Methods for pragmatic randomized clinical trials of pain therapies: IMMPACT statement.

ABSTRACT: Pragmatic, randomized, controlled trials hold the potential to directly inform clinical decision making and health policy regarding the treatment of people experiencing pain. Pragmatic trials are designed to replicate or are embedded within routine clinical care and are increasingly valued to bridge the gap between trial research and clinical practice, especially in multidimensional conditions, such as pain and in nonpharmacological intervention research. To maximize the potential of pragmatic trials in pain research, the careful consideration of each methodological decision is required. Trials aligned with routine practice pose several challenges, such as determining and enrolling appropriate study participants, deciding on the appropriate level of flexibility in treatment delivery, integrating information on concomitant treatments and adherence, and choosing comparator conditions and outcome measures. Ensuring data quality in real-world clinical settings is another challenging goal. Furthermore, current trials in the field would benefit from analysis methods that allow for a differentiated understanding of effects across patient subgroups and improved reporting of methods and context, which is required to assess the generalizability of findings. At the same time, a range of novel methodological approaches provide opportunities for enhanced efficiency and relevance of pragmatic trials to stakeholders and clinical decision making. In this study, best-practice considerations for these and other concerns in pragmatic trials of pain treatments are offered and a number of promising solutions discussed. The basis of these recommendations was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks.

Translating an intervention to address chronic pain in home care workers: The COMPASS-NP Pilot.

OBJECTIVE: Pilot test the COMmunity of Practice And Safety Support for Navigating Pain (COMPASS-NP) intervention for home care workers (HCWs) experiencing chronic pain. METHODS: HCWs with chronic pain participated (n = 19; 2 groups) in a 10-week online group program focused on workplace safety and pain self-management. Primary outcomes were changes in pain interference with work and life. Other outcomes related to ergonomics, pain levels, opioid misuse risk, mental health, sleep, and physical activity. RESULTS: The intervention produced a large reduction in pain interference with life (d = -0.85) and a moderate reduction in pain interference with work time demands (d = -0.61). Secondary outcomes showed favorable effect sizes, including a substantial increase in the use of ergonomic tools and techniques (d = 1.47). CONCLUSION: Findings were strongly encouraging. The effectiveness of COMPASS-NP will be evaluated in a future randomized controlled trial.

Use of patient-reported global assessment measures in clinical trials of chronic pain treatments: ACTTION systematic review and considerations.

ABSTRACT: Establishing clinically meaningful changes in pain experiences remains important for clinical trials of chronic pain treatments. Regulatory guidance and pain measurement initiatives have recommended including patient-reported global assessment measures (eg, Patient-Global Impression of Change [PGIC]) to aid interpretation of within-patient differences in domain-specific clinical trial outcomes (eg, pain intensity). The objectives of this systematic review were to determine the frequency of global assessment measures inclusion, types of measures, domains assessed, number and types of response options, and how measures were analyzed. Of 4172 abstracts screened across 6 pain specialty journals, we reviewed 96 clinical trials of chronic pain treatments. Fifty-two (54.2%) studies included a global assessment measure. The PGIC was most common (n = 28; 53.8%), with relatively infrequent use of other measures. The majority of studies that used a global assessment measure (n = 31; 59.6%) assessed change or improvement in an unspecified domain. Others assessed overall condition severity (n = 9; 17.3%), satisfaction (n = 8; 15.4%), or overall health status/recovery (n = 5; 9.6%). The number, range, and type of response options were variable and frequently not reported. Response options and reference periods even differed within the PGIC. Global assessment measures were most commonly analyzed as continuous variables (n = 24; 46.2%) or as dichotomous variables with positive categories combined to calculate the proportion of participants with a positive response to treatment (n = 18; 34.6%). This review highlights the substantial work necessary to clarify measurement and use of patient global assessment in chronic pain trials and provides short- and long-term considerations for measure selection, reporting and analysis, and measure development.

Patient engagement in designing, conducting, and disseminating clinical pain research: IMMPACT recommended considerations.

