Alternative Therapies: In Health & Medicine

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A PEER-REVIEWED JOURNAL • MAY/JUNE 2016 • VOL. 22, NO. 3 • $14.95 Psychological Distress, Physical Symptoms, and the Role of Attachment Style in Acupuncture • Acupressure and Transcutaneous Electrical Acupoint Stimulation for Uremic Pruritus • Perforators, the Underlying Anatomy of Acupuncture Points • Acupuncture Effective for Chronic Knee Pain • Chinese Medicinal Herbs for Upper Airway Cough Syndrome • Electromagnetic Field Devices and Their Effects on Nociception and Peripheral Inflammatory Pain Mechanisms • Strontium Chloride for Treatment of Osteoporosis • Conversations: Christie Fleetwood, ND, RPH

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MAY/JUNE 2016, VOL. 22, NO. 3

TABLE OF CONTENTS ORIGINAL RESEARCH 8

Psychological Distress, Physical Symptoms, and the Role of Attachment Style in Acupuncture Antigonos Sochos, PhD, CPsychol, AFBPsS; Ashley Bennett, BSc, MBPsS, DCHAc

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Acupressure and Transcutaneous Electrical Acupoint Stimulation for Improving Uremic Pruritus: A Randomized, Controlled Trial Nazan Kılıç Akça, PhD, RN; Sultan Taşcı, PhD, RN

REVIEW ARTICLE 25

Perforators, the Underlying Anatomy of Acupuncture Points Ding Zhi Wei, MD; Shi Yu, MD; Zhang Yongqiang, MD

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Acupuncture is Effective for Chronic Knee Pain: A Reanalysis of the Australian Acupuncture Trial Arthur Yin Fan, MD, PhD, LAc; Kehua Zhou, MD, DPT, PT, LAc; Sherman Gu, BMed, AdvDipMyother, MAppSc; Yong Ming Li, MD, PhD

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Chinese Medicinal Herbs in the Treatment of Upper Airway Cough Syndrome: A Systematic Review of Randomized, Controlled Trials Hongli Jiang, MD; Wei Liu, PhD; Guanhong Li, PhD; Tao Fan, MD; Bing Mao, MD

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Electromagnetic Field Devices and Their Effects on Nociception and Peripheral Inflammatory Pain Mechanisms Christina L. Ross, PhD; Thaleia Teli, PhD; Benjamin S. Harrison, PhD

CASE REPORT 66

Use of Strontium Chloride for the Treatment of Osteoporosis: A Case Report Sarah M. Westberg, PharmD, BCPS; Amy Awker, PharmD; Carolyn J. Torkelson, MS, MD

x Table of Contents

ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 3

CONVERSATIONS 72

Christie Fleetwood, ND, RPh: The Essential Role of Pharmaceutical Knowledge in Naturopathic Practice Interview by Craig Gustafson

DEPARTMENTS 78

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Table of Contents

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editor in chief Andrew W. Campbell, MD CONTRIBUTING EDITORS

Michael Balick, PhD • Mark Hyman, MD • Jeffrey Bland, PhD, FACN, FACB • Roberta Lee, MD • Tieraona Low Dog, MD Editorial Board Sidney MacDonald Baker, MD ◆ Autism Research Institute

Daniel A. Monti, MD ◆ Thomas Jefferson University

Mark Blumenthal ◆ American Botanical Council

Gerard Mullin, MD ◆ Johns Hopkins University

David M. Brady, ND, DC, CCN ◆ University of Bridgeport

John Neely, MD ◆ Pennsylvania State University

Kelly Brogan, MD, ABIHM ◆ George Washington University Jeffrey Dach, MD ◆ TrueMedMD, Davie, Florida

Paula J. Nenn, MD, ABIHM ◆ Optimal Health and Prevention Research Foundation Garth L. Nicolson, PhD ◆ The Institute for Molecular Medicine

James Dillard, MD, DC, LAc ◆ Integrative Pain Medicine

Xie Ning, PhD ◆ Heilongjiang University of Traditional Chinese Medicine

Jeanne Drisko, MD ◆ University of Kansas Andrea Girman, MD, MPH ◆ Genova Diagnostics

Thomas O’Bryan, DC, CCN, DACBN ◆ Institute for Functional Medicine, National Univ. of Health Sciences Dean Ornish, MD ◆ Preventive Medicine Research Institute

Ajay Goel, PhD ◆ Baylor Research Institute

Nicole Pietschmann, PhD ◆ Berlin, Germany

Garry F. Gordon, MD, DO ◆ Gordon Research Institute

Joseph E. Pizzorno, ND ◆ Seattle, WA

Junfeng He, PhD ◆ Hunan University of Traditional Chinese Medicine

Lawrence A. Plumlee, MD ◆ Chemical Sensitivity Disorders Association

Yuxin He, LAc, PhD ◆ Academy of Oriental Medicine at Austin

Keith S. Rayburn, MD ◆ Santa Clara County Health and Hospital System

Robert Hedaya, MD, DLFAPA ◆ National Center for Whole Psychiatry

William J. Rea, MD ◆ Environmental Health Center – Dallas

Leila Jabbour, PhD ◆ Franklin Pierce University

Sandeep Saluja, MD ◆ Saran Ashram Hospital, Dayalbagh

Alfred Johnson, DO ◆ Johnson Medical Associates

Eric R. Secor Jr, PhD, ND, MPH, MS, LAc ◆ Helen & Harry Gray Cancer Center, Hartford Hospital Ellen Kamhi, PhD, RN, AHG, AHN-BC ◆ Stony Brook University Stephen T. Sinatra, MD, FACC, FACN, CNS ◆ University of Connecticut School of Medicine Anup Kanodia, MD, MPH ◆ Ohio State University Martha Stark, MD ◆ Harvard Medical School, Massachusetts Mental Health Center Datis Kharrazian, DC, DHSc, MS, MNeuroSci ◆ Bastyr University of California; Alex Vasquez, DC, ND, DO ◆ University of Texas Institute for Functional Medicine Günver Kienle, DrMed ◆ Institute for Applied Epistemology Aristo Vojdani, PhD, MSc, CLS ◆ Immunosciences Lab, Inc James B. Lago, EMT, DDS, BA ◆ Chicago Dental Health

Roeland van Wijk, PhD ◆ International Institute of Biophysics

Changzheng Li, PhD ◆ Department of Chinese Internal Medicine, Nanfang James M. Whedon, DC, MS ◆ Southern California University of Health Sciences Hospital, Southern Medical University, China Erqiang Li, PhD ◆ East West College of Natural Medicine Shi Xian, MD, PhD ◆ General Hospital of the Chinese People’s Liberation Army Holly Lucille, ND, RN ◆ Humility Inc Cuauhtemoc Hernandez Maya, MD ◆ Tao Healing Arts Center

Arthur Yin Fan, CMD, PhD, LAc ◆ McLean Center for Complementary and Alternative Medicine Qinhong Zhang, MD, PhD ◆ Stanford University

Pamela Miles, Reiki Master ◆ New York, NY

Shun Zhongren, PhD ◆ Heilongjiang University of Traditional Chinese Medicine

Managing Editor, CRAIG GUSTAFSON • Creative Director, RANDY PALMER • Associate Editor, MICHAEL MILLER Editorial Assistant, CARALIN WALSH • Science Editor, PEGGY WRIGHT • E-mail: ATHM@innovisionhm.com Web: www.alternative-therapies.com

6 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

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ORIGINAL RESEARCH

Psychological Distress, Physical Symptoms, and the Role of Attachment Style in Acupuncture Antigonos Sochos, PhD, CPsychol, AFBPsS; Ashley Bennett, BSc, MBPsS, DCHAc

ABSTRACT Context • Attachment research has contributed significantly to the understanding of the origins as well as the treatment of psychological and somatic distress; however, no study so far has explored the role of attachment in acupuncture. The effects on endogenous opioids of both acupuncture and intimate interpersonal bonding as well as clients’ reliance on a practitioner’s care may suggest that individual differences in attachment style could be linked to individual differences in responses to acupuncture.

Objective • The study intended to investigate the role of attachment style in determining outcomes in acupuncture.

Design • A pre- and postintervention, single group, quasiexperimental design was used.

Setting • Treatment and data collection took place in an acupuncture clinic in London, England, United Kingdom.

Participants: Eighty-two acupuncture clients with a mean age of 46 ± 14.53 took part in the study. Participants suffered from a variety of somatic and psychological complaints.

Intervention • Traditional Chinese acupuncture was administered to all participants in weekly sessions, with

Antigonos Sochos, PhD, CPsychol, AFBPsS, is a senior lecturer in the Department of Psychology at the University of Bedfordshire in Luton, England, United Kingdom. Ashley Bennett, BSc, MBPsS, DCHAc, is a lecturer in psychology in the Department of Psychology at the University of Bedfordshire.

Corresponding author: Ashley Bennett, BSc, MBPsS, DCHAc E-mail address: ashley.bennett@beds.ac.uk

8 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

the mean number of sessions that participants received being 5 ± 3.5.

Outcome Measures • Psychological distress and somatic symptoms were measured using the General Heath Questionnaire (GHQ-12) and the Bradford Somatic Inventory (BSI), respectively. The Relationship Questionnaire (RQ) was used to assess attachment style, with the 4 styles being secure, dismissing, preoccupied, and fearful.

Results • After treatment, both somatic and nonsomatic distress were reduced (P < .001), whereas pretreatment associations between attachment insecurity and symptom severity ceased to exist. The strength rather than the quality of the attachment style moderated the reduction in somatic distress, whereas the preoccupied style of attachment moderated the effects of medically unexplained symptoms on distress.

Conclusions • Attachment style may have an impact on acupuncture outcomes by predisposing individuals to different patterns of opioid elicitation and a different manner of relating to the practitioner. (Altern Ther Health Med. 2016;22(3):8-16.)

A

ttachment theory is an important interpersonal framework suggesting that the attachment system is implicated in the origins and treatment of psychological distress as well as in the experience, communication, and alleviation of bodily pain and physical symptoms.1,2 Attachment security is perhaps the most central concept of the theory, referring to the expectation that intimate others will be available at times of need and that the self will be able both to manage life’s challenges and elicit caring responses from others.

Attachment researchers argue that attachment styles are rooted in different caregiving experiences. Many researchers agree that the attachment experience is organized along the 2 fundamental dimensions of anxiety and avoidance, which define 4 attachment patterns or styles: (1) secure, (2) dismissing, (3) preoccupied or anxious, and (4) fearful.3,4 Sochos—Attachment Style in Accupuncture

The secure style is characterized by low anxiety and low avoidance and is linked with the individualâ&#x20AC;&#x2122;s ability to manage stress effectively and establish mutually supportive human relationships. The dismissing style is characterized by high avoidance and low anxiety and is linked with an attitude of self-sufficiency and the avoidance of emotional intimacy.

The preoccupied or anxious style is characterized by low avoidance and high anxiety and is linked with overdependence, aggressiveness, and a restricted capacity for effective coping.

The fearful style is characterized by high avoidance and high anxiety and is linked with intense conflict between approaching and distancing, high interpersonal aggression, and a chaotic engagement with the environment.

In addition to strong empirical evidence suggesting an association between the quality of attachment and the experience of psychological distress,5 a number of studies have provided support for a link between attachment and the experience of physical pain. Some studies have found that physical contact with an attachment figure could increase the tolerance of experimentally induced pain6 and that individual differences in the experience and management of bodily pain were related to individual differences in attachment style. Meredith et al7 found that anxiously attached individuals exhibited lower pain thresholds, lower ability to control pain, and lower perceived control over pain. Those findings are consistent with animal research reporting that maternally deprived, adult rats responded to pain with greater pain affect than rats with no history of maternal deprivation.8 Moreover, an insecure attachment style has been related to more intense pain and greater disability in individuals suffering from arthritis,9 migraines,10 and other chronic pain.2,11 Two studies have found that patients attending primary care with medically unexplained symptoms were more likely to have an insecure attachment style and to suffer from a depressive or anxiety disorder than those with medically defined illnesses.12,13 Some researchers have claimed that such symptoms themselves are expressions of somatized distress.14 Some studies have suggested that the early family environment and attachment to a caregiver are important for understanding the somatization of distress, whereas attachment security has been linked to psychotherapy outcomes among somatizing patients.15,16 Although the role of attachment style in the conventional treatment of both psychiatric and general medical disorders has been well documented,5,17 no study so far has explored the role of attachment in acupuncture. Acupuncture consists of the needling of specific points on the body according to the medical concepts of meridian and the vital energy qi in traditional Chinese medicine (TCM). Substantial research has suggested that acupuncture brings about analgesic, anesthetic, and therapeutic effects in relation to a variety of health problems because needling and electrical stimulation positively interfere with neural pathways, neurotransmitters, and hormones that mediate autonomic regulation and pain relief.18 Sochosâ&#x20AC;&#x201D;Attachment Style in Accupuncture

Despite limitations in methodology and reporting, studies on the effects of acupuncture on depression and anxiety have suggested that benefits can be obtained.19,20 The evidence seems to identify increases in the levels of serotonin and enkephalins as the main underlying processes, although the exact mechanism by which such increases are attained is not well understood. Many reasons exist to believe that investigating the role of attachment in acupuncture could be relevant to treatment, both in relation to somatic pain and psychological distress.

Some empirical evidence has suggested that the analgesic and anti-inflammatory effects of acupuncture are attained mainly due to the elicitation of endogenous opioids that the body automatically generates to fight off pain.18,21 Strong evidence also suggests that endogenous opioids are implicated in human and animal bonding as well as in the regulation of both physical and social pain. Some research has suggested that endogenous opioids, such as endorphins, are elicited in the presence of intimate others, generating subjective feelings of joy, whereas the absence of such opioids is linked with increased closeness- and care-seeking behavior.22 Some researchers have argued that physical and social pain (eg, pain caused by social rejection) involve common neuroendocrinal and neurological systems, including the oxytocin and opioid systems, as well as the periaqueductal gray and the anterior cingulated cortex areas of the brain.23 The endogenous opioid system seems to be of particular importance, being the common thread between the regulation of pain and the regulation of intimate bonds.

Although endogenous opioids function as analgesics that are produced by the human body to defend against pain, they also function as motivators in bonding. If the elicitation of endogenous opioids is not only a main mechanism through which acupuncture achieves its analgesic effects but also a major physiological motivator for the establishment of human bonds, individual differences in attaining such effects may relate to individual differences in attachment.

As systematic differences in parent-child interactions result in individual differences in the attachment styles of offspring, they may also result in different established patterns of opioid activation. Zeifman and Hazan24 argue that early attachment relationships can condition the endogenous opioid system itself because repeated interactions with a caregiver could establish a pattern of endorphin activation so that both interpersonal bonding and pain regulation are facilitated. Such individual differences may result in differences not only in responding to the acupuncture needle itself but also in differences in responding to the acupuncturist as a person. Research has shown that the vulnerability that is a part of being a patient can activate the attachment system and that a range of health care professionals may be treated as attachment figures by their clients.13,14 The aim of the present study was to investigate the role of a clientâ&#x20AC;&#x2122;s attachment style in the acupuncture treatment of physical as well as psychological symptoms. Attachment ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 9

research strongly suggests a link between psychological and physical pain (ie, a link between the psyche and the body) and, as such, the research may provide useful insights into the effectiveness of an integrative treatment such as acupuncture. The current researchers also wished to explore whether acupuncture had any different effect on and whether attachment played different roles in the treatment of 2 types of patients, those with medically explained symptoms and those with symptoms that were not medically unexplained.

Because somatic symptoms would seem to relate more strongly to psychological distress in the latter group, the research team wanted to see whether those clients would respond differently to acupuncture. To achieve the current study’s aims, the research team formulated 3 hypotheses and 1 research question.

First, the team hypothesized that clients of Chinese acupuncture, after treatment, would experience a reduction in the symptoms of both somatic and psychological distress.

Second, the team theorized that the experience of treatment would weaken the link between insecure attachment and symptoms of distress, so that predictive associations between attachment style and distress symptoms that had been observed before therapy would become insignificant after therapy. Third, the team hypothesized that attachment style would moderate the posttherapy reduction in both physical and psychological symptoms, and, therefore, that the more insecurely attached clients would experience less improvement. The team expected that the 2 main mechanisms that potentially are implicated in the acupuncture-treatment effect—the establishment of a facilitating client-practitioner relationship and the elicitation of the endogenous opioid system—would be relatively compromised among the more insecure clients.

Finally, the team wished to explore the extent to which clients requesting acupuncture suffered from functional somatic syndromes and the extent to which clients who suffered from those syndromes differed from clients with identifiable physical illnesses, including differences in physical symptoms, psychological distress, and attachment style. The current research team also wanted to find out whether those 2 groups of clients would respond to treatment differently and whether attachment style had a different effect on treatment outcomes in the 2 groups.

METHODS The research team designed a pre- and posttreatment, nonrandomized study involving clients who received traditional Chinese acupuncture.

Participants Eighty-two individuals with a mean age of 46 ± 14.53 years took part in the study. Participants were patients who sought acupuncture treatment at the AcuMedic Clinic of Traditional Chinese Medicine (London, England, United Kingdom) for a variety of complaints, such as back, chest, or stomach pains; migraines; and insomnia.

Participants were predominantly female (67%) and white (80%); other ethnicities included Asian (6%), Black African (4%), and Black Caribbean (5%).

The research team obtained both clients’ and practitioners’ consents for participation in the study. The study obtained ethical clearance from the AcuMedic Clinic and a the Department of Psychology at University of Bedfordshire (Luton, England, United Kingdom).

Procedures Treatment was delivered by a total of 7 practitioners who were qualified in both TCM and Western medicine from institutions across China. The practitioners had at least 5 years of experience in delivering acupuncture. After obtaining their consents to participate and before treatment, participants were asked to complete a background questionnaire and the Relationship Questionnaire (RQ), an attachment-style questionnaire. Before their first and after their last sessions of acupuncture, participants also completed the General Health Questionnaire (GHQ-12) and the Bradford Somatic Inventory (BSI).

Intervention Treatment included a mean of 5 ± 3.5 sessions of acupuncture, 1 per week with each session lasting approximately 45 minutes. The maximum number of sessions was 16.

However, data collection itself lasted longer than that, as not all treatments happened at the same time. Each time, the number and location of the acupuncture points were decided by the practitioner, depending on the client’s presenting problem.

Outcome Measures In addition to demographic and health background information, the following self-report questionnaires were used.

General Health Questionnaire.25 The GHQ-12 is a widely used instrument, demonstrating good scale and test-retest reliability, with α = 0.94 in the current study, as well as convergent, discriminant, and criterion validity.26 The questionnaire’s 12 items are scored on a 4-point Likert scale (0–3). Most studies, including the present one, have used GHQ-12 as a unidimensional index of nonpsychotic psychological distress.

Bradford Somatic Inventory.27 The BSI is a 46-item questionnaire measuring physical symptoms of psychological distress, which has been validated in white and a variety of ethnic-minority groups in the United Kingdom. It identifies 7 common areas of somatic symptoms, forming an equal number of subscales: (1) head—7 items, Į = 0.82; (2) chest— 5 items, Į = 0.79; (3) abdomen—6 items, Į = 0.84; (4) fatigue—7 items, Į = 0.76; (5) heat—3 items, Į = 0.55; (6) globus—3 items, Į = 0.73; and (7) panic—3 items, Į = 0.66.

It also includes a measurement for an overall scale (α = 0.94).

In the present study, a 5-point Likert scale to measure the intensity of symptoms was used, and the results for the BSI correlated well with those for the GHQ-12—r = 0.52, P < .001, df = 80 pretreatment and r = 0.47, P < .001, df = 80 posttreatment.

10 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

Sochos—Attachment Style in Accupuncture

Relationship Questionnaire.3 The RQ is a classic questionnaire measuring adult attachment style. Numerous studies have provided evidence for its convergent, discriminant, and predictive validity.28 The questionnaire includes 4 small paragraphs, each providing a different attachment-related description of self and other. Using a 7-point Likert scale, each of the paragraphs measures the extent to which participants present the characteristics of 4 attachment styles: secure, dismissing, preoccupied, and fearful. The styles characterize 4 models of self and others: (1) secure style—positive model of self and others, (2) dismissing style—positive model of self and negative model of others, (3) preoccupied style—a negative model of self and a positive model of others, and (4) fearful style—negative model of both self and others.

Statistical Analysis To address the 3 hypotheses, the research team used the following measures: (1) first hypothesis—2 repeated measures, multivariate analyses of variance (MANOVAs), comparing preand posttreatment symptom scores; (2) second hypothesis—a series of linear regressions, using each of the 4 attachment styles as predictors or independent variables and all pre- and posttreatment BSI and GHQ scales as dependent variables and controlling for age and gender as well as for GHQ or BSI pretreatment scores as accordingly; and (3) third hypothesis— moderated regressions, using each time the pretreatment symptom score as the independent variable, the posttreatment score as the dependent variable, and each of the 4 attachment styles as the moderator and controlling for age, gender, GHQ or BSI pretreatment scores, and the remaining 3 attachment styles.

To compare clients who had medically unexplained symptoms with those whose symptoms were medically Table 1. Descriptive Statistics of the Study’s Variables Pretreatment

Posttreatment

Mean ± SD (total)

Mean ± SD (total)

GHQ/Total

12.36 ± 6.79

7.55 ± 5.11

BSI/Total

27.85 ± 22.25

16.83 ± 13.06

BSI/Heat

2.07 ± 2.98

0.78 ± 1.08

BSI/Chest

1.22 ± 1.82

1.22 ± 1.82

BSI/Abdomen

4.64 ± 4.75

2.65 ± 2.66

BSI/Fatigue

7.35 ± 4.73

4.82 ± 3.86

BSI/Head

3.00 ± 3.98

1.67 ± 2.05

BSI/Globus

1.61 ± 2.05

1.14 ± 1.43

BSI/Panic

1.51 ± 2.06

0.79 ± 1.34

RQ/Secure

4.31 ± 1.80

Variable

RQ/Dismissing

3.61 ± 1.75

RQ/Preoccupied

2.48 ± 1.67

RQ/Fearful

2.72 ± 1.65

Abbreviations: SD, standard deviation; GHQ, General Health Questionnaire; BSI, Bradford Somatic Inventory; RQ, Relationship Questionnaire.

Sochos—Attachment Style in Accupuncture

explained with respect to the study’s variables, the research team conducted a MANOVA. To investigate whether a participant’s group moderated his or her treatment outcome and whether attachment style moderated the effect of the participant’s group on posttherapy distress, the research team also conducted a moderated regression.

RESULTS The first hypothesis proposed that clients of Chinese acupuncture, after treatment, would experience a reduction in both somatic and psychological distress symptoms. The first analysis revealed that posttreatment scores for both the BSItotal and GHQtotal scales were significantly lower than those at pretreatment, with Hotelling’s trace = 0.971, F2,80 = 38.85, P < .001 (Table 1). The second analysis included only the BSI subscales and indicated that all posttreatment scores were significantly lower than those at pretreatment, with Hotelling’s trace = 0.75, F7,75 = 8.03, P < .001. The mean pretreatment GHQ score was 12.36 (ie, above 11/12), which is regarded as a clinical threshold.29 After treatment the mean GHQ score dropped to 7.55. No similar threshold was available to evaluate the BSI. The second hypothesis proposed that the experience of treatment would weaken the link between insecure attachment and symptoms of distress so that the predictive associations between attachment style and distress symptoms that had been observed before therapy would become insignificant after therapy. According to the findings (Table 2), all but 1 of the statistically predictive associations between attachment styles and distress symptoms that had been observed to be significant before therapy were not significant after therapy. The only Table 2. Predictive Associations Between Attachment Style and Symptoms Before and After Treatment Attachment Predictors

Fearful

Preoccupied Secure

Dismissing

Outcome Scales BSI/Total BSI/Heat BSI/Head BSI/Globus BSI/Panic BSI/Chest BSI/Total BSI/Abdomen BSI/Fatigue BSI/Total BST/Chest BSI/Panic GHQ/Total

Pretreatment β P

Posttreatment β P

0.27 0.28 0.23 0.26 0.26 0.31 0.24 0.21 0.33 -0.08 -0.15 -0.03 -0.25

0.15 0.05 0.10 0.10 0.10 0.27 0.09 0.06 0.13 -0.25 -0.27 -0.27 -0.19

.003 .012 .015 .030 .030 .003 .012 .044 <.001 .396 .152 .788 .012

.130 .686 .334 .375 .375 .014 .386 .582 .211 .011 0.15 .013 .075

Abbreviations: BSI, Bradford Somatic Inventory; GHQ, General Health Questionnaire.

ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 11

Table 3. Moderating Effects of Attachment Style on Changes from Pre- to Posttreatment for BSI Score Dependent Variable

Predictor Variables

β

P

-0.086

.403

R2

Adjusted R2

ΔF (P)

df

0.26

0.20

4.46 (P = .001)

6, 75

Step 1 Age

BSI-Post Total

Gender

0.071

.493

GHQ-Pre

0.372

.001

Dismissing

-0.124

.293

Fearful

0.193

.087

Preoccupied

0.091

.391

BSI-Pre Total

0.591

<.001

Secure

-0.226

.013

0.50

0.45

9.13 (P < .001)

8, 73

-0.841

<.001

0.60

0.55

12.06 (P < .001)

9, 72

Age

-0.127

.207

Gender

0.063

.533

GHQ-Pre

0.424

<.001

Secure

-0.249

.014

Preoccupied

0.078

.452

Dismissing

-0.54

.609

0.294

0.237

5.20 (P < .001)

6. 75

BSI-Pre Total

0.591

<.001

Fearful

-0.031

.764

0.500

0.445

9.13 (P < .001)

8, 81

-1.048

.000

0.627

0.581

13.47 (P < .001)

9, 81

Age

-0.127

.204

Gender

0.067

.504

GHQ-Pre

0.415

<.001

Secure

-0.221

.036 0.299

0.242

5.32 (P < .001)

6, 81

Step 2

Step 3 BSI-Pre Total (Secure) Step 1

BSI-Post Total

Step 2

Step 3 BSI-Pre Total (Fearful) Step 1

BSI-Post Total

Dismissing

0.119

.303

Fearful

-0.087

.444

BSI-Pre Total

0.591

<.001

Preoccupied

-0.045

.620

0.500

0.445

9.13 (P < .001)

8, 81

-0.973

<.001

0.617

0.569

12.89 (P < .001)

9, 81

Age

-0.118

.246

Gender

0.080

.416

GHQ-Pre

0.429

<.001

Secure

-0.224

.033

Fearful

0.074

.479

Preoccupied

0.058

.578

0.296

0.240

5.26 (P < .001)

6, 81

BSI-Pre Total

0.591

<.001

Dismissing

0.286

.286

0.500

0.445

9.13 (P < .001)

8, 81

-0.825

<.001

0.598

0.548

11.90 (P < .001)

9, 81

Step 2

Step 3 BSI-Pre Total (Preoccupied) Step 1

BSI-Post Total

Step 2

Step 3 BSI-Pre Total (Dismissing)

Abbreviations: BSI, Bradford Somatic Inventory; GHQ, General Health Questionnaire.

12 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

Sochos—Attachment Style in Accupuncture

Table 4. Moderating Effects of Attachment Style on Changes in Pre- to Posttreatment Score in Relation to Specific BSI Subscales Interaction Terms BSI/Head (Secure) BSI/Head (Fearful) BSI/Head (Preoccupied) BSI/Head (Dismissing) BSI/Chest (Secure) BSI/Chest (Fearful) BSI/Chest (Preoccupied) BSI/Chest (Dismissing) BSI/Abdomen (Secure) BSI/Abdomen (Fearful) BSI/Abdomen (Preoccupied) BSI/Abdomen (Dismissing) BSI/Fatigue (Secure) BSI/Fatigue (Fearful) BSI/Fatigue (Dismissing) BSI/Heat (Secure) BSI/Heat (Fearful) BSI/Heat (Preoccupied) BSI/Heat (Dismissive) BSI/Globus (Secure) BSI/Globus (Fearful) BSI/Globus (Preoccupied) BSI/Globus (Dismissive) BSI/ Frequency (Fearful) BSI/Frequency (Preoccupied) BSI/Panic (Secure) BSI/Panic (Fearful) BSI/Panic (Preoccupied) BSI/Panic (Dismissive)

Outcome Scales BSI/Head BSI/Head BSI/Head BSI/Head BSI/Chest BSI/Chest BSI/Chest BSI/Chest BSI/Abdomen BSI/Abdomen BSI/Abdomen BSI/Abdomen BSI/Fatigue BSI/Fatigue BSI/Fatigue BSI/Heat BSI/Heat BSI/Heat BSI/Heat BSI/Globus BSI/Globus BSI/Globus BSI/Globus BSI/Frequency BSI/Frequency BSI/Panic BSI/Panic BSI/Panic BSI/Panic

β -0.51 -0.89 -0.05 -0.05 -0.07 -0.10 -0.07 -0.06 -0.05 -0.09 -0.07 -0.59 -0.08 -0.07 -0.09 -0.08 -0.08 -0.12 -0.07 -0.10 -0.11 -0.10 -0.11 -0.10 -0.08 -0.12 -0.08 -0.07 -0.10

P .016 .0001 .0186 .0161 .0033 .0001 .0277 .0425 .0352 .0000 .0069 .0143 .0214 .0484 .0064 .0012 .0017 <.001 .0033 .0063 .0003 .0007 .0006 .0001 .0090 .0000 .0008 .0108 .0001

F 8.35 11.90 8.29 8.35 9.83 11.36 9.02 8.73 9.17 12.35 9.88 9.56 10.92 10.55 11.49 8.84 8.70 13.05 8.42 4.18 5.20 4.90 4.94 13.96 11.26 21.00 12.67 14.9 17.31

Abbreviation: BSI, Bradford Somatic Inventory. association that remained significant was that between the fearful attachment style and chest-related symptoms, although the association was significant at the .05 rather than the .01 level. The fearful attachment style was the one with the most pretherapy associations, of which all but 1 involved the BSI scales. The dismissing attachment style was the one not linked with any BSI variables and was the only one to be associated with the GHQ, but only before treatment. The secure attachment style became negatively associated with BSI after treatment.

The third hypothesis proposed that a participant’s attachment style would moderate the posttherapy reduction of both physical and psychological symptoms so that the more insecurely attached clients would experience less improvement.

The findings suggested that all attachment styles moderated the effects of pretreatment scores on post-treatment scores but only in relation to the BSI (Table 3 and Table 4). More specifically, individuals with the highest attachment scores before treatment had lower posttreatment BSI scores compared with those with lower scores on the same attachment style.

Differences in attachment style had no effect on the posttreatment reduction in the GHQ. Sochos—Attachment Style in Accupuncture

The research team also wished to explore the extent to which clients requesting acupuncture suffered from functional somatic syndromes and P the extent to which clients who suffered from those .000 syndromes differed from clients with identifiable .000 physical illnesses, including differences in physical .000 symptoms, psychological distress, and attachment .000 style. Exploring the question, the team noted that .000 40 clients (48%), according to their self-reports, .000 had received at least 1 functional syndrome .000 diagnosis by their GP and 35 (42%) had been .000 diagnosed with a medically explained physical .000 condition. A further 7 clients (8%) suffered from .000 an anxiety or mood disorder without a comorbid .000 physical disorder and were not included in the .000 analyses addressing the research question. .000 The research team found no differences .000 between the 2 groups (ie, functional syndrome .000 diagnosis vs medically explained diagnosis) (1) on .000 any of the symptom scales, either before treatment .000 (Wilks = 0.93, F6,68 = 0.73, P = .620) or after treatment .000 (Wilks = 0.98, F6,72 = 0.49, P = .615) and (2) on .000 attachment style. Moreover, the presence of a .000 diagnosed functional syndrome did not moderate .000 the reduction of any type of symptom; the interaction .000 .000 term in relation to the GHQ was marginally .000 nonsignificant, P = .053. However, the preoccupied .000 attachment style moderated the effects of the type of .000 diagnosis on posttreatment GHQ scores. Although .000 relatively high preoccupation score was linked with .000 lower posttreatment distress among clients with a .000 medically explained diagnosis, it was linked with higher distress among those with a medically unexplained syndrome—F10,64 = 5.01, P < .001; interaction β = -0.56, P = .016. No other attachment style moderated the effects of type of diagnosis on posttreatment distress.

DISCUSSION According to the current study’s findings, the participants reported less somatic and nonsomatic distress after receiving traditional Chinese acupuncture, whereas the predictive associations between attachment insecurity and the symptom scores changed after treatment. Moreover, the strength rather than the quality of the attachment style seemed to moderate the reduction in somatic distress because participants with higher scores in any attachment style reported lower scores on distress after treatment.

Approximately 48% of the current study’s sample had been diagnosed with at least 1 functional syndrome, but that subgroup did not differ in the results on symptom scores or attachment style from those with no such diagnosis. No moderating effects of a functional syndrome diagnosis on the reduction of symptoms were found, but the preoccupied attachment style did moderate the effects of the type of diagnosis on psychological distress.

ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 13

The posttreatment reduction of symptoms observed in the current study appears consistent with the results show found in the previous literature that has reported therapeutic effects for acupuncture on depression,20 anxiety,19 and somatic symptoms of various other etiologies.30 In those studies, acupuncture was found to increase the levels of serotonin and enkephalin in the brain, which could also account for the reductions in depression and anxiety in the present study. On the other hand, the analgesic effects of acupuncture as indicated by the reduced body pain and discomfort that the current participants reported possibly could be attributed to the elicitation of the body’s endogenous opioids, as has been suggested by previous research.18 The Western scientific understanding of the analgesic action of endogenous opioids seems compatible in some respects with TCM’s notion of acupuncture as affecting the body and mind by unblocking energy flow. According to scientific research, endogenous opioids attain their therapeutic effects by triggering biochemical activity in the nervous system. Although understood in different conceptual and sociocultural contexts, the traditional Chinese notion of energy flow and the scientific evidence of biochemical response as the results to acupuncture needle insertion seem to describe processes with some common characteristics.

However, the absence of a placebo or other no-treatment control group and the lack of controls for extraneous variables in the present study require that the possible causal mechanisms be considered with caution. It is possible that posttreatment changes were brought about by factors other than treatment, such as changes in current life stressors, the availability of social support, the effects of medication or other complementary and alternative therapies, or the number of acupuncture points used.

Although previous studies have suggested some placebo effects in acupuncture, they also have indicated that the effect could explain only part of posttreatment improvement.29 In a recently completed, double-blind, randomized trial, the current research team found that clients receiving real acupuncture attained a greater reduction in their BSI and GHQ scores compared to a placebo group receiving sham acupuncture.31 Moreover, the changes that were observed in the associations between attachment styles and symptom scores before and after treatment provide further evidence that treatment may have had a therapeutic effect in the current study. Such changes suggest that somehow acupuncture protected the participants from the vulnerability toward somatic distress that is linked with attachment insecurity.

Previous studies have associated interpersonal rejection, an experience central in both preoccupied and fearful attachment, with a deficit in opioid function.22 If the needle stimulation released endogenous opioids in preoccupied and fearful clients in the current study, then their attachment vulnerability may have been removed after treatment, at least partly and/or at least temporarily. Secure individuals, who did not present such deficits, may have been able to attain a further opioid elicitation, resulting in negative posttreatment associations between security and somatic symptoms.

On the other hand, individuals with the dismissing attachment type appeared unable to make gains in relation to somatic distress. The lack of association between the dismissing style and somatic distress and that style’s negative association with nonsomatic distress that was observed before treatment were consistent with previous studies.32 As those other studies have suggested, although the deactivation of the attachment system employed by dismissing individuals is defensive and limits their capacity for optimum psychosocial functioning, it does increase their competence in dealing with external stressors and protects them from psychological distress, at least to some extent.

However, attachment deactivation also involves at least some deactivation of the opioid system. As a result of their by-default suppressed opioids, acupuncture may have had some limited success with dismissing individuals in eliciting those substances and may have achieved a therapeutic effect similar to that attained by the secure. Moreover, the absence of an association between the dismissing style and the GHQ after treatment perhaps suggests that those participants with low scores on that style (ie, those less protected by dismissiveness) could have attained greater posttreatment increases in their serotonin and enkephalin. The lack of association between the other 2 insecure attachment styles and GHQ may suggest that preoccupied and fearful attachment in the current sample of acupuncture clients constituted a vulnerability factor toward developing somatic rather than nonsomatic distress.

In addition to opioid elicitation, it is possible that a placebo effect was attained also through a client’s interpersonal relationship with a practitioner. Many studies have suggested that a good client-professional relationship is linked with positive outcomes in both mental and general health interventions.33 Researchers have claimed that such relationships implicate the attachment system because patients are in a vulnerable, child-like position and health care professionals are in a supportive, parent-like role, often able to provide security and reassurance.34 Although more difficult to achieve, relationships of trust can also develop in short-term interventions, such as the present one. The above associations between distress and the preoccupied, secure, and dismissing styles are consistent with such a hypothesis, whereas those involving the fearful are less so, given the inconsistent ways in which fearful clients engage with health professionals.13 Interesting also were the findings related to the current research team’s third hypothesis, suggesting that it was the strength rather than the style of attachment that amplified the treatment effect. According to the current findings, the analgesic effects of acupuncture seemed to be stronger in those individuals who employed a particular attachment strategy more strongly, regardless of what that strategy was.

It may be the case that as the clients’ attachment system was activated in the context of the therapeutic relationship, so were their endogenous opioids, facilitating further elicitation through needle stimulation. Although the dismissing style

14 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

Sochos—Attachment Style in Accupuncture

involves the defensive deactivation of the attachment system, such deactivation is attained only at later stages of emotional processing.30 At the first most basic and biologically prepared stage, in the presence of relevant stimuli, the attachment system is activated automatically at an autonomic physiological level, without previous learning. It is reasonable, therefore, to expect some or even a minimal degree of opioid activation in dismissive individuals when they voluntarily seek care. Nonetheless, at the current point, those postulations are tentative, because neither opioids nor attachment to the practitioner were measured directly in the present study.

