I’m an anthropologist and a biologist, so really, I have no problem with the idea of a “placebo effect” in which people become convinced that they are being given an effective treatment and thus, because of that thought in their mind, improve.

Editorial Note: I’m classifying this post as a “falsehood” because it does fit nicely with that series, though this was not on the original list of falsehoods. Also note, this is a hastily dashed off first draft, so please be ruthless in your comments so I may move ever towards the unattainable perfection.

I doubt very much that this works for many ailments. The placebo effect will not cure a broken arm, for instance. And, I also believe that it must be understood in a rational, empirical, scientific manner. The power of positive thinking … the secular version of the “prayer” effect … is either based on a marshaling of the person’s immune system, or some other physiological thing that really happens, or it not real.

How does me being an anthropologist cause me to have no problem with the possibility of a placebo effect? Because as an anthropologist I have studied things, or sometimes just seen things, that I know would confound a western doctor, at least a little. I have observed people enter trances because of song or dance alone. I have observed catalepsy or something similar with no drugs and, I think, no prior or inherited condition or injury. Just plain old shamanism. On one occasion I observed an infant of about two or three months age do nothing but cry for four or five days, until his father treated both him and his mother with the same treatment: a cutting of the skin in dozens of places followed by the rubbing in of a mixture of leaves that had all been burned. I assume the burned leaves were essentially (semi-sterilized) carbon. I guess that the cuts caused the baby to stop crying because its HPAC hormonal axis was overtaxed and he essentially passed out. I suppose that the mother dying a few days later was not caused by the treatment, but was also evidence that the traditional treatment with the cuts and charcoal was not effective over the medium or long term for what must have been mastitis or something like that. The fact that the baby’s mother’s sister simply became the wife of the baby’s father and the (biological) mother of the baby was fascinating. But unrelated to the placebo effect.

I am also interested in the study of variation, and I prefer to look at the so called “Placebo Effect” as part of a system of variation. I think this way of looking at it may make it easier to parse the article recently written by Steve Silberman (“Placebos Are Getting More Effective. Drugmakers Are Desperate to Know Why“) and which is also the subject of discussion on White Coat Underground.

I think Steve’s article is well worth reading, but his piece and much of the other writing I’ve seen on this are somewhat limited by an incorrect understanding of the Placebo Effect. Well, I’m here to explain to you what the Placebo Effect really is. From a particular point of view and using particular analytical tools. You’ll find other writing on this to give a somewhat different perspective, but what I present here, in the form of an examination of Silberman’s article, may be helpful.

This is going to take a while, so I suggest you put on a pot of coffee….

A placebo is a tool used to establish a control in a scientific experiment in which a medical treatment is being tested for both safety and efficacy. The system of control (of which the placebo is only part) is important to determine if some outcome is really the result of the thing that is being tested, which may be a pill, an injection, or some other medical procedure. It is also important to see if side effects that arise during the experiment are likely associated with the thing that is being tested, as opposed to background stuff that happens anyway.

When this is done it is sometimes found that people who receive the placebo treatment have a result that is similar to, but often of a lower magnitude than, the desired effect of the treatment. Some people have incorrectly suggested or assumed that this is the result of something like “positive thinking” (call it what you will) in which the desired effect is obtained not directly from the treatment, but from within the person who takes the placebo (or some spiritual source). That person’s immune system is cranking up, or some other psychological effect is happening (or some spiritual thing is happening).

In a strange somewhat enigmatic large brained species in which individuals can enter a meditative state, sing a mantra for an hour, then suddenly enter a state of epilepsy or catalepsy for several minutes, and so on, one should not be surprised to find such effects (the psychological ones, that is). But the assumption that this “placebo effect” routinely explains what is seen in control groups in medical studies is not on the face valid. There is another explanation that as to be looked at first.

I would divide the control response into two types for the present discussion. All changes in the control group in a medical treatment experiment must fall into one of these two categories, by definition.

1) No-effect outcomes. This consists of random or structural shifts in the measured value that have no link to the desired effect. More on this later.

2) Effect outcomes. This would include an actual shift in the measured variables, one way or another, that result from the psychological (or other) effects of a person thinking they are taking a treatment. Or, in the case of non-drug treatments, these effects may be more subtle. Perhaps opening a person’s hip and digging around for a while has a positive effect on their hip pain, and thus, part of the post-operative relief from a hip-replacement surgery is because of the surgical invasion rather than the new artificial hip joint. That could be psychological or it could be because some powerful molecules rush to the site of the surgery and while there have a beneficial effect on the arthritic joint. For the placebo pills, maybe a tiny dose of sugar has a positive effect, or maybe it’s the gel material the capsule is made out of. Maybe it is the process of drinking more water because you are supposed to take six pills a day with water. It does not matter what you or I think of these possible explanations. My point is simply that if anything like this happens, it is by definition part of this second category of effect outcomes.

In order for the widely touted “placebo” effect to be real, effect type 1, the “no-effect” effect, has to be ruled out first. The problem is, that this no-effect effect can be huge.

Suppose there is a disease condition that varies up and down over time, like this:
i-b492b3b7d927c2871a640be3e014dfe9-Screenshot-Plot sine Wave.preview-thumb-500x389-18824.png

This is an oversimplification, but it serves well as a model. Randomly pick any point in time on this graph, and compare it to any later point in time randomly chosen. Over several tries, you’ll find that the second point is higher than the first point half the time, and lower the other half the time. If the y-axis was how sick you feel, and the starting and ending point along the x-axis were the start and end dates of a medical trial, then the default condition is that half the people feel better at the end. The “placebo” effect is 50% even if 100% of the effect is a type 1 “no-effect” outcome. A 50% improvement (and 50% worsening) in the condition is the null model. The average is no change, but the average is not what is being measured by the people who felt better with the sugar pill!

Now imagine a disease condition that looks like this:
i-a538f5bf33849337377a59c6a5b76d2d-sine_wave_two-thumb-500x692-18826.png

Imagine a scenario where people can enter a trial if they have this disease, and we are trying to see if the drug hastens the end of the period of illness. Everyone in this trial is gong to get better. Everyone in the sugar pill control group will get better. The drug group will all get better. The no-effect outcome is therefore huge.

