Professor & patients' paper on the solvable biological challenge of ME/CFS: reader-friendly version
Simon McGrath provides a patient-friendly version of a peer-reviewed paper which highlights some of the most promising biomedical research on ME/CFS ...
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Diseases the placebo effect works for, and ones it doesn't work for (it's to do with dopamine)

Discussion in 'Other Health News and Research' started by Hip, Dec 12, 2016.

  1. Hip

    Hip Senior Member

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    I agree, but I would differentiate the general positive feeling of "hope on the horizon" that a potential future treatment offers, from the subjective improvements in symptoms that the placebo effect can give you once you actually swallow a pill or have the treatment.

    The rituximab research gives me that positive "hope on the horizon" feeling, but it may be some years before most of us have the opportunity to try rituximab.
     
  2. Hip

    Hip Senior Member

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    I just came across this systematic review which found that the measured placebo effect in ME/CFS patients was much lower than predicted, and lower than in some other medical conditions.
     
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  3. thijs

    thijs

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    They mean the placebo response of the 'control' intervention like supportive listening or stretching exercises, right?
    Or the natural course of the no-treatment group?

    If it's the former, how they know these treatments are placebo treatments?
    And if it's a placebo, how do they know the other treatment (CBT/GET) isn't?
     
  4. Jenny TipsforME

    Jenny TipsforME Senior Member

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    Yes I think this is important too. Hope on the horizon staves off depression and suicidal thinking. Research is getting there, we won't be stuck like this forever...

    Coincidentally I was commenting on another thread that I think placebo effect can backfire in ME due to our PEM (I think this is specific).

    I'll just find that post.
     
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  5. Jenny TipsforME

    Jenny TipsforME Senior Member

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  6. Hip

    Hip Senior Member

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    A placebo is just a sham version of the real drug or treatment. So if you gave the treated ME/CFS patients drug X, the control group ME/CFS patients will get a pill looking just like drug X, but which in fact contains no active drug, just an inert substance.

    It is normal to get some degree of positive response in the placebo group in any study; what this systematic review found is that placebo effect in ME/CFS patients was much lower than predicted, and lower than in some other medical conditions.
     
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  7. Jenny TipsforME

    Jenny TipsforME Senior Member

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    In a Mendus experiment I had what seems like a nocebo effect (we had proper placebo tablets from the manufacturer) but on further consideration it seemed like placebo effect followed by ME crash.
     
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  8. Jenny TipsforME

    Jenny TipsforME Senior Member

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    @Hip might we be more inclined to nocebo effects due to general sensitivity to tablets? This could even be non psychological, e.g. we actually do respond negatively to an additive in the placebo!
     
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  9. Hip

    Hip Senior Member

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    That's what I think as well. ME/CFS patients often find that drugs and supplements can make them feel worse, rather than better, so anyone experienced with trying out medications for ME/CFS will have learnt to expect that a worsening of symptoms is just as likely as an improvement.

    Since the placebo effect is due to expectations of a positive result, because ME/CFS patients' expectations for a positive result may be low due to past negative experiences with trying drugs, then the placebo effect will be low as well.

    Certainly I know whenever I try out any new drug or supplement, the foremost thought and concern in my mind is that the medication could make me worse (and I am always on the lookout for feeling worse when trying new medications, as well as looking out for possible beneficial effects).



    I also think a low placebo effect in ME/CFS might be due to a dysfunctional dopaminergic system: if placebo effect physiology is keyed on the dopamine system (as the study in the first post of this thread suggests), then any dopaminergic dysfunction in ME/CFS might weaken placebo responses (and there have been suggestions that dopamine synthesis is low in ME/CFS).
     
  10. Jenny TipsforME

    Jenny TipsforME Senior Member

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    Also we are probably more experienced than most with disappointment. :(

    I'm just starting fludrocortisone. I do think it's helping in quite a significant way right now but I'm being really cautious with myself because I don't want to deal with getting my hopes up over placebo effects, and either there's no benefit, or I make myself worse from blocking out symptoms and then doing too much.

    Over the years with ME fluctuations I've also developed a silly superstition about not claiming improvements too soon. The logical part of me finds this ridiculous but I do still fear jinxing it.

    These experiences must affect my experience of placebo and nocebo effects.

    My personal experience of trying a double blinded placebo controlled tablet is here https://tipsforme.wordpress.com/2016/02/12/placebo-nocebo-mitoq/
     
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  11. Jenny TipsforME

    Jenny TipsforME Senior Member

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    A quote from that post is

    "
    Another idea that occurred to me is that a Placebo Effect may play out in quite a strange way in ME. My initial reaction to Bottle 2 was mainly positive in a cognitive/emotional way. I felt much more optimistic, like I could do more and concentrate longer. Physically I seemed to get worse and had much worse insomnia.
    What if a degree of pessimism is actually quite protective in ME? I used to be prone to a boom and bust cycle but usually now level it out with Pacing. In my burst of optimism, sensible Pacing evaporated and I did more because I believed I was taking something beneficial (although I also knew you’re meant to carry on Pacing!). The extent of my reaction was out of my normal spectrum, but if I get mentally over stimulated I do often have trouble sleeping. Doing too much without sleep will very quickly create a ME flare or relapse. A detail that supports this theory is my symptoms took a few days to go after stopping the experiment, knowing it had been a placebo. Fortunately I didn’t have a relapse."
     
  12. Woolie

    Woolie Senior Member

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    It is really astounding what passes for publishable research in this area.The writers of this publication don't even seem to have a basic grasp of what the placebo effect is.

