Contemp Clin Trials. 2018 (Oct); 73: 6874
Diane Flynn, Linda H. Eaton, Dale J. Langford, Nicholas Ieronimakis, Honor McQuinn,
Richard O. Burney, Samuel L. Holmes, Ardith Z. Doorenbos
Madigan Army Medical Center,
9040 Jackson Ave,
Tacoma, WA 98431, USA.
Chronic pain is a leading cause of disability among active duty service members in the U.S. armed forces. Standard rehabilitative care and complementary and integrative health therapies are used for chronic pain rehabilitation. However, the optimal sequence and duration of these therapies has yet to be determined. This article describes a sequential multiple assignment randomized trial (SMART) protocol being used to identify the optimal components and sequence of standard rehabilitative care and complementary and integrative health therapies for reducing pain impact and improving other patient outcomes. Active duty service members referred to Madigan Army Medical Center for treatment of chronic pain are being recruited to the Determinants of the Optimal Dose and Sequence of Functional Restoration and Integrative Therapies study.
Study participants are randomized to either standard rehabilitative care (physical and occupational therapy and psychoeducation) or complementary and integrative health therapies (chiropractic, acupuncture, yoga and psychoeducation).
Those participants who do not respond to the first 3 weeks of treatment are randomized to receive an additional 3 weeks of either
(1) the alternative treatment or
(2) the first-stage treatment plus the alternative treatment.
This study will also determine factors associated with treatment response that can support clinical decision making, such as baseline fitness, pain catastrophizing, kinesiophobia, post-traumatic stress, pain self-efficacy, and biological indicators. The information gained from this research will be applicable to all integrative chronic pain rehabilitation programs throughout the U.S. Department of Defense and the U.S. Department of Veterans Affairs, and the broader rehabilitation community.
KEYWORDS: Chronic pain; Complementary therapies; Integrative health therapies; Military; Rehabilitation; SMART design
TRIAL REGISTRY: ClinicalTrials.gov website (NCT03297905).
From the FULL TEXT Article:
Chronic pain is a leading cause of both short- and long-term disability
among U.S. Military service members ; and causes significant
attrition from active duty. Among 34,006 service members
evacuated from Operation Iraqi Freedom and Operation Enduring
Freedom, diagnoses of spinal pain and musculoskeletal or connective
tissue disorders were associated with significantly reduced odds of
returning to active duty (odds ratio of 0.41 and 0.46, respectively). 
The Department of Defense/Veterans Administration Pain Management
Taskforce Report emphasizes the need for prevention, early identification,
greater emphasis on nonpharmacologic therapies, and proper rehabilitation
and reintegration of service members and veterans suffering
from acute and chronic pain. [5, 6] To address these goals, each
Army medical center has established an interdisciplinary pain management
Many Army interdisciplinary pain management centers offer functional
restoration (FR) for chronic pain rehabilitation. This interdisciplinary
approach combines standard rehabilitative care (SRC),
such as physical therapy and occupational therapy, with quantitative
progression of exercise and disability management using psychological
and case management techniques.  Civilian FR programs typically
include more than 100 treatment hours. However, active duty service
members often find it challenging to commit to the time needed for the
most intensive level of FR treatment, and there is a lack of research
regarding the ideal duration of treatment for military populations.
Complementary and integrative health (CIH) therapies, in addition
to SRC and FR, are also used for injury rehabilitation in Army interdisciplinary
pain management centers. These therapies include acupuncture [8, 9], mind-body therapies (e.g., yoga, mindfulness-based
therapies, and biofeedback) , and manual therapies (e.g.,
chiropractic and therapeutic medical massage).  While SRC and
CIH treatment approaches have been implemented in Army interdisciplinary
pain management centers [21, 22], the optimal sequence of
these therapies has yet to be determined. Patients with chronic pain
may be reluctant to engage in conventional rehabilitative therapies
such as physical and occupational therapies due to kinesiophobia (fear
of movement).  However, they may be more willing to engage in
therapies that require less physical motion such as acupuncture, chiropractic
treatment, and some yoga practices. Thus, a sequence of CIH
therapies prior to SRC may be more acceptable to patients than the
Sequential multiple assignment randomized trial (SMART) research
design is a good way to evaluate the sequence and duration of therapies
that best improves patient outcomes. A SMART design can evaluate
sequences of treatment while adapting the treatment to individual responses
to achieve optimal long-term outcomes. [24, 25] A SMART
design randomly assigns each patient to each stage of treatment,
yet allows modifications to treatment intensity, type, or delivery to
balance patient benefits with potential risks. [24, 26] A tailoring variable
is assessed at baseline and at each stage of treatment to determine
if a participant is responding to treatment. [25, 27] This approach resembles
the way treatment and treatment decisions naturally evolve
over time in clinical practice. [24, 25] The SMART design is thus a
powerful tool for pragmatic clinical trials.