None of this is surprising to those who do this sort of research. This is all handled statistically. In fact, the placebo group is typically used as the assumed “no effect” baseline.

So that is the starting point for this discussion. Placebos are part of the control system designed to cover our bases on unknown factors that matter, most of which are probably random or non-meaningful (type 1 “no effect” outcomes).

So, now let’s see what Steve Silberman is saying in his article. He is making the claim that the difference between placebo outcomes and treatment outcomes is growing less and less, which makes it harder for drugs that may have been approved years ago to pass muster today. He is specifically saying that some scientists are claiming that the “placebo effect” has grown stronger, though in subsequent clarification he underscores that he does not mean that the sugar pills are getting stronger, but that something somewhat mysterious is happening.

To me, there are two likely explanations for this. One is that we are seeing nothing other than the outcome of re-examining existing research without understanding how variation works. The other is that something is really happening, but in my view the explanation for that is complex and potentially very interesting.

Let’s look at the article in more detail. First, I’m going to critique Steve for, maybe, leading the story with a bit of undue sensationalism. Putting a good lead on your story is a good thing and I don’t fault him for that, but I do think an outcome of this sort of thing is often the framing of the argument in a way that hinders rather than helps further analysis. So let’s take a hard look at some of Steve’s assertions.

The phrase “many test subjects” [had an apparent effect] in the first part of this paragraph …

Behind the scenes, however, MK-869 was starting to unravel. True, many test subjects treated with the medication feltIt’s not only trials of new drugs that are crossing the futility boundary. Some products that have been on the market for decades, like Prozac, are faltering in more recent follow-up tests. In many cases, these are the compounds that, in the late ’90s, made Big Pharma more profitable than Big Oil. But if these same drugs were vetted now, the FDA might not approve some of them. Two comprehensive analyses of antidepressant trials have uncovered a dramatic increase in placebo response since the 1980s. One estimated that the so-called effect size (a measure of statistical significance) in placebo groups had nearly doubled over that time.

It’s not that the old meds are getting weaker, drug developers say. It’s as if the placebo effect is somehow getting stronger. their hopelessness and anxiety lift. But so did nearly the same number who took a placebo …

… was transmogrified into something powerful in this latter part of the same paragraph:

The fact that taking a faux drug can powerfully improve some people’s health–the so-called placebo effect–has long been considered an embarrassment to the serious practice of pharmacology.

In the following paragraph, we see the logically fatal mistake of linking the failure of a drug to exceed the placebo’s ‘performance’ with the failure of the drug to be effective. The underlying assumption in the following words, and that assumption is made of whole cloth, is that the placebo and the effectiveness are in a kind of horse race:

Ultimately, Merck’s foray into the antidepressant market failed. In subsequent tests, MK-869 turned out to be no more effective than a placebo. In the jargon of the industry, the trials crossed the futility boundary. … MK-869 wasn’t the only highly anticipated medical breakthrough to be undone in recent years by the placebo effect.

These phrases I think set up the situation to be ripe for either misunderstanding or confusion. But enough of that, let’s continue on to the meat of the issue.

The following paragraph provides some of the key information on which the article is built:

From 2001 to 2006, the percentage of new products cut from development after Phase II clinical trials, when drugs are first tested against placebo, rose by 20 percent. The failure rate in more extensive Phase III trials increased by 11 percent, mainly due to surprisingly poor showings against placebo.

I’m not going to second guess these numbers, and I’ll assume they are accurate. But I will note that the numbers on which these percentages are based are very small. Percentages can, in this way, be misleading. Also, the clinical trial data itself is from the hidden, propietary laboratories of private pharm companies, or the research they contract out. A small change in the way this information is gathered and reported can easily account for these numbers. (Steve points this out in the article as well.)

Having said that, let’s assume that there is an actual decrease in the performance of trial drugs in relation to placebo, and for now, consider those cases where the drug does not do as well compared to the placebo (rather than the placebo getting better).

Over time, in a given sub area of research, we would expect that once “the” breakthrough is made, there will be big results quick, and over time diminishing returns on research as more and more of the obvious and easier routes are followed. Some time ago there was an argument about how different a new drug had to be to get a new patent. The fact that this is even an issue is a good thing, but what it means is that “new” drugs are better off more than a little different than older drugs, because of the liability of losing your patent if it is not different enough. Between the aging-subarea effect (less easy to get results over time) and the distance effect (biasing towards drugs that are molecularly different in a non-trivial way), perhaps these numbers could be explained.

Let’s take a look at this paragraph:

… Last November, a new type of gene therapy for Parkinson’s disease, championed by the Michael J. Fox Foundation, was abruptly withdrawn from Phase II trials after unexpectedly tanking against placebo. A stem-cell startup called Osiris Therapeutics got a drubbing on Wall Street in March, when it suspended trials of its pill for Crohn’s disease, an intestinal ailment, citing an “unusually high” response to placebo. Two days later, Eli Lilly broke off testing of a much-touted new drug for schizophrenia when volunteers showed double the expected level of placebo response.

Consider that this is research on new materials. If the unexpected never happened, there would be no research. When an engineer specifies a certain way to build a bridge using standard techniques, there are no unexpected results and nobody does new research. Copies of the bridge with variant engineering are not first constructed and tested. You take the engineering knowledge (which may well have arisen in part from prior experiment, but that is of no consequence to the present argument) and you build the bridge.

When building new drugs, you experiment. Experiments result in the unexpected. So, if we have knowledge of dozens of experiments over a given period of time, some of them are going to have results that are less than expected, some close to expected, some more than expected. Citing the cases that ended up on one end or the other of this spectrum of variable outcomes represents a poor understanding of the system, or an effort to make the argument at the expense of rationality.

Also note that the Parkinson’s drug was withdrawn from a trial after tanking. Well, if it was withdrawn prematurely, then how do we know it tanked? Putting a finer point on this… we are trying to draw scientific conclusions in a murky area form data that are self-destructing before we can use them. This reflects the interplay between decision making for corporate or economic purposes vs. scientific purposes.

