The day of Charles and Diana's wedding, I took part in an experimental pain (hand in icy water) trial. I knew that the treatment that day was either morphine or a placebo. A constipated week later, I was convinced I had had the morphine. It turned out later that that was the placebo day. In the absence of a better explanation, it was my belief that I had had morphine that made me (unusually) constipated. This book is about this placebo effect, about the intriguing phenomenon itself and about the underlying mechanism. How does the belief that you have had morphine cause constipation?
The structure of the book is, first, to look at placebos in the context of medical trials as (negative) controls to help scientists establish the difference between therapeutic effect, the effect of the test intervention and the effect of a control intervention. The control intervention is there to provide a comparison, and while one might think that a placebo pill or injection should do very little, in fact it can have an effect, as with the constipation. Dylan Evans then proposes a mechanism by which the placebo has its effect, and follows that with a chapter on the psychology - the foundation of the belief that triggers the physiological events through which the placebo has its effect. The evolutionary context follows, posing questions as to how and why the placebo effect evolved.
Later chapters focus on alternative medicine and psychotherapy, considering whether these therapies have any greater effect than taking a placebo.
Lastly, Evans discusses ethical issues around placebos, in the context of clinical trials and in clinical practice.
The historical background to the use of placebos in clinical trials is well written and clear. Henry Beecher was, as Evans suggests, the most influential writer on placebo in the mid-20th century, and the spin on his 1955 paper was that a third of us respond to placebo and the extent of that response is a third of the maximum possible effect. We know now that the proportion of us who respond in any given context varies widely, and that the extent of the response also varies. For me, this crucial information comes too late, in chapter four, separated from the Beecher work in earlier chapters.
These points are vital to the genesis of better clinical trials, and the bottom line is that much of the variation is due to chance, and is minimised by making trials as large as possible. This point does not come through strongly enough in the book. While Evans stresses the importance of statistics in making sense of placebo effects, he often digresses into intriguing results from individual small trials. This is a hazard of placebo. People have wasted years trying to work out why the placebo effect in a particular trial might be greater in one context than in another. The reality is that there is probably a "true" underlying value for the proportion responding and the extent of the response, which will be established only with data from thousands of patients. Individual trials may produce high or low values for placebo response due to chance. Had they been larger, they would come closer to that true underlying value.
All this technicality does not help us determine how it is that the placebo has its effect. This is the section of the book with which I have least sympathy. Evans argues that the placebo works by suppressing the acute phase response, our response to injury. To do this he invokes pretty tenuous biochemistry and immunology. Previous work cited in this section looked at whether reversing the body's endogenous opioids, endorphins with the opioid antagonist naloxone, could reverse the placebo effect. As Evans implies, subsequent attempts at replication have cast doubt on this explanation. Evans' acute phase response theory is testable, but perhaps we are just too simplistic in our crude attempts to discover the mechanism of placebo.
I have more sympathy with the belief explanation, though we have no idea how belief translates into a therapeutic effect, or side-effect, such as constipation. Beecher did try to categorise placebo responders, and they tended to be older, female, believers in authority and church-attending, if not God-believing. The one study I know of that looked at the question of whether if you were once a placebo responder then were you always a placebo responder, showed a waning response over time. Perhaps repeat testing strains the belief.
The charisma surrounding alternative therapies and therapists should work to enhance the belief. Consistent failure to show the credible therapeutic effects of many of these therapies stands. But it needs to be said that if a therapy makes people feel better that is no bad thing; just do not badge it as a bona fide analgesic or antidepressant. It is the charisma, the belief, the placebo response, that may make you feel better.
It is difficult to design clinical trials for alternative therapies such as acupuncture, or indeed for psychotherapy. There seems at the moment to be no easy control treatment. Sham acupuncture, no treatment or waiting-list controls all introduce biases into the trial, and small trials, even if randomised, can come up with the wrong answer.
I enjoyed the ethical discussion. I too would defend the legitimacy of the use of placebos in clinical trials in non-life-threatening conditions when the aim is to show whether or not treatment is better than placebo.
Patients are free to withdraw and have other treatment at any time. It is, after all, unethical to recruit patients to studies that cannot deliver an answer, and without placebo controls that would be the case in many contexts.
Placebo response is intriguing, and this book should bring that interest to a wider audience. I do not like Evans' proposed explanation as to how placebos work, and I do not think he does justice to Pat Wall's theory in his book Pain: The Science of Suffering . But as a one-stop well-thought-out compilation, this is the place to start.
Henry McQuay is professor of pain relief,University of Oxford.
Placebo: The Belief Effect
Author - Dylan Evans
Publisher - HarperCollins
Pages - 224
Price - £16.99 and £8.99
ISBN - 712612 3 and 712613 1