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S T U D Y P R O T O C O L Open Access
Acupuncture for combat post-traumatic
stress disorder: trial development and
methodological approach for a randomized
controlled clinical trial
Michael Hollifield
1,2*
, An-Fu Hsiao
1,3
, Kala Carrick
1
, Andrea Gory Munoz
1
, Teresa Calloway
1
, Karen Cocozza
1
,
Besa Smith
4
, Tyler Smith
4
, Tanja Jovanovic
5
, Seth Norrholm
5
, Estate Sokhadze
6
and Christopher Reist
1,7
Abstract
Background: Post-traumatic stress disorder (PTSD) is a significant public health problem, affecting approximately
7% of the general population and 13–18% of the combat Veteran population. The first study using acupuncture for
PTSD in a civilian population showed large pre- to post-treatment effects for an empirically developed verum
protocol, which was equivalent to group cognitive behavior therapy and superior to a wait-list control. The primary
objective of this study is to determine both clinical and biological effects of verum acupuncture for combat-related
PTSD in treatment-seeking US Veterans.
Methods: This is a two-arm, parallel-group, prospective randomized placebo-controlled clinical trial. The
experimental condition is verum acupuncture and the placebo control is sham (minimal) acupuncture in 1-h
sessions, twice a week for 12 weeks. Ninety subjects will provide adequate power and will be allocated to
group by an adaptive randomization procedure. The primary outcome is change in PTSD symptom severity
from pre- to post-treatment. The secondary biological outcome is change from pre- to post-treatment in
psychophysiological response, startle by electromyographic (EMG) eyeblink. Assessments will be conducted at
pre-, mid-, post-, and 1-month post-treatment, blind to group allocation. Intent-to-treat analyses will be
conducted.
Discussion: The study results will be definitive because both clinical and biological outcomes will be assessed
and correlated. Issues such as the number needed for recruitment and improvement, use of sham
acupuncture, choice of biological measure, and future research need will be discussed.
Trial registration: ClinicalTrials.gov NCT02869646. Registered on 17 August 2016.
Keywords: Post-traumatic stress, Acupuncture, Combat, Veterans, Psychophysiology
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* Correspondence: michael.hollifield@va.gov
1
Tibor Rubin VA Medical Center, 5109 E. 7th Street, Long Beach, CA 90822,
USA
2
The George Washington University School of Medicine and Health Sciences,
Washington, DC, 2300 I Street NW, Washington, DC 20052, USA
Full list of author information is available at the end of the article
Hollifield et al. Trials (2021) 22:594
https://doi.org/10.1186/s13063-021-05394-3
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Administrative information
Title Acupuncture for Combat Post-traumatic Stress
Disorder: Trial Development and Methodological
Approach for a Randomized Controlled Clinical
Trial
Trial Registration ClinicalTrials.gov ID: NCT02869646, registered
17
th
August 2016
Trial Registration
Dataset
Health conditions: posttraumatic stress disorder.
Intervention: verum acupuncture. Placebo: sham
acupuncture. Key inclusion criteria: combat
veterans with posttraumatic stress disorder
(PTSD), age 18-55. Key exclusion criteria: other
Serious mental illness, drug or alcohol depend-
ence, previous acupuncture treatment. Study
type: interventional, randomized allocation. Tar-
get sample size 90. Primary outcome: PTSD
symptoms. Key Secondary outcome: startle
reflex.
Protocol version 5
th
June 2020. Version 1
Funding This work was supported by the VA Merit Award
#l01 CX-001416-01 (Project ID: CLNA-02-15F)
from the United States (U.S.) Department of Vet-
erans Affairs, Clinical Sciences Research and De-
velopment, as well as, supported with resources
and the use of facilities at the Tibor Rubin VA
Medical Center in Long Beach.
Contributorship 1. Tibor Rubin VA Medical Center, 5109 E. 7
th
Street, Long Beach, CA 90822, USA - michael.
hollifield@va.gov,anfu.hsiao@va.gov,Kala.Carrick-
Harkin@va.gov,Andrea.munoz@va.gov,Teresa.
Calloway2@va.gov,Karen.Cocozza@va.gov,
christopher.reist@va.gov
2. The George Washington University School of
Medicine and Health Sciences, Washington, DC,
2300 I Street NW, Washington, DC 20052
michael.hollifield@va.gov
3. UC Irvine Health Policy Research Institute, 100
Theory, Suite 110. Irvine, CA 92697 - ahsiao@uci.
edu
4. Analydata, 3835 Centraloma Drive, San Diego,
CA. 92107 - besasmith@analydata.com,
tylersmith@analydata.com
5. Wayne State University School of Medicine,
Department of Psychiatry and Behavioral
Neurosciences, 3901 Chrysler Service Drive,
Detroit, MI 48201 –tjovanovic@med.wayne.edu,
snorrholm@wayne.edu,
6. University of South Carolina School of
Medicine - Greenville, 701 Grove Rd., Greenville,
SC 29605 - sokhadze@greenvillemed.sc.edu
7. University of California at Irvine, 680 California
Ave. Irvine, CA 92697 - creist@uci.edu,
All authors contributed to the study concept
and study design throughout study. As primary
investigators MH and AH conceived the study,
led the proposal and protocol development.
Acupuncture expertise contributions are by AH,
MH, KC, and TC. Design and statistical expertise
contributions are by MH, TS, BS and AGM.
Psychophysiology expertise is led by TJ, SN, ES,
MH, and KC. All authors critically revised and
approved the final manuscript.
Sponsor and contact
information
Department of Veteran Affairs, Veterans Health
Administration, Office of Research and
Development, Clinical Science Research and
Development; Merit Review Program
Administrative information (Continued)
Michael Hollifield, MD: Michael.hollifield@va.gov
Sponsor and funder The study sponsor and funder were not
involved in the study design, writing of the
protocol paper, or the decision to submit the
paper for publication.
Background
Post-traumatic stress disorder (PTSD) is debilitating and
characterized by re-experiencing aspects of the incident
trauma, avoidance and numbing of trauma reminders,
negative alterations in cognition and mood, and hyper-
arousal [1]. Lifetime prevalence of PTSD in community
samples is about 6.8% [2] and as high as 30% in Vietnam
Veterans [3] and rape survivors [4]. More recent OEF/
OIF/OND Veterans have 13–25% PTSD prevalence,
dependent on combat exposure [5,6].
The first known randomized controlled clinical trial
(RCCT) using acupuncture and a traditional Chinese
medicine (TCM) approach for PTSD was published in
2007 [7], showing verum acupuncture was superior to a
wait-list control and equivalent to group cognitive be-
havior therapy (CBT). A paper describing protocol de-
velopment and methodology for that study was
published in 2006 [8]. These novel findings led to a
broader adoption of acupuncture practice for PTSD in
the Veterans Administration Hospitals and across the
USA [9] as well as further research regarding the use of
acupuncture for PTSD [10–13]. These and other sum-
mative findings indicate a complex biology of PTSD in-
cluding hypothalamic-pituitary-adrenal (HPA) axis
dysfunction, autonomic nervous system (ANS) dysfunc-
tion, alterations in central nervous system (CNS) pro-
cesses, and inflammatory dysregulation, all under
complex gene x environmental interaction control, and
there is a large human and animal literature about bio-
logical effects of acupuncture in these systems [14]. Re-
ported research outcomes since the first publication
have generally supported the efficacy of acupuncture for
PTSD, though methodological limitations inhibit strong
supportive consensus [15].
Limitations in early studies were the lack of a placebo
(sham) arm, understanding best practices about placebo,
use of self-report assessment instruments as primary
outcomes, lack of a biological outcome, use of single
therapists, and lack of monitoring protocol adherence.
In general, scientific discourse about limitations of acu-
puncture clinical trials persist with the most common
concerns being the inability to conduct double-blind tri-
als, the lack of a true placebo, the variability of treatment
approaches, the rare assessment of protocol adherence,
and the inability to assess non-specific factors on treat-
ment outcome. The current study was designed to
Hollifield et al. Trials (2021) 22:594 Page 2 of 14
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address many of these limitations and raise the bar for
showing efficacy by having both clinical and biological
outcomes and using a sham control.
