et tu…? Acupuncture and pain in Nature, part deux

ResearchBlogging.org
Continued from Part 1

As I was saying, a study by Goldman et al. in the July 2010 issue of Nature Neuroscience, postulates that “Adenosine A1 receptors mediate local anti-nociceptive (i.e. pain reducing) effects of acupuncture.”

I stumbled a little right at the title. Anti-nociceptive effects of acupuncture? Where is the evidence that such an effect exists?

Evidence schmevidence. I needn’t have worried, for the introductory paragraph reassured me of the benefits of acupuncture in pain management, by indicating – no… not clinical evidence, but – that (a) acupuncture has become worldwide in its practice, (b) despite Western Medicine’s skepticism, a broader worldwide population has granted it acceptance, © WHO endorses acupuncture for at least two dozen conditions, (d) the US National Institutes of Health issued a consensus statement proposing acupuncture as a therapeutic intervention for complementary medicine (now, that wouldn’t be the basis of the US NCCAM, would it?), and (e) – what the article found “most telling” – the US Internal Revenue Service approved acupuncture as a deductible medical expense in 1973.

Comforted thusly, I now proceeded to the premises of the study. Accepting a priori the analgesic effect of acupuncture (which is ‘well documented’ according to the article), the study sought to find a biological basis for that effect.

Let us examine one of the articles used by Goldman’s group to formulate their hypothesis, namely, a review article written by ZQ Zhao, titled “Neural mechanism underlying acupuncture analgesia” (Prog. Neurobiol. 85, 355-375, 2008). Zhao notes in his review that

Traditional acupuncturists remarkably emphasize ‘’needling feeling’’ in clinical practice. It seems that acupuncture analgesia is manifest only when an intricate feeling occurs in patients following manipulation of acupuncture… described as soreness, numbness, heaviness and distension in the deep tissue beneath the acupuncture point. In parallel, there is a local feeling in the acupuncturist’s fingers, the so-called ‘’De-Qi.’’ The acupuncturist feels pulling and increased resistance to further movement of the inserted needle…

In other words, dermal and subdermal tissue reacts to the presence of a foreign body, so much so that even the patient is able to feel the sensation; in fact, in a recent clinical trial studying acupuncture as adjunct therapy to proton pump inhibitors in refractory heartburn, patients were told to expect “de Qi”, described as a heavy aching sensation. Quoting other studies, Zhao goes on to indicate that since the deep tissue beneath the acupuncture points (or ‘acupoints’), including epidermis, dermis, subcutaneous tissue, muscle and tendons, were found to be richly supplied by peripheral nerves, the process of acupuncture might involve the manipulation of pain carrying Aδ and C nerve fibers. Although Zhao dismisses the effect of C fibers in the putative acupuncture analgesia, the authors of the heartburn study used the effect of tactile sensation carried through C fibers to argue against the inclusion of sham acupuncture controls in their study!

Zhao also takes note of the clinical observation that acupuncture needles inserted into the lower limbs fail to produce the ‘’de Qi’’ feeling or have any analgesic effect on the upper part of the body in paraplegic patients, and goes on to conclude that mere insertion of acupuncture needles don’t relieve pain, and deeper manipulation of the needles (rotation, electrical stimulated or heating) that results in tissue soreness in the patient is essential to produce the desired analgesia. Goldman et al. used this hypothesis to design their protocol.

Of course, Zhao also concludes from some other studies that the effect of acupuncture analgesia is highly subject to individual differences; in one study he quotes, only 5 of 11 healthy volunteers reported reduction in pain. In addition, it has been shown in patients of osteoarthritis (Pariente et al., 2005, quoted in Zhao’s review), as well as patients following dental surgery (Bausell et al., 2005), that even sham acupuncture, or for that matter, the mere expectation of receipt of acupuncture by patients or the belief that it would work produced the same level of pain reduction as that by acupuncture. So much for various neurally-mediated mechanisms of acupuncture analgesia!

