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You know medicine's placebo effect. Now meet the nocebo effect

20 November 2019
A sugar tablet can be like medicine, and it’s not all in the mind
The placebo effect has been known for some time, but how it works has been a mystery. Now, Dr Ben Colagiuri is using new insights to identify the mechanisms at work and how they can be used to improve treatments.
Dr Ben Colagiuri holding a red pill and a blue pill suggesting choice

Dr Ben Colagiuri studies the placebo effect to find out why a treatment that shouldn't work, sometimes works anyway.

When asked for an example of the placebo effect, Associate Professor Ben Colagiuri tells the story of Dr Henry Beecher, a medic in World War II confronted with newly wounded soldiers when he had no access to morphine.

Desperate to give the soldiers a sense they were being helped, he administered a plain saline solution, calling it morphine. To his surprise, 40% of the soldiers reported that the saline had reduced their pain. Beecher went on to study what is now called the placebo effect where a treatment still has a benefit even when it’s been replaced by a look-alike sugar pill or other inactive substitute.

Even more mysteriously, in some circumstances, a placebo will work even when the patient knows they’re taking a placebo.

No-one fully understands why any of this happens, but Colagiuri, has dedicated his career so far, to finding answers. He is now immersed in an evolving field where the clinical possibilities of placebos are being uncovered by a small but determined international network of researchers.

“We’re finding that the main way placebos work, is to influence the person’s expectations, or their mindset, which then affects how their body reacts,” says Colagiuri.

This could explain why they work when people know they’re taking a placebo, referred to in medical circles as an ‘open label’ placebo. It suggests that an important part of how a patient reacts to a drug or placebo could be to do with the ritual of treatment; talking with the doctor, seeing the drug, taking it.

“Placebo effects on conditions like allergic reactions are pretty incredible. It’s not just, ‘oh, I feel better now’. You can actually see a reduction in the person’s inflammation.”
Dr Ben Colagiuri

Some other interesting insights; telling a patient they’re about to receive a pain killer like morphine, can make it almost twice as effective than if they’re not told; giving a patient two placebo pills is more effective than a single pill, even though they both only contain sugar; a person raised in a western medicine environment is more likely respond to a pill than an eastern medicine approach like acupuncture, and vice versa.

There are certainly mysteries in play, but one thing Colagiuri is sure of is that the placebo effect is not all in the mind, “Placebo effects on conditions like allergic reactions are pretty incredible,” he says. “It’s not just, ‘oh, I feel better now’. You can actually see a reduction in the person’s inflammation.”

Placebos have also been shown to offer a very real chance of relieving symptoms in conditions such as psoriasis, hayfever, Parkinson’s disease, irritable bowel syndrome, depression, ADHD, and sleep problems. But only where the body itself can produce chemicals that have beneficial effects.

In the World War II morphine example, the human body naturally produces pain relieving opioids and would have done that for the soldiers being given the saline injection who expected pain reduction. However, a placebo could not have actually helped heal the wounds because healing processes are a different mechanism.

Similarly, in asthma, some studies have shown that people taking placebos might report feeling better, but it’s only a perception because their lung function doesn’t improve. In Parkinson’s disease, on the other hand, taking a placebo can prompt the release of dopamine, which is the neurotransmitter that people with Parkinson’s lack, which explains why they feel an improvement.

This is part of a scenario where every day, our bodies manufacture a complex cocktail of pharmaceuticals to keep things functioning normally: endorphins, antibiotics, neurotransmitters, stimulants. Placebos tap into all this but there’s a lot more to learn about how.

Defining the territory has seen Colagiuri involved in trials for people with sleep difficulties, nausea, and a key area of placebo research, pain. In the latter, healthy volunteers agree to receive small electric shocks in tandem with pain-lessening drugs and/or placebos.

Dr Ben Colagiuri sitting in his office amid dramatic shadows and light streaming through blinds

Research on placebos has seen mainstream medicine accept the effect as a genuine phenomenon, says Associate Professor Ben Colagiuri.

The participants judge their own pain responses but also have assessments of measurable things like the changing conductivity of the skin and relaxation levels. This has shown physiological reactions to placebos in ways that confirm biomechanisms definitely come into play.

All this said, placebos are only part of the picture for Colagiuri. In fact, he thinks there may be more beneficial clinical applications for the lesser known and lesser studied evil twin of the placebo effect: the nocebo effect. Colagiuri devoted a PhD to this subject and remains fascinated by it.

When asked for an example of the nocebo effect, he tells the story of one of his own experiences.

“I was sitting at home after a nice lunch with friends, when the phone rang,” he says. “It was someone I’d been out with who told me her husband was feeling really sick. They were worried it was the oysters we’d eaten at the lunch. She asked me if I was alright. Suddenly my stomach was churning.  It wasn’t the oysters, which were fine. It was just the thought of being sick.”

Most people will have experienced something like this to one degree or another, but in a medical setting the nocebo effect could cause problems. Obviously, when a doctor explains the possible side effects of a treatment, you don’t want a patient to spontaneously develop those symptoms. Yet the nocebo effect means that it often does happen.

Essentially, the nocebo effect means if a patient is worried about a treatment regime, poor results are more likely. If you emphasise negative side-effects you’re more likely to get them.

Colagiuri is attempting to reverse this, “It’s about framing the patient experience,” he says. “So, instead of saying you have a 30 percent chance of getting nausea from this treatment, you say there’s a 70 percent chance of not experiencing nausea. In our trials, the second approach results in fewer side effects.”

Colagiuri is pulling together all the threads of the placebo effect and the nocebo effect at a research node he recently launched at the University’s Charles Perkins Centre, with the multidiscipline work in medicine, pharmacology, biology and psychotherapy drawing in ideas from all over the campus.

The question is, can placebos and nocebos make treatment approaches more effective or even reduce drug intake in some situations?

“The medication people receive obviously plays a critical role in how they feel – but placebo and nocebo effects show us that it’s not the only factor. The question is whether we can harness the placebo effect and minimise the nocebo effect to improve treatment outcomes,” Colagiuri says. “That’s what we need to find out now.”

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