
Strong placebo response thwarts painkiller trials, but only in US - DanBC
http://www.nature.com/news/strong-placebo-response-thwarts-painkiller-trials-1.18511
======
lovemenot
Why are placebos becoming increasingly effective only in the US ?

A couple of hypotheses were mentioned in the article. One is that only in USA
and New Zealand is direct-to-consumer drug advertising allowed. Another, which
seems to have some supporting evidence, is that size and length of the drug
trial may boost the placebo effect. The latter point is presumably about the
_production value_ of the trial, mandated by increasingly stringent FDA
regulations. The apparent cost sells the apparent effectiveness.

I wonder whether these results might be linked to USians sustained high level
of religiosity, which is also unique in the developed world.

~~~
hugh4
The worst part is that now the news is out that placebos are getting more
powerful, people are expecting it. The effect will grow exponentially.

Wait, I guess that's not really bad.

~~~
jobigoud
At some point people will start to experience the negative side effects
corresponding to the original drug, as advertised on the package.

And then when the first suicide by placebo pills comes, we'll know we nailed
it.

~~~
backlava
I personally only take placebos.

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jtokoph
Hmm. What if It's just that more Americans are complaining about pain that
isn't truly real? Like somewhat imagined.

So now a higher ratio of trial patients aren't I'll in the first place.

~~~
GordonS
A valid question, but it raises another question - why just Americans?

~~~
dagw
Watching TV in America is nothing but a continuous flow of commercials about
symptoms and diseases that they really want to convince you that you probably
have. We know advertising can make you want all kinds of things, so why not
symptoms and diseases?

~~~
cristianpascu
Funny fact, any commercial for a drug, here in Romania, is ending with a very
fast auction-style warning that last less than 5 seconds. In US you have like
5 minutes of country music and elder people having a picknic while all the
possible dangers in the world are softly planted in your mind. :)

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corin_
I'm not sure if I'm missing something either about statistics or about how the
trials work, so maybe someone can enlighten me:

> _Based on patients’ ratings of their pain, the effect of trialled drugs in
> relieving symptoms stayed the same over the 23-year period — but placebo
> responses rose. In 1996, patients in clinical trials reported that drugs
> relieved their pain by 27% more than did a placebo. But by 2013, that gap
> had slipped to just 9%._

Wouldn't an easier way to look at it be to completely ignore the effects of
the actual drugs in those trials, and just look at the data of how many people
took placebos and to what extent those people reported changes?

~~~
jobigoud
> In 1996, patients in clinical trials reported that drugs relieved their pain
> by 27% more than did a placebo. But by 2013, that gap had slipped to just
> 9%.

Wait, this can be read as "Drugs are less efficient" just as well as "Placebo
are more efficients".

