Placebo Effect - No proof that it exists

[athon]

So whether it is "proven" to "exist" or not depends on how it is defined. Obviously, "any improvement seen in the control group" exists, but tells us nothing about what caused the improvement.

This has always been my problem with the term. There's been a few discussions on the forum before about placebos, and inevitably the conflicts come down to how the word is defined as to whether it exists or not.

As fls said, there isn't much debate about whether you can use a dummy treatment to elicit a dichotomous outcome. I can't trick you into feeling zero pain, or make you think you're fixed. But treatments do influence the patient's state of mind regarding their health.

The problem is that treatment is not a dichotomous act. Treatment aims to make somebody feel better, which on a practical level cannot dismiss a patient's own perception of their state of well-being. It's quite difficult to tease apart the patient's psychology towards their ailment and the ailment itself, even if the biological problem is explicit and objective (i.e. broken bone, bullet wound, tumour etc.).

Athon

 

[sol invictus]

If the varying instructions merely cause patients to have an actual improvement in the drug's effect rather than just motivating patients to behave differently (to request more or less drugs regardless of how they actually feel) then we might placebo effects of similar size in studies of conditions where a change in patient behaviour could not be relevant to the measured health effects.

Again: what's the difference? How can you distinguish between an "actual improvement" in pain and mere "motivation...to behave differently"?

The only thing I can think of is some kind of brain scan. Since the patients were behaving differently, however, that might reveal a difference for the same reason this data did. It's going to take something extraordinarily sophisticated to do produce the evidence you seem to be demanding, and in fact it's not clear to me that the distinction you're drawing exists even in principle.

 

[quadraginta]

I'll go with this one.

n

The real or imagined effect of a placebo, which may actually be the same effect ordinarily associated with the administration of a therapeutically active agent.

In terms of issues like pain, there just isn't a good way to separate patient reporting from actual effect. Heck what does it even mean to parse the difference between feeling less pain and thinking that you feel less pain?

This is one reason I have so much respect for (some) orthopedic doctors, a group I've had way too much contact with. The ability to diagnose from a patient's self-referential descriptions is not just a matter of reading x-rays.

 

[gerdbonk]

Placebos Are Getting More Effective. Drugmakers Are Desperate to Know Why.

Interesting article that touches on many aspects of placebo.

Placebo response is changing?

...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. ... Half of all drugs that fail in late-stage trials drop out of the pipeline due to their inability to beat sugar pills....

It'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. ... 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.

Placebo is physiological:

Part of the problem was that response to placebo was considered a psychological trait related to neurosis and gullibility rather than a physiological phenomenon that could be scrutinized in the lab and manipulated for therapeutic benefit. But then Benedetti came across a study, done years earlier, that suggested the placebo effect had a neurological foundation. US scientists had found that a drug called naloxone blocks the pain-relieving power of placebo treatments. The brain produces its own analgesic compounds called opioids, released under conditions of stress, and naloxone blocks the action of these natural painkillers and their synthetic analogs...

Now, after 15 years of experimentation, he has succeeded in mapping many of the biochemical reactions responsible for the placebo effect, uncovering a broad repertoire of self-healing responses. Placebo-activated opioids, for example, not only relieve pain; they also modulate heart rate and respiration. The neurotransmitter dopamine, when released by placebo treatment, helps improve motor function in Parkinson's patients. Mechanisms like these can elevate mood, sharpen cognitive ability, alleviate digestive disorders, relieve insomnia, and limit the secretion of stress-related hormones like insulin and cortisol.

In one study, Benedetti found that Alzheimer's patients with impaired cognitive function get less pain relief from analgesic drugs than normal volunteers do. Using advanced methods of EEG analysis, he discovered that the connections between the patients' prefrontal lobes and their opioid systems had been damaged. Healthy volunteers feel the benefit of medication plus a placebo boost. Patients who are unable to formulate ideas about the future because of cortical deficits, however, feel only the effect of the drug itself. The experiment suggests that because Alzheimer's patients don't get the benefits of anticipating the treatment, they require higher doses of painkillers to experience normal levels of relief....

Placebo is cultural:

For instance, the geographic variations in trial outcome that Potter uncovered begin to make sense in light of discoveries that the placebo response is highly sensitive to cultural differences. Anthropologist Daniel Moerman found that Germans are high placebo reactors in trials of ulcer drugs but low in trials of drugs for hypertension—an undertreated condition in Germany, where many people pop pills for herzinsuffizienz, or low blood pressure. Moreover, a pill's shape, size, branding, and price all influence its effects on the body. Soothing blue capsules make more effective tranquilizers than angry red ones, except among Italian men, for whom the color blue is associated with their national soccer team—Forza Azzurri!...

