Jun 02 2010
Perhaps the most heavily studied of “alternative medicine” modalities is acupuncture. Although it’s hard to be sure as to the reason, I tend to speculate that part of the appeal to trying to do research in this area is because acupuncture is among the most popular of actual “alt-med” modalities, as opposed to science-based medical modalities co-opted by believers in alt-med and rebranded as “alternative” (diet and exercise, for instance, to which is all too often added the consumption of huge quantities of unproven nutritional supplments) or activities that make people feel better, whether they’re healthy or ill (massage, for instance). In contrast, acupuncture involves actually sticking needles into the skin. Never mind that the rationale for acupuncture, namely “redirecting” the flow of the “life energy” known as qi when it is blocked by sticking needles in “meridians” like some electrodes in some imaginary qi battery, is pure bunkum, as we’ve pointed out here at SBM time and time again. Somehow the image of needles sticking out of the skin, apparently painlessly and making some extreme acupuncture practices resemble Pinhead from the Hellraiser movie series, seems “sexy” as far as “alternative” therapies go, particularly since it’s “Eastern” as opposed to that reductionistically evil “Western medicine,” and, as we all know at SBM, “Western” is bad and “Eastern” is good.
So the fascination with acupuncture remains, so much so that an inordinate amount of research dollars are spent on studying it. Unfortunately, that money is largely wasted. As Steve Novella has pointed out, in general in medicine (at least these days), the trajectory of research is usually from bench research to animal models to small scale, less rigorous, pilot studies in humans to large scale, rigorously designed studies using many subjects. True, this order doesn’t always hold. For instance, if physicians make a compelling observation “at the bedside” of response to therapy or how a disease progresses, frequently, after making closer observations to confirm the initial observation, researchers will jump back to animal models and bench top research to try to figure out what’s going on. For such a progression to be useful, though, scientists have to be sure that the phenomenon in human patients under study actually exists.
Unfortunately, in acupuncture, the evidence is still unconvincing that there is any “there” there in that acupuncture effects appear to be no greater than placebo effects. As larger, more well designed studies using real placebo or sham acupuncture techniques, have increasingly shown that acupuncture does not function any better than placebo in human beings (and sometimes even worse), acupuncturists and acupuncture believers have been reversing the usual order of things, doing smaller studies and “pragmatic” (i.e., uncontrolled) clinical trials, where the placebo effect is not controlled for. Never mind that it doesn’t matter where the needles are placed (thus blowing the whole “meridian” idea out of the water) or even if the needles puncture the skin. Toothpicks work just as well as needles. Also never mind that the mythology of acupuncture as having been routinely practiced for over two thousand years (or, sometimes, four thousand years, is largely a creation of Chairman Mao, who elevated what was a marginal practice at the time to a modality that the state supported and promoted (1,2,3,4). Unfortunately, even the National Center for Complementary and Alternative Medicine (NCCAM) falls for this mythology.
Every so often, I’m amazed when an acupuncture study ends up in a high impact journal like Nature Neuroscience. Of course, when I read such articles, virtually inevitably I discover that what is being studied is not really “acupuncture” per se, but rather sticking needles into either people or animals. Sometimes, “electroacupuncture” (which is in reality not acupuncture at all, given that there was no source of electricity hundreds of years ago in China when acupuncture was supposedly invented) is misrepresented as acupuncture. Since a bunch of readers, both here and at my other blog, have deluged my mail box with this particular study, I felt obligated to have a look at it, even if Steve Novella has already weighed in with his excellent deconstruction. This particular study is especially annoying, because it’s been hyped to the nth degree, and even some news sources where the reporters should know better have fallen for it.
Before I get to the study itself, though, let’s take a look at the press release:
The research focuses on adenosine, a natural compound known for its role in regulating sleep, for its effects on the heart, and for its anti-inflammatory properties. But adenosine also acts as a natural painkiller, becoming active in the skin after an injury to inhibit nerve signals and ease pain in a way similar to lidocaine.
In the current study, scientists found that the chemical is also very active in deeper tissues affected by acupuncture. The Rochester researchers looked at the effects of acupuncture on the peripheral nervous system – the nerves in our body that aren’t part of the brain and spinal cord. The research complements a rich, established body of work showing that in the central nervous system, acupuncture creates signals that cause the brain to churn out natural pain-killing endorphins.
