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Research and Reporting Methods |

What's in Placebos: Who Knows? Analysis of Randomized, Controlled Trials

Beatrice A. Golomb, MD, PhD; Laura C. Erickson, BS; Sabrina Koperski, BS; Deanna Sack, BS; Murray Enkin, MD; and Jeremy Howick, PhD
[+] Article, Author, and Disclosure Information

From the University of California, San Diego, School of Medicine, San Diego, California; McMaster University, Hamilton, Ontario, Canada; and Centre for Evidence-Based Medicine, University of Oxford, Oxford, United Kingdom.

Acknowledgment: The authors thank Stephanie Cham, BS, for reviewing and confirming the exclusion categories for excluded articles and Asbjørn Hrobjartsson, David Mant, Jeffery Aronson, and Michael Clarke for useful comments on earlier drafts of the manuscript.

Grant Support: By University of California Foundation Fund 3929–Medical Reasoning. The manuscript was revised while Dr. Howick was a recipient of a Medical Research Council/Economic and Social Research Council Interdisciplinary Postdoctoral Fellowship (G0800055).

Potential Conflicts of Interest: None disclosed. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms/do?msNum=M10-1554.

Reproducible Research Statement:Study protocol and data set: Available from Dr. Golomb (e-mail, bgolomb@ucsd.edu). Statistical code: Available online at www.OpenEpi.com.

Requests for Single Reprints: Beatrice A. Golomb, MD, PhD, University of California, San Diego, School of Medicine, 9500 Gilman Drive, #0995, La Jolla, CA 92093-0995; e-mail, bgolomb@ucsd.edu.

Current Author Addresses: Dr. Golomb, Ms. Erickson, Ms. Koperski, and Ms. Sack: University of California, San Diego, School of Medicine, 9500 Gilman Drive, #0995, La Jolla, CA 92093-0995.

Dr. Enkin: 1001 Bay Street, Apt 2404, Toronto, Ontario M5S 3A6, Canada.

Dr. Howick: Centre for Evidence-Based Medicine, University of Oxford, Oxford OX3 7LF, United Kingdom.

Author Contributions: Conception and design: B.A. Golomb, J. Howick.

Analysis and interpretation of the data: B.A. Golomb, L.C. Erickson, S. Koperski.

Drafting of the article: B.A. Golomb, J. Howick.

Critical revision of the article for important intellectual content: B.A. Golomb, L.C. Erickson, S. Koperski, M. Enkin, J. Howick.

Final approval of the article: B.A. Golomb, L.C. Erickson, S. Koperski, D. Sack, M. Enkin, J. Howick.

Provision of study materials or patients: B.A. Golomb.

Statistical expertise: B.A. Golomb.

Obtaining of funding: B.A. Golomb.

Administrative, technical, or logistic support: B.A. Golomb, S. Koperski, J. Howick.

Collection and assembly of data: L.C. Erickson, S. Koperski, D. Sack.

Ann Intern Med. 2010;153(8):532-535. doi:10.7326/0003-4819-153-8-201010190-00010
Text Size: A A A

Background: No regulations govern placebo composition. The composition of placebos can influence trial outcomes and merits reporting.

Purpose: To assess how often investigators specify the composition of placebos in randomized, placebo-controlled trials.

Data Sources: 4 English-language general and internal medicine journals with high impact factors.

Study Selection: 3 reviewers screened titles and abstracts of the journals to identify randomized, placebo-controlled trials published from January 2008 to December 2009.

Data Extraction: Reviewers independently abstracted data from the introduction and methods sections of identified articles, recording treatment type (pill, injection, or other) and whether placebo composition was stated. Discrepancies were resolved by consensus.

Data Synthesis: Most studies did not disclose the composition of the study placebo. Disclosure was less common for pills than for injections and other treatments (8.2% vs. 26.7%; P = 0.002).

Limitation: Journals with high impact factors may not be representative.

Conclusion: Placebos were seldom described in randomized, controlled trials of pills or capsules. Because the nature of the placebo can influence trial outcomes, placebo formulation should be disclosed in reports of placebo-controlled trials.

Primary Funding Source: University of California Foundation Fund 3929—Medical Reasoning.


Grahic Jump Location
Appendix Figure.
Summary of evidence search and selection.

* Nine articles are counted twice because they have a placebo in 2 categories.

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Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).


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Placebo in clinical trials: are they justified and credible?
Posted on October 25, 2010
Alain Braillon
sacked by the French Dept. of Health (see HealthWatch Newsletter, issue 79, October 2010. Available
Conflict of Interest: None Declared

Golomb et al rightly questioned the composition of the placebo in clinical trials.(1) I crave that they use their database for 2 major questions yet unanswered.

In what percentage of cases the Helsinki declaration (point 32) which clearly requires "that patients are not randomized to a clearly inferior treatment." is implemented? Indeed serious breaches exit, even for diseases with a high short term mortality where patients can receive a placebo despite that an effective treatment is recommended.(2)

In what percentage of cases the placebo composition can allow for a credible "double-blind" statement?


1 Golomb BA, Erickson LC, Koperski S, Sack D, Enkin M, Howick J. What's in placebos: who knows? Analysis of randomized, controlled trials. Ann Intern Med. 2010 19;153:532-5.

