Accepted Manuscript Title: Is Acupuncture a Placebo Therapy? Author: Yong-chen Zheng Ting-ting Yuan Tao Liu PII: DOI: Reference:
S0965-2299(14)00069-7 http://dx.doi.org/doi:10.1016/j.ctim.2014.05.005 YCTIM 1343
To appear in:
Complementary Therapies in Medicine
Received date: Revised date: Accepted date:
20-11-2013 30-4-2014 6-5-2014
Please cite this article as: Zheng Y-c, Yuan T-t, Liu T, Is Acupuncture a Placebo Therapy?, Complementary Therapies in Medicine (2014), http://dx.doi.org/10.1016/j.ctim.2014.05.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Is Acupuncture a Placebo Therapy? Yong-chen Zheng 1 Ting-ting Yuan 2 Tao Liu 1
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(1) Central Research Laboratory, 2nd Teaching Hospital, University of Jilin Norman Bethune School of Medicine, P. R. China.
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(2) Department of Radiology, 1st Teaching Hospital, University of Jilin Norman
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Bethune School of Medicine, P. R. China.
Corresponding Author and Reprints:
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Dr. Tao Liu, Central Research Laboratory, 2nd Teaching Hospital, University of Jilin Norman Bethune School of Medicine, 218 Ziqiang Street, Changchun 130041, Jilin
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Province, P. R. China. E-mail: [email protected]; [email protected]
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Abstract
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Complementary therapies such as acupuncture are suggested to have enhanced placebo effects. Numerous high quality randomized controlled trials found that
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acupuncture is no better than its placebo control, however patients in both real and sham acupuncture groups report clinically meaningful symptom improvements. A possible interpretation of these trials is that acupuncture acts entirely by engaging placebo mechanisms. This article provides further evidence supporting that acupuncture might be a potent placebo, and explains how to address major concerns following this suggestion.
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Acupuncture is an ancient Chinese therapy mainly used for pain control.1 Although it is widely used in China and the rest of the world, the mode of action of acupuncture is incompletely understood, and there is no conclusive evidence supporting its specific efficacy.2-4 Because acupuncture induces therapeutic effects in direct response to
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site-specific needle insertion, it has long been believed that if acupuncture is efficacious, it must be specifically due to needle stimulation. Due to this seemingly
correct view, both clinical and basic science studies of acupuncture have to date solely
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focused their attention on detecting the specific effect associated with needle insertion. Despite great efforts made during the past several decades, little meaningful progress
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has been made in this aspect. Current dilemma in acupuncture research warrants a new look at acupuncture, with respect to its clinical effectiveness, specific efficacy,
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biological mechanisms, and its ethical controversy.
1. Robust placebo effects with acupuncture
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Medical care provision is surrounded by a complex psychosocial context which can significantly affect treatment outcome.5,6 Therapeutic effects caused by this dramatic context but not by the physical property of an active treatment are generally referred
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to as ‘placebo effects’ or ‘placebo responses’. Although it has been argued that calling
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these effects ‘placebo effects’ might lead to conceptual confusion,7,8 a unanimous ideal definition of this complex phenomenon is so far unavailable. In this paper, we
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use the term ‘placebo’, focusing not on its misleading ‘inert’ nature, but on the ‘active’ context in which it is given.
It has been long been suggested that alternative therapies such as acupuncture, characterized by a sophisticated invasive procedure and an elaborate treatment ritual, might have pronounced and clinically significant placebo effects.9,10 Randomized placebo (sham)-controlled trials (RCTs) of acupuncture have provided the most forceful support to this hypothesis, although their original purpose was not to evaluate placebo effects. For example, just list a few, multiple recent large RCTs with 3 or more arms11-16 have come to a rather similar conclusion—that is, patients receiving either real or sham acupuncture reported substantially greater symptom improvements than those in no-treatment or usual care groups, but no difference was found between real and sham acupuncture, compellingly pointing to a suggestion that “acupuncture has significant clinical effectiveness but has little or no specific efficacy.”17 These 2
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acupuncture trials were not selected through a balanced and systematic literature search (We selected these trials through a search of PubMed and Embase databases conducted on October, 2012, using search terms “acupuncture” and “randomized trial”. We mainly included trials of acupuncture for pain conditions published by
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highly prestigious general medical journals in the recent 10 years, which randomized patients to acupuncture, sham acupuncture, and no treatment (wait list) or standard
conventional care). It should be acknowledged, however, that they are undoubtedly of
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high quality due to their rigor, size and innovative research designs, thus representing the status in quo of clinical research of acupuncture. It is hard to believe that such a
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frequent and precise repetition of the same finding of “acupuncture is clinically
effective but not better than its placebo control” as demonstrated in these high quality
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trials of acupuncture for different pain conditions can be attributable to a mere coincidence (see the following). These RCTs of acupuncture were initially designed and conducted to verify the specific beneficial effect of acupuncture. Ironically,
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however, the most crucial information we get from them is actually to what a great extent nonspecific effects could potentially affect treatment outcome following acupuncture. Importantly, further evidence is available indicating that sham
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acupuncture procedures might be associated with larger nonspecific effects in
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comparison with other types of placebo interventions.18,19 A critical following
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question is how the trial results should be accounted for.
To have a reasonable interpretation of these clinical trials of acupuncture needs to address the question of why acupuncture fails to prove better than a placebo control. One possible answer to this question has been that acupuncture may have merely a small specific effect, as compared with its robust placebo effect. In an RCT of acupuncture, however, this small specific effect might be overridden and obscured by the large placebo effect of sham acupuncture and, thus, cannot be identified due to methodological issues. Systematic reviews are believed to be able to overcome methodological defects of individual RCTs, thus providing higher quality evidence. After analyzing individual patient data from 29 high quality RCTs (n=17922) which examined the efficacy of acupuncture for various chronic pain conditions, a latest systematic review by Vickers and colleagues20 found acupuncture to be “superior to both no-acupuncture control and sham acupuncture for the treatment of chronic pain,” possibly indicating that “acupuncture is more than a placebo.” While the authors 3
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stated that “acupuncture has effects over and above those of sham acupuncture” and that these effects are “of clear clinical relevance,” however, they also stated that “on average these effects are small,” and that “an important part of the total effects of acupuncture is not due to issues considered to be crucial by most acupuncturists, such
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as the correct location of points and depth of needling,” implicating that “nonspecific factors are important contributors to therapeutic effects following acupuncture.” In fact, an accompanying commentary of this work questioned the assertion that the
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small observed specific effect (0.5SD) of acupuncture is of clinical relevance.21
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Although current research data are not sufficient for us to ultimately determine
whether or not acupuncture possesses a small specific effect, it should be noted that
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even if this small effect does exist, and, hopefully, can be detected by future studies with methodologically improved research designs, it will not constitute any change to the fact that what is largely responsible for overall therapeutic effects of acupuncture
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is actually its robust placebo effect, rather than the assumed ‘small specific effect’. Under the circumstance of an overwhelming biomedical belief that the clinical value of a treatment is justified only by proven superiority over placebo,22 the verification of
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a specific effect with acupuncture, even though it is very small and of dubious clinical
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relevance, might make clinicians feel less uncomfortable in providing or referring patients to acupuncture.20,21 When it comes to clinical effectiveness of acupuncture,
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however, the debate centered on whether or not acupuncture has a specific effect does not make sense. From both clinical and research viewpoint, future studies should shift their focus from whether acupuncture is superior to its placebo control to why acupuncture can elicit particularly robust placebo effects which are primarily responsible for its observed clinical benefit.
