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, (c) 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 aggressive 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 observing 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.
Main articles cited:
- 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
- Zhao, Z. (2008). Neural mechanism underlying acupuncture analgesia Progress in Neurobiology, 85 (4), 355-375 DOI: 10.1016/j.pneurobio.2008.05.004