Pain Medicine, 2024, 25(S1), S7–S10

https://doi.org/10.1093/pm/pnae069
Commentary

Achieving two-part harmony: standardizing pain-related

phenotypes and outcomes
Robert Edwards, PhD1,�, Mary Geda, RN, BSN, MSN2, Diana J. Burgess , PhD3,
Alison F. Davis, PhD4, Lynn DeBar, PhD, MPH5, Natassja Pal, BS6,7, Peter Peduzzi, PhD8,

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Stephanie L. Taylor, PhD9,10, Robert Wallace, MD, MSc11, Stephen L. Luther, PhD, MA12
1
Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Harvard University, Boston, MA 02115, United
States
2
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, United States
3
Department of Medicine, Center for Care Delivery and Outcomes Research, Minneapolis VA Health Care System and University of
Minnesota Medical School, Minneapolis, MN 55417, United States
4
Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, United States
5
Public Health and Preventive Medicine, Kaiser Permanente Center for Health Research, Oregon Health & Science University, Portland, OR
97227, United States
6
Department of Psychiatry, Oregon Health & Science University, Portland, OR 97239, United States
7
Center to Improve Veteran Involvement in Care, VA Portland Health Care System, Portland, OR 97239, United States
8
Department of Biostatistics, Yale School of Public Health and Yale Center for Analytical Sciences, Yale University, New Haven, CT 06510,
United States
9
Center for the Study of Healthcare Innovation, Implementation and Policy, Greater Los Angeles VA Health Care System, Los Angeles, CA
91343, United States
10
Department of Health Policy and Management, School of Medicine; UCLA School of Public Health, University of California, Los Angeles,
Los Angeles, CA 90095, United States
11
Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA 52242, United States
12
Research and Development Service, James A. Haley Veterans Hospital, Tampa, FL 33612, United States
�Corresponding author: Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115, USA.
Email: rredwards@bwh.harvard.edu

Introduction nonpharmacological pain management research in real-world

settings. We believe that harmonizing phenotypic and out­
Military service members and veterans are especially vulner­
come data collection across similar trial networks has the
able to developing chronic pain conditions, given their high
potential to magnify the results emerging from those studies,
risk of musculoskeletal injuries and exposure to combat-
support comparisons across populations, and promote the
related trauma. Approximately half of active-duty military
wide adoption of evidence-based care.
service members experience significant pain, especially
women.1 Indeed, persistent back pain is among the most
common drivers of health care use and interruption of com­ Advantages of harmonization
bat duty.1 These realities highlight the need to develop and Data are maximally useful if collected in a standardized man­
deploy effective strategies for prevention and management of ner to facilitate reproducibility, subgroup analyses, data
pain, particularly nonpharmacological treatments, which are pooling, and cross-study comparisons. Moreover, variability
effective first-line therapies for military and veteran personnel in outcome measures across clinical trials hinders the field’s
but are underutilized in clinical practice. Pragmatic trials can ability to conduct evaluations of treatment efficacy and effec­
help to address this implementation gap. tiveness.2 Harmonized data collection is especially important
In this Commentary, we describe the benefits and the proc­ for research studies related to conditions such as chronic
ess of harmonizing data collection efforts through use of pain, in which many different types of participant data are
standardized measures across a pragmatic trial network (the collected, including many measurements that fall within the
Pain Management Collaboratory, PMC). Though harmoniza­ category of patient-reported outcomes.3 Collectively, the use
tion poses significant challenges (eg, possible delays in trial of a standard set of validated outcome measures across net­
initiation as measures are harmonized, slight elevation of trial work trials: (1) facilitates the process of developing individual
costs, potential increases in participant burden), its benefits study research protocols; (2) ensures that all trials within a
are likely to outweigh the costs. As a large trial network, the network will provide potentially actionable clinical informa­
PMC provides a model of how combining pragmatic trial tion; (3) simplifies the process of designing and reviewing
design with collaborative tools and multidisciplinary exper­ research proposals, manuscripts, and published articles
tise can advance the science and impact of within the network; (4) enhances study reproducibility; (5)

Received: 12 April 2024. Revised: 7 June 2024. Accepted: 20 June 2024

© The Author(s) 2024. Published by Oxford University Press on behalf of the American Academy of Pain Medicine.
All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
S8 Pain Medicine, 2024, Vol. 25, No. S1

provides a basis for determining treatment outcomes that Similarly, the PMC relies on interdisciplinary expertise to
constitute clinically important differences; (6) permits pool­ identify key domains and best practices to harmonize data
ing of data from different studies to enhance power and gen­ collection and analyses across trials. One unique characteris­
eralizability; and (7) aids future systematic reviews and meta- tic of the PMC is a set of work groups comprised of collabo­
analyses. rators with diverse expertise. Co-chaired by a pain
In addition, standardizing a core set of outcome domains psychologist and a health services researcher, the PMC
encourages investigation and reporting of outcomes that are Phenotypes and Outcomes (P&O) Work Group meets
relevant to research partners and end users, so that dissemi­ monthly to promote harmonization of measurement
nation of trial-related data does not involve selective presen­ approaches across studies to examine treatment effect modi­
tation of some outcomes while excluding others. Doing so is fiers (ie, subgroups of responders). P&O recommendations
have frequently been formulated in collaboration with the