~~~
corin_
They do say _" Based on patients’ ratings of their pain, the effect of
trialled drugs in relieving symptoms stayed the same over the 23-year
period"_, too

~~~
saalweachter
Yeah, but when they compare subjective measurements across studies like that,
it's really an apples and oranges comparison. The entire reason we use
placebos is because there is no objective measurement for things like pain or
sadness or "how well are you feeling in general?".

If the gap between placebos and pain medications is narrowing, my first
assumption is that the experimental designs have tightened over time, so that
the blinding is better, and subjects and doctors are less able to distinguish
between treatments. It's not that pain medication is "less" effective, it's
that it was always only (say) 9% better than placebo, but in crappy earlier
studies where it was less well blinded, some subjects (or researchers working
with the subjects) could tell they were taking the placebo, and reported
feeling worse, and some subjects could tell they were taking the treatment,
and reported feeling better.

If you tell me the gap has narrowed while the subjective reports of the
treatments' effectiveness has stayed the same, I still believe my first
assumption above, but now I'm a little bit suspicious of actual researcher
bias. There are a vast number of ways researchers could "tune" for a target
effect size, from classic ways like choosing the stopping point of the
experiment to more subtle things like interpreting patient responses up or
down based on whether a running analysis is coming in hot or cold.

(The later could be less overtly malicious than you might think -- imagine
that you're continually analyzing the results of your experiment, without
breaking blinding. You "know", from past experiments, that treatment X is 70%
effective. If you are seeing it as 80% effective in your running analysis, you
might assume your interactions with your subjects are subtly biased to
encourage over-reporting of the effect and consciously or unconsciously alter
them to encourage under-reporting, and vice versa if you only see a 60%
effect. If your blinding is still good, your gap in effectiveness will still
narrow, but the "absolute effectiveness" of the treatment will still narrow.)

------
austinjp
Placebo is highly sensitive to trial design, which is what I suspect is
happening here. This is an intriguing effect, meaning that trials are
increasingly reporting that all sorts of therapeutic effects are apparently
less effective than previously thought. Or are they?

More on this at the excellent Mind Hacks blog:

[http://mindhacks.com/2015/07/08/cbt-is-becoming-less-
effecti...](http://mindhacks.com/2015/07/08/cbt-is-becoming-less-effective-
like-everything-else/)

------
Phemist
There are several problems with double-blind testing that have become apparent
in the last few years, and that call for a new standard testing procedure.

Double-blind rests, among others, on the assumption that a) placebo effects
are independent of and additive with actual drug-effects, b) placebo effects
are nulled when participants know they're being given a placebo.

Although I'm currently without sources (hopefully I can rectify this soon)
both a and b are actually false. Certain drugs have been found to interact
with placebo, which decreases or enhances their effects, thus again conflating
the medicative effects of the drugs being administered and the effects of
actually taking a pill (or rather going through the process of administering
medication).

Second, placebo has become such a household term, that the original meaning as
a "fake" effect, seems to have been lost. Logically this makes sense, because
its the end result that matters (being cured), not the way in which the drug
is effective (placebo or not). The average person being told they're receiving
a placebo can actually increase the placebo effect, rather than nulling it.

A second variable should be introduced in double-blind studies, to account for
both factors I mentioned above. Variable 1 should be whether or not they're
receiving the actual drug (1a) or a placebo drug (1b) (as double-blind
currently tests for) and variable 2 should be whether participants are told
that they're receiving the actual drug (2a), or a placebo drug (2b).

Testing the effects of combination 1a/2b vs 1b/2a should test whether the drug
actually interacts with a placebo effect. Providing a measure of validity for
the 1a/2a vs 1b/2a test.

EDIT: Fixed some spelling mistakes

EDIT2: Found some sources: Guardian article on how placebo can be enhanced
when participants know they're being given a placebo:
[http://www.theguardian.com/science/2010/dec/22/placebo-
effec...](http://www.theguardian.com/science/2010/dec/22/placebo-effect-
patients-sham-drug)

Published paper that used the set-up I suggested to find caffeine-placebo
interaction effects -
[http://www.ncbi.nlm.nih.gov/pubmed/21092089](http://www.ncbi.nlm.nih.gov/pubmed/21092089)

EDIT3:

This is the paper I remember reading on the subject -
[http://www.ncbi.nlm.nih.gov/pubmed/24416197](http://www.ncbi.nlm.nih.gov/pubmed/24416197)