ABSTRACT: In the traditional clinical research model, patients are typically involved only as participants. However, there has been a shift in recent years highlighting the value and contributions that patients bring as members of the research team, across the clinical research lifecycle. It is becoming increasingly evident that to develop research that is both meaningful to people who have the targeted condition and is feasible, there are important benefits of involving patients in the planning, conduct, and dissemination of research from its earliest stages. In fact, research funders and regulatory agencies are now explicitly encouraging, and sometimes requiring, that patients are engaged as partners in research. Although this approach has become commonplace in some fields of clinical research, it remains the exception in clinical pain research. As such, the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials convened a meeting with patient partners and international representatives from academia, patient advocacy groups, government regulatory agencies, research funding organizations, academic journals, and the biopharmaceutical industry to develop consensus recommendations for advancing patient engagement in all stages of clinical pain research in an effective and purposeful manner. This article summarizes the results of this meeting and offers considerations for meaningful and authentic engagement of patient partners in clinical pain research, including recommendations for representation, timing, continuous engagement, measurement, reporting, and research dissemination.

Developing consensus on core outcome sets of domains for acute, the transition from acute to chronic, recurrent/episodic, and chronic pain: results of the INTEGRATE-pain Delphi process.

Background: Pain is the leading cause of disability worldwide among adults and effective treatment options remain elusive. Data harmonization efforts, such as through core outcome sets (COS), could improve care by highlighting cross-cutting pain mechanisms and treatments. Existing pain-related COS often focus on specific conditions, which can hamper data harmonization across various pain states. Methods: Our objective was to develop four overarching COS of domains/subdomains (i.e., what to measure) that transcend pain conditions within different pain categories. We hosted a meeting to assess the need for these four COS in pain research and clinical practice. Potential COS domains/subdomains were identified via a systematic literature review (SLR), meeting attendees, and Delphi participants. We conducted an online, three step Delphi process to reach a consensus on domains to be included in the four final COS. Survey respondents were identified from the SLR and pain-related social networks, including multidisciplinary health care professionals, researchers, and people with lived experience (PWLE) of pain. Advisory boards consisting of COS experts and PWLE provided advice throughout the process. Findings: Domains in final COS were generally related to aspects of pain, quality of life, and physical function/activity limitations, with some differences among pain categories. This effort was the first to generate four separate, overarching COS to encourage international data harmonization within and across different pain categories. Interpretation: The adoption of the COS in research and clinical practice will facilitate comparisons and data integration around the world and across pain studies to optimize resources, expedite therapeutic discovery, and improve pain care. Funding: Innovative Medicines Initiative 2 Join Undertaking; European Union Horizon 2020 research innovation program, European Federation of Pharmaceutical Industries and Associations (EFPIA) provided funding for IMI-PainCare. RDT acknowledges grants from Esteve and TEVA.

Evaluating the balance of benefits and harms in chronic pain clinical trials: prioritizing individual participants over individual outcomes.

BACKGROUND: Randomized clinical trials (RCTs) generally assess efficacy and safety separately, with the conclusion of whether a treatment is beneficial based solely on the efficacy endpoint. However, assessing and combining efficacy and safety domains, using a single composite outcome measure, can provide a more comprehensive assessment of the overall effect of a treatment. Furthermore, composite outcomes can incorporate information regarding the relationship between the individual outcomes. In fact, such outcomes have been suggested in the clinical trials literature for at least 15 years. OBJECTIVES: To (1) identify whether recent primary publications of chronic pain RCTs from major pain journals included a composite outcome measure of benefits and harms and (2) discuss the potential benefits of such outcomes in various stages of treatment development, including as outcome measures in RCTs, and to support decisions of Data and Safety Monitoring Boards and ordering of treatments in the context of treatment guidelines. EVIDENCE REVIEW: RCTs published in 6 major pain journals published between 2016 and 2021 that investigated interventions for chronic pain were reviewed. FINDINGS: Of 73 RCTs identified, only 2 included a composite outcome measure of benefits and harms. Both of these articles compared 2 active treatments. CONCLUSIONS: Composite outcomes of benefits and harms are underutilized in chronic pain RCTs. The advantages and challenges of using such outcomes are discussed.

The role of evolving concepts and new technologies and approaches in advancing pain research, management, and education since the establishment of the International Association for the Study of Pain.

