May 21 2012
Acupuncture has been a frequent topic on this blog because, of all the “complementary and alternative medicine” (CAM) modalities out there, it’s arguably the one that most people accept as potentially having some validity. The rationale behind acupuncture is, as we have explained many times before, little different than the rationale behind any “energy healing” method (like reiki, for example) in that it claims to redirect the flow of “life energy” (the ever-invoked qi). The only difference is that acupuncturists claim to bring this therapeutic qi rearrangement about by sticking thin needles into the pathways in the body through which this qi is fantasized to flow. These pathways, called meridians, are just as much a fantasy as qi itself or the “universal source” that reiki masters claim to be able to channel through themselves and into believers. Contributing to the popularity of acupuncture is its mythology as having been routinely practiced for over two thousand years, a myth that was the 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).
In addition, because acupuncture involves sticking actual metal objects into the skin rather than simply laying on hands or making magical gestures over the patient, it retains some credibility, even among doctors. It doesn’t matter that, reviewing the totality of the research, one finds that it doesn’t matter where you stick the needles or even if you stick the needles in the skin. The results are the same and indistinguishable from placebo. The inescapable conclusion is that acupuncture is placebo medicine with needles. Personally, I’d prefer my placebo medicine without needles, but that’s just me.
Yet, the studies keep rolling in, trying desperately to demonstrate that acupuncture works or assuming that acupuncture works . Two more popped up within the last couple of weeks, and one of them, if you read the press releases, sounds really convincing. As is frequently the case, for this latter study, there is less to it than meets the eye. I’ll start, however, with a study that is a followup to a study I blogged about a couple of years ago that I characterized as another overhyped acupuncture study misinterpreted. This one, thankfully, is not nearly as hyped as the study from two years ago—or as the second study I will discussed, but it is very instructive how the original misinterpreted story is leading to a classic CAM “bait and switch” applied to acupuncture.
Adenosine. It had to be adenosine.
Two years ago, I came across a study that claimed to have found the mechanism by which acupuncture “works.” It made quite the splash, having been published, as it was, in a high profile journal, Nature Neuroscience. It was an animal study using mice in which acupuncture was tested in a model of inflammation that involves injecting complete Freund’s adjuvant into the mice’s paws. As a result, the mice’s paws become inflamed by the irritant properties of the CFA and thus more sensitive to innocuous stimuli. This results in a measurably decreased latency period for withdrawal to painful or innocuous stimuli. To boil the test down to its essence, after CFA injection, the mice’s paws would be more sensitive, and the mice would react more strongly and rapidly to stimuli of heat or touching. The complete discussion by yours truly can be found here, but the CliffsNotes version is that the authors noticed a peak of adenosine after acupuncture and did some work that suggested that adenosine mediated the “effects” of acupuncture. As I put it at the time, I doubt this paper would have gotten into Nature Neuroscience if all the investigators did was to show that a bit of local inflammation (i.e., sticking acupuncture needles into the mouse’s limb at one of the “correct” acupuncture points) 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 adenosine A1 receptor as a target for the relief of neuropathic pain. Acupuncture sexed up the findings.
Fast forward two years.
Now we’re faced with the offspring of an interesting, but largely irrelevant, observation about the adenosine A1 receptor in acupuncture. This comes from a different research group than those who published the original A1 paper, a group at the University of North Carolina. Its authors, Julie Hurt and Mark Zylka, have made what I consider to be a rather…interesting decision with regards to how they spin their results. Let me just put it this way, even though this new paper didn’t appear in Nature Neuroscience but rather in an open-access journal called Molecular Pain, what Hurt and Zylka did is the same as what was done in the previous group, but on steroids. It is a classic bait and switch. Think of it this way. When I wrote about the previous results, which showed that locally released adenosine appears to block pain transmission through local nerves, I pointed out that that might well turn into a useful strategy to alleviate pain, if a way could be found to generate adenosine where you want it and when you want it. The problem with adenosine is that its half life is pretty short; so just injecting adenosine into the local area would not be nearly as useful as just injecting local anesthetic into the area. No acupuncture is necessary. Indeed, I rather suspected that the only reason acupuncture “worked” in the original study to generate measurable quantities of adenosine locally is because thin needles stuck into a mouse limb are like sticking a spear through a human leg, proportionally speaking. Unlike the case in humans, the needle is never far from a major nerve bundle, and the local trauma is much more as a fraction of the limb area.