The new findings add to the scientific heft underlying acupuncture, said neuroscientist Maiken Nedergaard, M.D., D.M.Sc., who led the research. Her team is presenting the work this week at a scientific meeting, Purines 2010, in Barcelona, Spain.
“Acupuncture has been a mainstay of medical treatment in certain parts of the world for 4,000 years, but because it has not been understood completely, many people have remained skeptical,” said Nedergaard, co-director of the University’s Center for Translational Neuromedicine, where the research was conducted.
I’ll cut to the chase before proceeding with my usual infamously in depth and long-winded discussion of the study. Nedergaard’s study is interesting, but it really doesn’t show that “acupuncture works” any more than it really shows compelling evidence for a specific mechanism behind acupuncture. Unfortunately, as is commonly the case, much of the press reporting this study earns a big fat F for the spin being put on it. The Guardian, for instance, states:
The discovery challenges a widely held view among scientists that any benefit patients feel after having acupuncture is purely due to the placebo effect.
“The view that acupuncture does not have much benefit beyond the placebo effect has really hampered research into the technique,” said Maiken Nedergaard, a neuroscientist at the University of Rochester Medical Centre in New York, who led the study.
“Some people think any work in this area is junk research, but I think that’s wrong. I was really surprised at the arrogance of some of my colleagues. We can benefit from what has been learned over many thousands of years,” Nedergaard told the Guardian.
I love the “arrogance” gambit, don’t you? This time, it’s even coupled with the “appeal to ancient wisdom” fallacy. Nice. If you want to irritate me, pull the “arrogance” gambit and then couple it with appeals to ancient wisdom. After all, physicians from ancient civilizations were heavily into bleeding and purging, not to mention treating with toxic heavy metals. Go back to the ancient Egyptians, and you’ll see that praying and believing that the gods were responsible for diseases, with physicians and priests often serving the same purpose, were the rule fo the day. Does that mean such treatments were “wise” or efficacious. Meanwhile The Daily Mail entitled its report Let’s get straight to the point, acupuncture DOES ease pain, and The Telegraph entitled its report Acupuncture does work as it stimulates a natural pain killer, scientists find, while The Raw Story exulted, Researchers prove acupuncture’s effectiveness in pain therapy and the Wall Street Journal opined How Acupuncture May Work: Adenosine is Key to Acupuncture’s Effectiveness. Perhaps the silliest and most credulous commentary on this study comes from Elizabeth Armstrong Moore on CNET, who even entitled her post Think Acupuncture’s a hoax? Think again (Scientific research shows natural healing compounds), where Moore represented herself as a “skeptic” being “converted” to believing that acupuncture works, while Ars Technica writer Yun Xie laps this story up credulously. Even what I would normally consider more scientifically rigorous sources were not immune to the woo. For example, ScienceNow entitled its article on the study How Acupuncture Pierces Chronic Pain; The New Scientist‘s blog Short Sharp Science, How acupuncture eases pain – maybe (which, despite the slightly skeptical title, was pretty much completely accepting of the spin placed on the study); and Nature‘s blog The Great Beyond, Acupuncture ‘works in mice’.
So, with all this hype going on, even during a holiday weekend in the U.S. and the U.K., what does this overhyped study actually show? Are the headlines of “acupuncture works” and “scientists discover how acupuncture works” justified? Not so fast, there, pardner.
Perhaps the most infuriating aspect of all the hype is that the study being hyped actually describes a fair bit of interesting biochemistry behind the pain response. Unfortunately, what it doesn’t show is that “acupuncture works,” despite all the whining about “arrogance” from the study’s lead investigator. All it shows are two things: (1) that a chemical called adenosine is released when needles are stuck into the skin of mice and twisted and (2) that adenosine decreases the pain response. These are actually very interesting findings, albeit, as people I’ve corresponded with have pointed out to me, nothing new at all. Contrary to the way these results are being spun, they in now way validate the belief system behind acupuncture or show that “acupuncture works.”
Let’s get to the science in more detail, although I hate to do it by pointing out the Weekly Waluation of the Weasel Words of Woo-worthy credulous and annoying opening paragraph of the paper that reviewers should have shot down in flames but didn’t:
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.