Finally, the absence of differences between the medically unexplained and medically explained groups in distressrelated variables is not surprising, because both subgroups appear to belong to a larger, clinically distressed client sample.

Nonetheless, the preoccupied style seemed to influence the treatment outcome in relation to nonsomatic distress in reverse ways in the 2 groups. Perhaps high attachment preoccupation hindered a positive treatment outcome among clients with unexplained medical symptoms compared to those without such known symptoms because the former group may have had a longer history of unsuccessful consultations with health professionals. Such a history may have increased mistrust and felt rejection among highly preoccupied clients with unexplained medical symptoms, making it more difficult for them to engage with acupuncture, both at a behavioral and a neurophysiological level.

Present findings suggest that investigating acupuncture from an attachment perspective can highlight the relevance of psychosocial processes in complementary and alternative therapies and can provide further support for the holistic approach to health and illness that those therapies advocate.

The current study has provided further evidence that health and illness need to be understood from a wider biologicalpsychological-social perspective because they implicate biological, intrapersonal, interpersonal, and wider sociocultural processes that are intrinsically linked with how individuals acquire vulnerability, experience illness, and respond to professional treatment.

The current study is the first to investigate the role of attachment style in acupuncture, and it has generated some potentially interesting findings. However, a number of limitations render those findings tentative and invite further research in the area. The lack of a control group and the absence of controls for extraneous variables make the accounts of what changed after treatment and how those changes occurred provisional, underlining the necessity for randomized trials in the future. In addition, the study included participants suffering from a wide variety of symptoms, making it difficult to know if particular client groups are more or less receptive to the effects of acupuncture and attachment style. Future research needs to differentiate between specific client groups and investigate any distinct ways in which those clients may be affected by acupuncture and attachment style. Finally, because exogenous opioids and attachment to the practitioner were not directly measured in Sochos—Attachment Style in Accupuncture

the current study, the accounts provided need to be verified by future studies measuring those important variables.

On the basis of the present findings, future studies could shed more light into how differences in attachment style are linked with differences in neurophysiological functioning, particularly the functioning of endogenous opioids. As a number of neurotransmitters and hormones are implicated in the processes of both physical healing and interpersonal bonding, attachment research may enrich scientists’ understanding of how individuals with different developmental histories have their psychophysiological processes organized differently and how they are likely to respond to mainstream and alternative medicine in diverse ways.

CONCLUSIONS Attachment style may affect acupuncture outcomes by predisposing individuals to different patterns of opioid elicitation and a different manner of relating to the practitioner. If this is the case, the quality of the practitionerclient relationship in acupuncture may warrant further attention. This new area of research could provide additional insight into how psychosocial and biological processes interact not only in compromising individual well-being but also in facilitating therapeutic intervention. Current findings provide further support for the appropriateness of a holistic approach to the treatment of psychological distress and somatic pain.

AUTHOR DISCLOSURE STATEMENT There was no conflict of interest in relation to this study.

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1. Su KP, Matsuoka Y, Pae CU. Omega-3 polyunsaturated fatty acids in prevention of mood and anxiety disorders. Clin Psychopharmacol Neurosci. 2015;13(2):129-137. 2. Crupi R, Marino A, Cuzzocrea S. n-3 fatty acids: role in neurogenesis and neuroplasticity. Curr Med Chem.

2013;20(24):2953-63. 3. Lynch AM, Loane DJ, Minogue AM, et al. Eicosapentaenoic acid confers neuroprotection in the amyloid-beta challenged aged hippocampus. Neurobiol Aging. 2007;28(6):845-855. 4. Heinrichs SC. Dietary omega-3 fatty acid supplementation for optimizing neuronal structure and function. Mol Nutr Food Res. 2010;54(4):447-456. 5. Saunders EF, Reider A, Singh G, Gelenberg AJ, Rapoport SI. Low unesterified:esterified eicosapentaenoic acid (EPA) plasma concentration ratio is associated with bipolar disorder episodes, and omega-3 plasma concentrations are altered by treatment. Bipolar Disord. 2015;17(7):729-742. 6. Sinn N, Milte CM, Street SJ, et al. Effects of n-3 fatty acids, EPA v. DHA, on depressive symptoms, quality of life, memory and executive function in older adults with mild cognitive impairment: a 6-month randomised controlled trial. Br J Nutr. 2012;107(11):1682-93. 7. Data on file, Prevention Pharmaceuticals Inc. New Haven, CT. omax3 is a registered trademark of Prevention Pharmaceuticals, Inc. ProResolv is a trademark of Prevention Pharmaceuticals, Inc. ©2015 Prevention Consumer Health Products. All rights reserved. OMPS007 12/2015

*These statements have not been evaluated by the US Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.

ORIGINAL RESEARCH

Acupressure and Transcutaneous Electrical Acupoint Stimulation for Improving Uremic Pruritus: A Randomized, Controlled Trial Nazan Kılıç Akça, PhD, RN; Sultan Taşcı, PhD, RN

ABSTRACT Context • Uremic pruritus, a frequent and compromising symptom for patients with advanced or end-stage renal disease (ESRD), strongly reduces the patient’s quality of life. Pruritus may be extremely difficult to control because therapeutic options are limited. Topical products are frequently used for easing pruritus, but their effects are generally temporary and marginal. Although acupressure and electrical-stimulation methods for the application of acupressure have been evaluated separately in terms of pruritus efficiency in different studies, the existence of any difference between the efficacies of the 2 methods has not been assessed yet.

Objective • The study intended to test the effectiveness of acupressure and transcutaneous electrical acupoint stimulation (TEAS) on uremic pruritus in patients who were receiving the routine hemodialysis treatment.

Design • The study was a randomized, controlled trial.

Setting • The study took place in hemodialysis units located in hemodialysis centers in Turkey.

Participants • Participants were patients in the hemodialysis units who were under hemodialysis treatment and had experienced uremic pruritus.

Intervention • Participants were randomly assigned to

Nazan Kılıç Akça, PhD, RN, is an assistant professor at Bozok University, Health School, Department of Medical Nursing, in Yozgat, Turkey. Sultan Taşcı, PhD, RN, is a professor, at Erciyes University, Faculty of Health Sciences, Department of Medical Nursing, in Kayseri, Turkey.

Corresponding author: Nazan Kılıç Akça, PhD, RN E-mail address: nazanakca7@hotmail.com

U

remic pruritus, defined as an unrestricted and uncomfortable sensation that elicits the desire to scratch, has been well recognized as a common complication in patients with end-stage renal disease (ESRD).

More than 40% of patients with uremic pruritus have undergone hemodialysis, and the symptoms range from localized and mild to generalized and severe. Although the association between ESRD and skin pruritus has been recognized for more than a

the acupressure group (intervention group), the TEAS group (intervention group), or the control group. For the 2 intervention groups, the treatment was applied 3 ×/wk during the 4 wk of the study on the large intestine (LI-11) acupuncture points in the arm, for a total of 12 sessions.

Outcome Measures • The study measured the severity of participants’ pruritus using a patient information form and a visual analogue scale (VAS). The data were collected at baseline and posttreatment.

Results • A total of 75 patients participated in the study.

The results indicated that patients in the acupressure and TEAS groups had significant reductions from baseline to posttreatment in their levels of discomfort from uremic pruritus compared with patients in the control group.

However, no differences existed between the acupressure and the TEAS patients in terms of outcome measures.

Conclusions • The research team concluded that both acupressure and TEAS applied to hemodialysis patients was effective in reducing uremic pruritus. The study provided support for an alternative method for health care providers in managing hemodialysis patients with symptoms of uremic pruritus. (Altern Ther Health Med. 2016;22(3):18-24.)

century, the pathogenic molecular basis of pruritus in ESRD remains elusive, mainly because of its subjective and capricious nature and the strong impact of psychological factors.1,2 Among the dermatological abnormalities associated with ESRD, pruritus is the most prevalent. Of all systemic disorders, uremia is the most important cause of pruritus.

The mechanism underlying uremic pruritus is poorly understood; secondary hyperparathyroidism, divalent-ion abnormalities, histamines, allergic sensitization, proliferation of skin mast cells, iron-deficiency anemia, neuropathy and neurological changes, or a combination of the conditions, have been hypothesized. Severe pruritus not only affects the quality of life but also is associated with poor outcomes in chronic hemodialysis patients.3,4 Pruritus is an unpleasant sensory and emotional experience associated with an actual or perceived disruption to the skin that produces a desire to scratch. Acute pruritus is a daily experience that can usually be abolished by briefly

18 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

Kılıç Akça—Acupressure and TEAS for Pruritus

Figure 1. Diagram of Participant Flow

Assessed for eligibility (N = 110) No pruritus (n = 31) Refused to participate (n = 4) Randomization (n = 75)

Acupressure 25 patients

TEAS 25 patients Lost to follow-up (n = 1)

CG 25 patients

Analysis (n = 25)

Analysis (n = 24)

Analysis (n = 25)

74 patients Abbreviations: TEAS, transcutaneous electrical acupoint stimulation; CG, control group. scratching near the area of pruritus. However, chronic pruritus can be debilitating, and local scratching often provides little relief and can instead exacerbate the problem.5,6 Pruritus may be extremely difficult to control because therapeutic options are limited. Topical products, such as moisturizers or emollients, and oral antihistamines, are frequently used for easing pruritus, but their effects are generally temporary and marginal. The most consequential approaches to treatment area topical treatment, with or without antiinflammatory compounds, or a systemic treatment, including (1) gabapentin, (2) μ-opioid receptor antagonists and κ-agonists, (3) drugs with an anti-inflammatory action, (4) phototherapy, or (5) acupuncture.1,2,6 Some patients benefit from pharmacological treatments, although the majority do not.

Therefore, uremic pruritus appears to be a problem seriously affecting the quality of life of patients and their families.

Acupressure is an ancient Chinese technique of pressing, electrically stimulating, and massaging numerous points on the surface of the entire body. It is proven to be effective in addressing various diseases and pathological conditions.

Acupressure is a technique related to acupuncture. Although it is less popular than acupuncture, it is indicated in similar pathological conditions and is noninvasive. Acupressure is accepted by many European and American physicians.

In traditional Chinese acupuncture, needles are inserted into proposed specific points on the body called acupuncture points. The effect of scratching on the reduction of itching from pruritus suggests that peripheral mechanisms of acupuncture may help relieve the pruritus. Because some qualities of pruritus, such as burning or tingling, may share the same pathways as pain, involving receptors for prostaglandins, bradykinin, serotonin, opioids, and capsaicin (vanilloid receptors), it seems reasonable to assume that the sensory transmission of pruritus may also be a target for acupuncture and acupressure.7-14 Acupoint injections, including those at the San Yin Jiao (SP-6), Xuehai (SP-10), Zusanli (ST-36), and Quchi (LI-11) acupoints, have been reported to be effective for relief of uremic pruritus.8,10,14-17 Because of those effects, acupressure is indicated to alleviate the severity of pruritus and to decrease the dosage and Kılıç Akça—Acupressure and TEAS for Pruritus

frequency of antihistaminic medications, when used with pharmacological agents or alone.10,15,17,18 Hemodialysis nurses are key health care professionals in management of uremic pruritus. The guidance of nurses in recommending, applying, and evaluating different treatment and care protocols is crucial. For patients who do not respond to conventional therapies, acupressure is considered the treatment of choice. Few studies, however, have examined the efficacy of acupressure for the condition. Testing the efficacy of acupressure in alleviating uremic pruritus is needed. The results may be useful to nursing and patients in making informed choices on the use of acupressure.10,11 Although acupressure and electrical stimulation methods in application of acupressure have been evaluated separately in terms of their efficiency in reducing pruritus in different studies, the existence of any difference between the efficacies of the 2 methods has not been assessed yet.

Various studies have shown that acupressure and transcutaneous electrical acupoint stimulation (TEAS) can decrease the severity of pruritus and the dosage of antihistaminic treatments while they can positively influence the patient’s quality of life, with no reports of adverse effects.

Although acupressure is an easy and important therapy to apply in clinics, it does not seem that nurses can apply it in clinics. However, acupressure nurses can be charged to use acupressure applications for symptom control at hospitals.

The present study was conducted to determine the effects of traditional acupressure and electro-stimulation acupressure as applied to the LI-11 acupuncture point and to identify the differences between the 2 methods on relief for uremic pruritus in hemodialysis patients.

METHODS Participants The present study was a randomized, controlled trial. To provide randomization, patients who met the inclusion criteria selected sealed envelopes in which their groups were identified.

Potential participants were 110 patients who visited hemodialysis units located in hemodialysis centers in Turkey and who were under hemodialysis treatment (Figure 1). Of ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 19

that number, 31 patients had not experienced uremic pruritus.

Seventy-nine eligible hemodialysis patients with pruritus were approached for participation in the study; 4 refused to participate, one person lost to follow-up, and 74 were recruited and 75 were recruited (Figure 1).

The researcher selected the participants. Data were collected by the hemodialysis nurse. The inclusion criteria comprised the following requirements: (1) having been on hemodialysis treatment for 6 months; (2) being older than 18 years; (3) receiving at least a 3 or higher score on a visual analogue scale (VAS) for pruritus; (4) being able to answer questions; (5) having no prior itchy-skin disease, liver disease, cancer, psychiatric disease, or disease of the soft tissue or vessels at the extremities; (6) having no current infections; (7) having had no prior surgical operations, amputations of an extremity, or neuropathy; and (8) accepting the acupressure application.

The desired sample size was estimated using a power analysis for 6 repeated measures, with a significance level of 0.05, a moderate effect size (f = 0.25), correlations of 0.5, and a power of 87%. A sample size of 25 per group was required to analyze the effects of the treatments on reducing the severity of the pruritus.19 Thus, a total of 75 patients were included in the research; 25 of the individuals were assigned to the acupressure group, 25 to the TEAS group, and 25 to the control group.

The study received formal ethical approval from the ethics committee of Bozok University and was conducted in conformance with the provisions of the Declaration of Helsinki (1995). A written informed consent was obtained from each patient.

The contents of the training included instruction in the correct identification of the acupoints (eg, skills on identifying landmarks and the application sensation) and in the acupressure techniques (eg, skills on sustaining the pressure with the fingers).

For the TEAS sessions, a portable, battery-powered TEAS unit was used (XFT-320; Shenzhen XFT Electronics Ltd, Guangdong, China). It had an acupuncture pen that was placed on the skin. Producing an electrical current that is small enough as not to be easily noted by the human body, the pen provides massage effects like thumb pressure and patting. The massage intensity range ranges between 1, the weakest massage; and 10, the most intense massage. The current output was titrated, with a maximum intensity of 06 mA. The frequency was between 5 and 10 Hz (densedispersed waveform), and pulse duration was 25 ms. The acupuncture pen requires no expertise for use. It has a blunt end and easily can be used by anybody. In addition, a member of the research team was trained about acupuncture by an acupuncture expert prior to its use.18 At the end of the fourth week, after completion of the acupressure interventions, participants’ pruritus was re-evaluated with a pruritus VAS. The current research team collected the data. Also, the amount of antihistaminic tablets that were ordered by the physician for each participant was followed for 4 weeks. If clear evidence existed of any threat to the safety of any of the participants during the study, the protocol required the end of the treatment.

Procedures In all the involved hemodialysis units, patients with uremic pruritus were prescribed antihistaminic agents and lotion, steroid pomade during advanced stages, and moisturizers for the fistula drop zone while nurses performed the hemodialysis. No other treatments were used other than those listed earlier for the pruritus problems in the hemodialysis units. During the study, the patients were under routine treatment and care, and no changes were made to the working operations of the units.

At baseline, data for the acupressure, TEAS, and control groups were collected from participants using a patient information form and a VAS through a face-to-face interview and from patient files.

An acupressure protocol for the study was developed based on the literature the current research team had reviewed and on consultations with acupressure specialists.20-22 Prior to the study, a member of the research team, who had received 12 credits from a training specialist in Chinese medicine nursing and who had published numerous empirical studies on acupressure points, also personally received a treatment with acupressure on the relevant points until the sensations of soreness, numbness, heaviness, and swelling occurred.

The training was intended to ensure that she complied with the research protocol.

Intervention To reduce pruritus, the research team used the large intestine 11 (LI-11) acupoint for the 2 interventions; that point had been recommended in the literature. The LI-11 acupoint (ie, the acupuncture point known as Qu Chi on the large intestine meridian) is located on the side of the elbow on the outer side of the arm. With the forearm bent and the hand pointed toward the neck, the point is located at the end of the crease at the elbow. It is halfway up the side of the arm (Figure 2).

For both the acupressure and the TEAS groups, the intervention was provided during the first half of every hemodialysis session due to the patient’s better emotional state and general status at that point. The treatments occurred 3 times per week for 4 weeks, for a total of 12 sessions.15,16,17 Figure 2. LI-11 Acupoint

20 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

Kılıç Akça—Acupressure and TEAS for Pruritus

Table 1. Demographic Characteristics of Individuals in the Groups

Demographic Characteristics Gender Female Male Level of education Untutored Primary school Secondery school and up Profession/work done Retired Homemaker Farmer Age, y (mean ± SD) Duration of hemodialysis, mo, (mean ± SD)

Acupressure (n = 25) n %

Groups TEAS (n = 24) n %

Control (n = 25) n %

15 10

60.0 40.0

11 13

45.8 54.2

13.0 12.0

52.0 48.0

11 8 6

44.0 32.0 24.0

9 11 4

37.5 45.8 16.7

3 18 6

12.0 72.0 16.0

12 48.0 10 41.7 11 44.0 11 45.8 2 8.0 3 12.5 55.24 ± 10.13 48.08 ± 9.05 48.92 ± 32.78 58.79 ± 35.56

8 32.0 12 48.0 5 20.0 45.84 ± 10.40 53.36 ± 27.32

Abbreviations: TEAS, transcutaneous electrical acupoint stimulation; SD, standard deviation.

Acupressure Group. For the acupressure intervention, the therapist used her fingertips, applying a consistent pressure on the correct acupoint with small rotational movements. The action was done rapidly at the rate of 2 rotations per second.23 Sensations that a patient experienced during an acupressure session, which could include soreness, numbness, heaviness, swelling, and warmth, were considered as indicating the accurate use of the acupuncture points. The force applied in the acupressure intervention was maintained between 3 and 5 kg and each therapy session lasted for 6 to 10 minutes.20-22 TEAS Group. The therapist applied a 3-minute TEAS with an acupuncture pen to LI-11 acupressure point.

Control Group. The participants received only normal clinical treatment, with no acupressure-related intervention.

After completing the study, they received a free course of acupressure sessions, identical to the stipulated in the acupressure protocol Outcome Measures Patient Information Form. The patient information form was developed by the researchers through a review of the relevant literature.7,8,10,15-18,24-26 It included questions about sociodemographic characteristics as well as the current medical status of a patient’s disease and pruritus conditions.

All data for the participants were collected by the clinical hemodialysis nurse.

Visual Analogue Scale. The severity of the patient’s pruritus was measured at baseline and postintervention using VAS that ranged from 0 to 10, with 0 = no pruritus and 10 = vunbearable pruritus. The scale showed adequate validity and reliability when used with patients having chronic pruritus.27 Statistical Analysis Data were analyzed using the SPSS software, version 13 (SPSS Inc, Armonk, NY, USA). Percentage, mean, and Kılıç Akça—Acupressure and TEAS for Pruritus

standard deviation (SD) were used to describe participant’s demographics and disease characteristics. Parametric tests were used for the data (t test analysis). Analysis of independent groups was done with 1-way analysis of variance (ANOVA), which was applied to measure the changes in the acupressure, TEAS, and control groups. Further analysis was done with a Bonferroni corrected t test. Antihistaminic usage of the patients was analyzed with a Kruskal-Wallis test due to the lack of a normal distribution of the relevant data. The level of significance was set at P < .05.

RESULTS Demographic Data The study was completed with the participation of a total of 74 patients. One participant was lost to follow-up in the TEAS group, as the patient changed center.

The mean age of the patients in the acupressure group was 55.24 ± 10.13 year, 60.0% were women, and 44.0% were illiterate. The group’s participants had been on hemodialysis treatments for 48.92 ± 32.78 months. The mean age of the patients in the TEAS group was 48.08 ± 9.05 years, 54.2% were men, and 45.8% were graduates from elementary school. The group’s participants had been on hemodialysis treatments for 58.79 ± 35.56 months. The mean age of the control group was 45.84 ± 10.40 years, 52.0% were women, and 72.0% were elementary school graduates. The group’s participants had been on hemodialysis treatments for 53.36 ± 27.32 months.

The participants in the 3 groups were similar in terms of sociodemographic characteristics, P > .05 (Table 1).

Pruritus Status The statuses of the uremic pruritus after hemodialysis treatments for the participants in the 2 intervention groups and the control group are shown on Table 2. Of the patients in the ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 21

Table 2. Characteristics of Uremic Pruritus of Individuals in the Groups

Uremic Pruritus Characteristics Pruritus area Local area All over the body Time of most intense pruritus On the day following hemodialysis In the evening before hemodialysis All the time During hemodialysis On the day of leaving hemodialysis Pruritus status Intermittent pruritus Insistent pruritus Severe pruritus, excoriations and irritation Use of medication for pruritus during the trial Antihistamine tablets used Antihistamine tablets not used Duration of pruritus, d, (mean ± SD)

Acupressure (n = 25) n %

Groups TEAS (n = 24) n %

n

%

10 15

40.0 60.0

9 15

37.5 62.5

12 13

48.0 52.0

3 4 5 5 8

12.0 16.0 20.0 20.0 32.0

5 3 6 3 7

20.8 12.5 25.0 12.5 29.2

12 5 2 2 4

48.0 20.0 8.0 8.0 16.0

8 8 9

32.0 32.0 36.0

6 5 13

25.0 20.8 54.2

8 6 11

32.0 24.0 44.0

7 18

28.0 72.0 5.24 ± 2.35

6 18

25.0 75.0 4.67 ± 2.28

14 11

56.0 44.0 4.96 ± 1.59

Control (n = 25)

Abbreviations: TEAS, transcutaneous electrical acupoint stimulation; SD, standard deviation.

Table 3. Distribution of the Averages of the Pre- and PostinterventionVAS scores for Patients in the Intervention Groups and the Control Group

VAS Score Preintervention pruritus VAS Postintervention pruritus VAS Test valueb (P value)

Acupressure (n = 25) Mean ± SD 6.84 ± 1.70 3.36 ± 2.37 t = 5.346 (<.001)

Groups TEAS (n = 24) Mean ± SD 7.37 ± 1.31 3.12 ± 2.15 t = 7.936 (<.001)

Test Control (n = 25) Mean ± SD 6.92 ± 1.41 5.08 ± 1.55 t = 3.942 (<.05)

Fa (P value) 0.918 (>.05) 6.672 (<.05)

a

One-way ANOVA. Paired sample t test.

b

Abbreviations: VAS, visual analogue scale; TEAS, transcutaneous electrical acupoint stimulation; SD, standard deviation; ANOVA, analysis of variance. acupressure group, 36.0% (n = 9) presented with severe pruritus, and 60.0% (n = 15) had general pruritus (ie, all over the body).

On the day that the hemodialysis sessions ended, 32.0% (n = 8) of the group had the condition with the duration of the pruritus after the end of treatment being 5.24 ± 2.35 days.

Of the patients in the TEAS group, 54.2% (n = 13) had severe pruritus, and 62.5% (n = 15) had general pruritus (ie, all over the body). On the day that the hemodialysis sessions ended, 29.2% (n = 7) had the condition, which lasted for 4.67 ± 2.28 days.

Of the patients in the control group, 44.0% (n = 11) had severe pruritus, and 52.0% (n = 13) had general pruritus (ie, all over the body). On the day that the hemodialysis session ended, 16.0 % had the condition, which lasted for

Table 4. Distribution of the Mean Differences Between the Pre- and Postintervention VAS Scores for Patients in the Intervention Groups and the Control Group

VAS Score Acupressure vs TEAS VAS Acupressure vs Control VAS TEAS vs Control VAS

Mean Difference 0.23 -1.72 -1.95

P Valuea 1.000 .013 .004

a

Bonferroni test.

Abbreviations: VAS, visual analogue scale; TEAS, transcutaneous electrical acupoint stimulation.

22 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

Kılıç Akça—Acupressure and TEAS for Pruritus

Table 5. Number of Antihistaminic Tablets for Pruritus During the Trial for the Intervention Groups and the Control Group Groups Use of Medication for Pruritus Antihistaminic tablets

Test

Acupressure (n = 25)

TEAS (n = 24)

Control (n = 25)

Mean ± SD

Mean ± SD

Mean ± SD

KWa (P value)

4.16 ± 2.83

4.08 ± 2.97

7.52 ± 4.76

7.208 (<.05)

a

Kruskal-Wallis test.

Abbreviations: TEAS, transcutaneous electrical acupoint stimulation; SD, standard deviation.

4.46 ± 1.59 days. All patients having pruritus were given antihistaminic tablets as a routine treatment; 28.0% of the acupressure group, 25.0% of the TEAS group, and 56.0% of the control group used the treatments during period of the study (Table 1).

Effects of Acupressure and TEAS Table 3 shows the means pretreatment and posttreatment VAS scores for the 3 groups. Mean preintervention and postintervention VAS scores for the acupressure group were 6.84 ± 1.70 and 3.36 ± 2.37, respectively. The severity of the pruritus of the acupressure group decreased significantly after the intervention (P < .001).

The mean preintervention and postintervention VAS scores for the TEAS group were 7.37 ± 1.31 and 3.12 ± 2.15, respectively, which was a statistically significant change (P < .001). The mean preintervention and postintervention VAS scores for the control group were 6.92 ± 1.41 and 5.08 ± 1.55, respectively (P < .05).

The difference between the mean postintervention scores on the pruritus VAS for the acupressure group vs the control group was -1.72 (P = .013) and for the TEAS group and the control group was -1.95 (P = .004), with both being statistically significant. The mean scores on the pruritus VAS for the acupressure, TEAS, and control groups had all decreased from baseline to postintervention, and the mean postintervention VAS scores for the acupressure and TEAS groups were not significantly different (Table 4).

Table 5 shows the number of antihistaminic tablets used during treatment for the 3 groups. During the study, antihistaminic tablets were ordered for 7 members of the acupressure group, to 6 members of the TEAS group, and to 14 members of the control group (Table 2). It was determined that the intervention groups used fewer tablets, with the acupressure group receiving 4.16 ± 2.83 and the TEAS group receiving 4.08 ± 2.97, compared with the control group, which received 7.52 ± 4.76, showing statistically significant differences between the control group and both intervention groups (P < .05).

No adverse effects were observed during the study.

Kılıç Akça—Acupressure and TEAS for Pruritus

DISCUSSION Acupressure, which is a complementary method for decreasing pruritus, may be learned by nurses and integrated into independent nursing functions. The differences in the efficacy of the 2 methods that were examined in the current study had not been evaluated previously for alleviating pruritus, although they have been tested separately. The present study assessed the impact of acupressure and TEAS, as applied to the LI-11 acupuncture point, on uremic pruritus in hemodialysis patients, with the acupressure and TEAS being applied 3 times per week for a total of 12 sessions. A randomized, controlled study, it was conducted with 74 patients, and it was determined that both the acupressure and TEAS interventions were effective in alleviating uremic pruritus and that the 2 methods yielded results that were not statistically different (P > .05).

Jedras et al10 had found similar results in a study using acupressure, in which a statistically significant decrease was found in the severity of pruritus for the intervention group as compared with the controls. In a study on electrical stimulation acupressure, Kılıç Akça et al18 indicated that it could reduce the severity of uremic pruritus in patients.

Other studies similarly have suggested that electrical stimulation acupressure can decrease the severity of pruritus.15,17 However, prior to the current study, no research in the literature had previously investigated whether a difference existed between the results for acupressure and TEAS in terms of their effects on pruritus. Tsay et al20 had compared the efficacy of acupressure and TEAS on fatigue, sleep quality, and depression and found no difference.

Because the severity of pruritus for hemodialysis patients is excessive, it is generally resistant to pharmacological agents.

Further, all hemodialysis patients have to use a wide range of medicines due to various symptoms.1,12 Therefore, use of medicine for symptoms that can be controlled without pharmacological treatments should be reduced. In the present study, the acupressure and TEAS groups were observed to use less medication than the control group during the study. A number of previous studies have also suggested a lower use of medicine in participants who received acupressure.17,18 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 23

In the current study, acupressure and TEAS decreased the severity of pruritus, and the 2 methods were not statistically different. Also, both methods reduced the number of antihistaminic agents used by the patients. Consequently, the current research team concludes that hemodialysis nurses could use both the acupressure and the TEAS methods for alleviating the pruritus of hemodialysis patients.

The main limitations of the current study were the short follow-up period after treatment and the fact that the study did not examine the laboratory findings that identify the changes associated with pruritus.

CONCLUSIONS Acupressure is a noninvasive, safe, and effective method and health professionals, patients, and their families could easily be trained to apply acupressure to those individuals who have pruritus. Assessments of ESRD with the aim of reducing patients’ pruritus can be a part of nursing practice, and clinicians can consider providing acupressure and TEAS as alternative methods for decreasing pruritus in hemodialysis patients.

18. Kılıç Akça N, Taşçı S, Karataş N. Effect of acupressure on patients in turkey receiving hemodialysis treatment for uremic pruritus. Altern Ther Health Med..

2013;19(5):12-18.

19. Polit DF, Sherman RE. Statistical power in nursing research. Nurs Res. 1990;39(6):365-369.

20. Tsay SL, Cho YC, Chen ML. Acupressure and transcutaneous electrical acupoint stimulation in improving fatigue, sleep quality and depression in hemodialysis patients. Am J Chin Med. 2004;32(3):407-416.

21. Kwan RYC, Leung MCP, Lai CKY. Acupressure for agitation in nursing home residents with dementia: Study protocol for a randomized controlled trial. Trials.

October 2014;15:410.

22. Weaver MT. Acupressure: An overview of theory and application. Nurse Pract.

1985;10(8):38-42.

23. Shariati A, Jahani S, Hooshmand M, Khalili A. The effect of acupressure on sleep quality in hemodialysis patients. Complement Ther Med. 2012;20(6):417-423.

24. Kılıç Akça N, Taşçı S. Using nonpharmacological methods for controlled itch.

TAF Prev Med Bull.2013;12(3):359-364.

25. Stellon A. The use of laser acupuncture for the treatment of neurogenic pruritus in a child: A case history. Acupunct Med.2005;23(1):31-33.

26. Hsu MC, Chen HW, Hwu YJ, et al. Effects of thermal therapy on uremic pruritus and biochemical parameters in patients having hemodialysis. J Adv Nurs 2009;65(11):2397-2410.

27. Phan NQ, Blome C, Fritz F, et al. Assessment of pruritus intensity: Prospective study on validity and reliability of the visual analogue scale, numerical rating scale and verbal rating scale in 471 patients with chronic pruritus. Acta DermatoVenereologica. 2012;92:502-507.

ACKNOWLEDGMENTS The current research team would like to thank all of the patients who participated in the study.

AUTHOR DISCLOSURE STATEMENT The authors received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors for the research. They declare that they have no conflicts of interests.

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4. Murtagh FE, Addington-Hall J, Higginson IJ. The prevalence of symptoms in end-stage renal disease: A systematic review. Adv Chronic Kidney Dis. 2007;14(1):82-99.

5. Davidson S, Giesler GJ. The multiple pathways for itch and their interactions with pain. Trends Neurosci. 2010;33(12):550-558.

6. Tey HL, Wallengren J, Yosipovitch G. Psychosomatic factors in pruritus. Clin Derma. 2013;31(1):31-40.

7. Carlsson CP, Wallengren J. Therapeutic and experimental therapeutic studies on acupuncture and itch: Review of the literature. JEADV. 2010;24:1013-1016.

8. Shapiro R, Stockard H. Successful treatment of uremic pruritus: The acupuncture approach revisited. Dial Transplant. 2003;32:257-265.

9. Tsay SL, Chen ML. Acupressure and quality of sleep in patients with end-stage renal disease: A randomized controlled trial. Int J Nurs Stud. 2003;40(1):1-7.

10. Jedras M, Bataa O, Gellert R, et al. Acupressure in the treatment of uremic pruritus. Dial Transplant. 2003;32:8-10.

11. Pearson A. Complementary therapies: The need for an evidence-based approach Internat J Nursing Practice. 2006;12:307.

12. Kim KH, Lee MS, Kang KW, Choi SM. Role of acupressure in symptom management in patients with end-stage renal disease: A systematic review. J Palliative Med. 2010;13(7):885-892.

13. Cowdell F. Care and management of patients with pruritus. Nurs Older People.

2009;21(7):35-41.

14. Kılıç Akça N, Taşçı S. Uremic pruritus in hemodialysis patients and acupressure practice . Maltepe Üniversitesi Hemşirelik Bilim ve Sanat Dergisi. 2011;4(l):90-96.

15. Duo LJ. Electrical needle therapy of uremic pruritus. Nephron. 1987;47:179-183.

16. Che-yi C, Yu Wen C, Min-Tsung K, et al. Acupuncture in hemodialysis patients at the Quchi (LI11) acupoint for refractory uremic pruritus. Nephrol Dial Transplant. 2005;20:1912-1915.

17. Stellon, A. Neurogenic pruritus: An unrecognized problem? A retrospective case series of treatment by acupuncture. Acupunct Med. 2002;20(4):186-190.

24 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

Kılıç Akça—Acupressure and TEAS for Pruritus

REVIEW ARTICLE

Perforators, the Underlying Anatomy of Acupuncture Points Ding Zhi Wei, MD; Shi Yu, MD; Zhang Yongqiang, MD

ABSTRACT Context • As a critical concept in acupuncture, acupuncture points, or acupoints for short, are currently believed to be 3-dimensional structures composed of skin, muscles, tendons, nerves, blood vessels, lymph nodes, and other special tissues. No known specific tissue or organ has been confirmed to be an acupoint. However, from a microsurgeon’s point of view, a special vascular structure exists around each acupoint (ie, perforators or arterioles of 0.3–1.5 mm that pierce deeply through the fascia).

Objective • The current research team investigated the theory that perforators are the anatomical basis of acupoints.

Design • A reference list of acupoints and of perforators near the acupoints was proposed, and the distributions were analyzed. Using the World Health Organization (WHO) list, “Standard Acupuncture Point Locations in the Western Pacific Region,” 2 experienced acupuncturists identified the needling depth and angle as well as verified the acupoint locations. Perforators with amplitudes of 1 cm or more were identified by 3 veteran microsurgeons.

Ding Zhi Wei, MD, is an orthopedist in the Department of Orthopedics, 89th Hospital of People’s Liberation Army, in Weifang, Shandong, China. Shi Yu, MD, is a physician in the Second Military Medical University in Shanghai China and is also a physician in the Department of Neurology at Jinan Military General Hospital in Jinan, Shandong, China.

Zhang Yongqiang, MD, is a neurosurgeon in the Department of Neurosurgery at Jinan Military General Hospital.

Corresponding author: Ding Zhi Wei, MD E-mail address: ding77966@163.com

A

cupuncture, one of the main pillars of traditional medicine in the western Pacific region, has become a global therapeutic method and has been proven effective in the management of numerous disorders in recent decades.1-4 Previously, much of the research has focused on the biomechanism and original anatomical basis of meridians and acupoints. Recent studies have found that acupuncture has a Wei—Perforators and Acupuncture Points

Setting • The study was carried out in an osteopathic research center at the 89th Hospital of the People’s Liberation Army, in Weifang, Shandong, China. From October 2013 to October 2014, patients who required skin flap transplantation were enrolled for observation.

Outcome Measures • To evaluate the theory, the current research team observed subcutaneous perforating points in flap donor sites and operative incision areas and compared those points with the acupoints located by acupuncturists.

Results • The perforators and acupoints were found to be closely correlated. Several distribution patterns of acupoints and perforators have emerged and further confirmed the research team’s theory.

Conclusions • The hypothesis could facilitate theoretical understanding of the mechanism and essence of acupuncture. (Altern Ther Health Med. 2016;22(3):25-30.)

substantial effect on the sympathetic nervous system, the endocrine system, and the immune system.5-8 However, no common conclusions have been reached. The philosophy and essence of acupuncture remain to be investigated more deeply.

At the same time, with advancing techniques and technology, completely different disciplines, such as microsurgery, plastic surgery, and replantation surgery, have made important progress in the last 3 decades. Researchers have been drawn to investigate perforator flaps and have made great achievements since the concepts of the perforator and angiosome were introduced by Taylor.9 The term variform flaps has since emerged in clinical practice. In 2003, as the result of a terminology consensus meeting that had been held on September 29, 2001, during the Fifth International Course on Perforator Flaps in Gent, Belgium, a consensus was reached that a perforator flap is a flap consisting of skin and/or subcutaneous fat that is supplied with blood by isolated perforator(s), whereas a perforator is a vessel that has its origin in one of the axial vessels of the body and that passes through certain subcutaneous structural elements.10 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 25

As microscopic surgeons, the current research team has performed operations for limb fractures, limb replantations, and reconstructions with flaps for decades. Through longterm clinical practice, the team gradually and intuitively recognized the distribution of the perforators and was impressed with the entire network of subcutaneous perforating points (ie, points where perforators pass through the fascia). It occurred to the team that the locations and distribution patterns of the perforating points seemed to resemble those of acupoints in the Chinese acupuncture atlas.

Accordingly, the team proposed a hypothesis that was based on clinical experience and anatomical physiology (ie, that the distribution pattern of acupoints is correlated with that of perforators). Moreover, the team suggested that needling around the perforating points could stimulate the smooth muscle of vessels, inducing biochemical and neuroendocrinal reactions. The team also proposed the hypothesis that perforators are the underlying anatomy and essence of acupoints.

METHODS Despite extensive research into the mechanisms of acupuncture, no well-acknowledged and objective technologies or methods exist for defining acupoints and meridians. In the current study, the correlations between perforators and acupoints were mainly examined subjectively.

A reference list of acupoints and perforators was proposed, and the distributions were analyzed.