Study design and methods
Design
This is a two-arm, parallel-group, prospective random-
ized placebo-controlled clinical trial at the Long Beach
VA Healthcare System (LBVA), with internal collabor-
ation with The Program for Traumatic Stress’Novel
Therapies Unit, the Integrative Medicine Clinic, the Re-
search Healthcare Group, and the PTSD psychophysi-
ology laboratory, and external collaboration with design
and analytic experts from University of California at San
Diego and The National University and psychophysi-
ology experts from Wayne State University School of
Medicine and the University of South Carolina at
Greenville.
The sample frame is treatment-seeking Veterans with
chronic combat-related PTSD at the LBVA or affiliated
programs. The sample size of 90 provides adequate
power to test the primary hypothesis. Withdrawals prior
to beginning intervention will be replaced and with-
drawals after beginning intervention will not be
replaced.
Ethical approval, monitoring, and personal information
management
This study was approved by the Institutional Review
Board and the Research and Development Committee
at the Tibor Rubin VA Medical Center. The reporting
of this trial is conducted according to
Recommendations for Intervention Trials (SPIRIT)
guidelines and the SPIRIT-TCM extension (Table 1).
Interim study monitoring is by the centralized Data
Monitoring Committee (DMC) of VA Office of
Research and Development. As noted in the DMC
assignment and charter dated 3/24/2016 and 6/23/
2016, respectively, the DMC is comprised of 4
members who are selected in part because they have
no conflict of interest with the study and who act
independently and advise the Director of VA
Research about study progress, adverse events, data
integrity, and whether to stop and/or start the study.
The study project manager will track any adverse and
serious adverse events per protocol. Interim analyses
for adverse events and study benefits will be
conducted at 6-month intervals by study statisticians
and, according to charter stopping rules, will inform
thestudyPIiftheserulesmayneedtobeimple-
mented. No other audits will be conducted. Personal
information of subjects will be kept separate in both
hard and electronic copies and de-identified in the
saved database.
Research questions
Study objectives
The main objective of this paper is to describe the
methodological approach of an RCCT designed to
determine the clinical and biological effects of verum
acupuncture for combat-related PTSD in US Veterans.
Secondary objectives of the RCCT are to determine the
effects of acupuncture on symptoms and biology associ-
ated with PTSD.
RCCT primary hypothesis
The efficacy of verum acupuncture (ACU) for PTSD
symptom severity will be large (pre- to post-treatment
Cohen’sd≥0.8) and significantly better than sham acu-
puncture (MIN), between-group Cohen’sd≥0.30, with
80% probability of detecting a true group difference at p
< 0.05 (2-sided).
RCCT secondary hypothesis
Compared to MIN, ACU will be associated with a
significantly larger change from pre- to post-treatment
in peripheral psychophysiological responses (PPRs) (de-
creased startle by EMG eyeblink during fear condition-
ing) with 80% probability of detecting a true group
difference at p < 0.05 (2-sided).
RCCT exploratory hypotheses
1. The efficacy of ACU for symptoms comorbid with
PTSD (depression, anxiety, somatic symptoms, sleep and
dreaming symptoms, and functional impairment) will be
large (pre- to post-treatment Cohen’sd≥0.8) and sig-
nificantly better than MIN (between-group Cohen’sd≥
0.25).
2. Compared to MIN, ACU will be associated with a
significantly larger change from pre- to post-treatment
in peripheral psychophysiological responses (PPRs) (de-
creased heart rate and skin conductance responses and
decreased sympathetic activation as measured by skin
conductance level and increased parasympathetic activa-
tion measured by heart rate variability during baseline
and fear conditioning).
Determining sample size
Extant clinical trials about acupuncture for PTSD—or
any condition for that matter—use variable measures
and outcomes, making sample size determination
challenging. Our own initial study utilized the
Posttraumatic Symptom Scale –Self Report (PSS-SR)
for The Diagnostic and Statistical Manual of Mental
Disorders IV (DSM IV) [35] as the primary outcome,
whereas the current study uses the Clinician-
Administered PTSD Scale (CAPS-5) for Diagnostic and
Statistical Manual of Mental Disorders-5th ed. (DSM-5)
[16], metrics of which were not published at the time of
Hollifield et al. Trials (2021) 22:594 Page 3 of 14
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Table 1 SPIRIT chart. CAPS-5 is the Clinician-Administered PTSD Scale-5; SCID is the Structured Clinical Interview for Diagnosis; DES-II
is the Dissociative Experiences Scale; DRRI is the Deployment Risk and Resilience Inventory-2; CES is the Combat Exposure Scale; LEC
is the Life Experiences Checklist; ACE is the Adverse Childhood Experience Questionnaire; MoCA is the Montreal Cognitive
Assessment; PCL-5 is the PTSD Checklist-Military-5; PPR is Psychophysiological Response; BDI-II is the Beck Depression Inventory –II;
HAM-A is the Hamilton Anxiety Rating Scale; NMCL-SOM is the New Mexico Symptom Checklist –Somatic Scale; The PSQI is the
Pittsburg Sleep Quality Index; VR-12 is the Veterans RAND 12-item Health Survey; EDS is the Emotion Dysregulation Scale; McGill is
the McGill Pain Questionnaire; Southampton is the Southampton Needle Sensation Questionnaire; AQ is the Aggression
Questionnaire; CRS is the Credibility Rating Scale
STUDY PERIOD
Enrollment Allocation and
Baseline
Treatment Follow-up
Timepoint Week -4 to -1 Week -4 to 0 Week 0 Week 6 Week 12 Week 16
Screening, Enrollment, Allocation and Baseline Data
Screening for Eligibility X
Informed Consent X
Inclusion and Exclusion
CAPS-5 [16]X
SCID [17]X
DES-II [18]X
DRRI [19]X
CES [20]X
Narrative-Exposure, Effects on Health and with
Treatment (unpublished)
XX
LEC [21]X
ACE [22]X
MoCA [23]X
Allocation X
Interventions
Verum Acupuncture
Sham Acupuncture
Assessments: Primary Outcomes
CAPS-5 Severity Score [16]XXXX
PCL-5 [24]XXXX
Assessments: Secondary Outcome
PPR (startle response) X X X X
Assessments: Exploratory
BDI –II [25]XXXX
HAM-A [26]XXXX
NMCL –SOM [27]XXXX
PSQI [28]XXXX
VR-12 [29]XXXX
EDS [30]XXXX
McGill [31]XXX
Southampton [32] Bi-weekly
PPR (HR, HRV, SCR) X X X X
Assessments: Safety and Control
AQ [33]. Weekly X X
BDI –II items 9, 11, 17 Weekly X X
Hollifield et al. Trials (2021) 22:594 Page 4 of 14
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study planning. Our first study design was active acu-
puncture vs. a wait-list control. The current study will
use a minimal needling (MIN) sham control to verum
acupuncture (ACU), and there are no published data
about this comparison in PTSD. A 2010 Cochrane sys-
tematic review of over 200 trials investigating 60 clinical
conditions found placebos to not have important clinical
effects yet may influence patient-reported outcomes in
some situations (e.g., pain and nausea). In that review,
the pooled relative risk calculated for placebo was 0.93,
an effect of only 7% yet significant. Confidence intervals
are generally wider in placebo vs. active condition. Sev-
eral clinical and methodological factors were associated
with higher effects of placebo. Since our study includes
some of these factors, we reasoned that MIN could pro-
vide as much as a 33% reduction in PTSD symptoms
with a wider variance than ACU. A conservative predic-
tion would be a mean CAPS-5 reduction of 25 points
with ACU and 16.5 points with MIN, which is an 8.5-
point between-group post-treatment difference with a
pooled SD of 14.4. A less conservative expectation is a
12-point between-group difference and a pooled SD of
15. The conservative assumption will result in pre- to
post-treatment Cohen’sd= 2.07 within group (ACU)
and d= 0.59 between group (post-treatment difference),
which will result in a rejection of the null hypothesis in
favor of the alternative and show a large treatment effect
for ACU and a moderate between-group effect size. The
conservative assumption requires a total of 90 patients
in a two-arm parallel design to provide a probability of
80% to detect a treatment difference at a two-sided 0.05
significance level. The modest assumption requires a
total of 50 patients with a power of 0.80 at alpha < 0.05.
We will randomize 90 subjects for this trial to be well
powered to achieve a more definitive conclusion than
previous trials.
