Tuesday, August 14, 2018

The Placebome.....can you believe that!

Is it only religion that feeds and reassures the gullible, no matter what catastrophes strike?

When a baby is born with serious health issues, this is apparently the loving God's will (to test the parents' faith; God can, after all, save the baby's soul).  But rather than just blaming God, perhaps one's faith in this same devilish Being, that faith itself, could have curative powers.  At least those powers might extend to the believer him or herself.

When a person's mood ameliorates a disease, yet no formal medical treatment has been involved, that is a psychological effect.  When the person is in a case-control drug trial study, in which s/he has (though unaware of it) been given a sugar pill--a placebo--rather than the drug under test, and that person's health improves anyway, that is called the placebo effect.

It is important when testing a new drug to have a way to determine whether it really does nothing (or, indeed, is harmful) rather than its intended effect.  Since people who are ill might get better or worse for various reasons, a drug trial often compares those patients given the drug with those who are given a placebo.  The drug is considered to be efficacious if it does something, rather than nothing--nothing, that is, as is assumed about the placebo.

But are some unjustified if convenient assumptions being made in this long-used standard comparison as a test of the new drug's efficacy?  Studies including placebo have long been relatively standard, if not indeed mandatory for drug approval.  But how well are the comparisons--and their underlying assumptions--understood?  The answer may not be as obvious as is generally assumed.

Back pain that's a headache
What about this paper by Carvalho et al., in the journal Pain (Carvalho et a., vol 157, number 12, 2016)?  The authors did a randomized control trial of open-label placebos (OLPs) taken in the usual dose way for the usual 3 weeks on patients suffering low back pain.  The authors found clear (that is, statistically significant) reduction in symptoms--even though the 'control' patients knew they were taking a placebo.  Perhaps they still thought they were taking medicine, or perhaps just being in a study seemed to them, somehow, to be a form of care, something positive--that is, systematically better than no treatment.  But this is not supposed to happen, and relates to a variety of very important, if equally inconvenient, issues about what counts as evidence, what counts as therapy and so on.

The samples in the Carvalho study were small and one can quibble about the quality of the research if one wants to dismiss it.  (E.g., if it were really true, why wasn't it published in a major journal? Did reactionary reviewers from these journals keep it from being published there?).  Still, if the placebo effect is real, the idea should not be a surprise.  Biologically, there really need be no reason why subjects must be blinded to being given placebos in order for them to work.  

But is it appropriate to ask whether, in a similar way, religious faith might have a placebo effect, and if so, should it be part of case-control studies of new drugs or treatments?  If so, then.....

....some things to consider
Here's an interesting thought:  If the placebo effect is real, then how do we know that actual medicines work?  They may seem better than placebos in comparison studies, but what if a substantial fraction of the treatment effect is for religious or other reasons?  That is, these subjects experience a kind of placebo effect?  Then, the case-control distinction is less than one thinks: perhaps as a result, the efficacy of the medicine is actually substantially less than is credited by the standard kinds of placebo-comparison study.  Perhaps placebo-response is part of the case side of the comparison, as well as the control side, and without them the 'case' effect would no longer be significant, or as significant?

If we are doing a placebo-based test of a new drug, should case and control religious or other beliefs be identified, and matched in the two groups?  What about atheists--is that also a comparable faith, or would it serve as a control on such faith?  

Even to acknowledge the possibility that we've under-rated the placebo effect, and over-rated the drugs that we rely on, and that belief systems can even have such effect, raises interesting and important questions.  What if we told a patient that s/he had a placebic genotype, and thus, say, tended to believe everything s/he heard or read?  Then would s/he realize this and stop believing, blocking the placebo effect?  In not knowing if s/he were a case or control, actually reduce even the 'case' effect?  Would we tell such people of some meds they could take to 'cure' this placebo-responsive trait?  Would they take it?  These could be interesting areas to explore, though deciding how to do definitive studies would, by the very nature of the subject, not be easy.

And yet. . . .
Of course, scientists being the way they are, there is now a proposed 'placebome' project (Hall et al., Trends in Mol Med, 21 (5), 2015). The researchers want to search for genomic regions that affect the effect which, they claim varies among people and hence assume it must be 'genetic' (this might even be reasonable, in principle, but way too premature for yet another GWAS project).  Is it as silly, bandwagonish, transparent, and premature a version of unquestioning belief and/or marketing as one can imagine?  I think so--you can, if you wish, of course, look at the paper and judge for yourself. 

But even if this is capitalizing on the 'omics fad, a transparent me-too money-seeking strategy that our venal system imposes, that doesn't vitiate the idea that placebic effects could, in fact, be both real and important.  Nor that truly thoughtful, systematic ways of investigating its nature, not just some statistical results related to it, would be possible and appropriate.  But to do this, how would such a study be designed?

One thing this all suggests to me is that we may not have defined placebos carefully (or knowledgeably) enough, or don't understand what is going on that could count for a physiological (as opposed to 'merely psychological') effect.  Since we have the embedded notion that science is about material technology, statistics, and so on, perhaps we just don't believe (and that's the right word for it) that things can happen that are not part of our science heritage, which largely derives from reductionist physics.  If we've not looked in a properly designed way for  this effect, perhaps we should.  At the very least, there may be much to learn.

But before rushing to the 'omics market, there are interesting qusetions to ask.  Why aren't religious believers who pray for God's grace, generally healthier than the non-believers?  Or is there, in fact, a notable but undocumented difference? Does serious religiosity serve as a placebo in daily life, and if not, why not? If there are measurable physiological or neural pathways that can be identified during placebic experience, are they potential therapeutic targets?  

But there's a deeper more serious question
The fact of placebo effects is generally interesting, but raises an important, very curious issue.   How can a placebo effect work on the diversity of traits for which it has been suggested?  If all a placebic effect does is make you feel better no matter how sick you are, then it's not really placebic in that it doesn't mimic the drug being taken and shouldn't affect the specific disease, just the patient's mood.  But if it can affect the disease, how can that be?

Placebos seem to work in many different drugs and treatments, for many physically and/or physiologically different and unrelated disorders.  At least, I think that is what has been reported.  But these involve different tissues and systems.  So how does the patient 'know' which tissue or physiological system to fix, that is, which cell type a real medicine would be targeting, when believing s/he has taken some effective medicine?  

I know very little about the placebo effect, and it doubtlessly shows in this post, to anyone who does.  But I think these are important, or indeed fundamental questions that include, but go beyond asking if the effect is real: they ask what the effect could actually be.  Before we untangle these issues, and understand what the placebo effect really is, we should be highly skeptical of any 'omic project claiming that it will map it and find out what genes are responsible for it.  Among other things, as I've tried to point out here, one needs to know what 'it' actually is.  And as regards genetic studies, is there the proper kind of plausibility evidence on which to build an 'omics case: is there, for example, any reason at all to believe the placebo is familial?

There is already huge waste of research money chasing  'omics fads these days, while real problems go under-served.  One need not jump on every bandwagon.  If there are real questions here, and there seem to be, then the groundwork needs to be laid before we go genome searching.

No comments: