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Placebo effects without deception? Well, not exactly…

In discussing “alternative” medicine it’s impossible not to discuss, at least briefly, placebo effects. Indeed, one of the most common complaints we at SBM voice about clinical trials of alternative medicine is the lack of adequate controls — meaning adequate controls for placebo and nonspecific effects. Just type “acupuncture” in the search box in the upper left hand corner of the blog masthead, and you’ll pull up a number of discussions of acupuncture clinical trials that SBM bloggers have written over the last three years. If you check some of these posts, you’ll find that in nearly every case we spend considerable time and effort discussing whether the placebo or sham control used was adequate, noting that, the better the sham controls, the less likely acupuncture studies are to have a positive result.

Some of the less clueless advocates of “complementary and alternative medicine” (CAM) seem to realize that much of what they do relies on placebo effects. As a result, they tend to argue that what they do is useful and good because it’s “harnessing the placebo effect” for therapeutic purpose. One problem that advocates of SBM (like those of us at SBM who have taken an interest in this topic) tend to have with this argument is that it has always been assumed that a good placebo requires on some level at least some deception of the patient by either saying or implying that he is receiving an active treatment or medicine of some kind. This, we have argued, is a major ethical problem in using placebos in patients, and advocates of placebo medicine appear to agree, because they frequently argue that placebo effects can be harnessed without deception. Indeed, just last week there was an example of this argument plastered all over multiple news outlets and blogs in the form of stories and posts with headlines and titles like:

Except for one, every one of these articles or blog posts discussing a new study in PLoS ONE that purports to have found that placebo effects can be elicited in irritable bowel syndrome (IBS) without deception buys completely into that very thesis. For example, here is an example, taken from the Reuters story about this study:

Placebos can help patients feel better, even if they are fully aware they are taking a sugar pill, researchers reported on Wednesday on an unusual experiment aimed to better understand the “placebo effect.”

Nearly 60 percent of patients with irritable bowel syndrome reported they felt better after knowingly taking placebos twice a day, compared to 35 percent of patients who did not get any new treatment, they report in the Public Library of Science journal PLoS ONE.

“Not only did we make it absolutely clear that these pills had no active ingredient and were made from inert substances, but we actually had ‘placebo’ printed on the bottle,” Ted Kaptchuk of Harvard Medical School and Beth Israel Deaconess Medical Center in Boston, who led the study, said in a statement.


From Robert Langreth:

The latest study, a randomized trial of 80 women and men published in Plos One by Harvard researchers, shows that even when clinicians told women with irritable bowel syndrome they are getting fake pills, the fake pills still worked.

From CBS News:

Incredibly, according to a new study of patients with irritable bowel syndrome, the placebo effect, even when patients were in on the secret, worked almost as well as the leading medication on the market.

It’s also a lot cheaper. And the best part about placebo – no side effects.

From NPR:

However, conventional wisdom is that placebos require deception. In order to work, a patient has to think it’s an active drug. So the American Medical Association and other authorities frown on the use of placebos in everyday medical care for ethical reasons.

But along came the “honest placebo” study.

And, the most overblown report of all comes from Steve Silberman:

A provocative new study called “Placebos Without Deception,” published on PLoS One today, threatens to make humble sugar pills something they’ve rarely had a chance to be in the history of medicine: a respectable, ethically sound treatment for disease that has been vetted in controlled trials.

So, does this study show what all these stories claim that it shows? In a word, no.

When in doubt, go to the study

As you will see, the claims for this study by people like Silberman are overblown compared even to the claims made for it by its authors. I’ll show you what I mean by heading right over to PLoS ONE to find the article Placebos without Deception: A Randomized Controlled Trial in Irritable Bowel Syndrome. Notice right away that the authors of this study, led by Dr. Ted J. Kaptchuk of Harvard’s Osher Research Center, have framed their findings as having shown that it is possible to use the placebo effect without deception. The investigators. The Osher Center, for those of you not familiar with it, is Harvard’s center of quackademic medicine; only this time its investigators seem to be trying to do some real research into placebo effects. I’ll also give them credit for describing concisely the ethical conundrum that results when practitioners use placebos, at least as they are currently understood:

Directly harnessing placebo effects in a clinical setting has been problematic because of a widespread belief that beneficial responses to placebo treatment require concealment or deception. [3] This belief creates an ethical conundrum: to be beneficial in clinical practice placebos require deception but this violates the ethical principles of respect for patient autonomy and informed consent. In the clinical setting, prevalent ethical norms emphasize that “the use of a placebo without the patient’s knowledge may undermine trust, compromise the patient-physician relationship, and result in medical harm to the patient.” [4]

For purposes of this study, Kaptchuk et al wanted to determine if an open-label placebo pill with a persuasive rationale was more effective than no treatment at all in a randomized but completely unblinded study. In this particular study, it was made clear to the subjects in the experimental group that the pills they were getting were placebos — sugar pills. In fact, the pills were even named “placebo,” and the bottles containing them labeled as such! I’ll discuss the serious problems I found in the study in a moment, but first I’ll just take a moment to summarize the results. 92 patients with irritable bowel syndrome were screened and 80 patients randomized either to no treatment (43 subjects) or placebo (37 subjects). The primary outcome measurements were assessed using questionnaires, such as the IBS Global Improvement Scale (IBS-GIS) which asks participants: “Compared to the way you felt before you entered the study, have your IBS symptoms over the past 7 days been: 1) Substantially Worse, 2) Moderately Worse, 3) Slightly Worse, 4) No Change, 5) Slightly Improved, 6) Moderately Improved or 7) Substantially Improved.” Other scales were used as well. The trial lasted three weeks, and the results were as follows:

Open-label placebo produced significantly higher mean (±SD) global improvement scores (IBS-GIS) at both 11-day midpoint (5.2±1.0 vs. 4.0±1.1, p<.001) and at 21-day endpoint (5.0±1.5 vs. 3.9±1.3, p = .002). Significant results were also observed at both time points for reduced symptom severity (IBS-SSS, p = .008 and p = .03) and adequate relief (IBS-AR, p = .02 and p = .03); and a trend favoring open-label placebo was observed for quality of life (IBS-QoL) at the 21-day endpoint (p = .08).

I find it rather interesting that the way the authors chose to frame their results in the actual manuscript, compared to how they described their results to the media. One wonders whether saying that 60% of subjects taking placebos felt better compared to 35% receiving regular care feeling better sounded more convincing that citing improvement scores like the ones listed above. The reason is that I very much wonder whether the improvements reported are clinically significant. For instance, in the main result reported, those in the notreatment arm reported an average IBS-GIS of 4 (no change). In the Open Placebo arm, the average reported was 5 (Slightly Improved). How clinically relevant is this? I don’t know, but it sure seems to skirt the borders of clinical relevance and might not even achieve it. Come to think of it, the reason why news stories reported the results the way they did becomes clearer.

Be that as it may, I think I know why this study is in PLoS ONE, which is not known for publishing high quality clinical trials, rather than in a better clinical journal. New England Journal of Medicine material, this is most definitely not. (Of course, given the NEJM’s recent propensity towards a bit of credulity to woo, perhaps being in the NEJM doesn’t mean what it once did.) The first thing one notices, of course, is that there isn’t a single objective measure in the entire clinical trial. It’s all completely subjective. This is fine, as far as it goes, given that placebo effects affect primarily subjective outcomes, such as pain, anxiety, etc. It would have been quite interesting if the investigators had included along with their subjective measurements some objective measurements, such as number of bowel movements a day, time lost from work, or medication requirements. Anything. The authors even acknowledge this problem, pointing out that there are few objective measures for IBS. This may well be true, but it doesn’t mean it wouldn’t have been worth trying measures that are at least related to IBS. Then there’s the potential issue of reporting bias. Because this wasn’t a double-blinded trial, or even a single-blinded trial, it was impossible to hide from the subjects which group they were assigned to. Combine this with the lack of objective measures, and all that’s there is subjective measures prone to considerable bias, all for a condition whose natural history is naturally one of waxing and waning symptoms.

Lie to me, after all

As I mentioned in the introduction, this study is being touted all over the media and blogosphere as strong evidence that the placebo effect can be induced without deceiving patients. Indeed, the authors argue as much themselves in the discussion:

We found that patients given open-label placebo in the context of a supportive patient-practitioner relationship and a persuasive rationale had clinically meaningful symptom improvement that was significantly better than a no-treatment control group with matched patient-provider interaction. To our knowledge, this is the first RCT comparing open-label placebo to a no-treatment control. Previous studies of the effects of open-label placebo treatment either failed to include no-treatment controls [27] or combined it with active drug treatment. [28] Our study suggests that openly described inert interventions when delivered with a plausible rationale can produce placebo responses reflecting symptomatic improvements without deception or concealment.

No, the reason I say this is because, all their claims otherwise notwithstanding, this study doesn’t really tell us anything new about placebo effects. The reason is that, even though they did tell their subjects that the sugar pills they were being given were inert, the investigators also used suggestion to convince their subjects that these pills could nonetheless induce powerful “mind-body” effects. In other words, the investigators did the very thing they claimed they weren’t doing; they deceived their subjects to induce placebo effects by exaggerating the strength of the evidence for placebo effects and using rather woo-ish terminology (“self-healing,” for instance). Here’s how the investigators describe what they told their patients:

Patients who gave informed consent and fulfilled the inclusion and exclusion criteria were randomized into two groups: 1) placebo pill twice daily or 2) no-treatment. Before randomization and during the screening, the placebo pills were truthfully described as inert or inactive pills, like sugar pills, without any medication in it. Additionally, patients were told that “placebo pills, something like sugar pills, have been shown in rigorous clinical testing to produce significant mind-body self-healing processes.” The patient-provider relationship and contact time was similar in both groups. Study visits occurred at baseline (Day 1), midpoint (Day 11) and completion (Day 21). Assessment questionnaires were completed by patients with the assistance of a blinded assessor at study visits.

This is a description of the script that practitioners were to use when discussing these pills with subjects recruited to the study:

Patients were randomly assigned either to open-label placebo treatment or to the no-treatment control. Prior to randomization, patients from both groups met either a physician (AJL) or nurse-practitioner (EF) and were asked whether they had heard of the “placebo effect.” Assignment was determined by practitioner availability. The provider clearly explained that the placebo pill was an inactive (i.e., “inert”) substance like a sugar pill that contained no medication and then explained in an approximately fifteen minute a priori script the following “four discussion points:” 1) the placebo effect is powerful, 2) the body can automatically respond to taking placebo pills like Pavlov’s dogs who salivated when they heard a bell, 3) a positive attitude helps but is not necessary, and 4) taking the pills faithfully is critical. Patients were told that half would be assigned to an open-label placebo group and the other half to a no-treatment control group. Our rationale had a positive framing with the aim of optimizing placebo response.

How is this any different from what is known about placebo responses? I, for one, couldn’t find anything different. It’s right there in the Methods section: The authors might well have told subjects that they were receiving a sugar pill, but they also told them that this sugar pill would do wonderful things through the power of “mind-body” effects, as though it was entirely scientifically clear-cut that it would.

Finally, the investigators recruited subjects thusly:

Participants were recruited from advertisements for “a novel mind-body management study of IBS” in newspapers and fliers and from referrals from healthcare professionals. During the telephone screening, potential enrollees were told that participants would receive “either placebo (inert) pills, which were like sugar pills which had been shown to have self-healing properties” or no-treatment.

Even the authors had to acknowledge that this was a problem:

A further possible limitation is that our results are not generalizable because our trial may have selectively attracted IBS patients who were attracted by an advertisement for “a novel mind-body” intervention. Obviously, we cannot rule out this possibility. However, selective attraction to the advertised treatment is a possibility in virtually all clinical trials.

In other words, not only did Kaptchuk et al deceive their subjects to trigger placebo effects, whether they realize or will admit that that’s what they did or not, but they might very well have specifically attracted patients more prone to believing in the power of “mind-body” interactions. Yes, patients were informed that they were receiving a placebo, but it must be emphasized again and again that that knowledge was tainted by what the investigators also told them about what the placebo pills could do. After all, investigators told subjects in the placebo group that science says that the placebo pills they would take were capable of activating some sort of woo-ful “mind-body” healing process.

In fact, I would say that what Kaptchuk et al did was no different than what we know about what is required to induce placebo effects. They were also far more suggestive than the explanations that investigators conducting placebo-controlled clinical trials offer subjects during the recruitment process. Consider: In most clinical trials, investigators tell subjects that they will be randomized to receive either the medicine being tested or a sugar pill (i.e., placebo). This, patients are told, means that they have a 50-50 chance of getting a real medicine and a 50-50 chance of receiving the placebo. In explaining this, investigators in general make no claim that that the placebo pill has any effect whatsoever. In fact, in most clinical trials, subjects are explicitly told that it does not. In contrast, Kaptchuk et al explicitly tried to “optimize the placebo response” for purposes of the study by telling their subjects that the sugar pill activated some sort of mind-body response that would make them feel better — but only if they religiously took the sugar pills. Yes, they did tell the subjects that they didn’t have to believe in mind-body interactions to experience the healing response. But did it matter? I doubt it, because people with authority, whom patients tend to believe (namely doctors) also told subjects that there was strong evidence showing that these placebo pills activated some sort of powerful “mind-body” mechanism. This alone makes proclamations about how the investigators triggered placebo effects without deception — shall we say? — not exactly in line with the reality of the situation. A far better design would have included at least one more group, namely a group receiving the placebo but without all the suggestion about how it would activate “powerful mind-body” effects using a neutral script that simply said it was a sugar pill and wasn’t expected to do anything. Lacking that additional group, this study tells us very little that we didn’t already know.

Reality versus perception versus reporting

I’ve been very critical of how this study was reported, but I will admit that, actually, the overall design wasn’t that bad. After all, it’s a pilot study, and, as such, wasn’t that large. We shouldn’t expect too much from it, other than potentially intriguing results that generate hypotheses and justify further study. Rather, what I had a problem with were two issues: execution and spin.. Of the two, by far the biggest problem I have is with how investigators spun their results and how that spin was reported by the press as though this study were evidence that placebo effects can really be triggered without at least some degree of deception or suggestion to the patient. It shows nothing of the sort. That’s the problem.

Think of it this way. How is what Kaptchuk et al did when they came up with a “convincing rationale” for their sugar pills to relieve IBS symptoms any different than what a homeopath does when he concocts stories of “like cures like” and how water “remembers” the therapeutic molecules with which it’s been in contact? Or what a reiki practitioner does when he claims he can channel “healing energy” from the “universal source” through himself an into his clients for healing effect? Or when acupuncturists claim that they are “unblocking the flow of qi” to healing effect? Yes, I know that, to supporters of SBM, claims of unblocking qi, channeling energy, or using the memory of water are not scientifically compelling. In fact, they’re totally ridiculous. However, we often forget that to average lay people without a medical or scientific background, these woo explanations might well be quite reasonable sounding — compelling even. In the case of this study, the investigators did the same thing, only with a somewhat — only somewhat — less woo-filled narrative as to why their sugar pill should relieve the symptoms of their subjects.

One last note. Take a guess who funded this study. Go on. Where did the investigators get the money for this study?

That’s right. The National Center for Complementary and Alternative Medicine (NCCAM) funded the study.

Why am I not surprised? Actually, in all fairness, this is one of the better studies that NCCAM has funded, which should give you an idea of how poor most NCCAM studies are. Even so, it’s only just a so-so study. It has a somewhat intriguing finding that could well be due to differences between the experimental groups, reporting bias, and/or recruiting bias. Or it might even suggest a way to activate placebo effects with a minimum of deception, a minimum of violation of patient autonomy. Maybe. But ground-breaking or somehow demonstrating that the placebo effect can be activated “without deception”? Not quite..

For more, note that SBM co-blogger Peter Lipson has also commented on this study.

Posted in: Clinical Trials, Neuroscience/Mental Health, Pharmaceuticals, Science and the Media

Leave a Comment (97) ↓

97 thoughts on “Placebo effects without deception? Well, not exactly…

  1. Badly Shaved Monkey says:

    Thanks, Dave, for that article. It really cuts through the fluff surrounding this study. I would like to extend your argument a little and emphasise the point that what it really does is place really quite narrow limits on any real power of the placebo effect, which is almost diametrically opposite to what the authors and the journalistic spinners of it have said.

    Let’s summarise the real position.

    1. The authors took a condition in which there is a large psychosomatic element.
    2. They preselected subjects who were probably most predisposed in favour of expressing that psychosomatic element.
    3. They took no objective measurements.
    4. There was no long-term follow-up to see whether the apparent improvements had in any sense ‘stuck’ with these patients
    5. They did not control in any way for the subjects giving biased and untruthful answers, at variance with their real experience, in order to please the investigators.

    In other words, this study was tuned very precisely to maximise a measured “placebo effect”. Of these, the fifth factor in that list is the most serious because it isn’t really even a true placebo effect, but a mere artefact of the model.

    And what did they find? A near-trivial clinical effect.

    So, a more accurate one-line summary would be Maximal placebo effect offers little real benefit to patients.

    Clearly this must be all set against the literature showing us how size or colour of pill, or invasiveness of intervention can modify the placebo effect, which necessitates that a placebo does effect exist in order for it to be modifiable, but the real issue is the potential size and permanency of any effect and it does seem to me that the size in almost all circumstances must be small and I strongly suspect it may largely be an artefact of the trialling system. In that latter respect it is really just the Hawthorne effect. What would be interesting would be a study design to show the size of the placebo effect, which has a secret follow-up section in which the outcome is measured for subjects at some period after the end of what the subjects thought was the study period- a questionnaire apparently from an independent source, or assessment of their condition by a person apparently unrelated to the organisation conducting the study. If subjects were blinded to the significance of that latter study element, I think some interesting results would appear.

    As a vet, I find particularly annoying the argument that Therapy X must work on animals because they can’t experience the placebo effect. I find it particularly ironic that the placebo effect is probably trivial anyway.

    From what I have observed of SCAM users, a consistent pattern is to wander from practitioner to practitioner over time. I think this is because, for real medical diseases, the condition returns to bite the patient on the bum and they simply cannot sustain the pretence that most recent round of treatment has worked. From the practitioner’s perspective these people are lost to follow-up, but almost certainly are counted as successes because their last conversation reported positive news. By the time the patient has reached their fourth therapist, the first one has long since been out of the loop. Real medicine, with proper record keeping, tends to know its failures and we recognise our heart-sink patients from the sheer length of the medial history that accompanies them. There is no such consistent record-keeping or habit of passing on records in the SCAM world.

  2. daijiyobu says:

    Kaptchuk is famous in woo circles for that tome of prescientific Asian mysticism The Web That Has No Weaver.

    One of the articles I’d read that was reporting on this study had him quoted enthusiastically stating that ‘thus further study is needed’ on the importance of ‘medical ritual’.

    Hmmmm.

    -r.c.

  3. Nescio says:

    I came across another of Dr. Kaptchuk’s papers on placebos, ‘“Maybe I Made Up the Whole Thing”: Placebos and Patients’ Experiences in a Randomized Controlled Trial’.
    http://www.ncbi.nlm.nih.gov/sites/ppmc/articles/PMC2716443/

    Here’s a quote from the abstract:
    ” The placebo treatment was a problematic perturbation that provided an opportunity to reconstruct the experiences of the fluctuations of their illness and how it disrupted their everyday life. Immersion in this RCT was a co-mingling of enactment, embodiment and interpretation involving ritual performance and evocative symbols, shifts in bodily sensations, symptoms, mood, daily life behaviors, and social interactions, all accompanied by self-scrutiny and re-appraisal. The placebo effect involved a spectrum of factors and any single theory of placebo—e.g. expectancy, hope, conditioning, anxiety reduction, report bias, symbolic work, narrative and embodiment—provides an inadequate model to explain its salubrious benefits.”

    Anyone else detect a distinct odor of post-modernism?

  4. wlondon says:

    You wrote:

    “Then there’s another rather large problem. Take a look at Table I, which shows the demographics of the subjects. Do they look well matched to you? They sure didn’t to me when I first read the article. Of course, given the relatively small sample size, it’s possible that my “eyeballing” of the numbers may be misleading. Unfortunately, there appear to be no statistics to tell me whether my impression was incorrect or not.”

    No such statistics can tell you whether your impression was correct. This wasn’t a matching study. It was a randomized clinical trial.

    Although some prestigious journals require authors to report statistical test results comparing treatment and control groups on baseline characteristics in randomized clinical trials, statisticians point out that doing so makes no sense at all. Here’s why:

    When comparing two groups on a particular variable, the null hypothesis is that there is no difference between the groups. The null hypothesis is normally rejected if the p value is very low because the p value indicates the probability of finding a difference at least as big as what was found assuming the null hypothesis is true. A low p value indicates the difference is unlikely due to chance alone. But the problem is that if the study was randomized, then any baseline differences between groups MUST be due to chance alone no matter how low the p value is.

    Randomization implies that any differences between groups will be due to chance. It doesn’t guarantee that groups will be comparable. It is always possible with randomization that the result will be large differences between groups at baseline. And it is always possible that groups will differ greatly on outcome variables by chance alone. That’s the whole reason for doing statistical inference when we look at the outcome variables. And when we get a result with a p value of slightly less than .05, we should recognize that a difference at least as extreme as what was found is expected by chance alone 1 in 20 times (and we shouldn’t get too confident that our treatment really works).

    Methods of statistical inference when properly utilized are aids to judgment about the role of non-systematic error (chance) in research studies. They do not make judgments for us, especially when inappropriately applied.

    Bill London

  5. David Gorski says:

    When the two groups turn out to have what appear to be (when eyeballed) significant differences in composition due to random chance alone, then is it so unreasonable to expect the authors at least to comment on these differences? I don’t think it is. Whether the statistics are helpful in doing this or not is, quite frankly, not that big a deal to me; the main point was that there was no commentary on an important aspect of the trial that might well have affected its outcome.

    While the apparent differences between the open placebo and no treatment groups might be “meaningless” from a purely statistical standpoint, clinical trials are far more than just statistics, as is their interpretation. From a scientific and clinical standpoint the possible differences between the control and experimental groups are very important, which makes it very disturbing that the authors didn’t even mention these differences as potential explanations for their results. Let’s just put it this way: As a clinician interpreting the results of this trial, I don’t really care all that much how the differences between the groups arose, by random chance alone or through some unsuspected or unreported bias, although admittedly it would be worse if they arose through an unrecognized bias. What I care about most is that the groups that resulted from the randomization process do not appear to be entirely comparable in key clinical categories, because that matters very much indeed in considering the outcome of the study. Again the authors didn’t discuss this issue. We can quibble over whether it would have been appropriate to do some statistics or not, but I stand by my criticism that the authors in essence ignored a potentially significant cause of bias. If I were the reviewer on this article, I would have insisted on a discussion of this aspect of the study.

  6. Can I “impress” patients into feeling better? Hey, maybe! Is it a non-deceptive placebo if I do it by saying “this fake medicine is really awesome”? Um, no.

    Kaptchuk is obviously trying to aggrandize placebo, to expand its definition in a way that would (just coincidentally!) make it seem more magical and awesome — thus reinforcing his own lie. “This fake medicine is really awesome as proved by studies like mine showing that this fake medicine is really awesome as proved by studies like mine showing …”

  7. geo says:

    I was reminded of this recent paper on treatments for depression:
    http://jme.bmj.com/content/early/2010/10/20/jme.2010.039313.abstract%20.

    I don’t think we’re going to have a system of medicine which excludes the deception of patients until we have a system which effectively and consistently penalises those practitioners who choose to mislead their patients. While it seems that we’re now over-coming the elitism which previously justified such deceit, it looks like it’s being replaced by pragmatic considerations rather than a new commitment to honesty.

  8. digaman says:

    David:

    For the record, I didn’t write this paragraph:

    An intriguing Harvard study in the online journal PLoS ONE seems to up-end conventional wisdom about placebos. It strongly suggests placebos can work even if patients know they’re taking a fake pill.

    And you could have chosen to quote paragraphs like this:

    Inevitably, the health of some people in both [experimental and placebo] groups improves, while the health of others grows worse. Symptoms of illness fluctuate for all sorts of reasons, including regression to the mean.

    or

    The study is hardly the last word on the subject, but more like one of the first. Its modest sample size and brief duration leave plenty of room for followup research. (What if “ethical” placebos wear off more quickly than deceptive ones? Does the fact that most of the volunteers in this study were women have any bearing on the outcome? Were any of the volunteers skeptical that the placebo effect is real, and did that affect their response to treatment?)

    …but I suppose those grafs don’t fit your hypothesis that my piece was “the most overblown report of all.” I didn’t see any mentions of the heterogeneity of response in placebo control groups or regression to the mean in any of the other reports — and both are obviously critical to understanding the statistics of placebo response in clinical trials.

    As for this paragraph of yours, which is crucial to the generally damning tone of your argument:

    In other words, not only did Kaptchuk et al deceive their subjects to trigger placebo effects, whether they realize or will admit that that’s what they did or not, but they might very well have specifically attracted patients more prone to believing in the power of “mind-body” interactions.

    I’m a little surprised that no one has pointed out that your definition of “deception” here is entirely circular. Simply put, you don’t believe that placebos can trigger healing processes that involve both mind and body, so you define any statement to that effect as deception, and then go on to accuse the researchers of lying to their patients.

    The only problem is the fact that suggestion and conditioning (the two primary elements of the placebo effect) have been proven in dozens of studies (i.e., not only those by Kaptchuk et. al.) to alter the operation of the body in ways that affect perception of pain, inflammation, and so on. See Fabrizio Benedetti’s overview of 30 years of research, “Placebo Effects.”

    Or this study:
    http://www.pnas.org/content/104/26/11056.long

    Or this one:
    http://www.jneurosci.org/cgi/content/full/25/45/10390

    Or this one:
    http://www.sciencemag.org/content/326/5951/404.abstract

    In other words, while it’s fine that you apparently don’t believe that suggestion and conditioning can affect physiological processes related to disorders in domains like pain, that’s a highly contested position, rather than a self-evident truth. That’s an important distinction.

    As for your other points, many of them are valid, which is why I said “The study is hardly the last word on the subject, but more like one of the first.”

  9. David Gorski says:

    Before I address the meat of your comments directly, I’ll point out that the paragraph that wasn’t yours was apparently a cut and paste error. It will be fixed just as soon as I finish this comment. My apologies. I really am embarrassed at that mistake.

    Now, let’s go to this:

    I’m a little surprised that no one has pointed out that your definition of “deception” here is entirely circular. Simply put, you don’t believe that placebos can trigger healing processes that involve both mind and body, so you define any statement to that effect as deception, and then go on to accuse the researchers of lying to their patients.

    Uh, no. But that is a nice straw man argument, given that you seem to have left out the rest of what I said, which, in context, was:

    In other words, not only did Kaptchuk et al deceive their subjects to trigger placebo effects, whether they realize or will admit that that’s what they did or not, but they might very well have specifically attracted patients more prone to believing in the power of “mind-body” interactions. Yes, patients were informed that they were receiving a placebo, but it must be emphasized again and again that that knowledge was tainted by what the investigators also told them about what the placebo pills could do. After all, investigators told subjects in the placebo group that science says that the placebo pills they would take were capable of activating some sort of woo-ful “mind-body” healing process.

    Having read the script that the investigators used (and which I quoted elsewhere in my post), I stand by my characterization. Note that earlier, I also said:

    No, the reason I say this is because, all their claims otherwise notwithstanding, this study doesn’t really tell us anything new about placebo effects. The reason is that, even though they did tell their subjects that the sugar pills they were being given were inert, the investigators also used suggestion to convince their subjects that these pills could nonetheless induce powerful “mind-body” effects.