Although Zhao has presented what he considers compelling evidence on a role of centrally-released endogenous opioids, such as β-endorphins and enkephalins, in the alleged analgesic effects of acupuncture, Goldman et al. in their paper disregard that possibility, noting that acupuncture has to be applied locally to the pain, or even on the same side as the pain focus.

The comparison with Tooth Fairy Science is getting stronger, then.

In the Goldman et al. study, induction of pain in a mouse model was achieved in two ways:

  • Neuropathic pain: Induced by ligation of the right leg sciatic nerve in anesthetized mice.
  • Inflammatory pain: Induced by injection of Complete Freund’s Adjuvent (which would cause painful peripheral inflammation) in the plantar surface of the right hind paw of mice. As a control, the study used injection of an equal amount of physiological saline (which should not cause any inflammation) in the left hind paw.

Effect of the inflammatory pain was assessed by two techniques. Once the paw was inflamed, the mouse became more sensitive to –

  • Mechanical allodynia (pain induced by agressive use of a normally-painful stimulus): Evaluated using repeated stimulations with a Von Frey filament exerting 0.02 g of force onto the plantar surface of the paw, and observring the withdrawal of the paw when the pressure becomes uncomfortable to the mouse. (Find here a description of the process.)
  • Thermal hyperalgesia (pain from heat): Assessed using a mobile radiant heat source focused on the hind paw (for a maximum of 20 seconds to avoid tissue damage), and observing the time taken for the paw withdrawal.

In addition, behavioral correlates of pain were evaluated in the certain mice – before intraplantar injection of CFA or nerve ligation, and a few days to a week after the process.

Building on the local effect hypothesis, Goldman et al. wanted to test if Adenosine – a by-product of the breakdown of the cellular energy currency, ATP, that is released during mechanical or electrical or thermal stimulation – could produce analgesia by binding to a receptor called the A1-Adenosine receptor. Indeed, acupuncture applied with deep manipulation sharply increased the extracellular concentrations of all purines, including Adenosine. The group also demonstrated the requirement of the A1-Adenosine receptor by showing that 2-chloro-N(6)-cyclopentyladenosine (CCPA), a substance that binds to that receptor, reduces the sensation of pain in the both above-mentioned mouse models when applied locally. The authors went on to postulate that the effect of CCPA was possibly mediated by C-fibers as well as Aδ fibers.

Acupuncture with deep manipulation achieved the same effect as CCPA in reducing pain. However, the local effect was evident, and – as authors note in supplementary data – acupuncture without deep manipulation did not achieve the same effect.

Substances (such as Deoxycoformycin, a nucleoside analog drug approved for Leukemia) which cause an accumulation of Adenosine were able to potentiate the analgesic effect of acupuncture in inflammatory and neuropathic pain. Strangely enough, Deoxycoformycin appeared to be subject to the same local effect phenomenon, and had no effect unless it was combined with acupuncture in the two models of chronic pain.

The authors admitted in the discussion that mechanical stimulation of the skin, including non-penetrating needles as placebo, can activate epidermal A1-receptors, as well as release adenosine, thereby decreasing pain, but they claimed that this is different than the deep penetration of the acupuncture needles reaching muscle and connective tissue. Is the adenosine release at the deeper level more difficult, since it requires the vigorous manipulation of the needles? Combine this with the fact that adenosine is rapidly cleared from the extra-cellular fluid. Is the length of the time for which adenosine is active and binds to A1-receptor sufficient to give rise to the putative analgesia through acupuncture?

Of course, the authors’ hypothesis does not explain the equally well-observed analgesic effect by sham acupuncture, or the expectancy of acupuncture, in human patients. The interventional mouse study, testing very specific types of experimentally induced pain, with a small sample-size (n=5-8) and without proper placebo controls could hardly be an adequate study to establish a causal relationship between acupuncture and analgesia.

Tooth Fairy science: despite low prior probability or weak premises, there is an over-dependence on deductive reasoning to arrive at a conclusion, and not enough application of inductive reasoning to check the falsifiability of the said conclusion.