The current study mainly referred to the World Health Organization (WHO) standard acupuncture point locations11 as the criteria for locating the acupoints. Two experienced acupuncturists helped to identify the needling depth and angle as well as verified the acupoint locations. Then, perforators with amplitudes of 1 cm or more that were clinically near the acupoints were identified by 3 veteran microsurgeons. The surgeons were experienced and had been performing limb-fracture-reduction surgeries and flaptransplantation surgeries for decades. The verification process depended on several methods, including clinical experience, anatomical atlases, observations made during surgery, and vascular ultrasounds.

In addition, the source arteries of the perforators and the intermuscular septa, through which the perforators pass, were reviewed and listed. Typical flaps were also documented with donor sites that enclosed perforators or that had incisions for which perforators could be viewed.

RESULTS A list of perforators near acupoints is presented in Table 1.

In the operative regions frequently involved in the research team’s microsurgeries, a total of 110 acupoints of 11 meridians were counted. Those acupoints and specific perforators co-existed in a particular section. Those features were more significant in the lower legs and forearms. In the forearm, 22 acupoints were found (LI-6/7/8/9/10, TE-5/6/7/8/9, SI-6/7, LU-6/7/8, PC-4/5/6, and HT-4/5/6/7) and in the leg,

27 acupoints were found (ie, SP-6/7/8/9, ST-36/37/38/39/40, BL-55/56, GB-34/35/36/37/38/39, LR-5/6/7, and KI-6/7/8/9), both unilaterally. Near all of those acupoints, perforators were observed iteratively by surgeons during operations. The viewpoint that acupoints and specific perforators are correlated has won the approval of the acupuncturists and surgeons involved in the study.

A comparative study of the pertinent literature on acupoints and perforators also supported that viewpoint. The WHO list of acupoint locations recorded 22 acupoints in the forearm and 27 acupoints in the lower leg unilaterally.

Yang et al12 has found that 24 and 20 perforators with diameters >0.5 mm are located in the arm and leg, respectively, on each side. An average of 374 and 440 significant perforators in the whole body were reported by Taylor and Yang, respectively,12,13 which are close to the total number of acupoints, 361, in the WHO standard. The differences might have been caused by the relatively fewer points in the thorax and back. Acupuncture in those regions can cause complications, such as pneumothorax.

The distribution and characteristics of the acupoints and perforators were also noted as follows.

Pipeline and Tributary Arteries The pipeline artery plays a role in the mainstream vasculature, which includes the femoral, popliteal, and anterior and posterior tibial arteries and the axillary, brachial, ulnar, and radial arteries. That type of artery is characterized by a high flow velocity, a high blood-vessel pressure, and the crossing of joints.

The pipeline artery gives off 3 types of branches—the cutaneous branches, articular branches, and tributary arteries.

With regard to the superficial layer, the pipeline artery migrates into cutaneous branches. The pipeline artery can also issue several articular branches, nourishing the articular cartilage and synovium. The tributary artery is a thick branch originating from the proximate of the pipeline artery, and it usually has a clear anatomical name, such as the lateral femoral circumflex artery, deep brachial artery, superficial peroneal artery, fibular artery, forearm interosseous artery, or forearm dorsal interosseous artery.

Those vessels feature a lower flow velocity, and they play roles in nourishing the skin, muscles, and skeleton. The tributary arteries cannot cross the joints, and they often join in terminal branches with articular branches, forming a vascular network around a joint. In the intermuscular septa, a tributary artery can issue secondary arteries of 1.5 mm in diameter, including muscle branches, musculocutaneous branches, and direct cutaneous branches or perforators. They can further gradually form dendriform clusters. The smaller the caliber of the artery is, the lower its flow velocity and vasoconstrictive capacity are.

Meridians The meridians in which the acupoints are located are not related to the pipeline artery of the corresponding cutaneous branch but are somewhat related to the tributary artery and are closely related to the secondary branches. For instance, the acupoints located in the blood-supplied area of the lateral

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Table 1. Anatomy of Perforators Near Acupuncture Points Acupuncture Points

Parent Artery of Perforators

Spatium Intermusculare Through Which Perforators Pass

LU-5 LU-6 LU-7 LU-8 LU-9 LU-10 LU-11 LI-1 LI-2 LI-3 LI-4

Recurrent radial artery/articular network of elbow Septocutaneous/myocutaneous perforator of radial artery Cutaneous perforator of radial artery Palmar carpal branch of radial artery Superficial palmar branch of radial artery Princeps pollicis artery Radial terminal dorsal cutaneous branch proper, digital arteries of thumb Radial dorsal terminal branch of proper digital arteries Radial dorsal cutaneous branch of proper digital arteries in proximal phalanx Second dorsal metacarpal arteries in head of metacarpal bone Second dorsal metacarpal artery arising from the radial artery

Brachioradialis muscle—brachialis muscle Brachioradialis muscle—forearm flexor Group muscles Brachioradialis muscle—flexor carpi radialis muscle Flexor carpi radialis muscle—flexor carpi ulnaris muscle Thenar muscles— trapezium Thenar muscles—first metacarpal bone Fascia—bone Fascia—bone Fascia—bone Dorsal interosseous muscles (bipennate)—second metacarpal bone Dorsal interosseous muscles (bipennate)—second metacarpal bone

LI-5 LI-6 LI-7 LI-8 LI-9 LI-10 LI-11 LI-12 LI-13 LI-14 ST-24 ST-25 ST-26 ST-27 ST-28 ST-29 ST-30 ST-31 ST-32 ST-33 ST-34 ST-35 ST-36

Extensor pollicis longus tendon—extensor pollicis brevis tendon Brachioradialis muscle—M flexor pollicis longus Brachioradialis muscle—M flexor pollicis longus Extensor carpi radialis longus/brevis muscle—brachioradialis muscle Extensor carpi radialis longus/brevis muscle—brachioradialis muscle Extensor carpi radialis longus/brevis muscle—brachioradialis muscle Triceps brachii muscle—brachioradialis muscle Brachialis muscle—triceps brachii muscle Biceps brachii muscle triceps—brachii muscle Deltoideus termination—biceps brachii muscle Rectus abdominis Rectus abdominis Rectus abdominis Rectus abdominis Rectus abdominis Rectus abdominis Rectus abdominis Sartorius muscle—rectus femoris muscle Vastus lateralis muscle—rectus femoris muscle Vastus lateralis muscle—rectus femoris muscle Vastus lateralis muscle—rectus femoris muscle Lateral patellar retinaculum Tibialis anterior muscle—tibia

ST-37 ST-38 ST-39 ST-40

Radial artery in anatomic snuffbox Septocutaneous perforator of radial artery Septocutaneous/myocutaneous perforator of radial artery Myocutaneous perforator of radial artery Myocutaneous perforator of radial artery Recurrent interosseous artery Articular network of elbow Radial collateral artery of deep brachial artery Radial collateral artery of deep brachial artery Radial collateral artery Septocutaneous perforator of arteria epigastrica inferior Septocutaneous perforator of arteria epigastrica inferior Septocutaneous perforator of arteria epigastrica inferior Septocutaneous perforator of arteria epigastrica inferior Septocutaneous perforator of arteria epigastrica inferior Septocutaneous perforator of arteria epigastrica inferior Septocutaneous perforator of arteria epigastrica inferior Septocutaneous perforator of lateral circumflex femoral artery Ascending branches of lateral circumflex femoral artery Ascending branches of lateral circumflex femoral artery Ascending branches of lateral circumflex femoral artery Middle genicular artery Myocutaneous perforator and nutrient artery of bone of anterior tibial recurrent artery Septocutaneous/myocutaneous perforator of anterior tibial artery Septocutaneous/myocutaneous perforator of anterior tibial artery Septocutaneous/myocutaneous perforator of anterior tibial artery Superficial fibular artery

ST-41 ST-42 ST-43 ST-44 SP-12 SP-13 SP-11 SP-10 SP-9 SP-8

Lateral anterior malleolar artery of anterior tibial artery Arcuate artery of foot of medial tarsal arteries Second dorsal tarsal arteries Dorsal digital arteries Superficial circumflex iliac vessels Superficial circumflex iliac vessels Terminal branches of profunda femoris artery Saphenous branch of descending genicular artery Medial inferior genicular artery Septocutaneous/myocutaneous perforator of posterior tibial artery

SP-7 SP-6 SP-5 SP-4 SP-3 SP-2 SP-1 HT-2 HT-3 HT-4–HT-7 HT-8 HT-9 SI-8 SI-7 SI-6 SI-5 SI-4 BL-55 BL-56 BL-57 BL-58 BL-59 BL-60 BL-61 BL-61 KI-3

Septocutaneous perforator of posterior tibial artery Medial malleolar branches of posterior tibial artery Calcanean branches of posterior tibial artery Superficial branch of medial plantar artery Superficial branch of medial plantar artery Plantar digital arteries Plantar digital arteries Superior ulnar collateral artery Anterior branch of ulnar recurrent artery Branches of supracarpal cutaneous of ulnar artery Fourth dorsal metacarpal arteries Dorsal branches of palmar digital artery of digitus minimus Posterior branch of ulnar recurrent artery Septocutaneous/myocutaneous perforator of ulnar artery Palmar carpal branch of ulnar artery Dorsal carpal branch of ulnar artery Perforator of deep palmar branch Septocutaneous perforator of popliteal artery Septocutaneous perforator of medial gastrocnemius artery Septocutaneous perforator of medial gastrocnemius artery Septocutaneous perforator of lateral gastrocnemius artery Septocutaneous perforator of peroneal (fibular) artery Communicating branch, peroneal (fibular) artery to posterior tibial artery Calcaneal branches of fibular (peroneal) artery Calcaneal branches of fibular (peroneal) artery Medial retromalleolar perforator

Flexor halluces brevis muscle—first metatarsal bone Flexor halluces brevis muscle—first metatarsal bone Fascia—bone Fascia—bone Triceps brachii muscle—biceps brachii muscle Triceps brachii muscle—biceps brachii muscle Flexor carpi ulnaris—ulnar bone Bipennate muscle-bone Fascia—bone Flexor carpi ulnaris—bone Flexor carpi ulnaris muscle—extensor carpi ulnaris muscle Extensor carpi ulnaris muscle—ulnar bone Extensor carpi ulnaris muscle—ulnar bone Antithenar—carpal bone Gastrocnemius muscle (medial and lateral heads) Gastrocnemius muscle (medial and lateral heads) Gastrocnemius muscle (medial and lateral heads) Medial gastrocnemius muscle—soleus muscle Soleus muscle—fibularis muscle Calcaneal (Achilles) tendon—fibularis muscle

KI-5

Medial retromalleolar perforator

Tibial muscle—tibia

PC-3 PC-4 PC-5 PC-6 PC-7

Branch of elbow’s artery network Septocutaneous perforator of anterior interosseous artery Septocutaneous perforator of anterior interosseous artery Septocutaneous perforator of anterior interosseous artery Artery network of wrist

Biceps brachii muscle—superficial flexor muscles Flexor digitorum profundus muscle—flexor pollicis longus muscle Flexor digitorum profundus muscle—flexor pollicis longus muscle Flexor digitorum profundus muscle—flexor pollicis longus muscle

Wei—Perforators and Acupuncture Points

Tibialis anterior muscle—extensor digitorum longus muscle Tibialis anterior muscle—extensor digitorum longus muscle Tibialis anterior muscle—extensor digitorum longus muscle Extensor digitorum longus muscle—fibularis (peroneus) longus/ brevis muscle

Fascia—bone

Adductor magnus muscle—sartorius muscle Anteromedial intermuscular septum Gastrocnemius muscle (medial head)—tibia Soleus muscle—gastrocnemius muscle (medial head) Tibialis posterior muscle—flexor digitorum longus muscle Tibialis posterior muscle—flexor digitorum longus muscle

Tibial muscle—tibia

Related Flaps Radial artery flap Radial artery flap Radial artery flap Radial artery flap

Digital arteries flap Dorsal metacarpal flap Second dorsal metacarpal artery, neurovascular island flap Superficial radial neurocutaneous flap Superficial radial neurocutaneous flap Superficial radial neurocutaneous flap Superficial radial neurocutaneous flap Superficial radial neurocutaneous flap

Radial collateral artery flap Deep inferior epigastric perforator flap Deep inferior epigastric perforator flap Deep inferior epigastric perforator flap Deep inferior epigastric perforator flap Deep inferior epigastric perforator flap Deep inferior epigastric perforator flap Deep inferior epigastric perforator flap Anteromedial thigh flap Anterolateral thigh flap Anterolateral thigh flap Anterolateral thigh flap

Superficial fibular artery flap Dorsal pedis artery flap Dorsal pedis artery flap Grafting of phalanges of foot Grafting of phalanges of foot Superficial circumflex iliac vessels flap Superficial circumflex iliac vessels flap

Musculocutaneous flap of caput mediale musculi gastrocnemii Lower medial leg fasciocutaneous flap Medial malleolar perforator flap Medial plantar flap Medial plantar flap

Supracarpal cutaneous of ulnar artery flap

Medial sural artery perforator flap Medial sural artery perforator flap Sural neurocutaneous vascular flap Peroneal artery flap Sural neurocutaneous vascular flap

Medial retromalleolar perforator adipofascial flap Medial retromalleolar perforator adipofascial flap

ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 27

Table 1. (continued) Acupuncture Points

Parent Artery of Perforators

PC-8 TE-6 TE-7 TE-8 TE-9 TE-5 TE-4 TE-3 GB-24 GB27 GB-28

Superficial palmar arch Septocutaneous perforator of posterior interosseous artery Septocutaneous perforator of posterior interosseous artery Septocutaneous perforator of posterior interosseous artery Septocutaneous perforator of posterior interosseous artery Interosseous artery, volar of forearm Interosseous artery, volar of forearm Third dorsal metacarpal arteries of dorsal carpal artery network Septocutaneous perforator of thoracodorsal artery Deep circumflex iliac artery Ascending branch of lateral circumflex femoral artery

GB-29 GB-31

Myocutaneous perforator of radial artery, superficial circumflex iliac vessels Septocutaneous perforator of second perforating arteries, from profunda femoris artery Septocutaneous perforator of third perforating arteries, from profunda femoris artery Lateral superior genicular artery Lateral inferior genicular artery

GB-32 GB-33 GB-34 GB-35 GB-36 GB-37 GB-38 GB-39 GB-40 LR-10 LR-9 LR-8 LR-7 LR-6 LR-5 LR-4 LR-3 LR-2 LR-1

Septocutaneous/myocutaneous perforator of peroneal (fibular) artery Septocutaneous/myocutaneous perforator of peroneal (fibular) artery Septocutaneous perforator of peroneal (fibular) artery Septocutaneous perforator of peroneal (fibular) artery Septocutaneous perforator of peroneal (fibular) artery Perforating branch, passing to the lateral malleolar network and dorsum of the foot Septocutaneous perforator of femur artery Septocutaneous perforator of perforating branches of femur artery Medial superior genicular artery Medial inferior genicular artery Septocutaneous perforator of posterior tibial artery Septocutaneous perforator of posterior tibial artery Medial anterior malleolar artery of anterior tibial artery Deep plantar artery Dorsal metatarsal artery migrating into dorsal digital artery Dorsal digital artery

Spatium Intermusculare Through Which Perforators Pass

Related Flaps

Extensor digitorum muscle—extensor carpi ulnaris muscle Extensor digitorum muscle—extensor carpi ulnaris muscle Extensor digitorum muscle—extensor carpi ulnaris muscle Extensor digitorum muscle—extensor carpi ulnaris muscle Extensor digitorum muscle—extensor carpi ulnaris muscle Extensor digitorum muscle—extensor carpi ulnaris muscle

Posterior interosseous flap Posterior interosseous flap Posterior interosseous flap Posterior interosseous flap Posterior interosseous flap Metacarpal dorsal artery flap Thoracodorsal artery flap Deep iliac circumflex artery osteocutaneous flap Superficial iliac circumflex artery osteocutaneous flap Tensor fasciae latae muscle skeletal flap

M latissimus dorsi—M iliocostalis lumborum Iliopsoas muscle—os illium Sartorius muscle beside Tensor fasciae latae muscle Iliotibial tract—biceps femoris muscle Iliotibial tract—biceps femoris muscle Iliotibial tract—biceps femoris muscle M peroneus longus/brevis—M tibialis anterior M peroneus longus/brevis longus /brevis M tibialis anterior M peroneus—lateral head of gastrocnemius M peroneus—lateral head of gastrocnemius M peroneus—M soleus M peroneus—M soleus Extensor digitorum longus tendon—fibula Sartorius muscle—rectus femoris muscle Sartorius muscle—adductor longus muscle Gastrocnemius muscle (medial head)—femur Gastrocnemius muscle (medial head)—tibialis posterior muscle Tibialis posterior muscle—tibia Tibialis posterior muscle—tibia Fascia—bone Fascia—bone Fascia—bone Fascia—bone

Capitulum fibulae pedicle with lateral inferior genicular artery Peroneal artery flap Peroneal artery flap Peroneal artery flap Peroneal artery flap Peroneal artery flap Lateral supramalleolar flap

Anterior malleolar flap Dorsum pedis flap Grafting of phalanges of foot

Abbreviations: LU, lung channel of hand-Taiyin; LI, large intestine channel of hand-Yangming; ST, stomach channel of footYangming; SP, spleen channel of foot-Taiyin; HT, heart channel of hand-Shaoyin; SI, small intestine channel of hand-Taiyang; BL, urinary bladder channel of foot-Taiyang; KI, kidney channel of foot-Shaoyin; PC, pericardium channel of hand-Jueyin; TE, triple-warmer channel of hand-Shaoyang; GB, gall bladder channel of foot-Shaoyang; LR, liver channel of foot-Jueyin; M, musculus. femoral circumflex artery belong to different meridians, whereas the acupoints located in the blood-supplied areas of the descending branches of the lateral femoral circumflex artery belong to a same meridian. Acupoints located along a perforator belong to the same meridian.

Taking acupoints HT-4/5/6/7 as examples, they are in the same area that is supplied by the supracarpal perforators of the ulnar artery. In clinical practice, acupuncturists localize the acupoints following the basic principle of “ning shi qi xue, wu shi qi jing,” which means that following the meridian is more important than focusing on acupoints. Scientists could deduce that acupuncture performs the functions of meridians by stimulating the vessels with a diameter of 0.5 to 1.5 mm and that acupoints are the needling places where the vessels are most likely to be punctured. The diameters of perforators located along each meridian range from 0.3 mm at the fingertips to 2 mm at secondary branches of tributary arteries.

A similar difference exists between acupoints in fingertips and larger points, such as GB-34 and ST-36.

Peripheral vascular networks exist around the joints of the ankle, elbow, wrist, and knee. The vascular network is composed of 2 branches, the terminal branch of the tributary artery and the articular branch of the pipeline artery. Around acupoints, perforators pierce the horizontal plane of the articular surface, but no 2 acupoints are in the same meridian.

Circumarticular skin is adapted to large degrees of flexion and extension, rendering it able to withstand more stress on the longitudinal than the transversal plane. That feature of circumarticular skin might have a significant impact on subcutaneous ramus anastomoticus.

A class of acupoints is located at the pleio furcation of the vessels, where the caliber varies greatly. For example, (1) the LI-4 acupoint is correlated to the deep palmar arch, the princeps pollicis artery, and the dorsal metacarpal arteries arising from the dorsal carpal branch of the radial artery; (2) the TE-5 acupoint is correlated to the cutaneous perforator and the nutrient branch of the radius arising from the anastomosis of the posterior interosseous artery and the anterior interosseous artery; (3) the ST-36 acupoint is correlated to the cutaneous perforator and the nutrient branch of the posterior tibial recurrent artery from the anterior tibial artery at the tibial plateau; and (4) the LR-3 acupoint is correlated to the deep plantar artery and the dorsal metatarsal arteries, which are dorsal digital arteries arising from the dorsalis pedis artery. Those acupoints are more widely applied in clinical practice than other acupoints.

During surgical procedures for skin-flap transfer of the forearm and calf, the axis direction of the flap is consistent with the invisible meridian line. Taking a sural nerve flap as an example, the axis of the flap perforator is parallel with the

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Wei—Perforators and Acupuncture Points

Figure 1. Needling Acupoints Causes Changes in Fascia Tension Around the Perforator

Figure 2. Ramus Anastomoticus Among Perforatorsa

a

Perforators naturally anastomose with each other’s thread in an axial ray. As shown in the figure, anastomoses are abundant between perforators 1 and 2 and perforators 3 and 4, which are located in same meridians, but few anastomoses exist between 1 and 3 and 2 and 4, which are located in different meridians.

bladder meridian and is reversed around acupoints BL-59 and BL-60. To some extent, the meridian agrees with the theory of the neuro-veno-fasciocutaneous flap, neurocutaneous vascular flap, and fasciocutaneous vascular flap/branches-chain flap.

In summary, all of those previously mentioned associations culminate in the theory that the perforators are the foundation of the function of acupoints. Acupoints could be considered dynamic and functional, and they cannot be physically defined in the body. The perforators are anatomical structures, objectively existing in the body. The current research team is the first to establish a connection between the 2 structures.

DISCUSSION Acupuncture has proven effective in treating various types of physiological disorders and malfunctions. For a long time, clinical practitioners have been attempting to determine the essence of the meridian system and the mechanisms of acupuncture in providing analgesia and treating various disorders. So far, although various hypotheses have been proposed to answer those questions, no descriptions have been comprehensive. The current research team’s findings might be consistent with some of those theories.

The perforator theory that the current team has proposed could explain the electrophysiology of acupoints and of propagated needle sensations.14,15 The electrolyte components of the blood differ from those of the skin. Intra-arterial blood flow in the perforators could lead to specific electrical characteristics around the vessel. Yu et al16 believed that the fascia could be the physical substrate referred to as the meridian system.

An interesting viewpoint about fascial meridians is that they favor a more holistic approach to medicine, in which the body’s interconnections are considered.17,18 During microsurgical operations, the current research team has Wei—Perforators and Acupuncture Points

often encountered vasospasms, which are a common complication. Treatments for vasospasm include local massage, vessel-wall expansion, papaverine injections into the adventitia, and local temperature improvement.

Acupuncture can have the same alleviative effects.

Because the perforator is too slender to be targeted by the needle directly, other needling techniques, such as prick, thorn, and twist, can stimulate the fascia around the vessel and relieve vascular spasm and pain. Needling the acupoints can cause changes in the fascia tension around the perforator, inducing variations in vascular tone and the triggering of dilatation or contraction (Figure 1).

Consequently, the effects of needling are amplified. Changes in the vessel caliber can also affect the bioelectric environment of the body. The application of acupuncture causes microvascular blood flow to increase, and it augments vasomotion (ie, spontaneous oscillation in the tone of the blood vessels). Together, that data support at least partly the theories mentioned previously.

A high degree of correlation exists between acupoints and perforators. Acupuncture, from Chinese medicine, is based on the theoretical system of yin and yang, whereas perforators are anatomic structures based on modern biomedicine. Thus, perforators are not equal to acupoints. In all probability, acupoints are not tissue structures but rather are dynamic, functional concepts concerning the microcirculation or the neuroendocrinology of the related perforators.

The microsurgical anatomy of the perforator could also explain the essence of meridians. Subcutaneous adjunct perforators naturally anastomose (ie, create connections) with each other and choke the vessels that compose a chain of blood vessels. Those anastomoses thread an axial ray, which resembles the channel of a meridian. However, few connections exist among axial lines (Figure 2). Acupoint SP-6, called Sanyinjiao, which means the convergence of 3 yin meridians (yin jing) in Chinese, is actually located near the piercing point of the ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 29

perforator arising from the posterior tibial artery. The perforator of the posterior tibial artery can anastomose with other perforators along 3 lines in 3 layers, as indicated in Figure 3.19,20 The 3 chains of perforators can anastomose separately, adopting separate courses along the 3 meridians.

Further, the cutaneous perforator anastomosis of the body might constitute the physical substrate of the meridians.

If that theory is true, important clinical and research implications exist. Specifically, if evidence continues to mount in support of that view, then perforators should receive greater attention in both physiology and clinical medicine. Further investigations resolving the chemical mediation or signal transmission among the perforators in the homomeridian should facilitate the examination of principles of acupuncture and in-depth investigations of the function of the microvascular network. Moreover, the pathologic mechanisms of many disorders, such as chronic pain, epilepsy, and others, have thus far been poorly understood. The new framework could elucidate those idiopathic conditions explicitly, and clearly, could facilitate the development of effective therapies.

Overall, the phenomenon of the correlation between perforators and acupoints still requires further validation and investigations.

CONCLUSIONS The current study found that specific perforators and acupoints are closely correlated. The theory that perforators act as the underlying anatomy of acupuncture points has won the approval of the acupuncturists and surgeons involved in the study. Further, several viewpoints about acupoints and perforators have emerged and confirmed the research team’s perforator theory. Although it requires further investigations, the hypothesis could facilitate scientists’ theoretical understanding of the mechanism and essence of acupuncture.

Figure 3. Posterior View of Perforator Anastomosisa

a

A perforator of the posterior tibial artery (a) can anastomose with 3 arteries: ᬅ the accompanying artery of the rami cutanei cruris medialis nervi sapheni along the great saphenous vein on the surface of the sarcolemma of the musculi tibialis posterior; ᬆ the perforator of the flexor retinaculum in the medial malleolus arising from the posterior tibial artery between layers of epifascial and subcutaneous tissue at the intermuscular septa of the imusculi tibialis posterior and the musculi triceps sura or Achilles tendon; and ᬇ the nutrient branch of the medial anterior malleolar artery arising from the anterior tibial artery between layers of the tibial periosteum and the subfascia.

REFERENCES 1. Rubik B. Can Western science provide a foundation for acupuncture? Altern Ther Health Med. 1995;1(4):41-47.

2. Manheimer E, White A, Berman B, Forys K, Ernst E. Meta-analysis: Acupuncture for low back pain. Ann Intern Med. 2005;142(8):651-663.

3. White A, Foster NE, Cummings M, Barlas P. Acupuncture treatment for chronic knee pain: A systematic review. Rheumatology (Oxford). 2007;46(3):384-390.

4. Berman BM, Langevin HM, Witt CM, Dubner R. Acupuncture for chronic low back pain. N Engl J Med. 2010;363(5):454-461.

5. Dhond RP, Yeh C, Park K, Kettner N, Napadow V. Acupuncture modulates resting state connectivity in default and sensorimotor brain networks. Pain.

2008;136(3):407-418.

6. Haker E, Egekvist H, Bjerring P. Effect of sensory stimulation (acupuncture) on sympathetic and parasympathetic activities in healthy subjects. J Auton Nerv Syst.

2000;79(1):52-59.

7. Hui KK, Liu J, Marina O, et al. The integrated response of the human cerebrocerebellar and limbic systems to acupuncture stimulation at ST 36 as evidenced by fMRI. Neuroimage. 2005;27(3):479-496.

8. Joos S, Schott C, Zou H, Daniel V, Martin E. Immunomodulatory effects of acupuncture in the treatment of allergic asthma: A randomized controlled study.

J Altern Complement Med. 2000;6(6):519-525.

9. Taylor GI, Palmer JH. The vascular territories (angiosomes) of the body: Experimental study and clinical applications. Br J Plast Surg. 1987;40(2):113-141.

10. Blondeel PN, Van Landuyt KH, Monstrey SJ, et al. The “Gent” consensus on perforator flap terminology: Preliminary definitions. Plast Reconstr Surg.

2003;112(5):1378-1383.

11. World Health Organization. WHO Standard Acupuncture Point Locations in the Western Pacific Region. Geneva, Switzerland: World Health Organization; 2008.

30 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

12. Yang DP, Tang ML, Geddes CR, Morris SF. Anatomical study of perforator vessel to the human skin. Chin J Clin Anat. 2006;24(3):232-235.

13. Taylor GI, Pan WR. Angiosomes of the leg: Anatomic study and clinical implications. Plast Reconstr Surg. 1998;102(3):599-616.

14. Ahn AC, Colbert AP, Anderson BJ, et al. Electrical properties of acupuncture points and meridians: A systematic review. Bioelectromagnetics. 2008;29(4):245-256.

15. Xie Y, Li H, Xiao W. Neurobiological mechanisms of the meridian and the propagation of needle feeling along the meridian pathway. Sci China C Life Sci. 1996;39(1):99-112.

16. Bai Y, Wang J, Wu JP, et al. Review of evidence suggesting that the fascia network could be the anatomical basis for acupoints and meridians in the human body.

Evid Based Complement Alternat Med. 2011;2011:260510.

17. Langevin HM. Connective tissue: A body-wide signaling network? Med Hypotheses. 2006;66(6):1074-1077.

18. Langevin HM, Sherman KJ. Pathophysiological model for chronic low back pain integrating connective tissue and nervous system mechanisms. Med Hypotheses.

2007;68(1):74-80.

19. Bulla A, De Luca L, Campus GV, Rubino C, Montella A, Casoli V. The localization of the distal perforators of posterior tibial artery: A cadaveric study for the correct planning of medial adipofascial flaps. Surg Radiol Anat.

2015;37(1):19-25.

20. Zhang FH, Zheng HP, Song YP, Tian WC, Yue SG. Microanatomy of artery network of the medial malleolar region and the design of distally based flap of the saphenous nerve nutritional vessels. Chin J Clin Anat. 2004;(6):568-572.

Wei—Perforators and Acupuncture Points

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REVIEW ARTICLE

Acupuncture is Effective for Chronic Knee Pain: A Reanalysis of the Australian Acupuncture Trial Arthur Yin Fan, MD, PhD, LAc; Kehua Zhou, MD, DPT, PT, LAc; Sherman Gu, BMed, AdvDipMyother, MAppSc; Yong Ming Li, MD, PhD

ABSTRACT Context • In the October 2014 issue of the Journal of the American Medical Association (JAMA), Hinman et al published the results of an Australian clinical trial on acupuncture in a paper entitled “Acupuncture for Chronic Knee Pain: A Randomized Clinical Trial” (JAMA report), in which they concluded that neither acupuncture nor laser acupuncture had any greater effects than sham laser acupuncture for pain or function for patients aged 50 y and older with moderate-to-severe knee pain. That study has been criticized extensively by international scholars for its validity because serious methodological flaws existed throughout the study’s design, implementation, and conclusions.

Objective • The current study intended to re-examine the prior study’s conclusions about the efficacy of acupuncture for chronic knee pain.

Design • The current research team performed a reanalysis of relevant data from the JAMA report.

Intervention • The original study included 4 groups: (1) an acupuncture group, which received needle acupuncture, inferred by the current authors to have been set up to be a positive control in the original study; (2) a laser acupuncture group, which received laser acupuncture; (3) a sham laser acupuncture group, which received sham laser acupuncture and acted as the negative controls for the laser acupuncture intervention; and (4) a control group, which received conventional care but no acupuncture or laser treatments. The study lasted 12 wk.

Outcome Measures • The measures included evaluations in the following areas: (1) poststudy modifications—an evaluation of the consistency of the JAMA report with the study’s intentions as identified for a grant that was originally approved and funded by the Australian National Health and Medical Research Council (NHMRC) in 2009, as indicated in the study’s trial registration, and as compared with the published protocols and to the study’s originally stated objectives; (2) high heterogeneity—an assessment of the heterogeneity among the 4 groups for the overall outcome related to pain; (3) ineffectiveness of laser acupuncture—an analysis of laser acupuncture’s

32 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

efficacy for chronic knee pain as stated in the JAMA report, using effect size (ES); (4) effectiveness of acupuncture—a reanalysis of acupuncture’s efficacy for chronic knee pain in comparison with the original analysis in the JAMA report, using ES; and (5) acupuncture after data adjustment—a new analysis of acupuncture’s efficacy for chronic knee pain using data from the original study that was discussed in the JAMA report, using ES, with an estimation after data adjustment and elimination of the dilution effect of the Zelen design.

Results • Contrary to a general impression that acupuncture was the focus, laser acupuncture was the primary intervention tested in the actual study, “Laser Acupuncture in Patients With Chronic Knee Pain: A Randomized, Placebo Controlled Trial.” The study discussed in the JAMA report was neither a truly randomized, controlled trial (RCT) for acupuncture nor was it an appropriately designed, randomized study in general. High heterogeneity was found among its groups in the evaluation of overall pain in patients. Both the ES of 0.60 that had been set by Hinman et al for the minimal clinically important difference (MCID) and the resulting interpretation of results in the JAMA report were not appropriate. Using the original study’s criteria of efficacy, the reanalysis has confirmed that the laser acupuncture was not effective, whereas the acupuncture was found to be moderately effective for chronic knee pain (P < .05) for both overall pain and function at 12 wk, with an ES of 0.58, or after the adjustment of the data, with an ES of 0.67.

Conclusions • The JAMA study was neither a conventional RCT nor an appropriately randomized trial, and its results are probably invalid. The ES of 0.60 for the MCID that was used in the JAMA study and the resulting explanation were not appropriate. Even with an ES of 0.60 for the MCID, acupuncture remained effective after data adjustment. Consequently, compared with conventional care, acupuncture treatment was found to be moderately effective for chronic knee pain in patients aged 50 y and older. (Altern Ther Health Med. 2016;22(3):32-36.)

Fan—Acupuncture and Chronic Knee Pain

Arthur Yin Fan, MD, PhD, LAc, is Chairman of the Scientific Study & Academic Affair Committee at Traditional Chinese Medicine American Alumni Association; Director at the McLean Center for Complementary and Alternative Medicine PLC in Vienna, Virginia. Kehua Zhou, MD, DPT, PT, LAc, is a clinical assistant professor in the Department of Health Care Studies and the lead physical therapist at the Wound Care Clinic at Daemen College in Amherst, New York. Sherman Gu, BMed, AdvDipMyother, MAppSc, is a registered Chinese medicine practitioner, and officer at the Federation of Chinese Medicine & Acupuncture Societies of Australia Ltd in Wantirna South, Victoria, Australia. Yong Ming Li, MD, PhD, is former President at the American Traditional Chinese Medicine Society in New York, New York.

Corresponding author: Arthur Yin Fan, MD, PhD, LAc E-mail address: arthurfan@chinesemedicinedoctor.us

I

n the October 2014 issue of the Journal of the American Medical Association (JAMA), Hinman et al1 published the results of an Australian clinical trial on acupuncture in a paper entitled “Acupuncture for Chronic Knee Pain: A Randomized Clinical Trial,” in which the researchers concluded that neither acupuncture nor laser acupuncture had any greater effects than sham laser acupuncture on pain or function for patients aged 50 years and older with moderate-to-severe knee pain. That study has been extensively criticized by international scholars for its validity because serious methodological flaws existed throughout the study’s design, implementation, and conclusions.2-12 Further, Hinman et al’s1 alteration of the original study’s objectives and protocols after completion of the trial and the fact that they failed to mention the changes in their final report has raised concerns about the integrity of the investigators.2-4,10-12 Those concerns may justify a finding that the results and conclusions reported by Hinman et al1 are probably not valid or appropriate.

Using relevant, available, supplementary data, together with the final published report of the Australian clinical trial on acupuncture in JAMA—referred to as the JAMA report in the rest of the current article—the authors have reanalyzed the effects of acupuncture for chronic knee pain as evaluated in the original study.

POSTSTUDY MODIFICATIONS Evidence from the trial report in JAMA1 and from information gathered through clinical-trial registration13 indicates that laser acupuncture rather than acupuncture was the primary intervention tested. Laser-acupuncture and acupuncture differ in many ways.2-4,9-12 Based on the traditional and official definition, in which the term acupuncture refers to needling therapy, an actual insertion of a solid needle into the body,14 the categorization of Fan—Acupuncture and Chronic Knee Pain

noninvasive, laser acupuncture as acupuncture is debatable.

Thus, the mixed usage of the term acupuncture in referring to both laser and needle therapy by Hinman et al1 was unprofessional and misleading.2-4,9-12 Therefore, the current article uses the word acupuncture to refer strictly to needling therapy, to be as clear as possible.

As per the JAMA report, 4 arms were designed for the study1: (1) an acupuncture group, which received actual needle treatments; (2) a laser acupuncture group, which received laser acupuncture; (3) a sham laser acupuncture group, which received sham laser acupuncture and acted as the negative controls for the laser acupuncture intervention; and (4) a control group, which received conventional care but no acupuncture or laser treatments. Because the primary aim of the trial was to test laser acupuncture only,13,15 the reasonable explanation for including acupuncture is that it was used as a positive control.2-4,10-12 In addition to the study’s published protocol,15 which stated that laser acupuncture was the primary intervention tested, a synopsis of the original research proposal that had been posted by Monash University and the funding application for the research to the Australian National Health and Medical Research Council (NHMRC) in 2009, also indicated the same objective.16,17 Even more clearly stating that objective, the title of the research proposal in both cases was “Laser Acupuncture in Patients with Chronic Knee Pain: A Randomized, Placebo Controlled Trial,” and it was funded by NHMRC in 2009.16,17 Acupuncture had been reported to be an effective therapy for knee osteoarthritis in a much larger trial in 2004, and the researchers for the study on laser acupuncture had cited that reference in their research proposal. They also stated clearly in their original proposal that one of their aims was to compare laser acupuncture with acupuncture but did not claim an intention to compare the acupuncture group with the control group.16,17 The power of the statistical test and other resources in the original study were optimized only to evaluate the laser intervention, instead of 2 interventions, laser and acupuncture, as was indicated in the JAMA report.3,4,7-13,15 Because the JAMA report mixed the terms laser acupuncture and acupuncture (Hinman et al1 named it as needle acupuncture) with the general term acupuncture, the authors blurred the focus of the original study’s design.

However, the title and contents of the published JAMA paper actually reported that acupuncture using needling rather than laser acupuncture was the primary intervention tested.

