Strategies for Prescribing Analgesics Comparative Effectiveness (SPACE) Trial
Phase: NA
Conditions: Back Pain, Osteoarthritis
Sponsor: VA Office of Research and Development

PROTOCOL  
 
Study Title: Strategies for Prescribing Analgesics Comparative Effectiveness 
(SPACE) Trial 
 
NCT01583985  
 
This protocol supplement contains the following items: 
• Summary of protocol changes (date of document: October 25, 2017) 
• Original IRB-approved protocol (date of document: May 1, 2012) 
 
Details of the final protocol and recruitment outcomes are in the following publication: Krebs 
EE, Jensen AC, Nugent S, DeRonne B, Rutks I, Leverty D, Gravely A, Noorbaloochi S, Bair MJ, 
Kroenke K. Design, recruitment outcomes, and sample characteristics of the Strategies for 
Prescribing Analgesics Comparative Effectiveness (SPACE) trial. Contemporary Clinical Trials. 
2017 Nov;62:130-139. PMID: 28893675 DOI 10.1016/j.cct.2017.09.003 
  

SPACE Protocol Supplement: Summary of Protocol Changes 
Table: Summary of protocol changes 
Date
Description of change
March 2013
Pre-enrollment refinement of outcome assessment batteries
x
Changed measures of sleep, medication beliefs, headache, and health
related quality of life domains; add treatment preference questions and
other items to baseline assessment
x
Changed fall calendar data collection to first 6 months only
x
Eliminated cold pressor pain sensitivity testing at 6 months
June 2013
Pre-enrollment changes to outcome assessments and intervention protocol
x
Added PROMIS pain and depression measures at baseline and 3
months for ancillary NIH-funded measurement study
x
Revised prescribing strategies
o
Non-opioid arm: Adjuvants and topicals are second-line.
Tramadol and non-formulary adjuvants are third-line. Will not
use any typical opioids (i.e., no hydrocodone or codeine)
o
Opioid arm: Always start with IR opioid unless there is a truly
compelling reason to start with SR therapy (almost never the
case). Due to availability without prior authorization,
oxycodone SA is a second-line option.
x
Clarified intervention visit content
x
Revised intervention medication safety and adherence monitoring
protocol
February 
2014
Refined recruitment strategy in response to difficulty recruiting
x
Increased incentive from $40 to $100 for in person assessments at 0, 6,
and 12 months
x
Changed recruitment to “opt in” for Veterans > age 80 or who live >50
miles from Minneapolis VA, due to low yield of proactive recruitment
July 2014
Revised opioid arm intervention approach to opioid dose adjustments
x
Decided not to increase opioid doses beyond 100 ME mg (no doses >
100 mg prescribed to date)
October 
2014
Revised outcome assessments:
x
Added brief 15-month mailed follow-up questionnaire
x
Eliminated fall calendar data collection due to participant and research
team burden and low completion rates
April 2015
Revised opioid arm intervention approach to opioid dose adjustments:
x
Decided if patients have not responded to an individual opioid at a dose
of 60 ME mg/day, rotate to an alternative opioid
x
Decided if patients have a partial response to an individual opioid, the
dose may be titrated above 60 ME mg/day to a maximum of 100 ME
mg/day
May 2015
Revised non-opioid approach to tricyclic TCA dose adjustments:
x
Redefined adequate trial as nortriptyline or amitriptyline 50 mg for
minimum of 2 weeks
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SPACE Protocol Supplement: Summary of Protocol Changes  
June 2015
Revised opioid arm intervention approach 
x
Decided to drop methadone from prescribing strategy (not prescribed 
to date)
x
Decided to keep fentanyl in prescribing strategy as third-line therapy; if 
prescribed, ensure potential excess risks are communicated to patient 
and patient agrees to not make any independent dose adjustments
September
2015
Revised prescribing procedures in response to strengthened FDA warning 
about cardiovascular risks of NSAIDs 
x
Decided not to prescribe etodolac or diclofenac in patients with high 
cardiovascular risk
Clarified prescribing for female patients of child-bearing age who decline to 
use contraception 
x
In non-opioid arm, decided to limit options to those safer in pregnancy 
x
In opioid arm, decided to use lower dosages and instruct patient to 
contact study ASAP and not abruptly stop opioids if she becomes 
pregnant. If a patient becomes pregnant while on opioids, would 
initiate a very slow taper and discontinue opioids
October 
2015
Clarified NSAID use in patients with higher cardiovascular risk
x
Document discussion of cardiovascular risks with patient
x
Allow patient to make informed decision about continued use of 
NSAIDs
May 2016
Revised non-opioid intervention approach
x
Added topical diclofenac due to its addition to VA formulary  
x
Decided PPIs not needed when topical diclofenac is prescribed
x
Decided to check creatinine with topical diclofenac as with oral 
NSAIDs
x
Decided to recheck AST & ALT within 3 months of starting oral 
diclofenac and at end of study if oral diclofenac continuation is 
recommended 
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SPACE Protocol Supplement: Original IRB-Approved Protocol  
PROTOCOL:  Strategies for Prescribing Analgesics Comparative Effectiveness (SPACE) 
PRINCIPAL INVESTIGATOR:  Erin E. Krebs, MD, MPH
BACKGROUND:
Chronic musculoskeletal pain conditions are among the most common problems seen in primary care. 
As the importance of these conditions for the health of individuals and society has been increasingly 
recognized, use of long-term opioid therapy for chronic musculoskeletal pain has grown 
exponentially.1;2 Unfortunately, research has not kept pace with this change in opioid prescribing 
practice. 
The balance of benefits and risks for patients receiving opioids for chronic pain is currently unclear. 
Available evidence for effects of opioid treatment on chronic pain is primarily from short-term placebo-
controlled trials with limited applicability to clinical practice.3;4 Guidelines support the use of opioid 
therapy when other treatments have not improved pain intensity and function, but these 
recommendations are based primarily on expert opinion due to limitations in the quantity and quality of 
evidence.5;6  
The long-term medical safety of opioids is poorly described in the literature. Clinical trials of opioids 
have been designed to primarily assess short-term side effects, such as constipation. Preliminary 
investigations suggest that long-term opioid therapy may adversely affect pain sensitivity, endocrine 
function, fall risk, and sleep, but the incidence and severity of these potential effects have not been 
well-quantified.7-9 Additionally, despite widespread concerns about opioid misuse and iatrogenic 
addiction, the magnitude of these risks is currently unknown. Estimates of 12-43% for misuse and 3% 
for addiction among patients receiving opioids are based on research with important methodological 
limitations.10  
