Carolyn Ee, MBBS; Charlie Xue, PhD; Patty Chondros, PhD; Stephen P. Myers, PhD; Simon D. French, PhD; Helena Teede, PhD; Marie Pirotta, PhD
This article was published at www.annals.org on 19 January 2016.
Note: Dr. Ee confirms, as primary and corresponding author, that she had full access to all of the study data and takes responsibility for its integrity and the accuracy of the data analysis.
Acknowledgment: The authors thank the research assistants, Kitty Novy, Mary Kyriakides, and others, for their hard work and dedication to the day-to-day running of the project; Melanie Gibson for assistance with recruitment and survey management; Annie Rahilly and the staff at Jean Hailes for Women's Health for assistance with recruitment; Ben Metcalf for designing the randomization spread sheet; Dr. Zhen Zheng, Professor Caroline Smith, and the other acupuncture experts for providing expert opinions on the treatment protocol; Vincent Cheong for producing the DVD on the Park sham device; Dr. Vicki Kotsirilos for providing a consultation space for Chinese medicine interviews; and Johannah Shergis for replacing Dr. Ee while Dr. Ee was on maternity leave. They also thank Mary-Jo Bevin, George Dellas, Suzy McCleary, John McDonald, Melanie Wells, Tanya Wilson, Richard Zeng, and all other project acupuncturists, as well as the study participants.
Grant Support: By the National Health and Medical Research Council (NHMRC) of Australia (project grant APP 1004406). Dr. Pirotta is supported by an NHMRC Career Development Fellowship. Dr. Ee is supported by an NHMRC Postgraduate Scholarship. Dr. Teede is supported by an NHMRC Practitioner Fellowship.
Disclosures: Dr. Pirotta reports grants and other from the NHMRC during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterest Forms.do?msNum=M15-1380.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.
Reproducible Research Statement:Study protocol: Available at www.trialsjournal.com/content/15/1/224. Statistical code: Available from Dr. Pirotta (e-mail, firstname.lastname@example.org). Data set: Certain portions of the analytic data set are available from Dr. Pirotta (e-mail, email@example.com).
Requests for Single Reprints: Carolyn Ee, MBBS, Department of General Practice, University of Melbourne, 200 Berkeley Street, Carlton, 3053 Victoria, Australia; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Ee, Chondros, and Pirotta: Department of General Practice, University of Melbourne, 200 Berkeley Street, Carlton, 3053 Victoria, Australia.
Dr. Xue: Professor, School of Health Sciences, Royal Melbourne Institute of Technology (RMIT) University, PO Box 71, Bundoora, 3083 Victoria, Australia.
Dr. Myers: NatMed Research Unit, Southern Cross University, PO Box 157, Lismore, Queensland, Australia.
Dr. French: Associate Professor, School of Rehabilitation Therapy, Queen's University, Louise D. Acton Building, 31 George Street, Kingston, Ontario K7L 3N6, Canada.
Dr. Teede: Director, Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Level 1, 43-51 Kanooka Grove, Clayton, 3168 Victoria, Australia.
Author Contributions: Conception and design: C. Ee, C. Xue, P. Chondros, S.P. Myers, S.D. French, H. Teede, M. Pirotta.
Analysis and interpretation of the data: C. Ee, C. Xue, P. Chondros, S.P. Myers, S.D. French, H. Teede, M. Pirotta.
Drafting of the article: C. Ee, C. Xue, P. Chondros, S.D. French, H. Teede, M. Pirotta.
Critical revision of the article for important intellectual content: C. Ee, C. Xue, P. Chondros, S.P. Myers, S.D. French, H. Teede, M. Pirotta.
Final approval of the article: C. Ee, C. Xue, P. Chondros, S.P. Myers, S.D. French, H. Teede, M. Pirotta.
Provision of study materials or patients: C. Ee, C. Xue.
Statistical expertise: P. Chondros.
Obtaining of funding: C. Ee, C. Xue, P. Chondros, S.P. Myers, S.D. French, H. Teede, M. Pirotta.
Administrative, technical, or logistic support: C. Ee, H. Teede.
Collection and assembly of data: C. Ee, P. Chondros, M. Pirotta.
Ee C., Xue C., Chondros P., Myers S., French S., Teede H., Pirotta M.; Acupuncture for Menopausal Hot Flashes: A Randomized Trial. Ann Intern Med. 2016;164:146-154. doi: 10.7326/M15-1380
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Published: Ann Intern Med. 2016;164(3):146-154.