ABSTRACT: The decades since the inauguration of the International Association for the Study of Pain have witnessed major advances in scientific concepts (such as the biopsychosocial model and chronic primary pain as a disease in its own right) and in new technologies and approaches (from molecular biology to brain imaging) that have inspired innovations in pain research. These have guided progress in pain management and education about pain for healthcare professionals, the general public, and administrative agencies.

Covariate Adjustment in Chronic Pain Trials: An Oft-Missed Opportunity.

Self-reported pain intensity, frequently used as an outcome in randomized clinical trials (RCTs) of chronic pain, is often highly variable and could be associated with multiple baseline factors. Thus, the assay sensitivity of pain trials (ie, the ability of the trial to detect a true treatment effect) could be improved by including prespecified baseline factors in the primary statistical model. The objective of this focus article was to characterize the baseline factors included in statistical analyses of chronic pain RCTs. Seventy-three RCTs published between 2016 and 2021 that investigated interventions for chronic pain were included. The majority of trials identified a single primary analysis (72.6%; n = 53). Of these, 60.4% (n = 32) included one or more covariates in the primary statistical model, most commonly baseline value of the primary outcome, study site, sex, and age. Only one of the trials reported information regarding associations between covariates and outcomes (ie, information that could inform prioritization of covariates for prespecification in future analyses). These findings demonstrate inconsistent use of covariates in the statistical models in chronic pain clinical trials. Prespecified adjustments for baseline covariates that could increase precision and assay sensitivity should be considered in future clinical trials of chronic pain treatments. PERSPECTIVE: This review demonstrates inconsistent inclusion and potential underutilization of covariate adjustment in analyses of chronic pain RCTs. This article highlights areas for possible improvement in design and reporting related to covariate adjustment to improve efficiency in future RCTs.

Effectiveness of Spinal Manipulation and Biopsychosocial Self-Management compared to Medical Care for Low Back Pain: A Randomized Trial Study Protocol.

Background Chronic low back pain (cLBP) is widespread, costly, and burdensome to patients and health systems. Little is known about non-pharmacological treatments for the secondary prevention of cLBP. There is some evidence that treatments addressing psychosocial factors in higher risk patients are more effective than usual care. However, most clinical trials on acute and subacute LBP have evaluated interventions irrespective of prognosis. Methods We have designed a phase 3 randomized trial with a 2x2 factorial design. The study is also a Hybrid type 1 trial with focus on intervention effectiveness while simultaneously considering plausible implementation strategies. Adults (n = 1000) with acute/subacute LBP at moderate to high risk of chronicity based on the STarT Back screening tool will be randomized in to 1 of 4 interventions lasting up to 8 weeks: supported self-management (SSM), spinal manipulation therapy (SMT), both SSM and SMT, or medical care. The primary objective is to assess intervention effectiveness; the secondary objective is to assess barriers and facilitators impacting future implementation. Primary effectiveness outcome measures are: (1) average pain intensity over 12 months post-randomization (pain, numerical rating scale); (2) average low back disability over 12 months post-randomization (Roland-Morris Disability Questionnaire); (3) prevention of cLBP that is impactful at 10-12 months follow-up (LBP impact from the PROMIS-29 Profile v2.0). Secondary outcomes include: recovery, PROMIS-29 Profile v2.0 measures to assess pain interference, physical function, anxiety, depression, fatigue, sleep disturbance, and ability to participate in social roles and activities. Other patient-reported measures include LBP frequency, medication use, healthcare utilization, productivity loss, STarT Back screening tool status, patient satisfaction, prevention of chronicity, adverse events, and dissemination measures. Objective measures include the Quebec Task Force Classification, Timed Up & Go Test, the Sit to Stand Test, and the Sock Test assessed by clinicians blinded to the patients' intervention assignment. Discussion By targeting those subjects at higher risk this trial aims to fill an important gap in the scientific literature regarding the effectiveness of promising non-pharmacological treatments compared to medical care for the management of patients with an acute episode of LBP and the prevention of progression to a severe chronic back problem. Trial registration: ClinicalTrials.gov Identifier: NCT03581123.

Effectiveness of spinal manipulation and biopsychosocial self-management compared to medical care for low back pain: a randomized trial study protocol.

