Jun 02 2010
Potential New Mechanism of Pain Relief Discovered
The development of drugs and other treatments for specific symptoms or conditions relies heavily on either serendipity (the chance finding of a beneficial effect) or on an understanding of underlying mechanisms. In pain, for example, there are limited ways in which we can block pain signals – such as activating opiate receptors, or inhibiting prostaglandins. There are only so many ways in which you can interact with these systems. The discovery of a novel mechanism of modulating pain is therefore most welcome, and has the potential of leading to entirely new treatments that may have a better side effect profile than existing treatments and also have an additive clinical effect.
A recent study by Nana Goldman et. al., published in Nature Neuroscience, adds to our understanding of pain relief by identifying the role of adenosine in reducing pain activity in the peripheral nervous system. The researchers, in a nice series of experiments, demonstrated that producing a local painful stimulus in mice causes the local release of ATP (adenosine triphosphate) that peaks at about 30 minutes. This correlates with a decreased pain response in the mice. Further, if drugs are given that prolong the effect of adenosine, the analgesic effect itself is prolonged.
Also, if drugs are given that activate the adenosine A1 receptor, the observed analgesic effect is replicated. When these experiments are replicated in knockout mice that do not have the gene for the adenosine A1 receptor, there is no observed analgesic effect.
Together these experiments are fairly solid evidence that local pain results in the local release of adenosine that in turn binds to the adenosine A1 receptor inhibiting the pain response. This is potentially very exiting – it should lead to further investigation of the adenosine A1 receptor and the effects of activating and inhibiting it. This may lead to the development of drugs or other interventions that activate these receptors and may ultimately be a very useful addition to our ability to treat acute and chronic pain.
Now Comes the Spin
In a rational science-based world the above would be the end of this blog entry. But that is not the world we currently live in. In this study the chosen method of provoking pain was the insertion of an acupuncture needle into the “Zusanli point” of the lower extremity and rotating it. This allowed the authors of this study to spin the results as if they were validation for acupuncture itself – and the mainstream press dutifully followed suit.
The introduction to this study is an apology for acupuncture itself, and sets the tone for the rest of the paper as well as the press release and comments to follow:
Acupuncture is a procedure in which fine needles are inserted into an individual at discrete points and then manipulated, with the intent of relieving pain. Since its development in China around 2,000 B.C., acupuncture has become worldwide in its practice. Although Western medicine has treated acupuncture with considerable skepticism, a broader worldwide population has granted it acceptance. For instance, the World Health Organization endorses acupuncture for at least two dozen conditions and the US National Institutes of Health issued a consensus statement proposing acupuncture as a therapeutic intervention for complementary medicine. Perhaps most tellingly, the U.S. Internal Revenue Service approved acupuncture as a deductible medical expense in 1973.
That this paragraphs appears in a high impact peer-reviewed journal is very curious (to put it mildly). It is full of misinformation and logical fallacies. Acupuncture is used for more than pain relief, and so making statements about the efficacy of “acupuncture” go way beyond the scope of this study, which only involves pain. The authors should have specifically pointed out that this study cannot be used to explain any indication for acupuncture that does not involve local pain relief. Acupuncture as it was practiced in China 4000 years ago bears little resemblance to what is practiced today, and may have been more of a form a bloodletting.
The authors then make a false dichotomy between “Western medicine” and, presumably, “Eastern medicine” – which is an anti-scientific and culturally bigoted point of view. This is followed by an argument from popularity, and a particularly bizarre argument from authority – noting that the IRS accepts acupuncture as a medical expense. I was unaware that the IRS is a scientific medical organization.
The authors also fail to put this study into its proper context by reviewing existing evidence – the more traditional use of the introduction to peer-reviewed research. The clinical research on acupuncture, which is quite extensive, finds that any measured symptomatic effect is almost certainly due mostly or entirely to placebo effects. Further, it does not matter where you stick the acupuncture needle, nor even if you do stick the need through the skin. Twisting toothpicks against the skin in random locations has the same effect.