I would guess that there is another element to this as well: If you are the corporate entity making decisions and leading investors, you will use phrases like “Holy crap, no one could have expected THAT failure” all the time (translated into the appropriate language for marketing investment opportunities, of course).

But wait, maybe there is something here. Have a look at this part of the article:

…Some products …, like Prozac, are faltering in more recent follow-up tests. … … if [previously tested drugs] vetted now, the FDA might not approve some of them. Two comprehensive analyses of antidepressant trials have uncovered a dramatic increase in placebo response since the 1980s. One estimated that the so-called effect size (a measure of statistical significance) in placebo groups had nearly doubled over that time.

It’s not that the old meds are getting weaker, drug developers say. It’s as if the placebo effect is somehow getting stronger.

Almost all the points I make above could apply here. Take all the drugs tested between, say, 1985 and 1995. Retest them with the same exact tests. Some are going to perform better than expected some less, but the range of expectation should be not too variable and the average outcome should be the same. Same with placebos. The effect of the placebo should be stronger in some cases, weaker in other cases, because there is a random component to the process. Then, you can cite the specific results you like and lull your investors, scare your readers, whatever. How, then, do these data hold up against the null model, not just some cherry picked data?

But maybe there is something here. Maybe this is a case of the difference between the trial drug and the placebo getting closer because the type 2 “effective outcome” part of the placebo effect gets stronger. Consider this: Pharmaceuticals might well have a stronger culture-bound self-affective “placebo effect.” In other words, people with certain kinds of depression (for instance) may feel better from interaction with other humans or other entities in their lives in a positive way. Just doing something about depression may itself help with that depression. Are you going to cure severe depression by paying attention to the patient or by giving a sugar pill while you talk nice? No. Are you going to get an effect of some kind? Probably.

Now, here is where the article may be correct, but I am only conjecturing here. The statistical and numerical objections to the argument I make above have to be cleared first. But it is possible, it seems to me, that a shift in self-healing of depression for non-drug related reasons, which would show up in the placebo measure in a given trial, could be stronger in a world in which we “know” as a culture that you can take a pill for depression vs a world in which we did not yet know or “believe” this to be possible.

I am a bit skeptical about the “then” vs. “now” comparison, however. For one thing, the method of measuring depression that would have been used at the time of the early trials is not, as far as I understand it, the same as the method used now. Somewhere along the line somebody had to translate between the two methods. That may (or may not) be a source of difficulty in drawing firm conclusions from these studies (which I hasten to say I have not read).

Continuing…

Beecher’s prescription helped cure the medical establishment of outright quackery, but it had an insidious side effect. By casting placebo as the villain in RCTs, he ended up stigmatizing one of his most important discoveries. The fact that even dummy capsules can kick-start the body’s recovery engine became a problem for drug developers to overcome, rather than a phenomenon that could guide doctors toward a better understanding of the healing process and how to drive it most effectively.

I am afraid that this paragraph makes the mistake of going from the idea that our experimental method has to account for non-medicinal effects of being in a study to it being established fact through rigorous scientific research that sugar pills affect disease.

Silberman’s description of the metastudy done by Potter and DeBrota supports some of what I say above: The data are often secret and strangely managed, so I’m a bit worried about that. But have a look at this:

Assumption number one was that if a trial were managed correctly, a medication would perform as well or badly in a Phoenix hospital as in a Bangalore clinic. Potter discovered, however, that geographic location alone could determine whether a drug bested placebo or crossed the futility boundary. By the late ’90s, for example, the classic antianxiety drug diazepam (also known as Valium) was still beating placebo in France and Belgium. But when the drug was tested in the US, it was likely to fail. Conversely, Prozac performed better in America than it did in western Europe and South Africa. It was an unsettling prospect: FDA approval could hinge on where the company chose to conduct a trial.

Since by the time this study was done everyone in the US who was also likely to show up for a drug trial was already habituated to diazepam probably explains this result. But putting that (bit of snark) aside, this statement is simply wrong. Well, yes, the scientists may have this wrong because they believe in their own mojo too much. There have been a couple of studies that showed various effects being different based on context (like what lab was doing the work) that surprised people, but still, we should have (and in fact do have, by definition) the same two effects across geographical/cultural/national space as across trials. What is happening her is that our all important variation is being examined, for the first time, across geographical space (like it was earlier examined across time). And we are finding …. variation!

It is not at all surprising that there is something about the context … Germany vs. the US for instance… that actually matters (type 2 “effective outcome”), but there is also random variation variation (type 1 “non-effective outcome”) across space. Think of the first category of explanation as the null model. Only if the variation is greater than that which can be explained by non-meaningful variation can the first category of explanation … that Germans have a stronger self-healing “placebo effect” (self-curing of some kind if you take a sugar pill) than Americans, for instance … be considered. I would not be surprised if Germans had more of that, by the way. But that’s the anthropologist coming out and a little personal history, so we’ll ingore that.

Also, Silberman points this out:

Mistaken assumption number two was that the standard tests used to gauge volunteers’ improvement in trials yielded consistent results. Potter and his colleagues discovered that ratings by trial observers varied significantly from one testing site to another. It was like finding out that the judges in a tight race each had a different idea about the placement of the finish line.

But again, this is not really a mistaken assumption. It is a bad assumption made post hoc, maybe, but it is not possible that people doing earlier studies did not realize that self-report and subjective ranking varied from site to site. This has been known for decades in all areas of medical and psychological research. I think maybe Potter and colleagues are overstating the case in this regard.

We have less of a handle on variation than we would like, especially in reporting by subjects but also in other areas. There’s piles of variation out there. And as long as there is lots of variation, the ends of the distributions of effects are always there to be pointed to and held up as an effect.

Potter and DeBrota’s data-mining also revealed that even superbly managed trials were subject to runaway placebo effects.

Now we are calling “more variation than we were hoping was happening in our science” a runaway placebo effect. By now I think you can easily see why I’m not buying that

I’m not going to touch Benedetti’s research in this essay. I don’t have the resources available to me right now to evaluate this fairly complex set of claims. Ted Kaptchuk’s work also requires a closer look. In both cases, I simply ask: Is the no-effect expectation exceeded?

