Antidepressants and the nocebo effect: people's negative expectations can undermine treatment - especially litigious FIDDAMAN

The nocebo effect: people's negative expectations can undermine treatment. Photograph: Alamy


Can just telling a man he has cancer kill him? In 1992 the Southern Medical Journal reported the case of a man who in 1973 had been diagnosed with cancer and given just months to live. After his death, however, his autopsy showed that the tumour in his liver had not grown. His intern Clifton Meador didn't believe he'd died of cancer: "I do not know the pathologic cause of his death," he wrote. Could it be that, instead of the cancer, it was his expectation of death that killed him?

http://www.guardian.co.uk/science/2011/nov/13/nocebo-pain-wellcome-trust-prize

This death could be an extreme example of the "nocebo effect" - the flip-side to the better-known placebo effect. While an inert sugar pill (placebo) can make you feel better, warnings of fictional side-effects (nocebo) can make you feel those too. This is a common problem in pharmaceutical trials and a 1980s study found that heart patients were far more likely to suffer side-effects from their blood-thinning medication if they had first been warned of the medication's side-effects. This poses an ethical quandary: should doctors warn patients about side-effects if doing so makes them more likely to arise?



The nocebo effect can also be highly infectious. In 1962, 62 workers at a US dressmaking factory were suddenly stricken with headaches, nausea and rashes, and the outbreak was blamed upon an insect arriving from England in a delivery of cloth. No insect was ever found, and "mass psychogenic illnesses" like these occur worldwide, usually affecting close communities and spreading most rapidly to female individuals who have seen someone else suffering from the condition.



Until recently, we knew very little about how the nocebo effect works. Now, however, a number of scientists are beginning to make headway. A study in February led by Oxford's Professor Irene Tracey showed that when volunteers feel nocebo pain, corresponding brain activity is detectable in an MRI scanner. This shows that, at the neurological level at least, these volunteers really are responding to actual, non-imaginary, pain. Fabrizio Benedetti, of the University of Turin, and his colleagues have managed to determine one of the neurochemicals responsible for converting the expectation of pain into this genuine pain perception. The chemical is called cholecystokinin and carries messages between nerve cells. When drugs are used to block cholecystokinin from functioning, patients feel no nocebo pain, despite being just as anxious.



The findings of Benedetti and Tracey not only offer the first glimpses into the neurology underlying the nocebo effect, but also have very real medical implications. Benedetti's work on blocking cholecystokinin could pave the way for techniques that remove nocebo outcomes from medical procedures, as well as hinting at more general treatments for both pain and anxiety. The findings of Tracey's team carry startling implications for the way we practise modern medicine. By monitoring pain levels in volunteers who had been given a strong opioid painkiller, they found that telling a volunteer the drug had now worn off was enough for a person's pain to return to the levels it was at before they were given the drug. This indicates that a patient's negative expectations have the power to undermine the effectiveness of a treatment, and suggests that doctors would do well to treat the beliefs of their patients, not just their physical symptoms.



This places a spotlight on doctor-patient relationships. Today's society is litigious and sceptical, and if doctors overemphasise side-effects to their patients to avoid being sued, or patients mistrust their doctor's chosen course of action, the nocebo effect can cause a treatment to fail before it has begun. It also introduces a paradox – we must believe in our doctors if we are to gain the full benefits of their prescribed treatments, but if we trust in them too strongly, we can die from their pronouncements.



Today, many of the fastest-growing illnesses are relatively new and characterised solely by a collection of complaints. Allergies, food intolerances and back pain could easily be real physiological illnesses in some people and nocebo-induced conditions in others. More than a century ago, doctors found they could induce a hay fever sufferer's wheezing by exposure to an artificial rose. Observations like these suggest we should think twice before overmedicalising the human experience. Our day-to-day worrying should be regarded as such, not built up into psychological syndromes with suites of symptoms, and the health warnings that accompany new products should be narrow and accurate, not vague and general in order to waive the manufacturer's liability.



As scientists begin to determine how the nocebo effect works, we would do well to use their findings to manage that most 21st-century of all diseases – anxiety.