A more likely interpretation of those RCTs of acupuncture is that acupuncture has no specific effect above and beyond a placebo at all; that is to say, acupuncture takes therapeutic effects entirely by virtue of a powerful placebo effect. RCTs of acupuncture were conducted to verify the hypothesis that the therapeutic effect following acupuncture is specifically due to site-specific needle insertion. To do this, different types of sham acupuncture were applied to control for various needle-related factors such as location and/or stimulation and/or depth of insertion. Although what is a valid placebo control for real acupuncture in an RCT has been a critically 4
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contentious issue,23 it is very important to note that no matter what ‘sham’ forms of acupuncture were used, they were essentially different from what is believed to be the ‘real’ acupuncture under evaluation. Since sham needling procedures could dramatically produce such robust therapeutic effects equal to those produced by real
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procedures, there is little space left for the assumed specific effect of acupuncture. In fact, the variety of sham procedures used in placebo-controlled trials of acupuncture increases the power of these trials in terms of informing the placebo nature of
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acupuncture.
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Notably, because RCTs are typically developed for testing the specific efficacy of pharmacological treatments, their validity and appropriateness for evaluating
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sophisticated invasive interventions such as acupuncture have long been under question.24 Defects inherent in currently available sham needling procedures give rise to an interesting conundrum when confronting the question of how to interpret
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sham-controlled studies of acupuncture. For example, among others, some commentators argue that unlike a placebo pill, physical placebos such as sham surgery and sham acupuncture are not ‘inert’.25 Necessarily involving touch, pressure,
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and so on, their administration may cause other types of nonspecific physiological
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effects which occur in addition to placebo effects (resulting from the therapeutic context). We believe this assumption should be given adequate attention and must be
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taken into account when seeking to understand and interpret placebo-controlled studies of acupuncture. On the other hand, however, there is indeed compelling evidence supporting the presumption that acupuncture is an enhanced placebo which acts by impacting patients’ beliefs and expectations (see section 2). Foreseeably, controversies over methodological issues concerning both clinical and experimental acupuncture research will remain until major progresses are made in understanding its underlying mechanisms.
If, as hypothesized here, observed therapeutic effects of acupuncture are a direct result of placebo effects, then it will be more relevant to look at nonspecific than specific elements of acupuncture. There have been several studies which focused on the role of nonspecific factors in the clinical effectiveness of acupuncture, and reported that manipulation of contextual factors, such as perceived treatment allocation, patients’ beliefs and expectations about acupuncture, and practitioner characteristics, could 5
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have marked impacts on outcomes after both real and sham acupuncture. 26-30 By showing that “it does not really matter whether patients received real or sham procedure; what matters is whether they believed in acupuncture and expected a benefit from it,”31 these studies add to the evidence supporting that nonspecific factors
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such as patients’ perception of and expectations toward treatment are central to self-reported effectiveness of acupuncture. Taken together, acupuncture as a type of invasive but safe intervention, characterized by an elaborate procedure and frequent
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clinician-patient interaction, is most likely to be a potent placebo. 4,15 It is noteworthy that even if acupuncture does prove to be no more than a placebo, it does not mean
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that acupuncture does nothing. Patients should not be denied potential benefits of acupuncture just because it has an enhanced placebo effect,9,21,32 especially when it is
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yet to be explained why acupuncture can induce particularly powerful placebo effects.
2. Further evidence supporting the attribution of acupuncture to a placebo
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It is always taken for granted that patients elect to receive a treatment because they want to obtain the therapeutic benefit this treatment is believe to have. This is
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especially the case for acupuncture which is, at any rate, an invasive procedure,
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depending on the insertion of fine needles in specific body areas to impart therapeutic effects. Letting a needle insert into the body is definitely an aversive experience. No
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patient would like to endure the aversiveness of an invasive procedure like acupuncture without expecting to obtain a therapeutic benefit from it. Due to its perceived invasive nature which inherently drives a benefit expectation, acupuncture is rarely, if ever, administered in the absence of patients’ positive expectations. Obviously, what allows a patient to associate needle insertion with a therapeutic procedure and, thereby, expect future therapeutic responses is the clinical context in which acupuncture is administered. A simple but meaningful question is, nevertheless, what the outcome of needle insertion is if it is administered under the condition where patients have no benefit expectations regarding it. Imaginably, inserting needles into the body, if it occurs elsewhere other than in the setting of clinical provision of acupuncture, can be nothing more than a painful injury to the body which we all have occasionally and accidentally experienced in our daily life. But it has never been 6
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heard that such a physical damage to the body can be of any benefits, not to mention clinically meaningful therapeutic effects. In a word, it is the patient’s positive beliefs and expectations that transform needle insertion—an otherwise painful injury to the
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body—into a therapeutic procedure. To suggest that acupuncture is a potent placebo does not mean that needle insertion
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plays no role in the formation of acupuncture-induced therapeutic responses; but
rather that it depends on engaging placebo mechanisms to impart therapeutic effects,
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in other words, needle insertion is not directly associated with therapeutic effects following it. This idea fits well with the clinical observation that acupuncture is not a dose-dependent therapy, and none of the physical components of needle
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administration, such as the depth and duration of needling and the method and intensity of needle stimulation, are directly associated with the magnitude of
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acupuncture-induced therapeutic effects. In fact, acupuncture itself is not a single historically stable therapy, and there are different ‘schools’ or ‘versions’ of acupuncture. Despite the considerable variation among different ‘schools’ of
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acupuncture practice, they all claim to be effective. A likely explanation for this
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phenomenon is that there is nothing specific to the needling procedure that contributes
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to therapeutic benefit following acupuncture.
On the surface, acupuncture can be defined as the practice of inserting one or more fine needles into specific sites (i.e., acupoints) on the body surface for therapeutic purposes. It should be acknowledged, however, that acupoint stimulation can be achieved in other manners, not only by needle insertion, such as moxibustion (the use of burning herbs to stimulate acupoints) and acupressure (the application of physical pressure to acupoints by the hand, elbow, or with various devices). In fact, the original Chinese term for acupuncture, Zhen Jiu (针灸), refers to not only ‘needle’ but also ‘moxa’. Thus, from the very beginning needle insertion is not one single means that can be used to stimulate acupoints. This possibly suggests that needle insertion does not stimulate acupoints in a specific manner; rather, some unknown mechanism common to real acupuncture, sham acupuncture, acupressure, and moxibustion is responsible for the therapeutic effect following these distinct meridian-based procedures. Actually, what commonly characterizes these different types of acupoint 7
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stimulation is most likely to be the underlying therapeutic context in which they are administered.
Acupuncture is a treatment modality of traditional Chinese medicine (TCM) that developed a different conceptual and theoretical basis to that of modern western
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medicine.1,3,4 Thus, without considering its traditional theory origin, acupuncture can by no means be appropriately understood and studied. One essential feature of TCM
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is that it focuses on the inseparability and unity of the mind and the body. Mental and emotional factors are believed to be inextricably linked with physical processes in
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maintaining health and precipitating illness,33 for example, changes in emotional state are believed to be able to selectively influence the functioning of internal organs.