I think that the difference between treatment and control may be diminishing. Well, if the people doing this research say it is, then it is. I think the reasons for that may be many, including the two I’ve described above: Diminishing returns on like research and changes for certain (but not most) drugs in the context-side of the self-healing side of the placebo effect. I strongly suspect that the first of these causes is real, and is large, while the second of these causes is possible and needs to be demonstrated because it is a little vague and we do not have a good handle on the mechanism. Having biological sense behind your statistical arguments is so critically important, let’s never forget that.

Silberman points out additional difficulties that modern pharm is having with testing, inluding finding people who are not already drugged up in one way or another. He also discusses proposed new research designs. You should look at the article.

And as you read Silberman’s article, please do this. Imagine the whole thing … the descriptions of the studies, the discussions of the “placebo effect” … redone with the idea that there are two separate result-changing outcomes from placebo controls: Those that are artifacts of the process or system that do not in fact actually have any curative properties at all ever (type 1 … “no effect”) and those that do. The first type are strong, ubiquitous, known of, but not fully understood, and the second type are probably rare, weaker, probably often don’t exist, and are very poorly understood. The problem is that many people assume that the whole “placebo” effect is this second type, while it is certainly mainly or wholly the first type.

Oh, and if you are thinking that the first type of effect is still a good thing, then stop right where you are. Get a cup of coffee (not decaf) and start at the beginning of this essay and read it again. Type one effects, by my definition used here, are the effects that are pure statistical outcomes and will not make you feel better ever. The burden of proof is on those who claim the second type of effect. The second type of effect is probably real, sometimes, but most of the times not, and it is poorly understood, and it probably varies enormously across time, space, culture, and so on.

Silberman ends:

Ironically, Big Pharma’s attempt to dominate the central nervous system has ended up revealing how powerful the brain really is. The placebo response doesn’t care if the catalyst for healing is a triumph of pharmacology, a compassionate therapist, or a syringe of salt water. All it requires is a reasonable expectation of getting better. That’s potent medicine.

Maybe potent. But only a small percentage of what is happening to people taking treatments, and only a small percentage of the cause of the incredible shrining difference between treatment and placebo that may be happening in some areas of research.

More Falsehoods !!!

This post is one of a series on the topic of falsehoods. The following is a list of falsehoods posts in order:

Comments

  1. #1 DrugMonkey
    September 8, 2009

    no doubt you are fond of E Fuller Torrey’s thoughts on witchdoctors and psychiatrists?

  2. #2 Greg Laden
    September 8, 2009

    DM: I haven’t actually read the book. Should I?

    I am very interested in “culture bound syndromes” though. Like anorexia or bulima but not those syndromes and in other cultures.

  3. #3 daedalus2u
    September 8, 2009

    There is a good discussion thread at SBM too.

    Research does show that placebos have greater effects in people who are under more stress, that the placebo effect does increase with stress exposure. The first observation of this was that soldiers wounded in battle required considerably less morphine than civilians with similar severity wounds.

    http://www.ncbi.nlm.nih.gov/pubmed/13798214

    If there is a decline in the effectiveness of placebos it may be due to a higher stress levels in present times.

  4. #4 DrugMonkey
    September 8, 2009

    I have found it to be an excellent way to think about how counseling and talk therapy work. Your comment about increasing belief in the power of psychopharmaceuticals to help affective and behavioral problems fits right into the general ideas being proposed.

    Beyond these sorts of personal health issues I even find it somewhat applicable to how people develop their ideas about public policy goals and what not.

    so yeah, you should give it a read.

  5. #5 Greg Laden
    September 8, 2009

    Answer’s Stephanie’s and Ahcuah’s comments from the old thread:

    I think there are different kinds of effects being implied or that could some to mind in reading these comments, divisible of course into the two categories I’ve defined above.

    So a patient has aches and pains and takes a pill.

    1) The aches and pains could reduce because the pill affects them. That is not a placebo effect. It is the pill working.

    2) The aches and pains could reduce because something else happened owing to the pill taking, but not the pill. For instance, the pill is to be taken six times a day with water. Normally this patient does not drink enough water. Now, the patient is taking an extra 24 oz of water a day which somehow helps with te aches and pains. That is the kind of effect you want ot control for in an experiment, and it is type two placebo effect.

    3) The aches and pains go away because they were going to go away. In fact, the disease is a transient 7-10 day affair, so most patients actually imporove over the first few days after entering the trial because the would improve anyway. That is a placebo effect, type one (as defined i the post).

    4) The patient claims that the aches and pains are reduced because they want to please the nice lady asking the questions. That is a type 1 placebo effect because it is a statistical change in the data caused by something not related to the pill (thus placebo) and not real (truly not real in this case).

    This fourth type of ‘improvement’ is good if the person was whining a lot to begin with but otherwise is not especially helpful. In this case, everyone ELSE feels better!

  6. #6 Greg Laden
    September 8, 2009

    DM: I’ll put it on my list!

  7. #7 MadScientist
    September 8, 2009

    Placebo seems to work against pain, discomfort, and anxiety and how the placebo is delivered is also relevant; I’d be surprised if there aren’t already papers out there showing how a placebo is more effective than a placebo – and I don’t mean nonsense like the claims of acupuncture to be “better than” placebo and yet without statistical significance. It is indeed possible to have a statistically significant difference in placebo effects- it’s a matter of choosing the right parameter to investigate.

    As far as disease goes, some diseases go away on their own; if a placebo can help someone deal with the discomfort, the patient (and others who don’t understand treatments) are likely to believe the placebo was a “cure”.

    In reality, placebos *never* cure a disease – the disease will either go away on its own or continue to plague the patient. For example (an unethical hypothetical situation), you can try a placebo on a cancer patient to reduce discomfort but the patient will never beat that disease because of a placebo. Cases of spontaneous remission have been reported but are extremely rare (nor have they been associated with placebo).

    Short story: placebos may make you feel better for a short period of time (but try chocolate – it’s more fun), but it does nothing to put an end to the disease, except for trivial illnesses in which case helping you to stress out less may help you recover quicker.

