Oxford, UK. Poor expectations for treatment can override the effect of a potent pain-relieving drug, a brain imaging study has shown. In contrast, positive expectations of treatment doubled the natural physiological or biochemical effect of the opioid drug among the healthy volunteers in the study conducted at the University of Oxford.

The study of the placebo effect — and the opposite nocebo effect — appears in Science Translational Medicine, suggesting that doctors may need to consider dealing with patient beliefs about the effectiveness of any treatment, as well as determining which drug might be the best for that patient.

"Doctors shouldn't underestimate the significant influence that patients' negative expectations can have on outcome", says Professor Irene Tracey of the Centre for Functional Magnetic Resonance Imaging of the Brain at Oxford, who led the research. For example, people with chronic pain often see many doctors and tried many drugs that don't work for them. They come to the clinician with negative experience, not expecting to receive anything that will work. Doctors have to work on that first before any drug will have an effect on their pain.

Placebo / Nocebo

The placebo effect describes the improvements seen when patients — unknowingly — are given dummy pills or sham treatments but believe it will do them good.

This is a very real physiological effect; it is not just about patients feeling better.

The nocebo effect is the opposite: patients see poorer outcomes as the result of doubts about a medical treatment.Previous studies have investigated the basis of the placebo effect, when using sugar pills or saline injections for example, and confirmed it can elicit a real response. This new research goes a step further by examining how manipulating participants' expectations can influence their response to an active drug.

The University of Oxford team worked with colleagues from the Universitätsklinikum Hamburg-Eppendorf (UKE) in Germany, the University of Cambridge, and the Technische Universität München.

The team set out to investigate these placebo/nocebo effects among 22 healthy adult volunteers by giving them an opioid drug and manipulating their expectations of the pain relief they might receive at different points.

The volunteers were placed in an MRI scanner and heat applied to the leg at a level where it begins to hurt — set so that each individual rated the pain at 70 on a scale of 1 to 100. An intravenous line for administration of a potent opioid drug for pain relief was also introduced.

Brain imaging used to confirm participant claims of pain relief

MRI scans showed that brain pain networks responded differently according to the volunteers' expectations at each stage, and matching their reports of pain.

Thhe volunteers experienced different levels of pain when their expectations were changed, although the administration of pain relief remained constant.After an initial control run, unknown to the participants, the team started giving the drug to see what effects there would be in the absence of any knowledge or expectation of treatment. The average initial pain rating of 66 went down to 55.

The volunteers were then told that the drug would start being administered, although no change was actually made and they continued receiving the opioid at the same dose. The average pain ratings dropped further to 39.

Finally, the volunteers were led to believe the drug had been stopped and cautioned that there may be a possible increase in pain. Again, the drug was still being administered in the same way with no change. Their pain intensity increased to 64. That is, the pain was as great as in the absence of any pain relief at the beginning of the experiment.

Professor Tracey notes that these results (cf. Left) have been seen in a small, healthy group of volunteers, and that these are short-term, not sustained, manipulations of the participants' beliefs about the treatment.

But she says it's important not to underestimate the strength of the effect of such expectations on any treatment, and that clinicians need to know how to manage that.

Professor Tracey says there may also be lessons for the design of clinical trials. These are often carried out comparing a candidate drug against a dummy pill to see if there is any effect of a drug above and beyond that of the placebo.

"We should control for the effect of people's expectations on the results of any clinical trial. At the very least we should make sure we minimize any negative expectations to make sure we're not masking true efficacy in a trial drug."