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Hi Michael,

 

There are some interesting oxygen papers that might provide insight. Interesting findings across ages and conditions.

 

Oxygen saturation targets in infants with bronchiolitis (BIDS): a double-blind, randomised, equivalence trial

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00163-4/fulltext?rss=yes

 

Cochrane Database Syst Rev. 2013 Aug 21;(8):CD007160. doi: 10.1002/14651858.CD007160.pub3.

Oxygen therapy for acute myocardial infarction.

Cabello JB1, Burls A, Emparanza JI, Bayliss S, Quinn T.

http://www.ncbi.nlm.nih.gov/pubmed/23963794

 

In stem cell regeneration the timing and amounts of oxygen influence the neurotrophic factors so it may be quite complex. The community effect is also interesting given that humans are prone to failure to thrive and the hippocampus shrinks with pain and sustained social exclusion. Meeting for therapy and shared hope on a regular basis may be its own effect. The pill does not involve interacting with non judgmental people.  TBI is often associated with incredible emotional vulnerability.  

 

Please keep me updated on your results as it is a hot discussion in brain injury groups, thank you for sharing this and so glad it is being researched.

 

Best

 

Amy

 

 

 

From: "[log in to unmask]" <[log in to unmask]> on behalf of Michael Bennett <[log in to unmask]>
Reply-To: Michael Bennett <[log in to unmask]>
Date: Monday, June 13, 2016 at 12:49 AM
To: "[log in to unmask]" <[log in to unmask]>
Subject: Re: placebos and side effects

 

Great thread comrades - placebo is a fascinating concept. Interested to hear how much overlap you guys feel exists between 'placebo effect' and 'participation effect'. To provide context, I am involved in a therapy theat requires confinement in an airtight chamber and breathing oxygen (hyperbaric oxygen therapy). In order to blind trial participants successfully, the best accepted sham procedure is to use the same confinement procedure, but breathing air at a low pressure rather than oxygen.

Several recent trials have suggested small treatment effects in both groups with no statistical or clinical differences between groups. Some colleagues are calling this a placebo effect, while others feel it is better described as an effect of participation in what is something of a 'ritual' on a daily basis. I incline to the latter and suspect this could be quite a powerful effect in some illnesses, but it seems to me the difference (if any) is pretty subtle. After all, would not an effect of taking a placebo tablet involve much the same cognitive process whereby the participant feels they are part of a treatment process?

As an aside, others take the view that this simply shows that hyperbaric air at lowish pressure has the same 'real' therapeutic effect as 100% oxygen at higher pressures - which would make an interesting dose-response curve. But that is a whole other story!

Mike Bennett

From: Evidence based health (EBH) [[log in to unmask]] on behalf of Bill Cayley, Jr [[log in to unmask]]
Sent: Monday, 13 June 2016 12:22 AM
To: [log in to unmask]
Subject: Re: placebos and side effects

 Returning to one of Mark Johnson's comments ("over the years I have so many times...heard claims of “placebo effect” used as a cover for provision of “treatment” is without evidence base"), as pointed out in a very good BMJ blog by Tim Caulfield (http://blogs.bmj.com/bmj/2015/10/22/timothy-caulfield-the-straw-men-of-integrative-health-and-alternative-medicine/): "by invoking the usefulness of the placebo effect as a justification for integrative health, CAM supporters are recognizing that the therapies in question have no actual physical effect beyond placebo."

 

"Placebo effect" cannot be used to cover for something implausible, unproven, etc. IF there truly is a genuine "placebo" effect, then using it as cover for something else (ie, unproven, unlikely, or something one chooses to 'believe' in despite evidence to the contrary) is subterfuge.

 

Bill Cayley, Jr, MD MDiv
[log in to unmask]

Work: 715.286.2270
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"I think some of the most celebrated moments in human achievement should be those times when everything is going against a person and they are down in the dumps but they simply choose to get up. That's real greatness."   -- Ryan Hall

 

On Sunday, June 12, 2016 6:39 AM, Rakesh Biswas <[log in to unmask]> wrote:

 

In light of the earlier comments on the placebo effect (deemed insignificant) I shall be grateful to the group to understand further this quote from a narrative by Sacket linked below, "the hero-statistician of the trial, Paul Canner, carried out a similar analysis for participants who did and didn’t take their placebos as instructed. He showed an even stronger association between compliance effect and mortality (0.151 vs. 0.282; Relative Risk Ratio=46%; z=-8.12; P=0.00000000000000047), implying that one premature death would be prevented for every 10 patients who took their placebo faithfully!" More:http://www.jameslindlibrary.org/articles/why-did-i-become-a-clinician-trialist/

 

best, 

 

rb

Dept of Medicine,

LN Medical College, Bhopal

 

 

On Sun, Jun 12, 2016 at 1:54 AM, Mayer, Dan <[log in to unmask]> wrote:

However, the difference that is considered clinically important in pain studies is about 1.3, making a 0.5 difference clinically unimportant, and doesn't help us with the question of whether a placebo effect actually exists.


