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The neurochemical reality of placebos

January 17th, 2012

The New Yorker had a great look at the placebo effect last month (unfortunately the full text isn’t available online), focusing on the work of Harvard’s Ted Kaptchuk. He’s the guy who did the study last year that found that placebos can be effective even when patients are aware that they’re receiving a placebo instead of “real medicine.” His hope is that doctors will learn to harness the placebo effect more effectively, and understand that it’s a real physical effect, not just in your head.

To that end, one of the most interesting nuggets in the article was a description of one of the classic placebo studies, from UCSF back in 1978. People recovering from dental surgery were given either morphine or a saline placebo; as expected, some patients responded to the placebo (their pain diminished) while others didn’t (their pain got worse).

What happened next, however, fundamentally reshaped the field. The researchers dismissed the subjects who had received morphine and then divided the remaining participants into those who responded to the placebo and those who didn’t. Then they introduced Naloxone into patients’ I.V. drips. Naloxone was developed to counteract overdoses of heroin and morphine. It works essentially by latching onto, and thus locking up, key opioid receptors in the central nervous system. The endorphins that we secrete attach themselves to the same receptors in the same way, so Naloxone blocks them, too. The researchers theorized that, if endorphins had caused the placebo effect, Naloxone would negate their impact, and it did. The Naloxone caused those who responded positively to the placebos to experience a sharp increase in pain; the drug had no effect on the people who did not respond to the placebo. The study was the first to provide solid evidence that the chemistry behind the placebo effect could be understood — and altered.

In other words, placebo responders were dulling their pain via exactly the same route as morphine recipients. It was a “real” effect. In the realm of sports science, that’s something to bear in mind when we read yet another report showing that some supposedly performance-enhancing substance doesn’t outperform placebos in a controlled trial.

  1. Bruce
    January 17th, 2012 at 20:44 | #1

    For a critical review of Kaptchuk’s work, the journalistic coverage of it, and what placebos can and cannot do, see here

    http://www.sciencebasedmedicine.org/index.php/the-rebranding-of-cam/

  2. alex
    January 17th, 2012 at 21:16 | #2

    @Bruce: Thanks for the link. I can’t say I find myself in agreement with the general argument there, which seems to run something along the lines of:
    (1) Stupid people make many stupid claims about stupid alternative medicine ideas like homeopathy, reiki and “energy healing.”
    (2) Some of these same stupid people argue that their stupid healing practices are harnessing the placebo effect.
    (3) Therefore the placebo effect is stupid.

    At one point, Gorski writes: “Placebo effects, more than anything else, appear to involve changes in how pain or subjective symptoms are perceived, not any physiological change that concretely affects the course of a disease.”

    To me, this is precisely the point that Naloxone study I describe above gets at. If the Naloxone blocks the placebo effect in responders but doesn’t affect non-responders, doesn’t this indicate that there has been a physiological change in the placebo responders?

    And if that’s true, then it seems to me that Gorski’s dismissal of Kaptchuk’s IBS study is misplaced. He argues that the subjects were deceived because they were told that placebo pills “have been shown in rigorous clinical testing to produce significant mind-body self-healing processes.”

    But that’s true, isn’t it? That’s exactly what the Naloxone study shows.

    I fully understand the ethical concerns about actually trying to harness placebo effects clinically; and I fully understand the general distaste for appearing to validate treatments whose efficacy likely runs in direct proportion to the ignorance and credulity of the patient. But that doesn’t mean we should pretend that those effects don’t happen.

  3. January 17th, 2012 at 22:03 | #3

    To me, the analgesic effect of endorphins introduces an unaccounted-for variable in the trial.

    It would have been interesting to see what would have happened if Nalaxone had been supplied before the placebo.

  4. RH
    January 18th, 2012 at 09:34 | #4

    @bruce
    @alex

    You seem to agree on the facts, but not on how to phrase them. The likely culprit is the phrase “mind-body self-healing processes.”

    If anything, the naloxone study proves that the placebo effect doesn’t cure any disease. It merely helps shutting off the alarm. From this perspective, there is no ‘mind-body healing-process’. This seems to be the position Gorsky takes. The price of this position is a rather narrow definition of disease, that appears less tenable where stuff like pain, formerly relegated to a non-physi(ologi)cal mind, are found to be hard core physical states of our central processor, that can be altered from outside. And from a practical point of view, I suppose no one would argue that chronic pain is merely a subjective perception that is of no concern to the medical profession.

    If a ringing alarm while the situation is under control is allowed to fall under your definition of disease, the placebo effect can (sort of) heal this disease. The price of this position is that it becomes difficult to place any limit on the inconveniences that can be medicalized. For example, you could be treated for being a non responder to the placebo effect.

    How you limit the class of medical conditions has implications for the moral question.

    On one end of the moral spectrum is the occasional horror story of an alternative healer keeping patients with treatable conditions from seeking adequate medical care. These concerns are real and framing the placebo effect in terms of physiology vs. subjective perception is perfectly fitted to state these concerns.

    On the other hand, suppose a terminal patient is suffering from constant, untreatable pain. That is, the cause can’t be treated. The pain might be treated with opiates. The patient is seeing some well meaning alternative healer who doesn’t charge a whole lot of money, and, as a result the body is producing its own’ endorphins. Would it be ethical to convince this patient that the treatment is a placebo, that the body is merely producing its own painkiller and that she should be taking painkillers instead? Yet, this type of case seems to fall within a rather narrow class of ‘alowable deception’.

    I think this is where research on the placebo effect is useful. Finding out what the placebo effect exactly does will help define the class of cases where relying on a placebo is allowable.

