Diseases the placebo effect works for, and ones it doesn't work for (it's to do with dopamine)

[Hip]

One or two interesting points are made in the following article:

Here's What Placebos Can Heal—And What They Can't

The article is an interview with biologist Erik Vance about his book Suggestible You: The Curious Science of Your Brain’s Ability to Deceive, Transform, and Heal.



Some excerpts from the article:

Do placebos and the power of the mind work?

What I’ve found is yes, but not with everything. There are rules and conditions in which healing can be incredibly effective. Parkinson’s, chronic pain, irritable bowel syndrome, depression, anxiety, certain types of asthma, and autoimmune deficiencies are all very placebo-responsive. But cancer is not.

Placebos have been particularly effective in the treatment of Parkinson’s disease. How do you explain that?

Parkinson’s is the perfect disease to talk about placebos. It is a chronic deficiency of dopamine, which is one of those brain chemicals that does a lot of jobs in our bodies. One of [dopamine’s] important roles is in reward processing: how we think about good things we might get in the future.

Expectation drives placebos. And dopamine is a chemical that’s very responsive to our expectations. Parkinson’s happens to be a deficiency in the very chemical that’s very important in placebo effects and rewards.

If you look at Alzheimer’s, which does not have a high placebo response, you start to see that there are rules at play when it comes to placebos. It’s not your brain magically doing all these crazy things. There are certain chemicals we have access to and others we don’t.

So what Erik Vance seems to be saying is that the placebo effect involves dopaminergic effects, and so stands a good chance of working for diseases where dopamine is low, or for diseases where increasing dopamine may be helpful.

 

[hixxy]

I think my dopamine is low. Where's my placebo effect?

 

[Hip]

I think my dopamine is low. Where's my placebo effect?

In this post, I suggested that focusing on an imaginary but wonderful destiny may have serotonergic or dopaminergic effects in the brain that create disease-modifying effects, and this may explain why in rare cases, some ME/CFS patients say they have improved from therapies such as the Mickel Therapy and the Lightening Process.

In short, the claimed improvements in ME/CFS from such therapies may come from using thoughts and the placebo effect to raise dopamine.

 

[wdb]

This was written in response to a different piece but I think it applies equally here.

I don't think it is any coincidence that the conditions mentioned as responsive to placebo are all largely measured subjectively but cancer which is not responsice can be qualtified objectively.

This is where the placebo narrative almost always breaks down – popular writers like Begley talk about physiological mechanisms like endorphins and dopamine without mentioning all the other effects that are being measured in those clinical trials they are citing as evidence for how powerful those mechanisms are. What is measured in the placebo response includes things like reporting bias, or the desire of subjects to feel better, to please their doctor or the researcher, and to justify their prior decisions (to trust the doctor, take the treatment, enter the study, etc.). Begley fails to distinguish, in other words, between the pain that patients feel and the pain that they report. In studies we never know and cannot measure how much pain patients feel, only how much pain they report. Anything that would affect that reporting will also be lumped into “the placebo response” that is measured in the placebo arm of the study.

This is not quibbling. There is good reason to believe that reporting bias may be the major component of measured placebo effects.

Begley also fails to mention non-specific responses. Anxiety reduction from the belief that one is getting treated can certainly improve one’s mood and outlook on their symptoms (and their reporting of symptoms). Being in a study also involves getting medical attention and is associated with better self-care as well. This is partly the Hawthorne effect – looking to see how patients do is likely to have an effect all by itself, improving compliance and self-care, for example.

The Placebo Narrative

 

[Hip]

I don't think it is any coincidence that the conditions mentioned as responsive to placebo are all largely measured subjectively

Yes, that's always an issue in subjectively reported symptoms: are the symptoms actually better, or does your more positive mood just tend to mask them.

 

[Barry53]

looking to see how patients do is likely to have an effect all by itself

This has engineering equivalents where, if care is not taken, the very act of making a measurement can influence the value of what you are attempting to measure. e.g. When measuring a voltage, the voltmeter's internal impedance must be a lot higher than the circuit's impedance where you are measuring, else the voltage reduces simply by connecting the voltmeter; the voltage you read is therefore artificially low. This is just one example.

 

[Hip]

At least with ME/CFS, you have the 2-day CPET test which can objectively measure the energy metabolism dysfunction in ME/CFS patients, so using this test, it should be possible to figure out whether a dopamine-raising placebo response is merely masking the symptoms of ME/CFS, or whether that raised dopamine is somehow having system-wide disease modifying effects that show up as improvements on the 2-day CPET.