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Interestingly, the key role of treatment context in routine medical practice was well recognized at the earliest stage of the development of TCM. In the oldest canonical classic, Inner Classic of Huang Di (Huang Di Nei Jing), which is believed to lay
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theoretical foundation for TCM, the text states, “if a patient does not consent to therapy with positive engagement, the physician should not proceed as the therapy will not succeed (“恶于针石者, 不可与言至巧; 病不许治者, 病必不治, 治之无功 34,35
The vital importance of this TCM tenet cannot be better manifested
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矣”).”
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elsewhere other than in the case of acupuncture.
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In Huang Di Nei Jing various basic needle-manipulation methods were first recorded,
which are still commonly used even today. Moreover, according to the classic, “acupuncture can be effective only when deqi (得气) (which is well documented,
referring to a composite of needling-induced unique sensations essential for the clinical effectiveness of acupuncture.36) is achieved (“刺之要, 气至而有效”).” This description makes most researchers and clinicians believe that acupuncture depends on needle stimulation to make impacts. However, this belief might not be entirely correct, because while stressing the importance of deqi for a successful acupuncture treatment, the text also states, intriguingly, “the key to acupuncture treatment lies in the engagement of spirit (“凡刺之真, 必先治神”; “凡刺之法, 先必本于神”; “ 补虚泻实, 神归其室”; “针之极也, 神明之类也, 口说书卷, 犹不能及也”).” This sentence could be
understood as that an effective acupuncture treatment requires a spiritual engagement on both the practitioner’s and the patient’s part. In other words, the spiritual
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interaction between the practitioner and the patient is a prerequisite for acupuncture to produce a therapeutic effect. This important principle is referred to as zhishen (治神), which is thought to be, at least, no less important than deqi in ensuring the effectiveness of acupuncture, as claimed in the classic, “a good practitioner pays more
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attention to spiritual interaction than needle manipulation itself (“粗守形, 上守神”)” when performing acupuncture. It is very important to note that emphasizing the
indispensible role of zhishen in the generation of acupuncture effects would become
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especially meaningful when considering the research finding that reciprocal
clinician-patient interactions significantly contribute to placebo effects.29,30,37
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Although zhishen is so highly valued as to be a sine qua non of acupuncture for the achievement of a therapeutic effect, when approaching to traditional acupuncture,
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current studies focus on deqi directly resulting from needle manipulation, and zhishen can hardly be found in the substantial English acupuncture literature. This reflects just how much the critical contribution of both practitioners’ and patients’ positive
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engagement to therapeutic outcomes of acupuncture might have been either intentionally or unintentionally ignored, possibly due to the deep concern that laying much emphasis on the importance of contextual factors associated with acupuncture
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will, as believed, fundamentally undermine its scientific basis.
In addition to clinical evidence, basic science evidence supports the association of
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acupuncture with placebo. Prior pharmacological studies reported that chemically blocking the endogenous opioid system via naloxone can reverse an otherwise clearly demonstrative placebo manifestation, 38,39 which provided the most definite
neurobiological evidence for the legitimate existence of placebo analgesic effects. Perhaps not coincidentally, this same drug has been shown experimentally to block acupuncture analgesia in human beings.40 A combination of these findings potentially
indicates that acupuncture and placebo-induced analgesic effects might be mediated by a shared opioid-dependent neural mechanism. Subsequent functional neuroimaging studies confirm this idea by demonstrating that both acupuncture and placebo analgesia are associated with an identical neural pathway—that is, cortical brain regions recruit the opioidergic descending pain control system in the brainstem. 41-43
3. Clinical and research implications
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Although underlying mechanisms of placebo effects are incompletely understood, it is now known that they are genuine psychobiological events accompanied by measurable physiological changes, but cannot be erroneously attributed to other factors, such as natural course of disease, symptom fluctuation, regression to the mean
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or report or publication bias.31,44-48 Resulting from nonspecific contextual factors involved in medical care provision, placebo effects have long been considered of no value, possibly due to the entrenched biomedical belief that clinical value of a
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treatment is justified only by its specific efficacy. However, accumulating research
evidence contradicts this old prejudiced view of placebo effects, explicitly showing
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that they, as an integral part of medical care, can have great impacts on treatment outcome, and thus might be potentially harnessed to improve patient care.6,49-52 These
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findings strongly implicate at least a possibility that placebo effects can become extraordinarily powerful and reliable under some specific conditions to such an extent of having clinical relevance. Acupuncture might be such an example where various
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nonspecific contextual factors can be brought into full play by the ritual of needle administration, thus producing clinically relevant placebo effects. On the basis of these considerations, it appears reasonable to suggest that acupuncture, as an effective
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clinical therapy, is most likely to act entirely by means of powerful placebo effects.
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Although we should be cautious about this hypothesis, it needs to be taken seriously.
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This view of acupuncture as a placebo will not only open a new window for our understanding mechanisms of acupuncture but also might provide a clue to addressing placebo-related controversies raised in other conditions, for example, in the case of the efficacy evaluation of antidepressant medication such as selective serotonin reuptake inhibitors (SSRIs). Just like pain, depression is also one of a number of conditions which are particularly subject to the influence of placebo effects.53,54 Precisely resembling what we have seen in RCTs of acupuncture for pain as analyzed in the above, meta-analyses of antidepressant clinical trials have shown that the double-blind antidepressant response is largely the result of the double-blind placebo response.55,56 Indeed, high placebo responses and small differences between drug and placebo outcomes have even resulted in refusal of drug approval.57 Most interestingly, considering the strong placebo response combined with the absence of adverse effects, some researchers have suggested to use open-label placebo as a first-line treatment for depression.58 10
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The remarkable symptom reduction in the patients in the placebo control groups of RCTs of acupuncture conceivably demonstrates what powerful impacts contextual factors can have on therapeutic outcome after acupuncture. It is important to note,
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however, that the improvement in the patients receiving a sham procedure in an RCT does not adequately reflect the exact role of placebo effects associated with
acupuncture in routine clinical practice. This is because RCTs are designed and
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conducted to detect the specific therapeutic effect of a treatment under study, but
contextual factors are treated with contempt and tolerated as nuisance that needs to be
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controlled for. In the setting of an RCT, for example, patients are fully aware that they have only a 50 percent chance to receive the real treatment. This uncertainty about
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whether or not they are on real treatment can absolutely prevent them from having as high levels of treatment expectations as when they do in real clinical settings. If ‘50 percent’ therapeutic beliefs and expectations can to such a great extent affect
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treatment outcome as demonstrated by RCTs of acupuncture, one can expect an even larger placebo effect of acupuncture with real clinical practice.