Potential trial volunteers in the US have been deluged with ads for prescription medications since 1997, when the FDA amended its policy on direct-to-consumer advertising. The secret of running an effective campaign, Saatchi & Saatchi's Jim Joseph told a trade journal last year, is associating a particular brand-name medication with other aspects of life that promote peace of mind... By evoking such uplifting associations, researchers say, the ads set up the kind of expectations that induce a formidable placebo response....

The contractors that manage trials for Big Pharma have moved aggressively into Africa, India, China, and the former Soviet Union. ... Doctors in these countries are paid to fill up trial rosters quickly, which may motivate them to recruit patients with milder forms of illness that yield more readily to placebo treatment. Furthermore, a patient's hope of getting better and expectation of expert care—the primary placebo triggers in the brain—are particularly acute in societies where volunteers are clamoring to gain access to the most basic forms of medicine. "The quality of care that placebo patients get in trials is far superior to the best insurance you get in America," says psychiatrist Arif Khan...

 

[Uncayimmy]

The patients who thought their IV contained a powerful pain reliever required 34% less of the analgesic than the patients who weren't told anything about their IV and 16% less than the patients who were told the IV could be either a powerful pain killer or a placebo. Each group got exactly the same amount of pain killer but their requests for the analgesic differed dramatically. The only significant difference among the three groups was the set of verbal instructions about the basal infusion. The study was too short for the differences to be explained by the natural history of recovery, regression, or any of the other alternatives found by Hróbjartsson and Götzsche.

I don't find this the least bit surprising based on my experiences with multiple episodes of moderate and severe pain. If you think you're already getting a powerful pain reliever, there's a hesitance to ask for more even if it really hurts. It's hard to describe, but in a way you feel like, "Oh, well. This sucks. Might as well get used to it. They might say no anyway because they don't want you to have too much painkiller. And who wants to be the sissy that can't take some pain despite already getting a potent painkiller." If your pain is mild to moderate, you figure it's already working, so you're grateful that what you've received seems to be doing the job. After all, imagine how bad the pain would be without it. No sense asking for more because what you have is doing the job.

If, however, you're in pain and you know you're not getting any painkillers, you ask for it, even if the pain is mild. No sense suffering needlessly, right? If you think there's a 50-50 chance you're not getting any painkiller and it hurts, why not ask for it? Then again, if the pain naturally subsided (as pain often does), you figure you're getting the strong painkiller, so you're back to the first scenario.

Then there's the fear factor. When I was younger I worked very hard to learn to tolerate pain as simply a warning signal from my body. It's almost a form of disassociation where you try to treat pain like any other sensation. Even so, when I've been in severe pain I found it a struggle to control my instinctive fear reaction. This can be especially difficult when I've had severe pain followed by relief. Any new pain that comes up during that same immediate time frame makes you think that it might come back full force.

So, if you're in the group that doesn't think there's anything in the saline solution, you're much more likely to ask for relief at the onset of a new wave of pain, even if it's mild. If, however, you think you're already getting relief, you might want a bit longer to request additional relief because your fear is alleviated by your belief that you're already getting treatment.

And since this study was based on requests for painkillers over a limited time frame, any delays in requesting additional painkillers can be easily explained. Personally, I think the whole study sounds like it was designed by people who have never really been in serious pain or who haven't really thought about the psychology behind it.

I prefer Sol's original premise, which is dividing the groups into treatment, sham treatment and not treatment. Combine that with a less subjective outcome, preferably a binary one like fls described, and there's your evidence, whatever it may be.

 

[Aepervius]

I got delivered in ER a morning a few summer ago for an extremely strong stomach pain. The doctor said me they would get me pain killer. I got a drip. I felt no relief so I asked them, some nurse went on checked the drip, then went off. I asked again. And again. And finally a doctor came after a few hours (well in the afternoon) and admitted there was only a solution in the drip but no painkiller. They simply did not want to give me a pain killer without a diagnose so they tried to "fake" it, apparently sometimes that works. I would not be too surprised that you are right and that a fear to pester the doctor is at work.

 

[Lothian]

Placebo effect seems to be just a catch all description for any improvement seen in the control group before and after.