This is yet another example of an appeal to ancient wisdom, but this time it’s coupled with argumentum ad populum, better known as the appeal to popularity. I never thought I’d see the introduction to a scientific article appeal to, much less mention, the fact that the IRS allows a modality to be a deductible medical expense, but here it is. Where the hell were the reviewers? I could equally point out that the IRS allows medical deductions for the services of Christian Science prayer healers. Does that mean that Christian Science prayer is an effective treatment for anything? No, it does not. Add to that the whole false dichotomy between “Western” and “Eastern” medicine (yes, I know I mentioned it at the beginning of this post), a particularly odious and borderline racist construct in which the mythical “East” is represented as more “wholistic” and “spiritual” compared to the “reductionistic” and scientific brand of medicine. True, in the second paragraph, Nedergaard does mention the possibility of the release of opiod receptors, but there is zero discussion of the evidence for and against acupuncture, not even much of an acknowledgment other than that nasty “Western medicine” being so nastily “skeptical” of the practice, as though that were a bad thing.
The model used by Nedergaard is a model of inflammation that involves injecting complete Freund’s adjuvant (CFA) into the mice’s paws. As a result, the mice’s paws would become inflamed by the irritant properties of the CFA and thus more sensitive to innocuous stimuli, with a decreased latency period for withdrawal to painful or innocuous stimuli; in other words, the mice’s paws would be more sensitive, and the mice would react more strongly and rapidly to the stimuli of heat or touching. This sensitivity peaked at day four or five and then decreased. As a preliminary experiment, the investigators noted that, after the insertion of acupuncture needles into the mouse limb at the “Zusanli point,” which is located near the knee a microdialysis probe inserted less than a millimeter away registered a spike in extracellular adenosine levels, as well as ATP (which is broken down to adenosine outside of the cells), ADP, and AMP, that peaked at around 30 minutes.
Having established that adenosine was increased within 30 minutes of an acupuncture stimulus, Nedergaard then injected an chemical that binds to the cell receptor activated by adenosine, the A1 receptor agonist, 2-chloro-N(6)-cyclopentyladenosine (CCPA). Injecting CCPA into the Zusanli point greatly improved touch sensitivity and in essence reversed the increased sensitivity to heat. So far, so good. Apparently in the mouse adenosine has a lot to do with modulating pain response in peripheral nerves, and apparently a fair number of pharmaceutical companies are interested in developing adenosine agonists to take advantage of this effect in humans. Even better, this effect was not observed in mice genetically engineered not to make the adenosine A1 receptor, known as A1 receptor knockout mice, strong evidence that it was the A1 receptor that was responsible for the observed blunting of the pain response. Investigators also tested CCPA in a model of neuropathic pain (pain due to nerve dysfunction) and found it worked as well as it did in their model of inflammatory pain.
So what’s the link to acupuncture? Actually, that’s what I was wondering myself. Up until now, this paper was a fairly straightforward neuroscience paper looking at some interesting results. However, I doubt this paper would have gotten into Nature Neuroscience if all the investigators did was to show that a bit of local inflammation resulted in the secretion of adenosine into the extracellular fluid and then showed that that adenosine blunted the pain response in nearby nerve endings. That would have been much less interesting, because there is already a fair amount of literature implicating the A1 receptor as a target for the relief of neuropathic pain. But add the acupuncture to it, and you sex it up and get a paper into a high impact journal, which is apparently what happened here.
The unfortunate “bait and switch” of this paper is that it failed to mention that the Zusanli acupuncture point that the investigators used, apparently to the exclusion of all others, is not actually a leg or a pain acupuncture point. Although it is located on the leg, just inferior and lateral to the knee, the Zusanli point is described among traditional Chinese medicine (TCM) practitioners as the leg portion of the stomach meridian. According to TCM, this point is also known as Stomach-36 and its current indications are:
The current standard indications for zusanli, as reviewed in Advanced Textbook of Traditional Chinese Medicine and Pharmacology (21) are: stomach ache, abdominal distention, vomiting, diarrhea, dysentery, indigestion, appendicitis, flaccidity and numbness of the lower limbs, edema, mastitis, mania, epilepsy, cough, vertigo, palpitation, and emaciation due to consumptive disease. This latter indication corresponds to the concept that needling this point can tonify the sea of qi and thereby help to stop the wasting disease and restore ones body weight and vitality.