In addition to determining optimal treatment sequence, a SMART
design can identify predictive variables that may allow tailoring of
treatment strategies to the unique needs of patient subgroups.  For
example, biochemical and genetic biomarkers may be valuable for
identifying patients who respond to specific pain management therapies.
Biomarkers of psychological and physiological stress constitute
intriguing candidates as both (i.e., salivary cortisol and urinary 8-hydroxy-
2'-deoxyguanosine (8-OHdG), respectively) have been implicated
in the experience of pain and functional outcomes following rehabilitation
programs. [28, 29] Evaluating biomarkers associated with
treatment responses makes it possible to develop more precise treatment
This paper describes a SMART trial protocol designed to
the optimal treatment combination, sequence, and duration of
SRC and CIH therapies among active duty service members with
chronic pain; and
 identify predictors (e.g., biomarkers) of positive
SMART study design and methods
All study procedures were approved by the institutional review
board of the U.S. Department of the Army, Regional Health
CommandPacific, the Human Research Protection Office of the U.S.
Army Medical Research and Materiel Command, and the University of
Washington institutional review board. The study is registered on the
National Institutes of Health U.S. National Library of Medicine
ClinicalTrials.gov website (NCT03297905).
Overview of the SMART study design
The Determinants of the Optimal Dose and Sequence of Functional
Restoration and Integrative Therapies study uses a SMART design, as
shown in Figure 1. For the first intervention stage, participants are randomly
assigned to 3 weeks of SRC or CIH. The SRC group receives
physical and occupational therapy. The CIH group receives chiropractic
treatment, acupuncture, yoga, and foam roller instruction; biofeedback
may also be included if indicated. Both groups receive psychoeducation
about pain management taught by a psychological technician. During
the third week of the first stage of intervention, the Pain Impact Score  is reassessed and compared with the baseline score. Those participants
who show an improvement of 3 points or greater in their Pain
Impact Score continue with their assigned treatment for an additional
3 weeks. Although the minimum clinically important difference for pain
impact score has not yet been empirically determined, the National
Institutes of Health (NIH) Task Force on Research Standards for Chronic
Low Back Pain propose that a change in 3 is a reasonable estimate of the
minimum clinically important difference for a wide range of musculoskeletal
pain conditions based on previous analysis of responsiveness
of pain impact score component measures. 
Nonresponders are randomly assigned to 3 weeks of
 the alternative treatment or
 a combination of their original treatment plus the alternative treatment.
The duration of 3 weeks of therapy for each phase was determined
based on the study clinicians' expertise who have found that it requires
a minimum of 56 treatments to determine if a patient is responding to
The study's primary aim is to determine the optimal treatment
combination, sequence, and duration of a 36 week program of selected
CIH therapies alone or in combination with a 36 week SRC program
and the corresponding effectiveness in improving pain impact.
The secondary aim is to identify the optimal combination, sequence,
and duration of therapies that result in the greatest improvement in
 patient-reported secondary outcomes (i.e., depressive symptoms, anxiety, anger, sleep disturbance, and fatigue)
 functional capacity tests
 biological indicators (i.e., cortisol and 8-OHdG levels), and
 force readiness.
The study's third aim is to identify factors that predict successful
primary and secondary outcomes at 6 weeks. These factors might include
sex, baseline fitness, pain catastrophizing, kinesiophobia, posttraumatic
stress, pain self-efficacy, injury, and biological indicators
(i.e., cortisol [levels and genotype], 8-OHdG).