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especially critical in trials for chronic pain, which affects
numerous life domains including those rated as very impor­ Patient Resource Group (PRG), which was developed to sup­
tant by individuals experiencing chronic pain (eg, physical port and advise patients, investigators, Work Groups, and
and emotional functioning).4 Notably, the PMC identified study leadership. The PRG is comprised of Veterans and
strategies for optimizing pragmatic clinical trials for pain Military Service Members and their dependents and/or family
management for military service members and veterans; members, all of whom have received education in research
development and use of a harmonized set of outcome meas­ principles and practices of clinical research. After being final­
ures endorsed by pain experts is an important element of this ized in consultation with the PRG and other stakeholders,
ongoing process. recommendations from the Work Group are submitted to the
Together with harmonizing outcome data collection, Steering Committee for approval, after which (if approved)
standardizing the assessment of patient phenotypes provides they are propagated to the relevant end users (eg, trial PIs).
robust advantages. It is widely recognized that there is signifi­ The P&O Work Group has been instrumental in contribu­
cant variability in treatment outcomes across patients, contri­ ting to the harmonization of phenotypic and outcome data
buting to difficulty interpreting clinical trial findings and within the PMC. For PMC trials of patients with chronic
their subsequent application to clinical practice.5 Although pain, 100% of the trials assessed high-impact chronic pain
substantial heterogeneity among patients can obscure out­ and incorporated the PEG as a secondary outcome measure,
allowing harmonization on the outcome domains of pain
comes in certain subgroups of a study cohort, this heteroge­
intensity and impact. In addition, over 90% of those trials
neity reflects the need for personalized pain therapeutic
are contributing harmonized data on phenotypes such as sub­
strategies. A cornerstone of precision pain medicine is the
stance use disorders, depression, opioid utilization, impact of
need to identify characteristics that render an individual
COVID, and complementary and alternative medicine.
patient, or subgroup of patients, more or less responsive to a
Additional P&O Work Group activities have included rapid
specific treatment. Many of the same benefits of harmonizing
development of a brief measure to assess PMC trial partic­
outcome measures apply equally to the development of a uni­
ipants’ perceptions of COVID-related impacts.8 These recom­
fied and standardized set of recommendations for phenotyp­
mendations derive from evaluation of best practices in the
ing. Chief among these benefits is the potential for pooling
PMC and related networks, as well as literature reviews that
phenotypic data across studies to achieve enhanced power for summarize key domains in pain-related pragmatic clinical tri­
subgroup analyses. Such activities will contribute to advanc­ als (Table 1). It is important to mention that not all assess­
ing the science of personalized pain management by helping ment domains were amenable to full harmonization. For
pain researchers and clinicians identify psychosocial and clin­ example, the assessment of physical function/disability was
ical pain phenotypes that are likely to respond to a given class highly heterogenous across trials,3 with some using
of interventions. condition-specific measures such as the Oswestry Low Back
Pain Disability Questionnaire, others opting for more general
The PMC phenotypes and outcomes work indices of physical function such as the PROMIS Physical
group Function Scale, and still others using even broader measures
such as the EQ-5D questionnaire (which assesses mobility,
In practice, a common method for standardizing data collec­ self-care, etc.).
tion and analysis is through the definition and use of com­
mon data elements (CDEs). For example, the NIH CDE
Repository provides access to structured definitions of rec­ Conclusions
ommended or required data elements to be used in research Harmonizing outcome and phenotype-related measures within
studies. Previously, in 2005, the Initiative on Methods, a trial network is complex and challenging but has substantial
Measurement, and Pain Assessment in Clinical Trials benefits. We note here that the categories of “phenotyping var­
(IMMPACT) consensus working group recommended the use iable” and “outcome” are overlapping; numerous factors such
of 6 core outcome domains in chronic pain clinical trials as pain intensity, psychosocial functioning, sleep quality, medi­
(pain intensity, physical and emotional function, global cation use, and many others may serve a phenotyping function
improvement, symptoms, and disposition).6 More recently, when assessed at baseline in a treatment study and may also
the NIH’s Helping to End Addiction Long-Term® Initiative serve as important outcomes over the course of the interven­
(HEAL Initiative®) established requirements for HEAL- tion.2,4,6 As encouraged by research initiatives such as HEAL,
funded clinical trials and large scale observational studies to standardization of measurement across studies is increasingly
collect a core group of CDEs and patient-reported outcomes common. Such practices help to accelerate the process of scien­
for 9 pain domains that were identified through partner con­ tific discovery and also enhance progress toward achieving per­
sensus across the NIH and the pain research community.7 sonalized pain medicine.2 It is important to keep in mind the
Pain Medicine, 2024, Vol. 25, No. S1 S9

