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.

Stepped Care for Patients to Optimize Whole Recovery (SC-POWR): An Effectiveness Trial Evaluating a Stepped Care Model for Individuals With Opioid Use Disorder and Chronic Pain.

Many patients who receive treatment for opioid use disorder (OUD) report experiencing chronic pain (CP), which is associated with high levels of ongoing nonmedical opioid use and low retention in OUD treatment. In pilot studies of patients with OUD receiving buprenorphine or methadone who had CP, cognitive behavioral therapy (CBT) attenuated nonmedical opioid use compared with treatment-as-usual (TAU), but patients in both treatment arms exhibited similar pain improvements. Adding exercise and stress reduction to this model may augment pain-related outcomes. With funding from National Institutes of Health, we plan to conduct a randomized clinical trial of 316 patients with OUD and CP to test the effectiveness of TAU compared with Stepped Care for Patients to Optimize Whole Recovery (SC-POWR) to reduce nonmedical opioid use and pain (primary outcomes) (Aim 1) and decrease pain intensity and interference, alcohol use, anxiety, depression and stress, and improve sleep (secondary outcomes) (Aim 2). Eligible participants will be randomized to receive TAU (buprenorphine or methadone and at least once a month individual or group counseling) or SC-POWR (ie, TAU and up to 12 CBT sessions) for 24 weeks. Based on prespecified nonresponse criteria, SC-POWR may be stepped up at week 6 to receive onsite weekly group sessions of exercise (Wii Fit, Tai Chi) and "stepped up" again at week 15 to receive weekly group sessions of stress reduction (relaxation training, auricular acupuncture). They will be followed for another 24 weeks to evaluate durability of treatment response for illicit opioid use, alcohol use, pain, anxiety, depression, stress, sleep, and retention in medications for OUD (Aim 3).

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.

The Association of Prescribed Opioids and Incident Cardiovascular Disease.

Opioid prescribing remains common despite known overdose-related harms. Less is known about links to nonoverdose morbidity. We determined the association between prescribed opioid receipt with incident cardiovascular disease (CVD) using data from the Veterans Aging Cohort Study, a national prospective cohort of Veterans with/without Human Immunodeficiency Virus (HIV) receiving Veterans Health Administration care. Selected participants had no/minimal prior exposure to prescription opioids, no opioid use disorder, and no severe illness 1 year after the study start date (baseline period). We ascertained prescription opioid exposure over 3 years after the baseline period using outpatient pharmacy fill/refill data. Incident CVD ascertainment began at the end of the prescribed opioid exposure ascertainment period until the first incident CVD event, death, or September 30, 2015. We used adjusted Cox proportional hazards regression models with matching weights using propensity scores for opioid receipt to estimate CVD risk. Among 49,077 patients, 30% received opioids; the median age was 49 years, 97% were male, 49% were Black, and 47% were currently smoking. Prevalence of hypertension, diabetes, current smoking, alcohol and cocaine use disorder, and depression was higher in patients receiving opioids versus those not but were well-balanced by matching weights. Unadjusted CVD incidence rates per 1,000-person-years were higher among those receiving opioids versus those not: 17.4 (95% confidence interval [CI], 16.5-18.3) versus 14.7 (95% CI, 14.2-15.3). In adjusted analyses, those receiving opioids versus those not had an increased hazard of incident CVD (adjusted hazard ratio 1.16 [95% CI, 1.08-1.24]). Prescribed opioids were associated with increased CVD incidence, making opioids a potential modifiable CVD risk factor. PERSPECTIVE: In a propensity score weighted analysis of Veterans Administration data, prescribed opioids compared to no opioids were associated with an increased hazard of incident CVD. Higher opioid doses compared with lower doses were associated with increased hazard of incident CVD. Opioids are a potentially modifiable CVD risk factor.

Graded chronic pain scale revised: validation in a Veteran sample.

OBJECTIVE: The Graded Chronic Pain Scale (GCPS) is frequently used in pain research and treatment to classify mild, bothersome, and high impact chronic pain. This study's objective was to validate the revised version of the GCPS (GCPS-R) in a US Veterans Affairs (VA) healthcare sample to support its use in this high-risk population. METHODS: Data were collected from Veterans (n = 794) via self-report (GCPS-R and relevant health questionnaires) and electronic health record extraction (demographics and opioid prescriptions). Logistic regression, adjusting for age and gender, was used to test for differences in health indicators by pain grade. Adjusted odds ratio (AOR) with 95% confidence intervals (CIs) were reported with CIs not including an AOR of 1 indicating that the difference exceeded chance. RESULTS: In this population, the prevalence of chronic pain (pain present most or every day, prior 3 months) was 49.3%: 7.1% with mild chronic pain (mild pain intensity and lower interference with activities); 23.3% bothersome chronic pain (moderate to severe pain intensity with lower interference); and 21.1% high impact chronic pain (higher interference). Results of this study mirrored findings in the non-VA validation study; differences between bothersome and high impact were consistent for activity limitations and present but not fully consistent for psychological variables. Those with bothersome chronic pain or high impact chronic pain were more likely to receive long-term opioid therapy compared to those with no/mild chronic pain. CONCLUSIONS: Findings highlight categorical differences captured with the GCPS-R, and convergent validity supports use of the GCPS-R in US Veterans.