So what do Hurt and Zylka do with this previous result? Do they propose a strategy for generating adenosine near local nerves? Yes, indeed, they do, and it appears, for the most part, to work, at least in this model. What do they call this proposed therapy? The title of their article says it all: PAPupuncture has localized and long-lasting antinociceptive effects in mouse models of acute and chronic pain. Why PAPupuncture? Here’s why, as described in the introduction:
We previously found that the transmembrane isoform of prostatic acid phosphatase (PAP) functions as an ectonucleotidase and hydrolyzes extracellular AMP to adenosine in nociceptive dorsal root ganglia neurons [10,11]. PAP is expressed in several other tissues, including skeletal muscle that surrounds the Zusanli acupuncture point, and could be the rate limiting ectonucleotidase at this location [9,12]. PAP is a very stable enzyme when administered in vivo, with an 11.7 d half-life in blood . Likewise, we found that intrathecal injection of a secretory version of human PAP (hPAP) had long-lasting (3 days), A1R-dependent antinociceptive effects in pre-clinical models of inflammatory pain and neuropathic pain [10,14]. These long-lasting antinociceptive effects could be transiently blocked with a short-acting A1R antagonist, providing strong evidence that hPAP remains in tissue for days [10,15]. In contrast, adenosine has a very short half-life in blood (a few seconds) . hPAP injections thus provide a novel way to generate a short-acting compound over a sustained time period .
So, basically, what PAPupuncture is, according to Hurt and Zylka, is injecting an enzyme near the nerves that breaks down AMP in the extracellular fluid into…drumroll, please…adenosine! To see the the blatantness of this bait-and-switch going on here, I can’t resist pointing out that the authors themselves write:
Essentially all acupuncture points are located in muscle and are in close proximity to peripheral nerves . The axons of nociceptive (“pain-sensing”) neurons course through peripheral nerves [3-5]. This proximity of acupuncture points to nociceptive afferents could explain why acupuncture is modestly effective at treating pain in humans [1,6-8].
So, let me see. If Hurt and Zylka are correct, acupuncture is a very inefficient method of “generating local inflammation” near peripheral nerves (i.e., sticking tiny needles into points not related to peripheral nerves by anatomy other than by sheer coincidence). In other words, it’s useless, even by their criteria. So what do they do? They turn it into regional anesthesia but still call it a variant of “acupuncture.” In fact, all Hurt and Zylka have done is to inject an enzyme that turns a substrate into adenosine in the local area. They even injected it into the popliteal fossa (in humans, the area right behind the knee), noting blithely that “clinicians inject local anesthetics into this same location for regional anesthesia.” No kidding. Anesthesiologists and surgeons do inject local anesthetic right there. It’s called a popliteal block or sciatic nerve block. A popliteal block can anesthetize the leg from the knee down without the need for a spinal or epidural anesthetic, making it useful for procedures involving the foot and ankle.
So what did this study find? Basically, it found that injecting PAP into the popliteal fossa relieved pain for up to three days in different models of pain; that there was a dose-response effect in which injecting more PAP resulted in more pain relief; and that adding more substrate (i.e., AMP, the starting material that PAP converts to adenosine) also increases the response and duration of the pain relief. It’s all fairly straightforward, and there’s nothing really glaringly wrong with the experimental design, which is basically all designed to determine the parameters under which this technique works. It’s also a potentially useful technique in that adenosine doesn’t affect motor nerve function (blocks targeted at nerves with motor and sensory components can result in temporary paralysis distal to the injection site) and that the enzyme can generate adenosine for a prolonged period of time. This latter aspect of the technique would be useful because prolonged analgesia from nerve blocks can require catheters to keep injecting local anesthetic.