As a result of these uncertainties, the proper place of opioids in chronic pain is controversial. Some 
experts argue for a reduced role, pending evidence of opioids’ long-term effectiveness and safety; 
whereas others argue for expanded use of strong opioids, such as morphine, as important weapons in 
the fight against chronic pain. Primary care clinicians are caught in a double-bind—concerned that they 
may cause more harm than benefit, but not wanting to under-treat pain. 
We propose to fill a critical gap in the evidence by conducting a pragmatic randomized trial 
comparing two clinically relevant prescribing strategies—opioid-intensive versus opioid-
avoidant—for chronic musculoskeletal pain. The Strategies for Prescribing Analgesics Comparative 
Effectiveness (SPACE) trial will evaluate multiple patient-centered pain and safely outcomes over 12 
months. It will compare two prescribing strategies that are both flexible algorithms, but differ strongly in 
their emphasis; the opioid-intensive strategy will use strong opioids early in treatment, whereas the 
opioid-avoidant strategy will optimize non-opioid medications while delaying and minimizing opioid use. 
Participants will be Veterans seen in primary care for chronic back or lower-extremity arthritis pain who 
have moderate-severe pain refractory to daily analgesics. 
SPECIFIC AIMS AND HYPOTHESES
Aim 1: To compare 12-month effects of opioid-intensive and opioid-avoidant prescribing 
strategies on pain-related function and pain intensity. 
Hypothesis 1: The opioid-intensive strategy will improve pain-related function and pain intensity 
more than the opioid-avoidant strategy.
Aim 2: To compare harms of opioid-intensive and opioid-avoidant prescribing strategies over 12 
months.
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SPACE Protocol Supplement: Original IRB-Approved Protocol  
Hypothesis 2: The opioid-intensive strategy will cause more adverse medication-related 
symptoms, more clinically important adverse events, and greater decrements in physical and 
cognitive performance than the opioid-avoidant strategy.
Aim 3: To compare effects of opioid-intensive and opioid-avoidant prescribing strategies on 
secondary outcomes, including health-related quality of life, pain sensitivity, and aberrant drug-
related behaviors. 
Aim 4: To elicit participants’ perceptions of their response to the intervention and of the value of 
intervention components.   
RESEARCH DESIGN AND METHODS
A. Conceptual model
As noted previously, chronic pain management is often complex and time-consuming. Many Veterans
with chronic pain are dissatisfied with pain management and many VA primary care providers feel
unsupported in their efforts to treat pain. The SPACE trial will compare two different analgesic
prescribing strategies, both delivered through an intervention model that is designed to address key
barriers to effective pain treatment in primary care. The SPACE intervention design draws on the Three
Component Model (TCM), which was initially developed and validated by Roudebush (Indianapolis) VA
Co-investigator Dr. Kroenke and colleagues in a multisite depression implementation trial.11 The TCM
was designed to provide a structured approach to depression interventions, addressing the main
barriers to effective depression care while maintaining feasibility in community practices. The barriers
that it was designed to address are equally applicable in pain care—primary care time pressures,
competing demands of acute concerns and medical conditions, suboptimal access to specialty care,
and lack of structured reassessment and action in response to failure of interventions that are
undertaken.  PI Dr. Erin Krebs, previously of the Roudebush (Indianapolis) VA and colleagues have
successfully used the TCM as the basis for two trials focused on management of pain symptoms,
INCPAD (an NCI-funded trial involving cancer patients with pain or depression)12 and SCOPE. By
enhancing primary care and creating a bridge to specialty consultation, the TCM complements the VHA
stepped care model of pain care described in the current VHA Pain Management Directive.13
The TCM is compatible with the Chronic Care Model, but is focused on the relationship among three 
care providers collaborating through structured communication to optimize symptom care processes. 
The three components of the TCM are primary care, care management, and enhanced specialty 
support. Figure 1 shows the relationships among the three types of providers and the central role of the 
care manager. In SPACE, care management will be delivered by a clinical pharmacist care manager 
and specialty supervision will be provided by clinician investigators. The four key process steps
addressed by the TCM are symptom detection, treatment initiation, monitoring of response and adverse 
effects, and adjustment of therapy when needed. Within the VA, the first step (symptom detection) has 
been widely implemented through the Pain as the Fifth Vital Sign Initiative. Participants in SPACE will 
have already had treatment initiated, but will not have experienced a meaningful response, so SPACE 
will focus on the monitoring and treatment adjustment processes, which will occur as a series of 
structured treatment trials. Use of measurement tools for interval reassessment is a key feature of the 
TCM that will be fully integrated into the SPACE interventions.
Figure 1: Three Component Model (TCM)
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SPACE Protocol Supplement: Original IRB-Approved Protocol  
B. Study design overview
SPACE is a pragmatic randomized clinical trial designed to compare the effectiveness at 12 months of 
two clinically-relevant prescribing strategies delivered within a care management model for chronic 
musculoskeletal pain. Rather than comparing simple uniform treatments, this study will compare two 
flexible prescribing algorithms that can each be tailored to individual patient preferences and 
responses. Patients will be assigned to either 1) the opioid-avoidant arm, which emphasizes non-opioid 
medications from several drug classes, or 2) the opioid-intensive arm, which emphasizes early use of 
strong opioid analgesics. SPACE will randomize 276 Veterans with chronic musculoskeletal pain of at 
least moderate severity to either the opioid-avoidant (n=138) or the opioid-intensive (n=138) arm (see 
Figure 2). In both arms, treatments will be titrated, added, or rotated as needed to achieve improvement 
in pain. The intervention structure and data collection protocol will be the same for both arms; only the 
prescribing strategy assignment will differ between them. 
Figure 2: SPACE Study Design
C. Recruitment
C1. Inclusion criteria
Veterans will be eligible for participation if they have chronic back or lower extremity osteoarthritis pain 
with moderate-severe intensity and interference with function despite analgesic therapy. Inclusion 
criteria are further defined as follows:
6

