Placebo effect discussion thread

I agree with Trish. I think the BPS types have managed to weaponise the initial “oh yes I do feel a bit better” as evidence that we are needy, attention-seeking, perfectionist, high achieving moaners who just need CBT and yoga.

I think that what we would describe as hopelessness, and the mental load (of having a disability, a hidden disability, a fluctuating disability, an incurable disability - but not depression)can be relieved for a short period by having a new thing to try, and someone overseeing you. It doesn’t last, though.

It’s the equivalent of giving a regular person working a 12 hour shift on a building site a cup of coffee and a chocolate biscuit for their afternoon tea break. A little pick me up which wears off soon enough.

 

If I’m reading things correctly Jonathan, is not only referring to the placebo-effect here which seems to be defined very vaguely but rather to the general concept of why people can report improvement as part of a trial without the trialled intervention having any efficacy.

These “reported improvement effects” can be due to a mixture of different things including but not limited to: placebo-effect, regression to the mean, natural recovery, Hawthorne like effects (possibly particularly relevant in ME/CFS where seeing a caring physician can be particularly rare), adapted behaviour in responding to subjective outcome measures (possibly taught as part of the trial), selection bias, outcome measures that show improvement despite treatments having no efficacy, no long-term follow-ups, publication bias, reporting bias, biased statistical analysis etc.

So any illness can show a "placebo-like effect". Avoiding all the above things can be extremely hard. That's why well-run trials are so important.

 

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Always sold out

 

I don't agree with that statement either.

On the extent of placebo response the evidence seems rather mixed - there are actually a few obscure trials that may help us understand this that I don't think have been discussed on S4ME before. One example, briefly - back in 1996 there was a small-scale study [1] of phenelzine (aka Nardil; a monoamine oxidase inhibitor that was used decades ago as an antidepressant before the class of drugs fell out of favour, mostly due to the food restrictions that are necessary with them) that used an unusual placebo phase-in design allowing for the magnitude of the placebo effect to be assessed - and it did not find the kind of effect that would be expected in conditions associated with high suggestibility. (Fukuda, but also stratified to exclude psychiatric conditions.)

There was a much more significant placebo effect than is seen in other treatment trials in the rituximab trial but I suspect that was trial-specific rather than being evidence of a generally high placebo response in ME/CFS.

Also, I wouldn't be at all surprised at an unusually high placebo response in FND, as hypersuggestibility seems to be a reasonably common feature of that condition. In some trials FND patients have not been specifically checked for & excluded.

[1] Natelson et al. Randomized, double blind, controlled placebo-phase in trial of low dose phenelzine in the chronic fatigue syndrome (Psychopharmcol. 124:226-230).

 

Book an appointment with Dr Oystein Fluge. He is the placebo incarnate. And it is not his fault because he is just very committed, very compassionate, very modest, very keen to get the science right and an overall loveable guy. And I think that caused him some problems but he and Olav Mella did things right and picked their way through all the confounders with huge skill.

So presumably these 'big improvements' with saline may be just the same placebo type response as with rituximab. Trish is right that I was using 'placebo' in a very broad sense in that context - all those confounding factors that lead to spurious 'benefits', as others have covered.

But there was something a bit weird about the rituximab open label follow up study because these spurious 'placebo' effects lasted exactly as long as they were supposed to based on the theory of rituximab mode of action - B cell depletion. People got better for six months, magically relapsed and got better again for another six months with another treatment. Even if saline had a benefit for more than half an hour it would not be regularly six months a go.

So I think everyone has made some cogent points above. It is all very messy and confusing. And that was the original point. We need well controlled trials.

 

I think placebo is potentially dangerous when trying to manage the reality of ME because it can prompt suppression and masking of significant symptoms leading to a failure to manage ME PEM and thereby cause crash and relapse.

I speak from experience during 10 years undiagnosed when I was willing to try anything to fix my "problem". I did a lot of meditation and used that to promote my own personal CBT to accentuate the positive, eliminate the negative and not mess with Mr. In-Between. A nice lady gave me copy of Louise Haye's "you Can Heal Your Life" so I gave NLP a go, which changed one's inner world for about 5 mins. I tried crystals, herbs, essential oils, Bach flower remedies, homeopathy, astrological counselling, aura cleansing, Tibetan lama medicine, yiddams, empowerments, bindu, chakras, tree hugging.

Its not like I didn't try, its just none of them worked. They all create a shift in your world (cosmological) view, your map of the universe as it were and can help let go of prior conditioning, which can be helpful psychologically sometimes, especially in people trying to transition from childhood to adulthood. If you try too hard and I did, you can make yourself psychologically unwell by farming dissociative states as well as having ME, which is what happened to me. By the time I was diagnosed I was in a very difficult state and although I accepted the diagnosis and twigged what I had done fairly quickly it took at least another decade for me to unravel the psychological mess I had gotten into. So be careful what you wish for @Sasha .