My interpretation of the research is that acupuncture (placing needles at specific acupuncture points to manipulate chi) does not work. There may, however, be non-specific physiological responses to the mechanical stimulation of sticking needles at random locations, or just poking toothpicks. This study, if anything, supports this interpretation – it, if fact, has identified a local mechanism of analgesia that can help explain a non-specific response to acupuncture, sham acupuncture, or placebo acupuncture and therefore is consistent with the clinical evidence showing no difference among these interventions.
This is also not the first study to identify potential local mechanisms of pain relief from mechanical stimulation. A 2002 study correlated insertional activity (depolarization of muscle fibers in response to needle insertion) or electrical stimulation with pain relief. This would explain why, in this study, constant twisting of the needle was needed to provoke pain relief – perhaps insertional muscle activity is needed to release adenosine, or increases its release.
By focusing on what is really going on here we can best understand how to develop methods to optimally capitalize on these local mechanisms for pain relief. It must be noted, however, that needle insertion gives very unimpressive results in clinical trials. It may be that the effect is too temporary to be worthwhile, at least as mechanically provoked – pharmacologically activating the adenosine A1 receptor may be a better strategy. Also, it is very difficult to extrapolate from mouse data as they are much smaller than humans, and therefore their nerves and motor end-plates (the location where the nerves innervate the muscles) are much closer together and superficial – closer to the skin.
Mechanisms are interesting, but net clinical outcomes in humans are the only kind of scientific data that really tells us if a modality works or not.
Conclusion
Finally, it has to be emphasized that this study says nothing about acupuncture itself, except for providing a possible mechanism for a non-specific local response. The term “acupuncture”, in fact, is becoming increasingly problematic and is confusing the scientific literature, not to mention the public. What is acupuncture? If we use the term broadly enough to mean any use of needles, with or without electrical stimulation, at any points, with or without skin penetration, etc. then the term is too broad to be useful. If we use the term narrowly – to mean sticking needles to a certain depth in specific acupuncture points that work through a novel mechanism specific to those locations, then we can say, based upon extensive research, that “acupuncture” does not work and its proposed underlying mechanisms are nothing more than pre-scientific superstition.
This study is an excellent example of the mischief caused by confusing the non-specific use of the term “acupuncture” with its more traditional use. Research involving acupuncture in its vaguest sense is used to promote “acupuncture” in the traditional sense. This is highly deceptive and scientifically sloppy.
The researchers of this current study could have used other controls to see if the effect they discovered is in any way specific to any acupuncture variables. For example – they could have used a non-acupuncture point as a control, or other forms of mechanical pain production that do not involve needles. I suspect any local pain production or mechanical trauma beyond a certain threshold would result in the same adenosine response – which certainly seems like a non-specific mechanism to modulate pain.
Because they did not do this they did not actually research “acupuncture”. The description of this research in the published paper and in the press should have been as I discussed in the opening of this post. Instead genuinely interesting research that may lead to novel pain treatments is being diverted as propaganda for an ancient superstition.
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Note: This article is cross-posted over at Science-Based Medicine
14 Responses to “Potential New Mechanism of Pain Relief Discovered”
I’m not a scientist, so please tell me where I missed something.
On the one hand you point out that there is no evidence that acupuncture (poking needles at chi points) works beyond placebo. But then you cite studies that show needles or even tooth picks produce some non specific pain relief. And if I understand the experiment, this might be due to the adenosine.Even as a layman I thought their introduction was full of illogical implications – in particular I thought it odd that the IRS is used to support medical efficacy.
So if I understand you – acupuncture is considered not effective because it doesn’t consistently predict a specific response to a specific mechanism/location. However, there is reason to suppose that stimulation to create a local pain does cause non-specific pain relief, but not predictably.
For something to be considered medical treatment, it should be a specific procedure leading to predictable results.
The main problem is the definition of acupuncture. Scientific terms need to be specific to be useful – hopefully they are “operational”, meaning there are specific features that must be present and others that must be absent.
So – what is acupuncture? Research has shown that anything which can be said to be specific to acupuncture has no effect.
Poking people in random locations, with or without penetration, however, has non-specific psychological and physiological effects. This is not “acupuncture” though, any more than some at-home stretching is chiropractic.