Published at www.annals.org on 19 January 2016
Hot flashes (HFs) affect up to 75% of menopausal women and pose a considerable health and financial burden. Evidence of acupuncture efficacy as an HF treatment is conflicting.
To assess the efficacy of Chinese medicine acupuncture against sham acupuncture for menopausal HFs.
Stratified, blind (participants, outcome assessors, and investigators, but not treating acupuncturists), parallel, randomized, sham-controlled trial with equal allocation. (Australia New Zealand Clinical Trials Registry: ACTRN12611000393954)
Community in Australia.
Women older than 40 years in the late menopausal transition or postmenopause with at least 7 moderate HFs daily, meeting criteria for Chinese medicine diagnosis of kidney yin deficiency.
10 treatments over 8 weeks of either standardized Chinese medicine needle acupuncture designed to treat kidney yin deficiency or noninsertive sham acupuncture.
The primary outcome was HF score at the end of treatment. Secondary outcomes included quality of life, anxiety, depression, and adverse events. Participants were assessed at 4 weeks, the end of treatment, and then 3 and 6 months after the end of treatment. Intention-to-treat analysis was conducted with linear mixed-effects models.
327 women were randomly assigned to acupuncture (n = 163) or sham acupuncture (n = 164). At the end of treatment, 16% of participants in the acupuncture group and 13% in the sham group were lost to follow-up. Mean HF scores at the end of treatment were 15.36 in the acupuncture group and 15.04 in the sham group (mean difference, 0.33 [95% CI, −1.87 to 2.52]; P = 0.77). No serious adverse events were reported.
Participants were predominantly Caucasian and did not have breast cancer or surgical menopause.
Chinese medicine acupuncture was not superior to noninsertive sham acupuncture for women with moderately severe menopausal HFs.
National Health and Medical Research Council.
John Varner, L.Ac
January 25, 2016
The claim that acupuncture is not superior to 'placebo acupuncture' is misleading. I am an acupuncturist and participated in a placebo acupuncture trial of acupuncture treatment of peri-menopausal symptoms in women taking estrogen suppressors. Participants kept journal records of their experiences, noting changes in hot flash numbers and intensities, sleep patterns, and general well-being. Conclusions: the 'placebo acupuncture' procedure was actually quite like a common Japanese style of acupuncture, where as 'real' acupuncture was a 'hobbled' version of traditional Chines style acupuncture; trying to design a study using placebo needles is problematic for a number of reasons, including: people know if they are being needled or not; practicing acupuncture clinically typically involves adapting point protocols to individual patients on a day-to-day basis, which makes per-programed sets of points unrealistic; 'placebo needles' require the use of tape and spacers over the points so that the needles stand up and appear to be inserted (they are like collapsible stage knives), which then makes inserting real needles cumbersome, and results in the blunt 'placebo needles' (which often do not retract easily) deeply indenting or even penetrating the skin.In the study in which I participated, 2/3rds of the participants responded positively to 'real' but not placebo acupuncture, and 1/3rd responded better to 'placebo' than 'real' acupuncture (the two groups were 'crossed over, i.e.: both got real AND placebo treatments, separated by a 'wash-out' period of several weeks). Bottom line: nearly all benefited, just not from the same style or type of treatment.It should be noted that the effects of acupuncture on hot flashes appears not to derive from altered levels of hormones, but in how the nervous system responds to hormones (this has been demonstrated in other studies). Another observation was that the group who responded better to 'placebo acupuncture' (i.e. mild sensation, delivered slightly off 'real' acupoints) tended to be patients with a higher baseline level of anxiety. These patients found 'real' (pseudo Chinese style) acupuncture to be quite uncomfortable, which increased their anxiety levels. It is worth noting that inserting needles that have just penetrated a layer of tape both impeded practitioners avoiding small blood vessels and left tape residue on needle shafts, which increased drag as the needles penetrated the skin. I would not try to make a case for the numerous differing ideas of what 'qi' is (beyond the integrated bioelectric/biochemical functioning of the body), or the validity of the 'meridian system' or the various paradigms used by practitioners of acupuncture (there are grains of truth among a goodly amount of chaff). However to deny that there is something interesting going on, or that acupuncture, for all its uses, is just a 'placebo effect' is to ignore the experience of millions of people over thousands of years. It also flies in the face of veterinary acupuncture, also practiced for millennia, the efficacy of which does not depend on 'patients' believing it works....
