Placebo effect literature search - discussion welcome :)

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Placebo effect literature search - discussion welcome :)

Postby Cece » Wed Jan 05, 2011 1:02 pm

Journal of Clinical Epidemiology
Volume 50, Issue 12, Pages 1311-1318 (December 1997)
1 of 11


The Powerful Placebo Effect: Fact or Fiction?

Gunver S Kienlea, Helmut Kienea


Accepted 20 August 1997.

Abstract
In 1955, Henry K. Beecher published the classic work entitled “The Powerful Placebo.” Since that time, 40 years ago, the placebo effect has been considered a scientific fact. Beecher was the first scientist to quantify the placebo effect. He claimed that in 15 trials with different diseases, 35% of 1082 patients were satisfactorily relieved by a placebo alone. This publication is still the most frequently cited placebo reference.

Recently Beecher's article was reanalyzed with surprising results: In contrast to his claim, no evidence was found of any placebo effect in any of the studies cited by him. There were many other factors that could account for the reported improvements in patients in these trials, but most likely there was no placebo effect whatsoever.

False impressions of placebo effects can be produced in various ways. Spontaneous improvement, fluctuation of symptoms, regression to the mean, additional treatment, conditional switching of placebo treatment, scaling bias, irrelevant response variables, answers of politeness, experimental subordination, conditioned answers, neurotic or psychotic misjudgment, psychosomatic phenomena, misquotation, etc.These factors are still prevalent in modern placebo literature. The placebo topic seems to invite sloppy methodological thinking. Therefore awareness of Beecher's mistakes and misinterpretations is essential for an appropriate interpretation of current placebo literature.

If anyone has access to the full article, MS is discussed, according to the snippet that shows up in the search
Immense placebo effects can be claimed when
they are based on response variables which are irrelevant for the condition in question [21]:
There is the claim of a 73% placebo effect in multiple sclerosis [17].

http://www.jclinepi.com/article/S0895-4 ... 5/abstract
Last edited by Cece on Wed Jan 05, 2011 4:27 pm, edited 1 time in total.
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Postby Cece » Wed Jan 05, 2011 1:15 pm

In another study, multiple sclerosis patients received intravenous treatments with
cyclophosphamide (US) paired with anise-flavored syrup (CS), and eight out of ten patients
displayed decreased ...

from this article:
http://www.annualreviews.org/doi/abs/10 ... e=pharmtox

Mechanisms of Placebo and Placebo-Related Effects Across Diseases and Treatments

Annual Review of Pharmacology and Toxicology
Vol. 48: 33-60 (Volume publication date February 2008)
First published online as a Review in Advance on July 31, 2007
Fabrizio Benedetti

but no access to the full article....
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Postby CureIous » Wed Jan 05, 2011 1:18 pm

This is why I say to people, often and as clearly as possible, to lay low for the first 3 months. There's a reason I did a one year follow up "lookie what I can do" video as opposed to a 3 month or so video. While all those are great, and I don't begrudge excited people from posting their immediate results, they should be and must be processed properly and not as ANY indication of anyone else's post-treatment.

Same goes for the negative findings, post away, shout it from the rooftops, we're all listening and absorbing, neither should that be taken as an indication of one's future prospects.

Neither should be discounted out of hand, nor embraced as representative of one's future results either.

There is a way to achieve some semblance of balance here without going "religiously" one way or the other.. That of course ties in with the placebo effect quite nicely, I doubt the vast majority of positive improvements reported can so easily and summarily be discounted with the dismissive hand wave as merely placebo, that's just a red herring thrown out there when there are no DBPC studies published, but we KNOW they are coming, so for now, we have the same long drawn out arguments/discussions in many different flavors for the past year, it's gets so redundant that I can write the pros and cons myself from point A to B just from memory.

And that's okay, new people bring those to the fore, the respective dogpiles form on either side, and people can make up their own minds which one they want to join, or just referee or spectate. It's all good in my book, if this was all bee-stingy I doubt it would have grown and continued to grow as it has to this point.
RRMS Dx'd 2007, first episode 2004. Bilateral stent placement, 3 on left, 1 stent on right, at Stanford August 2009. Watch my operation video: http://www.youtube.com/watch?v=cwc6QlLVtko, Virtually symptom free since, no relap
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Postby Cece » Wed Jan 05, 2011 1:18 pm

Parkinson's, not MS
http://www.neurology.org/content/54/3/710.abstract

Objective changes in motor function during placebo treatment in PD
Christopher G. Goetz, MD, Sue Leurgans, PhD, Rema Raman, MS and Glenn T. Stebbins, PhD