    And:

    How is this any different from what is known about placebo responses? I, for one, couldn’t find anything different. It’s right there in the Methods section: The authors might well have told subjects that they were receiving a sugar pill, but they also told them that this sugar pill would do wonderful things through the power of “mind-body” effects…

    It’s also hard to resist pointing out that you rather undermine your own argument when you later write:

    In other words, while it’s fine that you apparently don’t believe that suggestion and conditioning can affect physiological processes related to disorders in domains like pain, that’s a highly contested position, rather than a self-evident truth. That’s an important distinction.

    Leaving aside your repeating the same straw man argument, let’s just consider this: If it’s controversial whether or not suggestion and conditioning can affect physiological processes related to pain–and, if so, by how much–and the investigators simply told patients in very concrete terms (which they did) that these placebos activate powerful “mind-body” healing processes but that it’s absolutely essential that they take the pill twice a day, then my point stands. Deception by omission was used in that the investigators presented a controversial area of science that is nowhere near settled as though it were as cut-and-dried as you accuse me of representing my doubts about their claims regarding placebo effects. Perhaps I could have phrased things a bit better (it was the night after Christmas when I finished this, after all, and I didn’t spend as much time as I normally do polishing things up), but nothing you’ve said shows that the investigators didn’t use the power of suggestion in the form of at the very least exaggerating to patients the strength of the evidence and wrapping the terminology in a bit of woo. That seemed to be the very point, actually.

    In other words, I stand by my characterization of what the investigators did as being no different than a typical use of placebo effects and in fact using deception.

    Now, if you want to get to the “overblown” part, I’ll point out that, for length considerations (my post was already getting too long), I actually refrained from using some of the best quotes to back up this characterization, for example, this passage from your post:

    A lot of very smart people dismiss homeopathy, acupuncture, and other alternate treatments as nothing more than quackery for dullards — “woo,” as P.Z. Myers or Ben Goldacre might put it. But couldn’t the placebo response play the role of being, in a sense, the “active principle” of woo? For example, I recently saw a controlled trial of homeopathic therapy for rheumatoid arthritis that concluded that the effectiveness of the therapy was due to the homeopathic consultation process, not the little pills themselves. Your colleague Ted Kaptchuk spoke to me for my Wired article about the importance of “therapeutic ritual” in eliciting the placebo response, and homeopathic consultation — even if the notion that pills containing a few molecules at most of an active ingredient seems obviously ridiculous — is a good example of an elaborate therapeutic ritual. I think the door is still open on whether acupuncture does more than jump-start the placebo response…

    Steve Novella actually blogged about that very study, and convincingly demonstrated that the study didn’t actually show what you seem to think it shows (and what the investigators claimed it showed). But I’ve gone on long enough. Suffice to say that to me the entire tone of your article came across as decidedly unskeptical, your occasional notes of seeming skepticism notwithstanding.

    Finally, it’s not true that I dismiss placebo effects. What is true is that I dismiss the way this study is being sold as in any way supporting the concept of a placebo without deception, and I also find the differences in how this study was reported to the public versus how it was reported as a study. In reality, if there was even an effect at all, which is not clear given the small sample size, it isn’t even clear that the effect size reaches anything approaching clinical significance.

  10. digaman says:

    David, repeating the phrase “straw man argument” doesn’t refute my point, but I’ll just accept the truth of your statement that you don’t dismiss placebo effects out of hand.

    As for the paragraph that so “annoys” you, I’m not sure why. You seem to read it as if I’m somehow saying that people who use the word “woo” — as you do, rather often — must be wrong somehow. But that’s not what I’m saying. I’m just asking a question that any good skeptic should be asking these days. Just as it’s possible that the perceived benefits of antidepressants are due to placebo effects (as Irving Kirsch discusses at length in his book), it’s possible that the perceived effects of “woo” treatments like homeopathy and acupuncture are due to placebo effects, rather than the efficacy of homeopathic pills or realignment of ch’i (or what have you). That’s why I framed the issue as a question.

  11. David Gorski says:

    David, repeating the phrase “straw man argument” doesn’t refute my point, but I’ll just accept the truth of your statement that you don’t dismiss placebo effects out of hand.

    Except that I pointed out why your argument was a straw man by showing that in context I was not arguing what you claimed I was arguing. I didn’t even quote parts of the post where I pointed out that the investigators exaggerated the certainty regarding placebo effects.

  12. Badly Shaved Monkey says:

    @Digaman

    “it’s possible that the perceived effects of “woo” treatments like homeopathy and acupuncture are due to placebo effects, rather than the efficacy of homeopathic pills ”

    This is still missing the Big Point. The “effects” of homeopathic pills and acupuncture are not the placebo effect. Or anything of the sort. The whole point is that the placebo effect is trivial at best and the dramatic reports of significant clinical improvements are due to regression to the mean, spontaneous recovery and biased reporting.

    Small earthquake, no one hurt.

  13. stewiegriffin81 says:

    @digaman

    I don’t regard what occurred in this trial to be a non-deceptive use of a placebo at all.

    A truly non-deceptive way of giving a placebo to a patient would have to include revealing the fact that suggestion and the creation of expectation are what constitute the mechanism of placebo. That is, the placebo IS the suggestion and expectation (it is NOT the sugar pill), and so for the placebo to be properly and non-deceptively revealed to patients, they must be informed that suggestion and expectation will be used to attempt to elicit an improvement. Informing them only that the pill was a sugar pill misses the entire point, and tells them nothing about what is really being used.

    I think a non-deceptive way of explaining a placebo if prescribing a placebo would be something along these lines:

    “I will be giving you a placebo pill. This pill has no active ingredients capable of interacting with your body in any significant way. However, my ability to suggest the likelihood of improvement and your ability to expect improvement has the potential to increase the likelihood of you perceiving an improvement [although only some psychologically related improvements]”

    This was not revealed to the patients. Ergo, it was deceptive.

  14. digaman says:

    nothing you’ve said shows that the investigators didn’t use the power of suggestion

    Sorry, but wasn’t this study entirely a study of the power of suggestion? I’ve read people throwing that phrase around as if it clearly debunks the whole premise of the study — Aha! They’re not analyzing placebo effects at all, they’re analyzing the power of suggestion! — yet since placebo effects depend on suggestion and/or conditioning, it’s clear that the researchers believe that they were using suggestion to generate placebo effects.

    But I think Badly Shaved Monkey said it well here:

    They did not control in any way for the subjects giving biased and untruthful answers, at variance with their real experience, in order to please the investigators.

    That’s the most salient challenge to the study design. I look forward to more research on the subject.

  15. I certainly “believe that suggestion and conditioning can affect physiological processes.” And yet I agree with Dr. Gorski that Kaptchuk’s findings have been spun hard to make placebo and alt-med look better than they are. These ideas are not mutually exclusive.

  16. David Gorski says:

    And they used deception as part of that power of suggestion by exaggerating the certainty of the evidence for placebo effects!

  17. Exaggerated both the certainty and, crucially, the therapeutic potential. Placebo effects are erratic, small, transient, and conspicuously absent entirely with many pathologies. Try telling patients that about their sham medication and see how well it works.

  18. digaman says:

    I certainly “believe that suggestion and conditioning can affect physiological processes.” And yet I agree with Dr. Gorski that Kaptchuk’s findings have been spun hard to make placebo and alt-med look better than they are. These ideas are not mutually exclusive.

    No, they are not. And I’m obviously not responsible for coverage other than my own. I’m not sure if simply asking the question about the role of placebo effects in acupuncture and homeopathy can be counted as pro alt-med spin. It certainly didn’t seem so to the author of several alt-med books who emailed me angrily to tell me that I “just don’t get it” by suggesting that homeopathy and acupuncture work via placebo effects, rather than the Law of Similars and qi. But I can certainly understand how outright dismissing such things as “woo,” and worthy of no further investigation, could be seen as more stridently anti alt-med.

    Until the role of placebo effects in alt-med has been more thoroughly investigated, however, I’ll confess to being more open-minded about that possibility than I am about the actual existence of qi.

    I’m similarly agnostic about antidepressants. Kirsch’s argument that they work primarily via placebo effects is pretty convincing, but that doesn’t mean that there’s nothing else going on with those drugs that’s worthy of investigation.

  19. digaman says:

    Paul, until researchers have done many, many studies of the therapeutic potential of placebo effects (instead of the small handful that have been done), I’m not comfortable declaring them of no use in practice. After all, drugs-as-placebos are already used widely by doctors, though often sub rosa, as I indicated in my post; and if antidepressants do turn out to work primarily via placebo effects…well, since antidepressants are one of the largest-selling drug classes in the world, placebo effects may turn out to be quite effective for treating mild depression. And they’re not as transient as trial designers have assumed for decades. See “The persistence of the placebo response in antidepressant clinical trials,” by Arif Khan,
    doi:10.1016/j.jpsychires.2007.10.004.

  20. digaman says:

    conspicuously absent entirely with many pathologies. Try telling patients that about their sham medication and see how well it works.

    No one is suggesting using placebos in cases of cancer, Alzheimer’s disease, autism, infections, or broken bones. (Well actually, some people are, and they’re quacks.) But considering the amount of suffering caused by depression, anxiety, chronic pain, and Parkinson’s disease — all domains in which placebo effects have been observed –the fact that one approach might not be suitable for all diseases and disorders doesn’t strike me as reason enough to block further research into that approach.

  21. I am not comfortable declaring placebo of no use in practice either. However, I am concerned solely with the widespread disingenuous presentation of the study.

    Naturally many purveyors of acupuncture and homeopathy are shrilly outraged by any implication that they are selling only a placebo effect. However, many others have retreated to firmer ground by admitting that the evidence shows that their therapy cannot outperform placebos, but then they deftly twist that inside out and claim that their methods are “just as good” as a placebo. This is a relatively new tactic for lowering standards of evidence to a point that they can reach, while trying to keep it from seeming quite so lame by making placebo look as good as possible. A study like Kaptchuk’s plays into this perfectly.

    A coincidence, I’m sure.

  22. Digaman, you are having an debate with some alternate universe version of me, I think. I didn’t come within a rhetorical mile of suggesting that research on this question should be blocked. It was flawed, not verboten.

  23. psypro says:

    Whatever else may be true about this research, given the subjective dependent measure(s), it is highly-likely that there is not even a true placebo effect here, but rather, another example of an illusory placebo effect identified by Greenwald et al. (1991) (see http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.19.73&rep=rep1&type=pdf)—that is, the manipulation of testimony.

  24. daedalus2u says:

    If you are a practitioner of Medicine, then you use treatments only after they have been shown to be efficacious. You do not use treatments until they have been shown to be non-efficacious.

    If you use treatments that have not been shown to be efficacious, then you are a quack.

    There are reasons that some disorders are more susceptible to placebos than others. Those disorders happen to be disorders characterized by low nitric oxide. The physiological placebo effect is mediated though neurogenic increases in basal nitric oxide. There are some disorders that placebos make worse, for example nausea. A nocebo (an inert pill said to make nausea worse), actually makes nausea better.

    http://daedalus2u.blogspot.com/2007/04/placebo-and-nocebo-effects.html

    Of the disorders mentioned, Alzheimer’s, autism, IBD, Parkinson’s, depression, anxiety, chronic pain are amenable to placebo effects because they are characterized by low nitric oxide. So is ischemic heart disease, hypertension, allergies, asthma.

    Essentially every disorder that is made worse by stress will be made better by increasing nitric oxide levels. A state of “stress” is a state where metabolic resources are mobilized to deal with what ever that stressor is. Those metabolic resources are then unavailable to be used for things like healing. The state of stress triggers a “fight or flight” state. During that “fight or flight” state, resources are mobilized to either fight, or run away. For the duration of the fight, or the escape, there is no ATP to waste on luxuries such as healing. In the limit, healing gets turned off. In the extreme limit, organisms can run themselves to death. If you need to escape from a bear chasing you, being able to run yourself to death his a tremendous feature.

    During a myocardial infarction, the heart continues to beat, even though doing so can/will cause necrotic spots to form. Why? Because if the heart stopped to prevent necrosis, the organism would die in seconds. Being a living organism with a damaged heart with necrotic spots is infinitely better than being a dead organism with a heart with no necrotic spots. The same is true of the liver, the kidneys, the skeletal muscles, with every tissue compartment. Being a living organism with a damaged liver, kidney, muscle is infinitely better than being a dead organism with an intact liver, kidney, muscles.

    Heart muscle will continue to beat until it necroses from ATP depletion. Continuing to beat is the highest ATP priority, and so it is the last thing that a heart is capable of doing. Hearts need to do a lot of other things to stay healthy, angiogenesis, remodeling, mitochondria biogenesis, infection control, etc. All of those things get turned off before the heart stops beating because beating gets turned off last, and it is “turned off” by there not being enough ATP for the heart to stay alive.

    If the “housekeeping” pathways (healing, angiogenesis, infection control, etc.) get turned off (as in ischemic preconditioning), if they are not turned back on, eventually that tissue compartment will degenerate. That is what happens in Alzheimer’s. Ischemic preconditioning it turned on but then never turned off. The reduced metabolic activity observed in the Alzheimer’s brain is due to ischemic preconditioning.

  25. Werdna says:

    I have a question: I get a bit confused when people talk about placebo effects. Are we talking about some actual clinical event or – as Hróbjartsson and Gøtzsche postulated – just another kind of reporting error. Clearly the writers of the paper in question are in the former camp. I’ve kind of assumed though that most of the SBM folk are of the later variety. If true I don’t understand how any study of this kind would be worthwhile and I don’t get why would we care if it can be done with or without patent consent? It would seem to me that informed or uninformed it would be almost impossible to do this with proper disclosure (e.g. “This pill will do you no good but it might make you talk as if it was”).

  26. digaman says:

    That’s an excellent question, if not one easily answered. The problem is in the use of the word placebo. The CROs that run drug trials are not interested in teasing out the therapeutic response to the dummy pills or the clinical environment from other dynamics in the placebo group, including simple regression to the mean. One of the points I tried to make in my piece is that, until fairly recently, the notion that the response of volunteers to dummy pills or supportive staff would be worthy of study on its own — rather than to support the mission of minimizing those responses in drug trials — would have seemed far-fetched. There was very little research into placebo effects outside of drug trials paid for by pharmaceutical companies. The term “placebo effect” was used as a synonym for “the miscellaneous collection of responses and artifacts occurring in the control group.”