Ana Maria Lopez, MD, MPH (1,2); Angela Presson, PhD (2); Annie Budhathoki, MSTOM, L.Ac. (1,2); Shelley White, LCSW (1, 2)
Huntsman Cancer Institute (1); University of Utah Health Sciences (2)
February 11, 2016
Revisiting the interpretation
We commend Ee and colleagues for tackling 2 challenging topics--the clinically elusive pathophysiology and optimum treatment for menopausal hot flashes (HF) (1,2) and the methodologically problematic assessment of acupuncture with sham acupuncture (3). The authors conclude: “Chinese medicine acupuncture was not superior to noninsertive sham acupuncture for moderately severe menopausal HFs.” The general take away interpretation has been that acupuncture is ineffective for HF. We would like to revisit this conclusion.The authors note that limiting Chinese medicine to a standard acupuncture protocol does not mirror standard clinical practice and that developing and implementing a true placebo is difficult. In this study, a blunt needle tip was used for the sham noninsertive acupuncture. The sensation produced by the blunt needle tip has been documented to produce physiologic effects. Study participants were blinded to the treatment and were not required to be acupuncture naïve. About two-thirds were unsure of their assignment after the first acupuncture session and only seven percent correctly perceived that they were in the sham group. The paper delineates the innervation of the placebo treatment points but not of the insertive treatment points. Segmental innervation (dermatome, myotome) can help differentiate the treatment point from the sham point. The results revealed that both groups experienced a 40% improvement in HF, no significant side effects, and a sustained benefit at 3 and 6 months after treatment. A recent Cochrane review (4) similarly concluded that acupuncture is no better than sham acupuncture for HF while being effective when compared to a no treatment control. This finding may be attributed to the known effectiveness of non-insertive protocols in Chinese medicine—acupressure and moxibustion. Since a quick review of effective standard pharmacologic approaches for HF demonstrates symptom improvement in the range of 30-60% that is associated with multiple side effects and without a prolonged response (5), perhaps we need to ask what is effective about sham acupuncture.
Nobuari Takakura, Ph.D., Miho Takayama, Ph.D., Hiroyoshi Yajima, Ph.D
Tokyo Ariake University of Medical and Health Sciences, Showa University School of Medicine
March 3, 2016
Does sham needle always work as placebo?
To the Editor: In the article “Acupuncture for menopausal hot flashes: A randomized trial” (1), Ee et al concluded that there was no additional benefit from needle insertion over blunt needling for menopausal hot flashes in women who met criteria for signs of kidney Yin deficiency. In the real acupuncture group, unilateral acupoints were used to apply penetrating needles, and the patients had de qi. In the sham acupuncture group, bilateral non-acupoints were used to apply non-penetrating needles without seeking de qi. We considered possible causes of the negative result for the real acupuncture group based on the intergroup differences. To determine whether the benefit of needle insertion was superior to that of blunt needling, the acupoints—bilateral or not—should have been the same for both intervention groups. Although the authors used non-acupoints, as far as we know, there was no conclusive evidence showing that the non-acupoints were not effective points. It cannot be totally excluded that blunt needling applied to the non-acupoints worked as a diffuse noxious inhibitory control so that invasive stimulation of any points of the body inhibited pain (2). Blunt needling induces pain similar to needle insertion (3); thus, >60% of all the women were unsure of the treatment they received, and 31% of the sham group women believed that they received real acupuncture (1). One of dominant principles for acupuncture treatment is are “tonifying [gentle stimulation applied in deficiency-type disturbances (Yin type)] and sedating [intensive stimulation applied in excess-type conditions (Yang type)]” (4). Although real acupuncture was applied as tonification in Ee et al’s study, blunt needling without seeking de qi in the sham group, which is relatively gentler stimulation than needle insertion with de qi, seems more effective than real acupuncture for Yin-deficient patients. Further, brushing stimulation of the lower chest or hind limb skin decreases the adrenal nerve activity, while pinching stimulation of the skin in these areas increases adrenal nerve activity in rats (5). This suggests that weaker stimulation is better for patients with vasomotor symptoms (6), and that a stronger effect could be obtained for blunt needling compared to that of needle insertion if the acupoints were the same. Thus, all conditions should be the same, except penetration. Otherwise, a gentle effect of needle insertion or blunt needling may not be detected. It is also desirable to use no-touch placebo needles to detect a specific effect of blunt needling (3).References (1) Ee C, Xue C, Chondros P, Myers SP, French SD, Teede H, et al. Acupuncture for menopausal hot flashes: A randomized trial. Ann Intern Med. 2016;164(3):146-54.