Sunday, December 25, 2011

et tu...? Acupuncture and pain in Nature

Physician and blogger Harriet Hall, MD, once coined an exceptionally apt phrase to describe research in many alternative medicine modalities - "Tooth Fairy Science"; it refers to research undertakings into a phenomenon whose existence is yet to be established. In a post in her blog Science-based Medicine, she explained:
You could measure how much money the Tooth Fairy leaves under the pillow, whether she leaves more cash for the first or last tooth, whether the payoff is greater if you leave the tooth in a plastic baggie versus wrapped in Kleenex. You can get all kinds of good data that is reproducible and statistically significant. Yes, you have learned something. But you haven't learned what you think you've learned, because you haven't bothered to establish whether the Tooth Fairy really exists.
Priceless. And of all the modalities championed by modern peddlers of pseudoscience, acupuncture most certainly qualifies as a prime example of Tooth Fairy Science.

Acupuncture is a procedure under the system of Traditional Chinese Medicine (TCM), which involves shallow insertion of needles into the skin at specific points. This system relies on quaint notions that mix pre-scientific ideas about physiology and disease with Eastern mystical philosophy. In TCM, diseases are considered to stem from a disharmony between yin and yang, two abstract ideas that are supposedly complementary in nature; this disharmony may result in blocking of the flow of a vital (life) energy, known as Qi (pronounced 'chi'), along mystical pathways called meridians. Acupuncture supposedly unblocks Qi flow through meridians, resulting in the balancing of yin and yang, and consequently, cure. Never mind that no one has measured Qi ever, or that there are no anatomical structures that correspond to the prescribed locations of the meridians.

Acupuncture is currently the darling of the media as well as many Complementary and Alternative Medicine (CAM) professionals. Its popularity is attested to by the fact that many of the well-known medical centers and hospitals in the US are increasingly offering acupuncture as a therapeutic option. This situation per se is utterly amazing, considering that all the actual research involving acupuncture done till date seem to corroborate the hypothesis that it is nothing more than an elaborate placebo.

There is no dearth of studies on Acupuncture; a casual PubMed search of the term "Acupuncture" yielded more than 8000 English-language primary research articles (including clinical trials) and close to 2000 reviews (including meta analyses). Many of these studies have made extraordinary claims about the efficacy of acupuncture and related procedures in a variety of diseases and disorders. However, careful and meticulous scrutiny of these studies, as well as those claims, have often demonstrated that many of these studies are poorly designed or carried out, and that the claimed outcomes are based on wishful thinking on part of patients (a.k.a. conditioning) and investigators, as well as ignorance about the action of placebos and how inaccurate placebos can confound the interpretation of data. These have often necessitated prodigious hand-waving and post hoc rationalizations in the discussions.

One of the common themes that most studies in alternative medicine adhere to is that they are often NOT published in high-quality, prestigious, peer-reviewed journals. This observation, while attributable to the lack of rigorous science in those papers, have nevertheless engendered within the alternative medicine community the suspicion of a conspiracy. Rational researchers, dealing with empirically sound science-based medicine, are by and large content solely with the critical deconstruction of the absurd claims by CAM proponents, bolstering their arguments with published and verifiable experimental evidence and analysis.

Imagine my surprise, then, when I became aware of a relatively recent study claiming efficacy of acupuncture and offering a mechanism of action in... [Wait for it...]

Nature Neuroscience!!!

The study was republished as a part of a recent Nature Supplement on Traditional Asian Medicine. Curiously, the issue appeared to be sponsored by two entities which have a significant financial interest in the field of alternative medicine. There is, of course, no law that prohibits such an entity from advertising or popularizing its products, but that a premier scientific journal like Nature should be an instrument to such promotion of pseudoscientific modalities raised quite a few eyebrows. Physician and Scienceblogger Orac has eloquently expressed his outrage, which has found echoes in the skeptical blogosphere and Twitterverse. In this post, I, however, would restrict myself to discussing the study by Goldman et al., that appeared in the July 2010 issue of Nature Neuroscience. The study 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 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

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