A general thread on the PACE trial!

Snow Leopard said:
Again, how does that explain this?
https://www.ncbi.nlm.nih.gov/pubmed/15784798
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The placebo response in the treatment of chronic fatigue syndrome: a systematic review and meta-analysis, 2005, Cho HJ1, Hotopf M, Wessely S.
CONCLUSION:
In contrast with the conventional wisdom, the placebo response in CFS is low. Psychological-psychiatric interventions were shown to have a lower placebo response, perhaps linked to patient expectations.
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I haven't read all the preceding posts, but I am not surprised by low placebo response with CBT/GET because those patients who may start with hope of improvement and stick to the therapy may be made worse by it, over-riding any placebo response. Whereas with a blinded drug trial, the placebo group aren't made worse by the placebo, so placebo effect can still show up in the results.
Or have I completely lost the plot?
 
Trish said:
I haven't read all the preceding posts, but I am not surprised by low placebo response with CBT/GET because those patients who may start with hope of improvement and stick to the therapy may be made worse by it, over-riding any placebo response. Whereas with a blinded drug trial, the placebo group aren't made worse by the placebo, so placebo effect can still show up in the results.
Or have I completely lost the plot?
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The "placebo response" in patients is highly likely to be the same as it is in any other group of people. The problem is a variety of reporting biases are being bundled up as a "placebo effect" and then claiming that the placebo effect* is magically high in some cases and low in others. When the real reason is the reporting biases are better controlled in some contexts, compared to others.

*placebo effect defined as: a beneficial effect produced by a placebo drug or treatment, which cannot be attributed to the properties of the placebo itself, and must therefore be due to the patient's belief in that treatment.
 
Snow Leopard said:
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*placebo effect defined as: a beneficial effect produced by a placebo drug or treatment, which cannot be attributed to the properties of the placebo itself, and must therefore be due to the patient's belief in that treatment.
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The “placebo effect” can also be nothing to do with expectations, but can show up because of the chance that some individuals out of both groups will make a spontaneous improvement. Ie Regression to the mean.
 
This is to a large extent what my grand round presentation was about.

I think there is a simple sense in which the placebo effect for healing of a broken bone is small and the placebo effect for anything where the ascertainment of outcome is subjective, as for pain, is likely to be larger. ME is bound to fall more in the second category at least in the wider context of a spurious positive result that gets bundled under placebo effect.
 
BruceInOz said:
Is there a "real" placebo effect or is it just entirely due to hidden biases?
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Yes, the real placebo effect is a transient reduction in pain due to conditioning of the bodies endorphin system. There is some biological evidence of this. This system has obvious evolutionary advantage, namely being able to temporarily suppress pain for the purpose of escaping danger.
 
Snow Leopard said:
Regression to the mean is not a placebo effect
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But @Keela Too did put it in quotes - "placebo effect" so she was absolutely correct. Just as one might say, and Noam Chomsky did, that the "mind-body problem" has in fact been a body-body problem since Newton's theory of gravitation.

"Placebo effect" is all too often used to include regression to the mean by my colleagues.
 
"Contextual effects" is sometimes used in French instead of placebo effect. I don't know if it's the case in English? It seems more accurate as it aknowledges that a lot of processes are at play and gets rid of the kind of esoteric mind body thinking that often accompanies the term placebo.
 
The endorphin release associated with placebos could be part of the body's behaviour control system. It could be seen as the reward for finding a solution a for health problem.

It makes sense that it hurts until you find a solution to the pain. Then it no longer need to hurt as much and your efforts should be rewarded so that you continue to take care of yourself.

Seeing a doctor and leaving with the feeling that you've done something useful seems to count as "finding a solution". Even if the treatment is actually ineffective.
 
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Another thought on PACE, and probably other trials. Given it is often ethically unacceptable to include a control arm having no treatment, each arm therefore has one of the interventions plus SMC (standard medical care). But what about the case where SMC actually conflicts with the intervention, as would seem to have been the case with PACE. How does that work out?

For example, SMC for pwME pre-GET, would have been much more inclined towards real pacing, and not pushing yourself beyond sensible limits, and to listen to your body; this is the sort of advice my wife received in 2006'ish. So how could you be having that treatment, whilst also having treatment encouraging you to ramp up your activity levels and to ignore your symptoms. That alone sounds bonkers.