SPACE Protocol Supplement: Original IRB-Approved Protocol  
(a) Chronic back or lower extremity osteoarthritis pain: For this study, we define chronic pain as pain 
that is present nearly every day for at least 6 months. A standard definition of chronic pain is not agreed 
upon, but most studies have used 3-6 months as the required duration.14 Patients with a primary pain 
complaint of back pain or hip or knee arthritis pain are eligible. These two types of pain account for the 
majority of pain complaints and long-term opioid therapy.15 Patients with additional pain locations will 
not be excluded unless they have a primary location other than back, hip, or knee or meet criteria for 
fibromyalgia. 
(b) Moderate-severe intensity and interference with function: Eligible patients will have both moderate-
severe pain intensity nearly every day, defined using standard cutoffs as Brief Pain Inventory (BPI) 
average pain item RQDVFDOHRI-10), and interference with function, as defined by BPI interference 
VFRUH16,17  
(c) Despite analgesic therapy: To ensure that potential participants are appropriate for opioid therapy, 
we will require that their pain has persisted at a moderate-severe level despite analgesic use at least 
nearly every day for the past 6 months. Veterans already receiving current chronic opioid therapy will 
be excluded (see C2 below).
C2. Exclusion criteria
As a pragmatic clinical trial, this study will enroll a generalizable sample of primary care patients who 
would be considered eligible for either opioid or non-opioid analgesic therapy. We have therefore kept 
exclusion criteria to the minimum necessary to ensure both patient safety and internal validity. Veterans 
who meet any of the following exclusion criteria that may interfere with outcome assessment will be 
ineligible: a) schizophrenia, bipolar disorder, or other psychosis; b) moderately severe cognitive 
impairment, GHILQHGDV errors on a brief cognitive screener;18 c) anticipated back, knee, or hip 
surgery within 12 months; and d) anticipated life expectancy of less than 12 months. We will also 
exclude patients receiving current chronic opioid therapy and those with absolute contraindications to 
either prescribing strategy.
For exclusion purposes, we define current chronic opioid therapy as any long-acting opioid (i.e., 
methadone, transdermal fentanyl, or any sustained-release opioid) dispensed in the past 3 months or 
DQ\SUHVFULSWLRQIRUWDEOHWVFDSVXOHVRIVKRUW-acting schedule 2 or 3 opioids dispensed in the past 
3 months. Under this definition, patients who received a small number of short-acting opioids per 
month, but less than required to use them on a daily round-the-clock basis, would be eligible. Patients 
receiving current chronic opioid therapy will be excluded for two main reasons. First, whether to 
discontinue or rotate/escalate opioid therapy in patients without an adequate response to opioids is a 
different research question from those addressed by this study. Second, insufficient “washout” of 
preexisting opioid therapy could confound study results because chronic opioid therapy can induce 
physical dependence and because discontinuation of opioids may lead to changes in pain sensitivity of 
uncertain duration. 
Finally, because participants should be considered eligible in clinical practice for either opioid or non-
opioid analgesic therapy, patients with contraindications to all drugs in either arm will be excluded. In 
general, contraindications for specific medications include known allergy, previous serious adverse 
effect, or failure of a previous adequate trial of that medication. Specifically, in the opioid-avoidant arm, 
a patient who previously failed adequate trials of all three drug class steps would meet exclusion 
criteria; in the opioid-intensive arm, a patient who previously failed high-dose sustained-release opioid 
therapy would meet exclusion criteria.  
To determine adequacy of prior medication trials, the pharmacist care manager will conduct a 
medication history as described in Section E1. For each drug used, patients will be queried about 
adverse effects, pain response, and dose/duration of use. We will consider a patient to have “failed” a 
drug if they did not tolerate it or did not respond to an adequate trial. Adequacy of a drug trial is defined 
by both dose and duration of use. Figure 3 includes a flow chart for this assessment and a preliminary 
7

SPACE Protocol Supplement: Original IRB-Approved Protocol  
table of dose/duration specifications for key drugs; these specifications will be expanded and finalized 
by the study team during the start-up phase of the trial.
For opioid therapy, additional contraindications include those outlined by VA/DoD clinical practice 
guidelines,6 as follows: a) acute psychiatric instability, defined as current uncontrolled severe 
depression, severe PTSD, or suicidal ideation; b) substance use disorder not in remission or treatment; 
and c) documented or suspected diversion of controlled substances.
Figure 3: Determination of an adequate analgesic drug trial
C3. Identifying potential participants
Primary care providers (PCPs) will be informed of the study and asked to provide written consent to 
approach their patients for participation. The Minneapolis VA has 47 full-time equivalent primary care 
physicians. We have an excellent track record of recruiting PCPs in this manner; in previous trials at the 
Roudebush VA, >90% of PCPs have consented.  
The primary enrollment method will be a mail and phone strategy as used in our trials conducted at the 
Roudebush VA.19 Potentially eligible patients of participating PCPs will be identified through local VistA
searches, using the criteria in Table 1. Searches will be updated every month during the enrollment 
period. Potentially eligible Veterans will be mailed a recruitment letter describing the study and co-
signed by study Principal Investigator Dr. Krebs and their PCP. Potential participants will then be 
contacted by phone within a week after receipt of the letter to determine interest in participating and to 
assess eligibility. If the Veteran is eligible and interested in participating, an appointment will be 
scheduled for the informed consent process. After participants provide written informed consent and 
authorization, the baseline interview will be conducted.
Table 1.  Search Criteria to Identify Potential Study Participants
Criterion
Search variable
Pain
1) 715xx, 721.xx, 722.xx, 724.xx and
SDLQVFRUHRQPRVWUHFHQWYLVLW
8

SPACE Protocol Supplement: Original IRB-Approved Protocol  
Visit
Primary care visit in past 12 months
No chronic 
opioids
In the past 3 months…
1) No fentanyl patch, methadone, morphine SR, oxycodone SR dispensed
and
2) <60 short-acting opioid pills dispensed for 30 days
If enrollment falls below targets, a second method of enrollment will be in-clinic contact of potential 
subjects by cross-referencing of the potentially eligible list with the appointment schedule for each 
participating PCP. 
C4. Inclusion of women and minorities
This study will be performed at the Minneapolis VAMC, where we expect approximately 7-10% of the 
potentially eligible population to be women. Eligible women and racial/ethnic minorities will be 
encouraged to enroll. This study will not be powered for subgroup analyses with women or minority 
participants, but we will examine results for evidence of trends that can be prospectively evaluated in a 
future multisite trial. Gender and race/ethnicity will be considered in all multivariable analyses. 
Additionally, the purposive sampling technique we will use for the qualitative evaluation will specifically 
“oversample” female and minority participants in order to adequately represent their views.
D. Randomization
After providing informed consent and completing the baseline assessment, participants will be 
randomized to the opioid-intensive arm (n=138) or the opioid-avoidant (n=138) arm. Randomization will 
be stratified by primary pain location (back or hip/knee) to assure balanced numbers of participants with 
LBP or OA. Randomization will occur in randomly varying block sizes of 2 and 4.
D1. Masking and allocation concealment
Participants will not be masked to treatment arm assignment due to the complexity of the medication 
prescribing strategies. The pharmacist care manager and supervising clinical investigators who 
implement the interventions will also be aware of treatment assignment. To maintain allocation 
concealment, randomization will be conducted by the pharmacist care manager at the first treatment 
visit, using sealed envelopes prepared by the statistician. Outcome assessors will be masked to 
treatment assignment. The masking of outcome assessors and the structured nature of outcome 
measures are expected to minimize potential biased ascertainment.
E.  Interventions
E1. Intervention structure
A clinical pharmacist care manager will be the central intervention provider for both arms. Clinical 
pharmacists have an established role in Minneapolis VA primary care clinics that includes protocol-
driven adjustment of medication therapy. Clinical pharmacists assigned to each primary care clinic can 
currently be consulted to see patients with difficult to control hypertension or hyperlipidemia. They 
adjust medications, monitor response, and return disease management back to the primary care 
provider once blood pressure or lipid medications are optimized. This program has been both well-
received by primary care providers and associated with improvement in outcomes.20 The SPACE 
intervention protocol echoes this familiar and successful program. 
Participants will see the pharmacist care manager in a study clinic, with the first intervention visit 
scheduled as soon as possible after study enrollment. At this visit, the care manager will obtain a 
detailed history of current and past pain medications. The medication history will include review of 
current and past medications, including examination of patients’ medication packages they will bring to 
the visit and CPRS medication lists. Information from these sources will be supplemented by review of 
a checklist of analgesic and adjuvant medications, including photographs of drugs to stimulate patient 
9