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Placebo treatments do not have any physical properties with the potential of
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producing specific therapeutic effects of interest. Thus, what is responsible for the therapeutic effects following a placebo treatment is not the treatment itself but
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patients’ perception of the treatment heavily shaped by the surrounding psychosocial
context. One key component of this overall therapeutic context is treatment characteristics (i.e., the specific nature of a treatment and the manner in which it is delivered) which can greatly influence how a treatment is perceived, believed, and expected to be effective and hence the subsequent placebo effects. In terms of the nature of treatment administration, what essentially distinguishes acupuncture from pharmacological interventions is that it involves the application of an invasive needling procedure in a specific body area. Although acupuncture is minimally invasive in essence, its needling administration may look far more invasive than it actually is. Receiving such an invasive procedure cannot fail to make great impacts on patients’ mind. It is therefore most likely that perceived invasiveness of the performance of needling procedure should be responsible for the enhanced placebo responses following acupuncture. In support of this idea, there is evidence showing that sophisticated and invasive interventions tend to have enhanced placebo 11
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effects.59-62 Interestingly, this assumed correlation of perceived invasiveness with stronger placebo effects is further corroborated by sham-controlled clinical trials of a number of surgical interventions for pain, such as arthroscopic knee surgery63,64 and spinal vertebroplasty,65,66 where comparable outcomes were reported with real and
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sham invasive procedures as well. In short, the psychosocial context associated with the administration of an invasive procedure might represent a unique situation which
has the potential to produce particularly robust placebo effects. Future studies should
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examine into cognitive and emotional processes induced in the patient when receiving an invasive procedure, which may help understand under what conditions especially
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robust placebo effects can be elicited. In fact, as it has been done,29,59,67,68 acupuncture can be used as a good tool to investigate mechanisms of placebo effects both
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experimentally and clinically.
4. Ethical concerns
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To suggest that acupuncture might be a potent placebo will inevitably cause ethical, educational, and regulatory concerns about acupuncture in both biomedical and acupuncture community. Central to these concerns is actually the long-held and
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widespread view that beneficial responses to placebo treatment inherently involve
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concealment or deception, thus violating the principle of patient autonomy.69 However, this inveterate and prejudiced view of placebo effects is challenged by recent
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advances in placebo research. Our recognition of the importance of placebo effects began with the observation that people improved—some times dramatically—in the placebo control group of an RCT where placebo effects occur following a sham or inert treatment.22 However, this does not necessarily mean that deception must be involved in the generation of placebo effects under any circumstances. For example, a recent pilot study by Kaptchuk and colleagues,70 conducted in patients with irritable bowl syndrome (IBS), found that an openly described placebo treatment when given in the context of a supportive patient-practitioner relationship and a persuasive rationale could produce clinically relevant symptom relief that was significantly better than the no treatment group. This is the first study which directly compared open-label placebo to a no-treatment control, providing initial evidence that robust placebo effects can be generated free of deception and concealment in real clinical settings.
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As the first step towards resolving those major concerns induced by the suggestion of acupuncture as a placebo, it must be proved that acupuncture does not depend on deception to generate therapeutic effects. To do this, an open label clinical trial can be conducted, in which patients are openly and deliberately informed that acupuncture
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might be a placebo therapy. This study includes 3 groups: a real acupuncture group, a sham acupuncture control group, and a no-treatment or usual care control group. The patients should be informed that (i) they will receive either real or sham acupuncture
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treatment; (ii) acupuncture is a safe therapy, but its mode of action is unclear; (iii) there is evidence showing that acupuncture might be a placebo therapy with no
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specific therapeutic effect, and that placebos can often have therapeutic effects. If, as expected, the patients in both real and sham acupuncture groups experience
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significantly greater symptom improvement than those in the no-treatment or usual care group, and there is no difference between real and sham acupuncture, then it could be argued that the self-reported symptom relief following acupuncture is due to
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placebo effects, and, more importantly, these effects are generated independent of
5. Conclusions
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concealment and deception.
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Although placebo effects have long been disparaged as resulting from a sham and deceptive treatment, their critical contribution to routine patient care needs to be
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considered carefully and dealt with honestly. Despite great advances achieved in this area, there remains much to be discovered about taking advantage of placebo effects in routine medical practice. Current research data convincingly show that most of acupuncture’s observed clinical benefit is mediated by placebo effects. We believe that acupuncture is most likely to be a placebo therapy which has clinically relevant placebo effects, possibly due to its elaborate and invasive nature. If this is true, from both clinical and research perspective, we are obliged to have a completely new look at the various key components of this therapy, such as needle insertion, meridians, and acupoints. Future studies are needed to address the link between site-specific needle insertion, placebo manipulation, and subsequent therapeutic responses, in order to elucidate biological mechanisms underlying acupuncture.
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Conflict of interest statement We declare that we have no conflict of interest.
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28. Vase L, Baram S, Takakura N, et al. Specifying the nonspecific components of
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29. Kaptchuk TJ, Kelley JM, Conboy LA, et al. Components of placebo effect:
randomised controlled trial in patients with irritable bowel syndrome. British
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30. White P, Bishop FL, Prescott P, Scott C, Little P, Lewith G. Practice, practitioner, or placebo? A multifactorial, mixed-methods randomized controlled trial of
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31. Price DD, Finniss DG, Benedetti F. A comprehensive review of the placebo effect:
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32. Miller FG, Emanuel EJ, Rosenstein DL, Straus SE. Ethical issues concerning research in complementary and alternative medicine. Journal of American
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33. Tan S, Tillisch K, Mayer E. Functional somatic syndromes: emerging biomedical models and traditional Chinese medicine. Evidence Based Complementary and
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34. Anonymous. Huang Di Nei Jing. Beijing: People’s Health Publishing, 1963. [Chinese]
35. Gollub RL, Kong J. For placebo effects in medicine, seeing is believing. Science Translational Medicine 2011;3:70ps5.
36. Hui KK, Nixon EE, Vangel MG, et al. Characterization of the "deqi" response in acupuncture. BMC Complementary and Alternative Medicine 2007;7:33. 37. Jensen KB, Petrovic P, Kerr CE, et al. Sharing pain and relief: neural correlates of physicians during treatment of patients. Molecular Psychiatry, 2013 Jan 29. doi: 10.1038/mp.2012.195. [Epub ahead of print] 38. Levine JD, Gordon NC, Fields HL. The mechanism of placebo analgesia. Lancet 16
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1978;2:654-657. 39. Amanzio M, Benedetti F. Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems. Journal of Neuroscience 1999;19:484-494.
narcotic antogonist naloxone. Brain Research 1997;121:368-372.
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40. Mayer EJ, Price DD, Rafii A. Antagonism of acupuncture analgesia in man by the
41. Dhond RP, Kettner N, Napadow V. Do the neural correlates of acupuncture and
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42. Pariente J, White P, Frackowiak RSJ, Lewith G. Expectancy and belief modulate
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the neuronal substrates of pain treated by acupuncture. Neuroimage 2005;25:1161-1167.
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43. Wu MT, Hsieh JC, Xiong J, et al. Central nervous pathway for acupuncture stimulation: localization of processing with functional MR imaging of the brain--preliminary experience. Radiology 1999;212:133-141.
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44. Benedetti F, Mayberg HS, Wager TD, Stohler CS, Zubieta JK. Neurobiological mechanisms of the placebo effect. Journal of Neuroscience 2005;25:10390-10402.
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45. Colloca L, Benedetti F. Placebos and painkillers: is mind as real as matter?
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47. Benedetti F. Mechanisms of placebo and placebo-related effects across diseases and treatments. Annual Review of Pharmacology and Toxicology 2008;48:33-60.
48. Benedetti F. Placebo and the new physiology of the doctor-patient relationship. Physiological Reviews 2013;93:1207-1246.