  8. #8 Greg Laden
    September 8, 2009

    Mad Scientist: OK, but reread your post to yourself but every time you have the word “placebo” replace it in your mind with “control.”

    I’m not disagreeing (or agreeing) with anything you are saying here … just suggesting that little linguistic experiment to see how it goes.

  9. #9 Stephanie Z
    September 8, 2009

    Nope, Greg. What I was talking about doesn’t fit in any of those four categories. Like 2, it is a behavior, but it isn’t directly related to the thing being studied. Like 4, it is caused by wanting to please, but there is actual improvement.

    Basically, there are a lot of things we already know we should be doing if we’re ill or injured. We’re often lousy at doing them. This is merely an increase in compliance with those desirable behaviors.

  10. #10 Steve Silberman
    September 8, 2009

    Greg, I think your analysis is very smart and worthwhile. I’m not going to quibble with it point by point, I’m just going to say thank you for writing it and let my article speak for itself. By the way, one of the sources that was helpful to me was anthropologist Daniel Moerman, who did a tremendous amount of smart writing and research on the placebo response and cultural context in the ’90s. Moerman calls the placebo effect “the meaning response,” which gives you an idea of his approach. I highly recommend his book “Meaning, Medicine and the ‘Placebo Effect’” for more information on this, along with Fabrizio Benedetti’s excellent historical overview of the research, “Placebo Effects” (note the plural).

    Thanks again, Greg. Good work, even if I disagree with some of your emphasis and some — but not all — of your conclusions. Ultimately, no one knows at this point what’s really happening in the control arms of trials that fail due to “unexpectedly high” response. That’s why the drug companies are pooling their data to do the Placebo Response Drug Trials Survey, as I discuss in the piece.

    Since my article had to make a home for itself in the real world of science writing for a general readership, I *would* ask you to note how long it took you to get these complex distinctions across. In fact, your post is about as long as the article itself. That will give you an idea of the challenges that science journalists face every day.

  11. #11 MadScientist
    September 8, 2009

    Thanks for explaining the use of a placebo in a way that Joe Ordinary can understand. Silberman’s article is astonishingly ignorant. Given only what Silberman presents, I would interpret the numbers to mean that it’s pretty damn hard to develop a drug that works. I don’t see any evidence whatsoever for the “power of the brain” bullshit which seems to be sold on every TV show and newspaper article that deals with anything related to medicine.

  12. #12 Steve Silberman
    September 8, 2009

    One thing I should point out, Greg, is that I’m totally aware of the crucial distinction between data derived from placebo control groups and what researchers like Benedetti, Andrew Leuchter, Tor Wager, and Jon-Kar Zubieta call placebo response — that is, both psychological (self-reported) and measurable physiological changes produced by the act of taking a pill in a medical environment. It’s true that drug companies don’t yet know how much the latter is contributing to failed trials, because they don’t measure it. As you probably know, data from placebo control groups has been treated historically as little more than noise competing with the signal of the active drug (that’s a better metaphor than “horse race,” above.) Separating this noise into various signals related to “true” placebo response, undependability of rating scales like the HAM-D, cultural variations, rater problems, regression to the mean (your graphs above), the natural history of a disease, and other factors will require a lot of data-crunching that the drug companies haven’t done. Thus the Drug Trials Survey. Also note that I point out in the article that Henry Beecher confounded regression to the mean and natural history with placebo response in his influential 1955 paper “The Powerful Placebo.” Without getting into too much detail about the travails of writing for a general audience (e.g., the phrases “regression to the mean” and “natural history” were judged too technical for our readers), that sentence about Beecher was my attempt to sound a dog-whistle to readers like you. In this case, that point didn’t seem to get across, particularly with the headline that the piece ran with on the Web. (The headline in the magazine was “The Placebo Problem.”) But thanks again for such a thoughtful reading.

  13. #13 Ana
    September 8, 2009

    Why would a drug trial’s patient reported side-effects mirror those of the placebo group’s reported side-effects?

  14. #14 Steve Silberman
    September 8, 2009

    One possibility: all the trial participants read the same consent form, advising them of possible side effects.

  15. #15 Greg Laden
    September 8, 2009

    Ana: Type one (by my ad hoc classification) is pure coincidence. That is not unlikely for side effects such as mild headache, sniffles, etc. Tye two: as Steve suggests, some presumption made by the subjects. Antihistamines cause drowsiness or dryness, for instance.

    Steve [12]: I think that your article and the ensuing blogospheric discussion is a great case study in science reporting vis-a-vis the blosophere, and the potentials and limitations of both venues. I think we are also agreed on the fact that this overall conversation has been overall productive, and a certain amount of civility has helped (rather than being the conversation stopper civility usually is!)

  16. #16 Steve Silberman
    September 8, 2009

    I totally agree, Greg.

  17. #17 sailor
    September 8, 2009

    …Some products …, like Prozac, are faltering in more recent follow-up tests. … … if [previously tested drugs] vetted now, the FDA might not approve some of them.

    Here is an explanation that will be familiar to anyone that has read “overdosed America”

    A few years ago drug companies were blatantly cherry picking their results. They would pay researchers to run tests, if they came out positive they would publish them, if they came out negative they would hide them. The result was crappy but very profitable science.
    Since then the scientific community has tightened up on the regulations of how studies are to be done. If they are to be published they must be announced before they are carried out. So science is better.
    It is not that the placebo has got any stronger, it is that the testing of the drugs is now more rigorous and many are failing. Some that passed before should never have done so.

  18. #18 Greg Laden
    September 8, 2009

    Sailor, that particular effect was not explictly discussed in Steve Silberman’s piece (I don’t think) or my writeup, but yeah, there could be an effect. But that is partly why the metastudy Silberman talks about is getting access to all the “secret” results .

  19. #19 red rabbit
    September 8, 2009

    One part of the “improving placebo effect” that I think has not been addressed has been simple change in the population’s burden and definition of disease.

    Greg, you alluded to this when you noted that trials are conducted differently. But you note that if “old drugs” like Prozac underwent the same testing as they originally did, the results would on average be the same. I would beg to differ.