Study participants are active duty service members referred to the
Madigan Army Medical Center Interdisciplinary Pain Management
Center for treatment of chronic pain and determined to be candidates
for the Determinants of the Optimal Dose and Sequence of Functional
Restoration and Integrative Therapies study at initial evaluation by a
Eligible participants have
 chronic pain of 3 or
more months' duration
 Patient-Reported Outcomes Measurement
Information System (PROMIS) scores of at least 1 standard deviation
below the mean in the domains of pain interference or physical function
and/or average pain intensity of at least 3 on a scale of zero to 10; and
 the ability to speak, read, and write in English.
Patients are not
eligible for the study if they have
 prior surgery within the past
6 months, or are scheduled for an upcoming surgery (unless cleared by
 unstable psychological disorders; or  active
substance use disorder.
To determine the sample size for this study, we used the SMART
sample size calculator for continuous outcomes (http://methodologymedia.psu.edu/smart/samplesize).  The minimum
required sample size to test the primary hypotheses is n = 225, based
on a required power of 80% to detect a medium effect size (f = 0.25) in
the primary outcome (i.e., pain impact score) at alpha=0.05. From our
past experience with clinical trials at Madigan Army Medical Center, we
expect to observe approximately 20% attrition in this study, including
loss to follow-up. To account for the possibility of a 20% attrition rate
(10% following each randomization stage), and to ensure balanced
samples in each stage of the treatment arm, the goal is to enroll 280
Patients are screened, recruited, and consented after the first visit
with a medical provider (physician, nurse practitioner, or physician
assistant) at the Madigan Interdisciplinary Pain Management Center.
Baseline measures are also completed at this time. A patient who does
not consent to the study will receive either SRC or CIH at the discretion
of their health care provider.
After baseline data collection, participants are randomized to either
SRC or CIH. A second randomization occurs for participants who do not
respond to the first 3 weeks of treatment. Nonresponders are then
randomized to either the alternative treatment or to a combination of
the same first-stage treatment plus the alternative treatment for
3 weeks. Responders continue with the same first-stage treatment for an
additional 3 weeks. In the end, there will be 6 randomization groups to
analyze. Two groups will be comprised of those who respond to the
initial 3 weeks of therapy and continue the same therapy for another
3 weeks (i.e., SRC-SRC and CIH-CIH). Two groups will be comprised of
those who do not show favorable response to the initial 3 weeks of
therapy and randomize to the alternate approach (i.e., SRC-CIH and
CIH-SRC). The final two groups will be comprised of those who do not
respond favorably to the initial 3 weeks of therapy and randomize to a
combination of both approaches (i.e., SRC-CIH/SRC and CIH-CIH/SRC).
The SRC group engages in physical and occupational therapy and
psychoeducation. Physical therapy is conducted by a licensed physical
therapist alternating with a physical therapy assistant and uses therapeutic
exercises, assistive devices if needed, and patient education and
training about the preservation, enhancement, or restoration of movement
and physical function. Occupational therapy is conducted by a
licensed occupational therapist alternating with a certified occupational
therapy assistant and focuses on enabling or encouraging participation
in meaningful activities of daily life, such as self-care skills, or in work
activities. Physical and occupational therapies are scheduled for two
45min sessions of each per week for 3 weeks. The frequency and
duration of therapy is standardized for all participants and is based on
the clinical input of providers from each discipline.
The CIH group receives chiropractic treatment, acupuncture, and
yoga. Chiropractic treatment is conducted by a licensed chiropractor
and focuses on manual adjustment or manipulation of the spine and
joints and is provided for 15 min twice per week. Acupuncture is conducted
by a licensed acupuncture therapist and uses fine needles inserted
through the skin at specific points to relieve pain or discomfort.
Yoga is conducted by a certified yoga therapist and involves a system of
physical postures and breathing techniques. Both acupuncture and yoga
are tailored to each patient's presentation and provided 2 times per
week for 1 h.
Both SRC and CIH groups participate in health psychology education
classes. Classes are taught by a psychological technician, are 1 h in
duration, and provided 2 times per week. Class topics include automatic
thoughts, resiliency, healthy sleep habits, autogenics/imagery, priorities/
values/goal setting in regards to specific domains (relationships,
career, education, personal growth, community), pain behaviors, and
stress management tactics to reduce tension. During class, service
members are encouraged to disclose appropriately and apply the concepts,
strategies, and techniques to manage the impact their chronic
pain has had on their functioning, decision-making, and quality of life.