49. Colloca L, Miller FG. Harnessing the placebo effect: the need for translational research. Philosophical Transactions of the Royal Society B: Biological Sciences 2011;366:1922-1930.
50. Benedetti F, Carlino E, Pollo A. Hidden administration of drugs. Clinical Pharmacology & Therapeutics 2011;90:651-661. 51. Bingel U, Wanigasekera V, Wiech K, et al. The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Science Translational Medicine 2011;3:70ra14. 52. Kam-Hansen S, Jakubowski M, Kelley JM, et al. Altered placebo and drug 17
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labeling changes the outcome of episodic migraine attacks. Science Translational Medicine 2014;6:218ra5. 53. Mora MS, Nestoriuc Y, Rief W. Lessons learned from placebo groups in antidepressant trials. Philosophical Transactions of the Royal Society B:
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Biological Sciences 2011;366:1879-1888. 54. Walsh BT, Seidman SN, Sysko R, Gould M. Placebo response in studies of major depression: variable, substantial, and growing. Journal of American Medical
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55. Kirsch I, Deacon BJ, Huedo-Medina TB, et al. Initial severity and antidepressant
Public Library of Science One 2008;5:e45.
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57. Enserink M. Psychopharmacology: can the placebo be the cure? Science 1999;284,238-240.
58. Brown WA. Placebo as a treatment for depression.
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59. Kaptchuk TJ, Goldman P, Stone DA, Stason WB. Do medical devices have enhanced placebo effects? Journal of Clinical Epidemiology 2000;53:786-792.
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60. Kaptchuk TJ, Stason WB, Davis RB, et al. Sham device v inert pill: randomized controlled trial of two placebo treatments. British Medical Journal 2006;332:391-397.
61. Hróbjartsson A, Gøtzsche PC. Placebo interventions for all clinical conditions. Cochrane Database of Systematic Reviews 2010;1:CD003974.
62. Ernst E. Towards a scientific understanding of placebo effects. In: Peters D, editor. Understanding the placebo effect in complementary medicine. theory, practice and research. London: ChurchillLivingstone, 2001: 17-30. 63. Moseley JB, O’Malley K, Petersen NJ, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. New England Journal of Medicine 2002;347:81-88. 64. Sihvonen R, Paavola M, Malmivaara A, et al. Arthroscopic partial meniscectomy versus sham surgery for a degenerative meniscal tear. New England Journal of Medicine 2013;369:2515-2524. 18
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65. Kallmes DF, Comstock BA, Heagerty PJ, et al. A randomized trial of vertebroplasty for osteoporotic spinal fractures. New England Journal of Medicine 2009;361:569-579. 66. Buchbinder R, Osborne RH, Ebeling PR, et al. A randomized trial of
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vertebroplasty for painful osteoporotic vertebral fractures. New England Journal of Medicine 2009;361:557-568.
67. Kong J, Gollub RL, Rosman IS, et al. Brain activity associated with
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68. Wechsler ME, Kelley JM, Boyd IO, et al. Active albuterol or placebo, sham acupuncture, or no intervention in asthma. New England Journal of Medicine
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69. Miller FG, Colloca L. The legitimacy of placebo treatments in clinical practice: evidence and ethics. American Journal of Bioethics 2009;9:39-47.
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S0965-2299(14)00069-7 http://dx.doi.org/doi:10.1016/j.ctim.2014.05.005 YCTIM 1343
To appear in:
Complementary Therapies in Medicine
Received date: Revised date: Accepted date:
20-11-2013 30-4-2014 6-5-2014
Please cite this article as: Zheng Y-c, Yuan T-t, Liu T, Is Acupuncture a Placebo Therapy?, Complementary Therapies in Medicine (2014), http://dx.doi.org/10.1016/j.ctim.2014.05.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Is Acupuncture a Placebo Therapy? Yong-chen Zheng 1 Ting-ting Yuan 2 Tao Liu 1
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(1) Central Research Laboratory, 2nd Teaching Hospital, University of Jilin Norman Bethune School of Medicine, P. R. China.
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(2) Department of Radiology, 1st Teaching Hospital, University of Jilin Norman
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Bethune School of Medicine, P. R. China.
Corresponding Author and Reprints:
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Dr. Tao Liu, Central Research Laboratory, 2nd Teaching Hospital, University of Jilin Norman Bethune School of Medicine, 218 Ziqiang Street, Changchun 130041, Jilin
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Province, P. R. China. E-mail: [email protected]; [email protected]
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Abstract
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Complementary therapies such as acupuncture are suggested to have enhanced placebo effects. Numerous high quality randomized controlled trials found that
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acupuncture is no better than its placebo control, however patients in both real and sham acupuncture groups report clinically meaningful symptom improvements. A possible interpretation of these trials is that acupuncture acts entirely by engaging placebo mechanisms. This article provides further evidence supporting that acupuncture might be a potent placebo, and explains how to address major concerns following this suggestion.
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Acupuncture is an ancient Chinese therapy mainly used for pain control.1 Although it is widely used in China and the rest of the world, the mode of action of acupuncture is incompletely understood, and there is no conclusive evidence supporting its specific efficacy.2-4 Because acupuncture induces therapeutic effects in direct response to
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site-specific needle insertion, it has long been believed that if acupuncture is efficacious, it must be specifically due to needle stimulation. Due to this seemingly
correct view, both clinical and basic science studies of acupuncture have to date solely
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focused their attention on detecting the specific effect associated with needle insertion. Despite great efforts made during the past several decades, little meaningful progress
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has been made in this aspect. Current dilemma in acupuncture research warrants a new look at acupuncture, with respect to its clinical effectiveness, specific efficacy,
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biological mechanisms, and its ethical controversy.
1. Robust placebo effects with acupuncture
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Medical care provision is surrounded by a complex psychosocial context which can significantly affect treatment outcome.5,6 Therapeutic effects caused by this dramatic context but not by the physical property of an active treatment are generally referred
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to as ‘placebo effects’ or ‘placebo responses’. Although it has been argued that calling
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these effects ‘placebo effects’ might lead to conceptual confusion,7,8 a unanimous ideal definition of this complex phenomenon is so far unavailable. In this paper, we
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use the term ‘placebo’, focusing not on its misleading ‘inert’ nature, but on the ‘active’ context in which it is given.
It has been long been suggested that alternative therapies such as acupuncture, characterized by a sophisticated invasive procedure and an elaborate treatment ritual, might have pronounced and clinically significant placebo effects.9,10 Randomized placebo (sham)-controlled trials (RCTs) of acupuncture have provided the most forceful support to this hypothesis, although their original purpose was not to evaluate placebo effects. For example, just list a few, multiple recent large RCTs with 3 or more arms11-16 have come to a rather similar conclusion—that is, patients receiving either real or sham acupuncture reported substantially greater symptom improvements than those in no-treatment or usual care groups, but no difference was found between real and sham acupuncture, compellingly pointing to a suggestion that “acupuncture has significant clinical effectiveness but has little or no specific efficacy.”17 These 2
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acupuncture trials were not selected through a balanced and systematic literature search (We selected these trials through a search of PubMed and Embase databases conducted on October, 2012, using search terms “acupuncture” and “randomized trial”. We mainly included trials of acupuncture for pain conditions published by
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highly prestigious general medical journals in the recent 10 years, which randomized patients to acupuncture, sham acupuncture, and no treatment (wait list) or standard
conventional care). It should be acknowledged, however, that they are undoubtedly of
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high quality due to their rigor, size and innovative research designs, thus representing the status in quo of clinical research of acupuncture. It is hard to believe that such a
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frequent and precise repetition of the same finding of “acupuncture is clinically
effective but not better than its placebo control” as demonstrated in these high quality
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trials of acupuncture for different pain conditions can be attributable to a mere coincidence (see the following). These RCTs of acupuncture were initially designed and conducted to verify the specific beneficial effect of acupuncture. Ironically,
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however, the most crucial information we get from them is actually to what a great extent nonspecific effects could potentially affect treatment outcome following acupuncture. Importantly, further evidence is available indicating that sham
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acupuncture procedures might be associated with larger nonspecific effects in
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comparison with other types of placebo interventions.18,19 A critical following
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question is how the trial results should be accounted for.