SPACE Protocol Supplement: Original IRB-Approved Protocol  
recall. The care manager will confirm eligibility as described in Sections C, randomize the participant as 
described in Section D, and recommend initial medication adjustment according to the prescribing 
strategy for the assigned treatment arm. 
We expect that most adjustments in pain medications will occur in the beginning of the study period for 
most patients, so intervention visits will be scheduled at baseline and approximately monthly for the 
following two visits. Additional visits will be scheduled according to individual participants’ needs during 
the remainder of the 12 month intervention period, with a maximum of 6 months between visits for 
participants who achieve adequate pain control on a stable medication regimen. Because the extent of 
care manager contact may differ among patients over the course of the trial, we will track these 
contacts and examine between-group differences in care manager contact as a potential confounder. 
Before and between intervention clinic visits, patients will have their symptoms reassessed using 
automated symptom monitoring (see Section F).  
Case review meetings with the pharmacist care manager and supervising clinician investigators will be 
held each week to review progress with pain management, adverse effects, and any clinical problems. 
Clinical pharmacists are able to write prescriptions for non-scheduled medications. A physician 
investigator will sign paper prescriptions for DEA scheduled medications (i.e., opioids). All study 
medications will be dispensed through the Minneapolis VA research pharmacy and mailed to 
participants; from the participants’ perspective, this dispensing process will not differ from the usual 
non-research medication dispensing experience.
The primary method of communicating with primary care about routine patient progress and pain 
treatment decisions will be care management notes entered into CPRS; this is consistent with usual 
consultant practice at our VAMC. If indicated by emergent adherence or safety issues (e.g., repeated 
attempts by a participant to receive pain medication outside of the study, important adverse effects), a 
care manager or investigator will communicate directly with the patient’s primary care provider. At the 
end of the trial period, we will provide primary care providers with a synopsis of each patient’s individual 
response to therapy, including change in pain and function and any adverse effects. A plan for 
continuation or discontinuation of study therapy will be developed for each patient on an individual 
basis. The clinical pharmacist will facilitate tapering of opioids at the end of the study if, based on 
individual patient outcomes, discontinuation of study opioids is determined to be the appropriate 
course.
F. Automated symptom monitoring 
Interval reassessment of pain, adverse effects, and adherence will be done by automated symptom 
monitoring, through interactive voice recorded (IVR) phone calls. Automated symptom monitoring will 
be scheduled to occur prior to in-person study clinic visits and at the time of medication refill or renewal. 
It can also be scheduled at interval time points as customized by the care manager, such as 1-2 weeks 
after a medication change. The automated symptom monitoring assessment will include the following 
abbreviated measures: (a) the 3-item PEG, a brief measure of pain intensity and interference that is 
responsive to change;21,22 (b) a patient global impression of change rating;23 and (c) the PHQ-4, which 
includes the depression screening items of the widely used PHQ-2 plus two anxiety screening items.24
Also included will be single questions about medication underuse, overuse, and side effects, as well as 
the option to send a request for contact by the care manager. Participants who do not complete their 
scheduled automated assessments will receive a reminder; if this fails, they will have the option of 
completing a paper version of the assessment at the time of their next visit.
Automated symptom monitoring by IVR will be used solely as a clinical tool for the pharmacist care 
manager and supervising clinician investigators to monitor and adjust therapy. It will not be used to 
assess research outcomes. The Minneapolis VA has an existing contract with Audiocare for clinical 
and research IVR services. Appropriate VA data security, information privacy, and research oversight 
bodies have approved IVR use in prior studies. 
10

SPACE Protocol Supplement: Original IRB-Approved Protocol  
G.  Analgesic prescribing strategies
The analgesic prescribing strategies in this proposal were developed based on evidence-based 
recommendations from published disease and drug class-specific guidelines,5;6;25;26;27 systematic 
reviews,3;4;28-30 and our own published reviews 31;32 and refined through our experience with algorithm-
based pain medication adjustment in the clinical trials at the Roudebush VA. Each medication has 
demonstrated efficacy for relevant indications from randomized clinical trials and, in most cases, from 
meta-analyses or systematic reviews of multiple RCTs. Direct comparative data are not available for 
most medications, so sequencing is based on other factors, such as safety, tolerability, and VA 
formulary availability. As is the case with depression, regular monitoring and adjustment of pain therapy 
is likely as important in achieving good outcomes as the specific initial treatment chosen.33 Both 
prescribing strategies will be operationalized as a series of individual medication trials undertaken by 
the patient and pharmacist care manager using a structured shared decision-making approach.
Patients will enter the prescribing strategies at different levels, depending on their baseline medications 
and past medication history. Their baseline medications may be discontinued, adjusted to achieve an 
adequate therapeutic trial, or continued with the addition of adjunctive drugs, depending on their 
individual history of medication use (including dosing, scheduling, and adherence), therapeutic 
response, and adverse effects. In general, each level in each step of the prescribing strategies will be 
tried before moving to the next higher step. Importantly, both the opioid-intensive and opioid-avoidant 
prescribing strategies are titrated to clinical response rather than a specific type or dose of treatment. 
This pragmatic treat-to-target approach more closely mirrors real-world practice, which tailors evidence-
based treatments to patient-specific outcomes.12;34;35  
Decisions to change pain medications must be made in a shared process because, unlike assessment 
of conditions that are evaluated independent of patient report (e.g., hypertension), pain control is 
inherently subjective. Decisions about whether to continue a current medication or change to another 
drug or dose are necessarily influenced by factors unique to the individual patient with pain, such as 
internal weighing of pain and medication effects on valued roles and activities, beliefs and values about 
pain and pain medications, and personal coping styles. SPACE will use a structured decision-making 
approach to consider patient preferences along with results of symptom monitoring. The two main 
considerations included in the algorithm for medication change decisions (Figure 4) are the following: 1) 
presence of pain response, defined as improvement in both PEG score and patient global impression of 
change, and 2) whether the patient desires change in medications. 
11