    We saw this with the ARBs. More than ten years went by after ramipril was approved until the first ARB was tested (telmisartan I think). ON TARGET got equivalence for telmisartan with ramipril, great. Ramipril had had lives saved. A follow-up study for telmisartan was not able to prove that it saved lives.

    Now this could be simple variation, but more likely it has to do with all of the other changes in healthcare over that 10-year period, including but not limited to reduced smoking, better diabetes control, better access to cath and CABG.

    None of the newer antihypertensives have studies showing robust death data. Probably for the same reasons. Maybe placebos are getting better, if by placebo you mean basic care.

  20. #20 DrugMonkey
    September 9, 2009

    I look forward to your review, Greg. For all I know the anthro is all complete bollocks.

  21. #21 Steve Silberman
    September 9, 2009

    Sailor [20], I doubt that’s in play here, since William Potter — the drug developer for Merck and Lilly in the article — always had access to the unpublished studies, as I mention in the piece.

  22. #22 Alex
    September 9, 2009

    Great post Greg, and certainly cleared up some of the problems of understanding I had while reading PalMD’s post and the comments below it.

    Research does show that placebos have greater effects in people who are under more stress, that the placebo effect does increase with stress exposure. The first observation of this was that soldiers wounded in battle required considerably less morphine than civilians with similar severity wounds.

    But couldn’t there be other explanations for this? Like that soldiers are probably more likely to have experienced pain before, and so can handle it better? Or that perhaps the people who became soldiers were the type of people able to handle stress and pain better in the first place?

    I haven’t read the study (nor do I think I would understand it) so I don’t know whether they controlled for those factors or not (if it even is possible to control for those factors).

  23. #23 Greg Laden
    September 9, 2009

    Alex: First, I want to point out that the research cited (wartime pain) was incorporated into the original article by Silberman.

    One of the things that has not been explored in depth in this conversation (as far as I know) is the enormous difference between different medical conditions and thus different treatment objectives. What you do to a broken arm vs. conjunctivitis (eye infection) and how you would measure success is utterly different. “A” placebo effect of either type as I define them above is actually kind of a joke when looked at that way. (Not my definition, but the word “a” in this context!)

    Having said that, what is pain? There is a famous case of a woman who had neurological pain that was almost unbearable. Her life was miserable. She was in constant pain and since the pain started in her nervous system (and did not have a classic “cause” that could be removed or fixed) there seemed little to do to help her.

    So, they went in and cut the connections in part of her brain that were thought from prior research to be involved in pain, but not a lot else, so they figured that could be safe and effective. This of course was a last-ditch experimental procedure.

    After the operation she seemed in a better mood as she recovered but it was not clear if this was the effects of surgery. Eventually she was interrogated using the same data collection procedure as before, to assess the pain level comparatively (before vs. after treatment). All of her answers to the questions indicated that the pain was the same as before the operation, but she was strangely less upset and more calm about it.

    On further questioning she indicated that while the pain was the same, it simply did not concern her any more. It turns out that the region of the brain the surgery had targeted, a part of the anterior cingulate cortex, is now understood to be involved in ‘anxiety.’ She still had the pain, but was fine with that.

    The procedure did not cure the pain, but it made the pain no longer a problem for the patient.

    That was not a placebo effect. The story I just related has nothing to do with placebos directly. But it is one of many examples that demonstrate the complexity of disease and symptoms, and especially of pain in particular. Pain is not ‘a’ thing. It is a set of complicated processes. So are infections, to perhaps (but maybe not) a lesser extent. An infection, as a ‘disease,’ is made up in part by a set of responses. The person with the infection produces the fever. The fever is not produced by the microbe lighting tiny little fires everywhere.

    The possible fact that the Placebo effect (combined type 1 and 2) is seen not at all for a broken bone, somewhat for infectious disease, more for pain, and goes wild with depression tell us something, but what does it tell us?

    Does it tell us that there is a spectrum of disease and disorder that runs from objectively easily observable and measurable to more complex and more difficult, with more variation, and thus more type 1 placebo effect (non-effective) or is it telling us that there is more opportunity on one end of the spectrum for fiddling around with the actual condition (type 2) from somewhere inside one’s head.

  24. #24 daedalus2u
    September 9, 2009

    Alex, the original observation was in WWII, where there was a draft and so the population of men that became soldiers was not as highly skewed as with a volunteer army.

    We have to look at what pain is. Pain is a signal your body uses to tell you that there is ongoing damage that you need to deal with to prevent it from getting worse and from causing more damage.

    After you have survived a battle in a war, and are in a safe place where you are receiving treatment you know that you are in a safe place and are receiving treatment. You don’t need a pain signal to tell you to not go back into that battle. The signal to “get in a safe place and out of harms way” isn’t needed by those who survived the battle because they are in a safe place. In civilian life the “get in a safe place and out of harms way” isn’t as easy to figure out as in a war.

    That is the difference, the context in which the injury happened and the result that the pain signal is trying to accomplish.

  25. #25 Sven DiMilo
    September 9, 2009

    Quick shout-out to Silberman, whose writing on the Grateful Dead I have enjoyed for many years.

  26. #26 Steve Silberman
    September 9, 2009

    Thanks Sven.

    > for fiddling around with the actual condition (type 2) from somewhere inside one’s head.

    Yes, the higher cortical centers and other parts of the brain mapped by Wager, which I talk about in the third section of the piece. One of the central thrusts of the piece is that one possible explanation for the problems in clinical trials is that the drugs being tested target disorders that engage these areas of the brain — such as depression, anxiety, Parkinson’s disease, and so on.

  27. #27 Burt
    September 9, 2009

    All dis-ease is manifested by those who subconsciously choose that experience for their own reasons despite appearances and protestations to the contrary. Individuals who have decided to get sick or die will not improve through medical science’s intervention unless their outlook changes. If they are ambivalent about the condition then they may respond to treatment but as long as the root (psychological) conditions that caused one to manifest the illness are not addressed and resolved, that person will continue to create a condition of dis-ease and manifest new ailments. Conversely people who desire health and life will not succumb to such ailments and recover if afflicted or remain healthy and not involve themselves with such dramas.

