Editorial: Placebo and Nocebo Effects in Psychiatry and Beyond, 2020, Weimer at al

Andy

Andy

Senior Member (Voting rights)
The placebo effect is part of every medical intervention and plays a crucial role in randomized placebo-controlled trials (RCTs). It is beneficial to maximize the placebo effect when treating patients, but it should be minimized in RCTs to estimate the true drug effect (1). Studies have shown that the placebo effect is formed by learning mechanisms (2), and an expert consensus has suggested that the beneficial effects of placebo can be harnessed for clinical use to improve patient outcomes (3). In contrast to the placebo effect, adverse events can occur and symptoms can get worse through a negative placebo effect, the so-called nocebo effect (4). Yet, to exploit placebo mechanisms in clinical practice a lot of questions remain unanswered. For this Research Topic Issue, we called for the latest research articles in the field of placebo and nocebo research. The issue comprises 38 articles from “Hypothesis and Theory” to “Reviews” and to “Original Research” articles.

After giving an overview about the underlying mechanisms of the placebo effect, such as conditioning, expectations and influencing factors, Friesen summarizes ethical views regarding the use of the placebo effect. Until recently, it has been assumed that placebos take only effect when patients are deceived, but she encourages considering placebos as a “source of agency”, without deception and in agreement with patients’ autonomy. Babel complements the current view about classical conditioning in the placebo effect. In fact, many studies use a combination of classical conditioning and verbal suggestions to induce placebo and nocebo effects. Due to recent studies using hidden and subliminal conditioning procedures, Babel argues that classical conditioning is a distinct mechanism that works without conscious expectations. However, there are only a few studies limited to the area of pain and further studies are needed.
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Open access, https://www.frontiersin.org/articles/10.3389/fpsyt.2020.00801/full
 
Is it true that the placebo effect is apparent only in subjective reporting and not in objective measures? That is the placebo effect results in us feeling better and the nocebo effect results in us feeling worse without impacting any underlying condition.

You might argue then the placebo effect is a sort of self delusion, which might have positives when you are working on subjective phenomenon. For example in chronic pain there is something to be said for finding ways for the pain to feel less painful. For example I get very seasick and find it very incapacitating, whereas a friend who does a lot of sailing also gets seasick, but he just throws up over the side and carries on with what ever he is doing. I end up feeling very sick, but my friend has learnt not to feel sick.

However learning not to regard pain as painful has potential negatives. I get a lot of pain in my face and jaw as part of my ME, and I have learnt to just ignore it, to get on with life as best as possible; it is hard to distinguish this apparently idiopathic pain from concrete dental issues, so this ignoring pain means I have a number of times failed to go to the dentist with abscesses and, failing to get preventative treatment, lost teeth as a result.

If a placebo effect, also in the context of ME, reduces our subjective sense of feeling unwell without altering our underlying condition, could this mean that we are less aware of our thresholds for triggering PEM and ultimately worsen our condition by failing to respect our current limits.
 
The so-called placebo effect is a mix of different processes, including memory bias and the desire to say what the investigators want to hear. It is difficult to establish the relative contribution of the involved processes, and I don't think it has been convincingly demonstrated that the placebo effect results in any real subjective improvement in the sense that patients actually feel better. I would therefore like to question whether there is any therapeutic value at all of the placebo effect.
 
It is beneficial to maximize the placebo effect when treating patients, but it should be minimized in RCTs
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It's literally the control for nothing. Any sham intervention can act as placebo. Even excessively deliberate shams. Hell, you could use healing crystals or one of those balance bracelets as placebo. You can't maximize nothing any more than you can multiply zero by something and get anything other than zero. Unless of course you ask for imprecise feelings instead of objective things. You say that spaghetti sauce rates a 7/10? How convinced are you of that 7? Not very? Could just as well be a 6 or an 8 because it's not a precise thing? Oh, well. Now let's "measure" your anxiety by asking a bunch of questions and for sure those numbers will be just as precise a 10 digit precision temperature measurement vs. a ranking of cold, cool, warm and hot.
an expert consensus has suggested that the beneficial effects of placebo can be harnessed for clinical use to improve patient outcomes
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This has literally been tried for decades, there are literally multiple entire fields of health psychology/psychiatry dedicated to it: liaison psychiatry, FND, psychobehavioral therapy and MUS. In many circumstances and diseases in addition to but also with us, used with everything else being equal, it has been attempted over and over for decades. Why are they pretending this is all brand new and has never been attempted? There are literally thousands of papers and hundreds of trials on the topic. Other than of course for the fact that they know that it's a sham but continue to pretend because they want it to be true so bad they are willing to sacrifice millions of lives for a stupid belief system.

This field is a total joke. Might as well be stuck with ghosts and humors. I'd rather have humorous ghosts, quite frankly.
 
As I understand it the placebo effect includes regression to the mean.

The whole point of a placebo is to be able to keep everything, except the active ingredient under test, the same for both groups. That way any difference between the groups is hopefully due to the ONLY thing that is different between the groups.

That means that the group receiving the placebo must also have many other things kept as close to the treatment group’s experience as possible. Eg. They should visit the test centre the same number of times that the test group visit. This to ensure that the act of visiting the centre doesn’t have influence on one group but not the other. It isn’t easy to set up a good control group, as often differences other than the treatment under test are introduced, and these could have an effect.

It seems to me that the whole “placebo effect” label has gained traction in some circles as meaning mental effects because people “believe” they have had a “real treatment”. Whereas that is not the case.

Both groups will have regression to the mean over time. Both groups must have everything the same, so that only the active treatment is different between the groups.