To illustrate the uniformity of indications amongst the Chinese authorities, the following were listed in Chinese Acupuncture and Moxibustion (22, 23), with slight differences on translation between the original Chinese and later Western publications: gastric pain, hiccup, abdominal distention, vomiting, diarrhea, dysentery, emaciation due to general deficiency, constipation, mastitis, intestinal abscess (acute appendicitis), numbness (motor impairment) and pain of the lower extremities, edema (beriberi), manic depressive psychosis.
Thus, according to acupuncturists, most associated with stomach and abdominal problems far more than lower extremity pain. Strange that the investigators didn’t mention that. I must say, though, it’s such a multipurpose acupuncture point, that I suppose I can’t harp on the investigators too much for using it for this indication, although I can’t help but note that the point seems mighty close on the mouse to where the sciatic nerve divides in the leg.
Be that as it may, here’s a concise summary of what the investigators found:
- In normal mice of adenosine, acupuncture reduced discomfort by two-thirds.
- In A1 receptor knockout mice, acupuncture had no effect on the reactions of the mice to the stimuli of touch or heat.
- During and after an acupuncture treatment, adenosine levels in the tissues near the needles was 24 times greater than before the treatment.
- Deoxycoformycin, a drug that inhibits the removal of adenosine by the tissues, increased the length of time that the adenosine remained in the tissues (surprise! surprise! given its known mechanism of action) but also appeared to increase the length of time that acupuncture treatment was effective.
- In mice who had acupuncture but in which the needle wasn’t rotated every five mintues, acupuncture had no effect.
So what does this all mean? First of all, this study is actually interesting for its implications for adenosine as a mediator of both inflammatory and neuropathic pain. I can’t fault its methodology, at least as far as it implicates the adenosine A1 receptor as a mediator of neuropathic and inflammatory pain in the lower extremity. It’s pretty clear in supporting the conclusion that mimicking the action of adenosine or somehow increasing its local concentration around a nerve might be a good strategy for relieving pain in humans. But do the results of this study actually support the efficacy of acupuncture, as Nedergaard claims?
Not so fast, there again, pardner.
This study actually says very little about acupuncture. What this study shows is that sticking needles in mice causes adenosine production and that that adenosine can blunt the pain response in nerves by binding to the A1 receptor. Nothing more. That’s all well and good, but it doesn’t validate acupuncture. The only thing in common with acupuncture in this study is the needle sticking part, and the investigators might as well conclude that this study validates ear piercing for pain relief. (Egads! Battlefield acupuncture strikes back!) So, it’s quite possible that needles twisted in the area near a nerve might release a flood of adenosine that might bind to A1 receptors in nearby neurons and blunt the pain sensation. No “meridians” or qi is needed to explain that. Moreover, this study notwithstanding, Nedergaard seems at a loss to explain how her results might be reconciled with numerous studies in humans that show clearly that (1) it does not matter where you stick the needles and (2) it doesn’t even matter if the needles are stuck through the skin. As I’ve pointed out before, just twisting the end of a toothpick against the skin produces the same effect as acupuncture. She does, however, give it the old college try to explain this result, although she does so using the hated term “allopathic” to describe “Western” medicine:
One may speculate that other non-allopathic treatments of chronic pain, such as chiropractic manipulations and massage, modalities that involve the mechanical manipulation of joints and muscles, might also be associated with an efflux of cytosolic ATP that is sufficient to elevate extracellular adenosine. As in acupuncture, adenosine may accumulate during these treatments and dampen pain in part by the activation of A1 receptors on sensory afferents of ascending nerve tracks. Notably, needle penetration has been reported to not confer an analgesic advantage over nonpenetrating (placebo) needle application, as opposed to our observations (Supplementary Figs. 2 and 3) and those of others. However, it is possible that ATP release from keratinocytes in response to mechanical stimulation of the skin results in an accumulation of adenosine that transiently reduces pain, as A1 receptors are probably expressed by nociceptive axon terminal in epidermis. In fact, vibratory stimulation applied to the skin depressed the activity of nociceptive neurons in the lower lumbar segments of cats by release of adenosine. However, this effect differs from the anti-nociceptive effect of acupuncture, which does not depend on the afferent innervation of the skin. Acupuncture 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 pure speculation without any compelling evidence, no more convincing than saying that rubbing a boo-boo makes it feel better, which is in essence what she’s saying. Worse, her speculations would also have been easy enough to test, given that she had the experimental model up and apparently running smoothly. Contrary to her implication, Supplemental Figures 2 and 3 do not refute the results showing that non-penetrating acupuncture works as well as penetrating acupuncture. In Figure S2, all that is shown is that using acupuncture at the Zusanli point on the contralateral leg doesn’t affect the reaction of ipsilateral leg receiving the acupuncture. All Figure S3 shows is that failing to rotate the needle results in loss of the analgesic effect. Neither refute findings in humans that non-penetrating acupuncture “works” just as well as penetrating acupuncture, where the needles are inserted to the “correct” points. Absent evidence from the current study showing that stimulating the skin results in the release of adenosine and subsequent blunting of the pain response in the extremities of these mice, Nedergaard would have been better off leaving this entire paragraph out of the paper. Moreover, contrary to the claim that “merdians” map to ascending nerve tracts is stretching it a bit, if you look at these maps. For instance, the kidney, stomach, and spleen acupuncture points line up somewhat with nerves at certain points in the body but are nowhere near ascending nerves in other parts.
