Respectful Insolence

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. I wrote about one of them just last week. It was a study that purported to show that acupuncture is a useful modality for reducing breathlessness and air hunger in patients with chronic obstructive pulmonary disease (COPD). As you might also recall, I found it underwhelming. I also recently became aware of a study that I just had to write about because it builds on the results of a study I wrote about two years ago that I characterized at the time as an interesting study whose authors seemed almost willfully to misinterpret their results. This one, thankfully, is not nearly as hyped as the study from two years ago, but it is very instructive how the original misinterpreted story is leading to a classic CAM “bait and switch” applied to acupuncture. Normally, we like it when science builds upon previous results, but it’s not so great when a scientists “builds” upon an inappropriate interpretation of a study designed to legitimize quackery. Before I get to the present study, first let’s look at the original study that inspired this followup.

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 an arrow or 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, that is exactly what they do. It’s a reasonable idea, 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 [13]. 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) [16]. hPAP injections thus provide a novel way to generate a short-acting compound over a sustained time period [17].

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 brazenness 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 [2]. 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 or sciatic nerve 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.

Comments

  1. #1 MikeMa
    May 21, 2012

    Hurt and Zylka apparently found something potentially useful while trying to defend acupuncture. These sort of accidental leaps happen all the time in science. Looking for X, found (very cool) Y instead.

    The naming thing is unfortunate. Maybe it could be said they named it after their acupuncture inspiration, as an honorific, foolish as it might be? Depending on Aerial BioPharma’s marketing, the name will almost certainly be switched.

  2. #2 Calli Arcale
    May 21, 2012

    If anything involving needle insertion is a form of acupuncture, why don’t they just go all the way and claim spinal blocks as acupuncture? Seriously. It would make as much sense. I predict that this study will be touted as proof of acupuncture, and the anesthetic properties actually discovered will be forgotten.

  3. #3 Todd W.
    May 21, 2012

    Apart from PAPupuncture creating an inappropriate tie to acupuncture, it also brings to mind the unfortunate image of combining acupuncture with pap smears. I can’t imagine that it would make things any more comfortable for women.

  4. #4 Militant Agnostic
    May 21, 2012

    Aerial BioPharma sounds like they must be the company behind the “chemtrails”.

  5. #5 Denice Walter
    May 21, 2012

    Oh lord! This is what happens when you get to be over 50: you can remember when being science based was considered to be an _advantage_ in marketting- here we have a reasonable procedure falsely labelled as woo in order to make it more attractive to consumers!

    This causes me to speculate about what they will think of NEXT :
    calling real surgery *psychic* surgery
    calling vaccines *homeopathic immunity-stimulators*
    calling sedatives and anti-anxiotics *meditation substitutes*
    perhaps *in vitro* might be *concentrating the life force*
    any sort of diagnostic imaging may become *machine assisted aura reading*
    pharma products like pain meds would be *Nirvana producers*
    ED drugs will be *lingam assists*
    CPR would be *astral plane termination*
    HRT would be *Gaia empowering agents*
    caffeine is *Xi in a cup*
    and so on.

  6. #6 Shay
    May 21, 2012

    Todd@3

    it also brings to mind the unfortunate image of combining acupuncture with pap smears

    Part of me just winced.

  7. #7 Mu
    May 21, 2012

    Which is why I thought pap block isn’t helping much either.

  8. #8 sceptinurse
    May 21, 2012

    At Todd.

    My first reaction to the title was “What, they’re combining acupuncture and and pap smears now? Ow.”

  9. #9 Elizabeth
    May 21, 2012

    sceptinurse – I had the same first thought! My second thought was, “Ew, I don’t want a needle jammed in my cervix.”

    The East vs. West thing is a bit silly to me as well. Racist, yes, culturally insensitive, yes. And out of context.

    From what I’ve read and talks with folks from China (small sample, I’ll admit), a lot of this stuff is practiced along with modern medicine by physicians. Not some quack who did a correspondence course in crystals and enemas, but doctors who went to excellent medical schools. “Eastern medicine” is not practiced as a substitute for that which is modern (which a lot of alt. health folks push), and modern tends to trump traditional. But there are situations where the traditional seems to work and is quite a bit more affordable to folks than the latest drug by Pfizer, and thus it is utilized.

    I was once told a story by a teacher who worked in a hospital in London. He was speaking with a physician from Africa, and he asked the gentleman what he would suggest to psychiatric patients in rural areas. The doctor listed off herbs indigenous to a few different countries. My teacher, not realizing he was speaking to a medical doctor versus a shaman, was a bit astounded and asked why he would eschew modern drug treatments. The physician replied that while he went to Harvard Medical School, there are people in parts of the world who simply cannot afford modern medications and sometimes you just make do with what you have. Does it necessarily work as well? No, but sometimes it beats stuff like psychosis.