Inclusion criteria
These criteria were meant to recruit a relatively
homogeneous yet generalizable sample. Criteria are (1)
Veterans age 18 to 55, (2) DSM-5 criteria for chronic
PTSD on the CAPS-5, and (3) at least moderate PTSD
by having a total CAPS-5 score of ≥26 and meeting cri-
teria for each of 4 symptom clusters. Eligible persons
will be allowed to have other symptoms that are com-
monly comorbid with PTSD (e.g., anxiety, mild to mod-
erate depression).
We would have ideally included an older age range of
Veterans to increase sample frame and generalizability.
However, ANS function (sympathetic/parasympathetic
“balance”) begins to change at about age 55 [36–38].
Since acupuncture may work via the ANS, and since
secondary and exploratory hypotheses are dependent on
ANS functioning, and the ANS age-related changes are
Table 1 SPIRIT chart. CAPS-5 is the Clinician-Administered PTSD Scale-5; SCID is the Structured Clinical Interview for Diagnosis; DES-II
is the Dissociative Experiences Scale; DRRI is the Deployment Risk and Resilience Inventory-2; CES is the Combat Exposure Scale; LEC
is the Life Experiences Checklist; ACE is the Adverse Childhood Experience Questionnaire; MoCA is the Montreal Cognitive
Assessment; PCL-5 is the PTSD Checklist-Military-5; PPR is Psychophysiological Response; BDI-II is the Beck Depression Inventory –II;
HAM-A is the Hamilton Anxiety Rating Scale; NMCL-SOM is the New Mexico Symptom Checklist –Somatic Scale; The PSQI is the
Pittsburg Sleep Quality Index; VR-12 is the Veterans RAND 12-item Health Survey; EDS is the Emotion Dysregulation Scale; McGill is
the McGill Pain Questionnaire; Southampton is the Southampton Needle Sensation Questionnaire; AQ is the Aggression
Questionnaire; CRS is the Credibility Rating Scale (Continued)
STUDY PERIOD
Enrollment Allocation and
Baseline
Treatment Follow-up
Timepoint Week -4 to -1 Week -4 to 0 Week 0 Week 6 Week 12 Week 16
Satisfaction with Care and Provider Scale (Unpublished) X X
Intercurrent Health Resource Use Inventory (unpublished) X X X
Assessments: Fidelity and Credibility
Treatment Fidelity Assessment (Unpublished) selected
CRS [34] selected session 2 session 24
CAPS-5 is the Clinician Administered PTSD Scale-5; SCID is the Structured Clinical Interview for Diagnosis; DES-II is the Dissociative Experiences Scale; DRRI is the
Deployment Risk and Resilience Inventory-2; CES is the Combat Exposure Scale; LEC is the Life Experiences Checklist; ACE is the Adverse Childhood Experience
Questionnaire; MoCA is the Montreal Cognitive Assessment; PCL-5 is the PTSD Checklist-Military-5; PPR is Psychophysiological Response; BDI-II is the Beck
Depression Inventory –II; HAM-A is the Hamilton Anxiety Rating Scale; NMCL-SOM is the New Mexico Symptom Checklist –Somatic Scale; The PSQI is the
Pittsburg Sleep Quality Index; VR-12 is the Veterans RAND 12-item Health Survey; EDS is the Emotion Dysregulation Scale; McGill is the McGill Pain Questionnaire;
Southampton is the Southampton Needle Sensation Questionnaire; AQ is the Aggression Questionnaire; CRS is The Credibility Rating Scale
Chan A-W, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-JerićK, Hróbjartsson A, Mann H, Dickersin K, Berlin J, Doré C, Parulekar W, Summerskill W,
Groves T, Schulz K, Sox H, Rockhold FW, Rennie D, Moher D. SPIRIT 2013 Statement: Defining standard protocol items for clinical trials. Ann Intern Med.
2013;158(3):200-207.
Dai L, Cheng CW, Tian R, Zhong LL, Li YP, Lyu AP, Chan AW, Shang HC, Bian ZX. Standard Protocol Items for Clinical Trials with Traditional Chinese Medicine 2018:
Recommendations, Explanation and Elaboration (SPIRIT-TCM Extension 2018). Chin J Integr Med. 2019;25(1):71-79. PMID: 30484022
Hollifield et al. Trials (2021) 22:594 Page 5 of 14
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
difficult to detect in order to rationally exclude subjects,
the best choice was to exclude those older than 55 [39].
Exclusion criteria
These criteria were meant to rule out individuals with
characteristics that are known to be PTSD treatment
confounds, that might affect biological assessment, that
indicate past non-adherence or treatment resistance, or
that indicate risk of harm. Criteria are (1) current and
past 6-month psychosis; (2) substance dependence
within the past 6 months; (3) thyroid disease; (4) deci-
sional incapacity; (5) centrally acting medications that
have a potential effect on biological expression (e.g.,
beta-blockers, opiates, and ≥10 mg equivalent of diaze-
pam/day), (6) pain levels requiring opiate medications;
(7) known exposure to chemicals or physical trauma that
cause neuropsychiatric sequelae; (8) severe depression
(Beck Depression Inventory-II score ≥30) that is
deemed more clinically significant than PTSD; (9) a di-
agnosed and untreated sleep breathing disorder (SBD);
(10) a high risk of a SBD as indicated by snoring ≥50%
of nights plus one of (a) any witnessed apnea, (b) feeling
non-refreshed in the morning ≥50 of mornings, or (c)
daytime sleepiness indicated by falling asleep with rou-
tine tasks such as watching TV or reading; (11) non-
response to ≥2 evidence-based PTSD treatments (ad-
equate medication of 12 weeks or completion of Pro-
longed Exposure therapy, Cognitive Processing Therapy,
or an intensive program); (12) treatment non-adherence
indicated by stopping treatment or > 3 missed appoint-
ments in the course of a PTSD treatment; (13) high dis-
sociation as indicated by a score of ≥25 on the
Dissociative Experiences Scale –II (DES-II) [18]; (14)
past chronic PTSD prior to military service; (15) current
active psychotherapy for PTSD; (16) having had acu-
puncture in the past year; or (17) pregnancy. A person
who is on a stable dose (6 weeks) of medication for de-
pression, anxiety, PTSD, or sleep and who will continue
these medications for the duration of the trial will not
be excluded.
Discontinuation criteria and post-study care
Participation is voluntary, so a subject may discontinue
at any time. A subject has 15 weeks to complete the 24
sessions but will not be discontinued for proceeding at a
slow pace, as we will evaluate outcomes by the number
of sessions completed. Adherence to the protocol is thus
tracked as the number of sessions completed. A subject
may be withdrawn if they engage in exclusionary criteria
(e.g., obtain other PTSD-specific treatment). Subjects
may receive ancillary care during the trial if that care is
not a specific evidence-based treatment for PTSD (e.g.,
prolonged exposure therapy). All subjects will be
referred back to the initial referral source for post-study
clinical care.
Recruitment and screening
Figure 1shows the flow of subjects through the study. A
two-stage detection method will be utilized to identify a
sample of PTSD treatment seekers. For stage I, the Pro-
gram Manager (PM) will respond to interested patients
by conducting a phone screen. If a participant meets the
initial criteria during the phone screen, the PM will
schedule the patient to administer informed consent.
Those who consent will be assessed with screening in-
struments for inclusion and exclusion criteria, availabil-
ity, and willingness to participate in the study. For stage
II, inclusion/exclusion confirmation will be completed
by the PM and assessor. The PM will administer the
Montreal Cognitive Assessment (MoCA), DES-II, and
The Deployment Risk and Resiliency Inventory (DRRI)
combat experiences scale and preparedness scale [19]to
aid group allocation. The assessor will administer CAPS-
5 (past month) and a modified Structured Clinical Inter-
view for Diagnosis DSM-5 (SCID-5) [16]. The PM and/
or Primary Investigator (PI) will assess current medica-
tions as potential exclusions.
It is not known how many patients will need to be
contacted and introduced to the study in order to
randomize the desired 90 as subjects [40].
Recruitment will be from sources at the VA proven
to be successful in previous studies. Enhancements to
recruitment will be to advertise to Veteran groups in
the larger Los Angeles area. Retention is best
promoted during recruitment by being fully
transparent and providing disclosure about
procedures, timeline, and study payments. A subject
who withdraws will be provided the opportunity to
continue providing data on the planned schedule to
enhance study data. As part of informed consent,
subjectswillunderstandwheretogoandwhoto
contact for financial and/or clinical compensation if
they have been harmed by the clinical trial.