The cause of it could be error in measurement, regression to the mean, some psychological benefit to thinking one got treated or a demand characteristic. I think specific reasons for why a placebo effect might occur are well known (from hawthorne effects to subjects trying to be good subjects). The problem seems to be lumping all into one thing and calling it a placebo effect?

‘Placebo’ is not just the reaction in the control group.

The placebo effect is the benefits arising out of the ceremonial aspects of medicine. This could be the giving of a sugar pill, a sham operation or the ½ hour consultation with the patient.

It follows that if these ceremonial aspects have an effect they also effect on the real procedures not just the control group.

Ben Goldacre’s excellent book “Bad Science” has a very good chapter on the placebo effect. He reports on experiments that show how 2 sugar pills produce more of an effect than 1. How sugar pulls in known branded packaging give a greater effect than those in plain packages, how the colour of sugar pills changes the effect. How sham operations show more improvement than sugar pills. He talks about how placebos have been tested not just by “how well do you feel on a range of 1-10” but rather objective evidence measuring stomach ulcers. He also talks about pavlovian effects showing how ceremonial procedures elicit measurable chemical changes in the body.

 

[shuttlt]

So, is there any evidence at all of non-subjective benefits due to placebo, rather than regression to the mean?

 

[MRC_Hans]

So, is there any evidence at all of non-subjective benefits due to placebo, rather than regression to the mean?

That may be difficult to establish with certainty, since there are some objective benefits that may follow from subjective ones. Reduced axciety, for instance, which may be entirely subjective, can lead to objective improvements in stress-related conditions.

Since most diseases have at least some subjective vectors, the picture is very complex.

Hans

 

[fls]

So, is there any evidence at all of non-subjective benefits due to placebo, rather than regression to the mean?

You can train subjects to have a specific physiologic response to an inert substance. It has been done for the release of endogenous opioids, dopamine, bronchodilators, caffeine, etc. This is an attenuated and short-lived response compared to receiving the active drug. And it hasn't been demonstrated to be substantial enough to lead to clinically relevant effects. It also is not relevant to the what happens in the placebo group in clinical studies, as generally it is novel drugs which are being tested, so there is no opportunity for conditioning in the first place (other than general responses).

Almost all of the purported 'therapeutic' effects from placebo mentioned in this thread are based on variations in the reporting of pain.

Linda

 

[fls]

‘Placebo’ is not just the reaction in the control group.

The placebo effect is the benefits arising out of the ceremonial aspects of medicine. This could be the giving of a sugar pill, a sham operation or the ½ hour consultation with the patient.

It follows that if these ceremonial aspects have an effect they also effect on the real procedures not just the control group.

Ben Goldacre’s excellent book “Bad Science” has a very good chapter on the placebo effect. He reports on experiments that show how 2 sugar pills produce more of an effect than 1. How sugar pulls in known branded packaging give a greater effect than those in plain packages, how the colour of sugar pills changes the effect. How sham operations show more improvement than sugar pills. He talks about how placebos have been tested not just by “how well do you feel on a range of 1-10” but rather objective evidence measuring stomach ulcers. He also talks about pavlovian effects showing how ceremonial procedures elicit measurable chemical changes in the body.

You have to be careful about the specifics of these studies. When you are talking about the effects of the presentation of sugar pills, what these studies were measuring were reported pain. Objective changes are obtained without comparison to 'no treatment'.

Linda

 

[volatile]

I can't trick you into feeling zero pain

Actually, you can.

"
1 The placebo effect

Don't try this at home. Several times a day, for several days, you induce pain in someone. You control the pain with morphine until the final day of the experiment, when you replace the morphine with saline solution. Guess what? The saline takes the pain away.


This is the placebo effect: somehow, sometimes, a whole lot of nothing can be very powerful. Except it's not quite nothing. When Fabrizio Benedetti of the University of Turin in Italy carried out the above experiment, he added a final twist by adding naloxone, a drug that blocks the effects of morphine, to the saline. The shocking result? The pain-relieving power of saline solution disappeared.


So what is going on? Doctors have known about the placebo effect for decades, and the naloxone result seems to show that the placebo effect is somehow biochemical. But apart from that, we simply don't know.
Benedetti has since shown that a saline placebo can also reduce tremors and muscle stiffness in people with Parkinson's disease. He and his team measured the activity of neurons in the patients' brains as they administered the saline. They found that individual neurons in the subthalamic nucleus (a common target for surgical attempts to relieve Parkinson's symptoms) began to fire less often when the saline was given, and with fewer "bursts" of firing - another feature associated with Parkinson's. The neuron activity decreased at the same time as the symptoms improved: the saline was definitely doing something.
We have a lot to learn about what is happening here, Benedetti says, but one thing is clear: the mind can affect the body's biochemistry. "The relationship between expectation and therapeutic outcome is a wonderful model to understand mind-body interaction," he says. Researchers now need to identify when and where placebo works. There may be diseases in which it has no effect. There may be a common mechanism in different illnesses. As yet, we just don't know."