In addition, any patients with PASTOR assessments showing severe
levels of depression, anxiety or pain catastrophizing or screen positive
for problem opioid or alcohol use are referred for assessment by a
Treatment fidelity for the study is assured through established
methods outlined in the NIH Behavior Change Consortium Treatment
Fidelity Guidelines. [33, 34] Role-playing is used to ensure that team
members understand the protocol for interacting with participants. All
contact with participants is scripted and randomly and regularly reviewed
by the site principal investigator. Treatment delivery is monitored
by the interdisciplinary pain management center clinical team
leader who ensures that the treatment team discusses each study participant
at 3 weeks and 5 weeks. Discussion includes treatment adherence.
If participants miss several treatments, they are contacted by
the team leader who asks them to sign a letter of commitment in order
to proceed with treatment. Receipt of treatment is assessed by the research
team by monitoring participants' appointments. Enactment of
the treatment skills occurs during follow-up appointments, when participants
are asked about their use of the interventions.
The study uses the Pain Assessment Screening Tool and Outcomes
Registry (PASTOR) to collect participant demographic and outcomes
data. PASTOR was developed by the Defense and Veterans Center for
Integrative Pain Management in collaboration with Northwestern
University to collect outcomes data on multiple domains relevant to
pain management.  PASTOR includes the Defense and Veterans
Pain Rating Scale; several PROMIS measures, including sleep, fatigue,
anxiety, depression, pain interference, physical function, and satisfaction
with social roles; the pain catastrophizing scale; and screens for
PTSD, and alcohol and medication misuse. PASTOR is completed online
by use of a computer or smart phone and the PROMIS measures
apply computer adaptive testing to minimize the survey burden.
Primary outcome measures
Pain impact score. The primary outcome assessed in this study
is the Pain Impact Score, a validated composite of PROMIS measures
including pain intensity, pain interference, and physical function that
has been recommended by the NIH Task Force on Research Standards
for Chronic Low Back Pain for musculoskeletal pain. 
Secondary outcome measures
PROMIS measures. The PROMIS global health item pool [37, 38] assesses health in general with items that include global
ratings of the five primary PROMIS domains (physical function,
fatigue, pain, emotional distress, social health) as well as of
perceptions of general health that span domains. PASTOR also
includes the PROMIS item banks for depressive symptoms ,
anxiety , emotional distress (anger) , sleep disturbance ,
and fatigue.  These secondary outcomes are highly relevant to pain
Functional capacity tests.
Functional capacity tests on
endurance and lifting strength are standard outcomes that FR
programs use to complement patient-reported outcomes. These tests
include the Modified Naughton treadmill test, which measures the pace
and duration of time on a treadmill; the floor-waist lift test, assessing
the amount of weight an individual can lift from floor to waist height
without experiencing an increase in pain; the waist-shoulder lift test,
assessing the amount of weight an individual can lift from waist to
shoulder height; and the 40ft carry test, assessing the amount of weight
an individual can carry while walking a distance of 40 ft. These
functional measures are the standard assessments used by the
physical therapists at the study site to determine cardiovascular
fitness and motor strength.
Force readiness is assessed based on
participants' Military Readiness Category status recorded at baseline
and follow-up in the Army Medical Operational Data System. The
Medical Readiness Category is determined by whether an Army soldier
is physically able to perform military duties versus having a temporary
or permanent medical condition that interferes with the ability to
perform duties. 
Potential predictors of treatment response
Data on potential predictors of treatment response are collected
with the following instruments included in PASTOR:
A treatment modalities questionnaire asking about 9 types of prior
and current treatment modalities and their effectiveness.
PROMIS Prescription Pain Medication Misuse Measure. 
PROMIS Alcohol Use 
Activity goals, asking the patient to identify 3 important goals and
the degree to which pain interferes with those activities.
Defense and Veterans Pain Rating Scale , a color-coded 11point
numeric pain rating scale (010), with descriptive anchors of pain
severity for each number on the scale.