Finally, there are two remaining huge problems with this paper. Here’s the second biggest first. Mice are much, much smaller than humans. The Zusanli point in a mouse is going to be within a couple of millimeters of the sciatic nerve or one of its major branches. In the human, it’s going to be at least a couple of centimeters away, possibly considerably further. In the mouse, the size of the needle relative to the size of the leg and distance from the sciatic nerve, as well as the nerve’s branches, the tibial and peroneal nerves, is going to be very close. The tissue damage, virtually no matter where the needle is stuck, is going to be close to these nerves. In humans, this is unlikely to be the case, particularly since the nerves are much further beneath the skin than they are in mice; that is, unless we want to start scaling things up and sticking nails into people’s knees. Thus, there is no good reason to think that these results will be unlikely to translate easily to humans.
What really bugs me about this article, though, is that it’s actually pretty cool science, for the most part. It’s not as new as I thought it was before some of my readers corresponded with me and I did a few PubMed searches, but in general its conclusions about the role of the A1 receptor and local adenosine release in response to tissue trauma seem sound. These guys have found something that may even have a potential clinical application. For instance, they found that local injection of A1 receptor agonists works the same as the “acupuncture” and that adding compounds that slow the removal of adenosine from the tissues improves the efficacy of the adenosine released into the tissues by minor trauma. Scientists can work with that. Scientists could take these observations and use them as the scientific justification to work on better, more specific, and longer acting A1 agonists. Perhaps they could even develop oral drugs that are broken down into adenosine or A1 receptor agonists in the peripheral tissues. If this paper’s conclusions regarding the importance of adenosine in pain signaling are correct, these would represent stragies that could very well work and very well improve pain control. One could even envision implantable pellets that could be placed in wounds or near relevant nerves to release A1 receptor agonists right where they’re needed over a long period of time.
Unfortunately, Nedergaard and her team are too enamored of the woo that is acupuncture to emphasize the true significance and potential usefulness of their findings. Worse, they were rewarded for their infatuation with acupuncture with not just a paper in a high impact neuroscience journal but with all sorts of publicity around the world. Instead of working to turn these observations into usable therapies, now Nedergaard and her collaborators will likely use their preliminary data to apply to NCCAM for a grant to study adenosine in acupuncture further, rather than pursuing this observation in a manner far more likely to lead to a clinical benefit in human beings. So much the pity. Woo poisons the real science it touches.
Finally, when you see aficionados of acupuncture cite this paper as “evidence” that acupuncture “works,” remember this: This study says absolutely nothing at all about all the other myriad claimed benefits of acupuncture in fertility treatments, headache, or hot flashes after menopause, to name a few. Sadly, it doesn’t even say that much about the use of acupuncture for chronic pain.
Goldman, N., Chen, M., Fujita, T., Xu, Q., Peng, W., Liu, W., Jensen, T., Pei, Y., Wang, F., Han, X., Chen, J., Schnermann, J., Takano, T., Bekar, L., Tieu, K., & Nedergaard, M. (2010). Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture Nature Neuroscience DOI: 10.1038/nn.2562
- Acupuncture Works, Say Scientists
- A biological basis for acupuncture, or more evidence for a placebo effect?. (In this post, Ed Yong notes that one of the coauthors of this paper, Jurgen Schnermann, is married to Dr. Josephine Briggs. Dr. Briggs is the director of the National Center for Complementary and Alternative Medicine.
- Why was a study on ‘acupuncture’ reported so badly?
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