There are so many things beyond “belief in a treatment” that could change an outcome. So it’s vital to keep the groups as similar as possible and to constantly be looking for other factors that might influence one group but not the other.

To say that the “placebo” group improved only because they “believe they have had a treatment” is in my view, nonsense. Being given a placebo instead of the drug (or treatment) is only one small part of setting up an effective control group.

The reason a placebo is needed is because there is recognition that both groups will change over time, so this way the test group gets compared to a group that has been treated the same in every other way.
 
Obermann said:
The so-called placebo effect is a mix of different processes, including memory bias and the desire to say what the investigators want to hear. It is difficult to establish the relative contribution of the involved processes, and I don't think it has been convincingly demonstrated that the placebo effect results in any real subjective improvement in the sense that patients actually feel better. I would therefore like to question whether there is any therapeutic value at all of the placebo effect.
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I think this is the key point. The group that has been making a lot of noise in the USA about placebos being harnessed has completely screwed up the evidence by not taking 'desire to say what the investigators want to hear' into account. If someone knows they are taking a placebo the study is unblinded and we are back to the useless combination of unboundedness and subjectivity. It is astonishing that these people get slots to talk at all sorts of meetings because they are taken seriously.
 
It is beneficial to maximize the placebo effect when treating patients,

Why?

John Mac said:
The placebo effect may not be as great as people think.
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It is not.

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

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.
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Far as I am concerned there is no robust evidence that the placebo/nocebo effect has any significant sustained effect, let alone a therapeutic one (in the case of placebo).

The onus is very firmly on the placebo/nocebo advocates to establish their claim, and they are failing spectacularly at it.

Not that it hinders their certainty and power grab to any noticeable degree. :grumpy:
 
A more nuanced review of placebo. Have only skimmed it, so my summary may be a bit off.

The gist seems to be that under certain conditions, some placebos do create a physiological response. Mostly this requires pre-conditioning with an active intervention first, so if you've been using oxygen to counter altitude sickness successfully you then can experience the same beneficial effect from a placebo - but the placebo won't work if you haven't had the pre-conditioning (not sure if they say how long the pre-conditioned placebo effect lasted, a rather important point). They looked at a mix of subjective and objective outcomes. Mostly they found expectation of effect or otherwise had no impact - the big exception being fatigue. Hmm.

https://www.researchgate.net/public...cal_Life_Functions_Can_Placebo_Replace_Oxygen
 
Ravn said:
A more nuanced review of placebo. Have only skimmed it, so my summary may be a bit off.

The gist seems to be that under certain conditions, some placebos do create a physiological response. Mostly this requires pre-conditioning with an active intervention first, so if you've been using oxygen to counter altitude sickness successfully you then can experience the same beneficial effect from a placebo - but the placebo won't work if you haven't had the pre-conditioning (not sure if they say how long the pre-conditioned placebo effect lasted, a rather important point). They looked at a mix of subjective and objective outcomes. Mostly they found expectation of effect or otherwise had no impact - the big exception being fatigue. Hmm.

https://www.researchgate.net/public...cal_Life_Functions_Can_Placebo_Replace_Oxygen
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From that paper:

4.1. Oxygenation
In no case a change in SO2 was found after placebo administration (see the studies described below), which indicates that placebos cannot in any way affect blood oxygenation
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Minute ventilation and heart rate decreased during (pre-conditioned) placebo, so basically, the individual expected more oxygen and hypoventilation was the result.
But so what? This is a conditioned behaviour, not a physiological response. The author of the editorial also makes a number of speculative claims about the lowered reporting of fatigue and headache, without considering that this could entirely be due to response biases.

There is a lot of rampant (and false) discussion about placebo effects.

The only demonstrated physiological placebo effects are a modest acute suppression of pain and nausea due to conditioning of endogenous opioid and endogenous cannabinoid systems. The underlying system is an evolutionary adapted behavioural override of acute pain/nausea to allow an animal to escape danger after being injured/poisoned.
 
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Ravn said:
A more nuanced review of placebo. Have only skimmed it, so my summary may be a bit off.

The gist seems to be that under certain conditions, some placebos do create a physiological response. Mostly this requires pre-conditioning with an active intervention first, so if you've been using oxygen to counter altitude sickness successfully you then can experience the same beneficial effect from a placebo - but the placebo won't work if you haven't had the pre-conditioning (not sure if they say how long the pre-conditioned placebo effect lasted, a rather important point). They looked at a mix of subjective and objective outcomes. Mostly they found expectation of effect or otherwise had no impact - the big exception being fatigue. Hmm.

https://www.researchgate.net/public...cal_Life_Functions_Can_Placebo_Replace_Oxygen
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Key point being "a" physiological response. Same issue with the Scientology thetan-detecting machine or polygraphs. Measuring "an" effect does not mean anything, it's pretty much one of the bases of science to actually measure things that are directly relevant and not influenced by unrelated factors. If other fields of science were as loose with their criteria, the LIGO detectors would be beeping all the time from surrounding car traffic. People who are new to living at high altitude experience similar physiological changes. At first it's difficult, then the body adapts. This isn't rocket surgery.

In the specific cases that keep being cited, here oxygen but more often than not over deep meditation being able to lower heart rate, they are very narrow examples of responses that can be trained. Generously we can possibly add raising body temperature. Which is all very nice and impressive but still has nothing with making the body "better" or "worse" and still leaves some fingers hanging in trying to count all the things that the "mind" can affect. Like any of the immune system "boosters". It's possible to cause a change, whether that change is actually relevant and beneficial is a whole different matter on which pla/nocebo fail.

If people want something to be true they'll do everything they can to make it seem true, scientists included. That this lesson is completely waived off in medicine is an aberration in need of a massive correction.
 
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