(2) Le Bars D, Villanueva L, Bouhassira D, Willer JC. Diffuse Noxious Inhibitory Controls (DNIC) in animals and in man. Patol Fiziol Eksp Ter. 1992;(4):55-65.(3) Takakura N, Takayama M, Kawase A, Yajima H. Double blinding with a new placebo needle: a validation study on participant blinding. Acupunct Med. 2011;29(3):203-7.(4) Stux G. Technique of acupuncture. In: Stux G, Berman B, Pomeranz B, Kofen P, editors. Basics of acupuncture. New York: Springer-Verlag; 2003. p. 243-4.(5) Isa T, Kurosawa M, Sato A, Swenson RS. Reflex responses evoked in the adrenal sympathetic nerve to electrical stimulation of somatic afferent nerves in the rat. Neurosci Res. 1985;3(2):130-44.(6) Akiyoshi M, Kato K, Owa Y, Sugyama M, Miyasaka N, Obayashi S, et al. Relationship between estrogen, vasomotor symptoms, and heart rate variability in climacteric women. J Med Dent Sci. 2011;58:49-59.
Tae-Hun Kim, Jung Won Kang and Myeong Soo Lee
1 Korean Medicine Clinical Trial Center, Korean Medicine Hospital, Kyung Hee University, Seoul, South Korea, 2 Department of Acupuncture & Moxibustion, College of Korean Medicine, Kyung Hee Univer
March 19, 2016
Conflict of Interest:
THK is supported by the Traditional Korean Medicine R&D program funded by the Ministry of Health & Welfare through the Korea Health Industry Development Institute (KHIDI). (Grand Number: HI15C0089). MSL was supported by Korea Institute of Oriental Medicine (K16292).<br/><br/>
What is lost in the acupuncture trial compared with sham intervention: an addendum to currently published reports
Is acupuncture an effective intervention without health benefits? Amid of era of evidence-based medicine, should acupuncture be rejected and removed from regular practice? Currently published clinical research on the effect of acupuncture for menopausal hot flashes among climacteric women successfully induces this argument again. Ee et al. conducted a randomized control trial on hot flash patients in Australia (1). The result is simple: both interventions improved hot flash scores, which was the primary outcome of this study, by approximately 40% compared with baseline status, and the improvement continued up to 6 months after the end of treatment among both groups with no significant difference between groups. However, soon after the study was published, REUITER published an article “Acupuncture needling doesn't ease menopausal hot flashes” (2). What does that mean?What if different control interventions were used? When compared with no treatment, acupuncture revealed significant improvement in decreasing the frequency (standard mean difference, SMD -0.5 (-0.69 to -0.31)) and intensity (SMD -0.54 (-0.73 to -0.35)) of hot flashes (3). In addition, acupuncture exhibited effects equivalent to venlafaxine, which is one of the standard non-hormonal drug treatments for estrogen-contraindicated hot flash patients (4). There is another issue further discussed regarding the intervention termed “real acupuncture” in this study. To blind both interventions, the authors used “the base unit” in both groups, which is a necessary component supporting sham acupuncture needle retention on the skin (5). The troublesome point appears when using “real” acupuncture with this unit; a four centimeter tall “real” acupuncture needle body can be inserted into the skin approximately zero to four cm theoretically, but the actual depth of insertion might not exceed two cm because the handle of the acupuncture needle must soar upward over the Park tube to elicit “deqi” sensation through a twirling needle manipulation. In actual practice, the physician can hold the 2 cm handle of the acupuncture needle fully and insert, pull and rotate the needle to induce “deqi” at 0 to 4 cm in depth. In this sense, acupuncture with a sham base unit makes the needle stimulation different from treatment without it; only shallow insertion and weak stimulation are possible. If “real acupuncture” fails to meet the general practice of acupuncture in the acupuncture trial, the results of the study cannot reflect the true effect of acupuncture. This factor must be considered when drawing conclusion on the effect of “real acupuncture”.References1. Ee C, Xue C, Chondros P, Myers SP, French SD, Teede H, et al. Acupuncture for Menopausal Hot Flashes: A Randomized Trial. Annals of internal medicine. 2016.2. Doyle K 2016;Pages. Accessed at REUTERS at http://www.reuters.com/article/us-health-menopause-acupuncture-idUSKCN0UX2I6 on March 9 2016.3. Dodin S, Blanchet C, Marc I, Ernst E, Wu T, Vaillancourt C, et al. Acupuncture for menopausal hot flushes. Cochrane Database Syst Rev. 2013;7.4. Walker EM, Rodriguez AI, Kohn B, Ball RM, Pegg J, Pocock JR, et al. Acupuncture versus venlafaxine for the management of vasomotor symptoms in patients with hormone receptor–positive breast cancer: A randomized controlled trial. Journal of Clinical Oncology. 2010;28(4):634-40.5. Park J, White A, Stevinson C, Ernst E, James M. Validating a new non-penetrating sham acupuncture device: two randomised controlled trials. Acupuncture in Medicine. 2002;20(4):168-74.
