Potential New Mechanism of Pain Relief Discovered

The development of drugs and other treatments for specific symptoms or conditions relies heavily on either serendipity (the chance finding of a beneficial effect) or on an understanding of underlying mechanisms. In pain, for example, there are limited ways in which we can block pain signals – such as activating opiate receptors or inhibiting prostaglandins. There are only so many ways in which you can interact with these systems. The discovery of a novel mechanism of modulating pain is therefore most welcome, and has the potential of leading to entirely new treatments that may have better side-effect profiles than existing treatments and also have additive clinical effects.

A recent study by Nana Goldman et. al., published in Nature Neuroscience, adds to our understanding of pain relief by identifying the role of adenosine in reducing pain activity in the peripheral nervous system. The researchers, in a nice series of experiments, demonstrated that producing a local painful stimulus in mice causes the local release of ATP (adenosine triphosphate) that peaks at about 30 minutes. This correlates with a decreased pain response in the mice. Further, if drugs are given that prolong the effect of adenosine, the analgesic effect itself is prolonged.

Also, if drugs are given that activate the adenosine A1 receptor, the observed analgesic effect is replicated. When these experiments are replicated in knockout mice that do not have the gene for the adenosine A1 receptor, there is no observed analgesic effect.

Together these experiments are fairly solid evidence that local pain results in the local release of adenosine that in turn binds to the adenosine A1 receptor inhibiting the pain response. This is potentially very exciting – it should lead to further investigation of the adenosine A1 receptor and the effects of activating and inhibiting it. This may lead to the development of drugs or other interventions that activate these receptors and may ultimately be a very useful addition to our ability to treat acute and chronic pain.

Now Comes the Spin

In a rational science-based world, the above would be the end of this blog entry. But that is not the world we currently live in. In this study, the chosen method of provoking pain was the insertion of an acupuncture needle into the “Zusanli point” of the lower extremity and rotating it. This allowed the authors of this study to spin the results as if they were validation for acupuncture itself – and the mainstream press dutifully followed suit.

The introduction to this study is an apology for acupuncture itself, and sets the tone for the rest of the paper as well as the press release and comments to follow:

Acupuncture is a procedure in which fine needles are inserted into an individual at discrete points and then manipulated, with the intent of relieving pain. Since its development in China around 2,000 B.C., acupuncture has become worldwide in its practice. Although Western medicine has treated acupuncture with considerable skepticism, a broader worldwide population has granted it acceptance. For instance, the World Health Organization endorses acupuncture for at least two dozen conditions and the US National Institutes of Health issued a consensus statement proposing acupuncture as a therapeutic intervention for complementary medicine. Perhaps most tellingly, the U.S. Internal Revenue Service approved acupuncture as a deductible medical expense in 1973.

That this paragraph appears in a high-impact peer-reviewed journal is very curious (to put it mildly). It is full of misinformation and logical fallacies. Acupuncture is used for more than pain relief, and so making statements about the efficacy of “acupuncture” go way beyond the scope of this study, which involves only pain. The authors should have specifically pointed out that this study cannot be used to explain any indication for acupuncture that does not involve local pain relief. Acupuncture as it was practiced in China 4,000 years ago bears little resemblance to what is practiced today, and may have been more of a form a bloodletting.

The authors then make a false dichotomy between “Western medicine” and, presumably, “Eastern medicine” – which is an anti-scientific and culturally bigoted point of view. This is followed by an argument from popularity, and a particularly bizarre argument from authority – noting that the IRS accepts acupuncture as a medical expense. I was unaware that the IRS is a scientific medical organization.

The authors also fail to put this study into its proper context by reviewing existing evidence – the more traditional use of the introduction to peer-reviewed research. The clinical research on acupuncture, which is quite extensive, finds that any measured symptomatic effect is almost certainly due mostly or entirely to placebo effects. Further, it does not matter where you stick the acupuncture needle, nor even if you do not stick the needle through the skin. Twisting toothpicks against the skin in random locations has the same effect.

My interpretation of the research is that acupuncture (placing needles at specific acupuncture points to manipulate chi) does not work. There may, however, be non-specific physiological responses to the mechanical stimulation of sticking needles at random locations, or just poking toothpicks. This study, if anything, supports this interpretation – it, in fact, has identified a local mechanism of analgesia that can help explain a non-specific response to acupuncture, sham acupuncture, or placebo acupuncture and therefore is consistent with the clinical evidence showing no difference among these interventions.

This is also not the first study to identify potential local mechanisms of pain relief from mechanical stimulation. A 2002 study correlated insertional activity (depolarization of muscle fibers in response to needle insertion) or electrical stimulation with pain relief. This would explain why, in this study, constant twisting of the needle was needed to provoke pain relief – perhaps insertional muscle activity is needed to release adenosine, or increases its release.