    But the designers of this study — as well as researchers like Benedetti, Zubieta, Wager, Moerman, and others — are specifically interested in study therapeutic responses to dummy pills, creams, etc. in supportive environments.

    Using the phrase “placebo effect” to describe both is definitely confusing, but at this point, it’s hard to get around it.

  27. daedalus2u says:

    Werdna, I think that is much of the problem, people don’t want to define placebos precisely.

    There are a lot of good studies that show physiological effects from treatments that have no known active therapeutic mechanism. A mother’s “kiss it and make it better”, is the archetypal placebo. If you look at the state of arousal of the child, the levels of stress hormones, heart rate, pain status, all of those are elevated prior to receiving the “kiss it and make it better” treatment. By observation, the arousal status of the child is greatly reduced by the mother’s “kiss it and make it better”. Is the mother deceiving her child? When a crying child is picked up by his/her mother, and the child stops crying, has the mother deceived her child? The mother hasn’t performed a pharmacological treatment on the child.

    When bullies taunt and emotionally hurt their victim, is the hurt caused by the bullies deceiving their victim? Why should a placebo require deception and a nocebo (the hurt from the bullies) not require deception?

    There are surgical techniques that seem to “work”, until they are compared to placebo surgery and then they are found to be no better. Dr Gorski has written about poudrage, the application of talc to cause inflammation and (in theory) stimulate angiogenesis in the heart. It “works”, but then so do placebo treatments without the talc. There was a treatment where a laser was used to blast holes in the heart from the inside, with the idea that these holes would be sites for vascularization. It turns out they just filled up with scar tissue, but people “got better”. When they did placebo versions of the heart laser blasting, some of the placebo recipients got better too.

    That a treatment “works” should not be used as evidence that it is a non-placebo.

    Any treatment “working” can only “work” by some physiological mechanism. It should not be preposterous to think that mental states can cause physiological changes. We know that they can. If a bear came crashing through your door, your body would trigger the “fight or flight” state in a heart beat. Your heart rate would go from “at rest” to “as fast as possible” in a very few seconds. Your liver would pour glucose into your blood, you would start hyperventilating.

    There is no drug that is doing that, it is all neurogenic. The “fight or flight” state is not a state that can be maintained indefinitely. There has to be a neurogenic trigger that turns the “fight or flight” state off. My hypothesis is that one trigger that turns off the “fight or flight” state is the placebo effect.

    Is seeing a bear coming at you a “placebo” effect? I think it is more of a nocebo effect, it certainly isn’t a pharmaceutical effect or a surgical effect. What kind of treatment is a mother’s “kiss it and make it better”? It seems to me it can only be a placebo.

    Why people want to call a mother’s “kiss it and make it better” something other than a placebo is not something I understand.

  28. ConspicuousCarl says:

    Published by David Gorski
    One wonders whether saying that 60% of subjects taking placebos felt better compared to 35% receiving regular care feeling better sounded more convincing that citing improvement scores like the ones listed above. The reason is that I very much wonder whether the improvements reported are clinically significant.

    Is there a word for this misleading practice? This is the same thing I suspected in that study regarding cell phone use [supposedly] increasing behavior problems in children.

    First they convert a detailed or complex issue into a binary (overall behavior converted to a binary problem/normal, or bowel disorders converted into better/neutral), then they make a percent or fraction by summing up all of those blunted evaluations. The result can be a very large change in the incidence of subjects qualifying for an arbitrary bracket, even if the change in each subject’s experience is virtually nothing.

    100% of all test subjects gained weight after being handed a cursed pebble! Specifically, the average weight gain by subjects handed the cursed pebble was 1 gram. More research is recommended.

    Unless there is some critical and life-changing reason why the threshold for a particular bracket is in a specific place, this seems like a rather slimy trick.

  29. pmoran says:

    There may be less confusion if we sought some mutually agreed terminology.

    Why not talk about “expectancy effects” ? Expectancy seems to be the dominant requirement when eliciting placebo responses, and the term would allow a clearer distinction from “spontaneous evolution of symptoms” and “patient reporting biases” (answers of politeness/ experimental subordination). The latter probably always contribute to some extent to what are commonly regarded as “placebo effects” .

    It would also reduce focus upon the placebo agent itself, which should “do” absolutely nothing when isolated from the total therapeutic environment.

    How much is left after these spurious “effects” are eliminated?
    I don’t know for sure. The evidence is unclear.

    I would point out that the original observations of Beecher and others that even severe post-operative pain can be relieved by saline injection (plus expectation) have been repeatedly confirmed, that human suggestibility makes such responses very likely, and that they would have clear evolutionary survival value.

    Even paying less attention to symptoms having taken action regarding them would contribute to expectancy phenomena. It would be astonishing to me if they were not also to occasionally have a spectacular influence upon outcomes, such as helping some people to switch out of illness mode when conditions permit. Certainly some testimonials are suggestive of this.

    The collections of studies usually arrayed against the possibility of strong placebo influences are rather weak evidence. Those studies are designed in such a way as to discourage rather than enhance expectancy effects. Yet even they show positive results in some settings such as pain.

    Nevertheless, I agree that reporting bias is a major problem and I don’t know how we can isolate that with present methods.

  30. Badly Shaved Monkey says:

    @pmoran

    “Yet even they show positive results in some settings such as pain.”

    But, conversely, would we agree that pain may be peculiarly susceptible to psychosomatic processes; at its heart it is a psychosomatic process, which is why soldiers can fight on with a limb missing whereas severing of a limb in other circumstances requires complete anaesthesia to relieve pain.

    An important thing that I certainly lack is any kind of census of conditions that are more or less placebo-susceptible and both their relative severity and prevalence in medical practice.

    But to return to my parochial veterinary view, I think true placebo-susceptibility is close to zero whereas the potential for bias and false interpretation and reporting of clinical signs is vast. This is embodied in our technical language. I deal effectively exclusively with clinical signs whereas in human medicine, especially in SCAM, symptoms are very important, indeed this is almost a defining difference between what we do and what medics do.

  31. Badly Shaved Monkey says:

    To elaborate a little further on what I have just said, the present study rather suggests that IBS is a condition more characterised by clinical signs rather than by subjective symptoms so that, even is a situation tuned to maximise the placebo effect, the problem was stubbornly persistent and patients were only prepared to report a clinically trivial improvement.

    I have commented previously on one of the homeopaths’ favourite customer satisfaction surveys, the Spence (2005) report of patients at the Bristol hom “hospital”. In this 75% of patients reported improvement after hom treatment. But, turn that around, 25% of patients who had the typical range of chronic fluctuating conditions, who were self-selected to favour homeopathy and asked a leading question by their therapists still had the gumption to answer that question in the negative.

  32. Reductionist Nurse says:

    @Badly Shaved Monkey
    “..In that latter respect it is really just the Hawthorne effect.
    I was thinking the same thing, hence the whole point of blinding.
    As referenced by Dr. Gorski, the outcomes were subjective with zero objective controls. If it were something like white coat hyper-tension, then that would be something the everyday person couldn’t fake.

    No clinician starts out an expert at their job and when that job requires a patient relationship, I think at some small level we all at one time or another feign confidence to carry us though training.

    The difference between quacks and professionals is that professionals are aware effect and simply use of confidence to -prevent- maleficence via the mind, where as alt-med abuses it to invent beneficence (via the mind).

    Or maybe the people who applied for the add just read “The Secret” but became constipated after their check never came in the mail before they quantum-thought themselves back to reality. Or maybe the person who gave them the “placebo” winked.

  33. daedalus2u says:

    People who think that placebos can only work on subjective symptoms, or are only due to bias on the part of subjects and/or clinicians need to look at this study.

    http://www.ncbi.nlm.nih.gov/pubmed/16738082

    It is open access. They found that a placebo for nausea (an inert pill said to make nausea better) actually made it worse, and a nocebo (the same inert pill said to make it worse) actually made it better. A placebo-placebo (the same inert pill said to be a placebo) didn’t do much.

    Nausea was determined subjectively, but was also correlated with gastric tachyarrhythmia, an instrumental measure which correlates with subjective nausea.

    My explanation is that because the ANS of the gut is highly nitrergic, that changes in the basal NO level will affect gastric motility and so will influence subjective and objective measures of gut myogenic tone. High NO makes nitrergic responses faster, longer range, and longer duration, so will be associated with gastric tachyarrhythmia. Low NO reduces the onset time, range and duration of nitrergic signaling, so will tend to inhibit gastric tachyarrhythmia.

    This data is fully compatible with my conceptualization of the placebo effect as a trigger to transition out of a “fight or flight” state, and a nocebo as being a trigger to transition into a “fight or flight” state.

    I would be interested in hearing why everyone else here thinks this interpretation is wrong.

  34. pmoran says:

    But to return to my parochial veterinary view, I think true placebo-susceptibility is close to zero whereas the potential for bias and false interpretation and reporting of clinical signs is vast.

    That is a reasonable opinion, but not a solidly evidence-based one.

    It is not “false interpretation” that has created the necessity for sophisticated double-blinded clinical trials whenever we are assessing subjective outcomes from treatment, — it is the inevitability of placebo reactions +/- reporting biases, even under conditions that would tend to be unfavourable for them.

    And what proportion is biased reporting? We have no idea. I am aware of little evidence bearing upon that but am willing to be informed by anyone who has some.

    Would expectancy effects upon outcomes be as trivial as you suggest under the extreme conditions, such as can sometimes apply with charismatic healers? We cannot know.

    I don’t think we as scientists should be locking ourselves into any position on these matters. I suspect that our own biases have led us to accept without question Hrobjartsson-type studies which are not really well-designed to answer the crucial questions.

  35. qetzal says:

    The physiology behind at least some placebo effects may well overlap with the “fight or flight” response. That certainly makes sense for pain perception. However, I highly doubt that’s the underlying mechanism for all placebo “expectancy effects” (following pmoran’s terminology). E.g., it seems unlikely to account for the expectancy effects claimed for Parkinson’s Disease.

    Minor correction: in that study, the nocebo did make things better (counter-intuitively), but the positive-expectancy placebo did not make things worse. It was not stastically different from an open-label placebo.

  36. digaman says:

    An important thing that I certainly lack is any kind of census of conditions that are more or less placebo-susceptible

    Fabrizio Benedetti’s excellent book “Placebo Effects” provides a thorough rundown of conditions that are placebo-susceptible.

  37. digaman says:

    This is also a very helpful new paper by Benedetti that offers an overview:

    http://www.nature.com/npp/journal/v36/n1/full/npp201081a.html

  38. blahwhat says:

    A question:
    If giving a patient a placebo without informing them it is a placebo is unethical, then how are double blind tests ethical?
    Another question:
    If the ethical problem of placebo is that a doctor who knows his treatment has no pharmacological effect giving a patient who thinks it does, then if the doctor believes the treatment works, is he performing ethically?
    A third question:
    If your most woo-tastic object of hate is using the placebo effect because he thinks it works on a patient for whom it is working because he thinks it works and you stomp in and say “It doesn’t work! I can tell from the molecules!” are you not behaving unethically in damaging a working treatment?
    Finally, the reductio ad absurdum of these tired, tedious, fatuous “ethics” canards:
    If doctors “A” are using a treatment they think is effective, on patients for whom the treatment is effective, until doctors “B” conclusively prove using science that the treatment is placebo and that the patients must be notified of this to preserve their ethics, Can doctors “A” inform doctors “B” without violating the Hippocratic Oath?
    I’m not picking on this study. I’m picking on the tendency of “skeptics” to make broad, sweeping statements like “alternative medicine kills babies” on the one hand, but on the other say
    “Be that as it may, I think I know why this study is in PLoS ONE, which is not known for publishing high quality clinical trials, rather than in a better clinical journal. New England Journal of Medicine material, this is most definitely not. (Of course, given the NEJM’s recent propensity towards a bit of credulity to woo, perhaps being in the NEJM doesn’t mean what it once did.)”
    “So what if it’s in a peer-reviewed medical journal and the study was done at Harvard, it was done by a department at Harvard we hate and was published in a peer-reviewed medical journal that isn’t as good as this other peer-reviewed medical journal that isn’t as good as it used to be either and GOD DAMNNIT DO SCIENCE THE WAY I LIKE IT”
    Too harsh?
    “The first thing one notices, of course, is that there isn’t a single objective measure in the entire clinical trial. It’s all completely subjective. This is fine, as far as it goes, given that placebo effects affect primarily subjective outcomes, such as pain, anxiety, etc.”
    Okay….
    “It would have been quite interesting if the investigators had included along with their subjective measurements some objective measurements, such as number of bowel movements a day, time lost from work, or medication requirements.”
    What?
    “The authors even acknowledge this problem, pointing out that there are few objective measures for IBS. This may well be true, but it doesn’t mean it wouldn’t have been worth trying measures that are at least related to IBS.”
    So, despite the fact that they’re attempting to study placebo effects on a disorder freely acknowledged to have few objective measures, in order to avoid the wrath of The Holy Skeptic the scientists performing the study have to invent objective measures for a subjective phenomenon?
    I wonder how that would have gone over. Probably like this:
    (argument in the first)
    “For purposes of this study, Kaptchuk et al wanted to determine if an open-label placebo pill with a persuasive rationale was more effective than no treatment at all in a randomized but completely unblinded study. In this particular study, it was made clear to the subjects in the experimental group that the pills they were getting were placebos — sugar pills. In fact, the pills were even named “placebo,” and the bottles containing them labeled as such!”
    (argument in the 2nd)
    “Then there’s the potential issue of reporting bias. Because this wasn’t a double-blinded trial, or even a single-blinded trial, it was impossible to hide from the subjects which group they were assigned to.”
    THAT’S THE WHOLE POINT OF THE STUDY!
    What else can be criticized? It’s a Harvard study, but not the right Harvard study. It’s in a peer-reviewed journal, but not the right peer-reviewed journal (the author, of course, can’t resist his swipes even when it raises the question if there are any peer-reviewed journals he’d accept). It’s measuring subjective effects, but really it should assign importance to objective measures unused elsewhere in the literature. Oh, and the demographics are skewed and we don’t care if the demographics of IBS sufferers are skewed.
    And on and on and on and on and on.
    I’m all for “skepticism.” But all too often, “skeptic” seems to mean “axiomatic zealot for the status quo.” It’s like that old saw “if alternative medicine worked, they’d just call it medicine.” Okay… so what do they call it while they’re determining if it works? Sham medicine? And if 20 years from now greater society has settled on the fact that it works? It’s okay for you?
    So really – you’re saying that medicine isn’t medicine until SOCIETY calls it medicine?
    How is that skeptical? How is that scientific? How is that anything other than blind dogma?
    Michael Shermer is a skeptic. Bjorn Lomborg is a “skeptic.”
    Y’all can probably guess whether or not I think this article is deserving of the quotes.