In addition, the title of the JAMA report stated that the study was a randomized, clinical trial rather than a randomized, controlled trial (RCT). That change in title suggests that the investigators were aware that their post hoc modifications led to a nontypical RCT. A serious deficiency of the trial after the modification of objectives was a lack of a sham control for acupuncture.2-4,9-12 Modification of the research objectives after completing the study, without a reasonable explanation and with a failure to mention the changes in the final report, was unethical and a violation of professional standards.3,4,11-12 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 33

HIGH HETEROGENEITY Apparently, the JAMA report was not a conventional RCT report because a Zelen design was used. The high heterogeneity of the 4 groups in the study further decreased its reliability and validity as a randomized trial. Using Review Manager 5.3 (a software downloaded from http://www.tech.cochrane.org), the current research team pooled the data for the overall pain score, one of the primary outcome measures discussed in the JAMA report for week 12, to test the overall effects of acupuncture versus the control and laser acupuncture versus sham laser acupuncture. The team also evaluated the potential heterogeneity among the findings, following the method recommended by the Cochrane Collaboration.18 The measurements indicated that the overall effects were favorable to the groups who were treated with acupuncture or laser treatment although the effects were marginal—mean difference (MD), -0.56; 95% confidence interval (CI), -1.12 to -0.00; P = .05; n = 256 (Figure 1).

A statistically significant difference existed between the acupuncture group and the control group—MD, -1.10; 95% CI, -1.88 to -0.32; n = 133. However, a substantial heterogeneity (I² = 73%) among the 4 groups significantly weakened the strength of that positive estimate. The sources of that heterogeneity might have included (1) selection bias, because the acupuncture group had the worst scores at baseline in all of the primary outcome measures and in almost all of the secondary outcome measures; (2) the integrity of the intervention (ie, acupuncture and laser acupuncture are not comparable as the former involves skin penetration with solid needles placed at multiple acupuncture points during a single visit, whereas the latter uses a laser device with a single output point that was used to stimulate selected points during the treatment); (3) performance bias (ie, systematic differences among the groups in blinding) as detailed in number 4; and (4) an inconsistency that may have come from an attrition bias and a data dilution bias that was associated with the Zelen design4,7 (ie, systematic differences among the groups in withdrawals [dropouts]). In the JAMA report, at week 12 of the trial, the dropout rate was (1) acupuncture group—8.57% (ie, [70-64]/70); (2) laser acupuncture group—8.45% (ie, [71-65]/71); (3) sham laser acupuncture group—17.14% (ie, [70-58]/70); and (4) control group—2.82% (ie, [71-69]/71).1

INEFFECTIVESS OF LASER ACUPUNCTURE As per the JAMA report by Hinman et al,1 compared with the control at week 12, laser acupuncture did not induce significant improvements in function as assessed by the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and by 7 other secondary outcomes measures, with the exception of a slight improvement in the overall pain score, with a difference of -0.8 (P = .03). Using the calculation of effect size (ES) for mean differences between groups with unequal sample sizes within a pre-post design,19 the ES for pain relief was calculated as being 0.33 for the laser acupuncture group when compared with the control group.

That ES was much smaller than the ES of 0.60 for the minimal clinically important difference (MCID) that had been set by the investigators in the original design of the study.1,5 Compared with the ES for the sham laser-acupuncture group, the ES19 for the laser acupuncture group was -0.05.

Thus, as stated in the JAMA report by Hinman et al,1 laser acupuncture was not effective for chronic knee pain.

Consequently, negative results were found for the clinical trial, which had originally been designed for the assessment of laser acupuncture in patients with chronic knee pain.

EFFECTIVENESS OF ACUPUNCTURE Based on the NHMRC-approved proposal, the published RCT protocol, and the information from the trial registration,13,15-17 the acupuncture group was included as a positive control; thus, comparing acupuncture with sham laser acupuncture, a negative control, was not justifiable,3,4,9-12 nor was it a specific aim in any of the proposals. Moreover, the study’s blinding protocol covered only the laser acupuncture and sham laser acupuncture groups. No blinding was performed for treatments given to acupuncture group in comparison to the sham laser acupuncture group, and those 2 interventions do not have comparability in any setting.3,4, 9-12 Consequently, the assessment of the effectiveness of acupuncture should have been based only on a comparison with the group receiving conventional care, which was the true control group in the study.

In the current research team’s comparison of the results for the acupuncture group with those of the control group at

Figure 1. Pooled Data from Hinman 20141 for the Outcome Measure Overall Pain Score at Week 12a Study or Subgroup

Active intervention Control Mean SD Total Mean SD Total Weight

Mean Difference IV, Fixed, 95% CI

Hinman 2014a

3.3

2.2

64

4.4

2.4

69

51.0%

-1.10 (-1.88 to 0.32)

Hinman 2014b

3.4

2.2

65

3.4

2.3

58

49.0%

0.00 (-0.80 to 0.80)

127

100.0%

129 Total (95% CI) Heterogeneity: χ2 = 3.73, df = 1 (P = .05); I2 = 73% Test for overall effect: z = 1.97 (P = .05)

Mean Difference IV, Fixed, 95% CI

-0.56 (-1.12 to 0.00) -2 -1 Favors intervention

0

1

2 Favors control

a

Hinman 2014a represents data for acupuncture, an active intervention, vs the control receiving conventional care; Hinman 2014b represents data for laser acupuncture, an active intervention, vs sham laser acupuncture, a negative control.

Abbreviation: SD, standard deviation; CI, confidence interval.

34 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

Fan—Acupuncture and Chronic Knee Pain

treatment would not play any significant role in delaying such degeneration after 1 year.2-4,9-12 In addition, the trial lacked observations or comparisons of immediate and more short-term efficacy for acupuncture, at which times that acupuncture may be more effective.9

Table 1. Comparisons of the Pain Scores at Week 12 Using Original Data from Hinman et al1 Baseline Week 12 Improve Group M ± SD, n M ± SD, n (%)a Control 5.1 ± 2.1, 71 4.4 ± 2.4, 69 13.37 37.74 Acupuncture 5.3 ± 1.9, 70 3.3 ± 2.2, 64b

Effect Size19 0.58

a

Comparisons within the same group from baseline to postintervention. b Compared with the controls, t = 2.75, P = .0068.

Abbreviations: M, mean; SD, standard deviation. week 12, acupuncture did induce statistically significant improvements in the primary outcomes: (1) of overall pain score—difference, -1.1; P = .002; ES, 0.5819—and (2) the WOMAC Function—difference, -3.9; P = .04.1 Changes in the scores on the secondary outcome measurements were also statistically significant for (1) pain on walking (P = .003), (2) pain when standing (P = .05), and (3) WOMAC pain (P = .05).1 Although the ES of 0.58 for pain relief in the reanalysis (Table 1) was slightly less than the ES of 0.60 that had been set by Hinman et al1 for the MCID, that ES was larger than the moderate ES of 0.50 that has been proposed by the National Institute for Health and Care Excellence (NICE) for testing nonsteroidal anti-inflammatory drugs (NSAIDs).5,20 The ES for the MCID that was selected by Hinman et al1 was based on expert opinions, which can sometimes be invalid and unreliable; selection of an ES = 0.60 for the MCID in the study1 created a stricter requirement for proof of the efficacy of acupuncture than that set for NSAIDs.3,5 As per Cohen,21 who was a world-renowned statistician and psychologist, an ES of ≤0.20 is small, 0.50 is moderate, and ≥0.80 is large. That classification system for ES is well recognized in the academic community and is specifically recommended by NHMRC for the assessment of nonsurgical management of hip and knee osteoarthritis.22 Thus, based on the above analysis, the acupuncture had actually been moderately effective, even though its treatment protocol (ie, dose and frequency) was not optimally designed in the original study.2-4,6,9-12 It is worth noting that the control group in the study discussed in the JAMA report was not a pure no-treatment group because a significant portion, if not all, of the patients in that group received conventional care. Many participants in the group used various types of pain medications during the study.1 Consequently, the results of the study at week 12 indicate that a suboptimal acupuncture treatment was moderately effective, as compared with conventional care, for chronic knee pain in patients aged 50 years and older.

Hinman et al’s1 judgment on the effectiveness of acupuncture at 1 year was not appropriate and did not make any sense because chronic knee pain is mostly due to knee osteoarthritis, a degenerative process. Using a suboptimal dose of acupuncture and providing only 8 to 12 sessions of Fan—Acupuncture and Chronic Knee Pain

ACUPUNCTURE AFTER DATA ADJUSTMENT As pointed out by various researchers, the sample size calculation for the study discussed in the JAMA report was not appropriate. For a 4-arm study with a Zelen design, 780 to 800 participants were needed3,5,8,10-12; however, only 282 patients were included in the original study.1 In addition, for the JAMA report, the data for 10 patients who had never had an acupuncture treatment during the study was still pooled with that of the other participants in the acupuncture group.

In the acupuncture group, only 54 patients received acupuncture treatments. Consequently, a 31.27% dilution occurred in the efficacy assessment for the acupuncture group as a result of the Zelen design.7 Theoretically, any loss in statistical efficiency can be overcome by increasing sample size; however, because the JAMA report gave a post hoc analysis, that increase was not possible. Considering the small sample size of the study, the current research team decided that an adjustment was needed in the data to compensate for the dilution in the estimation of acupuncture’s efficacy for chronic knee pain. Therefore, the team allocated the 10 patients in the acupuncture group who did not receive any acupuncture treatment to the control group that was discussed in the JAMA report.

As Dr Hinman had declined the current research team’s request to provide the original raw data for further analysis, the team has been unable to reconduct the individual, patient-based data analyses to compare the differences among the groups. Nonetheless, the team used a student t test to evaluate the efficacy of the acupuncture in comparison with the control group. The data on overall pain for the acupuncture and control groups as shown in the JAMA report1 were recalculated after the earlier-mentioned data adjustment, shown in Table 2.

Table 2. Comparisons at Week 12 for the Pain Score After Data Adjustment Baseline M ± SD, n 5.1 ± 2.1, 71

Week 12 M ± SD, n 4.4 ± 2.4, 79

Group Control Needle acupuncture 5.3 ± 1.9, 70 3.09 ± 2.2, 54b

Improvea Effect (%) Size19 13.37 41.70

0.67

a

Comparisons within the same group from baseline to postintervention. b Compared with the controls, t = 3.20, P = .0017.

Abbreviations: M, mean; SD, standard deviation.

ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 35

Under the current research team’s re-evaluations, the new sample size would be 79 for the control group and 54 for the acupuncture group. The team has assumed that the 10 patients in the acupuncture group who did not receive any acupuncture treatment had the same mean score (4.4) and standard deviation (2.4) as those in the control group, because they did not receive any acupuncture intervention.

Assignment of those values would equate them to those participants in the control group who also did not receive any intervention.

The new calculation of means thus needed to consider the influence of these 10 patients after the data adjustment.

In the acupuncture group with 64 patients, as in the JAMA report, the total overall pain score was 3.3 × 64 = 211.2, whereas the total overall pain score for the 10 patients that were added to the control group under the adjustment was 4.4 × 10 = 44. Therefore, the total overall pain score for the new acupuncture group with 54 patients should be 211.2 − 44 = 167.2. The new mean would therefore be 167.2 / 54 = 3.09.

The current research team used the new means and standard deviations for the acupuncture group for the comparison of that group with the control group in Table 2.

Although a suboptimal acupuncture protocol was used in study discussed in the JAMA report,2-4,9-12,16 the acupuncture was effective in decreasing the overall pain score at week 12 (P < .01), and the ES19 was 0.67 when compared with the controls. An ES of 0.67 is higher than the ES of 0.60 for the MCID that had been set by Hinman et al1 in the JAMA report, with that report assigning an ES of 0.58, as calculated based on original data prior to the current research team’s adjustments, and is also higher than the NICE requirement of 0.50,20 indicating that even with the ES set as 0.60 for the MCID, acupuncture remained effective.

REFERENCES

CONCLUSIONS Based on the analyses presented, the study discussed in the JAMA report was neither a conventional RCT nor an appropriately randomized trial and, therefore, its results are probably invalid. The use of an ES of 0.6 for the MCID and the resulting interpretation were also inappropriate. Even with an ES of 0.60 for the MCID at week 12, acupuncture remained effective after the current research team’s data adjustment. Consequently, compared with conventional care, acupuncture treatment was moderately effective for chronic knee pain in patients aged 50 years and older. The original trial also lacked observations or comparisons of more immediate and short-term efficacy for acupuncture, in which acupuncture may be more effective.

1. Hinman RS, McCrory P, Pirotta M, Relf I, Forbes A, Crossley KM, et al.

Acupuncture for chronic knee pain: A randomized clinical trial. JAMA. 2014;312(13):1313-1322.

2. Li YM, He HJ, Lao L, Hinman RS, et al. Treating chronic knee pain with acupuncture, letters and reply. JAMA. 2015;313(6):626-629.

3. Zhou K, Fan AY, Wang T. Acupuncture for knee pain: A critical appraisal of an Australian randomized controlled trial. Med Acupunct. 2016;28(1):40-45.

4. Fan AY. The methodology flaws in Hinman’s acupuncture clinical trial, part I: Design and results interpretation. J Integr Med. 2015;13(2):65-68.

5. White A, Cummings M. Acupuncture for knee osteoarthritis: Study by Hinman et al represents missed opportunities. Acupunct Med. 2015;33(1):84-86.

6. Zhang Q, Yue J, Lu Y. Acupuncture treatment for chronic knee pain: Study by Hinman et al underestimates acupuncture efficacy. Acupunct Med. 2015;33(2):170.

7. Fan AY. The methodology flaws in Hinman’s acupuncture clinical trial, part II: Zelen design and effectiveness dilutions. J Integr Med. 2015;13(3):136-139.

8. Fan AY. The methodology flaws in Hinman’s acupuncture clinical trial, part III: Sample size calculation. J Integr Med. 2015;13(4):209-211.

9. Jin L, Jin B, Jin G. The paradox of acupuncture efficacy for chronic knee pain. Eur J BioMed Res. 2015;1(2):40-43.

10. Godwin J, Fan A. Evidence-based medicine skills for acupuncturists part I: The Hinman trial on chronic knee pain and the importance of critical appraisal skills.

Am Acupuncturist. 2015;71(summer):22-29.

11. Reddy B. Chinese doctors poke holes in Australian study. Acupuncture Today Web site. http://www.acupuncturetoday.com/mpacms/at/article.php?id=33043.

Published July 2015. Accessed April 7, 2016.

12. Gong C. Acupuncture storms JAMA. Int J Clin Acupunt. 2015;24(3):149-155.

13. Australia New Zealand Clinical Trials Registry. Acupuncture for chronic knee pain trial (registry identifier: ACTRN12609001001280). https://anzctr.org.au/ Trial/Registration/TrialReview.aspx?id=308156. Accessed April 7, 2016.

14. Kaptchuk TJ. Acupuncture: Theory, efficacy, and practice. Ann Intern Med. 2002;136:374-383.

15. Hinman RS, McCrory P, Pirotta M, et al. Efficacy of acupuncture for chronic knee pain: Protocol for a randomized controlled trial using a Zelen design. BMC Complement Altern Med. September 2012;12:161.

16. Monash University. Synopsis of the original research proposal. http://www.buseco. monash.edu.au/centres/che/current/laserknee.html. Accessed July 1, 2015.

17. McCrory P, Bennell K, Hinman R, Reddy P, Crossley K. Laser acupuncture in patients with chronic knee pain: A randomized placebo-controlled trial. Project Grant No. 566783, 2009-2012, funded by NHMRC. http://chesm.unimelb.edu. au/res/muscres/proj.htm. Accessed August 2, 2015.

18. Higgins JPT, Deeks JJ, Altman DG (eds). Special topics in statistics. In: Higgins JPT, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions.

Version 5.1.0. London, United Kingdom: The Cochrane Collaboration; 2011.

19. Lenhard W, Lenhard A. Computation of effect sizes. Psychometrica Web site. http://www.psychometrica.de/effect_size.html#cohc. Accessed April 7, 2016.

20. National Institute for Health and Care Excellence (NICE). Osteoarthritis: Care and management in adults. http://www.nice.org.uk/guidance/cg177. Published February 2014. Accessed April 7, 2016.

21. Cohen J. A power primer. Psychol Bull.1992;112(1):155-159.

22. The National Health and Medical Research Council. Guideline for the nonsurgical management of hip and knee osteoarthritis. https://www.nhmrc.gov. au/_files_nhmrc/publications/attachments/cp117-hip-knee-osteoarthritis.pdf.

Published July 2009. Accessed April 7, 2016.

ACKNOWLEDGEMENTS The authors would like to thank Ms Sarah Faggert for her editing support.

AUTHOR DISCLOSURE STATEMENT The authors are independent researchers and declare that they have no competing interests.

36 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

Fan—Acupuncture and Chronic Knee Pain

7th ANNUAL

CONFERENCE OVERVIEW

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Patients have better outcomes when these causes are successfully addressed and treated through a combination of specialized testing and nutritional therapies, even in combination with traditional approaches.

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VETERANS AFFAIRS HEALTH CARE SYSTEM Iowa City, IA 1st Year IMMH Speaker

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REVIEW ARTICLE

Chinese Medicinal Herbs in the Treatment of Upper Airway Cough Syndrome: A Systematic Review of Randomized, Controlled Trials Hongli Jiang, MD; Wei Liu, PhD; Guanhong Li, PhD; Tao Fan, MD; Bing Mao, MD

ABSTRACT Context • Upper airway cough syndrome (UACS), previously called postnasal drip syndrome (PNDS), has been considered universally to be one of the most common causes of chronic cough. As an important part of complementary and alternative therapy, traditional Chinese medicine (TCM) has found an exact curative therapy for chronic cough through clinical practice for thousands of years.

Objective • The aim of the current review was to investigate systematically the beneficial and adverse effects of Chinese medicinal herbs (CMH) in the treatment of UACS. Design • The research team performed searches in 11 main databases from respective inception to October 31, 2015, supplemented with manual retrieval of other data. Only randomized, controlled trials (RCTs) reporting on the effectiveness of CMH in patients with UACS were included.

Descriptive and quantitative data on the studies’ designs, population demographics, interventions, outcomes, and methodological quality were extracted and tabulated.

Methodological quality was assessed using the Cochrane risk-of-bias system and the quality of the evidence was evaluated using the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) system.

Participants • The reviewed studies included 1355 participants—720 in the CMH groups and 635 in the control groups—of both genders, from various professional and ethnic groups, and with a wide range of ages. They all had a duration of cough symptoms of longer than 8 wk and a clinical diagnosis of chronic cough induced by UACS that was supported by appropriate physical findings.

Hongli Jiang, MD; Wei Liu, PhD; Guanhong Li, PhD; Fan Tao, MD; Bing Mao, MD; are all part of the pneumology group in the Department of Integrated Traditional Chinese and Western Medicine at West China Hospital, Sichuan University, in Chengdu, China.

Outcome Measures • The primary outcomes included (1) TCM recovery rate and (2) TCM cough symptom score.

TCM’s curative effect was calculated as the cumulative percentage of the symptom-score reduction (PSSR), estimated between baseline and postintervention. The cough symptom scores were graded according to the Chinese Criteria Guiding Principle of Clinical Research on New Drugs of TCM, with the scores being classified into 4 grades. Those scores ranged from 0–3 (ie, 0, 1, 2, 3, respectively), or 0–9 (ie, 0, 3, 6, 9, respectively), with the higher scores signifying a more frequent and severe cough.

Results • A total of 16 studies that had been published in Chinese journals was ultimately identified for the review. The majority of methodological judgments demonstrated an unclear risk of bias. A meta-analysis was conducted using a random effects model due to the poor homogeneity of the studies. Compared with Western medicine (WM), patients in both the CMH groups and the integrated therapy groups showed (1) a higher TCM recovery rate; (2) better relief of primary symptoms, including cough and postnasal dripping; (3) a reduction in physical signs, including the cobblestone appearance of the oropharyngeal mucosa or mucus in the oropharynx; and (4) a lower risk of cough relapse. No severe adverse events occurred in either group.

Conclusions • CMH may be a safe and effective alternative for the treatment of UACS. The study highlighted the paucity of reliable clinical evidence for CMH and the need for RCTs of higher quality in the future. (Altern Ther Health Med. 2016;22(3):38-51.)

Corresponding author: Bing Mao, MD E-mail address: maobing2013@yeah.net

38 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

Jiang—Chinese Medicinal Herbs and Cough

C

hronic cough is one of the most common complaints resulting in medical consultation, and upper airway abnormalities are universally considered to be one of the most common causes of it.1 Upper airway cough syndrome (UACS), previously called postnasal drip syndrome (PNDS),2 is a condition that mainly manifests as a persistent cough secondary to upper airway abnormalities, such as rhinosinusitis and pharyngolaryngitis.3,4 Despite differences in their studied populations and diagnostic criteria, surveys in Western countries and China all suggest that upper airway abnormality has been consistently reported to be one of the most commonly identified causes of chronic cough (20%–40%) in specialized cough clinics,3-7 a result supported by epidemiologic studies in general populations.8,9 In addition to a persistent cough that lasts more than 8 weeks, the clinical presentations of patients with UACS commonly involve the following complaints: (1) a sensation of something dripping down from nose into the throat; (2) a sensation of something sticking in the throat, leading to frequent throat clearing; (3) nasal discharge and/or congestion; (4) hoarseness; (5) throat itching, and (6) dry throat. Patients might also have evidence of some main physical signs, such as a cobblestone appearance of the oropharyngeal mucosa or mucus in the oropharynx.4 Those clinical findings are relatively sensitive but are not specific. In addition, pathognomonic evidence is lacking.1,4 Therefore, diagnosis of UACS is frequently a challenge and largely rests on a patient’s report of unwellness.4,10 UACS-induced chronic cough significantly impairs patients’ health-related quality of life, leading to physiological complications, psychological imbalance, and social difficulty.

Moreover, an increasing prevalence of complications that involve the respiratory, cardiovascular, digestive, genitourinary, musculoskeletal, and nervous systems is in line with an aggravating and prolonged cough.11 Therefore, health care expenditures for managing UACS are substantial. However, due to the controversial mechanism of UACS,12,13 treatment options depend on exploring the reasons that cause chronic cough to some extent.4 For a patient whose cough is caused by apparent, specific reasons, therapy can be instituted that is directed at the condition. For example, nasal corticosteroids, antihistamines, and/or cromolyn are usually the initial drug choices for the treatment of UACS due to allergic rhinitis.14,15 For those patients whose explicit etiology of cough is not clear, empiric therapies that address symptom relief only, such as use of a decongestant,16 can be used. The symptomatic treatments may result in side effects, such as sedation; insomnia; difficulty with urination, primarily in older men17; jitteriness; tachycardia or palpitations; worsening of hypertension; or increased intraocular pressures in patients with glaucoma, which can lead to the discontinuation of the therapies.

As an important part of complementary and alternative therapy, traditional Chinese medicine (TCM) has found an exact curative therapy for chronic cough through clinical practice for thousands of years. Following a particular theoretical and methodological approach, TCM determines the cause and pathogenic mechanism of UACS in a specific Jiang—Chinese Medicinal Herbs and Cough

way and provides a unique treatment method. TCM offers extensive knowledge and experience in treating cough, not only for symptom relief, but also for the healing of the underlying condition. Many classical prescriptions and selfmodified formulas have been widely used in China18,19 and some other Asian countries such as Japan.20 Numerous clinical trials regarding the use of TCM for treatment of UACS have been conducted, which collectively and consistently report positive results. Moreover, the relative mechanisms of action have been researched. It has been found that a TCM application achieved a desirable effect in adjusting erythrocytic immune hypofunction, which was involved in the pathological injury of children with UACS.21 Due to the frequent prescription of TCM for patients with UACS, the recommendation and clinical value of TCM have been examined in the past in a previously published systematic review.22 However, due to a lack of randomized, clinical trials that satisfied the inclusion criteria, quasi-RCTs were also included in that review in which the method of allocation was not adequately concealed. That inclusion resulted in a greater risk of selection bias. In addition, no comparisons between TCM and a placebo were conducted in that review.

It has been generally accepted that TCM to some extent exerts a positive psychological effect or that it affects how some people feel, as a placebo treatment would, called the placebo effect. That effect may cause exaggerated positive results in favor of a TCM group. Therefore, in research a placebo is considered as a welcome and reasonable control for an effective estimation of the benefits of TCM.23 Moreover, the previously mentioned review assessed 2 outcomes only, the obvious effect rate and adverse reactions, without reporting other important outcomes, such as cough conditions, physical signs, quality of life, and recurrence. To evaluate the effects of TCM on UACS in a more comprehensive manner, the current research team conducted another systematic review.

METHODS The aim of the current review was to assess systematically the efficacy and safety of Chinese medicinal herbs (CMH) in the treatment of UACS. Only randomized, controlled trials (RCTs) were eligible for the review, irrespective of blinding.

Participants The reviewed studies included participants of both genders, from various professional and ethnic groups, and with a wide range of ages. They all had duration of cough symptoms of longer than 8 weeks and a clinical diagnosis of chronic cough induced by UACS or PNDS that was supported by appropriate physical findings. The study had no restrictions on previous treatments. For sake of unity and accuracy of diagnosis, the current review excluded studies in which patients had been diagnosed with rhinogenic cough or laryngeal cough.

Procedures Database and Search Strategies. A specified protocol developed according to the Preferred Reporting Items for ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 39

Systematic Reviews and Meta-Analyses (PRISMA) guidelines24 was followed to conduct the current review. Comprehensive literature searches for published reports of RCTs that had evaluated CMH for patients with UACS were performed in the following 11 databases: (1) the Cochrane Central Register of Controlled Trials (CENTRAL), (2) PubMed, (3) the Excerpta Medica Database (EMBASE), (4) Ovid (Medline), (5) Web of Science, (6) Google Scholar, (7) the Chinese Biomedical Database (CBM), (8) the Chinese National Knowledge Infrastructure (CNKI), (9) the Chinese Scientific and Technological Periodical Database (VIP), (10) the WANFANG database, and (11) the Scholarly and Academic Information Navigator (SAIN).

Because automated databases are incomplete,25-27 4 leading TCM journals that the research team believed had the highest relevance were searched manually. They were the (1) Journal of Traditional Chinese Medicine, (2) Journal of Integrative Medicine, (3) Chinese Journal of Integrative Medicine, and (4) Journal of New Chinese Medicine. Reference lists and bibliographies were checked from all retrieved articles.

Unpublished trials were researched on the Web site of the Chinese clinical trial registry and in relevant conference proceedings. Further, the current research team also contacted authors of registered trials and officials of relevant pharmaceutical companies for information not officially reported. All searches were completed on October 31, 2015.

No language or date restrictions were imposed.

Relevant Medical Subject Heading (MeSH) terms and keywords were used in various combinations, including cough, rhinitis, sinusitis, pharyngitis, upper airway cough syndrome, upper airway disease, postnasal drip syndrome, chronic cough, laryngeal dysfunction induced cough, nasal dysfunction induced cough, CMH, TCM, and RCT. The search terms were slightly modified to suit the instructions of different databases.

Study Selection and Data Extraction. The titles and abstracts obtained through searching were screened independently by 2 members of the research team for their relevance to the effectiveness of CMH and, if potentially relevant, the full-text article was retrieved. The conclusions of the 2 reviewers about inclusion of the studies were recorded. Disagreement about selection of a study was resolved either by consensus of those 2 investigators or by a decision by another member of the research team if the first 2 researchers could not reach a consensus.

Extracted data included (1) characteristics of the trials— the study’s year of publication, diagnostic criteria, definitions of efficacy, and design; (2) participants’ demographic characteristics—sample size and ages; (3) the studied interventions—type, treatment duration, and follow-up duration; and (4) outcome measures. Data of the included studies were summarized and tabulated independently by the same members of the team who selected the studies, using table cells that had been developed at the protocol stage. The results of the data extraction by each reviewer were double-checked and compared. Any discrepancies were

resolved by consensus of the 2 reviewers or by same team member who resolved issues regarding the determination of the studies to include.

Quality Assessment. Risk of bias was independently assessed by the same team members who selected the studies, using the 6 dimensions of the Cochrane risk-of-bias assessment.28 Those dimensions are (1) method of sequence generation; (2) allocation concealment; (3) blinding; (4) completeness of outcome data; (5) selectiveness of outcome reporting; and (6) other bias that could result from certain circumstances, mainly those related to particular trial designs, such as carry-over in crossover trials and recruitment bias in cluster-randomized trials.28 Each domain was classified as (1) yes, indicating a low risk of bias; (2) unclear, indicating an unclear risk of bias; or (3) no, indicating a high risk of bias.

The research team also evaluated the overall quality of the evidence for individual outcomes, based on 5 principal factors including (1) limitations in the study’s design, (2) inconsistency of results, (3) indirectness, (4) imprecision, and (5) other potential bias using the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach, as recommended by the Cochrane Back Review Group.29 If problems with the quality of any domain was considered to be serious, the research team rated the evidence quality down by 1 level. As to publication bias, funnel plots were not conducted to confirm the bias for outcomes that were reported in fewer than 5 studies.

Consensus about quality assessment was reached by discussion of the 2 reviewers who selected the studies. When disagreements occurred, the previously mentioned arbitrator was consulted.

Interventions In the review, comparisons between CMH and Western medicine (WM), integrated therapy (CMH+WM) and WM, or CMH and placebo were assessed. Only studies that used orally administered CMHs were considered to be eligible. Studies were not considered if any CMH was applied as a control or if traditional nondrug therapies, including acupuncture, cupping, or point application, were applied in any group.

Outcome Measures The primary outcomes included (1) TCM recovery rate and (2) TCM cough symptom score.

TCM Recovery Rate. TCM’s curative effect was calculated as the cumulative percentage of the symptom score reduction (PSSR), estimated between baseline and postintervention.

Following the Guidelines for Clinical Research of New Chinese Medicine,30,31 the scores were graded as (1) recovery— PSSR ≥ 95%, (2) excellent effect—95% > PSSR ≥ 70%, (3) modest effect—70% > PSSR ≥ 30%), or (4) no effect—PSSR < 30%. The TCM recovery rate was defined as the proportion of patients whose final clinical conditions were classified as a recovery.

TCM Cough Symptom Score. According to the Chinese Criteria Guiding Principle of Clinical Research on New Drugs of TCM,32-34 the cough symptom scores were classified

40 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

Jiang—Chinese Medicinal Herbs and Cough

into 4 grades, with scores ranging from 0–3 (ie, 0, 1, 2, 3, respectively), or 0–9 (ie, 0, 3, 6, 9, respectively), with the higher scores signifying a more frequent and severe cough.

The secondary outcomes were (1) a symptom score for TCM’s sensation of postnasal dripping; (2) a quality of life (QoL) score, using the Cough-specific QoL Questionnaire (CQLQ)35 or the Leicester Cough Questionnaire (LCQ)36; (3) a physical-signs score (ie, a score on the cobblestone appearance of the oropharyngeal mucosa or mucus in the oropharynx), which was classified into 4 grades, with scores ranging from 0–3 or 0–9, and the higher scores indicating more severe physical signs; (4) the cough recurrence rate, calculated as the percentage of patients who suffered from a cough again in a follow-up period after complete disappearance of the cough during the study, which was defined as a TCM cough symptom score = 0 when lasting for 48 hours31; and (5) adverse events (AEs).

Statistical Analysis Heterogeneity was assessed graphically using forest plots and statistically using the χ2 test and I2 test. The meta-analysis was performed using a fixed-effects model if no statistical heterogeneity (P < .05) was detected in the data from the individual studies. In the case of statistical heterogeneity, pooling data were analyzed with a random-effects model.

The causes of any heterogeneity were explored by subgroup analysis according to ages and interventions, if necessary. A descriptive analysis was conducted if a large amount of heterogeneity existed—P < .10, I2 ≥ 85%.28 Dichotomous data were presented as relative risks (RRs), and continuous data as mean differences (MDs), with corresponding 95% confidence intervals (CIs). Statistical analyses were carried out using the Review Manager software, version 5.3.4 (Cochrane Group, London, United Kingdom).

RESULTS Description of Included Studies The electronic database searches and manual retrievals PSSR = × 100% identified 401 citations and 13 citations, respectively (Figure 1).

No unpublished relevant studies were identified. A total of 16 RCTs published in Chinese, with 1355 participants—720 in the CMH groups and 635 in Figure 1. Flow Chart of Study Selection and Inclusion the control groups—met the inclusion criteria, with publication dates ranging from 2008 to 2015.

Additional records identified Records identified through Agreement was reached between through other sources database searching the reviewers in independent (n = 13) (n = 401) selection of 16 studies.

All participants among the 16 studies had been recruited from outpatient clinics and had Titles and abstracts a clinical diagnosis of UACS, Records excluded (n = 373) screened according to acknowledged Duplicates (n = 134) (N = 414) criteria developed by the Nonrandomized (n = 10) Asthma Study Group of the No outcomes required (n = 172) Chinese Medical Association.37 Rhinogenic cough (n = 32) Six studies had recruited Laryngeal cough (n = 25) children,38-43 and the remaining 10 studies had recruited adult Full-text articles assessed Records excluded (n = 25) patients.44-53 The majority of the for eligibility Pseudorandomized (n = 11) included studies were of a (n = 41) Different patient population (n = 12) moderate size (ie, 30–294 TCM nondrug therapies (n = 1) participants).

CMH as control (n = 1) In the included studies, CMH in different dosage forms was given orally for different treatment durations (7–90 days).

Studies included in Fifteen studies used self-modified qualitative synthesis decoctions that were composed (n = 16) of different herbs according to the individual participant’s TCM syndromes and symptoms, and one47 used a patented Chinese Abbreviations: TCM, traditional Chinese medicine; CHM, Chinese medicinal herbs. herbal medicine. symptoms score symptom score before treatment after treatment symptom score before treatment

)

Included

Eligibility

Screening

Identification

(

Jiang—Chinese Medicinal Herbs and Cough

ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 41

Dropout (T/C) No/No

Adverse Events (T/C) No/No

ᬅ

No/No

NS/NS

7

ᬅ; ᬆ

No/No

No/ Drowsiness (n = 2)

LD syrup + roxithromycin dispersive tablets + Myrtle Standardized Enteric Coated Soft Capsules or Acetylcysteine Granules

14

ᬅ; ᬉ

Lack of compliance (n = 4); lost to followup (n = 2)/ No

NS/NS

LD tablets + ambroxol and clenbuterol oral solution + Dibiling nasal dropsa

14

ᬅ; ᬉ

No/No

NS/NS

Amoxicillin and Clavulanate Potassium Chewable Tablets

5

ᬅ; ᬆ

No/No

NS/NS

LD tablets + Montelukast Sodium Tablets + Compound Liquorice Tablets

10

ᬅ; ᬆ; ᬉ

Lost to follow-up (n = 2)/ lost to follow-up (n = 2)

No/No

SMD + the LD tablets + control Dibiling nasal drops group treatments

30

ᬅ; ᬆ

No/No

Fatigue, drowsiness, and dry mouth (n = 2)/ headache, drowsiness, and dry mouth (n = 3)

SMD + the control group treatments

14

ᬅ

Lack of compliance (n = 2)/ lost to follow-up (n = 3)

NS/NS

TCM Group SMD

Treatment Duration in Days Outcomes 30 ᬅ; ᬆ; ᬇ; ᬈ

Number (T/C) 60 (30/30)

Design RCT; BU

Niu39 (2009)

60 (30/30)

RCT; BU

6.57 ± 2.13

3-12/ 2-16.5

SMD + BiYuan TongQiao Granules

LD tablets + Sodium Cromoglicate Nass Drops + Spleen Aminopeptide Oral Solution + Monteluk-ast Sodium Chewable Tablets + Ambroxol Hydrochloride Oral Solutiona

90

Yang40 (2011)

63 (34/29)

RCT; BU

5.90 ± 2.1/ 6.12 ± 2.7

18 ± 1.8/ 19.6 ± 2.1

SMD

Compound Pseudoephedrine Hydrochloride Oral Solution

Chen41 (2009)

84 (22/62)

RCT; BU

6.57 ± 2.13/ 6.09 ± 3.11

8.25 ± 3.23/ SMD + 8.30 ± 2.15 the control group treatments

Lin42 (2015)

56 (28/28)

RCT; BU

5.18 ± 2.28/ 5.5 ± 1.35

1.20 ± 0.42/ SMD + the 1.14 ± 0.33 control group treatments

Yu43 (2015)

80 (40/40)

RCT; BU

6.01 ± 0.9/ 5.8 ± 0.8

NS

SMD

Yang44 (2011)

63 (32/31)

RCT; SB

40.46 ± 5.93/ 42.41 ± 6.06

NS

SMD + the control group treatments

Li45 (2010)

60 (30/30)

RCT; BU

37.33 ± 11.35/ 38.00 ± 10.55

2-24/ 4-20

Xu46 (2013)

97 (59/38)

RCT; BU

49.45 ± 13.34/ 46.47 ± 12.13

9-336/ 7-276

Study Xu38 (2010)

Age in Years (T/C) 3-15/3-14

Course of Disease in Months (T/C) 2-9/2-11

Adults

Children

Subgroup

Table 1. Characteristics of the Included Studies

42 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

Control Group LD tablets + Bright Nose Nasal Spraya

LD syrup + roxithromycin dispersive tablets + Myrtol Standardized Enteric Coated Soft Capsules

Jiang—Chinese Medicinal Herbs and Cough

Subgroup

Table 1. (continued)

Study Shi47 (2013)

Number (T/C) 294 (196/98)

Design MC; RCT; DB; PC

Age in Years (T/C) 39.37 ± 13.00/ 38.46 ± 12.12

Course of Disease in Months (T/C) 2-21.5/ 2-21

TCM Group TCM patent medicine

Control Group Placebo

Treatment Duration in Days Outcomes 28 ᬅ; ᬊ

Dropout (T/C) No reason dropout (n = 1)/ no reason dropout (n = 2)

Adverse Events (T/C) No/No

Huang48 (2008)

60 (30/30)

RCT; BU

37.83 ± 10.43/ 36.40 ± 11.89

2-14/ 2-27

SMD

Dibiling nasal drops + Clemastine Fumarate Capsules

10

ᬅ; ᬆ; ᬇ; ᬈ

Lack of compliance (n = 1)/ No

No/No

Pan49 (2012)

60 (30/30)

RCT; BU

37.73 ± 12.01/ 38.83 ± 11.68

3.5-20/ 4-21

SMD

Dibiling nasal Drops + Clemastine Fumarate Capsules

14

ᬅ; ᬆ; ᬇ; ᬈ

No/No

NS/NS

Li50 (2015)

48 (24/24)

RCT; BU

20-53/ 22-50

0.5-3/ 0.6-3.1

SMD

LD tablets

14

ᬅ; ᬆ

No/No

NS/NS

Wang51 (2014)

86 (43/43)

RCT; BU

35.72 ± 14.12 39.61 ± 17.87

3-18/ 3.5-20.5

SMD

Compound Pseudoephedrine Hydrochloride Oral Solution

14

ᬅ; ᬆ; ᬊ

No/No

No/No

Chen52 (2015)

64 (32/32)

RCT; BU

18-67/ 18-68

3-14.5/ 3.5-16

SMD

Cetirizine hydrochloride tablets

14

ᬅ

No/No

NS/NS

Chen53 (2014)

120 (60/60)

RCT; BU

38.6 ± 12.3 39.3 ± 12.5

6.26 ± 3.13 6.78 ± 3.43

SMD

Budesonide nasal spray

14

ᬅ; ᬉ

No/No

No/No

a

Antibiotics used if necessary.