By focusing on what is really going on here we can best understand how to develop methods to capitalize on these local mechanisms optimally for pain relief. It must be noted, however, that needle insertion gives very unimpressive results in clinical trials. It may be that the effect is too temporary to be worthwhile, at least as mechanically provoked – pharmacologically activating the adenosine A1 receptor may be a better strategy. Also, it is very difficult to extrapolate from mouse data as the subjects are much smaller than humans, and therefore their nerves and motor end-plates (the locations where the nerves innervate the muscles) are much closer together and superficial – closer to the skin.

Mechanisms are interesting, but net clinical outcomes in humans are the only kind of scientific data that really tells us if a modality works or not.


Finally, it has to be emphasized that this study says nothing about acupuncture itself, except for providing a possible mechanism for a non-specific local response. The term “acupuncture,” in fact, is becoming increasingly problematic and is confusing the scientific literature, not to mention the public. What is acupuncture? If we use the term broadly enough to mean any use of needles, with or without electrical stimulation, at any points, with or without skin penetration, etc. then the term is too broad to be useful. If we use the term narrowly – to mean sticking needles to a certain depth in specific acupuncture points that work through a novel mechanism specific to those locations, then we can say, based upon extensive research, that “acupuncture” does not work and its proposed underlying mechanisms are nothing more than pre-scientific superstition.

This study is an excellent example of the mischief caused by confusing the non-specific use of the term “acupuncture” with its more traditional use. Research involving acupuncture in its vaguest sense is used to promote “acupuncture” in the traditional sense. This is highly deceptive and scientifically sloppy.

The researchers of this current study could have used other controls to see if the effect they discovered is in any way specific to any acupuncture variables. For example – they could have used a non-acupuncture point as a control, or other forms of mechanical pain production that do not involve needles. I suspect any local pain production or mechanical trauma beyond a certain threshold would result in the same adenosine response – which certainly seems like a non-specific mechanism to modulate pain.

Because the authors did not do this, they did not actually research “acupuncture”. The description of this research in the published paper and in the press should have been as I discussed in the opening of this post. Instead, genuinely interesting research that may lead to novel pain treatments is being diverted as propaganda for an ancient superstition.

Posted in: Acupuncture, Neuroscience/Mental Health

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18 thoughts on “Potential New Mechanism of Pain Relief Discovered

  1. Draal says:

    Both an interesting study and a disappointment. A couple observations: the pain was induced by sticking a needle into the flesh and twisting. Maximum pain relief was seen after 30 mins. Hmm, pain relief for the very treatment that is inducing the pain. Personally, I’d take an ibiprofin and wait the half hour for pain relief versus inflicting more pain to myself by inserting needles and waiting a half hour while in more pain that I started out in.

    Since ATP is used by so many enzymes, I am hesitant to believe that a ATP mimic drug would not have any non-target interactions, that is, only specific to the A1 receptor. I would predict a number of side effects would pop up. (thus, acupuncture is the only safe treatment for pain relief. …. /end sarcasm)

  2. kvanh says:

    So wait, they use acupuncture needles to CAUSE pain, and that proves it works?

    I guess they think they’re proving acupuncture can have some biological effect, but if you’re claiming it can block pain in a local area, wouldn’t the pain that is already in that same local area (and you’re trying to block) have exactly the same effect?

    Hopefully this provides a starting ground for new drugs, but WTF are they thinking with this other crap?

  3. kvanh – I thought of that. What I think is happening is that chronic low levels of pain do not produce chronic adenosine release. It makes sense that such a response would habituate to chronic pain. But an acute pain would result in a sudden release of adenosine.

    So essentially they are using the application of acute pain to cause a local response to that pain which temporarily also inhibits local chronic pain.

    If the clinical research is any guide – this is not a terribly useful modality. But, as you say, hopefully we can develop treatments that are more convenient and longer lasting.

  4. windriven says:

    The Nature Neuroscience article is being reported in the Wall Street Journal as “How Acupuncture May Work” and delivers non-critical reporting of the authors’ assertions. The only caveat notes that results of animal studies may not be replicable in humans.

    A joke was told some years ago about a man presenting to an old backwoods dentist with a throbbing pain in one of his teeth. The old dentist couldn’t find any reason for the pain. So he hit the patient’s toe with a hammer and asked, “How does your tooth feel now?” I guess those old country dentists used acupuncture and didn’t even know it.