    There are “natural” drugs that work, are FDA approved, and continue to be utilized (lithium carbonate is my favorite example). I’ve noticed that people don’t notice that the medical community just goes with what seems to have data to back it up and has benefits that outweigh risks, regardless of cost – because hey, doctors don’t like folks to die. The lack of understanding why societies in the past used herbal and body work treatments and why some still do is obnoxious and ignorant, and the notion of one big conspiracy theory to rake in dollars for rich doctors and pharmaceutical companies (never mind the large industry that is alt. health) is absurd.

  10. #10 demandabanana
    May 21, 2012

    Count me among the pap-smear-and-acupuncture confused. The punchline certainly caught me by surprise!

  11. #11 Phoenix Woman
    May 21, 2012

    Elizabeth @ 9 — Mao Tse-Tung in the 1950s pretty much invented “Traditional Chinese Medicine” — much if not most of which is useless if not outright dangerous — precisely because he felt actual, science-based medicine was too expensive to propagate on a large scale in China. (And probably also, like the emperors before him, because he figured China had too many people anyway and it wouldn’t hurt to lose a few tens of millions to keep from swamping the carrying capacity of the arable land.)

  12. #12 bad poet
    May 21, 2012

    Colposcopy. Ouch!
    PAPupuncture sCAMmers…
    Tired of these fraudsters.

    Had to say it, even if it doesn’t make it.

  13. #13 Noadi
    May 21, 2012

    There is still one way beyond placebo that acupuncture works for pain but it’s of course still a matter of subjective experience (and really with pain you can change your subjective experience drastically, just pick your preferred method). Have you ever been in pain and then something mildly painful or just irritating completely distracts you from the pain? Our brains tend to prioritize new sensations over older ones because we tend to not be able to focus on too many at once (like running your hand up and down your arm, you feel most of the sensation either in your hand or your arm, not both equally). This of course is a pretty good argument against actually sticking needles in someone when there are plenty of sensations available that don’t involve breaking skin and it’s only a very temporary measure, the effect doesn’t last long but may be of use to help a patient cope in situations where pain relief can’t be given immediately.

  14. #14 Michelle
    May 21, 2012

    Noadi @15 – someone correct me but isn’t that what TENS basically does? And no needles involved!

  15. #15 Stu
    May 23, 2012

    Noadi: so tickle them. Much cheaper and safer.

  16. #16 Leigh Jackson
    May 23, 2012

    Hurt and Zylka found that stimulated needling of the Weizhong acupuncture point acts as a pain killer in mice for about an hour for acute and chronic pain.

    Injection of prostatic acid phosphatase into the same space behind the knee – the politeal fossa – gave pain relief for six days.

    Traditional acupuncturists tell their patients that the needles stimulate the flow of energy at the acupuncture points. On the basis of this study what they ought to be telling patients is that the needles may be stimulating the production of pain relieving chemicals when they are positioned close – but not too close – to nerve bundles. Far from enabling a magical flow of energy, the needles encourage the chemical blocking of pain signals – very briefly.

    However, this test on twenty mice was carried out by a single person. No controls or blinding. Too early to say anything really.

    The authors are implicitly defining “acupuncture” to be nothing more and nothing less than simply sticking needles into parts of the body close to the peripheral nervous system. Since they detected a temporary pain killing effect from this they are giving acupuncture – as just defined – some credit. Fair enough, but to describe what they are doing as a combining acupuncture and western medicine is bull manure.

    PAPupuncture is all PAP and no acupuncture. All the mechanisms of scientific medicine are employed; none of acupuncture’s. A syringe is more than a needle. It’s not the puncture that matters. It’s what’s in the needle that counts.

    A syringe delivering molecules which will act on other molecules to block the action of pain producing molecules contains not a single mechanism of acupuncture. Acupuncture’s only other possible mechanism, the stimulation of the needles, is rendered redundant by PAP. Nor need PAP injections be limited to acupuncture points. Any point local to the pain and close to the peripheral nervous system will do. Acupuncture points as such become redundant.

    PAPupuncture, if it should work, sounds the death knell of acupuncture for pain. PAPupuncture would be good old scientific medicine with a ridiculous name.

  17. #17 BKsea
    May 25, 2012

    On a similar topic, I just opened the June issue of the magazine from Science Blogs new overlords. There is a lovely article about a rat study of accupuncture that proves how accupuncture works, complete with a picture of all the accupuncture points for rats. Really sad. Not a good sign for the new administration.