BACKGROUND: Chronic low back pain (cLBP) is widespread, costly, and burdensome to patients and health systems. Little is known about non-pharmacological treatments for the secondary prevention of cLBP. There is some evidence that treatments addressing psychosocial factors in higher risk patients are more effective than usual care. However, most clinical trials on acute and subacute LBP have evaluated interventions irrespective of prognosis. METHODS: We have designed a phase 3 randomized trial with a 2 × 2 factorial design. The study is also a Hybrid type 1 trial with focus on intervention effectiveness while simultaneously considering plausible implementation strategies. Adults (n = 1000) with acute/subacute LBP at moderate to high risk of chronicity based on the STarT Back screening tool will be randomized in to 1 of 4 interventions lasting up to 8 weeks: supported self-management (SSM), spinal manipulation therapy (SMT), both SSM and SMT, or medical care. The primary objective is to assess intervention effectiveness; the secondary objective is to assess barriers and facilitators impacting future implementation. Primary effectiveness outcome measures are: (1) average pain intensity over 12 months post-randomization (pain, numerical rating scale); (2) average low back disability over 12 months post-randomization (Roland-Morris Disability Questionnaire); (3) prevention of cLBP that is impactful at 10-12 months follow-up (LBP impact from the PROMIS-29 Profile v2.0). Secondary outcomes include: recovery, PROMIS-29 Profile v2.0 measures to assess pain interference, physical function, anxiety, depression, fatigue, sleep disturbance, and ability to participate in social roles and activities. Other patient-reported measures include LBP frequency, medication use, healthcare utilization, productivity loss, STarT Back screening tool status, patient satisfaction, prevention of chronicity, adverse events, and dissemination measures. Objective measures include the Quebec Task Force Classification, Timed Up & Go Test, the Sit to Stand Test, and the Sock Test assessed by clinicians blinded to the patients' intervention assignment. DISCUSSION: By targeting those subjects at higher risk this trial aims to fill an important gap in the scientific literature regarding the effectiveness of promising non-pharmacological treatments compared to medical care for the management of patients with an acute episode of LBP and the prevention of progression to a severe chronic back problem. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03581123.

COMMunity of Practice And Safety Support for Navigating Pain (COMPASS-NP): study protocol for a randomized controlled trial with home care workers.

BACKGROUND: Chronic pain is a prevalent and costly problem that often has occupational origins. Home care workers (HCWs) are at high risk for work-related injuries, pain, and disability. Current treatments for chronic pain emphasize medications, which are an inadequate stand-alone treatment and can produce significant adverse effects. METHODS: In this translational study, we will adapt an established work-based injury prevention and health promotion program (COMmunity of Practice And Safety Support: COMPASS) to address the needs of HCWs experiencing chronic pain. COMPASS employs peer-led, scripted group meetings that include educational content, activities, goal setting, and structured social support. The translated intervention, named COMPASS for Navigating Pain (COMPASS-NP), will be delivered in an online group format. Safety protections will be strengthened through an ergonomic self-assessment and vouchers for purchasing ergonomic tools. Educational content will integrate a self-management approach to chronic pain using proven cognitive-behavioral therapy (CBT) principles. We will use a mixed-methods hybrid type 2 evaluation approach to assess effectiveness and implementation. A cluster-randomized waitlist control design will involve 14 groups of 10 HCWs (n = 140) recruited from Washington, Oregon, and Idaho. Half of the groups will be randomly selected to complete the intervention during the first 10 weeks, while the waitlist groups serve as controls. During weeks 10-20, the waitlist groups will complete the intervention while the original intervention groups complete a follow-up period without further intervention. Our primary hypothesis is that COMPASS-NP will reduce pain interference with work and life. Secondary outcomes include injury and pain prevention behaviors, pain severity, changes in medication use, risk for opioid misuse, well-being, physical activity, and sleep. Qualitative data, including phone interviews with group facilitators and organizational partners, will evaluate the implementation and guide dissemination. DISCUSSION: The results will advance the use and knowledge of secondary prevention interventions such as ergonomic tools and cognitive behavior therapy, to reduce injury, pain, and disability and to encourage appropriate uses of analgesic medications among HCWs. TRIAL REGISTRATION: ClinicalTrials.gov NCT05492903. Registered on 08 August 2022.

Research objectives and general considerations for pragmatic clinical trials of pain treatments: IMMPACT statement.

