Clinical trials often test a causal association between intervention and outcome 1. However, Ernst has asserted that, "Viewed from a scientific perspective, acupuncture is rarely, if ever, a causal therapy" 2. Perhaps acupuncture is not causal – no more so than flipping a light switch "causes" illumination. However, if acupuncture is a causal intervention, investigators should be able to suggest a biological pathway, hypothesis or rationale for how it might work.

"How might acupuncture work?" is asked and answered on the website of the National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health: "It is proposed that acupuncture produces its effects through regulating the nervous system, thus aiding the activity of pain-killing biochemicals such as endorphins and immune system cells at specific sites in the body. In addition, studies have shown that acupuncture may alter brain chemistry by changing the release of neurotransmitters and neurohormones and, thus, affecting the parts of the central nervous system related to sensation and involuntary body functions, such as immune reactions and processes that regulate a person's blood pressure, blood flow, and body temperature"3. More detailed rationales for acupuncture are readily available 4.

The CONSORT (Consolidated Standards of Reporting Trials) Statement recommends that clinical trial authors "suggest a plausible explanation for how the intervention under investigation might work" 5. Clinical trials of acupuncture might be more useful if they had not just a hypothesis about efficacy, but also a hypothesis about a mechanism. The purpose of this study was to determine to what extent contemporary acupuncture clinical trials proposed physiologic rationales and present the findings in the context of other characteristics of the studies.

The author sought a fair sample of acupuncture clinical trials and conducted a PubMed search using the keyword "acupuncture," further limiting the search to "clinical trials" published in "English" in "2005." The author obtained and reviewed a copy of every article identified from this search; articles were excluded if they were not actually clinical trials of acupuncture; letters and brief articles were also excluded as they were unlikely to have the details sought. Each article was reviewed for a physiologic rationale; that is, a description of any human physiologic process as an explanation linking the intervention to the outcome. Articles were also reviewed for their objectives (indications or experimental conditions) and outcomes of interest, the experimental and control interventions, country of origin, funding sources and type of journal. Rationales were not counted if based only on acupuncture theory or practice or on published or historical reports; a description of some physiologic process was required. This study had no external funding.

The PubMed search on May 16, 2006, using the keyword "acupuncture" yielded 698 publications in 2005; 101 were indexed as acupuncture clinical trial reports, of which 93 were published in English. Five articles had an advance e-publish date in 2005 but were formally published in 2006 and were excluded. Six articles were excluded because they were not, in fact, clinical trial reports; also, two letters and one brief article were excluded. The study sample includes all remaining articles (n = 79) 6789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960616263646566676869707172737475767778798081828384. (Figure 1) After reviewing these papers, they were categorized according to their rationale: none, neurochemical, segmental ("gate control"), autonomic regulation, local effects, functional effects in the brain or other effects.

Seventy-nine acupuncture clinical trials reports were reviewed and 53 (67%) had some rationale for the use of acupuncture. The study interventions stimulated points using needles, electricity, lasers, pressure, heat or ointments compared to various controls. No rationale was proposed for stroke; otherwise, having a rationale was not associated with objective, positive findings, means of intervention, country of origin, funding source or journal type. The dominant rationale involved release of neurochemicals (usually endogenous opioids [beta endorphins, enkephalins and dynorphins] or serotonin).

No study proposed that the neurochemical effects of acupuncture depend on point selection. No study claimed to select points based on neurochemical effects. However, it should be noted that the

locations

The neurochemical rationale was proposed not just for analgesia, but insomnia, nausea/vomiting, obesity, Parkinson's and effects on blood pressure, immune function, colitis, vasomotor symptoms and lower esophageal sphincter relaxation. Further, it cannot be ruled out that other outcomes (e.g., autonomic regulation) may be secondary to neurochemical effects. Also, the same points may be stimulated for many different indications; alternatively, one indication may be treated with disparate point selections, not just between studies, but within studies, even varying by each treatment visit. This suggests that acupuncture simply stimulates self-regulatory processes and would account for acupuncture's reported benefits in so many disparate pathologic conditions.

Hypothesizing a mechanism can aid in selecting an appropriate control intervention. The sham needling with puncture may not be different in effect from "true" acupuncture and even the placebo needling is problematic: "Despite no skin penetration, the [placebo needle] tip exerted a mechanical stimulation... [which] may also excite nociceptive primary afferents. No ideal method of placebo stimulation acupuncture exists at present"48. In addition, placebos are also associated with neurochemical effects 2439. One study concluded that effects of acupuncture may well be "attributable to other mechanisms than perforation of subcutaneous tissue. Repetitive relaxation and being cared for may be just as important" 53. In an experiment or clinical trial, the control intervention should depend on (i.e., "control for") the hypothesized mechanism and also control for so-called placebo effects. Without a theoretical mechanism and in the absence of a truly inert placebo, it can be difficult to define an appropriate control.

Finally, why is a rationale important? It is not enough to lament that "the mechanisms underlying acupuncture are still poorly understood" 80. Understanding the physiologic basis of acupuncture may be critical to producing reliable (i.e., reproducible) results. A rationale should be offered as an explanation for the trial intervention, especially when the intervention is poorly understood. The rationale should offer a scientific hypothesis, either explanatory or pragmatic 5, to be tested explicitly or implicitly. Of course, pragmatic trials may proceed without a clear hypothesis about the mechanism involved. Ultimately, however, the effects of acupuncture must be mediated through human physiology and investigators should be able to suggest some possible mechanism(s). Proposing and testing ideas about the underlying mechanisms of acupuncture could eventually lead to a real understanding about how acupuncture does work.

Every clinical trial should attempt to explain the use of the intervention, but many acupuncture trials fail to offer any meaningful rationale. The dominant rationale for acupuncture involves neurochemical responses which appear to be independent of objective, point selection or the means or method of stimulation; this raises questions about the beliefs underpinning this intervention and deserves further investigation. Many studies have attempted to test traditional acupuncture without a physiologic rationale, but proposing a hypothesis for how acupuncture might work is good science and costs nothing; a rationale can help investigators to develop a causal hypothesis, choose an appropriate control and rule out placebo effects. Reviewers making decisions about funding or publication of acupuncture research should seek a physiologic hypothesis from investigators.

The author(s) declare that they have no competing interests.

The author conceived and designed the study; acquired, analyzed and interpreted the data; and wrote the manuscript.