SPACE Protocol Supplement: Original IRB-Approved Protocol  
Figure 4: Algorithm for medication change decisions
G1. Opioid-intensive prescribing strategy
Evidence for relative effectiveness of various opioid regimens, including different drugs and dosing 
schedules, is extremely limited;36 therefore, opioid initiation and adjustment will be guided by VA/DoD 
guideline-concordant principles, applied in a personalized manner.6 Figure 5 outlines principles of 
opioid adjustment and stepped medication options. 
Opioid medications will be titrated gradually, with frequent reassessment, until treatment goals are met, 
dosing is limited by adverse effects, or a morphine equivalent (MEq) daily dose of 200 mg is reached. 
The issue of opioid dosing limits is highly controversial and no well-accepted upper dosing limit has 
been established; however, evidence for use of high-dose opioids is limited and reports suggest a 
positive relationship between dose and serious adverse events.37 Current VA/DoD guidelines 
recommend dosing based on patient need, not on predetermined maximal dose.6 In contrast, opioid 
prescribing guidelines from a Washington State interagency group recommend specialty consultation 
for doses >120 mg/day.38 Given these data and remaining uncertainties, we will not increase doses 
beyond 200 MEq mg/day in this study. Participants reaching this limit may be rotated to another opioid, 
which can allow a decrease in the total daily dose. 
Figure 5: Opioid-intensive Prescribing Strategy
12

SPACE Protocol Supplement: Original IRB-Approved Protocol  
G2. Opioid-avoidant prescribing strategy
As in the opioid-intensive arm, medication initiation and adjustment in the opioid-avoidant arm will be 
guided by general principles applied in a personalized treat-to-target manner. Figure 6 outlines the 
opioid-avoidant principles and stepped medication options. Adjuvant medications (designated Steps A 
and B) are included as analgesia-enhancing steps that may occur in parallel with prescribing of 
analgesics in Steps 1-3. Tramadol, included in Step 2, is a centrally acting analgesic that affects mu 
opioid receptors, as well as serotonin and norepinephrine reuptake.28 Tramadol is not a DEA controlled 
substance due to its limited abuse potential. Some patients in the opioid-avoidant arm will advance to 
low-dose therapy with typical opioids (Step 3), but the nature of the prescribing strategies will create a 
clear separation between the arms in the incidence and intensity of opioid use.
Figure 6: Opioid-avoidant Prescribing Strategy  
13

SPACE Protocol Supplement: Original IRB-Approved Protocol  
H Medication safety considerations
Treatment agreements are widely advocated for use among patients receiving opioid medications, 
although evidence for their effectiveness in preventing opioid misuse is limited.39 VA/DoD guidelines 
recommend reviewing a written Opioid Pain Care Agreement before initiating opioid therapy.6 In the 
proposed trial, a Pain Care Agreement will be employed in both intervention arms (regardless of 
medication type prescribed) as a way to structure medication education and clarify roles and 
responsibilities. At the time of study enrollment, the SPACE Pain Care Agreement will be entered into 
the patient’s CPRS medical record and copies will be provided to the patient and his/her primary care 
provider. Violations of the agreement will be handled according to the nature of the behavior, as 
described in Section J.  
At each intervention visit, use of non-study medications, over-the-counter medications, and herbal 
therapies or supplements will be evaluated, along with risk of drug interactions. Participants will be 
informed of potential interactions and study therapy will be adjusted as needed to avoid or minimize the 
likelihood of adverse drug interactions and maximize therapeutic response. A number of medication or 
class-specific safety rules will also be employed, including but not limited to the following: 1) 
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have had a creatinine within 6 months of initiation. Patients with estimated GFR <60, heart failure, 
peptic ulcer disease, or liver failure will not be started on an NSAID. Patients initiating an NSAID who 
are older than 65, have diabetes, or use a diuretic will have a follow-up creatinine within 4-8 weeks.
Gastrointestinal prophylaxis will be prescribed in concordance with current guidelines.40 3) Tramadol 
will not be used in patients with a history of seizures. 4) Patients with a history of heart disease, 
arrhythmia, or syncope will not be started on methadone. Patients considered for methadone must 
have had an electrocardiogram (ECG) within 3 months. If the baseline QTc interval is >450 ms, 
methadone will not be started. Patients receiving methadone will receive a follow-up ECG 3-6 weeks 
14

SPACE Protocol Supplement: Original IRB-Approved Protocol  
after starting therapy; if the follow-up QTc is >450 ms and <500 ms, the potential risks and benefits of 
therapy will be reevaluated with the patient and the ECG will be monitored at least every 2 months. If 
any follow-up QTc is >500 ms, methadone will be discontinued or tapered.41
The American Geriatrics Society (AGS) recently published updated guidelines for pain treatment in 
patients who are fraiORU\HDUVROG42 For older adults, as well as participants with higher risk for 
adverse effects (e.g., those with chronic medical conditions), we will follow safety recommendations 
outlined in the AGS guidelines as well as the classic geriatrics maxim to “start low, go slow.” Examples 
of specific safety rules that will be employed include, but are not limited to, the following: 1) The lowest 
possible dose of a given drug will be used as the starting dose; 2) Nortriptyline will be titrated to a 
maximum dose of 50 mg; amitriptyline will not be used; 3) Tramadol will be titrated to a maximum dose 
of 300 mg; 4) An immediate-release opioid will be used prior to any long-acting opioid to determine the 
appropriate starting dose; 5) NSAIDs with high cyclooxygenase-2 inhibitor selectivity (e.g., diclofenac) 
will not be used. All participants will receive closer monitoring than is available in usual practice, with 
reassessment of pain and adverse effects after each medication change, and dose adjustments no 
more often than once a week.
I. Clinical management of adverse effects (AEs)
Reports of side effects from automated symptom monitoring (Section F) will be followed up by the 
pharmacist care manager. In response to patient reports of adverse effects (AE), medications may be 
adjusted or clinical strategies may be employed to address ameliorable or preventable minor AEs (e.g., 
itching). Recommendations for prevention of constipation will be provided to all participants in both 
study arms at the outset. Important AEs (e.g., rectal bleeding) will also be evaluated by a study 
physician and reported to the patient’s primary care provider. Potentially urgent AEs (e.g., chest pain) 
will be referred for immediate evaluation in the medicine clinic or emergency department. 
Patients with mood symptoms will be further evaluated with the PHQ-9 for depression or GAD-7 for 
anxiety.43;44 Clinically significant new or worsening psychiatric symptoms will be reported to the primary 
care provider and patients will be offered referral to their primary care team psychologist. Veterans who 
endorse thoughts of self-harm on item 9 of the PHQ-9 depression scale will be assessed with a suicide
risk algorithm. 
J. Clinical monitoring of adherence
Problems with medication overuse or underuse have many potential causes, including those related to 
the therapy (e.g., inadequate efficacy, side effects) and those related to patient (e.g., concerns about 
medication). When medication adherence issues are identified, they will be evaluated and addressed 
by the study care team on an individual basis with the goals of improving pain and tolerability of pain 
medications. 
Aberrant drug-related behaviors (ADRB) are a particular class of nonadherence behaviors that have 
been associated with opioid misuse and substance use disorders. Although ADRB are often discussed 
in relation to opioid analgesic therapy, they may occur in any patient with pain. Indeed, ADRB may
represent “pseudo-addiction” in the context of pain under-treatment, which may be more likely to occur 
among patients receiving only non-opioids or low-dose opioids. For these reasons, the clinical response 
to ADRB will be determined by the nature of the observed behaviors, rather than the medication 
prescribed or the study arm assigned. 
A validated checklist of potentially concerning ADRB will be completed by the care manager at each 
visit for participants in both arms.45 Any emerging pattern of ADRB will be reviewed at weekly case 
meetings and the study team will prescribe an individual monitoring plan to aid in diagnosing and 
ameliorating the behavior. This plan will be reassessed at each visit and may include any combination 
of the following actions: a) medication adjustment; b) more frequent study visits; c) adherence 
counseling or education; d) review of state prescription monitoring database to identify duplicate or 
unreported external opioid prescriptions; e) referral for evaluation by a mental health or addiction 
15