  39. mmorrisson says:

    While I agree that the phrase “mind-body intervention” seems really wooish, I’m unclear as to how that’s an inaccurate description of what is going on. You take something that is perceived to work, but physically does nothing and your mind tells you that it worked and you start to feel physically better. It’s certainly quite different than water vibrational memory and other purely fictional descriptions. Still, I think that they will not begin to really get any useful data until they increase the study size and include a third study group who are given hidden-label placebos and actually deceived.

    To avoid drawing in a group predisposed to “mind-body” healing, they should just advertise like it’s a drug trial and wait to tell the open-label group until they are assigned.

  40. ConspicuousCarl says:

    I was reading a book by some guy named Richard Heuer, and he thinks (or thought at the time, I haven’t followed up) that what he called the “expectancy thesis” was a better generalization than “wishful thinking”. That may not work well for medical issues (he was talking about intelligence analysis) because the subject is stricken with a rather invasive condition rather than just evaluating external information.

    I wonder if the nocebo effect was tainted by the subjects skepticism over being supposedly given something intended to make them feel bad. Maybe they were officially told that, but knew they were taking part in a deceptive study? I know that sounds like unrestrained imagination on my part, but I always wonder about the credulity factor because I often have a hard time getting over the absurdity of hypothetical questions when I am the test subject (a fat guy is totally NOT going to stop a train).

    I don’t think nausea is a good example of a non-subjective symptom. Pain has biology behind it as well, and having suffered from nausea as we all have, I can testify to the wide variation in suffering based on my mental state. Very much like pain, nausea can subside temporarily if my brain is occupied with other thoughts, and it can amplify a lot if I get stuck in the “woe is me” state of mind.

    Proposing the fight-or-flight response as the basis for [some] placebo effects only strengthens the subjectivity theory because those stress responses are usually the direct result of pure mental influence (except maybe in the case of physical injury). I agree that this is a strong possible cause, and that is exactly why subjective interpretation might be so powerful.

    HOWEVER… I am skeptical of any long- or medium-term results’ being caused by panic relief. The physical act of swallowing a pill might produce immediate comfort in the form of a sense of safety or control, but eventually the subject is likely to forget about the pill and notice that their pain is still there.

  41. daedalus2u says:

    Carl, did you read the study? They measured “butterflies” in the stomach. They had an instrumental measure of gut muscle hyperactivity. Why would all of the subjects have the opposite reaction through some weird reverse-psychology mechanism? I don’t know about you, but I can’t fake having butterflies in my stomach.

    What is wrong with the idea that what ever physiology the “placebo effect” triggers, it happens to make nausea worse, and the physiology of the “nocebo effect”, just happens to make nausea better? I mean, what is wrong with the idea other than people don’t like it?

  42. David Gorski says:

    If giving a patient a placebo without informing them it is a placebo is unethical, then how are double blind tests ethical?

    From your question, I really have to wonder if you know how randomized, double-blind clinical trials are performed. Placebos are ethical in double-blind randomized clinical trials precisely because in double blind clinical trials the patients are told in advance that they will receive either active medicine or a placebo, as well as exactly what the odds are that they will be in the group receiving the experimental drug or whether they will be receiving a placebo, and they are told that the placebo is inert, no suggestion or claims of efficacy made. Informed consent is given, and patient autonomy respected. These days, however, true placebo-controlled trials are becoming more uncommon, other than for minor or self-limited conditions. Most clinical trials now compare experimental drug either added to standard of care or versus standard of care.

    I’m all for “skepticism.” But all too often, “skeptic” seems to mean “axiomatic zealot for the status quo.” It’s like that old saw “if alternative medicine worked, they’d just call it medicine.” Okay… so what do they call it while they’re determining if it works? Sham medicine? And if 20 years from now greater society has settled on the fact that it works? It’s okay for you?

    So really – you’re saying that medicine isn’t medicine until SOCIETY calls it medicine?

    Wow. Now that’s a massive straw man argument.

    You got the statement all wrong, anyway. The statement goes like this: Medicine that has been scientifically validated and shown to work ceases to be “alternative” and becomes just “medicine.” It’s simply a means of pointing out that what has been called “alternative” by its own advocates is only “alternative” because it has either not yet been shown to work or has been tested and failed that testing.

    As for what we call things before they have been shown to work. That’s easy: Experimental. Not yet proven. Under investigation. We have lots and lots and lots of science-based experimental treatments that are being investigated, and we usually don’t give them to patients outside the context of a clinical trial. If the investigation leads to demonstration of efficacy to the point that a treatment becomes an acceptable treatment in science-based medicine, then the “experimental” label can be removed. So why aren’t “alternative” treatments called “experimental”? Because most of them have been in use and have been used on patients by “alternative” practitioners without testing to show whether they work or not, without a plausible mechanism, and without any science.

    One wonders at your extreme hostility towards my post, hostility that far dwarfs any that was actually in my post directed towards this study. Clearly, I’ve gored an ox of yours. In any case, you haven’t answered the central criticism of my post, namely that this study is old wine in a new skin. It’s nothing new, but it’s being sold as though it were some sort of revolutionary discovery about placebo effects, particularly by people who are prone to woo.

  43. pmoran says:

    http://www.scribd.com/doc/6481223/Review-Placebo-Efect

    Another extensive review of recent research into placebo from Benedetti and others. (A clunky site)

  44. blahwhat says:

    David Groski, I’m not the author of that comment (kleinbl00 is), you can find the author and replies in the following link: http://www.reddit.com/r/skeptic/comments/eskol/placebo_effects_without_deception_well_not/

    Incidentally, there are currently 19 thousand people in reddit’s skeptic community, and your article and kleinbl00′s comment is on their front page (SBM articles frequently make it to its front page). You’re obviously a busy person, but maybe you could engage in the comments of your articles that are posted there, and help answer the frequent (unfounded) criticisms.

  45. blahwhat says:

    Argh… sorry I misspelled your name.

  46. Jan Willem Nienhuys says:

    Gorski:

    “Then there’s another rather large problem. Take a look at Table I, which shows the demographics of the subjects. Do they look well matched to you?”

    Bill London (27 Dec 2010 at 6:38 am) commented correctly that doing statistics in this case doesn’t mean much.

    I don’t quite agree with either of them. I eyeballed the figures and I saw nothing special. Of course, when there had been a severe accidental imbalance then there had been something to worry about.

    If for example the symptoms in one group would have been a lot worse than in the other group, then mere regression to the mean might have produced a remarkable ‘improvement’ in the ‘bad’ group.

    In some researches one measures some aspect at baseline and after a certain period. One has then the option of looking only at the individual differences between before and after, or one can look at ‘afterwards’ only. If the two groups differed ‘non significantly’ at baseline, and the difference became a bit larger (but not much) afterwards, then the numbers afterwards might show a ‘significant’ effect. But that wasn’t done here.

    Another example: suppose you examine some treatment for asthma. Afterwards (after breaking the code) you discover that there is an enormous difference (p=0.01) between the two groups on the characteristic ‘family has cats, dogs or birds or similar pets’. Then you would have something to worry about, because such pets are often related to allergic complaints. Is the outcome merely a reflection of the different number of pets or has the experimental medication something to do with it?

    I took the liberty of crudely calculating a few p-values, just to check whether my eyeballing was correct.
    Here are the results:
    number of females: p=0.25 (one tailed, Fisher’s exact test)
    number of whites: p=0.12 (same)
    number of diarrhea type: p=0.23 (same)
    duration: p=0.12 (one tailed, normal distribution assumed)
    severity: p=0.22 (same)
    life quality: p=0.37 (same)
    symptoms: p=0.19 (same)
    medication: p=0.31 (same)

    I conclude that my impression was correct.

    This is a rather pointless exercise, because below the table it says ‘Group differences were examined…’. So the authors did check whether the differences were not too large.

    Summarizing: I fail to see the point of the remark quoted at the beginning of this comment.

  47. David Gorski says:

    Since Bill London and you have convinced me that I overstated the potential problem. Consequently, I have deleted the paragraph, given that it’s not central to the criticism of this study anyway and appears to be distracting attention and energy away from the criticisms of the interpretation of this study. I probably should have sat down and run the numbers myself. No excuses.

  48. David Gorski says:

    David Groski, I’m not the author of that comment (kleinbl00 is), you can find the author and replies in the following link: http://www.reddit.com/r/skeptic/comments/eskol/placebo_effects_without_deception_well_not/

    Then why didn’t you make it more clear that this is what you were doing front? You presented the overblown criticisms and straw men as though they were yours. In retrospect, I see the quotation marks but that didn’t really tell me where the criticisms were from. I thought the use of quotation marks curious at the time, but, without the questions being attributed to someone, I didn’t see them as meaning you weren’t the author.

    Incidentally, there are currently 19 thousand people in reddit’s skeptic community, and your article and kleinbl00′s comment is on their front page (SBM articles frequently make it to its front page). You’re obviously a busy person, but maybe you could engage in the comments of your articles that are posted there, and help answer the frequent (unfounded) criticisms.

    This is not likely to happen, except for rarely. Between my day job, editing SBM, writing for two blogs, and other skeptical activities, I quite simply do not have the time to participate actively in discussions on other blogs or discussion forums. There is only so much time in a day, and I already spend way too much of my “free” time on SBM- and blog-related activities. Something has to give. Indeed, regular readers might even have noticed that in general after three or four days I don’t even monitor the comments on my own posts here very actively anymore.

  49. Toiletman says:

    Just for curiousity’s sake: how could you blind a study where people are already given a placebo?

  50. mmorrisson says:

    @toiletman,

    How about advertising for a simple drug trial, and adding a third group into the mix? You’d have the two groups from before (Open-label placebo recipients, and the non-treated) but you’d add a group who has been lied to and thinks that there’s a 50/50 chance they could have been given an actual drug. Frankly, I couldn’t believe they didn’t include the 3rd group in the original study… to have a trial on placebos and not placebo control it seems almost laughable.

  51. daedalus2u says:

    mmorrisson, you can’t give actual drugs to people unless they actually have a medical need for them. It is completely unethical to do so.

    You can’t have an ethical study where you lie to people and say you are going to give people drugs they don’t need and then don’t give them the drugs (both the lying and the giving of unneeded drugs are unethical). No IRB would approve such a thing.

    If you think the patient selection for this study was bad, advertising a study that will give people drugs they don’t need would select for a unique population, a population that wants to abuse drugs.

  52. mmorrisson says:

    daedalus2u, I think you misunderstood me. I’m not saying to give anyone any actual drugs. I’m also not saying to pretend that this is for drugs that they don’t need. I’m saying they do basically the same thing they did this time around, but instead of advertising for a “novel mind-body intervention,” advertise AS IF (I know, I didn’t put those words in before) it is a simple drug trial to treat IBS or whatever ailment they choose this time around. The point is, the two groups from the original study will learn the truth about the study, but the third group will think there is a 50/50 chance that they will receive a drug, while in reality they will only be given the same placebo as the open-label group.

    As far as not giving them the drug (which doesn’t exist) and giving them the placebo, I’m not sure how that’s different or more unethical than the usual placebo control groups in trials other than instead of a 50% chance they might get a placebo, there is a 100% chance.

  53. blahwhat says:

    No Gorski, that entire comment is kleinbl00′s. It was reposted whole cloth with nothing added or removed.

  54. qetzal says:

    mmorrisson,

    The difference is that in a std placebo controlled trial, the subjects are told that they’ll receive either an investigational drug or a placebo, which is true. In your example, they’d be told the same thing, but it would be false, since there would be no investigational drug. IOW, the first group is given accurate information, while the second group is lied to.

    Deceiving subjects in a clinical trial can sometimes be justified, but I don’t know if your suggestion would qualify. In any case, I don’t see the relevance of your added group, given what the authors wanted to study. Their whole point was to see if open-label placebo could still induce perceived improvement, compared to no treatment.

    Adding your group would show if the open-label placebo effect was as large as a blinded placebo effect. But until you know that there is an effect in the open-label placebo group, I don’t think it makes sense that add a blinded placebo group. Especially if they have to be deceived.

  55. David Gorski says:

    No Gorski, that entire comment is kleinbl00′s. It was reposted whole cloth with nothing added or removed.

    That’s not what I complained about; I simply pointed out that you did not post the comment identifying it clearly as someone else’s. You posted it in such a way that it could easily have been interpreted as being yours.

  56. JMB says:

    Here is a link to the American Medical Assn. comments on medical ethics and use of placebo effect:

    http://www.ama-assn.org/ama/pub/physician-resources/medical-ethics/code-medical-ethics/opinion8083.shtml

    This is an excerpt of that statement,

    Physicians may use placebos for diagnosis or treatment only if the patient is informed of and agrees to its use. A placebo may still be effective if the patient knows it will be used but cannot identify it and does not know the precise timing of its use.