Conclusion: Based on a rigorous definition of placebo-associated improvement, prominent improvements in objective measures of PD disability occur during clinical trials. Because placebo-associated improvements occur throughout a 6-month trial, placebo-controlled studies in PD should be at least 6 months to capture early as well as late improvements.
Last edited by Cece on Wed Jan 05, 2011 8:36 pm, edited 1 time in total.
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Postby Cece » Wed Jan 05, 2011 1:21 pm

http://www.neurology.org/content/46/6/1613.abstract

Meta-analysis of the placebo-treated groups in clinical trials of progressive MS

Neurology June 1, 1996 vol. 46 no. 6 1613-1619

Brian G. Weinshenker, MD, Maher Issa, MSc and Jon Baskerville, PhD

Abstract
The behavior of the control groups can substantially affect the power and outcome of a clinical trial.We report a meta-analysis of the control groups of four large, double-blind, placebo-controlled clinical trials of immunosuppressive treatment of progressive MS to address the sensitivity of five hypothetical definitions of treatment failure (TF). The rate of TF in the aggregate control groups (n = 427) was 31% when a confirmed increase of 1.0 expanded disability status scale (EDSS) point was required at the end of the trial; it was 51% when confirmation was not required and TF was allowed at the first point where the criteria for TF were met. The rate of confirmed TF was 45% when the TF criteria were indexed to baseline EDSS, accounting for the observed differences in staying times at different EDSS levels. We developed models predicting TF in progressive MS. In addition to baseline EDSS, the pyramidal functional score and, for one definition, brainstem functional score were associated with probability of TF.

I think this is a good one but I don't understand what it's saying.
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Postby Cece » Wed Jan 05, 2011 1:24 pm

http://msj.sagepub.com/content/12/6/826.abstract
Regression to the mean in multiple sclerosis

S Martínez-Yélamos

Mult Scler November 2006 vol. 12 no. 6 826-829

Multiple Sclerosis Unit, Service of Neurology, Hospital Universitari de Bellvitge, IDIBELL, l’Hospitalet de Llobregat, Barcelona 08907, Spain

Abstract
In order to ensure sufficient disease activity, patients with relapsing remitting (RR) multiple sclerosis (MS) are often included in randomized placebo-controlled trials, only if they have a high baseline activity. These patients, whose evolution is unusual in the pre-study period, will tend to show a more usual behavior when followed up over a period of time. This phenomenon is known as regression to the mean. Regression to the mean should be taken into account in correctly interpreting long-term studies of cohorts treated without a placebo control group, which use the baseline period as control. The aim of this study was to evaluate the relevance of this phenomenon in a non-treated cohort of RRMS patients, selected with similar criteria to those used in randomized placebo-controlled clinical trials. Forty-four patients with definite RRMS, with two or more relapses in the previous two years, and a baseline EDSS ≤ 5.5 were prospectively followed. The mean number of relapses spontaneously decreased from 1.72 (SD: 1.4) in the year prior to enrolment, to 1.0 (SD: 1.3) during the first year of follow-up (PB < 0.05). Regression to the mean may explain as much as 40% of the reduction in the relapse rate from the baseline period to the period on-study.
Last edited by Cece on Wed Jan 05, 2011 6:18 pm, edited 1 time in total.
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Postby Cece » Wed Jan 05, 2011 1:35 pm

Annals of Neurology
Volume 49, Issue 5, pages 677–681, 1 May 2001

Placebo-controlled clinical trials in multiple sclerosis: Ethical considerations
Fred D. Lublin MD1,*, Stephen C. Reingold PhD2

Abstract
The availability of partially effective therapies for some forms of multiple sclerosis (MS) raises practical and ethical issues for future placebo-controlled clinical trials. An international Task Force of clinicians, statisticians, ethicists and regulators was convened to discuss these issues and develop consensus. The Task Force concluded that placebo-controlled clinical trials in forms of MS for which partially effective therapies exist were ethical, so long as study subjects were fully apprised of the availability of such therapies and were encouraged to pursue them outside of a clinical trial. Patients who decline to utilize available treatments, after proper education and counseling, or those that fail all therapies can be considered to have no treatment alternatives and thus may participate in a placebo-controlled trial.

http://onlinelibrary.wiley.com/doi/10.1 ... .1025/full
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Postby Cece » Wed Jan 05, 2011 1:39 pm

Placebo effects: clinical aspects and neurobiology
Barry S. Oken

Brain (2008) 131 (11): 2812-2823.
doi: 10.1093/brain/awn116

+ Author Affiliations
Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA
Correspondence to: Barry S. Oken, Department of Neurology, CR-120, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA E-mail: oken@ohsu.edu

Summary
Placebo effects are beneficial health outcomes not related to the relatively direct biological effects of an intervention and can be elicited by an agent that, by itself, is inert. Understanding these placebo effects will help to improve clinical trial design, especially for interventions such as surgery, CNS-active drugs and behavioural interventions which are often non-blinded. A literature review was performed to retrieve articles discussing placebo implications of clinical trials, the neurobiology of placebo effects and the implications of placebo effect for several disorders of neurological relevance. Recent research in placebo analgesia and other conditions has demonstrated that several neurotransmitter systems, such as opiate and dopamine, are involved with the placebo effect. Brain regions including anterior cingulate cortex, dorsolateral prefrontal cortex and basal ganglia have been activated following administration of placebo. A patient's expectancy of improvement may influence outcomes as much as some active interventions and this effect may be greater for novel interventions and for procedures. Maximizing this expectancy effect is important for clinicians to optimize the health of their patient. There have been many relatively acute placebo studies that are now being extended into clinically relevant models of placebo effect.

