Book Review

Placebo Effects: Understanding the Mechanisms in Health and Disease

N Engl J Med 2009; 360:1576-1577April 9, 2009

Article

Placebo Effects: Understanding the Mechanisms in Health and Disease
By Fabrizio Benedetti. 295 pp., illustrated. New York, Oxford University Press, 2009. $59.95. ISBN: 978-0-19-955912-1

Placebo Effects is a comprehensive monograph on placebo that appears at an auspicious time, after we have had a chance to digest recent research using brain imaging to determine possible placebo effects. Its author, Fabrizio Benedetti, and his group at the University of Turin have been involved in the three major types of studies that have advanced our understanding of placebo effects — brain imaging studies, agonist–antagonist studies, and studies of open versus hidden drug administration. It is no exaggeration to say that Benedetti heads the foremost laboratory for the study of placebo effects in the world.

Moreover, Benedetti possesses the sophistication to assess new information evenhandedly. He avoids adopting the superficial mind–body dualism implicit in the claim that placebo effects have achieved a new level of reality now that they can be seen on brain scans. Benedetti understands the subjective aspects of placebo effects and how objective findings can help to explain them. He also avoids writing romantically about the powers of the imagination here. Indeed, Benedetti sometimes seems too hesitant to acknowledge a real placebo effect, allowing that a change in a member of the placebo group might be due to the natural history of the illness.

The significance of the book's title is the use of the plural. Benedetti organizes the main part of the book by organ system, beginning with the nervous system and pain. The most data are available on this system. He shows that different placebo effects and placebo-like effects, which rely on different biochemical mechanisms, are at work in different symptoms and processes. Most are modulated primarily by expectations, but others rely instead on classical conditioning. He also catalogues organ systems whose response to placebo has not yet been extensively studied. Benedetti rightly debunks the old saw that, on average, one third of patients respond to treatment with placebo, saying that this figure is based on flawed studies, and he deals carefully with the data on whether personality traits predict responsiveness to placebo.

Benedetti also addresses the “nocebo effect” — a worsening of symptoms that is produced by negative expectancies. Some wonder whether it makes sense to consider nocebo a distinct concept. Benedetti's research has to some extent set this debate aside because it demonstrates that nocebo effects and placebo effects may be caused by different biochemical pathways. In particular, worsening of pain seems to be mediated by cholecystokinin pathways, whereas the relief of pain is mediated by endogenous opioid pathways. The two effects are blocked by different, specific chemical antagonists.

It is difficult to identify weaknesses in this comprehensive and thoughtful volume. I wish, nonetheless, that Benedetti had addressed in more detail the difficulty of predicting whether an individual patient or subject will display a placebo effect in a particular context. It also would have been interesting to read his speculation on how future research might be able to capitalize on individual variation. The relatively low probability that any given patient will experience a placebo effect also seems pertinent to the ethics of administering placebos in clinical practice, an issue that Benedetti addresses along with other ethical ramifications.

All physicians could learn much from this volume. Recent surveys indicate widespread use of placebos, especially impure placebos such as vitamins and antibiotics, in clinical practice. It is highly unlikely that the physicians who use these placebos to expedite office visits fully understand the mechanisms they are attempting to trigger. The fact that data show that open administration of a drug may be twice as efficacious as hidden administration highlights the importance of the presence of the healing figure for the patient.

Benedetti stresses his finding that the two-armed, randomized, double-blind, placebo-controlled drug trial generally does not detect true placebo effects or elucidate their mechanisms. He explains why multi-armed — even 12-armed — trials are necessary to address key questions about placebos. He concludes each chapter with questions to be addressed in future research, and in the last chapter he discusses considerations for the design of research studies.

Howard A. Brody, M.D., Ph.D.
University of Texas Medical Branch, Galveston, TX 77555
habrody@utmb.edu