Dan

From: Evidence based health (EBH) [[log in to unmask]] on behalf of McCormack, James [[log in to unmask]]
Sent: Saturday, June 11, 2016 4:16 PM


To: [log in to unmask]
Subject: Re: placebos and side effects

 

Regardless of study quality, I think the confusion often lies when people confuse what happens in the placebo group (often 20-25% “better” because of regression to the mean, natural history etc) versus the real placebo effect which is the difference between the placebo group and the no treatment group. The difference between the placebo group and no treatment group typically, other than for pain studies, shows no difference. For pain studies, the difference between the placebo group and the no treatment group is typically ~0.5 on a 10 point VAS if I remember correctly - so there is a placebo effect for pain.

 

James

 

 

On Jun 11, 2016, at 11:00 AM, Mark V Johnston <[log in to unmask]> wrote:

 

Over the years, I have heard and read many claims of dramatic placebo effects.    The claims of strong placebo effects have not been replicable, or if replicated, have been based on studies with poor control and subjective outcome scales without  blinding/masking, that is, measurement bias almost certainly occurred.   The belief in a strong, generalizable  placebo effects – a belief based on writings from the 1950s, as far as I know -- have been effectively disconfirmed.   “Placebo effects” need to be much better and more clearly defined.   More limited psycho-somatic effects still occur in certain situations, in my opinion, but not a strong generalizable real effect.   

 

Sorry If I sound dogmatic, but over the years I have so many times -- hundreds and hundreds of times --  heard claims of “placebo effect” used as a cover for provision of “treatment” is without evidence base.  

 

For this audience, I suspect that my message is just the need to clearly define what is meant by a “placebo effect” and how it can be distinctly measured. 

 

 

Mark V. Johnston, Ph.D.

Professor, College  of Health Sciences,

University  of  Wisconsin – Milwaukee,

(414)  229-3616

 

 

 

From: Evidence based health (EBH) [mailto:[log in to unmask]] On Behalf Of Klim McPherson
Sent: Thursday, June 09, 2016 6:39 AM
To: [log in to unmask]
Subject: Re: placebos and side effects

 

But also the placebo effect itself is sometimes surprisingly dramatic  - we do not know that they will not help.

Klim

 

From: "[log in to unmask]" <[log in to unmask]> on behalf of Jeremy Howick <[log in to unmask]>
Reply-To: Jeremy Howick <[log in to unmask]>
Date: Thursday, 9 June 2016 12:03
To: "[log in to unmask]" <[log in to unmask]>
Subject: Re: placebos and side effects

 

The reason this can happen is that, as Tom pointed out, placebo ingredients are not reported.

Jeremy

<image001.png>

 

T: +44 (0)1865 289 258 E: [log in to unmask]

 

Nuffield Department of Primary Care Health Sciences, University of Oxford
Radcliffe Primary Care Building, Radcliffe Observatory Quarter, Woodstock Road, Oxford, OX2 6GG

 

From: "[log in to unmask]" <[log in to unmask]>
Date: Wednesday, 8 June 2016 23:43
To: Tom Jefferson <[log in to unmask]>, Jeremy Howick <[log in to unmask]>
Cc: "[log in to unmask]" <[log in to unmask]>
Subject: Re: placebos and side effects

 

I cannot see how equipoise can be obtained under these circumstances: we know that placebo will not help but it may harm. 

Ben 

Sent from my iPad 

( please excuse typos & brevity)


On Jun 8, 2016, at 9:49 AM, Tom Jefferson <[log in to unmask]> wrote:

Jeremy, it does not quite work that way. The active placebo trick is not played to even out all potential harms across intervention and control arms, just one harm or a group of harms.

So for example for Relenza which is a dry powder for inhalation the placebo was the lactose based eccipient which could trigger asthmatic attacks in susceptibles just like the "live" arm. Explanation: lactose powder was the eccipient in the active arm so that's fair (Gardasil and alumiunium is similar although no explanation for the choice of placebo is reported in the CSRs). FDA did not agree.

Different for Tamiflu (dehydrocholic acid in low doses to mimick the bitter taste of oseltamivir powder). Except that d acid also causes diarrhoea and gut upset which is a known harm of oseltamivir. FDA seems to have missed this one.

Real? Mistake? Who knows?

Hope this helps,

Tom..  


Dr Tom Jefferson

Honorary Research Fellow

Centre for Evidence Based Medicine

Oxford OX2 6GG

 

On 8 June 2016 at 13:57, Jeremy Howick <[log in to unmask]> wrote:

Question:

  1. ‘Active’ placebos (that imitate some side effect of the experimental treatment) are sometimes used in clinical trials (http://www.ncbi.nlm.nih.gov/pubmed/14974002); this is good for improving success of blinding.
  2. However given that placebo ingredients are rarely reported (http://www.ncbi.nlm.nih.gov/pubmed/?term=howick+golomb+placebo) this creates a potential problem for side effect estimates in trials:
  3. The side effects of the experimental treatment are compared with the side-effects of the ‘placebo’. But if the placebo contains an ingredient that induces a side effect, there will (by definition) be no difference in side effects between the treatment and placebo groups.

Is anyone aware of a real example illustrating point (3): where the experimental treatment was reported to have ‘no side effects’ because there was no drug/placebo difference in side effects, yet where the placebo contained an ingredient that imitated a side effect?

 

Thanks in advance,

 

Jeremy

 

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