2 Braillon A. Sciensationalism. Am J Med. 2010 Sep 29. PMID: 20887967 In press, available on line

Conflict of Interest:

None declared

Re:Placebo in clinical trials: are they justified and credible?
Posted on October 28, 2010
Ann Elin Morkrid
No Affiliation
Conflict of Interest: None Declared

First: It has always been a huge ethical problem that patients have been exposed to randomized selection, with the result that a certain percentage of them has been treated with a non-effective placebo, despite the fact that the patients were seriously ill and in need of medical treatment. This while at the same time the rest of the patients were given what was believed to be "a proper" medical treatment.

Secondly: It becomes an even bigger ethical problem when the placebo in some cases now have been shown to actually have had adverse effects on these patients health, by not being acceptable zero point-standards for the actual medications on trial.

Thirdly: It is also of ethical concern when the patients having the luck of being selected for the "proper" medical treatment, have actually been subjected to medication where its positive effect has been overestimated, non- existing, or even of the negative kind; and all because the treatment effects has been compared to a placebo which was not a non-active zero- point-substance, but rather a substance having negative health effects, and thereby in the comparison ended up documenting a false positive medical healing effect of the medication.

Conclusion: We now have no way of knowing which medicines are being beneficial to the patients being treated, and which are having no effects at all, or which are actually having negative effects on the patients health.

With this report, the whole of pharmaceutical research have lost its credibility. It may or may not be a cynical act by the individual researcher and/or by his/her research group or leader. It is, however, not easy to make excuses for the pharmaceutical companies, since the actual research as a common universal procedure, should have been submitted to meticulous quality control by independant researchers hving no bonds to the company, before a final approval was being given, and the medication was being introduced to the medical community. This report is weakening the whole foundation wall of all pharmaceutical research. It is from now on not possible to trust any existing information about the effects and side-effects of pharmaceutical medicine. Unfair as it may be, this will affect honest and dishonest researchers alike!

Alternative medicine with remedies extracted from biological flowers, herbs, shrubs, trees and berries developed by nature over millions of years, and used and eaten by both mankind and animals since the beginning of time, suddenly seems preferable to the unreliable medicines made by the pharmaceutical industry. Maybe the way out of this newborn dilemma is to channel big money into formal scientific research documenting the effects of these nature-made remedies, instead of into the allegedly "well documented" but still highly questionable pharmaceutical chemicals with all their well-documented side- effects. However, big money cannot be expected to originate from the pharmaceutical sector, since natural remedies originating from nature is the inheritance of all humanity, and as such cannot be patented.

In Norway an investigation has just shown that about half the population prefers alternative medicine and natural remedies to treatment in the public healthcare sector where doctors are using allopathic treatment with pharmaceutical medicine. Considering the lack of research funding that has been a major hindrance for documentation of natural remedies, there is still an amazing amount of documentation about the positive health-effects that these remedies do have, as well as information about side-effects and restrictions for use. We can just imagine the effect a support of big money might have within the alternative health care sector.

Conflict of Interest:

None declared

What's in Placebos?
Posted on November 18, 2010
Wayne B Jonas
Samueli Institute
Conflict of Interest: None Declared

Golomb and colleagues should be commended for lifting the hood off the words "placebo composition" and looking underneath (1). We have argued that the term placebo is problematic because it bears negative connotations and instills confusion among patients, health care workers and scientists. It also obscures important information needed to evaluate the effectiveness of treatments (2;3).

However, in their discussion on the possible active effects of placebos, Golomb et al. neglect to mention a potentially important confounder in placebos given by injection; namely silica contamination from the glass vials in which the drugs and placebos are often stored. Silicates and borate leach from glass containers into the solutions stored in them reaching micromolar levels, and the levels in solution are increased substantially by heat sterilization (4). If sterile saline packaged in glass vials is used as placebo for studies where the test drug is injected intravenously or intramuscularly, micromolar levels of silica and borate are being administered to the control group. Silica has a number of direct biological effects at levels found in solutions stored in glass vials (5). In addition, we have shown that the levels of silica leaching from glass vials are high enough to stabilize enzyme reactions in water and therefore are likely to interact with many pharmaceuticals in solution (4). Since enzymes, immunizations, insulin, some pharmaceuticals and other substances are frequently stored for significant periods in glass vials or bottles, we believe the silica concentration needs to be carefully analyzed in both the placebo and active arms of studies that deliver treatments by intramuscular or intravenous routes.

Reference List

(1) Golomb BA, Erickson LC, Koperski S, Sack D, Enkin M, Howick J. What's in placebos: who knows? Analysis of randomized, controlled trials. Ann Intern Med 2010; 153(8):532-535.

(2) Walach H, Jonas WB. Placebo research: the evidence base for harnessing self-healing capacities. J Altern Complement Med 2004; 10 Suppl 1:S103-S112.

(3) Moerman DE, Jonas WB. Deconstructing the placebo effect and finding the meaning response. Ann Intern Med 2002; 136(6):471-476.

(4) Ives JA, Moffett JR, Arun P, Lam D, Todorov TI, Brothers AB et al. Enzyme stabilization by glass-derived silicates in glass-exposed aqueous solutions. Homeopathy 2010; 99(1):15-24.

(5) Zou S, Ireland D, Brooks RA, Rushton N, Best S. The effects of silicate ions on human osteoblast adhesion, proliferation, and differentiation. J Biomed Mater Res B Appl Biomater 2009; 90(1):123-130.

Conflict of Interest:

None declared

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