Pain Catastrophizing Scale , a 13item, 3dimension survey of
trait pain catastrophizing that include items measuring a patient's
tendency for  rumination , magnification, and  helplessness.
PROMIS neuropathic pain screen 
Primary Care Post-traumatic Stress Disorder Screen for DSM-5
(PC_PTSD-5) , a 5item tool that includes an introductory sentence
to cue respondents to traumatic events.
In addition, participants complete the following surveys, which are
not included in PASTOR:
Month and year pain began
How pain began (injury due to lifting, sports/recreation, training/
job, deployment, motor vehicle accident, following surgery; uncertain
cause; or other cause).
The Patient Activation Measure , a 22item survey on 4 stages of
: believing the patient role is important
, having the
confidence and knowledge necessary to take action
taking action to maintain and improve one's health, and
the course even under stress.
Tampa Scale for Kinesiophobia , an 11item survey assessing
pain-related fear in patients with back pain.
Pain Self-Efficacy Questionnaire , a 10item survey assessing
patients' self-efficacy beliefs with respect to their pain.
Chronic Pain Acceptance Questionnaire , an 8item survey of
 the degree to which one engages in life activities regardless of
pain (activity engagement), and
 one's willingness to experience
pain, or the inverse of engaging in behaviors to limit pain (pain
All participants are scheduled to complete assessments at baseline,
3 weeks, and 6 weeks, as illustrated in Figure 1.
Salivary cortisol samples are collected at baseline: participants are
asked to collect 3 samples using Sarstedt Salivette collection tubes on
the day preceding their first day of treatment in their first-stage intervention.
Samples are taken upon awakening (0 min), at 30 min after
awakening, and in the evening prior to going to bed. This collection
schedule allows for analysis of both cortisol awakening response and
diurnal cortisol variability (difference between peak cortisol and
baseline/evening cortisol levels). Participants are instructed to
avoid caffeinated or sugary drinks, food/breakfast, brushing teeth,
smoking, and physical exercise thirty minutes prior to taking their
morning samples, as these activities have been found to affect the
cortisol awakening response.  Participants are also instructed to
refrigerate the samples immediately following collection and to bring
them to the clinic on the first day of their rehabilitation program. 
Post-treatment salivary samples are collected using the same sampling
schedule on the final day of the second-stage intervention. Participants
refrigerate these post-treatment samples to the interdisciplinary pain
Oxidative stress (8-OHdG) urine samples are collected at baseline
and at the post-treatment period following completion of the secondstage
intervention. At baseline, participants are asked to provide a urine
sample immediately after their team intake appointment, which takes
place between 11 a.m. and 3 p.m. on the day of study enrollment. The
post-treatment urine sample is taken in person at the interdisciplinary
pain management center upon completion of the second-stage intervention.
Urine samples will be stored for the duration of the study at
?80 degrees Celsius for up to one year, until the recruitment period is
over and analyses are ready to begin. Of note, urinary 8-OHdg has been
shown to be stable when stored at 80 degrees Celsius for more than
two years. 
For CYP17A1 and CYP11B1 polymorphisms, next generation sequencing
is conducted using buccal swabs collected during enrollment.
Buccal swab is an efficient, easy, and reliable collection method for
targeted genomic DNA (gDNA) analysis.  Buccal swabs are collected
following saliva collection; samples are stored at 80 degrees
Celsius until sufficient numbers are accumulated for processing. gDNA
is purified using standard procedures with the Qiagen Gentra Puregene
Buccal Cell Kit, with the fidelity of each sample's gDNA confirmed by
the Agilent 2100 Bioanalyzer electrophoresis system. Samples that fail
quality control are omitted and a second buccal swab collected. Samples
that pass quality control are prepared for targeted sequencing of
CYP17A1 and CYP11B1 genes using the Illumina TruSeq Custom Amplicon
Kits. Sequences are read on the Illumina MiSeq NGS platform;
the read alignment is conducted using the Illumina BaseSpace applications.
Post-acquisition analysis and comparison of polymorphisms are
analyzed with Illumina BaseSpace reference libraries.