What I think we can say at this point is:
1 – Acupuncture is not based on scientific principles and does not work for anything.
2 – Low levels of mechanical trauma provoke local tissue and neurological responses that inhibit local pain and inflammation – not surprising at all, and entirely incidental to the application of “acupuncture.”
3 – These effects are temporary and short term, and probably local, and in clinical trials are of questionable significance and utility.
4 – However, understanding the underlying mechanisms may lead to more useful therapies with more convenient application and longer duration of effects. But we will need to go through the entire development process to see how these pan out.Superb write-up Steve. Posts like these is why I read your blog, and always hope you’ll write about stuff I send you. To gush a bit more, excellent work on being as neutral as possible. I haven’t seen anyone else (not that I’ve read a lot about this) praise the study’s discovery adenosine pain inhibition.
Also: are you going to write a formal response for Nature Neuroscience? That might be useful.
Discovery OF…
I second Michael’s suggestion that you write a letter to Nature Neuroscience on this. It would be interesting to see the author /journal reaction.
Two other excellent treatments of this article are:
Orac at Respectful Insolence: http://scienceblogs.com/insolence/2010/06/when_what_an_acupuncture_study_shows_is.php
And Ed Yong at Not Exactly Rocket Science: http://blogs.discovermagazine.com/notrocketscience/2010/05/30/a-biological-basis-for-acupuncture-or-more-evidence-for-a-placebo-effect/
Your suggestion about writing a comment to Nature Neuroscience is a good one.
Did they have Mercola write that intro or did they take it from some new-age website? I’m amazed that the study was allowed to be published with that terrible introduction included. The logical fallacies are all over the place, but even putting that aside the intro has little/nothing to do with the actual study.
I just briefly read over the paper. As a naive reader (I know nothing about apuncture or studies of acupuncture) I came away with:
1. Acupuncture is known to have analgesic properties (background of paper).
2. Acupuncture needles inserted near the ‘Zusanli point’ (basically a location place near the knee) and rotated supresses pain in rats. If the rotation isn’t done, you don’t have the analgesic effects.
3. Acupuncture needle insertion causes adenosine release, with much greater release with needle rotation.
4. This pain supression is A1-receptor dependent (that’s an adenosine receptor).
5. Introduction of an A1-receptor agonist (activator) is sufficient to reduce pain.
1-5 suggest that the well-established analgesic effects of acupuncture are caused largely by adenosine release.This all seems actually fairly reasonable. Two main “skeptical” questions that Steven brought up I address below.
1. Does the location matter?
The authors didn’t address whether this would work anywhere on the body. That is, are there specific “centers” on the body where acupuncture would be particularly effective? Their study doesn’t address this.My hunch is that there may actually be localized regions where it is more effective. Namely, locations of high concentration of A1-receptors that are part of the ascending sensory pathways. My hunch is the adenosine release is quite general, but the effects of adenosine will likely be anisotropic. This at least suggests further research, e.g., labelling of peripheral A1-receptors.
2. What about other stimuli besides needles?
Novella brought this up at the end. On page 5 the authors admit things like massage might also cause ATP release/adenosine buildup. They think this might be plausible, and mention vibratory stimuli presented to the skin supress pain by release of adenosine. But they claim acupuncture is different because it is “typically applied to deep tissue, including muscle and connective tissue, and acupoints may better overlap with their proximity to ascending nerve tracks than to the density of cutaneous afferents.”This is basically what I suggested above.
My response to this paper is that it is decent. They seem to have a pretty relaxed attitude, not particularly dogmatic. Needles cause release of adenosine, which supresses pain via A1-receptors. This explains acupuncture’s analgesic effects. It doesn’t seem particularly ludicrous to me.
The suggestion that they should have left out the acupuncture angle of the paper seems proposterous to me. That was the main motivation, the method used, everything hinged on this being a study of acupuncture.
Note, this is the response of a naive reader, I have done no investigations of acupuncture. There is a chance I have been mislead, but frankly I understand why this is in Nature Neuro, and frankly it doesn’t come off as new-agey or methodologically flawed. Yes, they left questions open, but no major flaws.