Note: Measured outcomes are identified as ᬅ TCM recovery rate, ᬆ TCM cough symptom score, ᬇ TCM postnasal dripping symptom score, ᬈ physical-signs score, ᬉ recurrence rate of cough, and ᬊ LCQ score.

Abbreviations: T, the TCM group; C, the control group; RCT, randomized, controlled trial; BU, blinding unspecified; SMD, self-modified decoction; LD, Loratadine; TCM, traditional Chinese Medicine; LCQ, Leicester Cough Questionnaire; NS, Not specified; MC, multicenter; DB, double-blinded; PC, placebo-controlled.

Nine RCTs compared CMH with WM.38,40,43,48-53 Six RCTs compared integrated CMH and WM with the same WM alone.39,41,42,44-46 Only 1 RCT compared CMH with a placebo.47 Three trials performed a 1-month follow-up,41,44,53 and 1 trial performed a 2-month follow-up.42 No trials reported severe side effects in CMH groups. The characteristics of all included studies are presented in Table 1. In all studies, curative efficacy was defined according to Guidelines for Clinical Research of New Chinese Medicine.30 With regard to TCM’s differentiations in diagnosis, patients recruited into the studies were mainly identified as having 4 syndromes: (1) wind-heat attacking the lung,41,43,44,47,52 (2) wind-phlegm blocking the lung,39,42,45-51,53 (3) spleen-qi deficiency,38,40,41 and (4) kidney-yang insufficiency.41,47 The diagnoses involved 3 crucial pathogens—wind, heat, and phlegm—and 3 principal organs—lung, spleen, and kidney.

Treatment principles based on the above syndromes were classified as (1) dispelling wind and reducing heat, Jiang—Chinese Medicinal Herbs and Cough

(2) dispelling wind and resolving phlegm, and (3) strengthening the spleen-qi and tonifying the kidney-yang, correspondingly.

Quality Assessment of Included Studies In general, the overwhelming majority of the studies showed an unclear risk of bias. The studies generally failed to earn a “yes” in the setting of allocation concealment and blinding reports.

All studies included were described as randomized. Of those, 7 studies identified the random sequence as being generated from a random number table, and the others mentioned only that patients were randomly allocated, without specific methods being reported.

All studies but one47 fell short on the appropriateness of the reporting on allocation concealment. The study was double-blinded (ie, patients, personnel, and outcome assessors were all blinded) and was placebo-controlled in only 1 multicenter study.47 That study gave accurate descriptions of ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 43

the method of achieving the blinding processes and illustrated the blinding of the outcome assessment. Meanwhile, reporting bias and other biases appeared to be unlikely in that study.

Five studies experienced withdrawals or losses during the treatment duration,40,44,45,47,48 with specific reasons being explained in 4 of 5. No differences were found on reasons and numbers of dropouts between treatment groups and control groups in any of them. All of the studies reported baseline comparability among groups and provided baseline data. The risk of selective reporting was unlikely to be proven because all the targeted outcomes that were specified in the Methods section were reported in the Results section of the included studies, although only 1 trial47 provided the study’s protocol in the published article.

The quality assessment for each study is summarized in Table 2 and Figure 2.

Table 2. Risk of Bias of Included Studies Random Sequence Generation

Allocation Concealment

Unclear

Niu (2009) Yang40 (2011)

Study Xu38 (2010 ) 39

Blinding

Incomplete Outcome Data

Selective Reporting

Other Bias

Unclear

Unclear

Yes

Yes

Unclear

Yes

Unclear

Unclear

Yes

Yes

Unclear

Yes

Unclear

Unclear

Yes

Yes

Unclear

41

Yes

Unclear

Unclear

Yes

Yes

Unclear

Lin42 (2015)

Unclear

Unclear

Unclear

Yes

Yes

Unclear

Yu43 (2015)

Unclear

Unclear

Unclear

Yes

Yes

Unclear

Yes

Unclear

Unclear

Yes

Yes

Unclear

Unclear

Unclear

Unclear

Yes

Yes

Unclear

Xu (2013)

Yes

Unclear

Unclear

Yes

Yes

Unclear

Shi47 (2013)

Yes

Yes

Yes

Yes

Yes

Yes

Chen (2009)

Yang44 (2011) Li45 (2010) 46

48

Huang (2008)

Yes

Unclear

Unclear

Yes

Yes

Unclear

Unclear

Unclear

Unclear

Yes

Yes

Unclear

Li (2015)

Unclear

Unclear

Unclear

Yes

Yes

Unclear

Wang51 (2014)

Unclear

Unclear

Unclear

Yes

Yes

Unclear

Chen (2015)

Unclear

Unclear

Unclear

Yes

Yes

Unclear

Chen53 (2014)

Unclear

Unclear

Unclear

Yes

Yes

Unclear

Pan49 (2012) 50

52

Figure 2. Summary of Risk of Bias of Included Studies Random Sequence Generation (Selection Bias)

Allocation Concealment (Selection Bias)

Blinding of Participants and Personnel (Performance Bias)

Blinding of Outcome Assessment (Detection Bias)

?

?

?

?

?

?

?

?

?

?

Chen41 (2009)

+ + +

?

?

?

Lin42 (2015)

?

?

?

?

Yu (2015)

?

?

?

?

44

+

?

?

?

Li (2010)

?

?

?

?

Xu46 (2013)

+ + +

?

?

?

+

+

+

?

?

?

?

?

?

?

Study Xu38 (2010 ) 39

Niu (2009) 40

Yang (2011)

43

Yang (2011) 45

Shi47 (2013) 48

Huang (2008) 49

Pan (2012) 50

Li (2015)

?

?

?

?

51

?

?

?

?

52

Chen (2015)

?

?

?

?

Chen53 (2014)

?

?

?

?

Wang (2014)

Incomplete Outcome Data (Attrition bias)

Selective Reporting (Reporting Bias)

+ + + + + + + + + + + + + + + +

+ + + + + + + + + + + + + + + +

Other Bias ? ? ? ? ? ? ? ? ?

+ ? ? ? ? ? ?

Note: The green circles marked with + indicate a low risk; the yellow circles marked with ? indicate an unclear risk. No studies showed a high risk.

44 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

Jiang—Chinese Medicinal Herbs and Cough

Table 3. Quality of Evidence for Individual Outcomes

Effect Size

TCM recovery rate

TCM cough symptom score

Subgroup Children’s subgroup Adults’ subgroup Children’s subgroup Adults’ subgroup

Children’s subgroup TCM PNDS score Adults’ subgroup Children’s subgroup Physical signs score Adults’ subgroup Adults’ QoL score subgroup Children’s subgroup Cough recurrence Adults’ rate subgroup

Type of Study CMH vs WM Integrated therapy vs WM CMH vs WM Integrated therapy vs WM CMH vs Placebo

No. of Studies 4 (38-40,43)

Factors That Can Reduce the Quality of Evidence Limitations in Study Design Publication or Execution Consistency Indirectness Imprecision Bias Not serious Not serious Seriousc Not serious Seriousa

2 (41,42)

Seriousa

6 (48-53)

a

3 (44-46) 1 (47)

Serious

Not serious Not serious

Not serious Not serious

Not serious Only 1 study

Serious

Serious

c

Not serious

Moderate

c

Not serious

Moderate

Not serious

d

Low Very low

Not serious

Not serious

Not serious

Moderate

Not serious

Not serious

1 (45)

Serious

a

Only 1 study

CMH vs WM

1 (38)

Seriousa

CMH vs WM

2 (48,49)

CMH vs WM CMH vs WM CMH vs. WM CMH vs Placebo Integrated therapy vs WM CMH vs WM Integrated therapy vs WM

Serious

Not serious

b

Serious

4 (48-51)

Not serious

c

Serious

a

CMH vs WM Integrated therapy vs WM

Seriousc

Not serious

Serious

3 (38,40,43)

Not serious

b

a

CMH vs WM

Quality Low

Serious Serious

Not serious

Moderate

Not serious

Serious

c

Not serious

Low

Only 1 study

Not serious

Seriousc

Not serious

Low

Seriousa

Seriousb

Not serious

Seriousc

Not serious

Low

1 (38)

Seriousa

Only 1 study

Not serious

Seriousc

Not serious

Low

2 (48,49)

Seriousa

Seriousb

Not serious

Seriousc

Not serious

Very low

c

a

1(51) 1 (47)

Serious Not serious

Only 1 study Only 1 study

Not serious Not serious

Serious Not serious

Not serious Not serious

Low High

2 (42)

Seriousa

Not serious

Not serious

Seriousc

Not serious

Low

1 (53)

a

Not serious

Serious

c

Not serious

Low

Serious

c

Not serious

Moderate

1 (44)

Serious

Only 1 study

Not serious

Only 1 study

Not serious

a

One-half or more of the studies had fewer than 3 “yes” answers in risk-of bias-assessment.

Considerable heterogeneity was detected between studies. c The confidence interval was too wide and/or comparison was too small (sparse data). d Publication bias was demonstrated by funnel plot; publication bias was not detected by funnel plot for subgroups with fewer than 5 members. b

Abbreviations: TCM, traditional Chinese medicine; CMH, Chinese medicinal herbs; WM, Western medicine; PNDS, postnasal drip syndrome; QoL, quality of life.

Regarding the quality of evidence for individual outcomes, the overall level ranged from high to very low (Table 3). It is noteworthy that the available evidence comes from 14 studies that administered herbal decoctions that were prescribed by researchers themselves, which may indicate their possible commercial interests.54 Sparse data were described as comparisons containing fewer than 200 participants in total for individual outcomes.29 Outcome Measures of Included Studies Subgroup analyses were performed on the basis of the age of participants—children’s subgroup and adults’ subgroup—and intervention styles: CMH versus WM, CMH versus placebo, and integrated therapy versus WM. TCM Recovery Rate. All included studies examined the TCM recovery rate. Six studies48-53 in the adults’ subgroup, with an RR = 1.99 and a 95% CI of 1.43 to 2.77; and Jiang—Chinese Medicinal Herbs and Cough

4 studies38-40,43 in the children’s subgroup, with an RR = 1.80 and a 95% CI of 1.16 to 2.79, showed that CMH had a significantly better curative effect than WM, with the overall analysis showing an RR = 1.92 and a 95% CI of 1.47 to 2.50 (Figure 3A).

Three studies44-46 in the adults’ subgroup and 2 studies41,42 in the children’s subgroup made a comparison between integrated therapy and WM (Figure 3B). The pooled results also demonstrated a statistical difference between groups, with an RR = 2.42 and a 95% CI of 1.13 to 5.18 for the children’s subgroup; an RR = 1.90 and a 95% CI of 1.05 to 3.46 for the adults’ subgroup; and an RR = 2.08 and a 95% CI of 1.30 to 3.33 for the total analysis.

The unique placebo-controlled study47 was also remarkably positive for CMH. Its TCM recovery rate in the CMH group was 9.6 times higher than that in the placebo group, with an RR = 9.60 and a 95% CI of 2.37 to 38.92 (Figure 3C).

ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 45

Figure 3. Analysis of TCM Recovery Rate 3A. CMH vs WM Treatment Control Study or Subgroup Events Total Events Total Weight Children subgroup Niu39 (2009) 6 30 2 30 3.4% Xu38 (2010 ) 10 30 7 30 12.0% 40 4 34 1 29 1.8% Yang (2011) 20 40 12 40 20.5% Yu43 (2015) Subtotal (95% CI) 134 129 37.7% Total events 40 22 Heterogeneity: χ2 = 1.15, df = 3 (P = .76); I2 = 0% Test for overall effect: z = 2.61 (P = .009) Adults subgroup 36 60 20 60 34.1 Chen53 (2014) Chen52 (2015) 5 32 3 32 5.1% Huang48 (2008) 6 29 0 30 0.8% 9 24 4 24 6.8% Li50 (2015) 49 4 30 1 30 1.7% Pan (2012) 51 Wang (2014) 12 43 8 43 13.7% Subtotal (95% CI) 218 219 Total events Heterogeneity: χ2 = 3.00, df = 5 (P = .70); I2 = 0% Test for overall effect: z = 4.06 (P < .0001) Total (95% CI) 352 348 100.0% Total events 112 58 Heterogeneity: χ2 = 4.21, df = 9 (P = .90); I2 = 0% Test for overall effect: z = 4.61 (P < .00001) Test for subgroup differences: χ2 = 0.13, df = 1 (P = .72); I2 = 0%

Risk Ratio M-H, Fixed, 95% CI

Risk Ratio M-H, Fixed, 95% CI

3.00 (0.66 to 13.69) 1.43 (0.63 to 3.25) 3.41 (0.40 to 28.84) 1.67 (0.95 to 2.93) 1.80 (1.16 to 2.79)

1.80 (1.19 to 2.72) 1.67 (0.43 to 6.40) 13.43 (0.79 to 228.16) 2.25 (0.80 to 6.32) 4.00 (0.47 to 33.73) 1.50 (0.68 to 3.30) 1.99 (1.43 to 2.77)

1.92 (1.47 to 2.50) 0.01 Favors control

0.01

0

10

100 Favors treatment

10

100 Favors treatment

10

100 Favors treatment

3B. Integrated Therapy vs WM Treatment Control Study or Subgroup Events Total Events Total Weight Children subgroup 40 59 9 19 18.3% Chen41 (2009) Lin42 (2015) 14 28 8 28 16.7% Subtotal (95% CI) 87 47 34.9% Total events 54 17 Heterogeneity: χ2 = 0.01, df = 1 (P = .931); I2 = 0% Test for overall effect: z = 2.27 (P = .02) Adults subgroup Li45 (2010) 7 30 3 30 9.6% 40 59 18 38 29.4% Xu46 (2013) 44 Yang (2011) 10 32 9 31 26.2% Subtotal (95% CI) 121 99 Total events 57 30 Heterogeneity: χ2 = 1.43, df = 2 (P = .49); I2 = 0% Test for overall effect: z = 2.11 (P = .03) Total (95% CI) 208 146 100.0% Total events 111 47 Heterogeneity: χ2 = 1.67, df = 4 (P = .80); I2 = 0% Test for overall effect: z = 3.95 (P = .002) Test for subgroup differences: χ2 = 0.23, df = 1 (P = .63); I2 = 0%

Risk Ratio M-H, Fixed, 95% CI

Risk Ratio M-H, Fixed, 95% CI

2.34 (0.82 to 6.71) 2.50 (0.83 to 7.55) 2.42 (1.13 to 5.18)

2.74 (0.63 to 11.82) 2.34 (1.01 to 5.41) 1.11 (1.05 to 3.46) 1.90 (1.05 to 3.46)

2.08 (1.30 to 3.33) 0.01 Favors control

0.01

0

3C. CMH vs Placebo Study or Subgroup Adults subgroup Shi47 (2013) Subtotal (95% CI) Total events

Treatment Events Total 39 39

195 195

Control Events Total Weight 2

96 96

100.0% 100.0%

Risk Ratio M-H, Fixed, 95% CI

Risk Ratio M-H, Fixed, 95% CI

9.60 (2.37 to 38.92) 9.60 (2.37 to 38.92)

30 0.01 Favors control

0.01

0

Abbreviations: TCM, traditional Chinese medicine; CMH, Chinese medicinal herbs; WM, Western medicine; CI, confidence interval.

46 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

Jiang—Chinese Medicinal Herbs and Cough

Figure 4. Analysis of TCM Cough Symptom Score 4A. CMH vs WM Treatment Control

Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight IV, Fixed, 95% CI Children subgroup 1.51 1.72 30 3.1 2.43 30 5.8% -1.59 (-2.65 to -0.53) Xu38 (2010 ) Yang40 (2011) 0.86 0.81 34 1.26 0.67 29 16.5% -0.40 (-0.77 to -0.03) 43 1.37 0.84 40 1.38 0.88 40 16.3% -0.01 (-0.39 to 0.37) Yu (2015) 104 99 38.6% -0.47 (-1.06 to 0.13) Subtotal (95% CI) Heterogeneity: τ2 = 0.19, χ2 = 0.21, df = 2 (P = .02); I2 = 76% Test for overall effect: z = 1.55 (P = .12) Adults subgroup 0.83 1.36 29 2.2 1.35 30 10.1% -1.37 (-2.06 to -0.68) Huang48 (2008) Li50 (2015) 0.83 0.64 24 1.67 0.71 24 16.2% -0.84 (-1.22 to -0.46) Pan49 (2012) 0.6 0.68 30 1.2 0.55 30 17.7% -0.60 (-0.91 to -0.29) 1.27 0.76 40 1.65 0.78 43 17.4% -0.38 (-0.72 to -0.05) Wang51 (2014) Subtotal (95% CI) 126 127 61.4% -0.71 (-1.03 to -0.39) Heterogeneity: τ2 = 0.06, χ2 = 7.84, df = 6 (P = .05); I2 = 62% Test for overall effect: z = 4.34 (P < .0001) Total (95% CI) 230 226 100.0% -0.61 (-0.91 to -0.31) Heterogeneity: τ2 = 0.11, χ2 = 20.78, df = 6 (P = .0002); I2 = 71% Test for overall effect: z = 3.97 (P < .0001) Test for subgroup differences: χ2 = 0.49, df = 1 (P = .48); I2 = 0%

Mean Difference IV, Fixed, 95% CI

-4 -2 Favors treatment

0

2

4 Favors control

4B. Integrative Therapy vs WM Study or Subgroup Adults subgroup Li45 (2010) Subtotal (95% CI)

Treatment Mean SD Total 1

0.61

30 30

Mean 1.74

Control SD Total Weight 0.76

30 30

Mean Difference IV, Fixed, 95% CI

Mean Difference IV, Fixed, 95% CI

100.0% -0.74 (-1.09 to -0.39) 100.0% -0.74 (-1.09 to -0.39) -4 -2 Favors treatment

0

2

4 Favors control

Abbreviations: TCM, traditional Chinese medicine; CMH, Chinese medicinal herbs; WM, Western medicine; SD, standard deviation; CI, confidence interval.

Figure 5. Analysis of TCM Cough Symptom Score Mean Difference Treatment Control Study or Subgroup Mean SD Total Mean SD Total Weight IV, Fixed, 95% CI Children subgroup 1.51 2.38 30 1.4 1.52 30 26.3% -0.90 (-1.64 to -0.16) Xu38 (2010 ) Subtotal (95% CI) 30 30 26.3% -0.90 (-1.64 to -0.16) Adults subgroup Huang48 (2008) 0.21 0.77 29 1.3 1.51 30 30.8% -1.09 (-1.70 to -0.48) 0.6 0.56 30 0.9 0.61 30 42.9% -0.30 (-0.60 to -0.00) Pan49 (2012) Subtotal (95% CI) 59 60 73.7% -0.65 (-1.42 to 0.12) Heterogeneity: τ2 = 0.25, χ2 = 5.23, df = 1 (P = .02); I2 = 83% Test for overall effect: z = 1.65 (P = .10) Total (95% CI) 89 90 100.0% -0.70 (-1.26 to -0.15) Heterogeneity: τ2 = 0.16, χ2 = 6.49, df = 2 (P = .04); I2 = 69% Test for overall effect: z = 2.47 (P < .01) Test for subgroup differences: χ2 = 0.21, df = 1 (P = .64); I2 = 0%

Mean Difference IV, Fixed, 95% CI

-4 -2 Favors treatment

0

2

4 Favors control

Abbreviations: TCM, traditional Chinese medicine; CMH, Chinese medicinal herbs; WM, Western medicine; SD, standard deviation; CI, confidence interval.

TCM Cough Symptom Score. Eight studies examined the cough-symptom score. Seven studies38,40,43,48-51 conducted a comparison of CMH and WM. Analysis of the children’s subgroup38,40,43 revealed that no statistically significant difference existed between the groups, with an MD = -0.47 and a 95% CI of -1.06 to 0.13, whereas the adults’ subgroup45,48-51 showed a statistically significant difference favoring the CMH group in both the individual and the pooled results, with a pooled MD = -0.71 and a 95% CI of -1.03 to -0.39 (Figure 4A). Taken together, CMH had a statistically better effect on cough symptom relief compared with WM, with an RR = -0.61 and a 95% CI of -0.91 to -0.31 Jiang—Chinese Medicinal Herbs and Cough

for the total analysis. One study45 carried out a comparison of integrated therapy and WM and reached a significantly positive result favoring the integrated group, with an MD = -0.74 and a 95% CI of -1.09 to -0.39 (Figure 4B).

TCM PNDS Symptom Score. The symptom score for the postnasal dripping sensation was reported in 3 studies between CMH and WM. One study in the children’s subgroup38 demonstrated a significantly better effect on relieving postnasal dripping sensation for CMH, with an MD = -0.90 and a 95% CI of -1.64 to -0.16 (Figure 5). After pooling, the subtotal analysis for the adults’ group showed a similar effect between CMH and WM in alleviation of the postnasal dripping sensation, ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 47

Figure 6. Analysis of Physical Signs Score: CMH vs WM Mean Difference Treatment Control Study or Subgroup Mean SD Total Mean SD Total Weight IV, Fixed, 95% CI Children subgroup 1.6 1.89 30 2.8 2.61 30 2.1% -1.20 (-2.35 to -0.05) Xu38 (2010 ) 30 30 2.1% -1.20 (-2.35 to -0.05) Subtotal (95% CI) Adults subgroup 1.86 1.48 29 2.9 0.96 30 6.8% -1.04 (-1.68 to -0.40) Huang48 (2008) Pan49 (2012) 1.97 0.32 30 2.93 0.37 30 91.1% -0.96 (-1.14 to -0.78) Subtotal (95% CI) 59 60 97.9% -0.97 (-1.13 to -0.80) Heterogeneity: τ2 = 0.00, χ2 = 0.06, df = 1 (P = .81); I2 = 0% Test for overall effect: z = 11.21 (P < .00001) Total (95% CI) 89 90 100.0% -0.97 (-1.14 to -0.80) Heterogeneity: τ2 = 0.00, χ2 = 0.21, df = 2 (P = .90); I2 = 0% Test for overall effect: z = 11.39 (P < .00001) Test for subgroup differences: χ2 = 0.16, df = 1 (P = .69); I2 = 0%

Mean Difference IV, Fixed, 95% CI

-10 -5 Favors treatment

0

5 10 Favors control

Abbreviations: CMH, Chinese medicinal herbs; WM, Western medicine; SD, standard deviation; CI, confidence interval.

Figure 7. Analysis of LCQ for Quality of Life 7A. CMH vs WM Treatment Study or Subgroup Mean SD Total 1.5.1 adult subgroup 4.99 0.92 43 Wang51 (2014) Subtotal (95% CI) 43 Heterogeneity: Not applicable Test for overall effect: z = 2.24 (P = .03)

Mean 4.56

Mean Difference IV, Fixed, 95% CI

Control SD Total Weight 0.86

43 43

100.0% 100.0%

Mean Difference IV, Fixed, 95% CI

0.56 (0.34 to 0.78) 0.56 (0.34 to 0.78) -2 -1 Favors control

7B. CMH vs Placebo Mean Difference IV, Fixed, 95% CI

Treatment Control Study or Subgroup Mean SD Total Mean SD Total Weight 3.2.1 adult subgroup 5.36 0.75 195 4.8 0.94 96 100.0% Shi47 (2013) Subtotal (95% CI) 195 96 100.0% Heterogeneity: Not applicable Test for overall effect: z = 5.09 (P < .00001)

0

1 2 Favors treatment

Mean Difference IV, Fixed, 95% CI

0.56 (0.34 to 0.78) 0.56 (0.34 to 0.78) -1 -.5 Favors control

0

.5 1 Favors treatment

Abbreviations: LCQ, Leicester Cough Questionnaire; CMH, Chinese medicinal herbs; WM, Western medicine; SD, standard deviation; CI, confidence interval. with an MD = -0.65 and a 95% CI of -1.42 to 0.12. However, a boundary difference between groups was still found in the final analysis when taking the 3 studies as a whole, with an MD = -0.70 and a 95% CI of -1.26 to -0.15 for the total analysis.

Physical Signs Score. In a comparison of CMH and WM, relief of the cobblestone appearance of the oropharyngeal mucosa was positively reported for CMH in 3 studies, 1 in the children’s subgroup,48 with an MD = -1.20 and a 95% CI of -2.35 to -0.05 and 2 in the adults’ subgroup,48,49 with and an MD = -0.97 and a 95% CI of -1.13 to -0.80. A statistically significant difference was demonstrated in the final pooled analysis, with an MD = -0.97 and a 95% CI -of 1.14 to -0.80 (Figure 6).

QoL Score. Two studies47,51 in the adults’ subgroup estimated a QoL score using the LCQ,55 with a total score (TS) calculated. Better effects favoring the CMH group were reported over WM, with an MD = 0.43 and a 95% CI of 0.05 to 0.81 (Figure 7A) and placebo, with an MD = 0.56 and a 95% CI of 0.34 to 0.78 (Figure 7B).

Recurrence Rate of Cough. Two studies in the children’s subgroup41,42 and 2 in the adults’ subgroup44,53 investigated the cough recurrence in the follow-up period. One study53

made a comparison between the CMH group and the WM group and reported a lower risk of relapse in the CMH group, with the statistical difference having an RR = 0.27 and a 95% CI of 0.08 to 0.91 (Figure 8A). Three studies41,42,44 indicated that integrated therapy had a better effect on preventing cough recurrence as compared with WM, with the children’s subgroup showing an RR = 0.29 and a 95% CI of 0.13 to 0.65, the adults’ subgroup showing an RR = 0.30 and a 95% CI of 0.11 to 0.82, and the total analysis showing an RR = 0.29 and a 95% CI of 0.15 to 0.55 (Figure 8).

Adverse Events. Seven studies evaluated the safety of CMH. Of those seven, 5 studies38,44,47,48,53 declared that no adverse reactions had occurred, and 2 studies40,45 reported AEs involving drowsiness, fatigue, dry mouth, and headache.

No significant difference, however, was detected between the CMH groups and the WM groups. No serious adverse effects were observed.

DISCUSSION Taken overall, the present review indicates that CMH alone or with integrated therapy can have a positive clinical effect in the treatment of UACS. According to individual

48 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

Jiang—Chinese Medicinal Herbs and Cough

Figure 8. Analysis of Cases of Recurrence 8A. CMH vs WM Treatment Control Study or Subgroup Events Total Events Total Weight 1.6.1 adult group 3 53 10 47 100.0% Chen53 (2014) Subtotal (95% CI) 53 47 100.0% Heterogeneity: Not applicable Test for overall effect: z = 2.11 (P = .03)

Risk Ratio M-H, Fixed, 95% CI

Risk Ratio M-H, Fixed, 95% CI

0.27 (0.08 to 0.91) 0.27 (0.08 to 0.91) 0.01 Favors treatment

0.01

0

10

100 Favors control

10

100 Favors treatment

8B. Integrated therapy vs WM Treatment Control Study or Subgroup Events Total Events Total Weight Children subgroup Chen41 (2009) 7 57 6 17 33.7% Lin42 (2015) 2 28 9 28 32.8% Subtotal (95% CI) 85 45 66.5% Total events 9 15 Heterogeneity: χ2 = 0.28, df = 1 (P = .59); I2 = 0% Test for overall effect: z = 2.99 (P = .003) Adults subgroup 4 23 7 12 33.5% Yang44 (2011) Subtotal (95% CI) 23 12 33.5% Total events 4 7

Risk Ratio M-H, Fixed, 95% CI

Total (95% CI) 108 57 100.0% Total events 13 22 Heterogeneity: χ2 = 0.28, df = 2 (P = .87); I2 = 0% Test for overall effect: z = 3.79 (P = .00002) Test for subgroup differences: χ2 = 0.00, df = 1 (P = .95); I2 = 0%

Risk Ratio M-H, Fixed, 95% CI

0.35 (0.14 to 0.90) 0.22 (0.05 to 0.94) 0.29 (0.13 to 0.65)

0.30 (0.11 to 0.82) 0.30 (0.11 to 0.82) 0.29 (0.15 to 0.55) 0.01 Favors control

0.01

0

Abbreviations: CMH, Chinese medicinal herbs; WM, Western medicine; CI, confidence interval trials that were available in the current review, a similar efficacy was generally reported for CMH alone or with integrated therapy and WM in resolving major symptoms, which is consistent with previous results reported by Fan.22 Desirable homogeneity was achieved after setting up subgroups. In the meta-analysis, the superiorities in the CMH group and the integrated group over the WM group and the placebo group were confirmed for all outcomes. The results favoring CMH presented in the current article encourage further research. Nevertheless, because of biases in individual studies, the conclusions in the current review should also be interpreted with caution.

As one of the most fundamental characteristics in the TCM system, the methods of syndrome differentiation and treatment distinguish TCM from WM and other complementary and alternative therapies. According to the characteristics and properties of chronic cough, the pathogenesis of UACS is theoretically considered to be “heat evil attacking the lung,” “wind-phlegm blocking the lung due to qi-stagnancy and blood-stasis,” and “qi and yin/yang deficiency.”56 Correspondingly, the treatment principles for the 3 pathogenic categories include clearing away heat, resolving phlegm, and supplementing deficiencies, although the components of TCM used in each trial in the current metaanalysis varied. However, up to now, a recognized standard for syndrome differentiation in diagnosis of UACS has been lacking. As a consequence, recognized criteria for TCM’s syndrome differentiation for diagnosis and its treatment principles for UACS should be developed and should be used as guidelines for further studies on the matter.

Jiang—Chinese Medicinal Herbs and Cough

Although the current research team did not include a language restriction in the limitations on its search strategy nor limit the regional boundaries in application of CMH, the included trials were all published in Chinese. Thus, a location bias should not be ignored in the current review. In addition, all yielded articles were indexed from 2008 to 2015, even though no limitation on publication dates was place on the search process. The reason may lie in a naming predicament.

UACS, which has been called rhinogenic cough or laryngeal cough, had not been officially named until 2006. For sake of unity and accuracy of diagnosis, the current review excluded studies in which patients had been diagnosed with rhinogenic cough or laryngeal cough. That exclusion might explain the small number of included trials to some extent.

Inevitably, several other potential limitations in the current study should be addressed. First, as with many systematic reviews, the individual trials varied somewhat in methodology, decreasing comparability between the studies and resulting in a heterogeneity that has been commonly observed in previous systematic reviews for TCM. Therefore, the current research team addressed heterogeneity by presenting stratified results according to the ages of participants and the styles of interventions for comparisons in each trial.

Although it is difficult to realize perfect consistency among trials for herbal medicines, except for patent drugs, some countries33,57 have published monographs that provide guidelines for manufacturing and development of herbal medicines. Therefore, researchers should follow those guidelines to conduct clinical research. Practically, the heterogeneity between the studies was due to 2 main reasons: ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 49

poor reporting and to a lack of clinical homogeneity. With respect to the former reason, most studies had reported without complying with the Consolidated Standards of Reporting Trials (CONSORT) statement58 and the Herbal Interventions Extension, which specifically aim to improve the quality of reporting of RCTs evaluating herbal interventions.59 As far as the latter reason is concerned, significant differences in study designs, such as different drug composition, dosage, and treatment duration, contributed significantly to crucial reasons.

A lack of adequate descriptions of the randomization procedures and allocation methods was common. Although randomization performance was reported in all trials, only 7 of them described details about generation sequence.

Meanwhile, of those 7 specific trials, blinding and allocation concealment were mentioned in only 1 study, which resulted in a doubt with regard to the randomization validity for others.

Second, outcomes assessed in each trial were different.

Consequently, several important outcomes were reported only in a few trials, which limited the ability to pool the results. That limitation reflected the difficulty of combining results from pragmatic randomized trials that examined outcomes based on illness in general practice.60 Broadly speaking, the current research found that lack of important, clinically related outcomes was a major drawback for most studies on chronic cough in the process of screening. Studies frequently paid more attention to curative effect on cough severity, whereas outcomes on the matter of cough duration, cough frequency, cough relapse, and cough-related QoL were relatively not a concern. Further well-designed studies that involve comprehensive clinically related outcomes are required.

In addition, most outcomes reported were short term.

The long-term effects of CMH on patients with UACS were scarcely discussed. As a chronic disease, patients with UACS usually require long-term treatment. Therefore, costeffectiveness with respect to patients’ livelihoods should also be measured. The idea that CMH contributes to savings compared with conventional Western therapy, which has been generally recognized, needs to be confirmed. That idea may provide a starting point for future studies.

Third, because of a relatively small number of eligible trials, insufficient contrasts existed for certain analyses, and some results were imprecise. Therefore, differences in the effects of CMH and WM could not be estimated for some outcomes, and CMH showed no increased safety and tolerability compared with WM in the current review.

to limitations in the study’s design, the results of the current review should be interpreted with caution. Future research of high-quality RCTs is needed to assess the benefits and safety of CMH fully, and the elements of CONSORT guideline should be addressed in the future reports.

ACKNOWLEDGEMENTS The authors thank the Cochrane Collaboration for providing the RevMan 5.3 software that was used for statistical analysis and construction of forest (or CI) plots.

AUTHOR DISCLOSURE STATEMENT No funding was provided by any governmental, public or private agency, or industrial entity for the current review. The research team declares that they have no conflicts of interest.

REFERENCES

CONCLUSIONS Desirable homogeneity was addressed after subgroup stratification, and a meta-analysis was achieved in the current review. The results indicated that CMH or integrated therapy had better effects than WM or a placebo in improving the major clinical symptoms and signs and the cough-related QoL and in reducing the risk of relapse in the treatment of UACS. CMH and integrated therapy represent alternative therapeutic options for those who would rather not try WM. However, due 50 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

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39. Niu YJ. Clinical Research of Traditional Chinese Medicine on Postnasal Drip Syndrome and the Relationship Between PNDs and the Red-cell Immune System [thesis]. Fuzhou, China: Fujian College of Traditional Chinese Medicine; 2009.

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41. Chen H, Cheng Y, Yang LY. Clinical observation of combination of traditional Chinese medicine and Western medicine on postnasal drip syndrome in children. Chin J Integr Tradit West Med. 2009;29(12):1135-1136.

42. Lin CC, Hao RF. Combined TCM and Western conventional medicine treatment for upper airway cough syndrome. Jiangxi Zhong Yi Za Zhi. 2015;46(9):54-55.

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48. Huang CM. An Observation of Treatment of Modified Three Leaf Decoction on Postnasal Drip Syndrome (PNDs) and Chronic Cough. Guangzhou, China: Guangzhou University of Chinese Medicine; 2008.

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52. Chen RL, Yang JC, Wang Z. Clinical effect of traditional prescription under the method of Dispelling Wind and Unblocking obstruction for patients with upper airway cough syndrome. Zhe Jiang Zhong Yi Za Zhi. 2015;50(7):493-494.

53. Chen KG, Xiao B, Zhu KM. Effectiveness of traditional Chinese medicine in treatment of chronic cough induced by upper airway cough syndrome. Jing Yan Jiao Liu. 2014;10:670-671.

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56. Pan WC, Zhao B. Patterns of Traditional Chinese medicine syndrome differentiations for upper airway cough syndrome—a study in 200 patients.

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REVIEW ARTICLE

Electromagnetic Field Devices and Their Effects on Nociception and Peripheral Inflammatory Pain Mechanisms Christina L. Ross, PhD; Thaleia Teli, PhD; Benjamin S. Harrison, PhD

ABSTRACT Context • During cell-communication processes, endogenous and exogenous signaling affects normal and pathological developmental conditions. Exogenous influences, such as extra-low-frequency (ELF) electromagnetic fields (EMFs) have been shown to affect pain and inflammation by modulating G-protein coupling receptors (GPCRs), downregulating cyclooxygenase-2 (Cox-2) activity, and downregulating inflammatory modulators, such as tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) as well as the transcription factor nuclear factor kappa B (NF-κB).

EMF devices could help clinicians who seek an alternative or complementary treatment for relief of patients chronic pain and disability.

Objective • The research team intended to review the literature on the effects of EMFs on inflammatory pain mechanisms.

Design • We used a literature search of articles published in PubMed using the following key words: low-frequency electromagnetic field therapy, inflammatory pain markers, cyclic adenosine monophosphate (cAMP), cyclic guanosine

Christina L. Ross, PhD, is a research fellow at the Wake Forest Institute for Regenerative Medicine (WFIRM) and a research fellow at Wake Forest Center for Integrative Medicine, Wake Forest School of Medicine, in WinstonSalem, North Carolina. Thaleia Teli, PhD, is a research fellow at WFIRM. Benjamin S. Harrison, PhD, is an associate professor at WFIRM. Corresponding author: Christina L. Ross, PhD E-mail address: chrross@wakehealth.edu

I

n humans, electromagnetic-field (EMF) therapy has proven to be a safe, noninvasive, easy-to-use method to treat the site of pain and inflammation.1 Research has shown that therapeutic applications at extra-low-frequency (ELF) levels (ie, 1-100 Hz) of EMF stimulate the immune system by suppressing inflammatory responses at the cell

monophosphate (cGMP), opioid receptors, G-protein coupling receptors, and enzymes.