~~~
heliumcraft
"Certain drugs have been found to interact with placebo" ??

~~~
kragen
Active placebos are chosen to have side effects similar to the drug being
tested.

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gus_massa
Were they using the same placebo? Perhaps 20 years ago they used a inert
placebo, like (a sugar pill) and now they use an active placebo that mimic the
side effects of the drug (for example, heartburn and indigestion). Both are
placebos, but may have changed the supposed inert drug.

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andy_ppp
If you double the amount of placebos people take do they get better twice as
fast?

A placebo placebo trial if you will. But what would you use as a control? ;-)

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ForkFed
Why not use psychological methods in the first place, if placebo is that
successful?

B/c people will rather eat pills to loose weight then to eat more vegetables
and do some sports ...

------
marincounty
Whole lot of speculation in this article. I would guess more people know about
the placebo effect in the U.S., than they did 20 years ago? Twenty years ago,
we didn't question the efficacy of these drugs? Everyone I know now is very
leery of any claims by drug companies, and their Wonder Drug.

"For companies trying to develop treatments, one remedy might be to compare
new drugs against their best competitors instead of against placebo — or to go
back to conducting smaller, shorter trials."

Lets Not do this. Lets continue to look for drugs that actually work on pain.
The last thing we need is another drug that works slightly better than an
ineffective pain drug that squeaked past the FDA? In the mean time there's a
whole bunch of patients who are in extreme pain, and doctors are afraid to
prescribe opioids. Doctors know opioid type medications work, but are afraid
to prescribe them for a lot of reason, but mainly they don't want the FDA
breathing down their backs.

My best friend died a horrid natural death a few years ago. He was in bad
shape, but the doctors couldn't find anything really wrong with him besides
being very old, and had a very bad case COPD. He was in constant daily pain.

I bought him to "the best pain clinic in San Francisco". They wouldn't
alleviate his pain? They offed to cut some nerve, but wouldn't medicate him.
(To that clinic, if you are going to stereotype patients, and offer no help--
Close down? You are of no service to anyone.)

I brought him back to his apartment, and offered my support every night. All I
could do is cook for him, and offer hope. He died in his sleep a few months
later. Those few months he were hell. All he had was ibuprofen, and some other
safe/no potential to abuse drug. We looked into Hospice, but his doctors said
he wasn't sick enough. Sometimes I think they have just seen too much, and
common sense is lost?

My point is I have seen too many people die in extreme pain, including my
father who was under medicated by Hospice.

I got off track. This is about painkiller trials, and placebo. I just don't
want ineffective pain medication on the market.

I am shocked this group of researchers are trying to blame patients. It's your
ineffective new medications? Lets not run off to some third world country and
get "positive" results, or rely on a bunch of smaller studies that can be
buried--if not satisfactory?. (By the way, this is going on as we speak, and
has been for years. They offshore these double blind studies to the lowest
bidder, and surprise, "Our drug worked better than we could have predicted!".
Present their wonder drug to the FDA, and start the Marketing Party.

Right now, a drug only has to be slightly better than placebo in order to get
past the FDA. That statistical difference is so small, in so many instances; I
think if some of you knew just how slightly your drug works better than
placebo, you might just go off the medication.

MY father died 11 years ago, and I still have weekly nightmares of his
absolute misery. His last words to me were "Son when will this end?". If I
could do it over, I would have gone to the bad part of my county, and bought
him Heroin.

~~~
frenchy
I don't know much about the American medical system, but in Canada, once you
get into palliative care, you basically get put on narcotics, so your father
probably would have been okay. For most people, this works well (there are
some kinds of pain originating from the CNS that as far as I know have no good
treatments).

The situation for out-patients is not that great though. All the strong
analgesics make you loopy. This is fine if you are in a hospital, and under
supervision, but it's dangerous if you're not in a hospital.

Unfortunately, the science just isn't there yet. Treating pain is like
treating cancer: there are so many different forms of pain, different
locations, different "causes", etc.

------
JumpCrisscross
> _USians_

Out of curiosity, where are you from?

~~~
sdrothrock
This is the second time recently that I've seen this demonym... it's really
confusing.

[https://news.ycombinator.com/item?id=10288270](https://news.ycombinator.com/item?id=10288270)

~~~
kragen
There isn't really a good alternative. "Americans" doesn't work; Simón Bolívar
went to war to liberate "the Americans" from the Spanish. I'm surrounded by
Americans here in Buenos Aires. But almost none of them are USians. And no, I
don't know how to pronounce "USian" either.

~~~
maxerickson
Would they, when speaking English, self identify as "Americans"?

I feel like the ambiguity exists only in some pedantic formal sense, that in
colloquial usage it's clear enough what is meant.

~~~
wodenokoto
I completely agree. In colloquial English, "An American" is someone from the
United States.

I don't think I ever heard anyone from outside the US being referred to as "an
American"

~~~
kragen
Well, I just gave you an example of people from outside the US being referred
to as Americans. It's a political issue, though, like the use of "men" to mean
"people", so you can't solve it by appealing to common usage. People who don't
like your usage are still offended by it even when they know it's common. And
they probably won't bother to talk to you, or, in many cases, even learn
English.

Me, I'd prefer to be able to listen to them, especially since I live in Buenos
Aires. So I'm going to continue to not use "American" in that sense, which
means I still don't have a better alternative to the abominable "USian".

~~~
wodenokoto
Okay, outside this thread, I have never heard it.