 

[alex3619]

Yes, that's always an issue in subjectively reported symptoms: are the symptoms actually better, or does your more positive mood just tend to mask them.

We know that in asthma the use of CBT can produce subjective improvement, but no actual improvement as measured by objective tests. Most conditions have some objective tests that can be run, but those promoting the power of the mind, positive thinking, or CBT, tend (but not always) to scrupulously avoid objective evidence. It makes the entire field dubious.

Having said that, as an hypothesis the idea that this is a dopaminergic phenomenon is something that is testable, and it would be interesting to see the data from objective measures relating to this in future studies.

Let me presume for a moment the hypothesis is correct. Because of our severe metabolic problems it may be that a proper placebo response has modified reliability in us. We also have to consider that much of the time people, particularly those in psychotherapy, often work with what they think is happening, and not what is actually happening, and so the psychotherapy can bias their response to questions.

Objective evidence. Period. I distrust subjective evidence in science.

 

[Hip]

Having said that, as an hypothesis the idea that this is a dopaminergic phenomenon is something that is testable, and it would be interesting to see the data from objective measures relating to this in future studies.

Dr Andrew Miller's ideas on how low dopamine may be responsible for an undesirable amplification of the effects of inflammation in the brain are interesting. To quote Cort's article:

Hypersensitized to Inflammation?

"Thus, the activation of inflammatory pathways by viruses or other pathogens may represent one mechanism of altered basal ganglia function leading to symptoms of fatigue in patients with CFS." – Miller et al.

Miller suggests reduced dopamine may be causing your system to get overly disturbed by whatever inflammation that is present. That could result in low levels of inflammation causing high levels of fatigue, motor slowness, cognitive problems, etc.

It actually can go both ways: an earlier primate study suggested inflammation may be knocking down dopamine which then exacerbates the effects of inflammation. Dopamine levels tanked in the basal ganglia of primates four weeks after they were given IFN-a. Studies suggest that dopamine-deprived individuals suffer from enormous fatigue, motor slowing, and depression when they’re immune-activated (i.e., given IFN-a). That means they could also be the people that get ME/CFS following an infection.

This presents the possibility that an infection-produced inflammation knocks out dopamine production permanently, leaving behind a hypersensitized reaction to inflammation and resultant chronic fatigue. The Dubbo studies finding that increased cytokine levels early in an infection predispose people to ME/CFS appears to fit this scenario well.

 

[Snow Leopard]

One or two interesting points are made in the following article:

Here's What Placebos Can Heal—And What They Can't

The article is an interview with biologist Erik Vance about his book Suggestible You: The Curious Science of Your Brain’s Ability to Deceive, Transform, and Heal.

Sounds like neurobabble to me (as Neuroskeptic puts it). (When people make gross generalisations about neurotransmitters...)

The placebo effect is simply distraction from one's symptoms (hence ticking different boxes on a questionnaire) - there is no magic healing going on due to the placebo effect.

 

[Hip]

The placebo effect is simply distraction from one's symptoms - there is no magic healing going on.

That's what they imply in the Wikipedia article about placebo effect:

Asbjørn Hróbjartsson and Peter Gøtzsche published a study in 2001 and a follow-up study in 2004 questioning the nature of the placebo effect. The studies were performed as two meta-analyses. They found that in studies with a binary outcome, meaning patients were classified as improved or not improved, the placebo group had no statistically significant improvement over the no-treatment group.

Likewise, there was no significant placebo effect in studies in which objective outcomes (such as blood pressure) were measured by an independent observer. The placebo effect could be documented only in studies in which the outcomes (improvement or failure to improve) were reported by the subjects themselves.

Although this study on Parkinson's found that the placebo effect led to objectively measurable improvements in motor symptoms in 16% of patients.

 

[duncan]

The study title seems to claim placebos heal. Heal.

It is one thing to suggest placebos might benefit in some way in some cases. It is altogether a different matter to declare placebos heal. Smacks of the recovery controversy.

 

[Sean]

Uncontrolled generic confounding factors are most likely explanation for the vast majority of reported placebo effect.

Also, the Hróbjartsson and Gøtzsche meta-analysis on placebo effect size was further updated in 2010, confirming the result from the two earlier versions of the analysis.

AUTHOR'S CONCLUSIONS: We did not find that placebo interventions have important clinical effects in general. However, in certain settings placebo interventions can influence patient-reported outcomes, especially pain and nausea, though it is difficult to distinguish patient-reported effects of placebo from biased reporting. The effect on pain varied, even among trials with low risk of bias, from negligible to clinically important. Variations in the effect of placebo were partly explained by variations in how trials were conducted and how patients were informed.

https://www.ncbi.nlm.nih.gov/pubmed/20091554

I think this is one of the most important (non-ME/CFS specific) papers for us to know about, because it places serious constraints on what can be claimed on the basis of placebo effect, and hence its inverse, the nocebo effect, which is one of the main justifications for psychogenic claims about ME/CFS.