None of this is surprising, and it all might actually be useful, but acupuncture it ain’t, not by any stretch of the imagination, which makes the authors’ insistence on calling this technique “PAPupuncture” puzzling indeed. A far better name would be something like a “PAP block” or just a nerve block using PAP. Similarly the insistence on using acupuncture point nomenclature is not justified either. Why not simply call it a different form of popliteal fossa block instead of “PAPupuncture”?
The discussion might give us a clue:
Clinicians inject local anesthetics into the popliteal fossa to treat pain following foot and ankle surgery. However, this regional anesthesia procedure requires catheterization to block pain for more than a day [21,30]. Local nerve blocks are administered at many other locations of the body to regionally treat pain. While our work was focused on the popliteal fossa, PAPupuncture could in principle be performed in any body region where acupuncture and nerve blocks are performed and has the potential to reduce pain for a significantly longer period of time. Given that PAP works via an A1R-dependent mechanism, PAPupuncture would also bypass side-effects associated with opioid-based analgesics, and hence could provide a novel abuse-resistant way to treat pain. Ultimately, our study reveals that key mechanisms associated with Eastern and Western medicine can be merged and exploited to locally inhibit acute and chronic pain for an extended period of time.
This is all, of course, utter nonsense. What Zylka has done is interesting from a scientific standpoint. It might turn out to be useful in humans. It might even turn out to be better than existing strategies for peripheral nerve blocks when long-lasting analgesia is needed. It is not, however, acupuncture, which makes Zylka’s insistence on calling it “PAPupuncture” the purest form of bait-and switch. His experiment was a good example of scientific medicine, a preclinical “proof-of-principle” animal experiment that could just as easily have been done without a single mention of acupuncture because acupuncture has nothing to do with it. It is not a merging of “key mechanisms associated with Eastern and Western medicine.” In fact, the reviewers who approved this paper need to be taken to task for falling for the false CAM meme that there is “Western” medicine, which is always portrayed as scientific medicine, and “Eastern” medicine, which is always portrayed as more mystical and “wholistic.” Personally, I find the whole construct not-so-subtly racist, and if I were Asian I’d be offended by having “Eastern” medicine associated with quackery based on mystical pre-scientific ideas. Everything else Zylka does appears to be rigidly science-based. So why does he muddy it up by associating it with woo like acupuncture, which is based on prescientific, vitalistic beliefs?
In fact, so little does this have to do with acupuncture that pharma is interested. According to the press release from UNC:
The next step for PAP will be refining the protein for use in human trials. UNC has licensed the use of PAP for pain treatment to Aerial BioPharma, a Morrisville, N.C.-based biopharmaceutical company.
Finally, what makes this more of a bait-and-switch is that acupuncturists don’t just claim that acupuncture can be used as a form of local or regional anesthesia. They claim it is good for nearly everything that ails you, be it infertility, asthma, chronic back pain, and any of a whole host of aches, pains, conditions, diseases and maladies. Calling regional anesthesia with PAP “PAPupuncture” is nothing more than a ploy to suggest that acupuncture works, when PAPupuncture is not acupuncture. It’s all about marketing, not science.
Speaking of other diseases and conditions, let’s look at our second study.
