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Thursday, July 29, 2010

Placebo response without placebos

Often, I hear that the placebo response is an artifact, merely a control for the "real" treatment. Today, I'd like to blog about a paper that suggests that every treatment is partially placebo. The paper is Benedetti et al 2003, and is probably one of the most interesting papers I have read.

Essentially, the study looked at whether or not the awareness of treatment had any impact on the response to real drugs. To do this, they used (mostly) post-operative patients and looked at pain & anxiety.

Each treatment was given in two conditions: open and hidden. In the open condition, patients were given a drug by a doctor who told them what they were getting. In the hidden condition, the drug was given without the knowledge of the patients.

The study also looked at open and hidden interruptions in treatment, and the results were essentially the same (i.e. pain/anxiety levels were higher after the open interruptions). 

The results were clear for pain and anxiety. Open infusions were much more effective than hidden ones, with pain decreasing much more in the open condition than in the hidden one.  The drug given for anxiety was diazepam (Valium) and this drug was COMPLETELY ineffective in reducing anxiety in the hidden condition. One could take these results to mean that Valium is a placebo, and only works because people believe it will. Is it the cultural lore thats developed around Valium be the only reason its effective? Shocking stuff, and food for thought the next time someone argues that placebos are "just" controls or have "no clinical significance".

Now, its worth being aware of a few caveats to this study. Firstly, the open condition was actually measuring the difference between the presence of a doctor and the awareness of a treatment. This could be gotten around by using a prerecorded voice telling participants that they were about to get medication.  Unfortunately, no one appears to have done this study yet, but its an interesting question nonetheless.

Benedetti, F., Maggi, G., Lopiano, L., Lanotte, M., Rainero, I., Vighetti, S., & Pollo, A. (2003). Open versus hidden medical treatments: The patient's knowledge about a therapy affects the therapy outcome. Prevention & Treatment, 6 (1) DOI: 10.1037/1522-3736.6.0001a

Tuesday, July 27, 2010

No (living) man is an island

Wow, just wow.

I just finished reading a new paper published in PLOS Medicine (Lunstad et al 2010), on the association between social support and health.

The take home message: social support can increase your odds of living longer by 50%. Thats frankly, amazing. As the authors themselves note, this is a larger increase in life comparable to that gained by quitting smoking (something that i really need to do).

They examined 180 studies involving large samples (mostly community based). They had four coders assessing quality of the studies (which is pretty impressive, one rarely sees more than two), and they estimated that there would need to be over 4000 studies to reduce their results to a clinically insignificant level.

Normally, I would start talking here about some of the flaws I saw in the study. However, from my perspective, there are none. Its a wonderful study, and you all should read it (especially since access is totally free).

The question that we need to ask now, is how are these effects mediated? Is it talking to friends, the idea that people care about you, or what? I foresee a huge interest in this paper, from sociologists, anthropologists, psychologists, doctors and everyone who is the least bit interested in health.

If you're still here, go call a friend - it might save your life.

Julianne Holt-Lunstad,, Timothy B. Smith,, & J. Bradley Layton (2010). Social Relationships and Mortality Risk: A Meta-analytic Review PLoS Medicine : doi:10.1371/journal.pmed.1000316

Woo reconsidered!?

Today, a very interesting paper was revealed to me, by the magic and mystery that is Google Reader.

Now, as some of you may know, I am currently researching placebo. As part of this, I've read a lot about alternative medicine and interviewed some of the practitioners. This has all been very interesting, but until quite recently, i wasn't aware of any high quality studies which suggested that there are measurable effects (apart from placebo). It appears that this may be changing. Lutgendoprf et al, writing in Brain, Behavior and Immunity suggest that Healing Touch may contribute to improved immune function in women with cervical cancer.

I read this paper quite closely, so here's the deal.
It was a randomised controlled trial, which had three groups.
The first group was the Healing Touch group, the second was a relaxation group, and the third was usual care. The study was not blind, given that its difficult to conceal treatment allocations to psychosocial interventions. This may (or may not) be a fatal flaw to your way of thinking.

Now, there were a number of outcomes and covariates. They were looking at immune function, depression, anxiety, you know, all the good stuff. The major finding of the study was that the patients in the Healing Touch group maintained NK cell activity throughout the course of chemotherapy, while the other two groups showed declines. Pretty crazy eh? Maybe faith healing does work after all....

Its interesting that the authors actually considered the biofield hypothesis, albeit seeming to prefer others.

Now, I have a few caveats about the study, coming from my perspective as a placebo researcher.