Randomization and blinding of staff to allocation and
data
Subjects will be allocated to the intervention group by a
computer-generated adaptive randomization procedure
called minimization. Because of the adequate but still
modest sample size in this study, simple randomization
may not provide group equality on variables that may
affect outcome. While minimization can risk subversion
or technical error [41], it has been shown to be the best
method of ensuring balance between groups for several
prognostic factors in small to moderate samples [42,43],
where blocking and stratification are not effective in
such trials. With minimization, the treatment allocated
Hollifield et al. Trials (2021) 22:594 Page 6 of 14
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
to the next participant enrolled in the trial depends on
the characteristics of those participants already enrolled
to minimize the imbalance across factors. While data
about factors that predict outcome in PTSD are not ro-
bust, one study in Veterans showed that combat expos-
ure and pre-deployment preparedness accounted for
significant outcome variance using standard exposure-
based psychotherapy [44]. There are also data suggesting
gender effects of emotional disclosure interventions for
PTSD in non-Veteran subjects [45]. As such, allocation
to the group will use minimization to provide group
equality in descending priority on (1) number in each
group, (2) combat exposure, (3) pre-deployment pre-
paredness, and (4) gender.
The Data Analyst (DA) will assign a subject the
next consecutive study ID number (i.e., SID# 1–90),
which will be the only number on hard copies of
documents in order to conceal allocation and
maintain blind of all investigators and other staff. The
DA will create a separate and password-protected
database that will contain randomized data on treat-
ment allocation for participants (ACU vs. MIN). One
letter is assigned to participants allocated for ACU
and another letter is assigned to participants allocated
for MIN. The DA will be the only study staff member
that will be able to link SID numbers to the assigned
treatment arm and the only staff member to know
the password for the randomization database. Other
study personnel will be blind to this process and will
only see the SID#. This procedure will keep the asses-
sor blind to intervention allocation, and investigators
and clinicians blind to assessment data to minimize
performance and outcome detection bias. Unblinding
is possible only if a subject experiences a serious
Fig. 1 Sample frame and flow of project
Hollifield et al. Trials (2021) 22:594 Page 7 of 14
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adverse event deemed to be possibly due to the inter-
vention. Unblinding may be conducted by the clin-
ician during or shortly after an ACU or MIN session
if the subject has a serious adverse event requiring
immediate medical attention, although this is highly
unlikely. Unblinding may be conducted by the PI at
any time if the subject is experiencing distress from
an adverse event that potentially compromises the
subjects’health, safety, or wellbeing. If unblinding oc-
curs, the subject is immediately withdrawn from the
intervention though may participate in further data
collection.
Intervention: selection of experimental and control
conditions
Selecting a control condition to verum acupuncture
(ACU) is not as straightforward as a placebo pill in a
medication trial where double blinding is possible. Many
factors may be responsible for improvement with
acupuncture—and thus could be controlled for—
including provider enthusiasm, positive expectation of
the patient, extra attention, physiological effects of
needling anywhere, physiological effects of needling at
the chosen acupoints, and natural history of the illness.
The choice of a control group in an acupuncture trial is
a critical one and dependent on study aims [46].
Alternative design options we considered include a
three-arm design (ACU vs. MIN and a non-needling re-
laxation group—RELAX), a two-arm design comparing
ACU with another type of sham acupuncture (a non-
insertive needle), and a comparative effectiveness trial of
ACU with a current Evidence-Based Therapy (EBT) for
PTSD. However, the three-arm design has potential
problems with adequate power and interpreting data if
the differences between the ACU and MIN groups are
small because we may not have been able to recruit 45
subjects per group at one site. The use of the non-
insertive needle is a good option, yet is expensive and
labor intensive, and perhaps no better a placebo than
MIN. A comparative trial of ACU with a standard EBT
is premature; better proof of efficacy for ACU for PTSD
needs to be first established. There are other important
questions and research designs about the effects of
ACU, such as evaluating the importance of meridians
versus individual points, the validity of point fatigue, the
mechanisms of action in specific biological systems, or
the most effective dose. These should be addressed after
efficacy is established.
Sham procedures are not fully inactive [47]. There
are essentially three ways to conduct sham
acupuncture using needles. Two involve needle
insertion: (1) insertion and manipulation in the same
manner but at purportedly “irrelevant”points, usually
a few millimeters from actual verum points, or (2)
superficial insertion at verum points, usually without
manipulation in order to not elicit the “DeQi”
sensation. Each, or a combination of each, has been
labeled “minimal needling.”Investigators have also
used various gauge-size needles and very small mono-
filamentsasinsertiveshams.Thethirdtypeofsham
(3) is non-insertive, where a blunt needle within an
adhesive O-ring mechanism hits the skin and retracts
without puncture. When this sham is used, the nee-
dles for verum acupuncture are also administered via
the adhesive O-ring for blinding. Both insertive and
non-insertive procedures probably influence expect-
ation, sensation, and contextualization, and both have
shown effects in brain areas controlling sensation,
cognition, and affect [48]. While non-insertive needles
have been developed and shown to be valid shams
from the subjective patient view (e.g., the “Streitber-
ger”and the “Park Sham Device”)[47,49], these are
farmorecumbersomeandveryexpensivecompared
to minimal needling. And, research has shown clinical
differences between verum ACU and MIN needling
techniques, for example in studies of chemotherapy-
induced emesis control [50] and blood pressure con-
trol [51]. In the Shen study where all patients were
provided pharmacotherapy for emesis, emesis events
and emesis-free days were significantly better with
ACU vs. MIN vs. pharmacotherapy only (events 5 vs.
10 vs. 15, respectively; free days 55% vs. 29% vs. 20%,
respectively). MIN is the best available sham control
to verum ACU because they both are similar in all
aspects except that MIN includes irrelevant acupoints
and shallow insertion without trying to obtain DeQi.
Acupuncture needles can be stimulated manually
by rotating, lifting, and/or thrusting or by using an
electrical stimulator or both. The majority of recent
acupuncture studies in animals and humans use
electrical stimulation, which delivers more
consistent stimuli to afferent nerves than the
manual-only approach and may have a stronger im-
pact on inhibiting neural cell activities than the
manual approach (MA) [52].
Intervention: protocols
Experimental group: verum acupuncture (ACU): Table 2
Individual treatment sessions are 1 h twice per week
for 12 weeks and reflect clinical practice with an
interview (10 min), pulse and tongue observation (5
min), standard needling, and needle retention (30
min). Subjects receive a standard acupuncture point
prescription defined in our previous study and chosen
for the most likely TCM diagnostic patterns for
PTSD. An alternating by session front and back
treatment will be used to avoid point fatigue
(tolerance due to frequent use). Bringing DeQi for
Hollifield et al. Trials (2021) 22:594 Page 8 of 14
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
each point is desired. The front treatment is
comprised of 11 needles, bilaterally at LV3, PC6,
HT7, ST36, SP6, and at the single Yintang point; the
back treatment is 14 needles, bilaterally at GB20 and
UB14, 15, 18, 20, 21, and 23. In addition to the
standard points, three additional points (chosen from
a list of 15 points) will be chosen to address a
subject’s constitution based on the TCM diagnostic
patterns, available in original published reports [7,8].
Control group: sham minimal needling (MIN): Table 3
Individual treatment sessions are 1 h twice per week
for 12 weeks. Three elements define minimal needling
in this study. The first is the location of the needles,
which are 2 cm lateral or medial to actual reference
points, which are not associated with PTSD and are
not expected to affect PTSD symptoms. The second
is the superficial insertion depth (< 0.25 inch)
compared to ACU. The third is the relative absence
of stimulation due to the depth and the use of a non-
functioning stimulator to complete the sham effect.
The actual distance between the acupuncture refer-
ence point and the sham site needled is approximate,
with consideration given to (1) nearby acupuncture
meridians; (2) superficial or deep anatomical features
such as skin abrasion, visible vessels, or palpable
nerves; and (3) the proportions of each patient’sbody.