To have a reasonable interpretation of these clinical trials of acupuncture needs to address the question of why acupuncture fails to prove better than a placebo control. One possible answer to this question has been that acupuncture may have merely a small specific effect, as compared with its robust placebo effect. In an RCT of acupuncture, however, this small specific effect might be overridden and obscured by the large placebo effect of sham acupuncture and, thus, cannot be identified due to methodological issues. Systematic reviews are believed to be able to overcome methodological defects of individual RCTs, thus providing higher quality evidence. After analyzing individual patient data from 29 high quality RCTs (n=17922) which examined the efficacy of acupuncture for various chronic pain conditions, a latest systematic review by Vickers and colleagues20 found acupuncture to be “superior to both no-acupuncture control and sham acupuncture for the treatment of chronic pain,” possibly indicating that “acupuncture is more than a placebo.” While the authors 3
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stated that “acupuncture has effects over and above those of sham acupuncture” and that these effects are “of clear clinical relevance,” however, they also stated that “on average these effects are small,” and that “an important part of the total effects of acupuncture is not due to issues considered to be crucial by most acupuncturists, such
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as the correct location of points and depth of needling,” implicating that “nonspecific factors are important contributors to therapeutic effects following acupuncture.” In fact, an accompanying commentary of this work questioned the assertion that the
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small observed specific effect (0.5SD) of acupuncture is of clinical relevance.21
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Although current research data are not sufficient for us to ultimately determine
whether or not acupuncture possesses a small specific effect, it should be noted that
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even if this small effect does exist, and, hopefully, can be detected by future studies with methodologically improved research designs, it will not constitute any change to the fact that what is largely responsible for overall therapeutic effects of acupuncture
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is actually its robust placebo effect, rather than the assumed ‘small specific effect’. Under the circumstance of an overwhelming biomedical belief that the clinical value of a treatment is justified only by proven superiority over placebo,22 the verification of
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a specific effect with acupuncture, even though it is very small and of dubious clinical
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relevance, might make clinicians feel less uncomfortable in providing or referring patients to acupuncture.20,21 When it comes to clinical effectiveness of acupuncture,
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however, the debate centered on whether or not acupuncture has a specific effect does not make sense. From both clinical and research viewpoint, future studies should shift their focus from whether acupuncture is superior to its placebo control to why acupuncture can elicit particularly robust placebo effects which are primarily responsible for its observed clinical benefit.
A more likely interpretation of those RCTs of acupuncture is that acupuncture has no specific effect above and beyond a placebo at all; that is to say, acupuncture takes therapeutic effects entirely by virtue of a powerful placebo effect. RCTs of acupuncture were conducted to verify the hypothesis that the therapeutic effect following acupuncture is specifically due to site-specific needle insertion. To do this, different types of sham acupuncture were applied to control for various needle-related factors such as location and/or stimulation and/or depth of insertion. Although what is a valid placebo control for real acupuncture in an RCT has been a critically 4
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contentious issue,23 it is very important to note that no matter what ‘sham’ forms of acupuncture were used, they were essentially different from what is believed to be the ‘real’ acupuncture under evaluation. Since sham needling procedures could dramatically produce such robust therapeutic effects equal to those produced by real
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procedures, there is little space left for the assumed specific effect of acupuncture. In fact, the variety of sham procedures used in placebo-controlled trials of acupuncture increases the power of these trials in terms of informing the placebo nature of
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acupuncture.
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Notably, because RCTs are typically developed for testing the specific efficacy of pharmacological treatments, their validity and appropriateness for evaluating
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sophisticated invasive interventions such as acupuncture have long been under question.24 Defects inherent in currently available sham needling procedures give rise to an interesting conundrum when confronting the question of how to interpret
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sham-controlled studies of acupuncture. For example, among others, some commentators argue that unlike a placebo pill, physical placebos such as sham surgery and sham acupuncture are not ‘inert’.25 Necessarily involving touch, pressure,
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and so on, their administration may cause other types of nonspecific physiological
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effects which occur in addition to placebo effects (resulting from the therapeutic context). We believe this assumption should be given adequate attention and must be
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taken into account when seeking to understand and interpret placebo-controlled studies of acupuncture. On the other hand, however, there is indeed compelling evidence supporting the presumption that acupuncture is an enhanced placebo which acts by impacting patients’ beliefs and expectations (see section 2). Foreseeably, controversies over methodological issues concerning both clinical and experimental acupuncture research will remain until major progresses are made in understanding its underlying mechanisms.
If, as hypothesized here, observed therapeutic effects of acupuncture are a direct result of placebo effects, then it will be more relevant to look at nonspecific than specific elements of acupuncture. There have been several studies which focused on the role of nonspecific factors in the clinical effectiveness of acupuncture, and reported that manipulation of contextual factors, such as perceived treatment allocation, patients’ beliefs and expectations about acupuncture, and practitioner characteristics, could 5
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have marked impacts on outcomes after both real and sham acupuncture. 26-30 By showing that “it does not really matter whether patients received real or sham procedure; what matters is whether they believed in acupuncture and expected a benefit from it,”31 these studies add to the evidence supporting that nonspecific factors
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such as patients’ perception of and expectations toward treatment are central to self-reported effectiveness of acupuncture. Taken together, acupuncture as a type of invasive but safe intervention, characterized by an elaborate procedure and frequent
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clinician-patient interaction, is most likely to be a potent placebo. 4,15 It is noteworthy that even if acupuncture does prove to be no more than a placebo, it does not mean
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that acupuncture does nothing. Patients should not be denied potential benefits of acupuncture just because it has an enhanced placebo effect,9,21,32 especially when it is
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yet to be explained why acupuncture can induce particularly powerful placebo effects.