1) The HT was given by nurses, while the relaxation technique was facilitated by graduate students. Its quite possible that the patients may have attributed more credibility to the nurses than too the grad students (a pain I know all too well....).
2) The second issue is that the nurses were licensed practitioners of HT, and as such may have been far more enthusiastic about the treatment, which can definitely exert influences on healing.
3) The authors note that they measured expectancies at baseline and after treatment, and that these did not contribute to outcomes. This is very weird, given that there is a lot of literature that suggests that perceived reality of treatment may be an important predictor of outcome, for acupuncture at least (Bausell et al 2005; Linde et al 2007)
4) The impact of touch - there was no touch in the relaxation group while there was in the Healing Touch group (obvious, but still important). It seems plausible (warning, speculation ahead) that the touch of others can contribute significantly to a placebo response). For my money, I would have preferred a real HT group given by professionals, versus a HT group given by naive patients who are taught the movements, but not the energy manipulations regarded as important by practitioners. Alternatively, use practitioners with different levels of training, to examine if there is a HT effect rather than a placebo/expectancy effect.

All of that being said, its an extremely interesting study, which builds on a recent meta-analysis of MBSR in cancer which suggests that psychosocial factors may have large impacts on the physical (d=.2) and psychological (d=1) measures of well-being. Interesting stuff.

Funnily enough, there was a Yale professor, Harold Saxton Burr, who claimed that electromagnetic fields were a prime mover in health and disease. He was mostly ignored, as were his students. I find it quite sad that such an obvious explanation for biofields (if they do exist) is ignored, given the potential for rewards from this kind of research. Then again, I'm not a biologist or physicist, so I might be horribly confused here. It does, however, remind me of the case of Wilheim Reich, a student of Freuds who claimed to have discovered a universal energy. I suppose at least Burr wasn't thrown into prison, which is progress (of a sort).

I do also note, however, a recent paper in Medical Hypotheses (i know, I know...) by Irmak where he argues that Merkel cells are specially adapted for electromagnetic perception and he hypothesised that these are responsible for the effects of Reiki and other healing touch modalties. Its all very strange, but it makes you think (or at least it makes me think).

That being said, I love a controversial theory, so your mileage may vary.

Coming up next: theories about the placebo (unless I get distracted again)

Susan K. Lutgendorfa, b, c, d, Corresponding Author Contact Information, E-mail The Corresponding Author, Elizabeth Mullen-Housera, Daniel Russelle, Koen DeGeestb, Geraldine Jacobsonf, Laura Hartg, David Benderb, Barrie Andersonb, Thomas E. Buekersb, Mich (2010). Preservation of immune function in cervical cancer patients during chemoradiation using a novel integrative approach Brain, Behavior and Immunity : doi:10.1016/j.bbi.2010.06.014

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.

Tuesday, July 20, 2010

Placebos: All you never wanted to know (Part 1)

Well, its that time of the week again when I cant put off blogging any longer. I have a terrible habit of putting off blogging (which i enjoy) to ensure that i actually complete my Phd. Therefore, I've decided to start blogging about my actual research.

To whit, everybody's favourite sugar pill: placebo!.

This will be a relatively long series, with about seven parts. Essentially, I'm updating my literature review this week, so I'll blog about each section as I do it (perhaps before, if i get really into this series).

Anyway, we'll start with the hard part: definitions. The placebo is something that most people in our society have an idea about, but it's a surprisingly difficult phenomenon to define. That being said, almost everyone in the field has had their hand at it, so there's a lot to choose from.

The first, classic definition is from Shapiro & Shapiro (1997) - the placebo effect is the result of a placebo treatment.
Pretty illuminating eh? The sad part is that this definition was the end of their long and ultimately fruitless search for a good way of describing the phenomenon.

That being said, it has its good points. Firstly, it can account for all placebo effects, it doesnt presuppose any mechanisms, and it doesn't limit the phenomenon unduly.

However, its bad points are legion also, the largest being that its a tautology, and not in the universal truth sense.

Probably the definition most people are familiar with is this one: the placebo effect is the effect seen in the placebo arm of a double blind trial. However, this one also has large problems. The major issue with this definition is that not all of the response in a placebo arm will be down to the placebo.

One thing that can happen to mess up this definition is a funny little phenomenon called regression to the mean. Regression to the mean is a statistical phenomeon that works as follows. There are sick people, whom you select for a trial on the basis of their sickness. Say if the sickness was measured on a ten point scale, they would be a seven. Now, even if the treatment you give them is harmful, it is likely that some of them will report less sickness after a week, because its more probable that the next measurement will be closer to the mean. I'm relatively sure that this could be eliminated with a perfectly reliable instrument, but we don't have any of those (certainly not in psychology).

Warning: previous example requires a normal distribution. If in doubt, consult a friendly statistician ( if you can find one). Update: apparently it only require a distribution with equal marginal probabilities - i do remember seeing an explanation that used the normal distribution though.

