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Thursday, July 22, 2010

Placebo commentary

placTaking a little break from my placebo run down, as I found these old blog posts on placebos, both inspired by a wired article which notes the problem of decreasing drug-placebo differences in recent clinical trials.

The link to White Coat Underground is here, and Greg Laden's rather more thoughtful peice is here .

The first point I would like to make about PaiMD's article is that he seems to be unaware of all the experimental work done on placebos, focusing instead on the clinical trial use of placebos.

Recent work has shown that the nature of clinical trials actually decreases the placebo effect, due to whats known as the expectancy theory. It goes like this: in a trial, participants are told that they may get placebo or they may get the drug. This is a conditional expectancy. In experimental research, they are told that it is a powerful painkiller (uncondtional expectancy). The UCE's have been shown to produce much better results, with less requirements for painkillers following surgery, with stronger coffee effects and indeed even when measuring sleep patterns. 

So, what does this tell us? To me, it seems to indicate that placebo effects are underestimated in clinical trials, and if they appear to be getting stronger here then something weird is going on. I actually agree with Greg Laden's idea that it may be down to stronger cultural associations between pills and healing, which creates stronger expectancies that then interfere with the testing of new drugs. This could be tested properly by a meta-analysis comparing drug advertsing and placebo response across countries, and hopefully I'll get a chance to do this review after i finish my doctorate.

Something else that struck me, as I read through the comments, was that they were recapitualting the history of studies of placebo. We had people claiming that placebos were useless, that they were only a control and an artifact, while others claiming that modern medicine was a lie and only the mind had power (the burt dude at the end of Greg Laden's comments was hilarious, especially the way he made so many people angry).

Anyway, a few issues came up and I thought i should post some more recent research which hopefully, can illuminate the debate.

Firstly, the meta-analysis by Hrobjarrtson and Goetzsche (god those names are hard to spell). Now, this meta-analysis claimed that placebo was not significantly different from no treatment across 114 clinical conditions.

Personally, i can't see how they were able to do this meta-analysis, considering the extreme heterogenity of the data base (which is supposed to mean that you avoid the meta-analysis). Anyway, this review drove a lot of placebo people into studying pain, as it was the only part which they didnt slate.

Now, more recently, another meta-analysis was done by Meissner, Distal and Colleagues. This meta-analysis actually seperated the trials they found into different components, and found that there was a large placebo effect (d=.5 approx) when the outcome variable was a physical parameter, but none when the outcome variable was a hormone level. They re-analysed H&G's sample and replicated their results. For some reason, this study didnt get nearly as much attention as the negative one.

So, essentially, we can see placebo effects in some areas but not in others, which makes a lot of sense, if you study the literature. An alternative explanation is that the clinical trials only activated the expectancy pathways which affect these outcomes, while the conditioning pathways were not activated. This makes sense if you look at some of the work by Benedetti et al.

Another canard that was raised in the comments was the notion of response bias. This was popularised by Allan and Siegel in their Signal Detection Theory of the Placebo Effect. While I like SDT,  i dont think that it can account for all of the observed placebo effects. Referring to the surgery paper above, what the results suggest is that most of the response variability to opioids is the result of placebo effects, which is the result (mostly) of the endoegnous opioid system. Response bias cannot account for these well documented effects.

Anyway, thats probably enough for now. Hopefully I'll get my second part of the placebo review done today, if not my cousin's wedding will intervene and it'll be next Monday or Tuesday.