    This statement was posted long before this study was published. It would indicate that placebo effects can be observed even after the patient is aware that they may receive the placebo. The study under discussion makes the point that placebo effects can be observed even after clear indication to the patient that they are receiving a placebo treatment. I think Dr Gorski is right in that the researchers simply chose an illness (irritable bowel syndrome) and outcome measures that would a priori have a likelihood of showing a difference. They could have magnified the observed difference in their careful choice of statements to the patient.

    The a priori estimate of probability of success comes from the clinical observations that characterized some of medical knowledge in the 50′s and 60′s. I would imagine that more time was devoted in medical education in the 50′s and 60′s to the selection of patients and techniques for magnification of placebo effects. The study that is the topic for this discussion may be the first randomized clinical trial, but it doesn’t rely provide new discoveries. It just revives some of the strategies for placebo use that used to be more common in mainstream medicine. There are reasons why placebo use became less common (I am not saying that it was ever common, it just used to be more common).

    I think back when placebo use and deceit were accepted for the justification that it could be used as a diagnostic test or improvement of the patient, the use of placebo effect was still limited. The decrease in use of placebo effect in my opinion can be traced to a few reasons. I think the number one reason was the recognition that most of the positive effects could be achieved by good bedside manner, without deceit of the patient. Changing attitudes also rejected the ends justified the means approach (the paternalistic approach). Improving therapeutic options also diminished the use of placebo treatments, just as improving diagnostic tests reduced the use of placebo for diagnosis. So if the public media were really enlightened and hadn’t forgotten history, they would report that placebo effects such as this have been well known for decades, that this is one bit of medical knowledge that has survived the test of time. However, the same reasons that placebo use declined is that it is of limited usefulness, and frankly goes against the idea that we should be as honest as we can be as part of professional ethics.

    Of course, based on this study, maybe we could push congress to grant the FDA the task of forcing CAM providers to clearly identify their treatments as PLACEBO (put a disclaimer label with big letters PLACEBO on every bottle/bag/box sold with CAM treatments, just as a warning must be placed on every pack of cigarettes). That way, the tax money spent on NCCAM might actually have some benefit for the taxpayer. Based on this study, CAM cannot argue that being forced to label their treatments placebo will reduce the effectiveness of the treatment.

    ************************

    Personally, I would characterize most placebo effects as operative on an emotional level. Just as reason cannot always rule over emotional responses, the knowledge that you are receiving a placebo does not automatically blunt the emotional response. As an example, consider that every first year medical student class is warned about “medical student’s disease” (the tendency for someone in the class to become convinced they are suffering from a particular disease they are studying). In spite of the knowledge imparted to the medical students, the development of medical student’s disease is almost inevitable in every class.

    Since emotions have physiologic effects, we can expect to see some physiologic effects of placebo. That “mind-body connection” they talk about measuring with fMRI and laboratory tests, we already know as the Central Nervous System and Autonomic Nervous System. Big mystery. Just because we have new ways of measuring it doesn’t mean it is something new and different from what me have already studied (same with ethics).

  57. JMB says:

    Sorry for my poor editing.

    “but it doesn’t rely provide new discoveries.”

    needs to be corrected to,

    “but it doesn’t really provide new discoveries.”

    “new and different from what me have already studied (same with ethics).”

    needs to be corrected as well,

    “new and different from what we have already studied (same with ethics).”

    Dr Gorski’s link to the one article that doesn’t buy wholesale into the hype actually references a study from 1965 supporting the same hypothesis (also providing an estimate of a priori probability). Kudos to Ed Yong for considering history when the rest of public media ignores it. Kudos also to Steve Silberman for mentioning the previous study (another link provided by Dr Gorski).

    However, the only thing emerging about the science of placebo effect is the newly available funding and more expensive tests to study them.

    It is kind of laughable that NPR makes the following comment,

    Because, after all, there are no big placebo manufacturers out there eager to fund this kind of research.

    Homeopathy doesn’t want to admit it is placebo. Maybe one of the big sugar companies would be willing to fund it. Perhaps we should guarantee C&H sugar exclusive rights to the manufacture of sugar pills for the next 15 years so they will fund the studies.

  58. Chris says:

    Dr. Gorski:

    There is only so much time in a day, and I already spend way too much of my “free” time on SBM- and blog-related activities.

    And most of us are glad that you do!

    blahwhat:

    No Gorski, that entire comment is kleinbl00′s. It was reposted whole cloth with nothing added or removed.

    Don’t do that, because it is really bad netiquette. Cut and pasting from another forum is both lazy, and very confusing. I actually did not read it because it was too long and not very well formatted. I am glad I did not waste the effort. In the future link to the comment (using HTML tags helps, though without a preview option here… that can be tricky) and explain briefly in your own words why it is worth clicking on the link.

    Don’t get upset about being reminded you on how to post a comment. It was quite common on Usenet to remind new users how to clearly state a message, especially since there were a few more rules. It was considered bad form to quote hundreds of lines of a message and only comment with a single sentence (very annoying when we only had phone modems). Ah, those were the days… and I made sure I read the posts by Dr. Gorki’s friend, Orac.

    mmorrisson:

    … to have a trial on placebos and not placebo control it seems almost laughable.

    There is actually a whole field of study on placebos. One thing is to make sure that it looks and tastes like the actual medication, and then that it does not have any effect itself. Unfortunately, I found out that those studies are really hard to find on PubMed. Because every which way I use “placebo” in the search terms I get tons of studies that include “tested in conjunction with a placebo group.” Sigh.

    One study I do know about (and used in my statistics class as a pertinent news story) was by Dan Ariely that showed that more expensive placebos work better than cheaper placebos. For that effort he won an Ig Nobel prize, which he is very proud of:

    “I’ve won quite a lot of academic awards; I can’t think of one that makes me happier than this one,” said Dan Ariely , a Duke University economist and author of the book “Predictably Irrational: The Hidden Forces that Shape our Decisions,” who said his deserving work has been passed over year after year and is elated to finally get an Ig Nobel.

    (oh, that is a very good book!)

  59. Jan Willem Nienhuys says:

    There’s something else with the study, at least I didn’t see it discussed. One reason to perform double blind tests is that when patients have to report about their subjective feelings, they don’t want to disappoint the nice doctor, and they say something that seems to be socially acceptable. Participants in any kind of test will often change their behavior to conform to the experimenter’s expectations.

    Now, because of the non-blinded nature of the test, all patients knew perfectly well what the experimenters expected. Those in the no-treatment arm must have known that they were expected to experience no change. Those in the open-placebo arm must have known that the idea was that they should feel better. No opportunity was lost to make this crystal clear to them.

    So the whole outcome may be nothing more than caused by the demand characteristics of the test situation. Maybe both groups were doing somewhat better (objectively) but the no treatment group denied it. There is simply no way of knowing.

  60. Chris “There is actually a whole field of study on placebos. One thing is to make sure that it looks and tastes like the actual medication, and then that it does not have any effect itself.” etc

    This alludes to what I wondered when I read this article. How many years has medicine known about the Placebo effect? Seems like something like this would have been done before. I can imagine alot of interesting psychological (or psychiatric) studies that could be done on the placebo effect and how the placebo is presented, this just doesn’t seem like one of them.

    But then I thought, maybe I’m missing something. :)

  61. David Gorski says:

    There’s something else with the study, at least I didn’t see it discussed. One reason to perform double blind tests is that when patients have to report about their subjective feelings, they don’t want to disappoint the nice doctor, and they say something that seems to be socially acceptable. Participants in any kind of test will often change their behavior to conform to the experimenter’s expectations.

    I did allude to this a bit, but not explicitly. It’s one reason why I mentioned that there should have been a placebo group in which the patients were told not only that they were getting a placebo but that there was no expectation that it would work. I also mentioned reporting bias briefly, but I admit that I didn’t explain what that is.

  62. wales says:

    “How many years has medicine known about the Placebo effect?” Michele, I was wondering the same thing. Depending upon the definition of “medicine”, opinions range from 50 years or 2000+ years….

    In his August 2009 Wired article on the placebo effect, Steve Silberman attributes the discovery of the placebo effect to a nurse during World War II “When the morphine supply ran low, the nurse assured a wounded soldier that he was getting a shot of potent painkiller, though her syringe contained only salt water. Amazingly, the bogus injection relieved the soldier’s agony and prevented the onset of shock.”

    However, this book review http://www.ncbi.nlm.nih.gov/pmc/articles/PMC546352/ gives a wider perspective

    “Evans writes that from the Second World War everything changed; from being a pious fraud, now placebo was supposed to heal people. Did everything really change here? I doubt it. In the nineteenth century also some physicians believed placebos could relieve symptoms, and after the Second World War many physicians were sceptical of the effect and the practice of giving placebos. There is much more to the developments of the last 200 years than a simple before and after the war. Also from an historical point of view it is interesting that there is still no agreement upon how important the placebo effect is and how to define it. There seem to be at least two different perspectives. One is that placebo effects have to do with placebos and can be investigated through research into the effect these have on groups of patients compared with treatment- or no-treatment-groups. This perspective has a fifty-year long tradition. The other is that placebo effects come from the mind’s influence upon the body. This perspective has a 2000-year long tradition.”

  63. daedalus2u says:

    The upsurge in interest and research in placebos following WWII was due to the experience of medics in the war. Soldiers injured with severe injuries in battle required much lower doses of morphine for equivalent pain relief than civilians with comparable injuries from accidents during peacetime needed. Soldiers were much more receptive to a placebo effect following surviving a battle than were civilians following an accident.

    My understanding of this observation is that it fits with the psychogenic regulation of the “fight or flight” state. A battle, where a soldier is wounded, is a life-or-death struggle for that soldier, a struggle that will invoke the “fight or flight” response in that soldier. Once the battle is over, and the soldier has survived, even if wounded the soldier realizes that they are not in a life-or-death fight or flight situation.

    Being tended to by a medic is the equivalent of the mother’s “kiss it and make it better”. The soldier knows that the medic is doing all that the medic can possibly to save his/her life and protect the soldier from harm. There is no need to stay in the fight or flight state, so transitioning out of that state is easier, so such individuals are more susceptible to the placebo effect.

  64. wales says:

    wow, glad you’ve got that all figured out. not having served in battle, I have no idea as to the accuracy of your assumptions.

  65. wales says:

    actually, I have heard that the “fight or flight” response can block the perception of pain, and that it’s when one is finally able to relax after the shock that the pain kicks in….not sure how that makes one “more susceptible to the placebo effect”…

  66. Zetetic says:

    I was thinking of a better way to blind this….

    - Use a placebo pill that has no taste if dissolved in water
    - Tell all the subjects that they MIGHT be receiving a placebo
    - Dissolve the placebo pill in water beforehand for the placebo group
    - Just give water to the non placebo group

    The fact that they know they’re getting a placebo is definitely a flaw! I’m sure the final analysis would be different.

  67. daedalus2u says:

    Wales, the placebo effect changes physiology so that more resources are devoted to healing and fewer resources are held in reserve to deal with what ever has triggered the fight or flight state.

    The placebo effect triggers the transition from the fight or flight state where healing is turned off, to a state where healing is turned back on.

    Healing isn’t under conscious control, so you don’t notice consciously when it is turned off, or when it is turned back on. In some cases when healing is turned off you may feel like you have more “energy” because you do have more “energy” to do voluntary things that are under conscious control because the things you don’t have conscious control over (such as healing) are turned off.

  68. qetzal says:

    deadalus, you have a bad habit of stating opinions and hypotheses as if they were well supported facts.

  69. daedalus2u says:

    Only when they are supported to such a degree that it would be perverse to withhold provisional assent.

    I appreciate that there is a great deal of “work not shown” behind my comments.

    In the case of the placebo effect, we know that inducing the “fight or flight” state long term causes pretty rapid degrading of health. There was work done with decorticated cats, where the “fight or flight” state could be induced and it wouldn’t turn off. Those cats all died in a few hours.

    This article by WB Cannon discusses death from a prolonged “fight or flight” state. That is essentially a nocebo triggered state, the ending of that state is what a placebo does.

    http://www.ncbi.nlm.nih.gov/pubmed/13432091

    He specifically mentions the work by P Bard, “A diencephalic mechanism for the expression of rage with special reference to the sympathetic nervous system.” On decorticated cats.

    My hypothesis is that without a cortex to trigger the ending of the “fight or flight” state, it remains until the cat drops dead.

  70. JMB says:

    @daedulus

    I don’t think there is a healing response invoked in irritable bowel syndrome by the placebo. Others may argue with me, but I would characterize irritable bowel syndrome as a bowel motility disorder with no detectable injury to bowel or the innervation. The reduction in stress might facilitate restoration of coordinated motility, but that is different that what a pathologist would typically identify as tissue healing (such as healing of an ulcer).

    There are diverse mechanisms through which placebos may have effect, but overall the effect is too unreliable and too weak to be of much use in modern medicine. However, it must be accounted for in many drug/treatment trials, because if you administer the placebo to a large number of people, and if your outcome depends on subjective subject reporting, then you will see a minority that will respond based on placebo and nonspecfic effects.

    Perhaps the US government thinks that the cost of healthcare can be reduced by replacing expensive treatments with placebo. I doubt that they will save the amount of money they have already spent on NCCAM by pushing the use of placebos. Placebos are not an effective replacement for back surgery, even if back surgery is largely unsuccessful. That is a simple conclusion from a bygone era in which placebo treatment with deceit was more commonly accepted. A saline injection might get the patient with back pain out of the ER, but not back to work.

  71. qetzal says:

    deadalus:

    In the case of the placebo effect, we know that inducing the “fight or flight” state long term causes pretty rapid degrading of health. There was work done with decorticated cats, where the “fight or flight” state could be induced and it wouldn’t turn off. Those cats all died in a few hours.

    Non sequitur. You haven’t demonstrated a link between the placebo effect and the fight or flight response.

    In your 7:23 AM post on 28 Dec 2010, the idea that the placebo effect is a trigger to transition out of a fight or flight state was your “conceptualization.” Now it’s “supported to such a degree that it would be perverse to withhold provisional assent?”