Table 1. PMC recommendations for domains on which to consider harmonizing data collection in trial networks. A current list of recommended
measures can be accessed here: https://painmanagementcollaboratory.org/research-researchers/research-tools-and-measures/.

Domain Individual variables PMC considerations

Sociodemographic Age, Sex, Race/Ethnicity, Education, For DoD trials, employment status may not be an optimal
characteristics Employment Status, Relationship status framing for individual differences (this variable is omitted
for DoD studies).
Pain outcomes Pain intensity, Pain impact, High-impact Trials used a variety of outcome measures, but all incorporated
chronic pain, Physical function, Quality of the construct of
life, Healthcare utilization high-impact chronic pain, as well as the PEG, as an outcome
measure, allowing harmonization on the outcome domains
of pain intensity and impact. Factors such as physical func­

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tion showed more heterogeneity of assessment across PMC
trials.
Psychosocial phenotype Depression, Anxiety, PTSD, Resilience PMC trials used brief, validated psychosocial measures such as
the PROMIS Depression and PROMIS Anxiety scales. Such
factors play an important role as both potentially crucial
phenotypic variables and secondary outcome measures for
many of the PMC trials.
Clinical pain phenotype Pain Location, Pain Duration, Long-term PMC investigators developed a harmonized definition of
opioid use, Use of non-pharmacologic pain long-term (ie, 90þ days) opioid use, an important pain
management phenotype that can be evaluated using either electronic
health records or information from participant self-reports.
Additional biopsychosocial Sleep disruption, Substance use disorder, In 2020, the P&O Work Group rapidly developed and
factors COVID impact, Self-management implemented a brief measure of COVID-19 impact within
approaches the majority of PMC trials.8

Many biopsychosocial factors act as both phenotypes (when measured at baseline) and outcomes. The formation of mutually exclusive and exhaustive
categories of phenotype vs outcome is not generally possible.

continued need to define measures that are clinically relevant, Chandler Street, Fort Detrick MD 21702–5014 is the award­
low-burden, broadly accessible, and publicly available.9 We ing and administering acquisition office.
acknowledge the need for flexibility and regular re-evaluation Research reported in this publication was supported by the
of these recommendations as the science and practice of pain NIH under Award Numbers UG3/UH3-AT009767 (Heapy/
medicine evolves. For example, researchers should routinely Higgins COPES-ExTRA trial), UG3/UH3 AT012257 (Lovejoy/
reassess the terminology and language they use to describe Morasco CORPs trial), and UG3/UH3AT009761 (Long/Goertz
populations and their experiences, exemplified by ongoing VERDICT trial).
efforts to promote the inclusion of individuals from under­ This work was supported [or supported in part] by HSR&D
studied groups in pain research.10 Collectively, movement Award # SDR-17–306 (Taylor/Zeliadt APPROACH trial) from
toward harmonization of measurement in pain trials has the United States (U.S.) Department of Veterans Affairs Health
immense potential to benefit the full pain community—includ­ Services Research and Development Service.
ing organizations, clinicians, researchers, and individuals and This (commentary) is a product of the NIH-DOD-VA Pain
families living with chronic pain. Management Collaboratory. For more information about the
Collaboratory, visit https://painmanagementcollaboratory.org/.
Acknowledgments Conflicts of interest: The authors have no disclosures to report.
The contents of this publication are the sole responsibility of
the author(s) and do not necessarily reflect the views, opin­ Supplement statement
ions, or policies of the National Center for Complementary
This article appears as part of the supplement entitled “Pain
and Integrative Health, the Office of Behavioral and Social
Management Collaboratory: Updates, Lessons Learned, and
Sciences Research, National Institutes of Health, the
Future Directions.”
Department of Defense, or the U.S. Department of Veterans
Affairs or the United States Government. This manuscript is a product of the Pain Management
Collaboratory. For more information about the Collaboratory,
Funding visit https://painmanagementcollaboratory.org/.
Research reported in this publication was made possible by
Grant Number U24 AT009769 from the National Center for References
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© The Author(s) 2024. Published by Oxford University Press on behalf of the American Academy of Pain Medicine.
All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Pain Medicine, 2024, 25, S7–S10
https://doi.org/10.1093/pm/pnae069
Commentary