For example, the lung and large intestine meridians
areclosetooneanotheratthelocationofLU7,so
care is taken to choose a sham needling site between
the two meridians. Some discretion is afforded the
acupuncturists with regard to sham needling sites
near SI 4 and SJ 12 based on the patient’s selection
of body position on the table, and in this case, we
have listed the sham site as either anterior or poster-
ior, with care taken to remain off-meridian. The acu-
puncturist will perform no manipulation to obtain
DeQi and sham needles will only be adjusted to more
superficial depth to minimize reported sensations
such as stinging or irritation. The protocol also uses
Table 2 Acupuncture points for the treatment of post-traumatic stress disorder
Primary patterns (standard points for all subjects)
HT Shen disturbance LV Qi stagnation Kidney deficiency Grounding points/Qi and blood
deficiency
Front
points
HT7, PC6 and Yintang
(even)
LV3, (PC6) (even) ST36, SP6 (even)
Back
points
UB14, 15 (even) GB 20, UB18 (even) UB 23 (reinforce) UB 20, 21 (even)
Secondary patterns (up to three points chosen)
LV overacting on SP LV overacting on
ST
ST fire LV fire Phlegm-heat Phlegm-damp
Front
points
LV13 (reinforce) LV14 (reduce) ST44 (reduce) LV2 (reduce) ST40 (reduce) SP9 (reduce)
Back
points
UB18 (reduce)
UB20 (reinforce)
UB18 (reduce)
UB21(reduce)
Du 14 (reduce)
UB21 (reduce)
Du 14 (reduce)
UB18 (reduce)
Du 14 (reduce)
UB21 (reduce)
UB20 (reduce)
HT Yin/blood
deficiency
SP Qi/Yang
deficiency
KI Yin/essence
deficiency
KI Yang/Qi
deficiency
LV Yin/blood
deficiency
ST Yin
deficiency
Front
points
HT6 (reinforce) SP3 (reinforce) KI6 (reinforce) KI7 (reinforce) LV8 (reinforce) ST44 (reinforce)
Back
points
UB17 (reinforce)
UB15 (reinforce)
UB20 (reinforce)
UB23 (reinforce)
UB52 (reinforce)
UB23 (reinforce)
Du4 (reinforce)
UB23 (reinforce)
UB17 (reinforce)
UB18 (reinforce)
UB21
(reinforce)
Table 3 Sham (MIN) points for the treatment of post-traumatic stress disorder
Point locations-front treatment
Reference
point
SI19 (left) SJ3 SI4 LU7 LU6 ST25 ST34 SP7
Adjusted
location
1cm
anterior
1cm
lateral
1–2 cm distal and 1 cm
posterior or anterior*
1 cm proximal and 1
cm posterior
1cm
lateral
2cm
lateral
2cm
medial
1–2 cm posterior
Point locations-back treatment
Reference
point
SI15 SI11 SI9 SJ12 GB30 GB32 GB33 GB34 UB57
(left)
Adjusted
location
1–2cm
lateral
1–2cm
lateral
1–2 cm lateral 1–2 cm anterior or
posterior*
2cm
lateral
2cm
posterior
1–2cm
posterior
2cm
posterior
2cm
lateral
Hollifield et al. Trials (2021) 22:594 Page 9 of 14
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11 front and 14 back points to match the number
and body position (alternating prone and supine) of
points in the ACU group.
Informing subjects and maintaining blind about group
allocation
Blinding may be compromised unless care is taken
during allocation, informed consent, and the actual
sessions. We will adopt practical steps after McManus
et al. [53], which include how to set up the room and
materials prior to treatment, the materials to have on
hand, and how to insert, manipulate, and remove the
needles. These procedures were shown in an RCT to
be successful by having 71% of those receiving sham
and 81% of those receiving verum (p = 0.20) believe
they received “real”treatment. Another important
procedure for maintaining subject blinding is the
construction and delivery of the informed consent.
Subjects will all be informed that there are “two types
of treatments that involve acupuncture needles”or
“two forms of treatment with needles”that will be
used during this clinical trial, and that they will be
randomly allocated to receive either one or the other
treatment. Subjects will not be offered the name or
type of the interventions. As part of the informed
consenting process, participants will be told
researchers do not know which group will be more
beneficial than the other and that figuring this out is
the goal of the study. Any questions they ask about
the needles or technique will be responded to with a
structured answer that has been part of the training
of all staff prior to the trial, such as “as mentioned in
the consent, there are two types of needle methods
being used, and you may receive either one during
any given session.”
Controlling for non-specific treatment-related effects
It is critical for those in the MIN group to receive an
equivalent amount and kind of time, empathy, setting,
and assessment as those in the verum ACU group. Both
ACU and MIN protocols will include language currently
in our acupuncture clinical trials manual for greeting,
interacting with, and closing a session.
Outcome measures and data entry, integrity, and
analyses
Primary outcome: clinical
The CAPS-5 [16] is a structured diagnostic interview
assessing DSM-5 criteria for PTSD. CAPS-5 items are
rated with a single severity score, in contrast to previous
versions of the CAPS which required separate frequency
and intensity scores for each item that were either
summed to create a symptom severity score or com-
bined in various scoring rules to create a dichotomous
(present/absent) score. CAPS-5 has 20 symptom items,
each rated from 0 (absent) to 4 (severe). A rating of > 2
is considered a positive score for diagnostic purposes.
There are 4 symptom clusters: the Criterion B (re-ex-
periencing) severity score is the sum of individual scores
for items 1–5, the Criterion C (avoidance) severity score
is the sum of items 6 and 7, the Criterion D (negative al-
terations in cognitions and mood) severity score is the
sum of items 8–14, and the Criterion E (hyperarousal)
severity score is the sum of items 15–20. The DSM-5
diagnostic rule requires the presence of at least one Cri-
terion B symptom, one Criterion C symptom, two Cri-
terion D symptoms, and two Criterion E symptoms in
addition to other impairment criteria.
Secondary outcome: biological, psychophysiological
response (PPR) startle eyeblink
Acoustic startle responses will be measured as part of an
established fear conditioning paradigm that employs
visual conditioned stimuli (CSs) paired with a 250-ms air-
blast with an intensity of 140 psi directed to the larynx
(unconditioned stimulus; US), a protocol that has been
used with numerous populations both psychiatrically
healthy and trauma-exposed [54]. This paradigm has been
shown to be sensitive to treatment effects for PTSD [55].
Startle responses are obtained from EMG recordings dur-
ing eyeblink muscle contractions induced by a 108-dB
burst of white noise [54] that is present on each trial of
the fear conditioning task. PPR data will be collected,
amplified, and digitized by the Biopac MP150 system for
windows (Biopac Systems, Inc., Goleta, CA), using the
EMG, electrodermal activity (EDA), and electrocardio-
gram (ECG) modules. Data will be exported to Mindware
software (Mindware Technologies LTD, Gahanna, OH)
for data reduction and generation of analyzable variables.
The final output will be analyzed to assess fear-
potentiated startle (the relative increase in the startle mag-
nitude elicited in the presence of conditioned stimuli) as
well as the reduction of fear during extinction.
EMG startle eyeblink responses will be recorded using
two 5-mm silver/silver chloride (Ag/AgCl) electrodes
placed over the orbicularis oculi muscle of the right eye.
One electrode will be placed directly below the pupil in
forward gaze while the other will be placed about 1 cm
lateral to the first. Both electrodes will be placed as close
to the eye as possible while still allowing the participant
to close his or her eyes comfortably. Skin conductance
will be acquired through two Ag/AgCl electrodes placed
on the palm, and ECG will be collected in the lead 2
position, with active electrodes placed below the collar-
bone and on the torso. Impedance between the two
EMG electrodes will be measured and deemed accept-
able if below 10 kΩ. EMG data will be filtered between
Hollifield et al. Trials (2021) 22:594 Page 10 of 14
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
28 and 500 Hz and peak amplitude occurring between
20 and 200 ms after startle probe onset will be scored.
Exploratory outcomes
We will evaluate the efficacy of ACU for symptoms
comorbid with PTSD (depression, anxiety, somatic
symptoms, sleep and dreaming symptoms, and
functional impairment) and for other PPR (heart rate
and skin conductance responses to assess sympathetic
activation and parasympathetic activity as measured by
high-frequency heart rate variability (HF-HRV) during
baseline and fear conditioning).
Treatment fidelity and subject expectancy
Assuring treatment fidelity is important in clinical trials.