http://brain.oxfordjournals.org/content ... 2.abstract
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Postby Cece » Wed Jan 05, 2011 6:23 pm

Furthermore, the magnitude of the placebo response increases with the extent of the placebo
intervention, suggesting that the response to any surgical procedure might be particularly pronounced.

http://rds.sfcc-cpmc.net/ticr/syllabus/ ... an1999.pdf
New England Journal of Medicine
Volume 341:988-992 September 23, 1999 Number 13 Next
Use of Placebo Surgery in Controlled Trials of a Cellular-
Based Therapy for Parkinson's Disease

here are the citations listed after that statement:

Clark PI, Leaverton PE. Scientific and ethical issues in the use of placebo controls in clinical trials.
Annu Rev Public Health 1994;15:19-38.[CrossRef][Medline]

Beecher HK. Surgery as placebo: a quantitative study of bias. JAMA 1961;176:1102-1107.

And now we've come full circle, because Beecher is the one being discredited in the article in my first post. :)
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Postby Cece » Wed Jan 05, 2011 6:36 pm

From an ethical standpoint (Table 1), Horng and Miller (8) have suggested that the use of a sham control can be ethically justified if (1) there is a valuable question to be answered by the research and the risk of the sham control is justified by the value of the knowledge to be gained, (2) the sham control is methodologically necessary to test the study hypothesis, (3) the risk of the sham control itself has been minimized and does not exceed a threshold of acceptable research risk, and (4) the nature of misleading involved in the administration of a placebo control is adequately disclosed to and accepted by the subject during the informed consent process.

http://pats.atsjournals.org/cgi/content/full/4/7/574

Does the CCSVI sham procedure arm of a RCT meet these four criteria?

yes, there is a valuable question to be answered

But is the risk justified (#1) or does it exceed acceptable research risk (#3)? Minimally invasive is still invasive and there might be sedation involved.
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Postby Cece » Wed Jan 05, 2011 8:29 pm

Ok, I've thought about all these and it's this one:
http://www.thisisms.com/ftopicp-149167.html#149167
that seems significant. It's about regression to the mean. When the drug trials pick their patients, they set the criteria to include patients with high disease activity. I've noticed this; I wouldn't qualify for many since I have been stable with low disease activity.

Well 'regression to the mean' means that if a patient has a high amount of activity, it'll slow down anyway and end up closer to the expected mean. So these patients who are chosen for their high disease activity, in both the main group and the placebo group, then regress toward the mean. According to the abstract, 40% of the effect of the placebo can be explained instead by this regression to the mean.

What does this mean to us? (Or at least to me?) When they say MS patients have a high placebo response, it is not true. It appears that way because the selection criteria of nearly every trial favors patients with high disease activity. This high disease activity will regress toward the mean, making it appear like a high placebo effect is in place. This does not affect the analysis because apples to apples they're comparing the drug group to the control group and all met the criteria to get into the study. But it has been damaging to our reputation as being highly susceptible to the placebo response.
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Postby NHE » Thu Jan 06, 2011 4:44 am

Cece wrote:
From an ethical standpoint (Table 1), Horng and Miller (8) have suggested that the use of a sham control can be ethically justified if (1) there is a valuable question to be answered by the research and the risk of the sham control is justified by the value of the knowledge to be gained, (2) the sham control is methodologically necessary to test the study hypothesis, (3) the risk of the sham control itself has been minimized and does not exceed a threshold of acceptable research risk, and (4) the nature of misleading involved in the administration of a placebo control is adequately disclosed to and accepted by the subject during the informed consent process.

http://pats.atsjournals.org/cgi/content/full/4/7/574

Does the CCSVI sham procedure arm of a RCT meet these four criteria?

yes, there is a valuable question to be answered

But is the risk justified (#1) or does it exceed acceptable research risk (#3)? Minimally invasive is still invasive and there might be sedation involved.


Here's another question that I believe is relevant to possible CCSVI placebo controlled trials. The placebo treatment should not have any unintended positive effects. In effect, the simple act of putting a catheter into either the jugular or azygos vein may release some blockages such as webs or a septum. Insert a catheter if you wish, but for the placebo arm, keep it in some other vein.

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Postby pairOdime » Thu Jan 06, 2011 5:58 am

What if the control (placebo) group receive a catheter angiogram and not the cath v-gram to insure they are not removing webs and membranes inadvertently. They would enter through the femoral artery and not the vein.
It's a paradigm shift
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Postby DrCumming » Thu Jan 06, 2011 6:53 am

pairOdime wrote:What if the control (placebo) group receive a catheter angiogram and not the cath v-gram to insure they are not removing webs and membranes inadvertently. They would enter through the femoral artery and not the vein.


I think the real problem with the placebo arm is that many patients will know if they have been treated. Many patients I have treated have had some neck discomfort after.

I am not too concerned with simple catheterization of a vein breaking down webs and/or membranes.
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Postby DrCumming » Thu Jan 06, 2011 7:08 am

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