Setting • The study took place at the Wake Forest School of Medicine in Winston-Salem, NC, USA. Results • The mechanistic pathway most often considered for the biological effects of EMF is the plasma membrane, across which the EMF signal induces a voltage change.

Oscillating EMF exerts forces on free ions that are present on both sides of the plasma membrane and that move across the cell surface through transmembrane proteins.

The ions create a forced intracellular vibration that is responsible for phenomena such as the influx of extracellular calcium (Ca2+) and the binding affinity of calmodulin (CaM), which is the primary transduction pathway to the secondary messengers, cAMP and cGMP, which have been found to influence inflammatory pain.

Conclusions • An emerging body of evidence indicates the existence of a frequency-dependent interaction between the mechanical interventions of EMF and cell signaling along the peripheral inflammatory pain pathway.

(Altern Ther Health Med. 2016;22(3):52-64.)

membrane level.2 Double-blind, placebo-controlled clinical trials have reported that EMF passes through the skin into the body’s conductive tissue,3-5 reducing pain and delaying the onset of edema shortly after trauma.6,7 In a randomized, double-blind, sham-controlled clinical study, low-frequency (LF), pulsed EMF (PEMF) at 0.1 to 64 Hz was reported to improve mobility and decrease pain and fatigue in patients with fibromyalgia (FM).8 Both clinical and in vitro studies have reported that EMF is effective in the treatment of osteoarthritis (OA).9,10 Although many drugs have been used recently for the treatment of OA, the majority of them relieve pain and increase function but do not modify the complex mechanisms that occur in the pathology.11 PEMF has a number of welldocumented physiological effects on cells and tissues, including the expression of the transforming growth factor beta (TGF-β) super family, an increase in the levels of glycosaminoglycan, and an anti-inflammatory action.12 Due

52 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

Ross—Effects of EMF on Inflammatory Pain Mechanisms

to those discoveries, a strong rationale exists for supporting the use of biophysical stimulation with PEMF for the treatment of inflammatory pain that is related to diseases such as OA, FM, and migraine headache. Although the treatment may be a promising therapy, investigators have reported conflicting outcomes, with obvious differences in their measuring techniques. Some studies do not report the frequency and intensity (ie, the field strength) of their treatment device; therefore, it is difficult to compare the parameters being used toward specific outcomes.

For this review, the authors performed a literature search of articles published in PubMed using the following key words: low-frequency electromagnetic field therapy, inflammatory pain markers, cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), opioid receptors, G-protein coupling receptors, and enzymes. The literature search was conducted from October of 2014 to May of 2015.

EMF NOMENCLATURE When discussing cellular influences by either endogenous or exogenous fields, it is important to define the nomenclature. The term EMF is used to summarize the whole field, which includes electric, magnetic, and combined electromagnetic effects.

An electric field (EF) involves a current that can be either direct (DC) or alternating (AC). Units of electrical current are measured in amperes (A), and differences in electrical potential are measured in volts (V). Units of magnetic-flux density (ie, intensity) are measured in either Gauss (G) or Tesla (T), which is 10 000 Gauss.

Faraday’s Law of Induction and Maxwell’s equations explain how an EMF is generated. A static electric field is generated by a static charged particle (q). The electric field or “E” component of an EMF exists whenever a charge (Q) is present. Its strength is measured in volts per meter (V/m) and is expressed as intensity for field strength. An electric field of 1 V/m is represented by a potential difference of 1 volt existing between 2 points that are 1 m apart.

A magnetic field (MF), or the “M” component of an EMF, arises from current flow. The Tesla or Gauss is used mainly to express the flux density or field strength produced by the MF. Both EFs and MFs are generated if a charged particle moves at a constant velocity. Combined, they generate an EMF when the charged particle is accelerated.

Most often, the acceleration takes place in the form of an oscillation; therefore, electric and magnetic fields often oscillate. A change in the EF creates an MF, and any change in the MF creates an EF. That interaction suggests that the higher the frequency of the oscillation is, the more the electric and magnetic fields are mutually coupled.

EMFs can affect biochemical reactions and the behavior of charged molecules near cell membranes. The magnetic aspect can influence cell behavior by (1) exerting a force on moving charge carriers, such as ions; (2) generating electric fields in conductive substances; (3) changing the rate of Ross—Effects of EMF on Inflammatory Pain Mechanisms

diffusion across membranes13; and (4) distorting bond angles, which affects protein-structure binding and, therefore, macromolecule synthesis.14 Unlike EFs, which are shielded by the highly dielectric properties of the cell membrane, magnetic gradients penetrate deeper through layers of living tissue,15 acting directly on cell organelles. Pulsing the EMF causes a rise and fall in ion fluxes, whereby changes in the membrane potential cause an inward current flow, resulting in hyperpolarization of its potential.16 Depending on the parameters involved in the EMF treatment and the biological process in question, either stimulation or inhibition can occur. In contrast to the membrane, the cytoplasm or fluids in extracellular spaces contain no free electrons to carry a charge; the current is carried by charged ions, such as sodium (Na+), potassium (K+), chloride (Cl-), and extracellular calcium (Ca2+).

TYPES OF EMF DEVICES EMF devices exhibit varying parameters that include (1) frequency—the number of cycles per time unit (Hz); (2) amplitude—the intensity or magnetic-field strength; and (3) exposure—the time duration.17,18 The objective of the devices is the production of a uniform EMF to expose cells or tissue to a consistent set of dosing parameters. For therapeutic purposes, the devices include the transcutaneous electrical nerve stimulation (TENS) and transcranial direct current stimulation (tDCS) devices, the solenoid, and the Helmholtz coil (Figure 1).

Figure 1. EMF Devices (A) TENS

(B) Solenoid

Magnetic Field

Wire Coil (C) Helmholtz Coil

Abbreviations: EMF, electromagnetic field; TENS, transcutaneous electrical nerve stimulation.

ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 53

Transcranial Direct Current Stimulation TENS has been used to treat a variety of conditions with battery-generated electric current that stimulates nerves to reduce inflammatory pain. The device is connected to the skin via 2 or more electrodes that modulate pulse width, frequency, and intensity. Although typically used at the site of an injury, it is possible that an application outside the injured site can be effective.

Ainsworth et al have confirmed that hypothesis by showing that application of TENS to the contralateral hind limb of rats reduces the hyperalgesia of an inflamed limb.19,20 The study presented the results for each animal by showing the differences in pressure between the measurements performed on the right hind paw, which had been injected with carrageenan, and those performed on the left hind paw, which had been injected with saline. A reduction in thresholds was interpreted as hyperalgesia; however, it must be taken into consideration that the analgesic effects of TENS might have been stress induced. Greater hyperalgesia stemming from the inflammatory process that had been induced by the carrageenan in the right paw would have required less pressure to provoke the removal of the paw from the algesimeter, thereby leading to a more negative value when comparing the inflamed and noninflamed paw.

Exposure applications in those 2 studies were either (1) an HF of >50 Hz), with an intensity below motor contraction (ie, sensory intensity) or (2) an LF of <10 Hz, with an intensity that produced motor contraction (ie, 20-40 pulses per second).21,22 It is generally thought that TENS produces analgesia by activation of cutaneous afferent fibers at the site of application; however, other reports have shown the importance of deep-tissue afferents in analgesia produced by TENS.23 Various theories have been proposed to explain the analgesic mechanism of TENS. Recent in vivo studies have demonstrated that part of the analgesia is mediated through neurotransmitters acting at peripheral sites. Sabino et al24 have interpreted TENS effects to be mediated by many neurotransmitters, including opioids, serotonin, acetylcholine, norepinephrine, and gamma-aminobutyric acid. In that study, LF but not HF TENS was shown to involve the mu-opioid 5-HT2 and 5-HT3 receptors.

HF but not LF TENS has been reported to involve deltaopioid receptors and to reduce aspartate and glutamate levels in the spinal cord. Santos et al have reported the effects of an LF at 10 Hz and an HF at 130 Hz of TENS on hyperalgesia and edema when applied before serotonin (5-HT) was administered to rats’ paws.25 In that study, both LF and HF TENS were applied to the right paw for 20 minutes, and 5-HT was administered immediately after the TENS. Santos et al used the Hargreaves method26 to measure nociception, and a hydroplethysmometer was used to measure edema. That method measures the level of cutaneous hyperalgesia from thermal stimulation in carrageenaninduced inflammation in rats’ paws, showing greater bioassay sensitivity and providing measurements of other behavioral parameters in addition to paw withdrawal, as well as

supplying a measurement of the nociceptive threshold. In the Santos et al study, neither the LF nor the HF TENS inhibited 5-HT-induced edema; however, the LF TENS, but not the HF, significantly reduced 5-HT-induced hyperalgesia.

Somers and Clemente27 have reported that administration of HF or a combination of HF and LF TENS daily can reduce mechanical, but not thermal, allodynia in the right hind paw of rats with right-sided chronic construction injury (CCI).

Daily HF TENS appeared to elevate the dorsal horn’s synaptosomal content of gamma-aminobutyric acid (GABA) bilaterally, and a combination of HF and LF TENS elevated the dorsal horn’s content of aspartate, glutamate, and glycine bilaterally over that seen in untreated CCI rats.

Fang et al28 have shown in an in vivo study that TENS may be an effective therapy in controlling inflammatory pain by inhibiting the activation of the spinal extracellular signalregulated kinase (ERK) 1/2-cyclooxygenase (COX)-2 pathway. Those researchers induced inflammatory pain in rats using carrageenan. Treatment was applied using TENS at an LF of 2 Hz and an HF of 100 Hz, with intensities ranging from 1 to 2 mA at 5 hours and 24 hours after the injection, with each treatment lasting 30 minutes. Although the outcome related to control of peripheral inflammation was found to be independent of anti-inflammatory activity, the analgesic effects of TENS on the inhibition of the ERK1/2COX-2 pathway was statistically significant at 2 Hz, but not at 100 Hz. Those trials suggest that adequate dosing, particularly the correct frequency, is critical to obtaining pain relief with TENS. Basic scientific studies using animal models of inflammation also report changes in the peripheral nervous system as well as in the spinal cord and descending inhibitory pathway in response to TENS.22 Transcranial Direct Current Stimulation In clinical trials, tDCS devices have also been reported to be effective in the treatment of migraine headache. Those devices look very similar to the TENS device, with electrodes placed on the patient’s forehead. In randomized, doubleblind, controlled study, Rocha et al29 studied 23 adults, 11 with and 12 without an aura, and compared them with 11 healthy patients to test the effects of 12 sessions of tDCS treatment on the visual cortex during a 90-day period. The phosphene threshold (PT) induced by the tDCS was recorded to measure the excitability of the visual cortex before and after each session. The measurements at baseline showed a higher level of cortical excitability in patients with migraines when compared with healthy volunteers. After the tDCS application, a significant decrease was observed in the number of migraine attacks, frequency of painkiller intake, and duration of each attack in the intervention group. PT analysis indicated that no differences existed in cortical excitability after treatment. The clinical improvements of the patients after tDCS treatment were not correlated with changes in cortical excitability.

Laste et al30 has reported that tDCS can induce changes in cortical excitability in rats (N = 18, with 9 in the treatment

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group and 9 in the sham group) and in humans, which lasted beyond the duration of the stimulation. To evaluate the effects of eight 20-minute treatments with tDCS for chronic inflammatory pain, the rats were injected with complete Freund’s adjuvant (CFA) in the right footpad to induce inflammation. Both the intervention and sham groups were exposed to a hot plate; then, Von Frey tests were applied immediately and at 24 hours after the last tDCS session of 500 μA. The results showed significant, lasting, neuroplastic effects related to the analgesic effects of tDCS on a chronicpain model of peripheral inflammation.

To study the analgesic effects of tDCS on postprocedural pain in healthy patients with abdominal pain after endoscopic retrograde cholangiopancreatography (ERCP), a randomized, sham-controlled study was conducted involving 21 patients who were exposed to 20 minutes of 2-mA treatment with tDCS immediately after the ERCP procedure.31 As outcome measures, the study used a visual analog scale, the McGill Pain Questionnaire, and a brief pain inventory and also documented the patient-controlled use of analgesics and adverse events. In the intervention group, 22% less hydromorphone was used by patients versus the sham group.

The tDCS patients also reported significantly less interference with sleep because of pain, with t17 = 3.70 and P = .002, and less throbbing pain as well, with t16 = 2.37 and P = .03. The visual-analog pain scale and mood scores at 4 hours postERCP showed no significant differences, despite hydromorphone use. The side effects of the tDCS treatment were limited to mild tingling, itching, and stinging under the site of the electrode placement.

As to the frequency-specific effects of tDCS, Khadka et al32 tested a range of 3 signals—39 and 76 μA at 1, 10, and 100 Hz—in an in vitro test creating electrode-failure modes. Both the DC and AC components of the voltages across the electrodes were compared, and participants were asked to rate subjective pain. The researchers’ results showed that average voltage and pain scores were not significantly different across the test-current intensities and frequencies.

Solenoids A solenoid consists of a thin loop of coiled wire that produces a uniform MF when an electric current passes through it. The device is used by exposing the painful or inflamed area to the field for a prescribed amount of time.

The EMF produced by solenoids has been used to affect the inflammatory biomarkers that are associated with oxidativestress plasma fibrinogen, nitric oxide (NO), L-citrulline, carbonyl groups, and superoxide dismutase (SOD) in rats with experimental myopathy.

Vignola et al33 have compared an EMF treatment with a sham treatment at a 50-Hz frequency and a 20-mT intensity, for 30 minutes per day per rat. The researchers’ results showed that the EMF decreased the levels of fibrinogen, L-citrulline, NO, SOD, and carbonyl groups, with significant muscle recovery.

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Sanserverino et al34 have reported that a solenoid at 50 Hz, which emitted field intensities between 3 mT and 6 mT, had relieved pain and improved joint mobility with 15 sessions at 15 to 40 minutes daily. Subsequently, an 82% improvement was observed when single-joint disease was considered as compared to a 66% improvement for multiple-joint disease (polyarthrosis). The absence of side effects also proved to be an added benefit. The researchers’ hypothesis for the mechanisms of action included transmembrane ionic activity.

Helmholtz Coils The Helmholtz coil consists of 2 identical, circular, magnetic coils (ie, solenoids), which are placed symmetrically along a common axis, 1 on each side of the experimental area and separated by a distance that is equal to the radius of the coil. Each coil carries an equal amount of electric current flowing in the same direction, producing a uniform MF via Faraday’s law.

Helmholtz coils have been used as the intervention in various studies (eg, animal models of arthritis, cell-culture systems, and clinical trials). In a review of these studies, Ganesan et. al35 indicated that EMF not only alleviated the pain of arthritic conditions, but also afforded chondrocyte protection, exerted anti-inflammatory action, and helped bone remodeling. Although clinical trials have reported beneficial effects with PEMF therapy, Ganesan et. al35 stated the results were not consistent, reporting little evidence was available showing PEMF is more effective than placebo.

Li et al9 have assessed both the beneficial and harmful effects of EMF for the treatment of OA as compared with placebo or sham. Evaluating controlled trials using EMF for OA with 4 or more weeks of treatment duration, the researchers found 9 studies of 636 patients in the Cochrane Database of Systemic Reviews that found EMF treatment provides a moderate benefit for OA sufferers in terms of pain relief. The researchers, however, suggested that further studies are required to confirm whether the treatment can provide clinical benefits in terms of physical function and quality of life.

In 2014, Adravanti et al36 reported as much as one year after total knee arthroplasty (TKA), a significant percentage of 33 patients had not attained complete recovery and indicated the patients’ long-term pain outcomes were unfavorable. Patients were treated 4 hours per day for 60 days and assessed before surgery at 1, 2, and 6 months postopertatively, using international scores. One month after TKA, the pain level of knee swelling and functional scores were significantly better in the treatment group as compared with the control group. Pain was significantly lower in the treatment group at the 6 month follow-up. Three years after surgery, severe pain and occasional walking limitations were reported in a significantly lower number of patients in the treatment group.

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Studies conducted by Qin et al37 have reported that a low-intensity, LF EMF from a Helmholtz coil provided substantial relief to rats with various types of chronic pain that triggered the activity of the thoracic spinal neurons in response to noxious visceral stimuli. In their study, the researchers recorded the T3-T4 spinal neurons in male rats that had been anesthetized with pentobarbital and administered with noxious chemicals producing cardiac stimulation. Noxious esophageal distention was also produced via inflation of a latex balloon. EMF frequencies of <1 Hz and <0.05 μG were applied to both sides of the rats’ chests.

The study’s results showed a 75% decrease in excitatory neuronal responses to intrapericardial chemicals for the intervention group. The inhibitory effect on the spinal neurons occurred at 10 to 20 minutes after EMF application, and the effects continued 1 to 2 hours after termination of the application. Seven of the 18 excitatory-response neurons related to esophageal distention (39%) were inhibited; 5 were excited (28%); and 6 were not affected by the treatment (33%). The authors concluded that application of EMF could reduce the nociceptive responses of the spinal neurons to noxious, cardiac chemical stimuli, whereas the treatment was not effective for nociceptive responses to esophageal mechanical stimulation.

Regarding responses to thermal stimuli in animal studies, Schaible38 exposed rats (n = 24) to EMF using a Helmholtz coil, either sham or frequency-modulated, at 2 mT for 30 minutes on 2 consecutive days. The rats exhibited strong analgesic effects to thermal stimulation applied to footpads immediately after treatment, and up to 30 minutes later. Schaible’s generalized speculations as to the mechanisms of action included an EMF modulation of ion flux.

MECHANISMS AT MOLECULAR LEVEL Tissue trauma, immune reactivity, and nerve injury are frequently associated with an inflammatory pain response.

Within peripherally damaged tissue, such as skin, muscles, joints, and viscera, the primary afferent neurons transduce noxious mechanical, chemical, and/or thermal mechanisms to activate specific receptors and ion channels in peripheral nerve endings.40 Those events result in the initiation of action potentials that propagate along the axons of primary, afferent pain fibers to synaptic sites in the spinal cord’s dorsal horn.

Peripheral sensory neurons express opioid receptors and opioid peptides, and the function of those neurons can be modulated by endogenous opioids derived from immune cells that seek to affect the mechanisms of inflammatory pain and its inhibition.

Peripheral sensitization contributes to the pain hypersensitivity found in inflammation and at the site of tissue damage. Peripheral inflammation in primary sensory neurons consists of changes in their neurochemical character due to alterations in transcription and translation. The electrical activity of primary afferent neurons is primarily governed by the expression and function of ion channels that

define the resting membrane potential, action-potential initiation, depolarization and repolarization, and transmitter release from terminals in the dorsal horn.39 LF EMF passes unobstructed through living tissue40,41 and has been shown to modulate ion flux along the cell membrane, thereby achieving opioid-mediated analgesia.42,43 Because EMF can alter ion flux, it can influence subsequent cellular events in the signal-transduction cascade.44,45 The effects of EMF on pain, nociception, and opiate-mediated analgesia have a number of potential cellular targets that are closely related (ie, Ca2+ ion fluxes, kinases, NO, and GPCRs), establishing a chain of events leading to an increase in analgesic affects.

Although the basic transduction mechanisms of EMF are still being investigated, a substantial body of theoretical work has focused on ion/ligand binding as a possible factor for the biomechanical interaction of exogenous EMF with the cell membrane. The application of any mechanical stimulus, such as fluid-shear stress or exogenously applied EMF, to the cell surface can activate mechanically sensitive ion channels, G-protein kinases, and other membraneassociated signal-transduction molecules, which trigger downstream signaling cascades that can lead to forcedependent changes in gene expression.46 It is now known that mechanical action at a distance occurs in living cells,47-50 and that a unique form of mechanical signaling provides a more rapid and efficient way to convey information over long distances during cell communication than does diffusion-based chemical signaling.

Panagopoulos et al proposed a simple hypothesis that an oscillating, external EMF can exert an oscillating force on each of the free ions that exist on both sides of the plasma membrane and that the force can move across the membrane via transmembrane proteins.51 The researchers have theorized that the external oscillating force can produce a forced vibration on each free ion, and when the amplitude of the ions’ force-vibration transcends some critical value, the oscillating ions can give a false signal to gating channels that are electrically sensitive, or even mechanically sensitive, thereby interrupting the electrochemical balance of the membrane and, therefore, of the entire cell function (Figure 2).

The types of channels include (1) voltage-gated channels (ie, voltage-sensitive channels); (2) mechanically gated channels (ie, channels gated by ion pressure); and (3) ligandgated channels (ie, chemically sensitive channels).52 Mechanical stimulation of the channels may help to explain how mitochondria located far from the cell surface can sense and respond to mechanical stressors by releasing reactive oxygen species (ROS) and activating signaling molecules, such as the GPCRs, that contribute to pain as well as nuclear factor kappa Β (NF-κΒ), a transcription factor that contributes to the inflammatory response.53 Voltage-dependent Ca2+ channels play a significant role in the cell-differentiation process by triggering intracellular events, such as the activation of enzymes that catalyze modulators of inflammatory pain.54,55

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Figure 2. Hypothesis for Mechanism of EMF (A) (B) Polarized Membrane

Ca2+ Ions EMF

Depolarized Membrane

Nonconductive Medium = ~3 nm Insulating Membrane Ca2+ Ions Note: The figure shows (A) a voltage-gated ion channel that controls intra- and extracellular ion flux due to a positive surface charge, prior to application of EMF; and (B) a voltage-gated ion channel that can attenuate the opening and closing of the ion channels, after application of EF or EMF, to trigger intracellular events due to a negative charge (-Q) that depolarizes the plasma membrane.

Abbreviations: electromagnetic field (EMF); EF, electric field.

One common theme in those studies is the biomechanics of Ca2+ and its ability to alter the cell membrane to play a significant role in the effects that EMF has on inflammatory pain mechanisms.56 For an effect to occur in ligand-gated ion channels, the interacting system must contain a Ca2+ molecular structure.57 For the EMF activation of the opioid receptors against inflammation of peripheral tissue, for the increased functionality of opioid receptors on peripheral sensory neurons, and for the local production of endogenous opioid peptides that have been observed in lymphocytes, Ca2+ appears to be the principal cellular component affected by the EMF exposure.58 And the Ca2+/calmodulin (CaM)dependent signaling to intracellular enzyme systems appears to act specifically as a primary transduction mechanism for EMF treatment. As for cytokines and chemokines, the NO activation of voltage-sensitive Ca2+ channels responds to EMF exposure through Ca2+/CaM stimulation of NO synthesis. Beneficial responses may be largely a result of the stimulation of the NO-cGMP-protein-kinase-G pathway.59 It has been reported that opiates induce analgesia by diminishing the cellular-Ca2+ flux,60,61 and EMF has the capability to reduce that flux to induce the same effect.42,62 It has also been documented that Ca2+ channel blockers can potentiate the effects of opiates by diminishing the inward Ca2+ flux, and that action has been reported to occur in snails and mice exposed to EMF.63,64 The Ca2+ channel agonists have been investigated, with the researchers observing the attenuating effects of opiates through enhancement of the inward Ca2+ flux and potentiation of the effects of EMF.58,65,66 The mechanisms through which the EMF exchanges information between cells and the ways in which the conversion of that biomechanical signaling is translated have been researched for decades. It has been reported that EMF can permeate both the plasma and nuclear membranes of cells, thereby affecting different types of tissues.67-69 The concept that the extended membrane regions may be sensitive to EMF was first proposed by Adey in 1974.70 Liboff has suggested that the Rossâ&#x20AC;&#x201D;Effects of EMF on Inflammatory Pain Mechanisms

transport of calcium ions through channels of the cell membrane involves a resonance-type response to the applied EMF, which is the mechanism that activates ion flux, receptors, kinases, and even transcription factors.71 Ursu et al72 found a strong correlation between the kinetics of calcium flux and transient receptor potential vanilloid 1 (TRPV1), the ligand-gated ion channel expressed predominantly in nociceptive primary afferents that plays a key role in pain processing. In that study, current-clamp recordings were performed in the neurons of ratsâ&#x20AC;&#x2122; dorsal root ganglia (DRG) to assess the consequences of TRPV1 activation on neuronal excitability. The researchers reported that the Ca2+ ion flux and the TRPV1 influenced the trigger-of-action potentials in sensory neurons. Due to that phenomenon, the electrical-potential gradient that exists across the cells exposed to the EMF can increase the activation of voltage-gated, Ca2+ ion channels on either side of the cell membrane, giving rise to a gradient of intracellular Ca2+ that alters cell morphology.

That effect modulates the changes by intracellular actin filaments in levels of cytosolic calcium73 and also produces a significant decrease in the production of cyclic adenosine triphosphate (ATP), which is a known master regulator of the functioning of innate immune cells and of the generation of inflammatory mediators.74,75 EFFECTS OF EMF Effects on Ion-ligand Binding Another focus of EMF biomechanics involves the ligandgated ion channels, which are a group of transmembrane, ion-channel proteins that open to allow ions such a Ca2+, Na+, Cl-, and K+ to pass through the cell membrane in response to the binding of an electrical or chemical messenger.76-80 Ion fluxes such as those moving through voltage-gated sodium and calcium channels are widely used to treat inflammatory pain. In particular, voltage-gated calcium channels (VGCCs) are the main source of depolarization-induced calcium entry into neurons.81 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 57

Primary afferent neurons express multiple types of VGCCs, with specific, subcellular, expression patterns and functions. Those channels are clinically validated drug targets for pain, and their roles in pain transmission have been extensively reviewed.82 On peripheral nociceptors, they are critical for nociceptive transmission beyond the peripheral transducers and are responsive to exogenous stimuli, such as waveform patterns emitted by EMFs.83 Although ion channels have a pervasive distribution, recent studies have identified a number of channels, in particular those of sodium and calcium, that appear to have a more selective role in nociception.84 Many cationic channels are responsible for the excitation of sensory neurons, and the activation of those channels in sensory neurons is critical to the generation of nociceptive signals. The main channels responsible for inward membrane currents in nociceptors are voltage-activated sodium and calcium channels, whereas outward current is carried mainly by potassium ions.85 In addition, the activation of nonselective cation channels is also responsible for the excitation of sensory neurons. Thus, the excitability of neurons can be controlled by regulating the expression of or by modulating the activity of those channels.

It is well known that large numbers of free ions, such as Ca2+, Na+, and K+, reside on both sides of every cell membrane and play an important role in signal transduction. Ion fluxes through cell membranes are elucidated by the ion concentration and voltage gradients between the 2 sides of the membrane.

Those ion fluxes affect primary afferent nociceptors that are the initial part of the pain pathway86,87 and the accumulation of ions creates an intense electric field on either side.18 Radhakrishnan and Sluka88 investigated cutaneous vs knee-joint afferents and the antihyperalgesia that was produced

by TENS. The research showed differentially blocked, primary afferents on use of local anesthetics. In the study, hyperalgesia was induced by kaolin-carrageenan and assessed by measuring a rat’s paw-withdrawal latency to heat. Both HF and LF TENS were applied. Control experiments were conducted using vehicles. Both frequencies completely reversed hyperalgesia, and an injection of lidocaine into the knee joint prevented the antihyperalgesia that would have been produced by the HF or LF TENS. Application of an anesthetic cream was shown to reduce the amplitude of the cord-dorsum potential by 40% to 70% for both HF and LF TENS, confirming the loss of largediameter, primary-afferent input. Therefore, the activation of joint afferents, but not cutaneous afferents, prevented the antihyperalgesia effects of the TENS. The researchers concluded that large-diameter primary-afferent fibers from deep tissue are required and that activation of cutaneous afferents is not sufficient for TENS-induced antihyperalgesia.

Effects on G-protein Coupled Receptors EMF has also been reported to affect inflammatory pain by modulating GPCRs, which are 7-transmembrane domain receptors that sense molecules outside the cell and activate inside signal-transduction pathways.89 When the molecules bind to a GPCR, that action is followed by a series of conformational

changes in the activated receptors, which are capable of signaling to downstream molecules. When it comes to the peripheral-pain pathway, inflammatory cells, such as polymorphonuclear leukocytes (PMN), monocytes, and macrophages, express a large number of GPCRs for chemoattractants and chemokines.90 GPCRs are critical to the migration of those phagocytes and their accumulation at sites of inflammation, where they not only can exacerbate inflammation but also can contribute to its resolution.

It has been hypothesized that the activation of GPCRs is affected by voltage,91,92 due to reports that nonactivated GPCRs do not appear to show any voltage-dependent activity.93 That effect is in line with the hypothesis that the binding of a charged agonist within an EMF that is present on a cell membrane, is a major mechanism for the voltage dependence of GPCR activation, indicating a definite voltage-dependent activation of GPCRs at the receptor level. The existence of voltage gradients on the cell surface and the ways in which the gradients respond to EMF is of great importance to inflammatory pain mechanisms.

Because endogenous EFs are generated by polarized ion transport and conductive extracellular pathways, polarized ion transport, which leads to the movement of a charge, can create electrical-potential differences across immune cells.93 In that process, the ion transport is dependent on the amount of energy per unit of charge that is needed to move the ion across the membrane. That amount is a measure of voltage potential.

Voltage potentials, such as those measured on lymphocyte membranes, can reach +50 mV,94 due to the net positive charge coming out of the cell by ions such as Na+, K+, and Ca2+.

The idea that the immune system can communicate with peripheral sensory neurons to modulate pain is based mainly on reported interactions between opioid receptors and their environments.95-97 One of the main aspects of inflammatory pain pathways is the presence of opioid receptors that are expressed on peripheral sensory nerve endings, cutaneous cells, and immune cells, such as granulocytes, monocytes, macrophages, and lymphocytes. During an inflammatory response, those cells can produce the opioid peptides of 3 different receptors (ie, μ, δ, and к), which on activation, can cause the dissociation of the GPCR subunits that inhibit cyclic adenosine monophosphate (cAMP) production and/or can interact with a membrane’s ion channels.98,99 Inflammation of peripheral tissue leads to the increased functionality of opioid receptors on peripheral sensory neurons and to local production of endogenous opioid peptides. Opioid receptors are widely expressed in the central and peripheral nervous systems as well as in numerous nonneuronal tissues. Both animal models and human clinical data support the involvement of peripheral opioid receptors in analgesia, particularly in inflammation, where both the opioid-receptor expression and efficacy are increased.100 EMF has been reported to reduce hyperalgesia and pain through the release of endogenous opioids into the central nervous system (CNS)101-106; specifically, LF EMF at <10 Hz can activate mu-opioid receptors, and HF at >50 Hz can activate delta-opioid receptors in the spinal and rostral ventral medulla (RVM).107

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Different frequencies used under the same conditions affect different opioid receptors. Experimental evidence has shown that using the same time exposure and field strength of EMF at ELFs <100 Hz, such as 4 Hz, will cause a spinal blockade of mu-opioid receptors, preventing hyperalgesia, while the same parameters used for EMF exposure at 100 Hz will prevent hyperalgesia in delta-opioid receptors but not in mu-opioid receptors.106,108 That frequency-dependent effect has been reported at 60 Hz and 141 μT, with a 15-minute exposure, in both mice109 and land snails.110 A 2-hour exposure of EMF at 1 Hz and a 20- to 27-μT field strength decreased the mu-opioid receptors concentration in the brain of pigeons,111 with similar outcomes at 50 Hz and 100 μT for 8 hours in rats.112 Studies have shown that exposure to a LF TENS device produces endogenous opioids in both humans113 and rats.114 According to the investigators in those studies, the activation of both the mu-opioid receptors and delta-opioid receptors induced a reduction of hyperalgesia and pain. It is important to note that animal studies tend to rely on reflex-based pain assessments, which are increasingly recognized as being a poor model of the pain experienced in humans compared to operant assays.115 That statement is especially true in studies pertaining to the effects of EMF on pain sensation in land snails.

Effects on Cytokines and Chemokines Cytokines and chemokines are the mediators of inflammation from within minutes to hours after injury during the activation of inflammatory pain. They serve as signals to engulf damaged tissue, destroy infectious agents, and clear the wound bed for healing.116 Damaged cells respond by activating stress-signaling pathways which produce trauma-associated molecular patterns that activate cue and chemotactic factors for other immune cells in the area.117,118 The mechanistic effects of EMF on protein molecules focus on the effects of gradients dependent on ion flux on cytokines, such as tumor necrosis factor alpha (TNFα), interleukin 1 (IL-1), and interleukin 6 (IL-6), and chemokines, such as interleukin 8 (IL-8) and regulated on activation, normal T-cell expressed and secreted (RANTES).

In vitro studies have demonstrated the effects of EMF on NF-κΒ, a downstream signal-transduction molecule,119 whereby researchers have reported that results can depend on frequency, indicating that 8-μL/mL concentrations of lipopolysaccharide (LPS)-challenged macrophages exposed to EMF with a Helmholtz coil emitted at a range of frequencies between 0 and 30 Hz. Those results showed a significant downregulation of both TNF-α and NF-κΒ at 5 Hz but not at 10, 15, 25, or 30 Hz.120 A selective inhibition of NF-kB by ELF EMF may also be involved in the decrease of chemokine production as reported

by Vianale et al,121 where the ELF-EMF exposure modulated NF-kB activation as well as the proinflammatory cytokines TNF-α and interleukin 1 beta (IL-1Β), growth factors, and viruses known to cause infections.

In OA fibroblasts in the presence of EMF under 24-hour exposure at 75 Hz and 1.5 mT, other investigators have reported that adenosine receptors downregulated the Ross—Effects of EMF on Inflammatory Pain Mechanisms

proinflammatory cytokine IL-6 and the chemokine IL-8 while stimulating the release of interleukin 10 (IL-10), an anti-inflammatory cytokine.122 At 50 Hz and 2.5 mT, EMF exposure was reported to increase IL-1β in mouse macrophages that had been activated with LPS after 24 hours but to decrease IL-1β in human fibroblasts when using the same parameters. Under those same conditions, EMF decreased IL-6 in LPS-activated human fibroblasts, and TNF-α decreased when the researchers used the same 50 Hz with a 2.5 mT field on human fibroblasts activated with LPS. Other in vitro studies have shown that human keratinocytes decrease IL-8 at an exposure to an EMF of 50 Hz and 1 mT for 4 hours, although they also have been shown to decrease RANTES in the same cell line under the same conditions.123 Mouse macrophages stimulated with LPS and exposed to a time-varying EMF at 30 Hz and 400 Gauss, were also reported to downregulate IL-6 and TNF-D after a 1-hour exposure.124 A range of EMF frequencies between 0 and 100 Hz appear to affect various proteins in inflammatory processes when studied in vitro.

In vivo studies have reported that a 27.12-MHz radio frequency emitted from a solenoid device, with 3-ms bursts repeating at 2 Hz, can suppress significantly the proinflammatory cytokine IL-1β, an early responder to injury in rats with traumatic brain injury.125 That same frequency has also been reported to cause a significant reduction in IL-1β cytokines in wound exudate of human patients who had been exposed to EMF for 20-minute treatments every 4 hours for the first 3 days postoperatively and then every 8 hours for the next 3 days.60,61 EMF modulation of both cytokines and chemokines may contribute to an increase in the NO that is involved in the regulation of inflammatory pain modulators, such as CaM, which in turn leads to the activation of endothelial NO synthase (eNOS), increasing NO, and, thereby, modulating cytokine expression through adenosine receptors and an early decrease in the activity of NF-κΒ.

Effects on Enzymes COX enzymes control the initial steps of the inflammation process.126 Among the proteins mediating that effect are dynorphin, an endogenous opioid that increases neuronal excitability, and COX-2, the enzyme that produces prostaglandin E2 (PGE2). PGE2 is a known lipid mediator that contributes to inflammatory pain.127 PGE2 increases the phosphorylation of NO production through the activation of cAMP-dependent protein kinase A (PKA).

In vitro studies have shown that adenosine receptors modulate PGE2 in OA fibroblasts after 24 hours of exposure to EMF at 75 Hz and 1.5 mT.122 EMF at 15 Hz and 0.6 mT for 72 hours has also been shown to affect that same analgesic process by acting on PGE2 and PKA, initiating the release of NO from osteoblasts and, thereby, increasing NO synthesis.128 NO appears early in biochemical cascades that are involved in the inflammatory phase of tissue repair and has been reported to be involved in the mechanism by which EMF devices achieve pain relief.129 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 59

At 15 Hz and 0.6 mT, no significant differences have been reported between unstimulated human monocytes that either had been exposed or had not been exposed to EMF; however, inducible NO synthase (iNOS) activity was significantly reduced in LPS-stimulated human monocytes that had been exposed to EMF at 15 Hz when compared to LPS-stimulated cells that had not been exposed. That reduced enzyme activity has been reported to be related to the reduction of iNOS mRNA and immunoreactive iNOS proteins that has been observed in rats induced with experimental myopathy.33 Evidence linking EMF exposure to protein kinase C (PKC) activity and analgesia provides an example of calcium-activated, phospholipid-dependent PKC that plays an important role in relaying transmembrane signaling inside diverse, calciumdependent, cellular processes during an inflammatory pain response.130-132 Although the activation of endorphins is a recurring theme in the process, compelling evidence has indicated that EMFs can modulate opioid gene expression.

Ventura et al133 found that the expression of opioid genes was significantly increased following the exposure of myocardial PKC inhibitors that suppressed the transcriptional effects of cells exposed to an EMF at 50 Hz and 1.74 mT. The researchers found that EMF-enhanced, myocardial, opioid gene expression and a direct exposure of isolated myocyte nuclei to EMF markedly enhanced prodynorphin gene transcription in the intact cell. That EMF action was mediated by nuclear PKC activation but occurred independently from changes in PKC-isozyme expression and enzyme translocation, suggesting the involvement of a nuclear endorphinergic system in the regulation of gene transcription.

DISCUSSION EMF, when used to affect inflammatory pain, has been shown to produce noninvasive outcomes while involving the application of different frequencies, field strengths (intensities), and time points that can affect nociception and analgesia.134,135 Several parameters, including the doses, frequencies, and phases of EMF devices are decisive as to whether or not the cells respond, and if they do respond, in what manner. For use of a TENS device, an application at 4 Hz and 10 to 18 mA for 20 minutes appears to activate the mu-opioid receptor best, whereas an application at 100 Hz and 10 to 18 mA for 20 minutes appears to activate the deltaopioid receptors. Thermal analgesic affects have been reported for applications at 20 Hz and 0.03 μT for 30 minutes in rats; however, a debate still exists as to whether the analgesic affect was stress induced.