    Placebos provide a psychological respite and allow persons to re-evaluate their situations and many times improve due to the belief that the medicine will help. All diseases and conditions are created and healed by one’s psyche in concert with bodily cooperation. Medicine, authority figures, and placebos are a form of hypnosis – when successful the patients improve – if not they don’t.

  28. #28 Greg Laden
    September 9, 2009

    I just want to say to my readers that obtaining medical advice from this blog, especially the comments, is not recommended.

  29. #29 Stephanie Z
    September 9, 2009

    I’ll go further than that. Burt, you’re evil, and in a long history of arguing online, this is probably the first time I’ve said that.

  30. #30 Wyatt
    September 10, 2009

    So, does this mean that if my placebo’s are expired I can still use them?

  31. #31 Burt
    September 10, 2009

    @Greg[28]

    I wholeheartedly agree for obvious reasons. I didn’t offer any medical advice – I merely posted an explanation of the cause and cure of dis-ease from a meta-perspective (I term it dis-ease to subsume all ailments not just those caused by pathogens.)

    If people believe that they are random victims of an indifferent universe’s organisms and that medical science will solve their ills, then they should seek medical treatment and I heartily recommend they do so. It doesn’t matter if it’s positive thought, hypnosis, antibiotics, or antibodies – whatever works for them. I believe as I stated above [27] and it works very well for me.

    @Stephanie[29]

    Evil? For rendering an opinion that is different from yours? Your characterization is a bit harsh don’t you think? If in all your point/counterpoint blogging you have only resorted to that epithet with me, it speaks well of your past writing, however I’m interested in why such innocuous philosophizing has piqued your wrath.

    It may come as no surprise to you that I don’t believe anything or anyone is evil – evil only exists as a belief in one’s mind if one subscribes to the concept. I’m sure that you and I would disagree on a good many beliefs (see my comments at your QM blog It is your fault but that is no reason to cast aspersions – for one who professes to an interest in communication, the barriers thereto are not aided by name calling.

    So what has set you off? I doubt that my post is the root cause of your ire. If everyone believed that each of us is responsible for everything in our experience and less than ideal actions beget less than ideal results and actions only reflect on the actors – there would be less strife and fewer problems in the world. I live by that precept and experience very few problems in life. Whenever challenges or problems do arise, it is instant feedback that I should behave differently and when the mental correction has been affected the physical counterpart is corrected as well.

  32. #32 Stephanie Z
    September 10, 2009

    No, Burt, I don’t find it the least bit harsh. Why? Because you’re treating people’s health as an intellectual exercise with no real-world repercussions.

    You have a theory. Yipee. What does it mean to anyone who gets caught up in your little theory? Gee, not only are they going to feel like crap physically, but they’ll think they must want somehow to feel like crap. They’ll blame themselves for something actually caused by genetics, foreign organisms, etc. Isn’t that lovely. Just what a sick person needs. More crap to deal with.

    On top of that, if they’re silly or desperate enough to believe you, they’ll think it really doesn’t matter how their health is treated, as long as something in their life changes. No matter what’s going on in your delusional head, that’s not how it works in reality. In reality, some things work; some things don’t. Some things make everything worse. There is a difference, and pretending otherwise is evil.

    You want to mess with your own health on the basis of whatever little intuition you rely on, go ahead. Leave everybody else alone.

  33. #33 Burt
    September 11, 2009

    @Stephanie[31]

    you’re treating people’s health as an intellectual exercise with no real-world repercussions.

    The only health I treat is my own – and any repercussions are mine alone – it is not merely an intellectual exercise as I have 30+ years of empirical evidence to support the theory.

    What does it mean to anyone who gets caught up in your little theory?

    It’s impossible to get caught up in my little (good things come in small packages) theory. The theory states that it is one’s beliefs that are responsible for events – if one believes that is true then they will act accordingly (which is actually tautological because all humans believe their beliefs are true.) If one isn’t happy with the results of one’s beliefs then one should adjust the beliefs. If one believes that medicine can cure one’s ills then by all means one should obviously avail oneself of whatever one believes can help. I have never recommended anyone eschew medical assistance when one is out of balance and urge anyone who is ill to seek help. I support a universal not-for-profit medical insurance solution, free for all, paid for by corporate and individual taxes so everyone who believes that they are in need of medical intervention may do so. I don’t presume to interfere in anyone’s reality – all are free to act as they will as long as they do not physically harm another or usurp another’s legitimate possessions.

    not only are they going to feel like crap physically, but they’ll think they must want somehow to feel like crap

    Yes – they feel like crap physically, which is a result of feeling like crap mentally. Most people are loath to take responsibility for their perceived negative experiences and seek to blame others or bad luck for their woes. They are highly unlikely believe that they actually wanted to feel like crap. Have you ever encountered anyone besides me who espouses this philosophy? I think not. It’s obvious that you would never be taken in by such a dangerous idea – it’s condescending to believe that others are more credulous.

    They’ll blame themselves for something actually caused by genetics, foreign organisms, etc. Isn’t that lovely. Just what a sick person needs. More crap to deal with.

    Genetics is a filter through which people choose to experience physical reality and a person’s genes do not cause anything. They are the basis from which each of us apprehends existence. In most of us, they are neutral and a non-issue beyond superficial phenotypical appearance, in others they represent challenges to overcome or opportunities to further human potential and scientific boundaries. Each case is personal and individual, the meta-aspect is what I address. Foreign organisms are ad hoc participants, invited by those who use them for their own reasons. Most of us are exposed to countless bacteria and viral pathogens every day and unless we consciously or subconsciously acquiesce to their potential to whatever degree of severity suits our purpose they are either helpful, deleterious, or neutral. Many times the knowledge of why dis-ease is manifested is enough to allow one to discard the ailment when it is no longer useful – utility being the crap’s deal – snarkiness notwithstanding.

    if they’re silly or desperate enough to believe you

    More condescension – if they are desperate, then conventional medicine and science has failed to help them and they will either decide to heal themselves or continue to grasp at straws and avail themselves of anything that they believe may help, be it quackery, charlatanism, religion or ritual sacrifice. The annals of medicine are replete with unexplained spontaneous recoveries – the explanation is usually chalked up to misdiagnosis, the actual reason is that the will to live or recover has trumped the will to die or remain ill.