With one practitioner, accuracy and consistency are
required, but of course there is no need for inter-
therapist reliability. Study acupuncturists are well-
trained, research experienced, and will be further trained
on study protocol by the investigators. At least five vol-
unteer patients each for ACU and MIN will be treated
and observed by each therapist; landmarks, needle inser-
tion and manipulation, electrical stimulation, and needle
removal will be judged and discussed for each case. Sec-
ond, non-specific elements of the intervention, such as
instructions for treatment preparation, and interactions
during treatment will be reliably delivered by using clin-
ical scripts adapted from our first study. Third, all treat-
ment sessions will be videotaped. The first 5 and a
random selection of 15% (18 total cases) thereafter
chosen by a computer randomizer will be scored by a
co-investigator (AH) using the Fidelity Assessment Rat-
ing Form adapted for this study.
Treatment credibility [34] will be examined as has
been done in previous acupuncture studies before
session 1 and after sessions 2 and 24 to explore the
effects of expectancy by group and total sample on the
outcome.
Data collection, entry, and integrity
Data will be collected by program managers and
assessors who are trained from other funded studies.
Data will be entered into a password-protected custom-
ized spreadsheet by a research assistant using the data
code book developed by the study team and statisticians.
Another assistant will conduct a second independent
pass of data checking. Discrepancies will be corrected by
both assistants reviewing the source documents together.
Once corrected, the spreadsheet is saved as final. A copy
is made for all subsequent entries. The spreadsheet is
formatted for seamless transfer to the statistical database
used by study statisticians, who will check the copy be-
fore conducting analyses. Source data forms and data
management protocols are kept in both electronic and
hard copy form in the research offices for review in the
case of an audit or interest by other investigators.
Data analyses
General linear mixed models (GLMM) are capable of
handling multiple underlying distribution and model
structures through link functions, such as repeated
measures random effects models of continuous
outcomes (identity link), repeated measures logistic
models (logit link), and Poisson and negative binomial
models (log link). In addition to modeling global fixed
effects across subjects, GLMM can also model individual
subject random effects. Cox proportional hazards
modeling can be used to evaluate the effect size of the
treatment by allowing subjects to contribute their
information to the model while they are being observed
and censored once they are no longer being observed
(loss to follow-up or end of the study period). In the case
where dropouts may be associated with the treatment
assignments, we will leverage intention to treat method-
ology and construct a piecewise random effects model
with both “on-”and “off-treatment”slopes. GLMM will
be used to evaluate the primary clinical hypothesized ef-
fects of treatment (ACU) on the clinical outcome of
PTSD symptom severity (CAPS) over time (mid- and
end-treatment, and 1-month follow-up), controlling for
baseline severity of symptoms and demographic charac-
teristics (e.g., age, gender) in comparison with the pla-
cebo control group (MIN) with the assumption of
intent-to-treat. Cohen’s d within and between subjects
will be calculated. Interaction terms will be included in
the models to evaluate treatment fidelity and treatment
expectancy as potential moderators. GLMM will also be
used to evaluate the secondary biological hypothesized
effects of treatment on pre- to post-treatment in PPR
(decreased EMG eyeblink). These same statistical proce-
dures (GLMM, survival analysis, and Cohen’s d with in-
tent to treat) will be applied to evaluate exploratory
outcomes: clinical symptoms comorbid with PSTD, PPR
(HR, HRV, SCR), and PTSD diagnosis. While this is a
comprehensive initial statistical plan for primary, sec-
ondary, and exploratory outcomes, investigators may
contact the PI for further details if desired and will be
able to further view statistical analytic plans in the sub-
sequent papers.
Possible protocol changes and communication
Any necessary changes to eligibility criteria, outcomes,
data collection, and/or management or data analyses will
be reported to the Institutional Review Board (IRB) at
the Long Beach VA and to the centralized DMC where
appropriate.
Hollifield et al. Trials (2021) 22:594 Page 11 of 14
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Discussion
This will be the first single-blinded RCCT study of
acupuncture for PTSD in a Veteran population using
a sham acupuncture control, a standardized protocol,
and assessing both clinical (CAPS-5) and biological
outcomes, primarily fear-potentiated startle and the
reduction of fear during extinction. Of the eight
known published clinical trials of acupuncture for
PTSD, three recruited Veterans and the dose of acu-
puncture was highly variable. Two used a sham com-
parator. Prisco and colleagues used group auricular
acupuncture vs. sham and wait-list control on sleep
quality and medication use in Veterans from the Iraq
and Afghanistan conflicts, not primarily for PTSD
[56]. Huang and colleagues reported the benefit of
acupuncture vs. a sham control in an RCCT, but this
was also primarily for persistent disturbed sleep in
Veterans with mild traumatic brain injury [57]. None
of the extant studies evaluated both clinical and bio-
logical outcomes.
A stated limitation of acupuncture trials is the inability
to use a double-blind design. A core component of ef-
fective acupuncture is obtaining the sensation of DeQi
[58], which cannot be achieved by a blind method with
current knowledge and techniques. This is similar to
psychotherapy research where the therapist is trained to
elicit specific responses from the subject and cannot be
blinded to treatment. A study could have multiple arms
with each therapist working only in one arm and blinded
to what arms exist, yet this would risk other kinds of
bias.
The current study will thus address previously noted
limitations in early studies by utilizing a placebo (sham)
arm, gold-standard clinical assessment as the primary
outcome, and a biological outcome. In addition, the
current study will have at least two acupuncturists,
allowing for comparison, and will monitor and assess
protocol adherence. Though limitations may persist, this
study presents the most robust methodological integra-
tion of best practices available in RCTs of PTSD therap-
ies to mitigate bias and achieve confidence in effect
sizes. Methodological repetition will be necessary to cor-
roborate and enhance the understanding of these
methods and forthcoming findings in future studies.
Trial status
This is protocol version 1.0, 5 June 2020. The initial
release was on 17 August 2016. Recruitment started on
5 April 2018, with an anticipated primary completion
date of 30 September 2021.
Abbreviations
PTSD: Post-traumatic stress disorder; EMG: Electromyographic;
RCCT: Randomized controlled clinical trial; TCM: Traditional Chinese
medicine; CBT: Cognitive behavior therapy; HPA: Hypothalamic-pituitary-
adrenal; ANS: Autonomic nervous system; CNS: Central nervous system;
LBVA: Long Beach VA Healthcare System; ACU: Verum acupuncture;
MIN: Sham acupuncture; PPR: Psychophysiological response; PSS-
SR: Posttraumatic Symptom Scale –Self Report; DSM IV: The Diagnostic and
Statistical Manual of Mental Disorders IV; CAPS-5: Clinician-Administered
PTSD Scale; DSM V: The Diagnostic and Statistical Manual of Mental
Disorders; SBD: Sleep breathing disorder; DES –II: Dissociative Experiences
Scale –II; PM: Program Manager; MoCA: Montreal Cognitive Assessment;
DRRI: Deployment Risk and Resiliency Inventory; SCID-5: Structured Clinical
Interview for Diagnosis –5; PI: Primary Investigator; DA: Data Analyst;
EBT: Evidence-Based Therapy; MA: Manual approach; CSs: Conditioned
stimuli; US: Unconditioned stimulus; EDA: Electrodermal activity;
ECG: Electrocardiogram; AG/AgCl: Silver/silver chloride; ms: Millisecond; HF-
HRV: High-frequency heart rate variability
Supplementary Information
The online version contains supplementary material available at https://doi.
org/10.1186/s13063-021-05394-3.
Additional file 1. Ethical Approval Document 1 of 2. IRB Approval
Letter.
Additional file 2. Ethical Approval Document 2 of 2. Data Monitoring
Review Approval Letter.
Additional file 3. Original Funding Documentation. Merit Review Award
Letter.
Additional file 4. Original Funding/Monitoring Documentation. DMC
Charter.
Acknowledgements
This work was supported by the VA Merit Award #l01 CX-001416-01 (Project
ID: CLNA-02-15F) from the United States (US) Department of Veterans Affairs,
Clinical Sciences Research and Development, as well as supported with re-
sources and the use of facilities at the Tibor Rubin VA Medical Center in
Long Beach.
The contents do not represent the views of the US Department of Veterans
Affairs or the United States Government.