 

[alex3619]

I think this is one of the most important (non-ME/CFS specific) papers for us to know about,

Worth noting the Cochrane library has the full text for free.

 

[A.B.]

Although this study on Parkinson's found that the placebo effect led to objectively measurable improvements in motor symptoms in 16% of patients.

This appears to be a case of a misleading title. The investigators were not blinded to the treatment and assessed the motor function according to this scale http://www.etas.ee/wp-content/uploads/2013/10/updrs.pdf which is subjective.

I haven't looked at the study they cite but it seems to be a standard RCT so there probably was no third control group that would allow comparison of placebo vs nothing.

In conclusion, this looks more like the authors don't really know what they are doing rather than placebo having a real effect.

 

[Skippa]

Just watched my FIL die of Parkinson's

It's a slow, cruel disease. Slowly dying over a period of years. Took 2 weeks without food at the end to finally find peace. No amount of therapies or pills brought any kind of placebo relief to him.

I am cynical.

 

[Barry53]

Likewise, there was no significant placebo effect in studies in which objective outcomes (such as blood pressure) were measured by an independent observer. The placebo effect could be documented only in studies in which the outcomes (improvement or failure to improve) were reported by the subjects themselves.

Which I am sure the PACE authors (being phsyciatrists and all that) were only too well aware of when they they opted for subjective outcomes instead of objective ones.

 

[Hip]

This appears to be a case of a misleading title. The investigators were not blinded to the treatment and assessed the motor function according to this scale http://www.etas.ee/wp-content/uploads/2013/10/updrs.pdf which is subjective.

Can I ask where you read that the investigators were not blinded, because I just had a look at the full paper on SciHub, and it says:

Patients were randomized to ropinirole or placebo treatment from a central computer-generated code, and the study was double blind.

I found this other paper on the placebo effect in Parkinson's disease. Although it does not measure symptoms, it did find via a PET scan that there is a release of endogenous dopamine in the dorsal striatum in placebo-responsive patients:

Recent advances in research on the placebo effect in Parkinson's disease (PD) have suggested that motor symptoms of PD can be essentially improved by placebo. A recent study using positron emission tomography (PET) with raclopride demonstrated that release of endogeneous dopamine in the dorsal striatum occurs in placebo-responsive patients with PD.

 

[A.B.]

Can I ask where you read that the investigators were not blinded, because I just had a look at the full paper on SciHub, and it says:




I found this other paper on the placebo effect in Parkinson's disease. Although it does not measure symptoms, it did find via a PET scan that there is a release of endogenous dopamine in the dorsal striatum in placebo-responsive patients:

In the abstract they don't describe it as blinded, so I assumed it wasn't.

The authors examined the placebo-treated group from a randomized, multicenter, placebo-controlled clinical trial of monotherapy ropinerole in PD patients without motor fluctuations.

I don't believe this changes anything. To evaluate the effectiveness of placebo, one would have to compare it to nothing.

 

[Hip]

I don't believe this changes anything. To evaluate the effectiveness of placebo, one would have to compare it to nothing.

I believe they did. This 2001 paper appears to be the actual study. From the full paper on SciHub, they say:

We examined the striatal RAC binding potential of six patients with PD (group 1, placebo group) under two conditions (15): Condition 1, a placebo-controlled, blinded study in which the patients did not know when they were receiving placebo or active drug (apomorphine) (16)—all patients received both placebo and active drug; and condition 2, an open study in the same patients without placebo.

We found a significant decrease in striatal RAC binding potential [17% for the caudate nucleus (range, 8 to 25%); 19% for the putamen (range, 8 to 28%); P 0.005 for both, two-tailed paired t test] when the patients received placebo compared with open baseline observations ( Table 1).

So this clearly shows an increase in dopamine release in the striatum as a result of the placebo effect.



This study is interesting:
Immediate placebo effect in Parkinson's disease--is the subjective relief accompanied by objective improvement?

They concluded that:

These results suggest that placebo interventions in PD may have an immediate subjective sensation of improvement but result in no significant objective motor changes compared with levodopa treatment. Although physiological changes are possible after a placebo intervention, our findings suggest that the acute placebo effect in PD may be the result of the subjective change in the motor rating only.