(http://www.newscientist.com/article/mg18524911.600)

 

[shuttlt]

That may be difficult to establish with certainty, since there are some objective benefits that may follow from subjective ones. Reduced axciety, for instance, which may be entirely subjective, can lead to objective improvements in stress-related conditions.

Since most diseases have at least some subjective vectors, the picture is very complex.

Hans

I think a lot of the more reasonable believers would take this to be some kind of weak support. I've talked to a few homeopaths and chiropractors who've said they would still do what they do even if it was just placebo. What I presume they are talking about is objective improvements stemming from reduced anxiety and stress.

 

[Lothian]

You have to be careful about the specifics of these studies. When you are talking about the effects of the presentation of sugar pills, what these studies were measuring were reported pain. Objective changes are obtained without comparison to 'no treatment'.

Linda

As I recall, they were not all measuing pain. Certianly I remember the ulcer experiment. If you haven't got the book a list of the studies it covered are given at the bottom of this article.

 

[fls]

(http://www.newscientist.com/article/mg18524911.600)

I encourage you to look at the actual article, rather than a journalist's interpretation. After all, the author includes homeopathy in his list, so what are the chances that he really understands what he's talking about?

http://www.jneurosci.org/cgi/conten...f7c0ced21a52fa4efd4e4984&keytype2=tf_ipsecsha

Linda

 

[volatile]

I encourage you to look at the actual article, rather than a journalist's interpretation. After all, the author includes homeopathy in his list, so what are the chances that he really understands what he's talking about?

http://www.jneurosci.org/cgi/conten...f7c0ced21a52fa4efd4e4984&keytype2=tf_ipsecsha

Linda

Oh, sure. I have read the actual paper and it's interesting. I just linked to the NS article because that's where I first came across this study. You would agree, would you not, that it does in essence demonstrate that placebo pain control is possible?

 

[JFrankA]

I think placebos is a real phenomenon. People are going to feel what they believe they feel. It will not cure a person of the real, physical sickness/injury, but it can change a person's mood.

For example, (and warning: anecdote coming), I do stage hypnosis as a side job. One of the most popular thing I do is getting people drunk on water or soda. I don't do this on stage, I start it off with a willing participant before the show. After a few hours, that person is completely drunk.

Also, I've done this type of things with friends in college. I'd buy some vitamins from the store, put the pills in a zip-loc bag that I've roughed up a little, go to a friend, and tell the person that this is a drug that will make them feel a euphoria. I describe the "effects" fully and completely. The result is that most of the people actually do feel the high.

Why? Desire. They want it to happen. Belief. They were sold on the fact that it would. Mix those two together and the body will feel whatever that person's mind wants to feel.

 

[fls]

As I recall, they were not all measuing pain. Certianly I remember the ulcer experiment. If you haven't got the book a list of the studies it covered are given at the bottom of this article.

For the ulcer experiments - objective measures (ulcer healing by endoscopy) were not compared with no treatment and subjective measures (pain) were compared with no treatment (in some cases).

Linda

 

[Angus McPresley]

To see if the placebo effect is real, they should have a test where they give one group placebos, while they give a control group sugar pills.

 

[fls]

Oh, sure. I have read the actual paper and it's interesting. I just linked to the NS article because that's where I first came across this study. You would agree, would you not, that it does in essence demonstrate that placebo pain control is possible?

I think that this is one effect specific to placebo which has been reasonably well established. And it may even represent a difference in the experience of pain, rather than just the reporting of pain. But it also demonstrates that conditioned responses are not the same responses as unconditioned responses (making attempts to conflate the two questionable). And the amount of pain control that is specific to the placebo is small. In those studies where it is compared to no treatment, while the difference is statistically significant, it fails to reach the minimum threshold considered clinically relevant (6.5 mm vs. 10 to 14 mm).

ETA: Also it should be pointed out that it doesn't demonstrate a difference in binary outcomes (pain present or absent), even though you brought it up as though it does in response to Athon's post.

Linda