Another feature that can cause issues in estimating the placebo effect is the natural history of a sickness. The major problem here is that people's health may wax and wane, and again if you select a person for inclusion on the basis of sickness, the natural history effect could cause them to report feeling better even in the absence of any real effect from your treatment.

So, if you actually want to estimate the placebo effect accurately, you need a no treatment group. These poor suckers are recruited into the trial on the basis of sickness, and then don't get anything to help, except to be poked and prodded by doctors and nurses. Many clinical trials don't include these groups, and its easy to see why. Bad enough that you have to give half the participants placebo, but to give another group of people nothing, thats way too harsh. (We'll get back to clinical trials with no treatment groups later, i promise).

So, following on from this long and rambling excursion into clinical trials, we can update our definition of the placebo effect to as follows: the placebo effect is the improvement seen in the placebo arm less the improvement in the no treatment arm.

So, this is the workhorse of placebo definitions, but it still won't do. This definition requires a particular setting which does not fit where many placebo effects take place. For example, the response shown by a patient to the archetypal sugar pill after a visit to the doctor cannot be accounted for with this particular definition. So, we'll have to move on.

A more recent definition came from Price et al (2008) where they claimed that a placebo was any effect which simulated a treatment.

A fascinating recent study by Oken et al gave us some interesting findings. Essentially it was an RCT which randomised seniors (65-80 years old) to either placebo or no treatment. They were told that the pill would improve their memory, and lo and behold it did. They scored better on measures of verbal and working memory (interestingly enough only the men showed this effect).

This is a problem for definitions of the placebo which rely on the notion of treatment. I can't really see how the effects of this pill could be considered such, they were a neuro-enhancer rather than something to stave off decline. So, it looks like we may have to confine the Price et al definition to the fire.

A definition which can account for the experiment noted above is that of Daniel Moerman, an anthropologist: a placebo is the positive mental or physical effects induced by the meaning of a substance or procedure. He prefers to call placebos the meaning response, which is a much nicer phrase than placebo (or at least has less negative associations).

I really like Moerman's definition (and his book is really very good, even if you're not a specialist). However, there are some weasel words in there, the main culprit being "meaning".
So, boys and girls, what does meaning mean?

Presumably it refers to the interpretation one gives to something, but its a hard word to define, and even worse, its a horrible word to attempt to operationalise (i.e. figure out how to define or measure it). Although, that being said, i suppose we could just substitute meaning for expectancy and get on with our research.

That, dear readers, would probably be letting you off a little lightly though. So, lets move on to another defintion, this one by a wonderful scientist and human being, Dr Zelda Di Blasi (2001) she and her colleagues renamed placebo (everyone loves doing this this) to context effects (which again, is nice and doesnt have negative associations) and said: a placebo is an inert substance which has an effect due to context.

This is nice, it again leaves open the mechanisms and wonderfully enough, doesn't preclude none health related placebos. However, context (to me at least) means what surrounds the patient, and this ignores the fact that focusing on bodily sensations increases the size of the placebo effect

The other issue with this definition is that it somewhat marginalises the role of the person who experiences the placebo effect, as it implies that all the impetus comes from outside, when clearly the internal experience is perhaps the defining characteristic.

Moving on, I think that the term placebo is growing more and more useless. These days, its used by many and seems (in psychology at least) to be a convenient shorthand for the effects of the mind on the body. My first exhibit for this kind of thing is the 2007 paper by Crum and Langer (if you're Irish you probably giggled at that last name, otherwise, carry on), which is called: mind set matters: exercise and the placebo effect.

The study itself is really interesting, they took a large group of hotels, matched them, and randomised hotels to either control or treatment. In each of the hotels which were in the treatment, they told the cleaning people how many calories they burned in the course of their work. In the other hotel, they just talked to them for a while and got them to fill out some forms.

The really interesting part was that the women (i believe the entire sample was female) who were told about their calorie burning habits lost more weight over the next month, and were both healthier and happier by the end of the study. I suppose the take home message from this study is that you should learn how many calories you burn in your daily activities if you want to lose weight.

However, my point here is that the use of the term placebo effect here is confusing and causing problems with our understanding of the concept. I personally would much prefer to have a placebo effect that only related to healthcare and medicine, along with mind/body effects or expectancy effects for the Oken and Crum studies I noted above.

To be honest though, I'm not going to lose too much sleep over the definition of the effect. Having read some of the Shapiro papers where they grapple with the construct over the years, I've come to the conclusion that its a waste of effort and time that could better be spent trying to figure out how to induce the damn thing (whatever we call it) reliably.

Tuesday, July 13, 2010

Science, Religion and Evidence

I read a lot of blogs, especially the ones over at Science Blogs. I'm also quite lazy, so I merely subscribed to the three channels I was most interested in (Brain and Behaviour, Humanities and Social Sciences and Medicine and Health).

