Book Review

The Placebo Response and the Power of Unconscious Healing

N Engl J Med 2009; 360:646-647February 5, 2009

Article

The Placebo Response and the Power of Unconscious Healing
By Richard Kradin. 278 pp., illustrated. New York, Routledge, 2008. $40. ISBN: 978-0-415-95618-5

Richard Kradin, as he explains in the acknowledgements section of his book, sets out to develop “an explanatory model for the placebo response,” with a particular interest in mind–body physiology and the possible mechanisms of the response — meaning beneficial responses to the fact of treatment, rather than to the treatment itself. Kradin does indeed describe in detail various beliefs about and explanations of placebo responses. One difficulty in attempts to explain and analyze placebo effects, as Kradin recognizes at least some of the time, is that the response is not measured in clinical trials. What we measure is the change in the placebo group — whatever its cause. This uncertainty makes it very hard to discover and describe the cause of the response.

Names matter. If placebo-controlled trials were instead called “blinded no-treatment controlled trials,” would people think that a change in the group that received no treatment was the result of a placebo effect? In fact, as Kradin recognizes and explains in a chapter called “A Brief History of Medicine and the Changing Implications of Placebos,” the placebo group is there to account for all changes in the patients that are not the result of treatment. Patients not receiving treatment may improve for many reasons other than that of having a true placebo response, including the natural history of a disease, other treatment or environmental change, and optimistic assessment of the patient's health by the patient or the physician.

With regard to the natural history of a disease, everyone would know that a placebo group in an upper respiratory infection trial, for example, would show marked improvement by 2 weeks and would consider that to be the result of the natural history of the disease — not a placebo response. People are less aware of how much spontaneous improvement there can be in patients with many other conditions, such as depression, insomnia, low back pain, and chronic fatigue. Apart from spontaneous variability, patients generally enter clinical trials when their symptoms are relatively severe (the entry criteria assure this), so that even for patients with chronic illness, “regression to the mean” will, on average, lead to improvement.

Other treatment or environmental change can also cause patients to improve. The treatment environment itself may lead to improvement. In depression trials, for example, the frequent conversations patients have with nurses and doctors and the assessments they receive from them, which are similar to some recommended therapies, have been thought to contribute to the striking improvements that are often seen in the placebo groups.

Patients may also seem to improve because of optimistic assessments that are given by themselves or their physicians. Symptomatic conditions are measured either by the patient's assessment of severity or by the physician's interpretation of the patient's status. Optimism arising from a hoped-for drug effect can influence these reports, even if there is no real change.

Kradin perceives all this, to some extent, and even notes that a failure to recognize these influences was at the heart of Henry Beecher's article, “The Powerful Placebo,” published in 1955 in the Journal of the American Medical Association, in which “placebo effectiveness” was reported about 35% of the time. But Kradin often slips into describing a change in a placebo group as a placebo effect when we do not know that it is truly a placebo effect. Of course, distinguishing an actual placebo effect from a change in the placebo group is not easy. Perhaps surprisingly, however, there have been a great many trials comparing a drug, a placebo, and in a third arm, no treatment. In such trials, the untreated placebo group and the openly untreated group can be compared. Presumably, the placebo group would be the one with the placebo effect.

Asbjorn Hrobjartsson and Peter Gotzsche, in a classic article entitled, “Is the Placebo Powerless? An Analysis of Clinical Trials Comparing Placebo with No Treatment,” published in the Journal in 2001, conducted a systematic review of these studies, which involved more than 8000 patients. They found that there was essentially no advantage for the placebo group as compared with the openly untreated group on binary outcomes, and there was only some evidence of a small effect on subjective continuous outcomes; the strongest effect was for pain, which had by far the most studies and the most patients. There is, of course, a potential observational bias against the openly untreated group that could account for the small suggestion of a response to placebo. There was almost no suggestion of any effect on pharmacologic binary end points. The best available data thus suggest at most a small effect of placebo, best shown for pain, where at least the known endogenous endorphins provide some mechanistic explanation. The experience of the Food and Drug Administration in other settings, such as the treatment of blood pressure, where one might think a placebo effect could occur, has shown that with automated blood pressure monitoring, there is essentially no effect in placebo groups.

If the change seen in a placebo group cannot be considered a placebo effect without further evidence, Kradin's attempts to explain that change and characterize it in various settings (which is what most of his book is about), although interesting and in many respects thoughtful, cannot really succeed.

Robert Temple, M.D.
Food and Drug Administration, Rockville, MD 20852
robert.temple@fda.hhs.gov