  72. daedalus2u says:

    JMB, “Healing” is not an on-off process. Healing is a very complicated process of many steps that work together “in sync”. We observe healing to occur at different rates, from very fast (and without scars) in utero, to very fast but with scarring in children, to pretty fast as young adults, to normal in the adult, to slow in the elderly, to very slow in diabetics.

    In all of these different healing rates, healing still occurs, the many steps are still working together “in sync”, to produce repaired tissue compartments that exhibit essentially normal morphology and function. The only way that can happen is if the control system that regulates healing is still functioning appropriately at each and every healing rate. Healing rate is (essentially) independent of healing fidelity.

    All tissue compartments are in a constant state of remodeling. Bone is continuously remodeled, the vasculature is continuously remodeled. This “housekeeping remodeling” can be considered to be an aspect of “healing” that goes on all the time that continuously repairs the minute damage that accompanies normal metabolism. Cells do die, even in normal tissues. Those dead cells need to be cleared or they will cause other problems. The “housekeeping” that does this is part of normal metabolism, and is part of what I call “healing”. The clearing of a single dead cell and the clearing of dead infarcted tissue comprising millions of cells are conceptually just different aspects of “the same” process.

    To maintain tissues in a healthy state, the damage that normal metabolism produces must be repaired as it occurs, or the damage will accumulate. This is a balance, if the damage rate exceeds the repair rate, then damage will accumulate and the tissue compartment will experience degradation, and eventual death. If the repair rate exceeds the damage rate, then the tissue compartment becomes healthier and has improved function. If a tissue compartment is healthy, it may take considerable time for enough damage to accumulate to cause problems even if the repair is zero. The repair system itself is subject to damage, and if the repair system is damaged, repair may become impossible.

    In the hierarchy of organism needs, keeping the organism alive (and reproducing) is the highest priority. Repairing the repair system is not.

    We observe healing to occur at different rates, healing rate must be something that physiology controls to occur at different rates. A treatment that turned the healing rate up, and did not use pharmacology or surgery to do so, would be a placebo.

    If we consider why organisms have evolved such that healing occurs at different rates, presumably it is because the evolved physiology doesn’t consider healing at a fast rate to be the highest priority allocation of resources at that moment. We know that if an organism is trying to escape from a predator, that healing does have a lower priority than escape.

    We know that in the fight or flight state, one of the first things that blood flow is reduced to is the gut. What symptoms would chronic reduced blood flow to the gut have? I think they would be pretty close to IBS.

  73. JMB says:

    @daedulus

    I am aware of the complexity of the healing process. There is insufficient data to indicate that between the exacerbation of symptoms of irritable bowel syndrome, and the (usually temporary) relief of symptoms, that there has been any healing response. There is insufficient evidence to indicate that diminished blood flow is the cause of irritable bowel syndrome (it is postulated to be a mechanism). Irritable bowel syndrome is likely to be a collection of different disease processes rather than a single disease process. It is a classification of patients with symptoms for which tests for inflammatory disease, infectious disease, neoplastic disease, ischemic disease, metabolic disease, mechanical obstruction, etc., are all negative. Stress has long been recognized as a factor in irritable bowel syndrome. Treating stress may diminish the patients complaints. Treatments that address the stress component in disease and diminish complaints, are not considered a disease cure (with a few exceptions), but adjunct therapy addressing the stress component. Stress in anybody will tend to increase their complaints, even for issues unrelated to their health. Treating stress will reduce complaints, even about those issues unrelated to health. There is a difference between saying a disease is caused by stress, and identifying that stress is a common component of the disease. This is an example of correlation does not equal causation. However, even if stress is not the cause, the stress must still be addressed in treatment strategies. Stress may well be the most important component of disease in some fraction of patients with irritable bowel syndrome (many will argue that it will be a majority fraction), but there certainly are those patients in which it is very hard to attribute exacerbation of symptoms to stress.

    Most diseases cause stress to the patient (that’s usually why they seek medical care), and treating the stress is a common component to the treatment strategy of disease processes. Is the use of placebo a more effective way of treating stress than rapport with the patient and education of the patient by the healthcare provider? I doubt it in most cases. Some healthcare providers may be more capable of reducing stress by providing a placebo effect than by establishing rapport with the patient, and having the knowledge required to give educational information. Mainstream medicine should still strive to produce healthcare providers capable of establishing rapport with patients, and with sufficient knowledge to educate the patient, rather than frequently relying on placebo effect to get the patient out of the office (after the fee is collected).

  74. daedalus2u says:

    JMB, how are you defining “healing response”. It isn’t something that can be measured except over time by measuring how long it takes for something to heal. We know that the “healing response” is very different for thriving infants and elderly diabetics. We know that as two very complex multi-dimensional, and overlapping multi-factorial processes, where “normal maintenance” stops and the “healing response” starts can not be clearly differentiated. I don’t see a need to differentiate them. To me the “healing response” is a part of “normal maintenance”; they are not two separate things. There is no way they could have evolved as two separate things. I don’t find it useful to discuss them as two separate things. If you want to discuss them as two separate things, you need to tell me how to differentiate them so they can be discussed separately.

    A good rapport with the patient is a placebo.

    It is doing something that has a positive effect not mediated through pharmacology, surgery or other physical means. Psychotherapy is a placebo because the positive effects are not mediated through pharmacology, surgery or other means. Pharmacology can be used in conjunction with psychotherapy, but that is a separate pharmacological treatment in addition to the non-pharmacological treatment of psychotherapy.

    I agree with what I think you are saying that giving a patient an inert pill to get them out the door is not good treatment, and (I think) would not work as a good placebo. I think spending time with the patient, developing a good rapport, listening to the patient’s problems and trying to address them would work better, even if there is no pharmacological intervention.

    I think it is unfortunate that insurance companies and patients don’t want to pay for the time for a physician to honestly develop a good rapport with the patient, but are willing to pay for quacks to poke needles in them, crack their backs, and wave hands over them.

  75. daedalus2u says:

    qetzal, they are both. My conceptualization of the placebo effect is as the opposite of things that trigger the fight or flight state. To me, it has been confirmed to such a degree that it would be perverse to withhold provisional assent. As far as I know, there is no data that contradicts or is incompatible with that conceptualization. I have looked pretty extensively in the literature for such data and have not found any. All the data I have been able to find is consistent with it. No one has suggested any data not consistent with it, they simply want to define “the placebo effect” such that it is incompatible with my conceptualization. Why they want to define it that way, I don’t know. If you know of any data that is inconsistent with my conceptualization I would appreciate it if you could provide me with a link.

    Triggering the “fight or flight” state causes a pretty rapid degradation of health. Doesn’t that make things that trigger the “fight or flight” state the opposite of a placebo? A mother’s “kiss it and make it better” can bring her child out of a “fight or flight” state. There is no pharmacology behind a mother’s “kiss it and make it better”, it is a placebo. If you don’t like calling it a placebo, then what is it?

    During development, the CNS needs to connect to the things it is going to control later in life. Infants are not mobile in part because their nervous system doesn’t connect to their muscles. Many animals, cows, horses, zebra are mobile at birth, they can walk and follow the herd at birth, meaning their muscles have neural connections, they have spinal reflexes, they can orient themselves. Humans not having a connected and voluntarily operating musculature at birth is a detail of human development that is not shared by other animals. Humans do have reflexes at birth, the Moro reflex is present at birth. The Moro reflex does show that the major muscles of the limbs are connected by nerves and are controlled by the CNS at birth.

    The CNS is not the only thing that needs to connect, the ANS needs to make connections too. Why can’t infants digest adult food? Because the process of development doesn’t give them that capability at birth. Why? It is not because infants lack the genetic resources to produce digestive organs that can digest adult food. I think it is for the same reason that infants can’t walk at birth even though they have muscles. They don’t have the neuronal connections to use those muscles. I suspect that infants don’t have the ANS neural connections to control the digestive system appropriately so as to digest adult food. Newly hatched birds eat adult food, so infant-like digestive systems can work on adult food.

    Entering a fight or flight state is easy, and humans have a startle reflex at birth. Coming down from that fight or flight state is more difficult. Children need a mother’s “kiss it and make it better” to be able to come down from a fight or flight state. Older children and adults do not. My presumption is that older children and adults have learned (i.e. their CNS and ANS controlling the “fight or flight state” has sufficiently developed) to come down from the fight or flight state so they don’t need an external signal (i.e. a social cue) to do so.

    Much of the ANS is nitrergic, that is neuronal signals are mediated by using NO as a neurotransmitter. The smooth muscle of the gut is relaxed by NO. Stress and the fight or flight state are low NO states. The low NO state of the fight or flight state has hysteresis. That is why decorticate animals that are put into the fight or flight state stay in that state until they die. It takes a signal to end the fight or flight state.

    When that signal is generated internally, it is called “calming down”. When the organism uses social cues to trigger the end of the fight or flight state, what should we call it? What should we call it when an individual is conditioned to respond to a needle being stuck into them to trigger the end of a fight or flight state? When the conditioned social cue is a pharmacologically inert pill, it is called a placebo. I don’t think it is useful to put every non-pharmacological and non-surgical “treatment” in its own special class and call it by its own special name. I lump them all together and call them all “placebos”.

    It is important to appreciate that it is not the inert pill that “causes” these effects, it is the physiology of the individual that is triggered by the inert pill.

    A great deal of the physiology of the fight or flight state can be triggered by epinephrine. I am not aware of anything that can be administered as simply as epinephrine that can trigger the opposite of the fight or flight state. I suspect there isn’t anything because there is no evolutionary need to trigger ending the fight or flight state rapidly. Ending the fight or flight state is only appropriate when there is the absence of environmental conditions that would trigger it. That is much more complex than triggering the fight or flight state. False positives in ending the fight or flight state are much more costly than false positives to enter the fight or flight state. The signal needs to be an emergent property of more complex systems, i.e. the cortex, which is why decorticated animals can’t end the fight or flight state.

  76. JMB says:

    @daedulus

    The way I would define healing response is the observations of the way the body responds to a disease process that results in amelioration of the disease. The observations may be recorded from various modalities including those from gross pathology, microscopic pathology, laboratory findings, physical exam findings, medical imaging findings, and patient reports. A more rigorous definition would include about one half of the text in a pathology textbook.
    ******************

    A good rapport with the patient is a placebo.

    That’s my point. Why use a deceitful placebo when an ethical placebo exists? Now to anticipate answers to my rhetorical question, it can be very difficult to establish rapport with some patients, and some patients are being deceitful. In days past, the scenario where placebos tended to be used was when the doctor felt the patient was seeking drugs, attention, or when the emotional response to the disease outweighed the disease process (which constituted only a small percentage of encounters).
    *******************

    I should qualify an earlier statement I made. It is better for NCCAM to fund studies on placebo effect than CAM. At least placebo effect in mainstream medicine has a background of ethics and a baseline of cost for comparative effectiveness. We have debated the ethics of deceit, saline injections, and sugar pills for some time. It may be possible for research to better quantify how correct selection of patients, selection of placebo, and deceit may increase the power of the placebo effect. Most of that information was only previously available from clinical observation.

  77. daedalus2u says:

    I don’t think that deceit adds anything to the placebo effect. Maybe self-deceit on the part of the quack gives the quack the false confidence that the quack is doing something beneficial for the patient, but deceiving the patient doesn’t do anything for the patient. Maybe if the patient is so delusional and set on some therapy and can’t be reasoned with, but then the treatment they need is something to give them better reality testing, not to encourage their delusional world view.

    Investigating the placebo effect should be what NCCAM does, not with the idea of using placebos as therapy, but to understand them as in basic science so that the physiology of the placebo effect can be understood so that it can be used more effectively in real medicine and so that all quackery becomes recognized as the placebos that they are.

  78. JMB says:

    Deceit is not necessary to witness a placebo effect, but in some proportion of patients and situations, it is likely to magnify it (opinion).

    Here is a parlor trick type experiment you can do to test the assumption that deceit does not magnify the placebo effect. Have a party where you provide two punches. One of the punches you tell the guests is nonalcoholic (and it is). Provide a second punch that you say you have added champagne (but don’t, just add some club soda). Then keep track of the number of people who drink the placebo punch, and the fraction that show signs of intoxication.

    Now have a second party, and tell the group both punches have no alcohol, but one has added club soda to recreate a placebo. Then keep track of the fraction that act intoxicated.

    This experiment probably works best on the selection of subjects who are college age and think it’s cool to be intoxicated (exhausted medical students and residents are ideal subjects), and light “social” drinkers. Heavy drinkers will complain it doesn’t have enough alcohol and won’t show any intoxication (which also makes it a diagnostic test for alcoholism).

    You may lose a few friends if they are subsequently informed of the deceit, but it is all in the name of science. You can report your results in this comment section.

    You can also witness the placebo effect on most Saturday mornings in teaching hospitals as resident hook themselves up to IV’s to help with hangovers. There, you can inform them it is a placebo effect, and they will still do it, in spite of the pain of having an IV started. In this case you don’t need deceit, the fact that their friends are trying it, is enough to produce the response (but there are always those that argue that you are rectifying the dehydration that results from drinking).

    ****************************

    My main point about NCCAM funding of research on placebo effect is not about production of knowledge of the physiologic pathways of placebo effect, but that ultimately the clinical application will be determined by the same clinical issues previously identified. I believe the largest, most powerful placebo effect ever reported was the sham surgery for relief of angina (splitting the sternum and ligation of the internal mammary artery– it happened so long ago, a reference for the study is hard to find). However, that placebo would never be used because of the real risk of surgery/anesthesia. It is interesting to note that in this case, the placebo effect corresponded to the induction of physiologic stress.

    It won’t matter that fMRI shows activity in the frontal lobes, amygdala, and hypothalamus (no, that’s not research I have read, just a shot in the dark) as components of placebo response, it’s clinical use is still limited by the same issues that became apparent in the 70′s and 80′s. Maybe integrative medicine is allowing us to sidestep those ethical issues (and the ethical issues of prescribing a substance for treatment, and then selling it to the patient).