All data are entered into a secure, web-based system. The amount of
missing data is quantified first. Where possible, and determined by the
amount of missing data, 3 indirect tests of the mechanism of missingness
will be explored
 Baseline demographic characteristics of those
who ever and never missed data by group allocation will be compared
(an indirect test to rule out missing completely at random)
difference between mean utility scores of participants with missing and
nonmissing data will also be compared (an additional indirect test to
rule out missing completely at random)
 Controlling for the probability
of providing missing data, the mean scores of those that never
missed an intervention will be compared with those in the control
groups (an indirect test of missing not at random).
While analysis using mixed models allows all observed data to be
included under the assumption that the data are missing completely at
random, where there is substantial missing data, multiple imputation or
mean conditional imputation will be used with subsequent sensitivity
analyses to explore the impact of imputation on results. To address the
issue of artificially reduced estimates of stochastic uncertainty produced
by imputation, bootstrapping procedures will be used on the
entire imputation and estimation process.
Analyses for aim 1
Hypothesis 1. Among service members who show a favorable response
to weeks 13 of either stage 1 treatment (SRC or CIH), they will
demonstrate additional reduction in pain impact score following a
second 3week course of the same therapeutic approach (SRC-SRC or
Hypothesis 2. Among service members who do not respond to CIH
during weeks 13, those who have SRC added during weeks 46 (CIHCIH+
SRC), will report greater decrease in pain impact compared to
those who randomize to three weeks of SRC alone during weeks 46
Hypothesis 3. Among patients who do not respond to SRC during
weeks 13, those who have CIH added during weeks 46 (i.e., SRCSRC+
CIH), will report greater decrease in pain impact than those who
randomize to three weeks of CIH alone during weeks 46 (i.e., SRCCIH).
Comparisons are carried out using statistical model 1, which relates
the outcome Y (pain impact) at weeks 1 to 3 to the group assignment
variable x1(SRC or CIH) and to pain impact at baselinex2:
Y=X?+Z?+?. In this model, Z is a known design matrix that corresponds
to repeated measures, and ? is an unknown vector of random
effects. If errors are normally distributed, this model will be fit as a
linear mixed effects model. Generalized linear mixed effects modeling
will be used with the appropriate link function and error distribution if
the outcome is not normally distributed and cannot be normalized
using transformations. We are primarily interested in the additive effect
of the group variable, and differences in the least square means will be
tested according to the levels of variable x1. Next, the definition of pain
impact response (improvement of more than 3 points on the Pain
Impact Score) will be applied to classify participants in each group as
responders or nonresponders to the intervention therapy. The characteristics
of responders will be compared to those of nonresponders
using t-tests, chi-square, or Fisher's exact tests.
The analytic strategy described above will also be implemented to
compare the groups created by the second randomization. The repeated
measures of pain impact (one at a time) during weeks 4 to 6 will be
related to study group (CIH alone versus CIH+SRC) and to the pain
impact measure at week 3. Additionally, this analysis will be conducted
among those participants who did not respond to SRC during weeks 1 to
3. Descriptive statistics will be used to analyze demographic data and
study variables for all randomization groups to ensure the groups are
Analyses for aim 2
Hypothesis. Service members who complete the six weeks of treatment
(CIH-CIH, SRC-SRC, CIH-CIH+SRC OR SRC-SRC+CIH) will
show significantly improved outcomes on depressive symptoms, anxiety,
anger, sleep disturbance, functional capacity tests, biological indicators,
and force readiness compared to those who complete three
weeks of treatment. (SRC or CIH).
The analysis for Aim 2 is the same as the analysis for Aim 1, but for
the secondary outcome measures. Separate analyses will be performed
for the PASTOR patient-reported outcomes, functional capacity tests of
strength and endurance, biological measures of salivary cortisol and 8-
OHdG, and force readiness status. To derive the quantitative measurement
of cortisol, the salivary abundance will be detected by enzymelinked
immunosorbent assay (ELISA). A global measure of cortisol response
will then be calculated, using area under the curve to determine
any changes in cortisol level between baseline and post-treatment intervals.
Changes (from baseline to post-treatment) in urinary 8-OHdG
levels will also be determined by ELISA and compared across treatment
groups. Raw biological measures may be log transformed to ensure that
appropriate assumptions are met for statistical analyses. Force readiness
among Army participants will be evaluated based on 5 h3 Medical
Readiness Category at baseline and follow-up, as recorded in the Army
Medical Operational System.