Because various parameters of frequency, intensity, and time of exposure are used for humans, animals, and cells, the consistency of outcomes is difficult to ascertain. For example, in a human keratinocyte model, Patruno et al have reported a healing effect that is related to the effects on enzymes of an EMF using an ELF of <100 Hz,136 and McKay et al have reported that the EMF waveform is what generates the effects. On the other hand, Kalra et al and Fleming et al have

suggested that the effects occur in the opioid receptors when using a 4 Hz or a 1 μT field, respectively.43,137 What Fleming does not explain is how an EMF would affect the receptor.

Table 1 identifies the different EMF frequencies, field strengths, and exposure times and how the proposed mechanisms along the peripheral inflammatory pain pathways are affected.

As shown in Table 1, the parameters of time and frequency can remain constant, but a change in field strength will elicit a different outcome. Martin et al has reported that the thermal analgesic effects were amplitude-(intensity-) dependent in producing analgesia more quickly in male rats.135 In that study, solenoids were used to emit an EMF, with burst-firing configurations at once every 4 seconds for 30 minutes. Using a maximum strength of exposure at 0.25 μT, the researchers reported an analgesic response that was significantly greater than the normal sham-field responses, whereas the exposure at 0.30 μT did not produce responses that differed significantly from the sham; the standard error of the mean (SEM) for sham exposure was 2.2 and for EMF exposure was 0.4.135 Fleming et al138 reported that the whole-body exposure of rats to a burst-firing EMF with intensities of 1 μT once every 4 seconds for 20 minutes, displayed the minimum intensity of stimulation needed to trigger the signal from the axon to the spinal cord. When the electric current was delivered to the rats’ footpads, its analgesic effect was still apparent at 20 minutes after the removal of EMF and was equivalent to the analgesia produced by 4 mg/kg of morphine.

Kalra et al106 reported that hyperalgesia and pain were attenuated in rats using 100 ms of exposure with a 10- to 18-mA field strength for 20 minutes; at 4 Hz, the outcome was due to the activation of the mu-opioid receptor, and at 100 Hz, the EMF activated the delta-opioid receptor.

The time of exposure appears to make a difference in the outcome, as shown by Kavaliers et al,63 who reported for snails that an application of EMF at 60 Hz and 100 μT altered the Ca2+ flux, and the channels associated with opioid receptors were dependent on the time of exposure. A significant reduction in the analgesic effects of mu- and kappa-opioid agonists occurred at 2 hours and 12 hours, but at 48 to 120 hours showed no more effects than the 12-hour application, and the 0.5-hour exposure had similar outcome to that of the controls.

Patruno et al139 reported that EMF at a 50-Hz frequency and a 1-mT field strength, with overnight exposure, enhanced the re-epithelialization of keratinocytes by decreasing the COX-2 expression and the downstream, intermediate PGE2 in vitro.

In conditions such as OA, controlling chondrocyte degradation and inflammation is currently the most important target. Some evidence has shown that PEMF can counteract late-stage OA progression at 2 different frequencies, 37 Hz and 75 Hz, in 21-month-old guinea pigs. After 3 months of stimulation with EMF for 6 hours per day, both histological and

60 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

Ross—Effects of EMF on Inflammatory Pain Mechanisms

Table 1. Conditions, Treatment Parameters, Mechanisms of Action, and Results Inflammatory Pain Condition Inflamed kneejoint pain54

Hz 4

Field Time Strengths Courses 100 ms 20 min 10-18 mA

Molecular Mechanisms Activation of mu-opioid receptor was frequencydependent.

Activation of delta-opioid receptor was frequency dependent.

Analgesic effects were EMF intensity dependent.

Inflamed kneejoint pain54

100

100 ms 10-18 mA

20 min

Thermal analgesic effects73

20

0.03, 0.3, 3 μT

30 min

Effect on endogenous opioid systems in burns56

60

100 μT

30 min, 2 h, Alterations in the Ca2+ flux and 12 h, 48 h, channels associated with opioid 120 h receptors were time-dependent.

Effect on endogenous opioid systems in burns130

60

100 μT

30 min, 1 h, Alterations in the Ca2+ flux and 2h channels associated with opioid receptors were time-dependent.

Outcomes The treatment produced antihyperalgesia by activation of mu-opioid receptors in the rostral ventral medulla of rats.

The treatment produced antihyperalgesia by activation of delta-opioid receptors in the rostral ventral medulla of rats.

The 0.03-μT field strength exhibited an analgesic response (rat-paw reflex) that was significantly greater than that of the sham treatment.

The treatment produced a significantly attenuated, morphine-induced analgesia and reduced basal nociceptive responses in snails via the reduced analgesic effects of the mu- and kappa-opiate agonists. The 0.5-h time course showed no significant effects. The 2-h and 12-h time courses showed significant effects. The 48-h and 120-h time courses showed effects that were more significant than the 12-h course.

The 2-h time course had greater inhibitory effect than the 0.5-h course, with the 1-h course having an intermediate effect in land snails for aversive thermal (nociceptive) responses and morphine-induced analgesia.

Abbreviation: EMF, electromagnetic field. histomorphometric analyses of the guinea pigs’ knees were performed. In comparison to the nontreated sham group, at both frequencies the EMF significantly reduced (1) the histological cartilage score, which measures the severity of cartilage pathology140; (2) the Fibrillation index (FI), which measures the pathological characteristic of fibrillation in OA; (3) the subchondral bone thickness, which reflects the fact that the damage in the cartilage matrix increases as the load duration increases; and (3) the trabecular numbers. The EMF also increased the trabecular thickness and separation (trabecular spacing), which basic bone research has shown are key measures characterizing the 3-dimensional structure of cancellous bone.141 EMF at 75 Hz produced significantly more beneficial effects on the histological score and the FI than did EMF at 37 Hz. At 75 Hz, EMF counteracted cartilage thinning, as demonstrated by significantly higher cartilage thickness values than either the sham or the group treated at 37 Hz. In cases of severe OA, both EMF frequencies were able to limit OA progression, but the 75-Hz stimulation achieved better results.

During clinical trials, certain frequencies and field strengths have produced different outcomes depending on the condition. In a randomized, double-blind, shamcontrolled clinical trial, a total of 50 patients with either chronic generalized pain from FM or chronic localized musculoskeletal or inflammatory pain were exposed to extremely weak pulses of EMF at 400 μT and 1000 Hz or less for 800 mT per second, using a portable solenoid device that fitted to patients’ heads during the twice-daily, 40-minute treatments for 7 days.142 The outcomes were recorded using a visual analog scale. A differential effect of EMF over sham Ross—Effects of EMF on Inflammatory Pain Mechanisms

treatment was noted in patients with FM that approached statistical significance at P = .06 for n = 17 but was not evident in those treated who did not have FM (ie, had musculoskeletal or inflammatory pain), P = .93 for n = 15.

In a double-blind, placebo-controlled clinical trial, 22 patients were assigned to treatment (n = 28) or sham (n = 26) groups to test the analgesic and antinociceptive effects of lowintensity (ie, 8 Hz) EMF on FM patients.143 Pressure pain thresholds before and after treatment were determined using an algometer during the 8 consecutive, weekly sessions. Also, blood serotonin levels were measured and patients completed questionnaires to monitor symptoms. Repeated-measures analysis of variance (ANOVA) indicated a statistically significant improvement in the treatment group compared with the controls with respect to somatosensory pain thresholds, ability to perform daily activities, perceived chronic pain, and sleep quality. Although improvement in pain thresholds was apparent after the first session, improvement in the other 3 measures occurred after week 6 of treatment. No significant differences were reported in depression, fatigue, severity of headaches, or serotonin levels, and no adverse side effects were reported. EMF is usually more effective at less than 3 mT, with frequencies lower than 100 Hz. Various research studies have given different outcomes, either beneficial or with no effects, due to a lack of standardization in the dosing parameters. Although most therapeutic dosages are <100 Hz and in the micro- and milliTesla and Ampere ranges, times of exposure have varied greatly. If the mechanism of action does indeed occur at the plasma membrane, and as is suggested by many investigators, ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 61

if it is driven by ion flux, then hours of exposure would not be necessary to obtain results. Ion diffusion and transport occur in seconds to minutes57; therefore, fewer sessions of shorter periods would prove to be far more beneficial than 1 or 2 sessions of long duration.

Of high importance is the lack of standardized nomenclature and experimental protocols when it comes to running trials. Like pharmaceuticals, where dosages vary from patient to patient, EMF treatments also are dose and tissue dependent.144-146 It has been suggested that the following dosing parameters should be required for all practitioners using EMF therapies147: (1) the type of tissue that the EMF is targeting; (2) the specific site of EMF application; (3) the distance between the EMF field and tissue; (4) the frequency of the EMF field; (5) the EMF field strength; (6) the exact composition of the EMF device; and (7) the exact time of exposure. Otherwise, it is difficult to compare results.

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CONCLUSION When it comes to modulating inflammatory pain mechanisms, numerous experimental findings have reported that EMF affects cell function through mechanical action on both the intracellular and plasma membrane levels, which includes ion channels, receptors, cytokines, and enzymes. Various EMF dosing parameters—frequency, intensity and duration of exposure—all contribute to different outcomes; however, frequencies of less than 100 Hz and intensities in the mT or mA range are reported to be most effective in the downregulation of peripheral inflammatory pain modulators.

From a clinical standpoint, the tDCS device appears to be the most beneficial for migraine headache, using dosing parameters of 100 Hz or less and intensities of 1 mA or less for twelve 90-minute sessions. For postprocedural abdominal pain in patients after endoscopy, treatment with a tDCS device set at 0.2 mA for 20 minutes is reported to be most beneficial. In conditions such as OA, controlling chondrocyte degradation and inflammation is optimized at 75 Hz and a 1.5-mT field strength, with treatment for 15 minutes twice daily for up to 42 days. The same parameters have been shown to be beneficial after arthroplasty. For FM, treatment at 8 Hz and 1 mA is reported to be beneficial if applied for 40 minutes twice daily for 7 days.

Although a multitude of research articles investigating the effects of EMF on inflammatory pain mechanisms exist, the methods for gathering the data have included an overwhelming array of experimental models, EMF devices, waveforms, and clinical applications. Therefore, a consensus of standardized methods for experimentation is greatly needed to determine which responses directly result from the EMF exposure. Because various parameters of treatment produce similar results, a report cross-referencing the frequencies, field strengths, and times of exposure of EMF treatments on inflammatory responses would be beneficial to both researchers and clinicians working in the field.

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110. Prato F, Kavaliers M, Thomas A, Ossenkopp KP. Modulatory actions of light on the behavioral responses to magnetic fields by land snails probably occur at the magnetic field detection stage. Proceed Royal Soc London. 1998;B265:367-373.

111. Papi F, Luschi P, Limonta P. Orientation disturbing magnetic treatment affects the pigeon opioid system. J Experim Biol. 1992;166:169-179.

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114. Sluka K, Deacon M, Stibal A, Strissel S, Terpstra A. Spinal blockade of opioi receptors prevents the analgesia produced by TENS in arthritic rats. J Pharmacol Exp Ther. 1999;289:840-846.

115. Olesen A, Andresen T, Staahl C, Drewes AM. Human experimental pain models for assessing the therapeutic efficacy of analgesic drugs. Pharmacol Rev. 2012;64(3):722-779.

116. Callaghan M, Chang E, Seiser N, et al. Pulsed electromagnetic fields acclerate normal and diabetic wound healing by increasing endogenous FGF-2 release.

Plast Reconstr Surg. 2007;121(1):130-141.

117. Yano S, Komine M, Fujimoto M, Okochi H, Tamaki K. Mechanical stretching in vitro regulates signal transduction pathways and cellular proliferation in human epidermal keratinocytes. J Invest Dermatol. 2004;122:783-790.

118. Bianchi M. DAMPs, PAMPs and alarmins: All we need to know about danger. J Leukoc Biol. 2007;81:1-5.

119. Vinale G, Reale M, Amerio P, Stefanachi M, DiLuzio S, Muraro R. Extremely low frequency electromagnetic field enhances human keratinocyte cell growth and decreases proinflammatory chemokine production. British J Dermatol.

2008;158:1189-1196.

120. Ross C, Harrison BS. Effect of pulsed electromagnetic field on inflammatory pathway markers in RAW 264.7 murine macrophages. J Inflamm Res. 2013;6:45-51.

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121. Vianale G, Reale M, Amerio P, Stefanachi M, Di Luzio S, Muraro R. Extremely low frequency electromagnetic field enhances human keratinocyte cell growth and decreases proinflammatory chemokine production. Br J Dermatol.

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122. Ongaro A, Varani K, Masieri FF, et al. Electromagnetic fields (EMFs) and adenosine receptors modulate prostaglandin E(2) and cytokine release in human osteoarthritic synovial fibroblasts. J Cell Physiol. 2012;227(6):2461-2469.

123. Pesce M, Patruno A, Speranza L, Reale M. Extremely low frequency electromagnetic field and wound healing: Implication of cytokines as biological mediator. Eur Cytokine Netw. 2013;24(1):1-10.

124. Ross C, Harrison BS. Effect of time-varied magnetic field on inflammatory response in macrophage cell line RAW 264.7. Electromagn Biol Med. 2013;32(1):59-69.

125. Rasouli J, Lekhraj R, White N, et al. Attenuation of interleukin-1beta by pulsed electromagnetic fields after traumatic brain injury. Neurosci Lett. 2012;519:4-8.

126. Nandakishore R, Ravikiran Y, Rajapranathi M. Selective cyclooxygenase inhibitors: Current status. Curr Drug Discov Technol. 2014;11(2):127-132.

127. Norberg J, Sells E, Chang HH, Alla SR, Zhang S, Meuillet EJ. Targeting inflammation: Multiple innovative ways to reduce prostaglandin E2. Pharm Pat Anal. 2013;2(2):265-288.

128. Diniz P, Soejima K, Ito G. Nitric oxide mediates the effects of pulsed electromagnetic field stimulation on osteoblast proliferation and differentiation.

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129. Cheng J, Zhang C, Han JS. TENS stimulates constitutive nitric oxide release via opiate signaling in invertebrate neural tissues. Med Sci Monit. 2007;13:163-167.

130. Adey W. Joint actions of environmental non-ionizing electromagentic fields and chemical pollution in cancer promotion. Environ Health Perspect. 1990;86:297-305.

131. Carson J, Prato FS, Prost DJ, Diesbourg LD, Dixon SJ. Time-varying magnetic field increase cytosolic free Ca2+ in HL60 cells. Am J Physiol.

1990;28:C686-C692.

132. Wolsko P, Eisenberg DM, Simon LS, et al. Double-blind placebo-controlled trial of static magnets for the treatment of osteoarthritis of the knee: Results of a pilot study. Altern Ther Health Med. 2004;10:36-43.

133. Ventura C, Maioli M, Pintus G, Gottardi G, Bersani F. Elf-pulsed magnetic fields modulate opioid peptide gene expression in myocardial cells. Cardiovasc Res. 2000;45:1054-1064.

134. Del Seppia C, Ghione S, Luschi P, Ossenkopp KP, Choeris E, Kavaliers M. Pain perception and electromagnetic fields. Neurosci Biobehav Rev. 2007;31(4):619-642.

135. Martin L, Koren SA, Persinger MA. Thermal analgesic effects from weak, complex magnetic fields and pharmacological interaction. Pharmacol Biochem Behav. 2004;78(2):217-227.

136. Patruno A, Amerio P, Pesce M, et al. Extremely low frequency electromagnetic fields modulate expression of inducible nitric oxide synthase, endothelial nitric oxide synthase and cyclooxygenase-2 in the human keratinocyte cell line HaCat: Potential therapeutic effects in wound healing. Br J Dermatol. 2010;162(2):258-266.

137. Fleming J, Persings MA, Koren SA. Magnetic pulses elevate nocicieptive thresholds: Comparison with opiate receptor compounds in normal and seizureinduced brain-damaged rats. Electro-Magnetobiol. 1994;13:67-75.

138. Fleming J, Persinger MA, Koren SA. Magnetic pulses elevate nociceptive thresholds: Comparison with opiate receptor compounds in normal and seizureinduced brain-damaged rats. Electro-Magnetobiol. 1994;13:67-75.

139. Patruno A, Amerio P, Pesce M, et al. Extremely low frequency electromagnetic fields modulate expression of inducible nitric oxide synthase, endothelial nitric oxide synthase and cyclooxygenase-2 in the human keratinocyte cell line HaCat: Potential therapeutic effects in wound healing. Br J Dermatol. 2010;162(2):258-266.

140. Rutgers M, van Pelt MJ, Dhert WJA, Creemers LB, Saris DB. Evaluation of histological scoring systems for tissue-engineered, repaired and osteoarthritic cartilage. Osteoarthritis Cartilage. 2010;18(1):12-23.

141. Veronesi F, Torricelli P, Giavaresi G, et al. In vivo effect of two different pulsed electromagnetic field frequencies on osteoarthritis. J Orthop Res. 2014;32(5):677-685.

142. Thomas A, Graham K, Prato FS, et al. A randomized, double-blind, placebocontrolled clinical trial using a low-frequency magnetic field in the treatment of musculoskeletal chronic pain. Pain Res Manag. 2007;12(4):249-258.

143. Maestú C, Blanco M, Nevado A, et al. Reduction of pain thresholds in fibromyalgia after very low-intensity magnetic stimulation: A double-blinded, randomized placebo-controlled clinical trial. Pain Res Manag. 2013;18(6):e101-106.

144. Adey W. Physiological signaling across cell membranes and cooperative influences of extremely low frequency electromagnetic fields. In: Biological Coherence and Response to External Stimuli. New York, NY: Springer-Verlag; 1998:148-170.

145. Sisken B, Walker J. Therapeutic aspects of electromagnetic fields for soft-tissue healing. Amer Chem Soc. 1995;10(1):277-285.

146. De Geeter N, Crevecoeur G, Dupré L, Van Hecke W, Leemans A. A DTI-based model for TMS using the independent impedance method with frequencydependent tissue parameters. Phys Med Biol. 2012;57(8):2169-2188.

147. Colbert A, Markov M, Souder J. Static magnetic field therapy: Dosimetry considerations. J Altern Complem Medicine. 2008;14(5):577-582.

Ross—Effects of EMF on Inflammatory Pain Mechanisms

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CASE REPORT

Use of Strontium Chloride for the Treatment of Osteoporosis: A Case Report Sarah M. Westberg, PharmD, BCPS; Amy Awker, PharmD; Carolyn J. Torkelson, MS, MD

ABSTRACT Context • Strontium ranelate is an approved prescription medication for the treatment of osteoporosis in Europe. In the United States, the only available forms of strontium are those that are nonprescription, dietary supplements.

Some patients with osteoporosis use those products because they prefer an alternate treatment to conventional therapy. Currently, no controlled trials have been conducted on the effectiveness of the supplements for treating osteoporosis.

Objective • The study intended to examine how one woman responded to the use of strontium chloride.

Design • This was a retrospective case study.

Setting • The woman in the case study was a patient in an academic urban women’s health clinic in Minneapolis, MN, USA. Participant • The participant was a postmenopausal woman with a history of vertebral fracture.

Sarah M. Westberg, PharmD, BCPS, is an associate professor in the Department of Pharmaceutical Care and Health Systems, College of Pharmacy, University of Minnesota–Twin Cities, in Minneapolis, Minnesota. Amy Awker, PharmD, is a pharmacy practice resident at the Minneapolis Veterans Affairs Medical Center in Minneapolis, Minnesota. Carolyn J. Torkelson, MS, MD, is an associate professor in the Department of Family Medicine and Community Health, School of Medicine, University of Minnesota–Twin Cities.

Corresponding author: Sarah M. Westberg, PharmD, BCPS E-mail address: swestber@umn.edu

O

steoporosis is a common bone disease in postmenopausal women that is characterized by a decreased bone density and a disruption in bone architecture. Those individuals with osteoporosis are at increased risk of bone fracture due to a decrease in bone strength. Therefore, treatment of osteoporosis is targeted at reducing the incidence of vertebral and nonvertebral fractures.1

Intervention • The participant took 680 mg daily of strontium chloride for 2.5 y.

Outcome Measures • The patient had begun receiving dual-energy X-ray absorptiometry (DXA) scans in 2004 and continued to receive follow-up scans every 2 y. After beginning strontium therapy in December 2011, she received DXA scans in March 2012 and May 2014.

Results • During the study, the analysis of the patient’s DXA scans showed a positive increase in the bone mineral density (BMD) of her vertebrae and her right hip and maintenance of her BMD in her left hip.

Conclusions • Although the current case report does not provide enough evidence to conclude that US dietary supplements of strontium are effective in preventing fractures, it demonstrates a positive experience for one patient. (Altern Ther Health Med. 2016;22(3):66-70.)

Calcium is a key mineral that contributes to bone strength. Strontium is a naturally occurring trace element that is structurally related to calcium. In the intestine, strontium is absorbed into the body through the same transporter system as calcium, although the transporter has a stronger affinity for calcium. Once absorbed, strontium is incorporated into bone at the same rate as calcium.2 In animal studies, strontium has increased bone mineral density (BMD) by a dual mechanism that inhibits the maturation of osteoclasts and increases osteoblast differentiation. Thus, it has shown both antiresorptive and anabolic effects.2-4 Strontium exists in numerous salt forms. Strontium ranelate is a distrontium salt available in Europe as an approved product for the treatment of severe osteoporosis in those individuals at high risk of fracture.5-6 It consists of 2 strontium molecules bound to ranelic acid, and the ranelic acid is poorly absorbed. Multiple studies in Europe have shown that strontium ranelate reduces the risk of both vertebral and nonvertebral fractures and increases BMD.7-9 In 2 phase-3 studies over 3 years, strontium ranelate was found to reduce the risk of vertebral fractures by 41% in those patients with a previous history of fracture (P < .001)8

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Westberg—Strontium Chloride for Osteoporosis

and of hip fractures by 36% in those at high risk of hip fracture (P = .046).9 One of the studies found an absolute reduction of the risk of vertebral fractures of 11.9%.8 In addition, the studies saw an increase in BMD from baseline of 12.7% in the lumbar spine and 5.7% to 7.2% in the femoral neck.8-9 Extensions of the studies to 5 and even 10 years of therapy have shown a sustained reduction in risk and a continuous increase in BMD.10-12 Combined results of studies on the safety of the medication led the European Medicines Agency to add contraindications for those with a history of cardiovascular disease, venous thromboembolism (VTE) and currently uncontrolled hypertension.6 Safety results showed an increased risk of myocardial infarction (MI) and VTE for individuals with a previous history of those conditions but no increased risk for patients without a prior history.

Although approved as a prescription medication in Europe, strontium ranelate has not been submitted for approval to the US Food and Drug Administration and, therefore, is not available in that form in the United States.

However, other salt forms of strontium, including chloride, citrate, carbonate, gluconate, and sulfate, are available as nonprescription, dietary supplements.

A study in mice showed that strontium chloride increased trabecular bone formation in vertebrae, and administration of strontium carbonate in rats after ovariectomy reduced the increase in bone turnover and restored the bone-mineral loss caused by estrogen deficiency.2 However, to date, no controlled studies have occurred on the effectiveness of the other salt forms of strontium for reducing the risk of fractures in patients with osteoporosis.

One small case study found that strontium citrate was incorporated into the finger and ankle bone of a healthy female taking 680 mg daily of strontium citrate, suggesting that strontium citrate is absorbed and taken up into bone.13 However, it is largely unknown how the other salt forms of strontium compare to strontium ranelate in terms of bioavailability and incorporation into bone, differences in which could potentially alter their effectiveness in the treatment of osteoporosis. For those patients who are looking for an alternate option to treat osteoporosis, clinicians have very little information to determine if a strontium supplement in the United States would be appropriate to include as part of an integrative therapeutic approach. The current case study demonstrated how one woman responded to the use of strontium chloride.

METHODS Participant The patient in the current case report was a 61-year-old, postmenopausal, Asian female who was a widow and was retired. She was an established patient at an academic, urban women’s clinic (Minneapolis, MN, USA) who had been seeking care from the primary care physician at this clinic since 2010. She was 152.4 cm tall and weighed 50.3 kg. She had no parental family history of osteoporosis or hip fracture and did not drink alcohol or smoke. She lived in her own Westberg—Strontium Chloride for Osteoporosis

home and remained active, and her diet was excellent, with a high consumption of vegetables and lean meats.

The patient had received treatment with weekly alendronate for osteopenia beginning in 2005 and ending in 2008, with the discontinuation being due to stomach upset and poor appetite. She had begun receiving dual-energy X-ray absorptiometry (DXA) scans in 2004 and had received follow-up scans every 1 to 2 years after that first one.

In August 2011, the patient fell from a standing position, causing a compression fracture in the L2 vertebra. At that time, other secondary causes of osteoporosis were ruled out, and osteoporosis was officially diagnosed. After the fracture to her L2 vertebra, the patient had an X-ray in October 2011, and the interpreting radiologist noted that she had mild disc spurring in the L4 vertebra.

At the time of her fracture, her daily activities included walking 15 to 60 minutes each day and using exercise digital video discs (DVDs). She had never been on medications that would increase her risk of osteoporosis, such as steroids, thyroid medications, antiepileptics, blood thinners, chemotherapy, or medroxyprogesterone acetate. She went through menopause at the age of 45 years and was never on hormone therapy. Her other chronic health conditions included type 2 diabetes, hypertension, depression, glaucoma, and chronic dry eye.

After the fracture, she went to physical therapy regularly to help with lower back pain. She continued walking and using exercise DVDs, and in December 2013, she began doing additional yoga stretches and t’ai chi.

Following the fracture, pharmacotherapy was indicated for the treatment of osteoporosis and the prevention of future fractures. The patient’s primary care provider and medication therapy management pharmacist thoroughly educated her on the recommended treatments, hich included zoledronic acid, ibandronate, denosumab and teriparatide.

However, due to her personal preferences about medications, she declined prescription therapy.

The current case report was reviewed by the University of Minnesota–Twin Cities (Minneapolis, MN, USA) institutional review board, and it was determined that the study did not meet the regulatory definition of research.

Therefore, no formal review was necessary. The patient provided written consent to use her information in a case report that would be published.

Procedures During the period of the current report, which began in December 2011, and ran until August 2014, the patient regularly saw her primary care physician, and her health conditions were appropriately managed throughout that timeframe. Her concurrent medications included fish oil, metformin, glimepiride, losartan/hydrochlorothiazide, zinc, calcium carbonate with vitamin D, vitamin B complex, a multivitamin, lidocaine patches, travoprost ophthalmic, levobunolol ophthalmic, olopatadine ophthalmic, and carboxymethylcellulose ophthalmic. In addition, she added ranitidine and St John’s Wort in 2014.

ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 67

Intervention In December 2011, the patient began therapy with 680 mg of strontium chloride, once daily. It was welldocumented that the patient had been taking adequate supplementation of calcium and vitamin D, using 600 mg of calcium carbonate and 200 international units of vitamin D twice daily. Because calcium and strontium compete for absorption in the intestine, she took the strontium at a time separated by 4 hours from her calcium doses.

Outcome Measures The use of DXA scans is the gold standard to establish or confirm the diagnosis or osteoporosis. The BMD is expressed in grams of mineral per square centimeter (g/cm2) scanned.

This reading is then expressed in relationship to the average BMD of a patient of the same sex, age, and ethnicity (z score) and compared with a young adult reference population of the same sex (t score). A t score between -1.0 and -2.5 is considered osteopenia, and a t score of equal to or less than -2.5 is considered osteoporosis.1 After beginning strontium therapy in December 2011, the patient received DXA scans in March 2012 and May 2014. Because the abnormalities to the L2 and L4 vertebrae might invalidate the BMD for them, only data for the L1 and L3 vertebrae were examined for the current case study.14 RESULTS Overall, the changes in the patient’s BMD between 2012 and 2014 were the most reflective of strontium use. At the time of her DXA in March 2012, the patient had been on strontium for 3 months. Table 1 shows the detailed results from the patient’s DXA scans, all of which were completed on the same machine. Figure 1 shows the changes in the patient’s BMD. The current research team speculates that the decrease in BMD from 2011 to 2012 may have been the result of the lack of treatment for the patient’s osteoporosis for the majority of that time. After starting strontium at the end of 2011, the patient had the following improvements in her BMD results: (1) 3.4% for the L1 vertebra, (2) 4.8% for the L3 vertebra, (3) 4.3% for the right total hip, and (4) 2% for the left total hip. A change of 3% or greater is considered a clinically significant change.1,15 Those changes correlate with the initiation of strontium. The patient’s comorbidities remained the same, and only modest changes in her physical activity had occurred in December 2013, as described above.

To date, the patient has not sustained any further fractures and continues to be extremely pleased with her current therapy. She reports that she never misses doses of strontium or calcium and denies experiencing any side effects from the strontium. Pertinent lab results for her bone health remained stable as of July 31, 2014, showing a calcium of 8.6 mg/dL, a vitamin D level of 42 μg/L, and a phosphorus of 4.0 mg/dL. A parathyroid hormone test was last completed on June 25, 2013, and was 22 pg/mL.

DISCUSSION Currently, it is unknown whether a strontium supplement, such as strontium chloride, is effective in the treatment of osteoporosis, because it has not been formally studied.

Considering the natural progression of bone-density decline, the significant increase in BMD in the current patient’s L1 and L3 vertebrae and right total hip between 2012 and 2014 could potentially reflect her use of strontium chloride.

Previous studies of strontium ranelate have reported BMD increases of 12.7% at the spine and 5.7% to 7.2% at the femoral neck after 3 years of treatment.8-9 Therefore, although the current patient’s bone-density increase was clinically significant, it did not reach the magnitude reported in randomized trials of strontium ranelate. That fact could suggest that alternative salt forms of strontium may not perform as well as strontium ranelate. However, any magnitude of BMD increase may still provide benefit.

In a study of strontium ranelate looking at the relationship between a BMD increase and a reduction in the risk of fracture, the researchers found that each percentage-point increase in BMD at the femoral neck corresponded to a 3% reduction in the risk of a vertebral fracture.16 That finding suggests that even an increase in hip BMD could help prevent fractures in the spine. That possibility was particularly salient for the patient in the current case, because her history of a vertebral fracture puts her at a high risk of future vertebral fractures, and she did see increases in the BMD in her hips.

Previous studies of strontium ranelate have reported a relative reduction in the risk of vertebral fractures of approximately 40%. In the largest study of strontium ranelate looking at its effect on preventing hip fractures, a significant 36% reduction in the risk of hip fracture was seen in a group at high risk of a hip fracture (ie, those individuals with an age ≥74 y and a femoral neck t score ≤-3), whereas only a 15% risk reduction was seen in the overall group, which did not reach statistical significance.9 Conventional therapies for osteoporosis include bisphosphonates—alendronate, risedronate, ibandronate, and zoledronic acid, denosumab, and teriparatide. In general, those therapies reduce the risk of vertebral fracture by approximately 40% to 60% and nonvertebral fractures by approximately 20% to 40% (excluding ibandronate), with differences among the treatments being modest.17 Those figures indicate that the conventional treatments are more effective than strontium ranelate.

The European Medicines Agency released new restrictions on the use of strontium ranelate in March 2014.

The restrictions stated that the supplement should be used only for the treatment of severe osteoporosis in those individuals at high risk of fracture and for whom treatment with other medicinal products that have been approved for the treatment of osteoporosis is not possible due to intolerance or contraindications.6 In addition, new contraindications were added to include patients with an established, current, or history of ischemic heart disease, peripheral arterial disease, cerebrovascular disease, or uncontrolled

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Table 1. Timeline and DXA Scan Results

Lumbar spine (t score) L1 BMD L1 BMD % Δ for L1 (previous) Lumbar spine (t score) L3 BMD L3 BMD % Δ for L3 (previous) Right total hip (t score) BMD right total hip BMD % Δ (previous) Left total hip (t score) BMD left total hip BMD % Δ left total hip (previous)

May 2005 Calcium Vitamin D Alendronate -2.0 0.896 g/cm2 -1.8 0.959 g/cm2 0.2 1.031 g/cm2 0.0 1.011 g/cm2

July 2007 Calcium Vitamin D

November 2009 Calcium Vitamin D

January 2011 Calcium Vitamin D

-1.6 0.996 g/cm2 +10% -1.6 0.990 g/cm2 +3.2% 0.1 1.023 g/cm2 -0.8% 0.0 1.010 g/cm2 -0.1%

-2.0 0.896 g/cm2 -10% -1.5 1.020 g cm2 +3% 0.0 1.007 g/cm2 -1.6% -0.1 1.00 g/cm2 -1.0%

-1.5 0.951 g/cm2 +6.1% -1.5 1.021 g/cm2 +0.09% -0.2 0.982 g/cm2 -2.5% -0.3 0.975 g/cm2 -2.5%

March 2012 Calcium Vitamin D Strontium -2.2 0.864 g/cm2 -9.1% -1.7 0.958 g/cm2 -6.1% -0.2 0.984 g/cm2 +0.02% -0.1 0.997 g/cm2 +2.2%

May 2014 Calcium Vitamin D Strontium -2.0 0.894 g/cm2 +3.4% -1.6 1.004 g/cm2 +4.8% 0.1 1.026 g/cm2 +4.3% 0.1 1.017 g/cm2 +2.0%

Abbreviations: DXA, dual-energy x-ray absorptiometry; BMD, bone mineral density.

Figure 1. Change in Bone Mineral Density 1.05

1.00

0.95

0.90

0.85

0.80

0.75

May 2005

July 2007

November 2009

January 2011

March 2012

May 2014

BMD L1 (g/cm2) BMD L3 (g/cm2) BMD right total hip (g/cm2) BMD left total hip (g/cm2)

Abbreviations: BMD, bone mineral density.

Westberg—Strontium Chloride for Osteoporosis

ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 69

hypertension, due to an increase in MI in the population.

Without formal studies of other formulations of strontium, such as strontium chloride, no data are available on whether those same risks and contraindications may apply.

Another limitation of the current case report is the fact that the determiniation of the effects of strontium on BMD occurred through a DXA scan. An increase in the strontium content of bone can potentially lead to a falsely elevated BMD when measured by a DXA scan, due to the fact that strontium is a element that is heavier than calcium.18-19 One study found that a direct linear relationship existed between the strontium content in bone and the amount of overestimation of bone density.19 Those researchers proposed a calculation to account for that overestimation that would require knowing the percentage of strontium concentration in the bone.

However, no routine test is available in the clinical setting to measure the strontium content in a patient’s bone.

As that test was not possible in the current case study, the imaging center was not able to calculate the potential effect in its reports. Therefore, it can be assumed that a portion of the increase in BMD in the current patient could be due to that effect. In addition, the increases in BMD could be due to degenerative changes in the spine. Although the current case study removed the data from the L2 vetebrae, where the patient had had a vertebral fracture, it is possible that osteoarthritic changes in the spine could have contributed to the BMD increases in the L1 and L3 vertebrae.

REFERENCES

CONCLUSIONS The 2.5 years of extended, continuous therapy, with a high level of compliance from the patient and the availabilty for follow-up through DXA scans, is a significant strength of the current case report. The current article demonstrates that the patient potentially could have experienced an increase in BMD from taking an over-the-counter supplement of strontium chloride. It cannot be assumed that the increase in BMD lowered her risk of fracture, because outcome data for strontium chloride are not available. Controlled studies are needed to assess the usefulness of the therapy more fully as an option for patients suffering from osteoporosis who prefer an alternative approach to the available prescription medications.

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15. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: Results from the Fracture Intervention Trial. JAMA. 1998;280(24):2077-2082.

16. Bruyere O, Roux C, Detilleux J, et al. Relationship between bone mineral density changes and fracture risk reduction in patients treated with strontium ranelate. J Clin Endocrinol Metab. 2007; 92(8):3076-3081.

17. Crandall CJ, Newberry SJ, Diamant A, et al. comparative effectiveness of pharmacologic treatments to prevent fractures: An updated systematic review.

Ann Intern Med. 2014;161(10):711-723.

18. Christoffersen J, Christoffersen MR, Kolthoff N, Bärenholdt O. Effects of strontium ions on growth and dissolution of hydroxyapatite and on bone mineral detection. Bone. 1997; 20(1):47-54.

19. Nielsen SP, Slosman D, Sørensen OH, et al. Influence of strontium on bone mineral density and bone mineral content measurements by dual X-ray absorptiometry. J Clin Densitom. 1999;2(4):371-379.

AUTHOR DISCLOSURE STATEMENT The authors have no conflicts of interest to report.

70 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

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CONVERSATIONS

Christie Fleetwood, ND, RPh: The Essential Role of Pharmaceutical Knowledge in Naturopathic Practice Interview by Craig Gustafson

Christie Fleetwood, ND, RPh, earned a bachelor of science degree in pharmacy from the Medical College of Virginia/ Virginia Commonwealth University in 1988. After practicing as a retail pharmacist in the greater Richmond area for a decade, she attended Bastyr University, earning a doctorate in naturopathic medicine in 2004. She is currently in private practice. Dr Fleetwood serves on the faculty of the Kenwood, Washington, and San Diego, California, campuses of Bastyr University, and she also serves as faculty at the National College of Natural Medicine in Portland, Oregon. (Altern Ther Health Med. 2016;22(3):72-77.)

Alternative Therapies in Health and Medicine (ATHM): How early in life did you get interested in health care and was there any particular event in your early life that pushed you in that direction?

Dr Fleetwood: Interestingly enough, I had a great-aunt who gave me a book called School Years where, each year from kindergarten through my senior year of high school, there was a spot to put my picture, how heavy and how tall I was, and what I wanted to be when I grew up. Every year, what I wanted to be when I grew up changed. I wanted to be a teacher, I wanted to be a math teacher, I wanted to be an actress, I wanted to be a model. I think at some point I said that I wanted to be a doctor, but every year, it was something different. I wanted to be a little bit of everything that I ever came in contact with.