And yet…

Nature Neuroscience!!!


Main articles cited:

1. 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, 13 (7), 883-888 DOI: 10.1038/nn.2562

2. Zhao, Z. (2008). Neural mechanism underlying acupuncture analgesia Progress in Neurobiology, 85 (4), 355-375 DOI: 10.1016/j.pneurobio.2008.05.004

10 Comments

  1. The acupuncturists I know treat Qi and meridians as a useful metaphor, and are frustrated that they get results which can’t be explained by physiological mechanisms. They’d be ok if it was proven that they were just particularly effective at triggering the placebo effect – relief or cure is good, no matter the mechanism – but their results, in practice, include both positive and negative side-effects that just don’t seem to fit how the placebo effect usually works.

    Scientific tests of “acupuncture”, by necessity, test a very limited subset of the whole field – the different schools of acupuncture teach very different methods of detecting and using acupuncture points (whatever those are).

    Reading through the studies that have been done so far, I’m not yet convinced that we have debunked acupuncture – unlike homeopathy, there are too many questions left, too many unexplained effects. We certainly don’t know enough yet to support the knee-jerk Skeptic belief that all acupuncture is woo.

    My favorite example of an acupuncture point which raises questions is called “colon 4” (in one model of acupuncture). It is a tender spot inside the Y right where the bones of your thumb and index finger meet in your hand. If you are having intestinal cramps, that spot gets much more tender – and if you massage the tender spot vigorously on both hands, your intestines relax temporarily.

    Whether you believe in acupuncture points or not.

    Now, what’s going on there? What mechanism is being triggered? What is the connection between that little spot of soreness where finger and thumb bones meet and the smooth muscles of the intestines, and what evolutionary story is it telling? Because no designer would set up such an odd thing; that tender spot (whatever it is) has all the hallmarks of a very old evolutionary artefact.

    An MD first showed me that point, by the way. Said it was very useful to his patients, but he had no idea how it worked. Like the “three mile” point on the calf below the knee, which a different MD showed me many years later.

    I’m waiting for a western, evidence-based, testable physiological mechanism to explain the effects of both Colon 4 and the Three Mile point. A mechanism in the brain, if that’s where it happens, or a mechanism in the body.

    Why those two points? Because they seem to work whether or not a person believes in acupuncture’s effectiveness.

    When we reach that level of physiological understanding, I’ll be more trustful of “scientific” evaluations of acupuncture as a whole.

  2. Thank you for commenting, Mr. Carpenter. Please allow me to respond to your comments in line.

    The acupuncturists I know treat Qi and meridians as a useful metaphor

    What is the point in manufacturing metaphors when one has the benefit of excellent knowledge gained through empirical studies of anatomy and physiology over the years?

    …are frustrated that they get results which can’t be explained by physiological mechanisms.

    Exactly what kind of “results” are we talking about? In general, quack therapies depend heavily upon (a) placebo effects, including psychological effects; (b) “regression to the mean”, i.e. natural variations in repeated data misinterpreted as real change; and © many self-healing conditions. These so-called ‘therapies’ turn out to be completely ineffective when the disease needs precise treatment of the etiology, for instance, when there is an active infection.

    They’d be ok if it was proven that they were just particularly effective at triggering the placebo effect – relief or cure is good, no matter the mechanism – but their results, in practice, include both positive and negative side-effects that just don’t seem to fit how the placebo effect usually works.

    “They”, or the acupuncturists you refer to, seem not to understand at all what placebo or placebo effect is, and in making this statement, neither do you. Placebo effect is a non-specific physiological effect caused by factor(s) unknown. One cannot ‘trigger the placebo effect’ intentionally, and it is grossly unethical to treat patients hoping that placebo effect takes over.