SPACE Protocol Supplement: Original IRB-Approved Protocol  
clinician; f) shorter prescription renewal intervals; g) urine drug testing; and h) pill counts. Serious 
ADRB, such as illicit drug use or potential diversion of prescribed medication, may result in medication 
changes, including tapering or discontinuation of opioids. These behaviors will not be considered 
reasons for withdrawal from the trial and all participants will be evaluated in their assigned arm.
K. Data Collection
Study measures include both patient-reported outcomes that will be collected in interviews at baseline
and 3, 6, 9, and 12 months and test-based outcomes that will be completed in person at baseline, 6, 
and 12 months.  Interviews will require approximately 50 minutes at 0, 6, and 12 months and 
approximately 15 minutes at 3 and 9 months. In-person outcome assessment visits will require 50-60
minutes. A small incentive ($20) will be provided for each outcome assessment call and visit. Incentives 
of this magnitude offset costs of participation and are in the standard range used in our previous VA 
and non-VA effectiveness trials. No incentives will be provided for study clinical visits nor for automated 
symptom monitoring, which is conducted for clinical intervention purposes.
Patient-reported outcome measures and timing of administration are displayed in Table 2 and
described in Section K1. Although participants will be asked to complete a substantial battery of patient-
reported measures in this proposed study, we believe this outcome assessment protocol is both 
appropriately comprehensive and reasonable in terms of respondent burden. Outcome assessment 
protocols of similar length have been well tolerated in multiple symptom management trials involving 
thousands of patients with depression or pain.12;34;46 Indeed, many participants in these trials have 
reported that they appreciated the sustained attention to their symptoms and perceived benefit from 
therapeutic disclosure. 
Table 2: Patient-reported Outcome Assessment Protocol
Domain
No
Measure
Items*
Schedule
0
mo
3
mo
6
mo
9
mo
12
mo
Pain 
1
Brief Pain Inventory
11
X
X
X
X
X
2
Roland Disability-short form 
11
X
X
X
3
Global Rating of Change
1
X
X
X
X
Health-related QOL
4
SF-12
12
X
X
X
X
X
Adverse effects
5
Symptom checklist
15
X
X
X
X
X
Fatigue & sleep
6
Multidimensional Fatigue Inventory
20
X
X
X
7
Athens Insomnia Scale
5
X
X
X
Headaches
8
Headache Impact Test
6
X
X
X
Sexual function
9
Arizona Sexual Experience
5
X
X
X
Mental health 
10
PHQ-9
9
X
X
X
11
GAD-7
7
X
X
X
12
Primary Care-PTSD
4
X
X
X
Substance use
13
AUDIT
10(3)
X
X
X
14
Drug use & smoking items
11(5)
X
X
X
Medication beliefs
15
Medication Beliefs Questionnaire
5
X
X
Expectations
16
Treatment expectation items
4
X
X
Co-interventions
17
Treatment checklist
5
X
X
X
X
X
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SPACE Protocol Supplement: Original IRB-Approved Protocol  
QOL= quality of life; PTSD = Posttraumatic Stress Disorder
*Items completed for repeat assessment are in parentheses when they differ from those completed at 
baseline.
K1. Description of patient-reported measures
The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) guidelines 
recommend assessment of multiple core outcome domains in pain clinical trials, including pain 
intensity, function, patient ratings of improvement, and symptoms and adverse events.47 We will assess 
each of these pain outcome domains with validated patient-reported measures. 
1. The Brief Pain Inventory (BPI) is a multidimensional measure that includes two scales, which we will 
use as the primary measures of pain intensity and pain-related function. The BPI severity score is the 
average of four 0-10 items assessing current, least, worst, and average pain intensity in the past week. 
The BPI interference score is the average of seven 0-10 ratings of interference with general activity, 
mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life. The BPI 
was originally developed for use in cancer-related pain, but has been validated for use in numerous 
other populations, including primary care patients with non-cancer chronic pain.47;48;49 IMMPACT has 
recommended the BPI as a core outcome measure for chronic pain clinical trials. We have used the 
BPI successfully as the primary pain outcome measure in recent and ongoing trials at the Roudebush 
VA.  
2. The Roland Disability Scale is a pain-specific measure of physical function that was originally 
validated in back pain.50 An 11-item short form that was developed and validated among diverse 
chronic pain patients will be used as a secondary measure of pain-related function.51
3. A 7-grade patient-reported global impression of change rating will assess patients’ views of overall
improvement or worsening in pain.52
4. The Medical Outcomes Study Short Form-12 (SF-12) is a well-validated measure of health-related 
quality of life that will be used as a primary measure of general mental and physical function.53  
We will assess adverse effects with an inventory of medication-related symptoms as well as targeted 
assessment of key adverse effect domains: fatigue, sleep, headache, and sexual function.
5. A validated adverse effects Symptom Checklist54 will assess the number and severity of common 
symptoms and participants’ beliefs about whether or not they are medication-related. In addition to the 
ten common symptoms included in the original checklist (problems with sleep, changes in mood, 
gastrointestinal problems, dizziness and problems with balance, headache, fatigue, muscular aches, 
incontinence, sexual problems, and rash or itching), we added the following symptoms, which represent 
five of the most common patient-reported side effects of analgesic medications: memory problems, dry
mouth, trouble concentrating, sweating, and weight gain.55  
6. The Multidimensional Fatigue Inventory has been validated among adults with chronic illness, 
chronic fatigue syndrome, and cancer, as well as among healthy adults.56
7. The Athens Insomnia Scale-5 item version is based on ICD-10 criteria and has been recommended 
by the OMERACT group for use in clinical trials on the basis of both its feasibility and psychometric 
properties.57
 8. The Headache Impact Test is a brief validated measure of headache severity.58 
9. The Arizona Sexual Experience (ASEX) scale assesses 5 domains of sexual function in men and 
women.59  
Mental health and substance use disorders are commonly comorbid with chronic pain and can affect 
outcomes of pain treatment. These domains will be assessed with several brief measures. 
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SPACE Protocol Supplement: Original IRB-Approved Protocol  
10. The Patient Health Questionnaire (PHQ)-9 is a well validated brief measure of depression severity
that is based on DSM criteria for major depression.43
11. The General Anxiety Disorders questionnaire (GAD-7) has been validated as an anxiety screening
and severity measure in primary care.44
12. The Primary Care Post-traumatic Stress Disorder (PC-PTSD) Screen is a screening test for PTSD
that was developed and validated in VA primary care.60
13. The AUDIT questionnaire is a well-established assessment tool for alcohol use disorders that
accurately identifies primary care patients with at-risk drinking.61 The full AUDIT will be used at baseline
and the brief 3-item AUDIT-C will be used at follow-up.
14. To assess past and current drug use, we will use a single item drug use screener that predicts drug
use disorders in primary care, plus 6 history items we developed for a previous study.62 Four questions
from the National Survey on Drug Use and Heath assess past and current smoking.63
Finally, we will include additional secondary measures that that may help explain response to therapy. 
15. The Medication Beliefs Questionnaire64 assesses beliefs that may mediate opioid misuse.
16. Treatment expectation questions adapted from prior pain trials will be asked at baseline (prior to
intervention group assignment) and the first follow-up assessment (after group assignment).65
17. Participants will be asked to report prior pain treatment history at baseline and to report co-
interventions at each outcome assessment, including new medications, pain-related procedures, and
physical and psychological therapies.
K2. Description of test-based measures
At 0, 6, and 12 months, participants will undergo an in-person assessment of domains that cannot be 
adequately captured with self-reported measures. A research assistant will administer tests of pain 
sensitivity, physical performance, and cognitive function. 
Painful conditions are associated with risk of falling among both middle-aged and older patients; this 
risk may be exacerbated by medications with psychomotor effects. We will test 3 physical performance 
factors that may be especially important in determining risk for falls—balance, lower extremity strength, 
and gait speed. The Fullerton Advanced Balance scale is a 10-item test that evaluates multiple 
dimensions of balance in independent adults. It was designed to be more challenging than balance 
measures developed for frail elderly persons and has been validated as a predictor of falls risk among 
middle-aged and older adults with chronic pain.66;67 Participants will also complete the Chair Stand test,
a brief assessment of lower extremity strength. The Chair Stand measure assessed healthy adults’ 
(age 20-85) time to stand from a seated position ten times, but subsequent studies found substantial 
floor effects among older adults and arthritis patients, who were often unable to complete ten stands. In 
our population of patients with functional limitations due to back and lower-extremity arthritis pain, we 
will use a modified version that counts the number of stands completed in 30 seconds.68 Gait speed 
tests are commonly used as performance measures in osteoarthritis.69 We will use a timed 8-meter 
walk protocol that has been shown to reliably assess normal and fast-paced walking speeds among 
moderately-impaired osteoarthritis patients.70  
Cognitive function will be assessed with a brief battery of tests, the Indiana University Telephone-Based 
Assessment of Neuropsychological Status (IU-TBANS), which includes four standard clinical 
instruments covering the following domains: attention, learning and recall, information processing 
speed, and verbal fluency.71 This test battery was developed as a sensitive measure of subtle cognitive 
dysfunction among community-dwelling cancer survivors (at least one year post-treatment) so we 
18