Acupuncture for COPD
The second acupuncture study being touted in the press recently was a lot more highly touted. I suspect that the reason for this is that it claims to provide relief for a condition that, given the number of people who smoke, is very, very common, namely chronic obstructive pulmonary disease (COPD). More importantly, the story doesn’t involve explaining things like an adenosine receptor, using an enzyme to generate adenosine in the tissues, and other scientific details that bog down the story. This other study is much simpler to explain, and try to explain it several journalists did, with a distinct lack of skepticism:
- Acupuncture May Help Ease Symptoms of COPD
- Acupuncture May Be Worth a Shot for COPD: Small Study Shows Acupuncture May Help People With COPD Breathe Easier
These news stories refer to a study from Japan by Suzuki et al published online a week ago in the Archives of Internal Medicine entitled A Randomized, Placebo-Controlled Trial of Acupuncture in Patients With Chronic Obstructive Pulmonary Disease (COPD): The COPD-Acupuncture Trial (CAT). It is just what it sounds like: A test of acupuncture on COPD. First, let’s see what these news stories say about it, beginning with U.S. News and World Report:
For patients with chronic obstructive pulmonary disease (COPD), acupuncture may help relieve shortness of breath during activity, Japanese researchers suggest.
COPD is a progressive lung condition that makes it hard to breathe; it is commonly caused by smoking or exposure to other toxins.
“The effects of acupuncture are large,” said Dr. George Lewith, from the University of Southampton in Hampshire, England, co-author of an editorial accompanying the study. “This is particularly remarkable in a condition that seems largely unresponsive to more conventional treatments.”
And WebMD, whose writers should know better but apparently do not:
Exactly how acupuncture improves symptoms of COPD is not fully understood. Researchers speculate that needling the acupuncture points on the rib cage area may help relax muscles involved in breathing.
This makes perfect sense to Tong-Joo Gan, MD. He is a professor of anesthesiology at Duke University Medical Center in Durham, N.C. It also may help reduce anxiety levels, he says. “When you become breathless, your anxiety goes up, so relaxation is another possible explanation for the benefit.”
Acupuncture has been shown to release chemicals that relax the lungs and dilate the airways, he says.
“Clearly it looks like a viable alternative to treat chronic COPD,” Gan says. “The downside is so little and the upside is so huge that acupuncture is well worth a try for those who find it difficult to control their COPD despite medications.”
Wow! If this study is any indication, acupuncture is the greatest thing since sliced bread, at least for COPD. I’d also be interested in seeing the studies that claim that acupuncture “releases chemicals that relax the lungs and dilate the airways.” I wonder if she meant this study, which looked at acupuncture with electrical stimulation (which is not acupuncture but TENS) and appeared to find an elevation in endorphin levels. Be that as it may, if you believe the hype machine that revved up to promote this study, just as it does for any seemingly “positive” acupuncture study, you’d think acupuncture is the greatest thing since sliced bread for COPD. But is it right this time? Is this study really good evidence that acupuncture “works” for COPD? Not so fast, there, pardner. The study, despite the breathless descriptions of it popping up in the press yesterday, is—shall we say?—underwhelming.
The study itself is fairly straightforward in that it is a randomized study of patients with chronic obstructive pulmonary disease (i.e., COPD) treated with standard therapy plus either “real” acupuncture or sham acupuncture. In this case, the sham acupuncture consisted of needles that didn’t puncture the skin rather than needling the “wrong” acupuncture points. The device used was a Park sham device, which comprises a needle (real or blunt-tipped placebo) with a guide tube. The blunt needles appear to penetrate the skin but actually telescope back into the tube. The primary endpoint measured was breathlessness as measured by an instrument called the modified Borg scale after a test known as the six-minute walk test. The modified Borg scale measures from 0 (no breathlessness) to 10 (maximal). They also measured lung functions. Acupuncture treatments (sham or “real”) were administered once a week for twelve weeks, and the acupuncture points chosen were as shown below:
After twelve weeks of sham acupuncture or “real” acupuncture, the placebo acupuncture group (PAG) and real acupuncture group (RAG) were compared for various measurements after the six minute walk test. Again, the primary outcome measured was the modified Borg scale, which is a subjective measurement of breathlessness, with a whole bunch of other secondary endpoints. Whenever I see such a large number of endpoints, I wonder about whether any control was made for multiple comparisons, and, as far as I can tell from reading the methodology, there wasn’t. So what did Suzuki et al find? After randomizing 68 patients, the found a significant improvement in the Borg scale after the six minute walk test. They also reported a small improvement in oxygen saturation (86% to 89%) while FEV1 didn’t change. (The significance of FEV1 was discussed in a previous post about acupuncture and asthma.)