Analyses for aim 3
Hypothesis. Service members' sex, baseline fitness, pain catastrophizing,
kinesiophobia, post-traumatic stress, pain self-efficacy, and/or
biological indicators will predict successful primary and secondary
treatment outcomes at 6 weeks.
For the Aim 3 analyses, we will use Q-learning , which is a
method for using data to construct the decision rules that operationalize
the optimal intervention. The Q-learning method will be implemented
in SAS PROC QLEARN, developed by Murphy et al.  Tailoring for
predictive variables that are not embedded in the SMART design (e.g.,
pain catastrophizing, baseline fitness, cortisol levels, 8-OHdG levels,
CYP17A1 and CYP11B1 polymorphisms, sex) will be explored. For example,
we will start by assessing the best stage 2 intervention for
nonresponders. We will use data only from the nonresponders, to determine
(e.g., at a given 8-OHdG level or for a given genotype) if the
decision rule recommends increasing the amount of the stage 1 intervention
or adding the alternate intervention.
Salivary enzyme immunoassays will be conducted to derive the
quantitative measurement of salivary cortisol levels. The cortisol awakening
response (area under the curve of 2 morning measures) and
diurnal cortisol variability (difference between the 30min post-awakening
and the evening measures) will be evaluated as potential biomarkers
for successful treatment outcomes. The relationship between
baseline urinary 8-OHdG levels and successful treatment outcomes will
also be evaluated.
Polymorphisms in CYP17A1 and CYP11B1 examined by NGS will be
compared with cortisol levels to determine potential functional effects
and with treatment outcomes to investigate potential associations with
responses to the intervention(s). Sequence analyses for each participant,
as well as cortisol and 8-OHdG measurements, will be conducted
blinded to the treatment group, by assigning participants a random
code at the time of sample collection. The principal investigator will
retain the code key and reveal the treatment group for each sample at
the conclusion of the study. At that point, genetic polymorphisms,
cortisol, and 8-OHdG values, for each participant sample will be matched
with therapy outcomes to provide a comprehensive assessment of
the utility of cortisol and 8-OHdG as measures that predict as well as
assess treatment response.
Discussion: Benefits of SMART research design
To achieve health care advances that enhance the health of military
service members and promote a fit and ready force, it is important that
service members participate in well-designed research studies that result
in findings directly applicable to their health care and clinical
practice. Furthermore, with the growing emphasis on the importance of
nonpharmacologic approaches in relieving chronic pain, it is critical
that the optimal dose and sequence of these therapies are established.
These findings may ultimately shorten the rehabilitation period and
improve service member's quality of life; thus, leading to a healthier
military force. The potential benefits of nonpharmacologic treatment
modalities include pain relief, improved mood, and improved functional
The study's SMART design will identify the optimal components and
sequence of nonpharmacological interventions for reducing pain impact
and improving other patient outcomes.
Specifically, the SMART design allows us to
 compare the effectiveness of two nonpharmacological interventions
 identify subgroups of service members who do and do not respond to the interventions
 determine the most effective duration and sequencing of the interventions, and
 determine factors associated with treatment response that can support clinical decisionmaking.
Identification of service members who respond to treatment
and factors that predict successful outcomes will support development
of tailored treatment strategies that promote service members' reintegration
and fitness. The information gained from this study will be
applicable to all integrative rehabilitation programs throughout the
Department of Defense and the Department of Veterans Affairs, and the
broader rehabilitation community including civilian populations.
National Institute of Nursing Research of the National Institutes of
Health under award number K24NR015340. The content is solely the
responsibility of the authors and does not necessarily represent the
official views of the National Institutes of Health.
The authors (Burney, Flynn, Holmes, Ieronimakis, and McQuinn)
are employed by the U.S. Military or by the Federal Government. The
views expressed are those of the author(s) and do not reflect the official
policy of the U.S. Department of the Army, the U.S. Department of
Navy, the U.S. Department of Defense, or the U.S. Government. The
investigators have adhered to the policies for protection of human
subjects as prescribed in 45 CFR 46.
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