SPACE Protocol Supplement: Original IRB-Approved Protocol  
believe it will be sensitive to small deficits in cognitive function among patients with pain. IU-TBANS has 
been validated in both telephone and in-person forms and can be completed in 15-20 minutes.
Participants will also have blood collected by VA clinical staff according to their routine procedures. 
Urine for drug testing will be collected at 0, 6, and 12 months. All participants will have total 
testosterone measured at 0 and 12 months; women will also have estradiol measured at 0 and 12 
months.8 We will assess pain sensitivity at baseline and follow-up visits with the Cold Pressor task, a 
method that has been used in clinical research with adults and children since the 1960s and is the most 
sensitive measure of opioid-associated pain hypersensitivity.7;72 Following recommended protocols for 
testing, participants will submerge their non-dominant hand up to the wrist in 1º C water continuously 
circulated by a commercial cooling bath.72 They will be asked to keep their hand submerged until it 
becomes too uncomfortable to continue, at which time they are instructed to withdraw it from the water. 
Pain threshold is time until the stimulus is first perceived as painful; pain tolerance is time until 
withdrawal of the hand. 
K3. Description of additional measures
Adverse events will be ascertained using a combination of patient report and medical record review. 
Participants will also be asked to report occurrence of any falls, hospitalizations, or emergency visits at 
each outcome assessment call. 
Additionally, falls will be assessed using a prospective calendar and postcard monitoring protocol.73
Participants will track falls on monthly falls calendars and will be asked to complete a postcard and mail 
it to the research team if a fall occurs. When postcards are received, a research assistant will follow-up
with a phone call to obtain information about the cause and outcome of the fall. To ensure no falls are 
missed, the calendars will be collected every three months and outcome assessors will follow-up on 
any additional falls recorded on the calendars but not previously reported by postcard. This method of 
fall ascertainment is consistent with recommendations based on a systematic review of fall outcome 
assessment.73  
Hospitalizations and emergency visits will be identified and confirmed using medical record review at 
the end of the study. VA hospitalizations and emergency visits will be ascertained using complete data 
available in VistA; non-VA hospitalizations and emergency visits will be ascertained from patient report 
and confirmed by medical records. These events will be considered as adverse outcomes regardless of 
where they occurred. To determine whether the events were analgesic-related, two physicians who are 
masked to study arm assignment will review records of emergency visits and hospital admissions. The 
World Health Organization system for standardized case causality assessment will be used to 
determine whether the relationship between an event and analgesic use is probable or greater.74 Initial 
reviews will be conducted independently to allow for calculation of inter-rater reliability. Subsequently, 
reviewers will meet and attempt to reach consensus; if the two reviewers disagree and cannot reach 
consensus, a third reviewer will break the tie. 
No single measure is adequately predictive or diagnostic of opioid misuse,5 so data from patients, 
clinicians, records, and laboratory tests will be use to assess the occurrence of behaviors suggestive of 
opioid misuse or addiction. In addition to previously described measures, patient-reported substance 
use history75 will be evaluated at baseline. The Addiction Behavior Checklist (ABC) will be completed 
by the clinical pharmacist at each intervention visit. The ABC was developed within a VA chronic pain 
setting to provide a brief measure for longitudinal clinician assessment of ADRB.45 Urine drug testing
will be obtained at 0, 6, and 12 months as part of outcome assessments for all participants. 
Additionally, medical record reviews will be completed at the end of the study. Research assistants 
trained in chart abstraction will review the electronic medical record over the 12 month study period for 
documented ADRB and evidence of potential opioid misuse.
L. Prevention of missing data
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SPACE Protocol Supplement: Original IRB-Approved Protocol  
In pain clinical studies, dropouts often occur due to intervention-related factors (e.g., adverse effects, 
lack of treatment efficacy) and missing data can pose a substantial threat to internal validity. SPACE 
has several design features meant to enhance participant retention and reduce missing data.76 First, 
the interventions are flexible treat-to-target prescribing strategies that allow tailoring to each patient’s 
needs. Medications will be adjusted individually, reducing dropouts due to lack of efficacy or 
intolerance. Second, both study arms are active interventions, which should reduce differential dropout 
that can occur among patients assigned to a control arm. Third, all randomized participants will be 
strongly encouraged to complete all outcome assessments, whether or not they continue in the 
intervention. Fourth, to reinforce participants’ sense of commitment to the study, we will send a 
quarterly SPACE newsletter to participants including tips on pain self-management and positive news 
from pain research. Finally, if participants are at risk of dropping out due to assessment burden, they 
will be given the option of completing a minimum core assessment comprising primary pain (i.e., BPI) 
and adverse effect (e.g., symptom checklist) measures. 
M. Qualitative recruitment and data collection
We will recruit four subgroups of SPACE participants for qualitative interviews—those who respond to 
paint treatment and non-responders from each of the two arms. Within each of the subgroups, we will 
purposefully sample participants with a broad range of intervention adherence behavior (e.g., number 
of completed care manager contacts).77 Experience with conduct of the trial will inform our sampling 
strategy; for example, we may identify patterns of non-adherence that merit further exploration. During 
the initial consent process for the SPACE trial, all participants will be asked for permission to contact 
them after intervention completion. The data analyst will provide names of potential participants for the 
qualitative phase and the study coordinator will contact them within four weeks of completing the 
SPACE trial. 
Throughout data collection and analysis, the research team will remain masked to participants’ 
responder and adherence status. We will use individual semi-structured interviews to address our 
qualitative aims. Development of the semi-structured interview guide will be informed by the 
collaborative management framework and TCM as well as questions that arise during the conduct and 
analysis of the main SPACE trial. Based on experience with the main trial, questions will be further 
developed, revised, and piloted prior to the beginning of the qualitative phase. The project coordinator, 
will conduct interviews in a private VA office within 2 months of each participant’s trial completion. 
Interviews will be digitally audio-recorded and transcribed for analysis as they become available. We 
will continue to conduct interviews with patients until theoretical saturation is reached. Based on our 
experience and recommendations for sampling subgroups,77 we expect to conduct up to 10 interviews 
for each group (responders and non-responders in each study arm), for a total of 40 participant 
interviews.
N.  DISSEMINATION PLAN 
Results of the SPACE trial will be interpreted not in isolation, but in the context of results from 
complementary VA-funded pain clinical trials designed to address different gaps in our knowledge of 
chronic pain management. Together, these distinct but complementary studies will provide necessary 
data for clinicians and policy-makers working to improve VA pain care. 
The primary knowledge gap SPACE addresses is the long-term benefit of an opioid-intensive 
prescribing strategy compared with an opioid-avoidant strategy. Information about the magnitude of 
benefit, along with additional information about the likelihood of harm, is necessary for providers to 
make the best decisions with individual patients about their pain treatment options. Meanwhile, results 
of complementary studies, including SCOPE and ESCAPE at the Roudebush VA, will inform VA on 
how to address provider and structural barriers to pain care. 
To disseminate pain research findings, we will take full advantage of the robust pain care infrastructure 
that exists within the VA. The National Pain Management Strategy Coordinating Committee is an 
20