    Scientific tests of “acupuncture”, by necessity, test a very limited subset of the whole field – the different schools of acupuncture teach very different methods of detecting and using acupuncture points (whatever those are)… Reading through the studies that have been done so far, I’m not yet convinced that we have debunked acupuncture – unlike homeopathy, there are too many questions left, too many unexplained effects. We certainly don’t know enough yet to support the knee-jerk Skeptic belief that all acupuncture is woo.

    Ah, the old trope – a typical CAM excuse – that science can’t study the Eastern mystical woo properly. It is otherwise known as special pleading. I don’t know how many of “the studies that have been done so far” you have read through and in what manner, but I can always point you to valuable resources, freely available on the internet, that have taken apart the feeble attempts by the CAM community to legitimize their quackery by using science-y sounding work. If that doesn’t convince you, I doubt what will.

    My favorite example of an acupuncture point which raises questions is called “colon 4” (in one model of acupuncture). It is a tender spot inside the Y right where the bones of your thumb and index finger meet in your hand. If you are having intestinal cramps, that spot gets much more tender – and if you massage the tender spot vigorously on both hands, your intestines relax temporarily.

    No, it does not. The same acupoint, a.k.a. LI4, has been used as treatment of migraine, in contemporary acupuncture literature. So, unless your head is in your large intestine, and both start paining at the same time (Well, if my head is up my… large intestine, I would be in pain!), there is no way this old-(Chinese)-wives’ tale does anything to either intestinal cramps or the migraine. There is at least one Cochrane meta-analysis (document: CD005111) that has shown that it is unlikely that acupuncture has any effect on irritable bowel syndrome.

    Like the “three mile” point on the calf below the knee, which a different MD showed me many years later…

    In a rather roundabout way, you are trying to talk about the Zusanli (ST36) acupoint, which has been used in acupuncture literature to treat just about anything, but so far, none of them have documented any outcome that is significantly different from the placebo controls.

    When we reach that level of physiological understanding, I’ll be more trustful of “scientific” evaluations of acupuncture as a whole.

    No, I somehow think you won’t be. A true believer in a pseudoscientific CAM modality, such as acupuncture, starts with a highly improbable foundation. When study after study shows little effect from acupuncture, the believer dismisses them. Then the believer cherry-picks those studies that seem to show some effect, and engages in statistical legerdemain to show a p of <0.05 somewhere (never mind the inconvenient details such as the null hypothesis, or power of the study, proper controls, study bias and so forth). If that shows up, victory is claimed; if the magical p value is not forthcoming, vigorous handwaving ensues, testimonials pour forth, and so on – none of which can overshadow the fact that quack therapies are worthless.

  3. I haven’t read the literature on “colon 4”, “LI4”, or “three mile” points.

    But I think it’s worth pointing out that “western” medicine has a reasonably good understanding of Referred Pain, which can be simply illustrated by the well known “ice-cream headache”, where nerve sensations from the back of the mouth are experienced as a brief, intense pain in the skull.

    So, we already understand potential physiological explanations for the reported, but not robustly verified, effects of acupuncture.

  4. I’m not a fan of woo – what I said above can be boiled down to:

    Some repeatable, dependable things are going on here, but the Western explanations offered so far do not explain the observable phenomena (calling something “the placebo effect” does not explain it, saying that referred pain (some instances of which aren’t very well understood and may not fit the model of those which are) is a potential explanation does not explain it). Chinese traditional explanations certainly do not explain the observable phenomena (what the hell is qi?).

    Qi, to me, sounds as valid as phlogiston.

    Like phlogiston, it’s an incorrect attempt to explain an observable thing. But it’s incorrectness is not proof that the observable thing does not exist.

    The effect of the sore spot in the hand I described on the smooth muscle of the intestine does happen, and is repeatable for me and for the people I have asked to try it who I’ve followed up with. I know skeptics (both skeptics and Skeptics) who, very quietly, use that point when they get a touch of food poisoning, or the flu, and are in pain.

    I make no claim other than that there is a mystery here that I think needs proper explaining. Like I said, no one designing a body or designing woo would make such a thing, it’s too odd.