ABSTRACT: Many questions regarding the clinical management of people experiencing pain and related health policy decision-making may best be answered by pragmatic controlled trials. To generate clinically relevant and widely applicable findings, such trials aim to reproduce elements of routine clinical care or are embedded within clinical workflows. In contrast with traditional efficacy trials, pragmatic trials are intended to address a broader set of external validity questions critical for stakeholders (clinicians, healthcare leaders, policymakers, insurers, and patients) in considering the adoption and use of evidence-based treatments in daily clinical care. This article summarizes methodological considerations for pragmatic trials, mainly concerning methods of fundamental importance to the internal validity of trials. The relationship between these methods and common pragmatic trials methods and goals is considered, recognizing that the resulting trial designs are highly dependent on the specific research question under investigation. The basis of this statement was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) systematic review of methods and a consensus meeting. The meeting was organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership. The consensus process was informed by expert presentations, panel and consensus discussions, and a preparatory systematic review. In the context of pragmatic trials of pain treatments, we present fundamental considerations for the planning phase of pragmatic trials, including the specification of trial objectives, the selection of adequate designs, and methods to enhance internal validity while maintaining the ability to answer pragmatic research questions.

Real-world data and evidence in pain research: a qualitative systematic review of methods in current practice.

The use of routinely collected health data (real-world data, RWD) to generate real-world evidence (RWE) for research purposes is a growing field. Computerized search methods, large electronic databases, and the development of novel statistical methods allow for valid analysis of data outside its primary clinical purpose. Here, we systematically reviewed the methodology used for RWE studies in pain research. We searched 3 databases (PubMed, EMBASE, and Web of Science) for studies using retrospective data sources comparing multiple groups or treatments. The protocol was registered under the DOI:10.17605/OSF.IO/KGVRM. A total of 65 studies were included. Of those, only 4 compared pharmacological interventions, whereas 49 investigated differences in surgical procedures, with the remaining studying alternative or psychological interventions or epidemiological factors. Most 39 studies reported significant results in their primary comparison, and an additional 12 reported comparable effectiveness. Fifty-eight studies used propensity scores to account for group differences, 38 of them using 1:1 case:control matching. Only 17 of 65 studies provided sensitivity analyses to show robustness of their findings, and only 4 studies provided links to publicly accessible protocols. RWE is a relevant construct that can provide evidence complementary to randomized controlled trials (RCTs), especially in scenarios where RCTs are difficult to conduct. The high proportion of studies reporting significant differences between groups or comparable effectiveness could imply a relevant degree of publication bias. RWD provides a potentially important resource to expand high-quality evidence beyond clinical trials, but rigorous quality standards need to be set to maximize the validity of RWE studies.

Examining the Relationships Among Treatment, Pain, and Physical Function in Patients With Osteoarthritis: A Mediation-Modeling Approach.

OBJECTIVES: To better understand the relationships among treatment, pain, and physical function (PF). METHODS: Data were collected from 2 published randomized clinical trials of osteoarthritis patients who received tanezumab or a placebo. PF was measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) PF domain. Pain (WOMAC pain domain) was a mediator of the effect of treatment on PF. A set of mediation models were investigated. Variables were treatment (tanezumab vs placebo), WOMAC pain domain, and WOMAC PF domain. Cross-sectional mediation models were assessed separately at different weeks. Longitudinal mediation models used data from all weeks simultaneously. Results could identify a steady-state period. RESULTS: The cross-sectional and longitudinal mediation models showed a stable indirect effect of treatment through the pain on PF across time, indicating that a pseudo-steady-state model was appropriate. Therefore, the longitudinal steady-state mediation models were used with all available data assuming relationships among variables in the model being the same at all time points; results showed that the indirect effect of the treatment on PF was 77.8% in study 1 (NCT02697773) and 74.1% in study 2 (NCT02709486), both P <0.0001, whereas the direct effect was 22.2% for study 1 ( P = 0.0003) and 25.9% for study 2 ( P = 0.0019). DISCUSSION: At least 75% of the treatment effect of tanezumab on physical functioning can be explained by the improvements in pain. However, tanezumab had an additional effect on physical functioning (~25%) that, was independent of improvements in pain. Such independent effects are of considerable interest and require further research to determine their mechanisms.