It’s one of the mysteries that has confounded scientists for over a century – if you offer sick people fake pills and say it will help cure them, it often will. Now, researchers are working out exactly how the placebo effect operates in the brain and how it can be enhanced in order to harness its power in a new approach to treating disease.
‘When I went to medical school, I was taught that patients whose condition improved after taking a placebo were not ill to start with,’ said Professor Christian Büchel at the University Medical Center Hamburg-Eppendorf in Germany. Over the past decade, his research on the human brain has turned this view inside out.
‘Advances in neuroscience have been the real game-changer,’ he said. ‘In the 1970s, scientists noticed that the placebo effect could be toned down by blocking certain receptors in the nervous system.’ This made it possible to define and quantify the mechanisms of placebo action for the first time.
Moving from subjective feelings to chemistry helped establish placebo research as a scientific discipline. But the potential of the field was initially limited by the risks involved in testing its predictions on live human brains.
Over the past decade, Prof. Büchel has met this challenge with medical imaging techniques that can track physiological responses in the brain without even touching it, and even produce live video streams of brain areas while administering drugs and emotional stimuli to test subjects.
As part of a research project funded by the EU’s European Research Council (ERC), Prof. Büchel has compared brain activity in patients receiving painkillers, respiratory medication and performance-enhancing drugs.
Common trends suggest that some physiological reactions have nothing to do with the content of the pills that are taken, but are produced by the mind regardless of the substance ingested. ‘We are finally looking into the neurobiological channels of the placebo effect itself,’ said Prof. Büchel.
Last year, his team published magnetic resonance images that show how painkillers reduce activity in an enigmatic region of the brain called the anterior insular cortex, which is known for its role in functions as diverse as consciousness, cigarette cravings and orgasms.
‘What surprises me is that nobody is designing treatments around patient expectations yet.’
Prof. Andrea Evers, Leiden University, The Netherlands
Prof. Büchel demonstrated that raising patients' expectations of a painkiller not only affects how stoically people respond to pain, but the mental cue also decreases activity in the anterior insula. ‘Expectations do not just affect how we experience pain stimuli,’ said Prof. Büchel. ‘They can reduce the stimulus itself.’
In contrast, patients who take performance-enhancing drugs often feel that they are doing better at a task, although Prof. Büchel measures no change in their physiology or performance. He is working on untangling the cues and substances that cause neural activity, with an eye open for changes that could affect how the body responds to disease.
The potential of placebos to affect our immune response presents an opportunity for improving public health, according to Prof. Andrea Evers, at Leiden University in the Netherlands, who says that there is more to treatment than the composition of a particular drug.
‘Drug manufacturers report the effects of medical treatments as averages over populations, but every doctor knows that drugs work very differently from one patient to another,’ she said.
While this variation depends in part on genetics and environment, placebo screening during clinical trials has made it abundantly clear that psychological factors, such as stress, optimism and trust in your doctor, can overshadow the effects of the drug itself.
Suggestions and conditioning
‘Every time we take a pill, our minds build up complex expectations based on the suggestions and conditioning that they receive.’
Suggestions include the impact of a patient’s environment, a doctor’s attitude or seemingly innocent words like ‘this may hurt a little’, on what will be thought and felt by the patient throughout the treatment, while conditioning is the body’s automated response to a repeated stimulus. For example, frequent aspirin takers may find that their symptoms fade after swallowing a pill, when the active ingredients in it will only get to work fifteen minutes later.
As a clinical psychologist, Prof. Evers is not surprised that mental processes shape health outcomes. ‘What surprises me is that nobody is designing treatments around patient expectations yet,’ she said.
She has received a grant from the ERC to learn how psychological responses can be manipulated to boost the effectiveness of treatments against itching and pain.
Prof. Evers has succeeded in instilling both types of cues in human subjects. In one study, a green light lit up each time that she diminished an itching sensation on the skin of volunteers. As her test subjects grew used to the routine, Prof. Evers occasionally withheld the stimulus reduction, but the green light still soothed volunteers without it. This effect was enhanced when she verbally suggested that it would do so.
She is now investigating whether she can achieve similar results by periodically removing the medication that she administers to patients in tasty milkshakes. If the body can produce the same hormones and immune reactions just by reacting to the milkshake, placebo interventions could eventually reduce drug doses.
‘Our best results were achieved by combining the right suggestion and conditioning processes, but we are still optimising the cues,’ she said.
The implications could offer welcome news to Europe’s aging population. Prof. Evers points out that chronic conditions of the kind that are spreading in Europe, such as respiratory complications, inflammations, Parkinson’s disease, multiple sclerosis or cancer, tend to be multifactorial. They have no single cause and no single treatment.
By reducing drug doses, placebo research could relieve patients from unnecessary treatment-linked side-effects and alleviate healthcare budget problems. Perhaps more importantly, it could open new avenues towards addressing the multifactorial influences of diseases, and meet them with better, broader treatments.
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