    I am pinning my hopes on solid Western scientific study to eventually clear this stuff up. That’s the only verifiable, reliable, sensible way to go – when it’s done out of curiosity and good faith, with no dog in the race except to find the mechanism of observable phenomena.

    What I object to is people insisting that no, nothing unexplainable is going on. Because I have not yet heard a scientific explanation of the physiological effects of manipulating this particular point from anyone. And sciency explanations, as we all know, are just sciency. They sound nice, in a wooish way, but they have little to do with the strength and power of real science done properly.

    And, I must say, Skeptiwoo is no more sweet smelling than CAMwoo.

  5. Some repeatable, dependable things are going on here…

    Please provide concrete examples of ‘repeatable’ and ‘dependable’.

    calling something “the placebo effect” does not explain it

    Hehehe! I am sorry, but your statement sounds so much like Bill O’Reilly’s, “You can’t explain why the tide goes in” piece. Please re-read my comment above re: placebo effect. Perhaps you would benefit from the ‘Mind’ issue of February 2009 of the Scientific American. Also, read this 2005 column by Ben Goldacre in the Guardian discussing the same concept.

    But it’s [sic] incorrectness is not proof that the observable thing does not exist.

    Are you familiar with Carl Sagan’s immortal phrase, “Extraordinary claims require extraordinary evidence”? Starting from an a priori implausible stance, acupuncture makes extraordinary claims about efficacy, but so far any evidence in favor of the same has been lacking. The existence of the ‘observable thing’ may not be in dispute, but the idea that it is not merely random, purely a chance phenomenon must be established empirically. Do remember that you are not talking about finding ghosts in your cellar, but real people and real diseases that affect their lives. A putative therapy must be based solidly in science.

    I have not yet heard a scientific explanation of the physiological effects of manipulating this particular point from anyone.

    Much like the woomeisters, whom you claim not to like, you are already convinced that ‘something happens’ when you rub that spot in your hand. Would any evidence convince you otherwise? Let me ask you: how would you falsify that hypothesis?

  6. One repeatable theme in the world of CAM is that science is somehow unable to properly test the modality in question. It would be really interesting to see a proper scholarly analysis of why this is supposed to be. After all, we can by now see individual atoms and even subatomic particles, we can detect forces unimaginably smaller than the human senses can perceive, and we have an excellent understanding of the nature of matter.

    As a skeptic it seems to me that the main reason CAM proponents assert that this modern scientific technology cannot properly assess their preferred modality, is precisely because it can, and it shows it to be fallacious. I think in particular of homeopaths and their attempts to excuse the fanciful claims made for dilution beyond the point of non-existence – claims which, if true, would have profound implications for virtually every advanced technology.

    As I understand it (being a lowly engineer rather than a proper scientist) the scientific method requires that, in order to be accepted, a theory must convincingly refute the null hypothesis. I have yet to see a single CAM proponent even accept this as a basis of any argument, virtually every one reverses this fundamental scientific burden of proof, instead challenging skeptics to comprehensively refute their claims – i.e. to prove a negative. Some even have the gall to follow this up by saying that since science rarely if ever says X cannot be so, only that it is highly unlikely, thus science’s inability to prove a negative is absolute and therefore the CAM modality must be allowed equal weight with science.

    And then we see, as here, a weird hybrid world where science is purportedly used to quantify that which, at root, cannot be scientifically verified. Here, I think, we begin to expose a fundamental truth: CAM practitioners yearn for the legitimacy provided by science, but recognise that their fields are fundamentally unscientific. They seek to erect ring-fences around certain concepts, so that they may not be tested, and seek scientific endorsement of the periphery. And then they complain when science turns its lens on their core concepts and finds them wanting, finds them unable to convincingly refute the null hypothesis.

  7. Guy,

    CAM practitioners yearn for the legitimacy provided by science, but recognise that their fields are fundamentally unscientific. They seek to erect ring-fences around certain concepts, so that they may not be tested, and seek scientific endorsement of the periphery. And then they complain when science turns its lens on their core concepts and finds them wanting, finds them unable to convincingly refute the null hypothesis.

