of side effects from a medication with no actual therapeutic effects.

German researchers at University Medical Center Hamburg-Eppendorf applied a cream to the arms of their subjects and told them that one of the possible side effects was pain in the area.

The subjects that were given the ‘expensive’ cream not only reported higher pain levels, but scans of their brains showed greater activity in areas associated with the experience of pain.

The nocebo effect causes people to experience negative side effects whether or not a medication can physiologically cause them. A new German study showed that the nocebo effect is intensified when people think their medication is more expensive

The placebo effect has been demonstrated in numerous studies. Whether or not people are given drugs with active ingredients, they generally experience the presumed effects of those drugs.

The nocebo effect occurs when a patient experiences negative effects of a drug, when, physiologically, it is doing nothing to them.

Both the placebo and nocebo effects have been known to scientists since the 1960s, says Dr Ted Kaptchuck, a professor of global health and social medicine at Harvard Medical.

‘The placebo effect has long been a blind spot in medicine. The nocebo effect is an even bigger, more important blind spot,’ says Dr Kaptchuck, who has done his own extensive research on the placebo effect. 

 Worrying and anticipation can really cause some people to experience side effects of drugs
Dr Ted Kaptchuck, Harvard Medical School placebo researcher 

Dr Kaptchuck says that the placebo effect complicates clinical trials, but ultimately does less harm to real patients. If someone experiences improvements from taking a sugar pill, nobody really loses.

The nocebo effect, on the other hand, is more devious. It may cause patients to ask to switch from or stop taking a medication before its benefits have really even set in, because they believe that they’re having negative side effects.

The prevailing theory, expressed by Dr Tinnerman, Dr Kaptchuck and others, is that the effect is linked to anxiety developed when a person expects a negative outcome.

Lead study author Alexandra Tinnerman and her team designed two variations of packaging for skin creams. None of the creams had any active ingredients that would cause pain. After applying the cream, the researchers placed hot plates on the arms of the subjects, at the same temperatures.

Those that were given the more expensive-looking creams felt more pain than those with the cheaper-looking creams. Brain scans revealed activity in areas like the hippocampus, that are related to anxiety.

But they also showed increased blood flow to the prefrontal cortex, where the brain processes the experience of pain, meaning the subjects weren’t just imagining pain, but feeling it.

‘Ultimately, it’s about how the context: the words and behaviors’ with which the drug is introduced, says Dr Kaptchuck. ‘Worrying and anticipation can really cause some people to experience side effects of drugs.’

He says this is an issue that Dr Tinnerman’s paper raises, but doesn’t address, but nor does other past literature, including his own. Dr Kaptchuck says that the medical community largely ignores the nocebo effect and its detrimental impact for both clinical trials and treatment of patients.

‘The first thing is for doctors to understand the effect. Second, we have to develop ways of relieving anxiety,’ he says. But doing so quickly becomes complicated.

‘A doctor has to be honest. So what does honesty mean in medicine?’ he asks.

Research has shown that the side effects most likely to be induced by the nocebo effect – pain, nausea, dizziness, depression, anxiety – are ones that the brain can modulate, meaning that context can change the way that we experience them.

‘In terms of evolution, all of those symptoms are protective for people, and necessary for survival,’ Dr Kaptchuck says. But, a ‘nocebo or placebo effect…shuts off those protective mechanisms’ in certain contexts.

Dr Kaptchuck uses the example of soldiers on the battlefield, who will not feel the pain from an injury until they are out of the action. In this situation the brain modulates pain for the sake of survival, given the context. But this mechanism works against us in the placebo or nocebo effects.

 A doctor has to be honest. So what does honesty mean in medicine?
Dr Ted Kaptchuck, Harvard Medical School placebo researcher

‘A doctor-patient relationship, in my opinion, is a very strongly-encoded ritual that puts people in a context that lets the brain modulate symptoms,’ he says. ‘In some ways, its cultural, not animal.’

‘We know that nocebo effects exist, and you can increase or decrease them, but what is ethically allowed?’ Dr Kaptchuck asks.

There are, of course, many side effects that a patient must be aware of, like drowsiness that makes them unfit to drive. But the nocebo effect indicates that patients could develop side effects simply because they are worried that they might.

This suggests to Dr Kaptchuck that doctors may be able to leverage the ways that they present a drug and its side effects in a way that minimizes the chances of a nocebo effect.

Dr Tinnerman’s research shows that responses can be modulated even within the nocebo effect, in this case, by perception of price. It’s unclear why, exactly, those who thought they were given a more expensive cream experienced more intense nocebo effects, but it falls in line with previous studies in which more expensi
ve placebos were also more effective.

Dr Kaptchuck says he has ‘no idea’ why the nocebo effect would be stronger for medication that was presented as more expensive. ‘Maybe they think it’s stronger. But patients think more expensive medications work better…I’m not sure that gullibility is the same thing as a patient wanting to get better.’ 

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