  5. According to the National Emergency X-Radiography Utilization Study (NEXUS) Low-Risk Criteria (NLC) decision rules to guide the use of cervical-spine radiography in patients with trauma, “distracting injuries” are a reason to do a CT scan even when the patient denies neck pain. “No precise definition of a painful distracting injury is possible. This category includes any condition thought by the clinician to be producing pain sufficient to distract the patient from a second (neck) injury.”

    Are twirling acupuncture needles a “distracting injury”?

  6. Watcher says:

    One thing that we have to do in rodent CNS research is prove that the area we are targeting with a viral vector, lesion, etc. is actually fully, partially, or not at all affected by the method of change. I realize that this may be a bit more difficult in the periphery, but why aren’t they required to show this meridian as a definitive point in the anatomy and prove that they are affecting the same point in each treatment? Did they have a control site, one not located in a meridian? I can’t believe this made it into Nature Neuroscience …

  7. Watcher says:

    I guess those old country dentists used acupuncture and didn’t even know it.

    LOL :D

    I mean, there is evidence for any type of mechanoreceptor stimulation dulling peripheral pain. They both probably work by inhibitory coding in the brain. One signal drowns out the other.

  8. tommyhj says:

    Thanks for quickly dismissing this horrid study! I can’t believe that this got peer-reviewed. Or that a researcher would go to such lengths to get the press to cover his research (which is the only reason I can think of for him to link it to acupuncture, if he isn’t just an acupuncture-fanatic. Oh, I’m just seeing that almost the entire research team is Chinese…).

  9. nitpicking says:

    Steve, you’re a Yale Medical School professor. You have prestige. I’m sure that you’re going to write to Nature about this?

  10. SchreiberBike says:

    I can remember my dad telling me. So your stomach hurts? Come here and I’ll step on your foot and see if that doesn’t make it go away. Quit your belly-aching and get to work.

    I wonder why this was in Nature?

  11. Ken Hamer says:

    “Further, it does not matter where you stick the acupuncture needle, nor even if you do not stick the needle through the skin. Twisting toothpicks against the skin in random locations has the same effect.”

    Perhaps there’s a market for a discount version called approxipuncture.

  12. Deetee says:

    Steve, you’re a Yale Medical School professor. You have prestige. I’m sure that you’re going to write to Nature about this?

    Please do this Steve.

  13. wertys says:

    i’d have been more impressed if this was published in Pain or one of the IASP journals. There is a wealth of preclinical research on mechanisms of pain, and the complexity of the signalling is one of the reasons that the lab is so far ahead of the clinic in treating painful conditions. We already know a lot about segmental descending inhibitory activation with noxious stimulation of deep tissues. The essential thing that happens is that if a deep tissue such as muscle or ligament send a noxious signal (usually hypertonic saline rather than a needle, bit a needle will still do it) the descending inhibitory tone from the brainstem increases for the myotome concerned. Defects in this inhibition contribute to soft tissue pain syndromes such as myofascial pain and fibromyalgia syndrome. the minutiae of what molecules are involved is where the research is at, and this looks like more of the same sort of stuff. Not really revolutionary, just more grist to the mill.

    Oh yeah, the whole acupuncture spin is just more timewasting.

  14. JoshSN says:

    I have a snake-oil-salesman in the family who trains other people to sell snake oil! My aunt, in her 60s, teaches at an acupuncture college.

    Please keep up the good work.

  15. botbml says:

    Many thanks for commenting on this study Steve and pointing out the faults. I have a number of family members who are avid acupuncture receivers and a cousin who administers it!! Your rational insights are always helpful

  16. doc.nemo says:

    How the hell did they work out the meridians and acupuncture points in mice?

  17. Harriet Hall says:


    Bigger question: How the hell did they work them out in humans?

  18. blackie1 says:

    Please do the Nature article suggested above. In it, I hope you include comments on the the farce that is the NIH’s own alternative medicine institute, NCCAM. Check out their page on acupuncture (

    The entire site is alarming – how are non-scientists supposed to know what to think when our own esteemed organizations promote this tripe. Can you believe the NIH funds research into the laying on of hands (“biofields”) to treat cancer in mice? Yes, mice?

    Check this out:
    “One of these centers is examining the potential role of Therapeutic Touch in healing bone fractures by studying the effect that the therapy has on markers of bone formation and resorption over time in women who have suffered a recent wrist fracture. The practice of Therapeutic Touch is an intentionally directed process of energy exchange during which the practitioner uses the hands as a focus to facilitate the healing of patients with “unbalanced energy fields.” The other center is exploring the hypothesis that biofield therapies involve a common set of bioelectromagnetic and psychosocial mechanisms that together affect cellular functioning, thereby reducing pain and increasing wound healing.”


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