SPACE Protocol Supplement: Original IRB-Approved Protocol  
important channel for disseminating findings to VA providers, administrators, and policy makers. Dr. 
Bair serves on this committee and will facilitate reporting of findings in the form of reports and 
presentations at their meetings. Findings will be further disseminated through VISN Pain Points of 
Contact, the Office of Quality and Performance, and VA Center for Medication Safety. We will also 
present to the large clinically-oriented audience of the VA pain list-serve and monthly national VA pain 
educational teleconferences.
Findings will be disseminated to our research audiences through scientific presentations and 
publications, HSR&D cyber seminars, and presentations to VA and non-VA interest groups. Principal 
Investigator Dr. Krebs and Co-Investigator Dr. Bair are both active members of the VA Pain Research 
Working Group and Society of General Internal Medicine (SGIM) Pain Interest Group. Both groups 
have active list-serves and annual face-to-face meetings. The VA Pain Research Working Group has 
monthly telephone conferences to promote coordination and dissemination of VA-relevant pain 
research. In addition, we will disseminate study findings to the Substance Use Disorder and Polytrauma 
QUERIs and the HSR&D Center for Information Dissemination and Education Resources (CIDER).
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SPACE Protocol Supplement: Original IRB-Approved Protocol  
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(5)  Chou R, Fanciullo GJ, Fine PG et al. Clinical Guidelines for the Use of Chronic Opioid 
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(20) Bex SD, Boldt AS, Needham SB, Bolf SM, Walston CM, Ramsey DC et al. Effectiveness of a 
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evidence for an American Pain Society/American College of Physicians clinical practice 
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(28) Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis: a systematic review 
and metaanalysis. J Rheumatol 2007;34:543-555. 
(29)  Mason L, Moore RA, Derry S, Edwards JE, McQuay HJ. Systematic review of topical 
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(30)  Salerno SM, Browning R, Jackson JL. The effect of antidepressant treatment on chronic back 
pain: a meta-analysis. Arch Intern Med 2002;162:19-24. 
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recommendations from systematic reviews. Gen Hosp Psychiatry 2009;31:206-219. 
(33)  Adli M, Bauer M, Rush AJ. Algorithms and collaborative-care systems for depression: are they 
effective and why? A systematic review. Biol Psychiatry 2006;59:1029-1038. 
(34)  Kroenke K, Bair MJ, Damush TM et al. Optimized antidepressant therapy and pain self-
management in primary care patients with depression and musculoskeletal pain: a randomized 
controlled trial. JAMA 2009;301:2099-2110. 
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