Now, many of the science bloggers seem to be quite virulently sciency, in that they appear to regard the mere existence of religion as a personal affront. Now, personally I don't follow any religion (raised catholic, abandoned it following reading up on church history at around 12), but I am very interested in the experiences recorded throughout time by mystics, monks and saints.

I personally reckon that there may be some truth in all this religion stuff, at least the idea that humans can experience the numinous and/or sacred by working at particular practices. It is a fact that religiosity is associated with better health, and that forgiveness, gratitude and compassion appear to have substantial health benefits.

Now, finally we reach the meat of the post. Recently, a science blogger wrote an article entitled does theology progress. His major point appears to be that science jettisons theories the moment they contradict the evidence (well mostly, but thats a whole other post), while religions do not typically do this. While I would agree that many religious believers do not do this, i would suggest that the impetus of religion and spirituality is to keep searching until whatever it is that humans look for has been found.

Another issue that illuminates the science/religion divide is this: science offers descriptions, religions seem to offer interpretations. Put another way, science deals with information while religion deals with meaning. Now, I would argue that the social sciences, properly done can investigate particular sets of meanings, but i am doubtful that we will ever be able to reduce them to information or discover mathematical laws that guide their experience (then again, i could well be wrong on that).

I suppose my major point here is that while religion defined as the book or practices on which particular faiths are founded may not progress, the people reading the book certainly do, and this is what causes such wildly different interpretations of the same book and teachings. Of course, many people who profess to believe do not follow the teachings exactly (or even at all - how you can be a Christian and refuse benefits for the long term unemployed is beyond me), but the point is that the interpretation and meanings given to a particular scripture are not inherent in the text but rather emerge from the interaction of text and reader, and as such, the idea that religion is stale and unchanging seems to me to be absurd.

Woah, went a bit post-modern there. I think I should set out my stall somewhat more clearly though. I believe (this is my faith) that what people call God is an experience which we all have the potential to achieve through dilegent work. I believe that this process is entirely amenable to the study of well conducted science. I do not believe that the experience itself can be reduced to neural firings, but again I could be wrong there. The remembrance of it certainly is related to particular patterns of neural activity though.

Here's the kind of research agenda I would like to see:

1) Large, globally diverse sample
2) Longitudinal design
3) Measurement of practice, mood and other personality variables daily
4) Measurment of physiological data either by self administration (BP, HRV etc) and by clinicians on a monthly or weekly basis
5) Examination of different cultural beliefs and their relationship to the outcomes of practice.

This study would probably need to continue for 5 years minimum, to give us a decent chance of observing one of these experiences in controlled conditions.

Now, the funny thing is that the groundwork for this study has been done. The use of Mindfulness Based (insert problem here) therapies has become very popular in the last few years, and these are the kinds of people we should follow. They tend to come from different walks of life and cultures, and they have already been trained in meditation with minimal preconceptions.

Of course, we'd need to examine the different kinds of meditative practices, as they may well have differential effects. Again, some of the groundwork has been done on this but the long term focus is lacking.

Thats where I stand on this whole thing, anyway.

Also, i regard evolution (the arguments about, not the FACT of) as a distraction from this grand project, in many ways its more important to understand where we are going than where we came from. Of course, the two are not mutually exclusive either.

Wednesday, July 7, 2010

Placebos and Power

My research is very much focused on placebos. Therefore, I'm at least tangentially interested in homeopathy and its use. Recently, the BMA came out against homeopathy (and by extension, the placebo). This has been picked up by a BMJ blogger and the Guardian

Now, this is obviously a subject of great interest to me, regardless of the efficacy or otherwise of homeopathy. The placebo has been demonstrated to be very effective in relieving pain, depression and ulcers. The issue then becomes, if one is aware that placebo can help, what is the grounds for denying this effective treatment to a patient?

Many doctors would argue that the use of placebos has the possibility to diminish trust, and research has shown that this trust can be a powerful healing force (the therapuetic alliance, as it were).

However, in this case, they should probably not have come out against homeopathy, and indeed should probably encourage people to try alternative medicines more generally. My reasoning for this is as follows:
a) Doctors do not wish to prescribe placebos due to the deception
b) Even if they did, their knowledge that they were doing so would probably reduce the efficacy of the placebo
c) Homeopathy is a placebo (just assume this is true for the moment)
d) Homeopathists beleive in their treatments.

Therefore, its a win win for doctors to encourage (privately of course) patients to see homeopathists. The patients will gain some benefit, the homeopathist will be able to give them more time and attention (which is critical for placebo) and the doctors need not engage in any unethical behaviour.

Its simple really, but I'm not really surprised that the BMA didnt go for it. The placebo and this kind of stuff pushes against most of what doctors believe, and its very difficult to go against one's beliefs, even for the best of causes.