Carolyn Ee, MBBS, Charlie Xue, PhD, Marie Pirotta, PhD
University of Melbourne
April 19, 2016
Takakura, Varner and Lopez highlight the complexities of performing acupuncture clinical trials. Takakura suggested that acupuncture points should have been the same in both groups to test the hypothesis that gentle stimulation is more effective for hot flashes (HF) than needle insertion. This is an interesting hypothesis, however we note that previous RCTs had not shown a difference between superficial and deep needling(1-3) while a pilot study reported greater improvement in HF severity with acupuncture compared to blunt needling(4). This contradicts the hypothesis presented by Takakura et al. Takakura also refers to no-touch placebo needles(5). This design is innovative and is undergoing validation, but was not available at time of study design. Lopez suggested that sham acupuncture could be an effective treatment for HFs. We agree that sham needling can have important physiological effects. However, blunt needling of non-acupuncture points is not consistent with what is considered Chinese medicine acupuncture, with its emphasis on point specificity, needle insertion and subsequent de qi. Lopez enquired about location of sham points; these were described in Appendix Table 2. Varner discussed some of the problems with acupuncture research. However, we disagree with his statement “people know if they are being needled or not”. This is not supported by studies validating the Park Sham Device(6), and credibility data from our study. Varner concluded that “to deny there is something interesting going on…is to ignore the experience of millions of people over thousands of years”. We agree that it would be amiss to deny that “something interesting” is going on; this is the reason we embarked on this trial. What our study suggests is that factors unrelated to needle insertion and point specificity played a part in symptom improvement. These may include but are not limited to the placebo effect, the natural tendency of HFs to improve, and the effects of frequent therapist-patient interaction. Some of these non-specific factors may also explain improvements after veterinary acupuncture. Our attempt to separate the specific and non-specific effects of acupuncture for HFs has some limitations, but it is clear that using this treatment protocol, and for this population, needle insertion at classical acupuncture points did not demonstrate superiority than blunt needle stimulation using the Park Sham Device. However, contrary to media reports, this is not synonymous with acupuncture being no better than placebo, as there is no placebo for acupuncture treatment. On this point, we agree with Varner. Carolyn EeCharlie XueMarie PirottaReferences1. Avis NE, Legault C, Coeytaux RR, Pian-Smith M, Shifren JL, Chen W, et al. A randomized, controlled pilot study of acupuncture treatment for menopausal hot flashes. Menopause. 2008;15(6):1070-8.2. Wyon Y, Wijma K, Nedstrand E, Hammar M. A comparison of acupuncture and oral estradiol treatment of vasomotor symptoms in postmenopausal women. Climacteric. 2004;7(2):153-64.3. Wyon Y, Lindgren R, Lundeberg T, Hammar M. Effects of acupuncture on climacteric vasomotor symptoms, quality-of-life, and urinary excretion of neuropeptides among postmenopausal women. Menopause. 1995;2(1):3-12.4. Nir Y, Huang MI, Schnyer R, Chen B, Manber R. Acupuncture for postmenopausal hot flashes. Maturitas. 2007;56(4):383-95.5. Takakura N, Yajima H. A double-blind placebo needle for acupuncture research. BMC complementary and alternative medicine. 2007;7:31.6. Park J, White A, Stevinson C, Ernst E, James M. Validating a new non-penetrating sham acupuncture device: two randomised controlled trials. Acupunct Med. 2002;20(4):168-74.
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