Authors’contributions
All authors contributed to the study concept and study design throughout
the study. As primary investigators, MH and AH conceived the study and led
the proposal and protocol development. Acupuncture expertise
contributions are by AH, MH, KC, and TC. Design and statistical expertise
contributions are by MH, TS, BS, and AGM. Psychophysiology expertise is led
by TJ, SN, ES, MH, and KC. All authors critically revised and approved the final
manuscript.
Funding
Funded by the Clinical Sciences Research and Development –VA Office of
Research and Development (CX-15-006). The funder has had no role in the
study design, collection, management, analysis, and interpretation of data;
the writing of the report; or the decision to submit the report for
publication.
Availability of data and materials
Only the core team will have access to the final dataset. Data and materials
may be made available from the corresponding author upon request and
with VA IRB approval only. Data sharing within VA for full trial or individual
participant will conform to VA ORD guidelines.
Declarations
Ethics approval and consent to participate
The project was registered on ClinicalTrials.gov ID: NCT02869646, registered
on 17 August 2016. Tibor Rubin VA Medical Center IRB approval #MIRB 1414.
Written informed consent was obtained from all participants. Study methods
including informed consent procedure and any project modifications are
reviewed and approved by Tibor Rubin VA Medical Center Institutional
Review Board.
Hollifield et al. Trials (2021) 22:594 Page 12 of 14
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Consent for publication
Not applicable. Results will be communicated to the scientific and lay
communities through publication in and presentation at various fora.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Tibor Rubin VA Medical Center, 5109 E. 7th Street, Long Beach, CA 90822,
USA.
2
The George Washington University School of Medicine and Health
Sciences, Washington, DC, 2300 I Street NW, Washington, DC 20052, USA.
3
University of California at Riverside, 900 University Ave, Riverside, CA 92521,
USA.
4
UC Irvine Health Policy Research Institute, 100 Theory, Suite 110, Irvine,
CA 92697, USA.
5
Analydata, 3835 Centraloma Drive, San Diego, CA 92107,
USA.
6
Department of Psychiatry and Behavioral Neurosciences, Wayne State
University School of Medicine, 3901 Chrysler Service Drive, Detroit, MI 48201,
USA.
7
University of South Carolina School of Medicine –Greenville, 701
Grove Rd, Greenville, SC 29605, USA.
Received: 14 November 2020 Accepted: 23 June 2021
References
1. APA. Diagnostic and statistical manual of mental disorder. 5th ed. Virginia:
American Psychiatic Association; 2013.
2. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress
disorder in the national comorbidity survey. Arch Gen Psychiatry. 1995;52:
1048–60.
3. Kulka RA, Schlenger WE, Fairbank JA, Hough RL, Jordan BK, Marmar CR, et al.
National Vietnam Veterans readjustment study: description, current status,
and initial PTSD prevalence estimates. Research Triangle Park: Research
Triangle Institute; 1988.
4. Resnick HS, Kilpatrick DG, Dansky BS, Saunders BE, Best CL. Prevalence of
civilian trauma and posttraumatic stress disorder in a representative national
sample of women. J Consult Clin Psychol. 1993;61(6):984–91.
5. Fulton JJ, Calhoun PS, Wagner HR, Schry AR, Hair LP, Feeling N, et al. The
prevalence of posttraumatic stress disorder in Operation Enduring
Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans: a meta-analysis. J
Anxiety Disord. 2015;31:98–107.
6. Wisco BE, Marx BP, Wolf EJ, Miller MW, Southwick SM, Pietrzak RH.
Posttraumatic stress disorder in the US veteran population: results from the
national health and resilience in veterans study. J Clin Psychiatry. 2014;
75(12):1338–46.
7. Hollifield M, Sinclair-Lian N, Warner TD, Hammerschlag R. Acupuncture for
posttraumatic stress disorder: a randomized controlled pilot trial. J Nerv
Ment Dis. 2007;195(6):504–13.
8. Sinclair-Lian N, Hollifield M, Menache M, Warner TD, Viscaya J,
Hammerschlag R. Developing Traditional Chinese medicine diagnostic
structure for posttraumatic stress disorder. J Altern Complement Med. 2006;
12(1):45–57.
9. VA Office of Patient Centered Care and Cultural Transformation and VA
Complementary and Integrative Health Evaluations Center. Library of research
articles on veterans and complementary and integrative health therapies. 2020.
Available from: https://www.va.gov/WHOLEHEALTH/docs/OPCCCT-CIHEC-Libra
ry-of-Research-Articles_Veterans-CIH-Therapies_April2020.pdf
10. Engel CC, Cordova EH, Benedek DM, Liu X, Gore KL, Goertz C, et al.
Randomized effectiveness trial of a brief course of acupuncture for
posttraumatic stress disorder. Med Care. 2014;52(12 Suppl 5):S57–64.
11. Kim YD, Heo I, Shin BC, Crawford C, Kang HW, Lim JH. Acupuncture for
posttraumatic stress disorder: a systematic review of randomized controlled
trials and prospective clinical trials. Evid Based Complement Alternat Med.
2013;2013:615857.
12. King HC, Spence DL, Hickey AH, Sargent P, Elesh R, Connelly CD. Auricular
acupuncture for sleep disturbance in veterans with post-traumatic stress
disorder: a feasibility study. Mil Med. 2015;180(5):582–90.
13. Moiraghi C, Poli P, Piscitelli A. An observational study on acupuncture for
earthquake-related post-traumatic stress disorder: the experience of the
lombard association of medical acupuncturists/acupuncture in the world, in
Amatrice, Central Italy. Med Acupunct. 2019;31(2):116–22.
14. Hollifield M. Acupuncture for posttraumatic stress disorder: conceptual, clinical, and
biological data support further research. CNS Neurosci Ther. 2011;17(6):769–79.
15. Grant S, Colaiaco B, Motala A, Shanman R, Sorbero M, Hempel S. Acupuncture
for the treatment of adults with posttraumatic stress disorder: a systematic
review and meta-analysis. J Trauma Dissociation. 2018;19(1):39–58.
16. Weathers FW, Bovin MJ, Lee DJ, Sloan DM, Schnurr PP, Kaloupek DG, et al.
The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5): development
and initial psychometric evaluation in military veterans. Psychol Assess.
2018;30(3):383–95.
17. Osorio FL, Loureiro SR, Hallak JE, Machado-de-Sousa JP, Ushirohira JM, Baes
CV, et al. Clinical validity and intrarater and test-retest reliability of the
Structured Clinical Interview for DSM-5 - Clinician Version (SCID-5-CV).
Psychiatry Clin Neurosci. 2019;73(12):754–60.
18. Bernstein EM, Putnam FW. Development, reliability, and validity of a
dissociation scale. J Nerv Ment Dis. 1986;174(12):727–35.
19. Vogt DS, Proctor SP, King DW, King LA, Vasterling JJ. Validation of scales
from the Deployment Risk and Resilience Inventory in a sample of
Operation Iraqi Freedom veterans. Assessment. 2008;15(4):391–403.
20. Keane TM, Fairbank JA, Caddell JM, Zimering RT, Taylor KL, Mora CA. Clinical
evaluation of a measure to assess combat exposure (PDF). Psychol Assess.
1989;1(1):53–5. https://doi.org/10.1037/1040-3590.1.1.53 Available from:
https://www.ptsd.va.gov/professional/articles/article-pdf/id01555.pdf.
21. Gray M, Litz B, Hsu J, Lombardo T. Psychometric properties of the Life
Events Checklist. (PDF) Assessment. 2004;11(4):330–41. https://doi.org/10.11
77/1073191104269954 Available from: https://www.ptsd.va.gov/professiona
l/articles/article-pdf/id26825.pdf.
22. Felitti V, Anda R, Nordenberg D, Williamson D, Spitz A, Edwards V, et al.
Relationship of childhood abuse and household dysfunction to many of the
leading causes of deaths in adults. Am J Prev Med. 1998;14(4):245–58.
23. Nasreddine ZA, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin
I, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for
mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695–9. https://doi.
org/10.1111/j.1532-5415.2005.53221.x Available from: https://doi.org/1
0.1111/j.1532-5415.2005.53221.x.
24. Bovin MJ, Marx BP, Weathers FW, Gallagher MW, Rodriguez P, Schnurr PP, et
al. Psychometric properties of the PTSD Checklist for Diagnostic and
Statistical Manual of Mental Disorders-Fifth Edition (PCL-5) in veterans.