    Bravo!

    I had once touched upon the same idea on a post about so-called homeoprophylaxis. Alternative medicine practitioners, who crave the legitimacy of science and evidence-based medicine, are pretty adept at appropriating the language from scientific disciplines. Therefore, since “protection” immediately conjures up an image of a vaccine-like, prophylactic activity, homeopaths I referred to in my post renamed their “nosode” quackery as ‘homeoprophylaxis’.

  8. These posts are devastating and brilliant,

    Not only do they destroy the claims of acupuncture (they were already in tatters for anyone who’s been following the story. But they also destroy the myth that a study is reliable because it has been published in a high-impact peer-reviewed journal.
    Nature Neuroscience owes the world an apology for this. But I doubt if we’ll get one, any more than we got one from the British Journal of General Practice after they were deceived by acupuncturists.


  9. Much like the woomeisters, whom you claim not to like, you are already convinced that ‘something happens’ when you rub that spot in your hand. Would any evidence convince you otherwise?

    As you can clearly see from my prior posts, I am not defending the theory of acupuncture, or the profession of acupuncture. I’m merely saying that some of the odd things that acupuncturists have observed have not yet been explained properly by scientific methods (or acupuncturists), but they do exist experientially.

    Yes, I’m convinced that the cramping of smooth muscles in my intestine relaxes temporarily when I rub that specific sore point in my hand.

    What kind of evidence would convince me that my senses were lying to me, and my intestinal cramps were not, in fact, lessening? I really don’t know, but I’m open to actual evidence. You know, the kind the hard sciences are built on.

    If my senses are lying and someone could show the details of the physiological mechanisms by which those mistaken sensations are generated and perceived, that would be brilliant. I’d love that. And it would have a multitude of useful applications.

    On the other hand, it’s certainly possible that my senses are not lying. And a proper, detailed explanation of how that’s working would also be brilliant, useful and have a multitude of applications.

    That kind of difficult, tedious teasing out of a complex biological system, either of falsely or truly perceived sensations, and finding out how and where they are generated, moderated and perceived, would take real science and many years. I’d be happy to see it done, no matter where it led.

    You point to Ben Goldacre’s excellent piece on homeopathy and the placebo effect – I had read it before, and enjoyed it both times. Mr. Goldacre would, I think, be delighted if some group traced the complete physiological chain of events for even one example of the placebo effect.

    The 2009 issue of Scientific American you pointed me to – well, it does have a number of interesting bits and pieces. But it doesn’t address the coordinated chain of events which would have to happen in my hands, intestines, spine, brain, and the rest of me for the “placebo effect” to occur when I rubbed that sore spot in my hand.

    So – this is clearly not the place for discussing unexplained phenomena like the one I brought along.

    It was my mistake to think that curiosity, scientific thinking and actual observations might be valued here. I will leave you to your games.

  10. Regarding the assurance by Goldman et al. that the WHO endorses acupuncture for at least two dozen conditions.

    Google “WHO acupuncture” for access to the WHO page on Traditional Medicine. Then click the Q&A link question “How safe is traditional medicine?”

    The linked answer page states that the WHO does NOT recommend acupuncture but promotes an evidence-based approach to addressing safety, efficacy and quality issues for traditional and complementary medicine.

    Regarding the assurance by Goldman et al. that the US National Institutes of Health have issued a consensus statement proposing acupuncture as a therapeutic intervention for complementary medicine.

    Here’s the url to the relevant NIH consensus statement of 1997: http://consensus.nih.gov/1997/1997Acupuncture107html.htm

    In bold red lettering the NIH warns that the relevant statement is more than five years old and is provided solely for historical purposes. They warn that some material is likely to be out of date, or even wrong.

    The FAQ page also states that NIH Consensus statementes are NOT official policy statements of NIH or of federal government.

    For evidence of the benefits of acupuncture we are left with Goldman et al. assurances: (a), (b) and (e) as above.

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