The first sentence of the Introduction (quoted in the post)
“Acupuncture is a procedure in which fine needles are inserted into an individual at discrete points and then manipulated, with the intent of relieving pain.”
Any complaints about how poorly the term ‘acupuncture’ is defined do not belong with this article or its authors.
The mention of the IRS is to point out
“a broader worldwide population has granted it acceptance.”
To call this mention an argument from authority and to note that the IRS isn’t a scientific medical organization is nonsequitur.It is a sad and regretful state of affairs when genuine scientific research is hijacked for unscrupulous commercial entities. This is also potentially very dangerous as the general public will be further duped in to spending vast sums of money annually towards a near useless “specialist” pain relieval method.
Is this another case of sloppy journalism or is it a case of deliberate misguiding?@sonic
“To call this mention an argument from authority and to note that the IRS isn’t a scientific medical organization is nonsequitur.”
Agreed. If we’re dealing with labeling here in place of analysis, label that IRS jab as the fallacy of necessity.Sonic – it is not a non sequitur – saying that it has broad acceptance is just an argument from popularity. It is irrelevant and does not belong in a scientific paper. This paper is not a study of how acupuncture is used or accepted. The IRS statement is an absurd non sequitur – acceptance by the IRS is not even related to broad worldwide acceptance, it is a reflection of local politics.
And you further missed my point about definition. While they may have given one definition of “acupuncture” in their article, they did not test one of the main components – “discrete points” – that was not tested as a variable. They also did not test whether needle insertion is a necessary variable either. So by their own definition – they did not test acupuncture.
Their further discussion of acupuncture and its acceptance is not limited to their somewhat narrow definition, so they are doing exactly what I described – using research into a narrow definition of acupuncture (and not really doing that) to promote a more broad and vague definition of acupuncture.
They did not even acknowledge that the definition they used is just one definition, that there are other ways to define it, and that acupuncture is used for many non-analgesic indications. Nor did they review the literature at all to give a sense that acupuncture in fact does not work for analgesia. Perhaps this is because their animal data does not extrapolate well to humans.
In short – they totally dropped the ball. This was not a neutral scientific treatment of the topic. It was some interesting science wrapped up in bullshit.
I had a go at this one too, at http://www.dcscience.net/?p=3136. After the Nature news people got a bit upset about a comment I left on their blog, I thought I should explain.
Essentially all of the newspaper reports misinterpreted the work. apparently because the press release from Nature Neuroscience misrepresented it too. But the press release just copied the tendentious spin in the paper itself. In the end, the people to blame were the authors themselves, and the reviewers for Nature Neuroscience who failed to spot the spin.
Steve,
Michael Meadon’s suggestion of writing to Nature Neuroscience reminded me of something I had been kicking around. I remember that you described the difficulty of getting the university to recognize the role of your blogging and internet contributions, as it all gets lumped under the umbrella of service.Perhaps, by taking your meticulously thought out criticisms to the editorials of the scientific literature, you may be able to bridge the academic world with that of your public outreach. Might such contributions make the educational and academic value of your blog more apparent as a serious medium for debating research (at least more serious than your typical run-of-the-mill blog)? Is it reasonable to think that such high-profile academic criticism might bring more academic attention to your web-based contributions?
You also seemed to have made some substantive criticisms of the Cochrane Review on Homeopathy (a while back). Might you have a shot at the Bill Silverman prize for such a published critique?
I hope that this suggestion is not viewed as presumptuous, trivial, or insulting. I know I have enough problems getting my own publications out the door, so I might roll my eyes at the suggestion that I just “publish more” (and I don’t contribute to four blogs and two podcasts and am not a clinician/professor/researcher/professional skeptic/father/birder). However, it seems you are already doing much of the work already in your spare time (not to diminish the time required to find the ideal references and formulate/edit your rhetoric carefully for a scientific publication). It would be inspiring to see your conviction to fight for high scientific standards pay off in academia, as opposed to largely being a trade-off with service.
Best of luck!
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Wednesday, 2 June 2010
Potential New Mechanism of Pain Relief Discovered
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