Psychol Assess. 2016;28(11):1379–91.
25. Beck AT, Steer RA, Brown GK. Manual for Beck Depression Inventory-II. San
Antonio: Psychological Corporation; 1996.
26. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol.
1959;32(1):50–5.
27. Hollifield M, Warner TD, Krakow B, Jenkins J, Westermeyer J. The range of
symptoms in refugees of war: the New Mexico Refugee Symptom Checklist-
121. J Nerv Ment Dis. 2009;197(2):117–25.
28. Buysse D, Reynolds C, Monk T, Berman S, Kupfer D. The Pittsburg Sleep
Quality Index: a new instrument for psychiatric practice and research.
Psychiatry Res. 1989;28(2):193–213.
29. Selim AJ, Rogers W, Fleishman JA, Qian SX, Fincke BG, Rothendler JA, et al.
Updated U.S. population standard for the Veterans RAND 12-item Health
Survey (VR-12). Qual Life Res. 2009;18(1):43–52.
30. Powers A, Stevens J, Fani N, Bradley B. Construct validity of a short, self
report instrument assessing emotional dysregulation. Psychiatry Res. 2015;
225(1-2):85–92. https://doi.org/10.1016/j.psychres.2014.10.020 Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268361/.
31. Melzack R. The McGill Pain Questionnaire: major properties and scoring
methods. Pain. 1975;1(3):277–99. https://doi.org/10.1016/0304-3
959(75)90044-5 Available from: https://pubmed.ncbi.nlm.nih.gov/1235985/.
32. White P, Bishop F, Hardy H, Abdollahian S, White A, Park J, et al.
Southampton Needle Sensation Questionnaire: development and validation
of a measure to gauge acupuncture needle sensation. J Altern Complement
Med. 2008;14(4):373–9.
33. Buss AH, Perry M. The aggression questionnaire. J Pers Soc Psychol. 1992;63(3):452–9.
34. Borkovec TD, Nau SD. Credibility of analogue therapy rationales. J Behav
Ther Exp Psychiatry. 1972;3(4):257–60.
35. Foa EB, Riggs DS, Dancu CV, Rothbaum BO. Reliability and validity of a brief
instrument for assessing post-traumatic stress disorder. J Trauma Stress.
1993;6(4):459–73.
36. Pascualy M, Petrie EC, Brodkin K, Peskind ER, Veith RC, Raskind MA. Effects of
advanced aging on plasma catecholamine responses to the cold pressor
test. Neurobiol Aging. 1999;20(6):637–42.
37. Shibasaki K, Ogawa S, Yamada S, Iijima K, Eto M, Kozaki K, et al. Association
of decreased sympathetic nervous activity with mortality of older adults in
Hollifield et al. Trials (2021) 22:594 Page 13 of 14
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
long-term care. Geriatr Gerontol Int. 2013;14(1):159–66. https://doi.org/1
0.1111/ggi.12074 Available from: https://onlinelibrary.wiley.com/doi/pdf/1
0.1111/ggi.12074.
38. Veith RC, Raskind MA. The neurobiology of aging: does it predispose to
depression? Neurobiol Aging. 1988;9(1):101–17.
39. Parashar R, Amir M, Pakhare A, Rathi P, Chaudhary L. Age related changes in
autonomic functions. J Clin Diagn Res. 2016;10(3):CC11–5.
40. White D, Hind D. Projection of participant recruitment to primary care
research: a qualitative study. Trials. 2015;16:473.
41. Hewitt CE, Torgerson DJ. Is restricted randomisation necessary? BMJ. 2006;
332(7556):1506–8.
42. Scott NW, McPherson GC, Ramsay CR, Campbell MK. The method of
minimization for allocation to clinical trials. a review. Control Clin Trials.
2002;23(6):662–74.
43. Treasure T, MacRae KD. Minimisation: the platinum standard for trials?.
Randomisation doesn't guarantee similarity of groups; minimisation does.
BMJ. 1998;317(7155):362–3.
44. Price M, Gros DF, Strachan M, Ruggiero KJ, Acierno R. Combat experiences,
pre-deployment training, and outcome of exposure therapy for post-
traumatic stress disorder in Operation Enduring Freedom/Operation Iraqi
Freedom veterans. Clin Psychol Psychother. 2013;20(4):277–85.
45. Ironson G, O'Cleirigh C, Leserman J, Stuetzle R, Fordiani J, Fletcher M, et al.
Gender-specific effects of an augmented written emotional disclosure
intervention on posttraumatic, depressive, and HIV-disease-related
outcomes: a randomized, controlled trial. J Consult Clin Psychol. 2013;81(2):
284–98.
46. Langevin HM, Hammerschlag R, Lao L, Napadow V, Schnyer RN, Sherman
KJ. Controversies in acupuncture research: selection of controls and
outcome measures in acupuncture clinical trials. J Altern Complement Med.
2006;12(10):943–53.
47. Park J, White A, Stevinson C, Ernst E, James M. Validating a new non-
penetrating sham acupuncture device: two randomised controlled trials.
Acupunct Med. 2002;20(4):168–74.
48. Kong J, Gollub RJ, Rosman IS, Webb JM, Vangel MG, Kirsch I, et al. Brain
activity associated with expectancy-enhanced placebo analgesia as
measured by functional magnetic resonance imaging. J Neurosci. 2006;26:
381–8.
49. Schnyer RN, Luliano D, Kay J, Shields M, Wayne P. Development of
protocols for randomized sham-controlled trials of complex treatment
interventions: Japanese acupuncture for endometriosis-related pelvic pain. J
Altern Complement Med. 2008;14(5):515–22.
50. Shen J, Wenger N, Glaspy J, Hays RD, Albert PS, Choi C, et al.
Electroacupuncture for control of myeloablative chemotherapy-induced
emesis: a randomized controlled trial. JAMA. 2000;284(21):2755–61.
51. Flachskampf FA, Gallasch J, Gefeller O, Gan J, Mao J, Pfahlberg AB, et al.
Randomized trial of acupuncture to lower blood pressure. Circulation. 2007;
115(24):3121–9.
52. Zhou W, Fu LW, Tjen-A-Looi SC, Li P, Longhurst JC. Afferent mechanisms
underlying stimulation modality-related modulation of acupuncture-related
cardiovascular responses. J Appl Physiol. 2005;98(3):872–80.
53. McManus CA, Schnyer RN, Kong J, Nguyen LT, Hyun Nam B, Goldman R, et
al. Sham acupuncture devices--practical advice for researchers. Acupunct
Med. 2007;25(1-2):36–40.
54. Norrholm SD, Anderson KM, Olin IW, Jovanovic T, Kwon C, Warren VT, et al.
Versatility of fear-potentiated startle paradigms for assessing human
conditioned fear extinction and return of fear. Front Behav Neurosci. 2011;5:
77.
55. Jovanovic T, Duncan EJ, Kaye J, Garza K, Norrholm SD, Inslicht SS, et al.
Psychophysiological treatment outcomes: corticotropin-releasing factor type 1
receptor antagonist increases inhibition of fear-potentiated startle in PTSD
patients. Psychophysiology. 2020;57:e13356. https://doi.org/10.1111/psyp.13356
Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/psyp.13356.
56. Prisco MK, Jecmen MC, Bloeser KJ, Mccarron KK, Akhter JE, Duncan AD, et al.
Group auricular acupuncture for PTSD-Related Insomnia in veterans: a
randomized trial. Med Acupunct. 2013;25(6):407–22. https://doi.org/10.1
089/acu.2013.0989 Available from: https://www.liebertpub.com/doi/pdf/10.1
089/acu.2013.0989.
57. Huang W, Johnson TM, Kutner NG, Halpin SN, Weiss P, Griffiths PC, et al.
Acupuncture for treatment of persistent disturbed sleep. J Clin Psychiatry.
2018;80:18m12235. https://doi.org/10.4088/jcp.18m12235 Available from:
https://www.psychiatrist.com/JCP/article/_layouts/ppp.psych.controls/Bina
ryViewer.ashx?Article=/JCP/article/Pages/2019/v80/18m12235.aspx&Type=
Article.
58. Hui KK, Liu J, Mariana O. The integrated response of the human cerebro-
cerebellar and limbic systems to acupuncture stimulation at ST 36 as
evidenced by fMRI. Neuroimage. 2005;27(3):479–96.
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