When I was a junior in high school, we all had to go talk to the guidance counselor and try to figure out where we should go for a college education and what we should major in. I took a test that said that I was well positioned for anything in the healing arts and I thought, “Okay, doctor, nurse, dentist, or pharmacist.” I did not really want to be a doctor at that point. What I really wanted, by the time I had made it to the final years of high school, was to major in drama and minor in music. My mother said, “Christie, you’re a woman, and I hate to tell you this, honey, but you’re going to have to work twice as hard to make half as much as any man, so please find a job that will pay you enough so that you can support yourself and then do the fun things on the side.”

After taking this test that said I would be well suited for the healing arts, I figured, “Gosh, doctors are working with sick people day in and day out. I don’t know that I want to do that.” That would also rule out a nurse because they are dealing with the nitty-gritty of the sick—cleaning the bedpans and cleaning up the puke and drawing blood and measuring urine. I also did not want to have my hands up to my elbows in someone’s mouth all day long. So I chose pharmacy.

I loved science, loved chemistry, loved to mix things together, and I figured I could probably make more money as a pharmacist and have a better reputation about it than if I became a bartender and mixed things together behind a bar. My parents would also probably foot the bill for me to become a pharmacist rather than a bartender or a barista.

Without having ever been behind a pharmacy counter and without knowing a pharmacist, I applied to, got accepted, and went through pharmacy school. I was a pharmacist for about 10 years, working in the retail sector. Over time, it occurred to me that I was not really helping people. I was a legal drug pusher and people kept getting sicker. People would come in with their 1 prescription and then months or a year later, they’d come in with 2 prescriptions or 3 prescriptions. There were the people who came in who maybe got an antibiotic and then I would see them a week later and they were fine. But then there were people who came in with the antibiotic prescription for the kid with the ear infection and then again 3 or 4 more times in the same year—sometimes in the same season. These kids were getting recurrent infections and taking antibiotic after antibiotic.

ATHM: So what caused you to change perspectives?

Dr Fleetwood: Somewhere in my mid-20s, I had a serious emotional trauma, which shook the foundations of my world. Every belief that I had ever grown up with I questioned and I got very ill—physically, very ill—but the medical doctors did not know what was wrong and they could not help me. I was so emotionally full of pain that I could not even talk about my experience and, therefore, my body produced a really brilliant display of physical problems that, of course, were not going to be addressed by physical means because they did not have a physical etiology.

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They put me on different drugs, they referred me to different specialists, and no one could figure out what my problem was. Clearly no antibiotic was going to help me and no specialist was going to be able to help me until somebody would be willing to ask me the hard questions about the trauma that I had experienced.

At that point, I figured there had to be something else.

Conventional medicine could not be it. There had to be something better. So through self-study and exploration, I started looking at Ayurvedic medicine and traditional Chinese medicine, reflexology, massage, homeopathy, botanical medicine, and nutrition. … Oh, hey, novel concept: food as medicine.

About that time, this would have been in 1997, I ran across a magazine—some natural sort of magazine—that talked about the 3 accredited schools of naturopathic medicine in the United States. About that same time, a jeweler I knew, who was crafting some jewelry for me, had said, “Christie, you remind me an awful lot of my crazy friend Candace, who is an herbalist. You should meet crazy Candace. You would like her.” When I went to see crazy Candace, the herbalist, we were in conversation for about half a minute and she said, “Christie, you have got naturopath written all over you. Why don’t you go to Bastyr University, get a degree in naturopathic medicine, get your doctorate, and go take care of people? That is what you were made for.”

I thought, “Excellent. … What did she say? A nature guy? What is that?” Of course, the 3 accredited schools in the United States were all on the West Coast and I am an East Coast girl. But there is a school you can go to and get a doctoral degree? “Heck, yeah! Let me quit my career and go tell my newlywed husband that I have quit my career. We’ll sell everything that we have, leave everyone that we know, and move to the other side of the universe for me to go back to school, full time, to become a naturopathic doctor.”

ATHM: Did you really have any other choice?

Dr Fleetwood: I think crazy Candace was right. I was built and purposed to be a naturopathic doctor and I love what I do. I love this profession and cannot imagine being or doing anything else. I get to teach people how to eat food, drink clean water, and change their lives for the better on a day-by-day basis. My patients come back to me and tell me that I am a miracle worker and that “the reason that you are here, Dr Fleetwood, is for me.

God sent you to me because you just saved my life.” I reply, “I saved your life because I taught you how to eat real food and drink clean water? Okay, good. I am glad all of your issues have resolved.” Now certainly, there is more to it than that.

In my case, multiple physical ailments presented, including swollen lymph nodes to the point where I could not turn my head without pain. And yet, antibiotics were not going to help that—and no, I really did not need to go see a hematologist-oncologist. I was not dying from some rare form of leukemia or lymphoma. I had some serious emotional issues that needed to be dealt with.

Conversations With Christie Fleetwood, ND, RPh

That is what naturopaths get to do because by definition, we are holistic practitioners. We take care of the whole person using those symptoms as clues to figure out what is the real thing that needs to be fixed here. Because we are trained in so many different modalities, we have got all kinds of things that we can employ that are not going to hurt our patients while we are gaining their trust and developing that rapport to go deep and get well under the tip of that iceberg.

Bless them, the poor conventional docs, they have got 2 tools: They have got a prescription pad and a scalpel. They are just not trained in all the other aspects like naturopaths are.

ATHM: Did your pharmacist’s training give you a unique perspective as a naturopath?

Dr Fleetwood: Oh, yes, and how. When I was a pharmacist, I was able to see that some of these drugs actually set people up for nutritional deficiencies. Statins had come on the market. We know statins deplete coenzyme Q10. Why aren’t the people taking statins being put on coenzyme Q10? So I started ordering coenzyme Q10 in the powdered form of ubiquinol and made coenzyme Q10 capsules to offer any of my customers coming in for their statin refills.

My last retail pharmacy experience was actually inside a grocery store, where I had a real “a-ha” moment. People would come in and say, “Oh, Christie, the lines are backed up. Can I buy my few groceries back here with my prescriptions?” Sure. It was a new pharmacy and I was filling 30 prescriptions a day when I was used to over 300. So yeah, give me something to do. Let me ring up your groceries.

The folks who were asthmatics were getting their inhalers from me … and their cigarettes. The diabetics were getting their metformin and their glipizide from me … and their bacon and their doughnuts and all their enriched bread products. I started asking folks, “Hey, I am offering free nutritional consults. Has your doctor talked with you about lifestyle changes that you could make that would maybe get you off of some of these medicines?” I heard 1 of 2 comments to that question. One was, “My doctor does not have time to talk with me about anything. I get about 5, maybe 10 minutes with him—15 if it is for my annual gynecological exam. I tell him what is bothering me and he writes me a prescription.”

Or I would see this incredulous look on my customer’s face.

“What? Do you mean I might be doing something that is causing my health complaints?”

I thought, “Wow, media has done its job. We have gotten so far away from the origins of our food that we do not understand anymore that that is fuel for this amazingly welldesigned machine. We load it up with fast food and processed food and nutrient-devoid entities that taste good, and then we wonder why the machine is not running well.”

This one guy came in every few days because he could only afford a few days’ worth of his statin drug prescription to lower his cholesterol. I offered some nutritional counseling and offered some coenzyme Q10 to offset the worst of the side effects possible with taking statin drugs. He said, “Christie, I ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 73

really appreciate your concern for my well-being, but I have to tell you, I like my life just the way it is and I am not willing to make any changes to it even if it were to make me well.” I thought, “Ding, ding, ding! Oh, there is a problem in the American culture.”

ATHM: Did this additional perspective affect the path of your career?

Dr Fleetwood: So, the crazy thing is, I have never wanted my naturopathic career to be based on my pharmacy background, and yet that is exactly what my naturopathic profession needs. As we are having our scope expanded in the various licensed states and becoming licensed in more states as primary-care providers, we are becoming the first point of reference for, “Hey doc, I’m on this list of drugs. Can you get me off of them?”

My profession really needs to understand the pharmaceuticals and how they can cause nutrient deficiencies.

Some disease states start because of these induced nutritional deficiencies. If the nutritional deficiencies are not recognized then, hey, the first line of treatment when only 2 tools are available becomes: “We do not have to cut you just yet, so let me start you with this prescription.” We need to understand how the different prescriptions cause the next disease state.

That is what I was witnessing as a pharmacist but could not quite figure it out.

Now that I have been asked by my naturopathic profession to teach on pharmacy issues, I have been given extra time to go deeper into the literature to find that beta blockers actually cause dysglycemia, type 2 diabetes, and dyslipidemia—cholesterol issues. Someone starts off, maybe, with a little bit of hypertension, and how often do we see high blood pressure, type 2 diabetes, and high cholesterol walking around all braided together? Unfortunately, when you are not addressing the underlying condition, which more often than not is lifestyle, then the drugs—the well-chosen drugs— push people into that next disease state. Again, if you have only got 2 tools in your pocket, now the person with hypertension comes in again with the hypertension and now high cholesterol. You put him on a statin for the high cholesterol. There is a huge class-action suit against the manufacturer of atorvastatin because, particularly in women, there is a much-increased risk of developing type 2 diabetes.

So now you have got the third member in that triad.

As a naturopath, I get to go to my peers in the naturopathic profession and say, “Hey, guys, listen up. These are the things that we are dealing with because of our current medical model, where conventional medicine reigns supreme. These are the things that we now have to undo because, unfortunately, they are not trained in undoing it.”

And the wild and crazy bit is that they do not read their own literature. I’ll have a conventional doctor call me and ask, “Why are you doing this? Why did you put my patient on this, that, or the other?” or, “Why do you want this patient?” Because in an unlicensed state, I cannot order any

lab work, so I send my clients back to the conventional medical doc to get additional labs or whatnot. Then the question became, “Why do you need this? What are we looking at this for?”

I have to explain that it is because I suspect that the drug has pushed our patient into this arena. We have not looked at nutritional deficiencies. A particular drug causes a deficiency in this list of nutrients. I need to know how deficient that doctor’s patient—my client—is, so I know how aggressively to work with him. I may even ask patients keep records of their blood glucose and blood pressure while they are making the lifestyle adjustments to correct the underlying issue.

Eventually they go back to the prescribing physician to say, “I’ve been making some lifestyle changes and look, my other doctor the naturopath, says I’m over-medicated. Could you take me off of some of these meds?”

It is really fun to teach my naturopathic doctor colleagues how to talk with the conventional medical world. If I did not have my pharmacy background, I would not know how to do that. Which drugs you can, as the objective and subjective parameters that you’re watching to keep your patient safe, abruptly discontinue and which ones really need to be tapered very slowly so you do not precipitate a heart attack or a stroke or a manic event—a bipolar episode, major depression to the point of suicide, or homicidal ideation that is carried through.

Then, speaking of depression, I am honored to teach some of Bastyr’s dual-track students in nutrition and health psychology. They get a lot of focused attention on just mental-health drugs, which gives me the luxury of looking deeply into these drugs and being able to report back.

You know what? While we do drug trials with thousands of people over many years in multiple kinds of settings for cardiovascular drugs, when we are looking at mental-health drugs, we have 4 or 5 clinical trials done on a sample group of, maybe, 14. Now we have antipsychotics on the market that we use as mood stabilizers. The DSM-5 now gives clear criteria that bipolar type 2 can be caused by antidepressants. Wow, when you look at any class of antidepressant, every class shows worsening of depression to the point of suicidal ideation.

I think our students need to know this because, while we teach them the standards of care, standards of care in medicine are written by conventional doctors for conventional medicine. They are not written by naturopaths for naturopaths, but our students are being taught the standards of care. I feel like they need to see the evidence alongside the standards, so that they can make a decision for themselves. It is going to be up to us as we educate our patients. If they are working with other doctors, we need to educate the other doctors, too—in a respectful, professional capacity.

ATHM: The effects of the depression drugs are pretty substantial, but having acceptance based on an N of 14—that is the same blade that gets used on studies that examine supplement effects. “You’ve only got an N of 23? That doesn’t prove anything.”

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Dr Fleetwood: Right. It is pretty unequal, the persecution that we face with our nutrients.

ATHM: With all the polypharmacy going on now, there is growing recognition that the side effects of a particular drug may be this other condition that you are now medicating for.

But there is an art to untying that. Could you discuss a couple of examples?

Dr Fleetwood: Take, for example, beta blockers. Beta blockers are used for a host of things. They’re useful with hypertension because they decrease the sympathetic nervous system firing. They block norepinephrine and so for people who are anxious and, therefore, their blood pressure goes up, we can decrease their anxiety and lower their blood pressure by administering beta blockers. Those drugs do their job by blocking norepinephrine from coming in and docking into those beta receptors.

If you are working with someone from a naturopathic standpoint and teaching them mindfulness, teaching them how to eat the foods that are going to be the preferred fuel for their particular bodies, teaching them to take blood-pressure readings at home, then maybe doing a gratitude journal in the evening to lower the blood pressure, get better sleep, and wake unstressed or less stressed. Now you start to see that the blood pressure is coming down. If that same person were on an ace inhibitor, you could stop the ace inhibitor, checking in with the objective parameter of decreasing blood pressure over the time frame that you have been working with changing lifestyle and checking in subjectively with the patient: “Hey, how anxious are you? Are you experiencing a drop in blood pressure when the phone rings and you jump up from the sofa? Are you getting dizzy? Are you, maybe, having to sit right back down?”

Once the subjective parameters, what the patient can tell you, and the objective, what does the machine tell you, are in the range where your patient is clearly overmedicated, the blood pressure is now too low. They are not functioning all that great because they are getting dizzy when they go from sitting to standing. Then it is time to either reduce the medication or discontinue it altogether.

If the patient were on a diuretic, you could discontinue.

Hydrochlorothiazide, furosemide, spironolactone, amiloride— any of those—there are a couple of different classes of diuretics.

Those can just be discontinued. Ace inhibitors, angiotensin receptor blockers, calcium channel blockers, those can just be discontinued, but beta blockers, oh, no, sir. No, no, no! Beta blockers must be ramped up and then at the other end, tapered down. Whether your patient has been put on a beta blocker for hypertension or for decreased cardiac remodeling after a heart attack or for arrhythmias, there are a different set of objective and subjective parameters you would be looking at for each of these different means or each of these different scenarios where a beta blocker might be employed.

Back to that hypertensive piece, now obviously overmedicated, you would reduce the dose of the beta blocker. You would not dare just stop it because now that you Conversations With Christie Fleetwood, ND, RPh

have allowed norepinephrine to come in and dock into all those recently blocked receptors, norepinephrine, of course, is going to increase heart rate, increase blood pressure, and you could precipitate what is called a rebound hypertensive crisis—a heart attack in your patient or a stroke.

I teach my students that it is not a good idea to have a negative outcome on your watch. This is a drug where if you needed to increase it, you would increase it slowly and, therefore, when you need to decrease it, you must decrease it slowly. Taper your patient off over time, keeping an account of both the subjective and the objective parameters to make sure that you are keeping your patient safe. In the meantime, of course, you are replenishing those depleted nutrients and teaching your patient how to live in such a way that they are not going to need the medicine, they are not going to need you as a doctor, and they are not going to need their other doctors either.

That begs the question, then: If we are so stinking healthy that we do not need doctors anymore—and we currently have a massive shortage of primary care providers—then who is going to be making the money? Another topic for another day, but health care in this country is among the highest in dollars spent of any country in the world and yet our health statistics are among the very worst. Something needs to shift.

ATHM: What kinds of issues are presented by acid blockers?

Dr Fleetwood: Another of the interesting pieces concerning the harder-hitting acid blockers—the proton pump inhibitors and the H2 antagonist—is that if any long-term studies have been done, they have not been published. So, unless you have esophageal cancer or Barrett’s esophagitis, which is a precursor to cancer, then there are no long-term studies saying that these are safe for you to be on for any length of time past 12 weeks. And yet, these things are available over-the-counter at Costco. When do you go into Costco and buy anything small? You don’t. So people are buying these Costco-sized boxes of omeprazole and ranitidine and there is a long list of nutrient depletions with these agents that will precipitate other disease states, including—but not limited to—osteoporosis and protein deficiencies.

People will begin to waste away, especially on the proton pump inhibitors because they bind irreversibly and they are noncompetitive. You cannot displace them once they have disrupted that proton pump. No hydrogen ions are getting through—period, end of story—for about 26 hours, and they are sold over-the-counter. People are on them for years … years! And we now have a much higher percentage of overfed, undernourished people whose bones are breaking and who are wasting away from protein loss. The problem was never corrected because these used to be targeted mostly at the middle-aged-and-over crowd. I say used to be because now they target them for everybody. That is actually one of the reasons in my long list of why I am not a practicing pharmacist anymore.

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Middle-aged people tend to start losing some of the reserves that they were born with. As we age, we diminish some of those extras that we were gifted with at birth. We do not make as much acid. We do not have the same sort of kidney potential. Two kidneys, 2 lungs, 2 eyes, 2 ears, but presbyopia happens in your 40s and you can’t read things that are up close. Presbyacusia happens with the ears, as well.

We just are not as spot-on as we were in our 20s once we are in our 40s, 50s, or 60s. But media is really good about saying “You, consumer, you don’t have to take responsibility for really anything. Eat what you want, when you want, overconsume if you want, and then all you have to do is take our product to make all your aches and pains go away.” Now we are seeing people with GERD and heartburn at much, much younger ages because of the outrageous way that we shovel food into our gullets.

Back to “Hey, there’s not quite enough acid.” Acid is a necessary thing. We have to have very low pH in the stomach in order to break down the food, absorb the nutrients from the food and get them into the bloodstream, and then to go around to the rest of the body and be utilized where they are needed. Now you can see why there would be a list of nutrient depletions for somebody who is been on H2 blockers or proton pump inhibitors continuously for a long period of time—and that long period is 12 weeks or more. When we have sufficient acid, we can kill the bugs that might come in with our food. That low pH signals the pancreas, the duodenum, and the stomach to get ready for food. It also closes down the lower esophageal sphincter, which is not really a valve, but a gathering. Think of it as a drawstring at the bottom of the esophagus, where the esophagus hooks into the stomach. So strong acid equals strong digestion.

As we age, if we are not making that strong acid, but we are still eating food, the food comes in, but the strong acid is not there. There is acid and there is a warm, moist environment, and the stomach will still wiggle in 3 different directions, so there will be some breakdown—mechanical breakdown and chemical breakdown of the food in the gut— but the acid is not sufficient to close down that lower esophageal sphincter, so the drawstring remains open. Now if you put food into a warm, moist environment and you stir it up a little bit—think of your compost bucket if you have one, or wine if you make wine, or beer if you make beer— things begin to bubble. They begin to ferment. There is a type of decomposing that happens and with fermentation, there are bubbles. And now, if that drawstring is left open, that lower esophageal sphincter, those bubbles come up and there is a sense of acid regurgitation—not because of too much acid, but physiologically because there is not enough.

Yet, thinking about how conventional medicine works, conventional medicine is fabulous for acute conditions. If I am in a car accident or a motorcycle accident—because I am so much cooler than I look, I actually ride a motorcycle most of the time—as much as I love the naturopathic profession, if I am hemorrhaging or if I have got broken bones, yarrow and arnica are not going to cut it. I am going to want a trauma

team there with some morphine for pain, with some antibiotics for infection, and to take care of my acute issue.

But when we apply the acute fix to the chronic complaint, we are seeing more and more problems arise. That is one of the issues with these acid blockers—whether you are talking about these powerful drugs or chewing Tums—a calcium tablet, which is marketed to also help your bones. Think about that. If it is going to neutralize your stomach acid, can you then absorb the calcium? No, you can’t, so chewing the calcium supplement will not strengthen your bones.

What calcium does is causes an irritation in the colon.

So if you tend to produce colon polyps, definitely take calcium carbonate or calcium citrate daily to produce that topical irritant, which will then slough off your polyps. In the meantime, yeah, you will neutralize the stomach acid. You will not absorb many of your nutrients, which means your bones will suffer and we know that is the case with both H2 blockers and proton pump inhibitors.

From the lower level, over-the-counter antacids to the heavier-hitting H2 blockers and proton pump inhibitors, short-term, acute use can be helpful—particularly if somebody has developed an ulcer. This is the classic example: They are taking nonsteroidal anti-inflammatories for rheumatoid arthritis. They are in pain all the time, so they are taking NSAIDs constantly. NSAIDs cause gastric bleeding—gastric ulceration. We know this, so you end up in the hospital because you are bleeding. We give them cytoprotectants and antibiotics to kill off H pylori and proton pump inhibitors so they do not make the gastric acid to further irritate that already ulcerated area. Then when we heal up the ulcer, we put them right back on the NSAIDs because they are in chronic pain and we put them on a prostaglandin analog to help prevent gastric erosion that will happen because of the drugs.

Wow! Why don’t we just deal with why this person might have an autoimmune condition? What might have happened that would cause, unconsciously, this person to begin fighting against himself? Maybe there are some hard questions that need to be asked. Maybe that is why we are not asking, because they are hard.

ATHM: It seems that your perspective on naturopathic medicine and pharmaceuticals has, as you said, pigeonholed you whether you like it or not. It has, however, put you in an interesting position to be able to teach and to synthesize and create some understanding of the issues that are going on here. How do you employ that in teaching?

Dr Fleetwood: I do teach a clinical pharmacology course based on the top drugs in both prescription volume and sales that students are going to be seeing in private practice. That is an elective class. I love teaching that class because it is all about what patients are going to be dealing with from the conventional medical community. It is what you are going to see walking into the office on a daily basis.

At first I will say, “You have one tool in your doctor bag and that is a prescription blank. Write a prescription for this

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person.â&#x20AC;? Of course, they say, â&#x20AC;&#x153;Oh, my gosh. I donâ&#x20AC;&#x2122;t want to do that. I want to give this person a homeopathic.â&#x20AC;? Or, â&#x20AC;&#x153;I want to use botanical tincture.â&#x20AC;? My response is, â&#x20AC;&#x153;Get comfortable writing the drug. This might be the only place that you ever write it and I want to make sure you do not kill your patient.

You have got me here to be your safety net, so letâ&#x20AC;&#x2122;s talk through why you picked this drug over that drug when they could both have the same end results. Why would you choose this for a performer? Why would you choose this one for a female? How do we change the drug depending on how the scenario might change over time or across cultures or across sexes because some agents are going to be better in different ethnic populations than other agents and here is why.â&#x20AC;?

Then, at the end of whatever that module is, letâ&#x20AC;&#x2122;s say weâ&#x20AC;&#x2122;re talking about blood pressure, when we have exhausted the drugs, I say, â&#x20AC;&#x153;Okay, naturopaths, put that prescription blank down. Letâ&#x20AC;&#x2122;s return to our naturopathic principles and look at the therapeutic order. Youâ&#x20AC;&#x2122;ve got a patient walking in and all these prescriptions that you have just written for him or herâ&#x20AC;&#x201D;how are you going to teach this person to live differently? What are the subjective and objective plans to keep your patient safe while watching for overmedication, and then do you taper or do you abruptly discontinue? How do you treat hypertension? How do you treat the patient who has blood pressure issues?â&#x20AC;?

Then, â&#x20AC;&#x153;What are the questions to ask when you and your patient are doing everything right on the physical plane, but

blood pressure is still high? What are you going to do? You have got to start asking the harder questions that impact the emotional and mental aspects of your patient. Ask those questions.â&#x20AC;? â&#x20AC;&#x153;Well, what are they, Dr Fleetwood?â&#x20AC;? â&#x20AC;&#x153;How do you listen to your patient recognizing their own metaphors, using their own language to help guide you to what the next best question is.â&#x20AC;? Itâ&#x20AC;&#x2122;s so much fun teaching that.

ATHM: Bottom line, what is it you hope that your students walk away with after a semester with you?

Dr Fleetwood: I hope they are better grounded in their naturopathic roots while having a better appreciation and respect for the nuances of the power behind both the prescription agents and the naturopathic modalitiesâ&#x20AC;&#x201D;using critical thinking skills and keeping their patient in the center of the care at all times. Meaning, sometimes the most naturopathic thing that I can do for my patient, in that moment, is to find a good surgeon. Sometimes, the most naturopathic thing that I can do for my patient, in the moment, is write a prescription for a really heavy-hitting, interventive pharmaceutical agent. But I have to remember to come back to the lower levels of intervention so that my patient can get back to a healthy state. That is what I hope my patients remember. That is what I hope my students remember. It is what I want my profession to remember.

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CONFERENCE CALENDAR Food as Medicine—Center for Mind/Body Medicine June 2-5, 2016—Marriott Waterfront, Portland, Oregon This universally acclaimed professional training program provides health professionals with the foundation they need to effectively integrate nutrition into clinical practice—and their own lives. Food As Medicine’s remarkable faculty includes the country’s leading lifestyle medicine clinicians and researchers as well as some of our most gifted holistic nutritionists, mindbody practitioners, patient advocates, and chefs. Participants will leave grounded in the fundamentals of sound nutrition, knowledgeable about cutting-edge research, and prepared to confidently and compassionately guide their patients toward practical life-giving healthy nutrition. For more information, please visit http://cmbm.org/.

Functional Medicine Advanced Practice Modules (AFMCP) June 6-10, 2016—Hyatt Regency, Austin, Texas Applying Functional Medicine in Clinical Practice (AFMCP) teaches health care practitioners to more effectively integrate science, research, and clinical insights to treat and prevent disease and maintain health. Established and emerging diagnostics, therapeutics, and prevention strategies are extensively covered. AFMCP integrates these approaches through the Functional Medicine Matrix Model (an innovative and practical assessment tool) and the emphasis on a therapeutic partnership between patient and practitioner.

For more information, please visit https://www.functionalmedicine.org/.

Organic Acids Testing Workshop June 18, 2016—Philadelphia, Pennsylvania (Cherry Hill, NJ) The Organic Acids Test (OAT) from the Great Plains Laboratory is a diagnostic tool that every healthcare practitioner should know about. It is invaluable for helping discover the underlying causes of chronic illness. All physician attendees receive a FREE Organic Acids Test - a $299 value. For more information, please visit https://www.organicacidworkshop.com/.

The American Academy of Anti-Aging Medicine (A4M): BHRT Symposium June 23-25, 2016—San Diego Marriott Marquis, San Diego, California In this exclusive 2.5-day seminar, you will be able to analyze the medical evidence on BHRT, listen to experts who are actively practicing this specialty, and get the information needed to merge BHRT safely into your practice. The traditional medical view of aging is a process with inevitable complications such as cardiovascular disease, diabetes, cancer, dementia, and the general steady decline of quality of life. For more information, please visit http://www.a4m.com/anti-aging-conferences.html/.

3rd ICNM Congress on Naturopathy July 1-3, 2016—Barcelona, Spain The 3rd International Congress on Naturopathic Medicine is the premier International Congress for the most influential and inspiring naturopathic medicine practitioners and health care professionals who are dedicated to improving patient care. You have the opportunity to network with the finest naturopaths from more than 50 countries and update your knowledge and skills learning from more than 40 internationally recognized researchers and clinicians. For more information, visit http://www.icnmnaturopathy.eu/.

Functional Medicine Advanced Practice Modules (APMs) July 15-17, 2016—Gaylord Hotel, National Harbor, Maryland “Hormone—Re-establishing Hormonal Balance in the Hypothalamic, Pituitary, Adrenal, Thyroid, and Gonadal Axis.” This Functional Medicine Advanced Practice Module will clarify exactly how to approach hormonal dysregulation, with discussions on the most important evaluations to make and integrative treatment approaches to apply. We will help you analyze the controversies and provide you with tools that you can use immediately in your practice. Our expert faculty team will supply you with the foundational background, insight, and in-depth clinical thinking to confidently assess and treat patients who present with hormonal dysfunction. This program will provide a unique, experiential, case-based, clinically practical experience from which you will acquire the tools you need to apply a comprehensive functional medicine approach to hormone dysfunction in your patients. For more information, please visit https://www.functionalmedicine.org/.

Functional Medicine Advanced Practice Modules (APMs) July 15-17, 2016—Gaylord Hotel, National Harbor, Maryland “Energy—Illuminating the Energy Spectrum: Evidence and Emerging Clinical Solutions for Managing Pain, Fatigue, and Cognitive Dysfunction.” This Advanced Practice Module will investigate the science of mitochondrial function and dysfunction, the impact of oxidative stress, as well as nutritional and lifestyle influences on both health and disease. Clinicians will learn how to regenerate compromised mitochondrial function and how to address the varied underlying causes of fatigue, depression, headache, and neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Evidence-based modalities to address pain will be introduced, and the profound potential of the healing partnership will be both explored and experienced. For more information, please visit https://www.functionalmedicine.org/.

4th Colorado Integrative Medicine Conference: Focus on Mind-Body Medicine & Lifestyle Management July 22-24, 2016—Assembly Hall at YMCA of the Rockies, Estes Park, Colorado Learn the latest evidence-based medicine for clinical practice in epigenetics, neuroplasticity, genomics, diet/weight management, fitness, trauma management, female hormones, CBD, methylation, breathing as medicine, acupuncture, and personalized medicine: new systems management for the whole body. Assess and apply these new cutting edge tools to meet growing demand for integrative medicine. For more information, please visit http://www.altermedresearch.org/cimc2016/.

GPLUniversity Workshops by The Great Plains Laboratory, Inc. August 6-7, 2016—San Jose, California Learn how to effectively integrate our comprehensive testing into your practice to enhance your bottom line and achieve greater outcomes for your patients.

Upcoming workshops include those on organic acids testing and genetic testing in San Jose, CA and Dallas, TX. For all workshop details, including all dates and locations, and to register, go to www.GPLUniversity.com/.

14th Annual International Restorative Medicine Conference September 16-18, 2016—Sonesta Resort, Hilton Head Island, South Carolina The 14th Annual International Restorative Medicine Conference is an extraordinary opportunity to hear expert speaker’s present emerging research and up-to-date protocols that empower you to effectively treat your patients. The annual conference consistently lives up to its reputation for providing innovative educational opportunities for practitioners. For more information, please visit http://restorativemedicine.org/aarm2016/.

American College for Advancement in Medicine Annual Conference September 15-18, 2016—Hilton El Conquistador, Tucson, Arizona ACAM will host its annual conference titled “What’s Next: An Interdisciplinary Approach to Advanced Prevention.” For more information, please visit http://www.acam.org/.

Applying Functional Medicine in Clinical Practice (AFMCP) September 19-23, 2016—Marriott Baltimore Waterfront, Baltimore, Maryland AFMCP teaches health care practitioners to more effectively integrate science, research, and clinical insights to treat and prevent disease and maintain health. Established and emerging diagnostics, therapeutics, and prevention strategies are extensively covered. AFMCP integrates these approaches through the Functional Medicine Matrix Model (an innovative and practical assessment tool) and the emphasis on a therapeutic partnership between patient and practitioner. AFMCP is a wellorchestrated, comprehensive, patient-centered education program that helps you deepen your clinical understanding and practical application of the Functional Medicine Matrix Model. For more information, please visit https://www.functionalmedicine.org/.

78 ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3

Conference Calendar

The American Academy of Anti-Aging Medicine (A4M): BHRT Symposium September 21-24, 2016—Hyatt Regency Dallas, Dallas, Texas In this exclusive 3.5-day seminar, you will be able to analyze the medical evidence on BHRT, listen to experts who are actively practicing this specialty, and get the information needed to merge BHRT safely into your practice. The traditional medical view of aging is a process with inevitable complications such as cardiovascular disease, diabetes, cancer, dementia, and the general steady decline of quality of life. For more information, please visit http://www.a4m.com/anti-aging-conferences.html/.

7th Annual Integrative Medicine for Mental Health Conference September 29-October 2, 2016—Reston, Virginia This international conference will explore the field of integrative medicine in the treatment of mental health, autism, and related disorders. The current trial-and-error, polypharmacy approach to the treatment of psychiatric disorders may not work for everyone. Research studies have revealed that many disorders such as depression, bipolar disorder, anxiety, OCD, eating disorders, and autism spectrum disorders often have dietary and biological causes, which contribute to symptoms. Patients have better outcomes when these causes are successfully addressed and treated through a combination of specialized testing and nutritional therapies, even in combination with traditional approaches. For more information, please visit http://www.IMMH2016.com/.

Cooling the Heat: Battling Inflammation September 30-October 1, 2016—Hilton Scottsdale Resort and Villas, Scottsdale, Arizona InnoVision Professional Media is sponsoring a unique health care symposium that will focus on inflammation. The event will combine the latest research and applications into a 2-day event with CMEs. Attendees will hear from leading health care thought leaders who will share their perspective on inflammation for your patient’s health. For more information, please visit http://ivpmeducation.com/.

The American Academy of Anti-Aging Medicine (A4M): Metabolic Medical Institute October 5-8, 2016—Sheraton Boston Hotel, Boston, Massachusetts A4M “MMI Module IV—Gastroenterology” and “MMI Module VI— Toxicology” will be presented at this event. For more information, please visit http://www.a4m.com/anti-aging-conferences.html/.

AAEM 2016 Annual Meeting October 6-9, 2016—Marriott San Diego La Jolla, La Jolla, California The goal of this conference is to present current data regarding mitochondria as a therapeutic target in many disease states. The information presented will better train primary care clinicians with the knowledge and skills needed to help prevent chronic disease in their patients, as well as identifying mitochondrial dysfunction and formulating a more comprehensive and effective approach to managing and even eliminating many modern complex chronic disease states. For more information, please visit http://aaemconference.com/fall/.

IVC & Cancer Symposium October 13-15, 2016—Hotel at Old Town, Wichita, Kansas Biannually, Riordan Clinic IVC Academy holds an IVC and Cancer Symposium in Wichita that offers doctors from around the world the opportunity to visit our facilities, learn more about high-dose IV vitamin C (IVC), listen to leading doctors in functional medicine, and learn how to use IVC in their offices. For more information, please visit https://riordanclinic.org/riordan-ivc-academy-symposium/.

Functional Medicine Advanced Practice Modules (APMs) October 28-30, 2016—Hyatt Regency, Chicago, Illinois “GI—Restoring Gastrointestinal Equilibrium: Practical Applications for Understanding, Assessing, and Treating Gut Dysfunction.” This Advanced Practice Module takes a whole-systems approach to evaluating and treating not only local gastrointestinal disease, but many systemic diseases that are linked to GI dysfunction. This course will supply you with the foundational background, insight, and in-depth clinical thinking to confidently work up and treat patients who may present with conditions, signs, and symptoms indicative of gastrointestinal dysfunction. We will discuss in detail the important laboratory evaluations to be considered, the appropriate clinical connections that must be made, and the treatment approaches that should be used. For more information, please visit https://www.functionalmedicine.org/.

Functional Medicine Advanced Practice Modules (APMs) October 28-30, 2016—Hyatt Regency, Chicago, Illinois “Detox—Understanding Biotransformation and Recognizing Toxicity: Evaluation and Treatment in the Functional Medicine Model.” There is persuasive evidence that even low-level toxic exposures contribute to the development of a variety of chronic health conditions, including fatigue, endocrine disruption, and chronic degenerative diseases such as Parkinson’s.

Given the ubiquitous nature of chemicals in the environment, it is likely that the single exposure model of toxicology is more the exception than the rule.

It is therefore critical for clinicians to learn how to assess both exposures and total toxic load to appropriately assess and address each individual’s toxicological situation. Our expert faculty team will review the foundational biochemistry and genetics of biotransformation pathways, connect organ system dysfunctions to potential toxic exposures, and detail the available laboratory evaluations useful in working up a toxin-exposed patient. Once these important clinical connections are made, the team will detail specific treatment approaches. This program also uses a case-based, integrated approach to deliver effectively the tools necessary for clinicians to diagnose and treat the toxic component of their patients’ total health pictures. For more information, please visit https://www.functionalmedicine.org/.

AIHM Annual Conference: People Planet, Purpose October 30-November 3, 2016—Paradise Point, San Diego, California Join the Academy of Integrative Health & Medicine annual conference and workshops. For more information, please visit https://www.aihm.org/.

GPLUniversity Workshops by The Great Plains Laboratory, Inc. November 5-6, 2016—Dallas, Texas Learn how to effectively integrate our comprehensive testing into your practice to enhance your bottom line and achieve greater outcomes for your patients.

Upcoming workshops include those on organic acids testing and genetic testing in San Jose, CA and Dallas, TX. For all workshop details, including all dates and locations, and to register, go to http://www.GPLUniversity.com/.

13th International Conference of Society for Integrative Oncology November 6-8, 2016—Miami, Florida Multidisciplinary oncology practitioners from around the globe, including stakeholders from major cancer centers, convene at SIO annual international conferences to discuss the evolution of evidence-based integrative oncology in practice, the steadily growing science base, and its continued rise in popularity use as patients demand a whole-person approach to cancer care with mind, body, and spirit. For more information, please visit https://integrativeonc.org/.

Gut-Brain Relationship Conference November 11-12, 2016—Marriott Marina del Rey, Marina del Rey, California InnoVision Professional Media is sponsoring a unique health care symposium that will focus on the unique relationship between the gut and the brain. The event will combine the latest research, testing techniques, and applications into a 2-day event with CMEs. Attendees will hear from leading health care thought leaders who will share their perspective on this important relationship for your patient’s health. For more information, please visit http://ivpmeducation.com/.

For additional listings, please visit http://alternative-tehrapies.com/.

Conference Calendar

ALTERNATIVE THERAPIES, MAY/JUNE 2016 VOL. 22 NO. 3 79

COOLING THE HEAT BATTLING CHRONIC INFLAMMATION

THE GUT BRAIN RELATIONSHIP CONFERENCE

SEPTEMBER 30-OCTOBER 1, 2016 SCOTTSDALE, ARIZONA

NOVEMBER 11-12, 2016 MARINA DEL REY, CALIFORNIA

PRESENTED BY:

FOR MORE INFORMATION, VISIT HTTP://IVPMEDUCATION.COM

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