The problem is they can only change so much, as above, they can release endorphins, give a little insight into counterproductive reflex cognition and behaviour, which can change your world if you have a psychological issue causing behavioural trouble but the problem with ME is it is not cognitive in nature, so placebo effect cannot touch it, only how you feel about it.

Its like having a broken leg, the best medicine is putting it straight, in a cast to let the bone mend. What makes you feel good about it is doodling on the cast, which is the metaphor I would use to describe the usefulness of placebo type effects in dealing with ME.

 

I find a six-month placebo effect a very weird concept in ME/CFS, if it's merely based on expectation. If a PwME suddenly feels better without any change in their biology, I don't see how they can possibly become and remain more active - as they would, if they felt better - without having a massive crash within days or, at most, a very few weeks. We all live up to our energy envelopes because we're so heavily constrained and are desperate to be more active. This just seems a very strange scenario.

I know we're throwing the concept of what a placebo is around quite loosely but I can't see any amount of changed expectations powering a PwME through six months of improved function.

 

Well if you raise all these interesting and difficult questions, @Sasha, you may be obliged to start answering them one day!!

 

Fat chance there, I'm afraid! I'll be at the front of the queue once people start handing out massive placebos, though.

 

I think the strength of the placebo effect depends on the strength of your belief that the treatment has a real biological effect. One person say "X worked for me!" isn't all that convincing. Thousands of people confirming that would lead to stronger belief that it would work for you. Of course, we all differ, so one person reads "Amazing Health Stories" and believes even scientifically silly claims, while others read reliable studies about a treatment, but still has doubts.

 

One possibility to consider is that the treatment actually works for a few. I'm not a fan of "subtypes" as that is often used as an excuse for failed trials, but I wouldn't discount patient accounts purely as a placebo effect either. That's not scientific, I know. But I do have experience of being able to do more without keeling over the next day when I'm in dopaminergic/adrenergic environment. I've seen a few other patients with similar experience, but they are few and far in between. (Abilify that triggered this thread is a dopamine modulator, btw.) And that is why I tell people keep on trying different things as long as it is safe and cheap. If it doesn't work, you haven't lost much. If it does, then you hit a life-changing jackpot.

 

We can consider the possibility but I think the probability is vanishingly small. What I think people forget sometimes is that for any given chemical compound that might be called drug D, the chances of producing any improvement in Illness I is unbelievably small. Thee are probably at least 200,000 chemical compounds used as drugs. And for 90% of illnesses none of them are up to much. Relatively few illnesses respond to drugs. Public health measure and surgery are much more important.

I would be prepared to bet that none of the agents recommended for ME/CFS anywhere actually work on anybody.

 

I'm convinced that LDN did work on my ME's pain symptom. It shouldn't be a placebo effect, since I didn't have much confidence that it would work, and more importantly, it didn't have the effect expected from the claims. It very effectively blocked the pain, but didn't affect any other ME symptoms. LDN was the only recommended agent that worked for me. Other agents did provide significant benefits for me, but were accidental discoveries (Hey, what made me feel better?), so the placebo effect shouldn't apply.

Does desperation affect the placebo effect? I wonder whether anyone has studied that. I tried LDN simply because I was desperate enough to try something that at least a few people found effective and wasn't seriously expensive or risky.

 

Is that the case? I had the impression that there were also people reporting permanent recovery, which as I understand it wouldn't suit the original hypothesis too well?

 

I wouldn't limit myself to the agents recommended for ME/CFS either. I started taking Sudafed to relieve the head pressure that comes with my PEM. I found that it partially relieved the nagging discomfort (fatigue, ache, weakness) as well. Is it a placebo effect? Could be. I wasn't expecting or anticipating the effect though. I'm still taking it occasionally.

 

I think there was one who reported permanent recovery from the blinded phase. And what makes it all the more spooky is that of course at that stage the expectation was for permanent benefit or perhaps indeterminate benefit. The expectation of a six month optimum came later after I had pointed it out in a letter to PLOS One supporting Fluge and Mella's note that there was a statistically significant difference at that point, that might be relevant even though it was not the primary endpoint. So the six month expectation applied to the unblinded follow on phase but not the initial blinded phase so much!

 

That might not be at all surprising. Wikipedia says:
In accordance with its partial agonism, although naltrexone is described as a pure opioid receptor antagonist, it has shown some evidence of weak opioid effects in clinical and preclinical studies.[6]

It is a painkiller!