2. Further evidence supporting the attribution of acupuncture to a placebo
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It is always taken for granted that patients elect to receive a treatment because they want to obtain the therapeutic benefit this treatment is believe to have. This is
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especially the case for acupuncture which is, at any rate, an invasive procedure,
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depending on the insertion of fine needles in specific body areas to impart therapeutic effects. Letting a needle insert into the body is definitely an aversive experience. No
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patient would like to endure the aversiveness of an invasive procedure like acupuncture without expecting to obtain a therapeutic benefit from it. Due to its perceived invasive nature which inherently drives a benefit expectation, acupuncture is rarely, if ever, administered in the absence of patients’ positive expectations. Obviously, what allows a patient to associate needle insertion with a therapeutic procedure and, thereby, expect future therapeutic responses is the clinical context in which acupuncture is administered. A simple but meaningful question is, nevertheless, what the outcome of needle insertion is if it is administered under the condition where patients have no benefit expectations regarding it. Imaginably, inserting needles into the body, if it occurs elsewhere other than in the setting of clinical provision of acupuncture, can be nothing more than a painful injury to the body which we all have occasionally and accidentally experienced in our daily life. But it has never been 6
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heard that such a physical damage to the body can be of any benefits, not to mention clinically meaningful therapeutic effects. In a word, it is the patient’s positive beliefs and expectations that transform needle insertion—an otherwise painful injury to the
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body—into a therapeutic procedure. To suggest that acupuncture is a potent placebo does not mean that needle insertion
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plays no role in the formation of acupuncture-induced therapeutic responses; but
rather that it depends on engaging placebo mechanisms to impart therapeutic effects,
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in other words, needle insertion is not directly associated with therapeutic effects following it. This idea fits well with the clinical observation that acupuncture is not a dose-dependent therapy, and none of the physical components of needle
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administration, such as the depth and duration of needling and the method and intensity of needle stimulation, are directly associated with the magnitude of
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acupuncture-induced therapeutic effects. In fact, acupuncture itself is not a single historically stable therapy, and there are different ‘schools’ or ‘versions’ of acupuncture. Despite the considerable variation among different ‘schools’ of
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acupuncture practice, they all claim to be effective. A likely explanation for this
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phenomenon is that there is nothing specific to the needling procedure that contributes
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to therapeutic benefit following acupuncture.
On the surface, acupuncture can be defined as the practice of inserting one or more fine needles into specific sites (i.e., acupoints) on the body surface for therapeutic purposes. It should be acknowledged, however, that acupoint stimulation can be achieved in other manners, not only by needle insertion, such as moxibustion (the use of burning herbs to stimulate acupoints) and acupressure (the application of physical pressure to acupoints by the hand, elbow, or with various devices). In fact, the original Chinese term for acupuncture, Zhen Jiu (针灸), refers to not only ‘needle’ but also ‘moxa’. Thus, from the very beginning needle insertion is not one single means that can be used to stimulate acupoints. This possibly suggests that needle insertion does not stimulate acupoints in a specific manner; rather, some unknown mechanism common to real acupuncture, sham acupuncture, acupressure, and moxibustion is responsible for the therapeutic effect following these distinct meridian-based procedures. Actually, what commonly characterizes these different types of acupoint 7
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stimulation is most likely to be the underlying therapeutic context in which they are administered.
Acupuncture is a treatment modality of traditional Chinese medicine (TCM) that developed a different conceptual and theoretical basis to that of modern western
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medicine.1,3,4 Thus, without considering its traditional theory origin, acupuncture can by no means be appropriately understood and studied. One essential feature of TCM
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is that it focuses on the inseparability and unity of the mind and the body. Mental and emotional factors are believed to be inextricably linked with physical processes in
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maintaining health and precipitating illness,33 for example, changes in emotional state are believed to be able to selectively influence the functioning of internal organs.
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Interestingly, the key role of treatment context in routine medical practice was well recognized at the earliest stage of the development of TCM. In the oldest canonical classic, Inner Classic of Huang Di (Huang Di Nei Jing), which is believed to lay
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theoretical foundation for TCM, the text states, “if a patient does not consent to therapy with positive engagement, the physician should not proceed as the therapy will not succeed (“恶于针石者, 不可与言至巧; 病不许治者, 病必不治, 治之无功 34,35
The vital importance of this TCM tenet cannot be better manifested
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矣”).”
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elsewhere other than in the case of acupuncture.
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In Huang Di Nei Jing various basic needle-manipulation methods were first recorded,
which are still commonly used even today. Moreover, according to the classic, “acupuncture can be effective only when deqi (得气) (which is well documented,
referring to a composite of needling-induced unique sensations essential for the clinical effectiveness of acupuncture.36) is achieved (“刺之要, 气至而有效”).” This description makes most researchers and clinicians believe that acupuncture depends on needle stimulation to make impacts. However, this belief might not be entirely correct, because while stressing the importance of deqi for a successful acupuncture treatment, the text also states, intriguingly, “the key to acupuncture treatment lies in the engagement of spirit (“凡刺之真, 必先治神”; “凡刺之法, 先必本于神”; “ 补虚泻实, 神归其室”; “针之极也, 神明之类也, 口说书卷, 犹不能及也”).” This sentence could be
understood as that an effective acupuncture treatment requires a spiritual engagement on both the practitioner’s and the patient’s part. In other words, the spiritual
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interaction between the practitioner and the patient is a prerequisite for acupuncture to produce a therapeutic effect. This important principle is referred to as zhishen (治神), which is thought to be, at least, no less important than deqi in ensuring the effectiveness of acupuncture, as claimed in the classic, “a good practitioner pays more
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attention to spiritual interaction than needle manipulation itself (“粗守形, 上守神”)” when performing acupuncture. It is very important to note that emphasizing the
indispensible role of zhishen in the generation of acupuncture effects would become
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especially meaningful when considering the research finding that reciprocal
clinician-patient interactions significantly contribute to placebo effects.29,30,37
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Although zhishen is so highly valued as to be a sine qua non of acupuncture for the achievement of a therapeutic effect, when approaching to traditional acupuncture,
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current studies focus on deqi directly resulting from needle manipulation, and zhishen can hardly be found in the substantial English acupuncture literature. This reflects just how much the critical contribution of both practitioners’ and patients’ positive
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engagement to therapeutic outcomes of acupuncture might have been either intentionally or unintentionally ignored, possibly due to the deep concern that laying much emphasis on the importance of contextual factors associated with acupuncture
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will, as believed, fundamentally undermine its scientific basis.
In addition to clinical evidence, basic science evidence supports the association of
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acupuncture with placebo. Prior pharmacological studies reported that chemically blocking the endogenous opioid system via naloxone can reverse an otherwise clearly demonstrative placebo manifestation, 38,39 which provided the most definite
neurobiological evidence for the legitimate existence of placebo analgesic effects. Perhaps not coincidentally, this same drug has been shown experimentally to block acupuncture analgesia in human beings.40 A combination of these findings potentially
indicates that acupuncture and placebo-induced analgesic effects might be mediated by a shared opioid-dependent neural mechanism. Subsequent functional neuroimaging studies confirm this idea by demonstrating that both acupuncture and placebo analgesia are associated with an identical neural pathway—that is, cortical brain regions recruit the opioidergic descending pain control system in the brainstem. 41-43
3. Clinical and research implications
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Although underlying mechanisms of placebo effects are incompletely understood, it is now known that they are genuine psychobiological events accompanied by measurable physiological changes, but cannot be erroneously attributed to other factors, such as natural course of disease, symptom fluctuation, regression to the mean
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or report or publication bias.31,44-48 Resulting from nonspecific contextual factors involved in medical care provision, placebo effects have long been considered of no value, possibly due to the entrenched biomedical belief that clinical value of a
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treatment is justified only by its specific efficacy. However, accumulating research
evidence contradicts this old prejudiced view of placebo effects, explicitly showing
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that they, as an integral part of medical care, can have great impacts on treatment outcome, and thus might be potentially harnessed to improve patient care.6,49-52 These
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findings strongly implicate at least a possibility that placebo effects can become extraordinarily powerful and reliable under some specific conditions to such an extent of having clinical relevance. Acupuncture might be such an example where various
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nonspecific contextual factors can be brought into full play by the ritual of needle administration, thus producing clinically relevant placebo effects. On the basis of these considerations, it appears reasonable to suggest that acupuncture, as an effective
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clinical therapy, is most likely to act entirely by means of powerful placebo effects.