Many of the usual caveats with a study of this type apply. First of all, it’s a small study, and it’s very easy to have a false positive in a small study like this. I have a hard time making much of this study without replication or a larger study. Second of all—and this is the biggest flaw in the study, a flaw so large that in my mind it pretty much invalidates the study—the study was only single-blinded. The subjects were blinded to experimental group, but the researchers and acupuncturists were not. There is no good excuse for this lapse, given how many other investigators have successfully carried out double-blinded acupuncture studies. The authors simply state that “we were unable to mask the acupuncture therapists.” Again, other groups have managed to blind the acupuncturists using specially constructed needles; why couldn’t Suzuki et al?
Another thing that drove me crazy about this article was that the authors piled endpoint after endpoint into tables. About half the endpoints appeared to be statistically significantly different, but with wide confidence intervals. For example, adjusted differences between PAG and RAG in three of eight biomedical measures listed in one table (Table 5) and six of eleven physiological measures (Table 6) were not statistically significant. Others that were “statistically significant” appeared not to be particularly impressive. A lot of these measurements, such as pulmonary function tests and the like, can also be influenced by patient effort, which could easily be affected, either intentionally or unintentionally, by how much the investigators measuring ventilatory function encouraged them. In other words, what we have here is a bunch of outcome measures, subjective and objective but potentially influenced by investigators, that are not particularly impressive in a trial that is not double-blind.
Another thing that one has to remember. For a treatment that does absolutely nothing to the outcome measures being examined, at a statistical significance level of p < 0.05 (like homeopathy, for example), by random chance alone we would expect about 5% of studies to find an apparent “statistically significant” difference between treatment group and control. That’s the random noise inherent in doing research, and long ago it was somehow decided that we could tolerate a one in twenty chance in a perfectly designed study of a false positive even in the case where the treatment does nothing. Of course, it’s worse than that, as I’ve written about many times before. As John Ioannidis has taught us, because no clinical trial is designed and executed flawlessly and because there are always biases and imperfections in any clinical trial, the number of false positive trials for something like homeopathy (which, being water, does absolutely nothing) will actually be considerably higher than 5%. That’s why one has to fall back on the totality of the scientific literature filtered through the lens of plausibility as estimated by basic science considerations.
For COPD, the plausibility that acupuncture would be expected to have a physiological effect is slim to none. Perhaps it’s not as close to “none” as homeopathy is (acupuncture does, after all, involve sticking needles into the body and it’s just barely plausible that that might do something), but it’s pretty darned low, particularly considering the vitalistic ideas that underlie acupuncture. Thus, filtering this study through the considerations of prior probability, the lack of double blinding, and the lack of controlling for multiple comparisons, and I am profoundly underwhelmed. That doesn’t even take into account the fact that I don’t see any evidence that the data were analyzed in a strict intent-to-treat analysis, in which all the endpoints were chosen before the study was undertaken and included in its design from the beginning. There were drop-outs in both groups, but in the RAG group three dropped out because they suffered acute exacerbation due to a respiratory infection. In such a small study, that could easily have skewed the results if a strict intent-to-treat analysis weren’t used.
