Sham in acupuncture trials – a vital component of robust research, or just confusing?

In December of 2012, Alexander Molassiotis, then of the School of Nursing, Midwifery, and Social Work at the University of Manchester, appeared as the lead author of a paper titled "Acupuncture for Cancer-Related Fatigue in Patients With Breast Cancer: A Pragmatic Randomized Controlled Trial," which appeared in the Journal of Clinical Oncology  (http://www.ncbi.nlm.nih.gov/pubmed/23109700).  The study was labelled "pragmatic" because it sought to measure effectiveness (how well a treatment works in medical practice) rather than efficacy (how well it works in a laboratory setting or clinical trial). The results were promising for breast cancer patients and for the credibility of acupuncture, in the words of the authors:

This study determined that women with breast cancer and CRF [cancer related fatigue] reported significant improvements in overall fatigue, physical and mental fatigue, activity, motivation, psychological distress, and all domains of quality of life after 6 weeks of acupuncture. To our knowledge, this s the first large multisite trial of its kind and provides some evidence of the effects of acupuncture.

The acupuncture treatments, received by 181 women who completed the trial, were remarkably simple: three sets of points (ST36, SP6, and LI4) were needled once a week for six weeks (with some variability if a given point could not be needled in case of lymphedema). These women were also given fatigue information booklets. The control arm of the trial (those not receiving acupuncture) were only given the booklets. The researchers devote a paragraph of their discussion to explaining why they did not include a sham ("pretend acupuncture") arm in the trial. The reasons were numerous and include this statement:

Experimental and clinical studies have also shown that minimal or sham acupuncture used as placebo control is not necessarily inert from a physiologic perspective, and its relevance as placebo acupuncture must be questioned, even when it is not used as per acupuncture principles.

They go on to suggest other sorts of control arms, such as attention control, educational intervention, or exercise, along with a non-treatment group, to better assess non-specific and placebo effects of the active treatment. This is what a sham arm is designed to do in scientific trials; however, the authors, having decided that sham acupuncture may not be a sham at all, are looking for an alternative. In any case, Molassiotis et al are fairly modest in their conclusions:

Although this trial provides some evidence of effectiveness, further effectiveness trials using appropriate controls, where hypotheses and study design are formulated based on conditions in routine practice, and outcomes essential for clinical decisions are warranted before recommending widespread use of acupuncture in patients with breast cancer.

So far, so good. But in 2013 this mild-mannered paper stepped into a phone booth and emerged (or its lead author, now at Hong Kong Polytechnic University, did) as a hard-swinging hero of an increasingly vocal group of sham-detractors. The battle began two months after the initial paper's publication, when the journal Support Cancer Care ran a systematic review of randomized controlled trials (RCTs) using acupuncture for cancer-related fatigue (http://www.ncbi.nlm.nih.gov/pubmed/23435597). The paper, by Paul Posadzki (then of the University of Exeter's Peninsula Medical School and the Korea Institute of Oriental Medicine in South Korea) et al, narrowed a rather larger field of possible trials down to seven - of which the Molassiotis study was one (an earlier feasibility study, also led by Molassiotis, was another of the seven).

The Posadzki group's findings were bluntly critical of the trials they reviewed - whatever their results - often simply due to the small number of participants. (For the record, four studies found acupuncture to be beneficial in treating CRF, while three found no difference between acupuncture and control.) The Molassiotis trial had "serious limitations," the authors concluded, among them that the study failed to control for the placebo effects of acupuncture.

Fast forward to last August: Support Cancer Care features a letter to the editor titled "Evidence is in the eye of the beholder", from Alex Molassiotis (http://www.ncbi.nlm.nih.gov/pubmed/23955025). A missive with the trajectory of a missile, it is aimed squarely at Posadzki et al. Molassiotis begins by casting doubt on the process of systematic review, an interesting discussion in itself but one that we will set aside for now.

To highlight his points relevant to sham acupuncture, he notes that a growing number of experts - including some funding bodies - now consider sham to be inappropriate for acupuncture trials. He describes the reasoning behind this view, including that we do not know whether sham acupuncture is inert or not, that even minimal needling can have neurophysiological effects, and this bomb: "that our scientific community has 'manufactured' a sham way to control for placebo effects in acupuncture trials desperate to give some 'science' credentials to such trials and mimic drug trial placebo-controlled designs."

Molassiotis continues by saying that he is both for scientific trials and pro-placebo control, but that he advocates for widespread agreement on how to do this while remaining "respectful of the principles of a traditional treatment" such as acupuncture. He finally emphasizes that"...we should not deny patients the possibility of experiencing symptom relief and health improvements because of sterile and incapacitating arguments about how to carry out 'proper' acupuncture trials".

That wasn't the end of it. In October, Support Cancer Care published a reply from Paul Posadzki and Edzard Ernst, another author of the systematic review. By this time the arguments had become more ad hominem, but the pair fairly counter the statement about mimicking drug trial placebo-controlled designs by saying the reason for doing so is to be able to differentiate between specific and non-specific therapeutic effects. They add that this differentiation is critical to ethical research. They conclude by saying that "rigorous research" is necessary to ensure that patients receive more benefit than harm from health-related interventions.

From one angle, just a scientific spat. From another, this back-and-forth provides valid views expressed fairly passionately from both sides. I know which side most, if not all, acupuncturists would take. But we acupuncturists still have to contend with finding some reasonably confident footing in scientific circles if we want to be fully accepted by, say, health insurers. And because we are so confident ourselves that our practice works, we are frustrated that it is proving so fiendishly difficult to prove this in a scientific way - since most of us, certainly, believe in science and the general validity of its method.

But we are not alone in struggling to prove that our thing works well (let alone how it works). As one scientist friend who I brought into this discussion remarked, "Unless you have a bunch of highly inbred mice in a perfectly controlled environment, biology is messy."

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