    No matter what’s going on in your delusional head, that’s not how it works in reality.

    Are you an expert in how reality works? – Highly unlikely – your animosity toward a neutral collection of words which opines on the meta-nature of illness demonstrates a less than firm grasp on the subject. Your certainty in the belief that you understand the nature of reality, and that your beliefs are correct is no less delusional and faith-based than the creationists and others you berate or dismiss due to their beliefs. You term me delusional because I don’t believe as you do, which besides being a disparaging statement is a function of the ad populum fallacy. If a majority of people believe in something then it is considered delusional not to believe as they whether it’s true or false – witness the ID/creation/evolution stalemate. Truth is determined by consensus – absent others, people have to assume what they believe is true until they supplant their beliefs with other ones perceived to be more likely by their lights. They have only personal perception to guide their choices and those perceptions may or may not comport with other’s beliefs.

    In reality, some things work; some things don’t. Some things make everything worse. There is a difference, and pretending otherwise is evil.

    In reality “working” is the perception of the believer. Things are largely neutral and “worse” is a pejorative perception. Some things appear to be worse than others but seen from a larger perspective many times the apparent negativity turns out to be for the best. There may be a difference in perception but that doesn’t mean anyone is evil (another perception – strictly in the eye of the beholder – declaring something evil doesn’t make it so – only the shadow knows…) and there is no pretense on my part.

    You want to mess with your own health on the basis of whatever little intuition you rely on, go ahead. Leave everybody else alone.

    I do manage my health by my intuition – why the need to be snarky by using the “little” descriptor (meaning insignificant – but your responses belie the sentiment?) Your condescending attitude is indicative of one who is unable to communicate effectively, cannot articulate a reasoned rebuttal and resorts to emotional criticism to bolster one’s position. Perhaps you should practice your self-styled moderate obsession and edit your vitriol.

    You order me to leave everybody else alone – I presume you mean for me to stop opining – are you really so threatened by opinion that you resort to overly emotional frustrated fiat? I sincerely hope you are not as angry as you seem in your responses, it’s unhealthy.

    Disclaimer: In the words of Dennis Miller: “It’s just my opinion – I could be wrong.”

  34. #34 CyberLizard
    September 11, 2009

    Disclaimer: In the words of Dennis Miller: “It’s just my opinion – I could be wrong.”

    No, Burt, you are wrong. Your concept of “empirical evidence” is obviously far from the true definition. Your pontification about your crackpot theories are dangerous and have a deleterious effect amongst those poor fools who are susceptible to such self-destructive thought patterns.

    And if you think that Stephanie is “one who is unable to communicate effectively, cannot articulate a reasoned rebuttal and resorts to emotional criticism to bolster one’s position” then you’ve got a lot to learn about communication.

    In other (less reasoned) words: fuck you (cause that’s just the way I roll)

  35. #35 Alice
    September 11, 2009

    Thinking hard with eyes closed really tight: Burt does not really exist. … Burt does not really exist. … Burt does not really exist. … Burt does not really exist. … Burt does not really exist. … Burt does not really exist. … Burt does not really exist. …

    Open eyes…

    Hey, it worked!

  36. #36 Burt
    September 14, 2009

    @CyberLizard[34]

    My definition of empirical evidence is the standard one: Evidence obtained via observation and experiment. I live by my tenets and they have only benefitted me and my family – I doubt you can honestly say the same – given your response. So much antipathy…

    I am wrong because you say so? My theories are dangerous and deleterious to fools who are susceptible to my putative self-destructive thought patterns because you say so? How about some qualification, reasoning, or support for your claims rather than the flaming, hyperemotional criticism that you and Stephanie resort to for lack of cogency? Both of you condescend to those you believe are less mentally acute than yourselves, those who may be taken in by my evil plot to their detriment. Perhaps they would appreciate your regard for their well being if they were aware of your machinations on their behalf.
    Your expletive that concludes your emotional screed is equal in content to your unreasoned premises. Neither one of you appears to be capable of communication except possibly with those who mirror your beliefs but Stephanie states that she is interested in communication – apparently just not with those who have contrary ideas.

    @Alice[35]

    Your technique for banishment merely reinforces your belief in my existence. You are quite correct – for you, I don’t exist except as an idea which you imbue with whatever qualities as suits your whim, you have created me part and parcel. If you would like your incantation to be efficacious, cease all imagining of your bête (Burt) noire and skip all posts with my name attached.

  37. #37 Stephanie Z
    September 14, 2009

    No, Burt. I have no interest in communication with anyone who thinks that all this…stuff [waves hands vaguely at reality; whacks knuckles on remarkably solid desk] is arbitrary. Solipsists are pointless.

  38. #38 Burt
    September 15, 2009

    @Stephanie[37]

    How do you know solipsists are pointless? Do you know any? I don’t – although I’d like to – the concept seems interesting.

    I have never said that I think reality is arbitrary – my desk appears solid to me even though it is more than 99% empty space. I say that reality is created in each of our brains and apprehended by our minds – the only way any phenomena can be reified.

    Solipsists believe that their mind is all that exists – I believe everything that exists for me is a function of my brain/mind apprehension, however I also believe the same is true for everyone else. You have your own reality that is independent of everyone else and your you (wholly created by your mind) is infinitely different from my you. My Stephanie (created wholly by my mind in response to symbols which I caused to appear on my CRT) is a rather bossy, short tempered, fearful, and religious (the concept of evil comes from religion – and the faith you appear to have in the Temple of Science – which is no less faith based than other disciplines) sort of entity who is not well acquainted with Eastern and other Philosophy and prefers not to question dogma and wants to remain in the comfort of sycophants and not venture very far from safe ideas and solid desks.

    I’m sure that my you (a caricature at best – but that’s what I get from the characters on the screen) is totally different from your perception of yourself (as well as your other acquaintance’s perceptions of you.) The Burt you create is as abstract and totally your idea as the Stephanie I create is mine. I also construct a caricature of the me my you describes somewhere in the abstract of cyberspace. I don’t expect my you to accept this formulation but maybe your you’s mind can stretch a skosh. Peace…