  79. Jan Willem Nienhuys says:

    The ref. for the internal-mammary artery ligation is:
    Leonard A. Cobb, M.D., George I. Thomas, M.D., David H. Dillard, M.D., K. Alvin Merendino, M.D., and Robert A. Bruce, M.D., An Evaluation of Internal-Mammary-Artery Ligation by a Double-Blind Technic. N Engl J Med 1959; 260:1115-11,18, May 28, 1959

    http://www.nejm.org/doi/pdf/10.1056/NEJM195905282602204

    It seems that this surgical procedure was in use since 1939.

  80. Diane Jacobs says:

    This has been a very interesting discussion of placebo thus far. Thank you to those who contributed the links to Benedetti’s work, and to Jan for the artery ligation reference.

    I thought this was a great example of provision of ethical placebo:
    http://www.nytimes.com/2011/01/01/health/01care.html?_r=3&partner=rss&emc=rss&pagewanted=all
    Giving Alzheimer’s Patients Their Way, Even Chocolate
    How sensible – reduce the distress of patients whose frontal lobe capacity to manage themselves and their reactions is disintegrating. Take care to avoid nocebo. Enter their reality and be with them a bit. Stop insisting they conform to something they can no longer understand or track, such as outside scheduling or coercion of any kind.

    Stress can take two pathways from the cortical levels to the body – one is through flight/flight as has been pointed out – it generally will operate (decreasing pain via noradrenergic descending modulation of second-order afferents in the spinal cord) through the dorsolateral part of the periaqueductal gray, connected with brainstem nuclei that raise blood pressure etc..

    But, if flight/flight aren’t possible, i.e., if the stress is inescapable, the ventrolateral part of the PAG (connected to nuclei that bring on hypotension, ‘faint and play dead’ behaviour) is activated and the descending (pain-reducing) modulation is different, opioidergic.

    Human stress is a play-by-play interpretation of experience, meaning, and context. It will vary as do the individuals who experience/interpret it.

    There is even a nocebo system which involves a cholecystokinin mechanism, according to the Benedetti paper – pain perception increases as the result of a suggestion by an authority figure that pain may not be well-controlled – good one to avoid activating.

    Diane
    Human Primate Social Groomer, Neuroelastician

  81. There were at least 3 placebo-controlled trials of mammary artery ligation for CAD, discussed by Beecher here:

    Beecher HK. Surgery as placebo: a quantitative study of bias. JAMA. 1961;176:1102–1107.

    Another useful article, looking at several popular treatments for angina pectoris that were eventually shown, in placebo-controlled trials, to be ineffective, is this:

    Benson H, McCallie DP Jr. Angina pectoris and the placebo effect. N Engl J Med. 1979;300:1424–1429.

  82. I almost forgot: the old procedure of ligation of the internal mammary arteries did not require a sternal split; it was a percutaneous operation (actually two operations; it was bilateral) typically done with local anesthesia. The IMAs are lateral to the sternum, and can be approached intercostally (between ribs).

  83. JMB says:

    @Kimball Atwood

    Thanks for correcting my error about internal mammary artery ligation.

  84. JMB says:

    Just another reference about placebo effect, somebody who remembers that placebo originally meant “dummy pill” or “sugar pill”, and apparently was in practice in the 50′s and 60′s.

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1305558/?page=1

  85. pmoran says:

    My vote for the most elegant, practical use of placebo goes to the crew of a boat cruise up the Gordon river out of Strahan, Tasmania.

    It was quite rough crossing the bay, and some began looking quite seedy.

    The crew pounced. Producing wisps from a roll of cotton wool, they pronounced “Quick, put this in your LEFT ear. IT WORKS!”

    We can be pretty sure that it usually did, saving the crew from cleaning up a lot of messes.

    In this instance, distraction from the discomfort building up in passenger’s innards could be the main mechanism.

  86. Diane Jacobs says:

    @pmoran –> “The crew pounced. Producing wisps from a roll of cotton wool, they pronounced “Quick, put this in your LEFT ear. IT WORKS!”

    We can be pretty sure that it usually did, saving the crew from cleaning up a lot of messes.

    In this instance, distraction from the discomfort building up in passenger’s innards could be the main mechanism.”

    Directing of attention toward a novel somatosensory input of a most benign kind, but which stimulates the trigeminal ganglion through sensory afferents, then does who knows what after that to neighbouring nuclei. I like it. Sensory soothing.

    Diane
    Human Primate Social Groomer and Neuroplastician

  87. JMB says:

    @Diane Jacobs

    Describing the placebo effect in science terms used to be one of the methods used to deceive patients when they were receiving a placebo. The doctor could argue to other doctors that they did not lie to the patient, they told them the truth! However, the patient could not understand what the doctor told them, so that is now considered unethical for patient encounters. Telling subjects they will be getting somatosensory soothing might magnify the placebo effect compared to “we’re going to distract you for a minute with a ritual that is unrelated to sea sickness”.

  88. Diane Jacobs says:

    @ JMB
    In an imaginary study, I get that we would have to not talk about somatosensory soothing, as that might count as leading expectation (which is all about how placebo works in the first place one suspects). There is a kind of simplicity to “Quick, put this in your LEFT ear. IT WORKS!” delivered by an authority figure in a moment of elevated stress.

    I’m imagining a tooth fairy-type study to determine whether or not it’s more effective to have the cotton wad in the left ear or the right – if there were three groups, one of which received no cotton, just were told to put their own finger in their own ear or something, it would sift out the social responders (those who were doled out the “placebo object” by an authority figure, a crew member) from the rest, maybe. Maybe a 4th group with limited verbal support and an object (“You feel sick? So sorry about the weather. Here is a airline bag for your personal use, just in case, courtesy of our crew and cruise line.”) – but no somatosensory support/distraction, even from self. See which group has the highest throw-up rate. The groups would have to be kept isolated from each other somehow.

    Anyway, just playing.
    Diane
    Human primate social groomer and neuroelastician

  89. @ Diane- and fun with jargon – “Directing of attention toward a novel somatosensory input of a most benign kind, but which stimulates the trigeminal ganglion through sensory afferents, then does who knows what after that to neighbouring nuclei. I like it. Sensory soothing.”

    This is not intended as a criticism, just a humorous observation. As a layperson, I don’t know whether to be impressed by the level of your vocabulary or anxious because I know that you could just be making up the words and I wouldn’t know the difference. :)

    As a secondary question to seasickness placebo interventions. Does it work if you are deaf in your left ear?

  90. also diane – “I’m imagining a tooth fairy-type study to determine whether or not it’s more effective to have the cotton wad in the left ear or the right” etc…

    If I could humbly add from a non-sciency background. Considering the auditory system role in balance and hearings connection to other senses, it seems to me possible that blocking one ear might have a small chance of working for seasickness on a mechanical level. Maybe it subtlety shifts ear pressure. Also, losing hearing in one ear also means the lose of the ability to localize sound. So possibly seagoers might change how they are looking around in response to the temporary hearing loss…which could change the visual input that can be a part of motion sickness. (That’s not still placebo, is it?)

    So in your experiment I might add a group that has a non-auditory placebo…perhaps a wristband that is a bit tight or is lined with menthol to create a tingling sensation. I’d be curious to see if the results are different with the same presentation “Quick, put this on your wrist. It works!.

  91. baldape says:

    I think these (admittedly spot-on) criticims miss a deeper point: this experiment is provably useless and should never have been funded.

    If we accept that the placebo pill itself has no physiological effect (which certainly seems reasonable), the experiment is testing one question only: do the beliefs of IBS sufferers influence their [reported] symptoms? Since the variable is “the beliefs of IBS sufferers”, then the two experimental groups are:

    Group A: IBS sufferers who believe that
    B1) mind-body experiments are worthwhile
    B2) they are engaged in a mind-body experiment
    B3) “science says” that a placebo pill can trigger positive mind-body responses and may alleviate IBS symptoms
    B4) they are taking sugar pills with no active ingredients.

    Group B: IBS sufferers who believe that
    B1) mind-body experiments are worthwhile
    B2) they are engaged in a mind-body experiment
    B3) “science says” that a placebo pill can trigger positive mind-body responses and may alleviate IBS symptoms
    B4) they are not taking sugar pills with no active ingredients.

    The results: Group A reported better results than Group B.

    The claim in the article (and surrounding hype) is that since Group A and Group B differed on belief B4 and that Group A performed better, we must conclude that BELIEFS MATTER! and believing B4 gives patients better results than not believing B4.

    However, by publishing in a medical journal, the researchers are simultaneously implying BELIEFS DONT MATTER! Specifically, they are implying that these results are relevant to people who disbelieve B2 (and probably don’t believe B1 or B3).

    They can’t have it both ways; and the logical flaw should have been spotted before the experiment was even started.

    As an analogy: imagine an experiment that claims to be testing the effect of cars appearances on the speed policemen estimates cars to be traveling.

    Group A: Cars are painted red with outlandish purple polka-dots and white stripes.
    Group B: Cars are painted blue with outlandish purple polka-dots and white stripes.
    Results: Police officers evaluated Group A as being slightly faster than Group B, (mean 57 mph vs mean 55 mph, p<.01)

    Claim 1: APPEARENCE MATTERS! Policemen tend to estimate red cars are slightly faster than blue cars.

    Claim 2: APPEARENCE DOESN'T MATTER! These results are perfectly applicable to general traffic (which would never have outlandish purple polka dots and white stripes).

  92. Diane Jacobs says:

    @micheleinmichigan,
    1. As a secondary question to seasickness placebo interventions. Does it work if you are deaf in your left ear? There’s a good question! :D I think we could add your fifth group to this little thought experiment. Or maybe a better idea would be add it in the next round of testing.

    I was still working on the question, ‘does it work, period? If so, why the left ear?’ And trying to rule out all possible inputs apart from purely non-sensory expectation placebo effect. Mostly as just a thought exercise.

    1. somatosensation, directing attention toward one kind (exteroceptive) could, possibly, theoretically, distract patient attention away from a noxious, interoceptive kind, i.e., sense of nausea. Pathways involved in nausea have something to do with overstimulation of vestibular function, then nuclei involved in visceral sensation and motor response to it. Vomiting is a protective behaviour from a brainstem POV – brain tries to protect its ‘organism’, keep it alive/help it survive/get rid of all that overstimulation the only way it knows how. Expelling visceral contents.
    2. maybe the exteroceptive somatosensory input in the left ear stimulates right insular cortex (right and left insular cortices have somewhat different functions in the brain – I don’t know all of them but I know the right one has a “body map”)
    3. maybe the right insular cortex then has enough new non-threatening information with which to help inhibit the “too much information” problem in the brainstem nuclei somehow.
    4. getting cortex (even just insular cortex) attention through exteroceptive pathways thereby “distracting” one part of the brain from what’s going on in some other part, might be enough to prevent summation, therefore vomiting.
    5. Meanwhile, dorsolateral prefrontal cortex, anterior cingulate cortex are on the same page, with no major objection, having got the exact same somatosensory information from the cotton via the thalamic relay nuclei. So the insular cortex is clear to go ahead with whatever it can manage to accomplish.

    Thinking about the brain (and how it is supposed to work) is an interesting exercise in and of itself. Trying to figure out ideas re: how to test placebo hypotheses is harder, but still fun. ACTUALLY testing all possible brain intra-relational hypotheses instead of just calling all of it “placebo” (with a tone to suggest placebo response is some kind of evil villain instead of something normal, useful and ethically elicitable) not as much fun, but it’s slowly being done, by Benedetti and people like him.

    Diane
    Human primate social groomer and neuroelastician

  93. daedalus2u says:

    Baldape, there is abundant evidence that placebos do have physiological effects. They do cause effects in the physiology of subjects that are objectively measurable with instruments. Your premise that they have no physiological effects has been disproven multiple times.

    The physiological effects of placebos are not mediated through pharmacology. Exactly how they are mediated is not known. Since they have physiological effects, their effects must be mediate through physiology.

    I think the problem is that people want to buy into some kind of “brain-mind” dualism, that isolates the mind from the body so there are no “mind/body” effects, or that the effects are one way, the body can affect the mind, but the mind can’t affect the body. We know this is not correct, that there is no non-material mind, there is only the body which includes a brain. We know that everything important in physiology is under feedback control, and that the nervous system exerts a lot of control on a lot of different things, including the state and function of the brain. Mostly that control is not at the level of consciousness, so we can’t direct our liver to raise our blood sugar, but we can condition our ANS to raise our blood sugar when a bell is rung.

  94. JMB says:

    In my opinion, placebo effect is fascinating, but don’t expect any cures or measurable healthcare savings from it.

  95. baldape says:

    daedalus2u, please reread. I was saying the pill itself has no effect – only the beliefs about the pill (otherwise it would be a very poorly designed placebo pill, no?)

  96. daedalus2u says:

    You said the pill has no physiological effect, which is either incorrect or insufficiently precise. I think it is premature to conclude that the effects are mediated through “belief” without more research, or at least without much better definitions of what “belief” actually means. Is it still “belief” when you are told it is a placebo?

    Harriet has mentioned getting a placebo effect for hay fever by taking a non-antihistamine and thinking that maybe she would get a placebo effect from it.

    In thinking about my own experience, when I first started drinking alcohol-free beer, I “thought” I was getting a buzz from it. I knew it was alcohol-free, but my physiology may have been conditioned to anticipate alcohol when drinking beer-like substances. The “buzz” may have been at the level of the unconscious (which is where much of the placebo effect is mediated).

    I am not sure that “belief” is the right term to use when talking about an unconscious conditioned state.

  97. Diane Jacobs says:

    “I am not sure that “belief” is the right term to use when talking about an unconscious conditioned state.”

    Exactly.

    And if a “belief” (or an anticipation based on past experience, or culture whether peer, familial or societal, an assumption, expectation, habit of thought, bit of information, etc., etc.) makes the frontal lobes fire in certain patterns, releasing neurotransmitters in the process, strengthening some synapses while weakening others, providing IPSPs in some places and EPSPs in others, summation here and inhibition there, how is this not also “physiology”?
    It is also “agency”. Right? (Maybe the only agency we have, however socially inextricable it may also be, depending on the individual and his/her context).

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