    The paper defines the 'placebo effect' as an improvement in any 'control' group in any MECFS treatment study. That included proper double-blinded placebo groups (you know those taking a sugar drug but not knowing it), non-blinded control groups received a non-target treatment, like specialist medical care or 'relaxation therapy' or the like. It also included people who got nothing and knew they got nothing.

    Then they measured how much improvement these groups showed. Not much.

    Then they went on to conclude that MECFS patients are resistant to expectancy effects!

    But spontaneous improvement rates do not equal expectancy effects. Spontaneous improvement is an observation, and it can have many causes. Expectancy effects are only one of the possible reasons why spontaneous improvement occurs.

    Others are:
    * natural fluctuation in symptoms
    * spontaneous remission
    * regression to the mean (the fact that people often enrol in studies when they are feeling particularly bad, so there will be a natural trend for thing sot be not so bad several months later).

    The rate of spontaneous improvement in a control group will depend on a lot of things:
    * How 'generous' the outcome measure is. Using the measure of overall improvement presented in the PACE Lancet paper, a whopping 45% of usual medical care patients improved!
    * The degree to which symptoms fluctuate. Diseases that fluctuate a lot will tend to show more improvement in your control group.
    * Time to diagnosis. If the disease is diagnosed quickly, there will likely be a greater incidence of improvement than if the disease takes long time to diagnose (and MECFS takes at least 6 moths, and in most cases, years).

    This awful 'placebo' paper has been used by various pro-PACE authors to argue that it was okay for PACE to upsell CBT and GET to the patients that got it. It makes no difference, you see, because MECFS patients are immune to the placebo effect!

    Astoundingly bad science.
     
  13. Hip

    Hip Senior Member

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    I always appreciate your incisive critique of studies, @Woolie.

    If you were going conduct a study to measure susceptibility to the placebo effect in ME/CFS, in comparison to other medical conditions, is there any particular way that you would approach it, in order to get reliable results?
     
    Last edited: Sep 12, 2017
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  14. Woolie

    Woolie Senior Member

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    I wouldn't want to ask this question, because my personal view of the placebo effect is that its a boring artefact and not a real source of health benefits.

    But let's just say I did want to ask the question. Then I would carefully randomly assign a large number of patients to one of two groups. I'd give the first group dummy pills and tell them they were trialling a real drug (that is, I'd lie to them). Then I'd ask them to report various aspects of their symptoms regularly over a specified period.

    Then the second group, I would tell them that I am interested in how their symptoms vary across a specified period, and ask them to do the same type of reporting as the first group.

    Then I would compare outcomes for the two groups. In this design, the only thing you vary is expectation.

    This a simple and well known type of design for looking at expectancy effects, and its impossible to believe that the authors of the Cho study (the one I canned above) would not have known about it. I think they probably just wanted a quick paper.

    If I did do this study, I would also vary the reporting instructions. Some people would have to report their current symptoms every few hours, others would only assess their health retrospectively once a week. I would also include a variety of measures, including some that don't involve symptoms (e.g. activities performed or number and duration of walks).

    I would be interested in whether the were any group differences, and if so, if these were higher for some types of reporting than for others (for example, I would predict the hourly reporting to be less vulnerable to expectancy effects than the retrospective weekly reporting because there, recall bias can creep in).
     
  15. Hip

    Hip Senior Member

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    I agree, but I am interested in this idea that there might be a low placebo response in ME/CFS, because if that were the case, it helps validate ME/CFS patient observations when they report benefits from a treatment they are trying.

    You often see on these forums that when major benefits are reported from a treatment that seems unlikely (on theoretical grounds) to be able to help, people will often dismiss the reported benefit as a placebo effect. But if we could reliably show that ME/CFS is not very susceptible to the placebo effect, then one would question such dismissals.
     
  16. liverock

    liverock Senior Member

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    What else would you expect with Simon Wessely as a co-author of the study.:rolleyes:
     
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  17. A.B.

    A.B. Senior Member

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    But we already have evidence ME/CFS patients are susceptible to the placebo effect. See the CBT/GET literature.

    Having ME/CFS might make you less of a believer in certain things and more of a believer in other things but you won't stop being a human that wants to get better and believes in treatments enough to try them. If somebody tried a treatment they probably believed in it at least a little.
     
  18. Hip

    Hip Senior Member

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    Not saying that ME/CFS does not have some susceptibility to the placebo effect, but rather asking whether the placebo response is high or low in ME/CFS, in comparison to other illnesses.

    The article linked to in the first post of this thread is about which diseases respond well to the placebo effect, and which respond poorly. To quote the article:
     
  19. A.B.

    A.B. Senior Member

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    Whatever, I don't have the energy to explain this again. It's surprising that after all these PACE discussions people here are making the same mistake as the PACE authors.
     
  20. Woolie

    Woolie Senior Member

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    If by the placebo effect you mean expectancy effects (higher chance of reporting success if one believes one has had a potentially helpful treatment than if one doesn't), then they are a human universal.

    MECFS people are likely to be just like other mere mortals, they will be vulnerable to confirmation bias, recall bias, and all the other things that may contribute to expectancy effects.

    I think this is what the PACE study shows - that PwMEs are normal in that they show expectancy effects. This is why the CBT and GET groups self-reported greater symptomatic improvement after treatment (but it didn't persist, and it didn't extend to objective measures).

    The PACE patients were mainly new to CFS treatment, I think? One factor that might influence PwMEs' response to expectancy effect is past experience. So I suppose if we've had a lot of past experiences of things not working, this might get incorporated into the heuristic.

    Maybe experience reading your body signals might help reduce expectancy effects too. We have a lot more experience in that department than healthies.
     

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