None of this stops the authors from speculating wildly about a “mechanism” by which acupuncture can allegedly improve lung function in COPD:
We therefore speculate that a similar phenomenon is evoked in the accessory respiratory muscles by needling on the acupuncture points on the rib cage. Decreased muscle tone consequently caused the recovery of the muscle strength in the rib cage, resulting in the increased mobility in the rib cage. Relaxation of accessory respiratory muscles may also contribute to rib cage motion. In fact, the present study showed increases in maximum inspiratory mouth pressure, maximum expiratory mouth pressure, and range of motion in the rib cage at the end of acupuncture treatment.
In this study, vital capacity, FVC, percentage of FEV1, and percentage of DLCO significantly increased after acupuncture treatment. These findings suggest that acupuncture treatment might improve DOE and exercise endurance, at least to some extent, through the improvement of pulmonary function. It is not clear why acupuncture improves pulmonary function; however, we speculate that the relaxation of hyperactivated respiratory muscles and the correction of the autonomic tone might cause the beneficial effect on pulmonary function.22 Further investigations are needed to clarify this.
Go back and take a look at the acupuncture points used. Look at how few of them are actually over the ribcage. Is it the least bit plausible that a mere six needles in the ribcage could accomplish this result? I think not. In fact, I think the acupuncture apologists are doing some major contortions reaching for this “explanation.”
Finally, there is another issue to consider. This study came from Japan, and the corresponding author Dr. Masao Suzuki is listed as being affiliated with the Department of Clinical Acupuncture and Moxibustion, Meiji University of Integrative Medicine, Kyoto, Japan. As both Kimball Atwood and Steve Novella have pointed out in the past, good evidence has been reported that acupuncture studies from certain countries are significantly more likely to produce positive results, and Japan is one of those countries. True, its published studies are not as uniformly positive as those from China or Taiwan, but they appear to be significantly more likely to be positive than European studies. R. Barker Bausell discussed this very problem in his excellent book Snake Oil Science.
Given the inherent implausibility of acupuncture, combined with the large body of evidence that shows that it doesn’t matter where you stick the needles or even if you stick the needles in the skin. You get the same result, which is indistinguishable from placebo effects. For a study to overcome that large body of evidence, it has to be far more compelling than Suzuki et al. In the end, Suzuki et al is not nearly as rigorous as it has been represented and, as a result, not nearly as persuasive as acupuncture apologists would like you to think.
Acupuncture is a CAM modality that is considered part of traditional Chinese medicine (TCM), although acupuncture in its current form appears to be a phenomenon that is much more recent than it is portrayed by its supporters. In particular, it was popularized, along with the rest of TCM, by Mao as a means of giving the appearance of providing adequate health care to his people when he did not have the resources to provide them scientific medicine. Despite its roots in bloodletting, mysticism, and vitalism, acupuncture remains popular, so much so that even apparently conventional neuroscientists like Dr. Zylka take the claims of its practitioners at face value and somehow find reasons to “rebrand” acupuncture. Because acupuncture appears not to work as anything other than an elaborate placebo, it is not surprising that using PAP injections is far more effective than actual acupuncture. That is why there is no reason to “brand” PAP anesthesia as “PAPupuncture.” Yet Zylka did it anyway. Meanwhile, true believers like Suzuki (who is an acupuncturist, which is why I refer to him as a “true believer”) produce studies that on the surface appear sound but are riddled with problems when examined more closely.
No wonder, of all the CAM modalities other than supplements, people tend to think that acupuncture “works” more than any others. It is, after all, sticking needles into the skin. That’s one reason why acupuncture also makes a most excellent Trojan horse. After all, doctors stick needles into people, don’t they? So it’s easy enough for a scientist curious about acupuncture and perhaps not so well-versed in placebo effects to allow his curiosity to lead him to stick some needles into some mice, measure some adenosine levels, and then rebrand a science-based mechanism of analgesia that could be turned into a new technique of anesthesia as somehow being based on acupuncture, and the message is that acupuncture works. As that message, as unjustified as it is, spreads, by extension the idea spreads that there might just be something to all this CAM stuff.
That is how and why quackademic medicine is on the rise.
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