ETA: Just discussing this with my wife, and she reminded me that the ME specialist we saw in 2007, recommended pacing, and enquired at great length how my wife managed her days, and how she paced herself. He told her that although they could offer CBT they were not doing so for my wife because he felt it would provide no additional benefit to her. So I'm just clarifying the advice my wife was given at the time.
 
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Barry said:
Another thought on PACE, and probably other trials. Given it is often ethically unacceptable to include a control arm having no treatment, each arm therefore has one of the interventions plus SMC (standard medical care). But what about the case where SMC actually conflicts with the intervention, as would seem to have been the case with PACE. How does that work out?
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This is from the SMC manual:
Specialist medical care is the most usual treatment for CFS/ME, and it helps many people improve. You get a confirmed diagnosis, an explanation of why you are ill, and general advice about managing your illness. Your specialist might either prescribe medicine to help you manage troublesome symptoms such as insomnia and pain or advise your GP about what medicine is appropriate.

Here is some of the advice you may get as part of specialist medical care.

• Avoid extremes of activity. Many people with CFS/ME get into a pattern of being very active and then very inactive. It is better to give yourself a pattern of activity that you can keep going. This may be a lower level of activity you are used to.
• Set a daily level of activity. It will help to set a simple level of activity that you do every day. Stretching exercises, for example, will minimise the weakening effects that creep up if you don’t use your muscles for a time.
• Make only gradual changes to your activity level. If you feel you can increase your level of activity, and not everyone does, make changes carefully and gradually. A sudden increase in activity may make your symptoms worse.
• Try to reduce stress in your life. When we are ill, stresses such as excessive work demands don’t help us. If you can reduce these stresses, it will help you recover.
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But it also says:
It is important that this advice:
...
• Does not contradict the principles of practice of any of the supplementary therapies, for example, does not argue against increasing activity or pacing.
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So I guess the SMC doctor would need to tailor the advice they gave depending on which group the participant was in.
 
Barry said:
Another thought on PACE, and probably other trials. Given it is often ethically unacceptable to include a control arm having no treatment, each arm therefore has one of the interventions plus SMC (standard medical care). But what about the case where SMC actually conflicts with the intervention, as would seem to have been the case with PACE. How does that work out?

For example, SMC for pwME pre-GET, would have been much more inclined towards real pacing, and not pushing yourself beyond sensible limits, and to listen to your body; this is the sort of advice my wife received in 2006'ish. So how could you be having that treatment, whilst also having treatment encouraging you to ramp up your activity levels and to ignore your symptoms. That alone sounds bonkers.

ETA: Just discussing this with my wife, and she reminded me that the ME specialist we saw in 2007, recommended pacing, and enquired at great length how my wife managed her days, and how she paced herself. He told her that although they could offer CBT they were not doing so for my wife because he felt it would provide no additional benefit to her. So I'm just clarifying the advice my wife was given at the time.
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Now this is getting weird. The current NICE guidelines (CG53) recommending CBT & GET were put in place in 2007. I’m not sure of timescales, but is it possible that some PACE trial participants were getting CBT/GET as part of SMC?

Or had the trial period ended before CG53 came into effect?
 
Unable said:
Now this is getting weird. The current NICE guidelines (CG53) recommending CBT & GET were put in place in 2007. I’m not sure of timescales, but is it possible that some PACE trial participants were getting CBT/GET as part of SMC?

Or had the trial period ended before CG53 came into effect?
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My memory is that recruitment to PACE was 2005-2007? The SMC patients clearly did not get CBT or GET but it does all seem very muddled and I think Barry's point is basically valid. Adding CBT or GET to SMC is not necessarily a reality.
 
And as patient experiences of conventional care differ widely, it is likely there was nothing standard about SMC!

On top of that many GPs use the less formal version of GET - it goes along the lines of “I’ve heard that exercise helps with ME, you should make sure to fit some exercise into your day if you want to improve.”

If SMC had to be defined by PACE (eg don’t offer CBT/GET to any trial patients as part of the SMC you offer them) then it really wasn’t “standard” medical care, but yet another form of care.

All very muddy indeed.
 
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