PAPupuncture? On the rebranding of regional anesthesia as acupuncture

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.