Intended for healthcare professionals

Rapid response to:

Endgames Statistical Question

The nocebo effect

BMJ 2013; 347 doi: (Published 11 October 2013) Cite this as: BMJ 2013;347:f6130

Rapid Response:

Re: The nocebo effect

In his interesting paper Dr Sedgwick states (BMJ 2013;347:6130)
“…placebo and nocebo effects are psychogenic, originating from mental and emotional processes rather than physiological ones.”

This separation of physiological and psychological substrates is as artificial (1) as it is simplistic. It is yet another example of Patrick Wall ‘s remark:
“… myths are invented claiming that placebos … are the equivalent of doing nothing or that they act only on the mental results of pain and not on the pain itself.” He outlined several placebo myths.

Objective physiological changes related to placebo are well reported, e.g.:
1. Placebo treatment affected measured endogenous opioid activity in a number of predicted μ-opioid receptor-rich regions including periaqueductal gray, dorsal rap he and nucleus cuneiform is, amygdala, and other cortical areas.(2)
2. An old example reported 12 of 17 angina patients who had sham internal mammary artery ligation consisting only of a skin incision experienced improvement, including 22% with objective improved exercise tolerance and ECG changes: similar changes to the group in which the artery was ligated. (3)
3. In a double-blind controlled study in 150 patients following removal of impacted molars, facial swelling, truisms, pain, and serum C-reactive protein (CRP) were significantly reduced both in the ultrasound-treated and in a 'mock' ultrasound groups. (4)
4. Parkinsonian patients respond to placebo by objective decrease in firing rate in neurons of the sub thalamic nucleus and substantial nigra, and increased firing in thalamic nuclei.(5)
5. Immune mechanisms can also be influenced. In a two-period crossover study of live oral cholera vaccine, subjects who received placebo first showed stronger vibriocidal antibody responses and antitoxin titres two weeks after vaccination compared with subjects who received vaccine first. (6)

But many still erroneously regard the placebo reaction as exclusively psychogenic: a means of separating functional from organic states, ignoring the objective changes attendant on using placebos. (7)


1. Pearce JMS. The placebo enigma. Quart J Med.1995; 88: 215-220
2. Wager TD, Scott DJ, Zubieta JK. Placebo effects on human mu-opioid activity during pain Proc Natl Acad Sci U S A. 2007;104(26):11056-61. Epub 2007 Jun 19.
3. Dimond, E. G., Kittle, C. F. and Crockett, J. E.: Comparison of internal mammary artery ligation and sham operation. Am J Cardiol. 1960;5:483–486.
4. Hashish I, Harvey W, Harris M. Anti-inflammatory effects of ultrasound therapy: Evidence for a major placebo effect. Brit J Rheumatol 1986;25:77-81
5. Benedetti F, Lanotte M, Colloca L, Ducati A, Zibetti M, Lopiano L. Electrophysiological properties of thalamic, subthalamic and nigral neurons during the anti-parkinsonian placebo response. The Journal of Physiology, 2009; 587:3869-83.
6. Wasserman SS, Kotloff KL, Losonsky GA, Levine MM .Immunologic response to oral cholera vaccination in a crossover study: a novel placebo effect Am J Epidemiol. 1993 Dec 1;138(11):988-93.
7. Pearce JMS. The placebo enigma revisited. Clin Med 2011;11:340-343.

JMS Pearce

Competing interests: No competing interests

14 October 2013
Emeritus Consultant Neurologist
Hull Royal Infirmary
Anlaby, HU10 7BG