    More on topic of this blog, harnessing the placebo effect in sports doesn’t seem such a bad idea. If someone tries to win the Olympics on some placebo effect, who cares? Worst thing that can happen is not winning the Olympics.

  5. alex
    January 18th, 2012 at 15:19 | #5

    @RH: I agree with most of what you’ve written. And of course, I share the visceral dislike of quacks who pretend to heal with a bunch of made-up mumbo-jumbo, just as I loathe companies like PowerBalance that knowingly sell bits of plastic cloaked in lies. But on the flip side, any definition of healing that doesn’t include the relief of pain seems to me to be laughably narrow and inadequate. By that standard, doctors shouldn’t be allowed to prescribe opioids or other painkillers, since they don’t “concretely affect the course of a disease.”

    You cite the following as one of the “acceptable” outcomes of placebo work:

    “The patient is seeing some well meaning alternative healer who doesn’t charge a whole lot of money, and, as a result the body is producing its own’ endorphins.”

    I think that’s one of the nightmare scenarios that Gorski is worried about: giving credibility to “faith healers” who have nothing to offer except deception. But that’s not the desired outcome in my mind. I think we should try to understand exactly how the placebo effect works, and how it can be most optimally triggered. And then maybe doctors can make use of it — and not necessarily through deception. The doctor-patient relationship itself has been shown to exert a powerful placebo effect; that’s not deception, it’s just an effect of how the mind works. People get hung up on the idea of a placebo as a sugar pill, but that’s an overly narrow definition. So why not try to understand how it works?

  6. Bman
    January 18th, 2012 at 18:54 | #6

    @RH: I believe you are actually wrong. Pain actually has been shown to likely be the cause of physical change in your body that causes more damage (inflammation, among other things). Also, while maybe no better than anecdotal evidence, there is significant anecdotal evidence that frame of mind during an injury can make significant physical differences in the speed of recovery, with a very large difference in the first minutes after an injury (including injuries such as stab wounds and others that do physical severing of skin and tissue. One theory is that it is the production of endorphins and other hormones at a super accelerated rate that is responsible. There has to be some reason why a few hockey players have been known to play the third period of a Stanley Cup Final game with a broken leg where doctors have deemed it inexplicable and the players could not walk for two weeks following the game.

    I understand these theories are still not well understood and whether the observations are real, but to me they seem more likely than not from what I have read (and for that matter, experienced). And regardless, reduction in pain has been shown to cause physical differences.

    As far as the moral ground goes, I do not think it is ever moral to tell someone they are getting something they are not or vice versa. That does not mean that we cannot learn how to affect change/healing with our minds.

    [Note: I am not someone who believes in these goofy alternative health solutions in general, but to state that the mind and the chemicals it produces does not cause real physical changes in the body is just not true]

  7. RH
    January 19th, 2012 at 08:58 | #7

    @Bman

    I am not stating that the mind and the chemicals it produces do not cause real physical changes. Id it assume that the placebo effect was limited to merely killing pain, because that was what the research Alex blogged about was about and I thought matters were complicated enough assuming the placebo effect is merely about pain relief.

    You may be right that endorphins do more than merely kill pain. They are connected to positive feeling and a positive outlook seems to be connected to quicker recovery. But the effect of a positive outlook, is that really a placebo effect? I’d say only if you are deceived into it.

    On the moral question, you state that it is always wrong to tell someone he’s getting something while he’s not. I totally agree with you. This is the sugar pill Alex is talking about.

    Does this mean you think that, while the placebo effect is much broader and much more beneficial than the free painkiller I took it to be, we are not allowed to use it? Or do you think some milder forms of deception are allowable? How about an emergency doctor telling his patient that he’s gonna make it, when he is likely not? A doctor telling his patient that he remains positive, while there is no progress? Or a coach telling his team before a crucial match that they’re the best, while they are not?

    Or, alternatively, do you think it is allowable to harness the placebo effect, but only through means not involving untrue statements, like showing empathy (but no “you re looking great today!”, if youre not’:)), clowns in a children’s hospital etc. If so, how about an alternative therapist who treats his patients with a mix of mumbo-jumbo and empathy? And, lastly, should a doctor who knows that his patient is seeing an emphatic alternative healer try to convince his patient it is a mere placebo, even if the patient is experiencing some benefits?

  8. Scott
    February 4th, 2012 at 18:46 | #8

    I don’t think that study is generalizable to all placebos. There’s a difference between using a placebo in pain management, where the goal of treatment is alter symptoms, and a performance supplement, where the goal of treatment is to alter some underlying function. In that case, the placebo is like reducing the mortgage payment for someone who bought a house they couldn’t afford: reducing the payment lessens the pain of the debt, but it doesn’t address the underlying cause of the pain, which is the debt itself.

  9. alex
    February 4th, 2012 at 19:01 | #9

    @Scott: I’m not sure I agree that you can draw a neat line between “symptoms” and “underlying causes” in athletic performance. If I’m a 30:00 10K runner, there are fundamental physiological reasons that I don’t run 25:00 for 10K. But the reasons I run 30:00 rather than 29:45 are mediated, at least in part, by my brain.

    For example, there was a study back in 2010 in which cyclists rode about 2% faster when they were given Tylenol. The Tylenol didn’t provide more fuel or oxygen for their muscles; it only affected how their brain interpreted the pain signals from the rest of the body. If a placebo can also change the neurochemistry of the brain (as the study I blogged about above suggests), then its performance-enhancing effects are just as “real” as the Tylenol.

  1. January 22nd, 2012 at 21:41 | #1
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