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Although we should be cautious about this hypothesis, it needs to be taken seriously.
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This view of acupuncture as a placebo will not only open a new window for our understanding mechanisms of acupuncture but also might provide a clue to addressing placebo-related controversies raised in other conditions, for example, in the case of the efficacy evaluation of antidepressant medication such as selective serotonin reuptake inhibitors (SSRIs). Just like pain, depression is also one of a number of conditions which are particularly subject to the influence of placebo effects.53,54 Precisely resembling what we have seen in RCTs of acupuncture for pain as analyzed in the above, meta-analyses of antidepressant clinical trials have shown that the double-blind antidepressant response is largely the result of the double-blind placebo response.55,56 Indeed, high placebo responses and small differences between drug and placebo outcomes have even resulted in refusal of drug approval.57 Most interestingly, considering the strong placebo response combined with the absence of adverse effects, some researchers have suggested to use open-label placebo as a first-line treatment for depression.58 10
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The remarkable symptom reduction in the patients in the placebo control groups of RCTs of acupuncture conceivably demonstrates what powerful impacts contextual factors can have on therapeutic outcome after acupuncture. It is important to note,
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however, that the improvement in the patients receiving a sham procedure in an RCT does not adequately reflect the exact role of placebo effects associated with
acupuncture in routine clinical practice. This is because RCTs are designed and
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conducted to detect the specific therapeutic effect of a treatment under study, but
contextual factors are treated with contempt and tolerated as nuisance that needs to be
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controlled for. In the setting of an RCT, for example, patients are fully aware that they have only a 50 percent chance to receive the real treatment. This uncertainty about
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whether or not they are on real treatment can absolutely prevent them from having as high levels of treatment expectations as when they do in real clinical settings. If ‘50 percent’ therapeutic beliefs and expectations can to such a great extent affect
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treatment outcome as demonstrated by RCTs of acupuncture, one can expect an even larger placebo effect of acupuncture with real clinical practice.
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Placebo treatments do not have any physical properties with the potential of
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producing specific therapeutic effects of interest. Thus, what is responsible for the therapeutic effects following a placebo treatment is not the treatment itself but
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patients’ perception of the treatment heavily shaped by the surrounding psychosocial
context. One key component of this overall therapeutic context is treatment characteristics (i.e., the specific nature of a treatment and the manner in which it is delivered) which can greatly influence how a treatment is perceived, believed, and expected to be effective and hence the subsequent placebo effects. In terms of the nature of treatment administration, what essentially distinguishes acupuncture from pharmacological interventions is that it involves the application of an invasive needling procedure in a specific body area. Although acupuncture is minimally invasive in essence, its needling administration may look far more invasive than it actually is. Receiving such an invasive procedure cannot fail to make great impacts on patients’ mind. It is therefore most likely that perceived invasiveness of the performance of needling procedure should be responsible for the enhanced placebo responses following acupuncture. In support of this idea, there is evidence showing that sophisticated and invasive interventions tend to have enhanced placebo 11
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effects.59-62 Interestingly, this assumed correlation of perceived invasiveness with stronger placebo effects is further corroborated by sham-controlled clinical trials of a number of surgical interventions for pain, such as arthroscopic knee surgery63,64 and spinal vertebroplasty,65,66 where comparable outcomes were reported with real and
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sham invasive procedures as well. In short, the psychosocial context associated with the administration of an invasive procedure might represent a unique situation which
has the potential to produce particularly robust placebo effects. Future studies should
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examine into cognitive and emotional processes induced in the patient when receiving an invasive procedure, which may help understand under what conditions especially
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robust placebo effects can be elicited. In fact, as it has been done,29,59,67,68 acupuncture can be used as a good tool to investigate mechanisms of placebo effects both
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experimentally and clinically.
4. Ethical concerns
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To suggest that acupuncture might be a potent placebo will inevitably cause ethical, educational, and regulatory concerns about acupuncture in both biomedical and acupuncture community. Central to these concerns is actually the long-held and
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widespread view that beneficial responses to placebo treatment inherently involve
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concealment or deception, thus violating the principle of patient autonomy.69 However, this inveterate and prejudiced view of placebo effects is challenged by recent
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advances in placebo research. Our recognition of the importance of placebo effects began with the observation that people improved—some times dramatically—in the placebo control group of an RCT where placebo effects occur following a sham or inert treatment.22 However, this does not necessarily mean that deception must be involved in the generation of placebo effects under any circumstances. For example, a recent pilot study by Kaptchuk and colleagues,70 conducted in patients with irritable bowl syndrome (IBS), found that an openly described placebo treatment when given in the context of a supportive patient-practitioner relationship and a persuasive rationale could produce clinically relevant symptom relief that was significantly better than the no treatment group. This is the first study which directly compared open-label placebo to a no-treatment control, providing initial evidence that robust placebo effects can be generated free of deception and concealment in real clinical settings.
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As the first step towards resolving those major concerns induced by the suggestion of acupuncture as a placebo, it must be proved that acupuncture does not depend on deception to generate therapeutic effects. To do this, an open label clinical trial can be conducted, in which patients are openly and deliberately informed that acupuncture
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might be a placebo therapy. This study includes 3 groups: a real acupuncture group, a sham acupuncture control group, and a no-treatment or usual care control group. The patients should be informed that (i) they will receive either real or sham acupuncture
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treatment; (ii) acupuncture is a safe therapy, but its mode of action is unclear; (iii) there is evidence showing that acupuncture might be a placebo therapy with no
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specific therapeutic effect, and that placebos can often have therapeutic effects. If, as expected, the patients in both real and sham acupuncture groups experience
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significantly greater symptom improvement than those in the no-treatment or usual care group, and there is no difference between real and sham acupuncture, then it could be argued that the self-reported symptom relief following acupuncture is due to
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placebo effects, and, more importantly, these effects are generated independent of
5. Conclusions
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concealment and deception.
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Although placebo effects have long been disparaged as resulting from a sham and deceptive treatment, their critical contribution to routine patient care needs to be
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considered carefully and dealt with honestly. Despite great advances achieved in this area, there remains much to be discovered about taking advantage of placebo effects in routine medical practice. Current research data convincingly show that most of acupuncture’s observed clinical benefit is mediated by placebo effects. We believe that acupuncture is most likely to be a placebo therapy which has clinically relevant placebo effects, possibly due to its elaborate and invasive nature. If this is true, from both clinical and research perspective, we are obliged to have a completely new look at the various key components of this therapy, such as needle insertion, meridians, and acupoints. Future studies are needed to address the link between site-specific needle insertion, placebo manipulation, and subsequent therapeutic responses, in order to elucidate biological mechanisms underlying acupuncture.
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Conflict of interest statement We declare that we have no conflict of interest.
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