Mapping the Design Space of Technology-Based Solutions for Better Chronic Pain Care: Introducing the Pain Tech Landscape.

OBJECTIVES: Technology has substantial potential to transform and extend care for persons with chronic pain, a burdensome and costly condition. To catalyze the development of impactful applications of technology in this space, we developed the Pain Tech Landscape (PTL) model, which integrates pain care needs with characteristics of technological solutions. METHODS: Our interdisciplinary group representing experts in pain and human factors research developed PTL through iterative discussions. To demonstrate one potential use of the model, we apply data generated from a narrative review of selected pain and technology journals (2000-2020) in the form of heat map overlays, to reveal where pain tech research attention has focused to date. RESULTS: The PTL comprises three two-dimensional planes, with pain care needs on each x axis (measurement to management) and technology applications on the y axes according to a) user agency (user- to system-driven), b) usage time frame (temporary to lifelong), and c) collaboration (single-user to collaborative). Heat maps show that existing applications reside primarily in the "user-driven/management" quadrant (e.g., self-care apps). Examples of less developed areas include artificial intelligence and Internet of Things (i.e., Internet-linked household objects), and collaborative/social tools for pain management. CONCLUSIONS: Collaborative development between the pain and tech fields in early developmental stages using the PTL as a common language could yield impactful solutions for chronic pain management. The PTL could also be used to track developments in the field over time. We encourage periodic reassessment and refinement of the PTL model, which can also be adapted to other chronic conditions.

Impact of COVID-19 pandemic on nonpharmacological pain management trials in military and veteran healthcare settings: an evaluation informed by implementation science.

The coronavirus disease (COVID-19) pandemic disrupted healthcare and clinical research, including a suite of 11 pragmatic clinical trials (PCTs), across clinics within the Department of Veterans Affairs (VA) and the Department of Defense (DOD). These PCTs were designed to evaluate an array of nonpharmacological treatments and models of care for treatment of patients with pain and co-occurring conditions. The aims of the study are to (a) describe modifications to PCTs and interventions to address the evolving pandemic and (b) describe the application of implementation science methods for evaluation of those PCT modifications. The project used a two-phase, sequential, mixed-methods design. In Phase I, we captured PCT disruptions and modifications via a Research Electronic Data Capture questionnaire, using Periodic Reflections methods as a guide. In Phase II, we utilized the Framework for Reporting Adaptations and Modifications-Expanded (FRAME) taxonomy to develop a focus group interview guide and checklist that would provide more in-depth data than Phase I. Data were analyzed using directed content analysis. Phase I revealed that all PCTs made between two and six trial modifications. Phase II, FRAME-guided analyses showed that the key goals for modifying interventions were increasing treatment feasibility and decreasing patient exposure to COVID-19, while preserving intervention core elements. Context (format) modifications led eight PCTs to modify parts of the interventions for virtual delivery. Content modifications added elements to enhance patient safety; tailored interventions for virtual delivery (counseling, exercise, mindfulness); and modified interventions involving manual therapies. Implementation science methods identified near-real-time disruptions and modifications to PCTs focused on pain management in veteran and military healthcare settings.

Active-duty personnel and veterans often report pain and seek treatment in military and veteran healthcare settings. Nondrug treatments, such as self-care, counseling, exercise, and manual therapy, are recommended for most patients with chronic pain. The COVID-19 pandemic has affected clinical trials of these nondrug treatments in military and veteran populations. In this study, we explored how 11 research teams adapted study trials on pain to address COVID-19. Team members completed online questions, brief checklists, and a one-time focus group about how they modified their trials. Each of the 11 trials made 2 to 6 changes to their studies. Most paused or delayed recruitment efforts. Many shifted parts of the study to a virtual format. Goals for adapting treatments included improved feasibility and decreased patient exposure to COVID-19. Context or format changes increased virtual delivery of study treatments. Content changes focused on patient safety, tailoring treatments for virtual delivery, and offering varied manual therapies. Provider concerns about technology and patient willingness to seek in-person care during the pandemic also were factors driving changes. These findings may support the increased use of virtual care for pain management in military and veteran health settings.

Complementary and Integrative Health Approaches and Pain Care Quality in the Veterans Health Administration Primary Care Setting: A Quasi-Experimental Analysis.

Background: Complementary and integrative health (CIH) approaches have been recommended in national and international clinical guidelines for chronic pain management. We set out to determine whether exposure to CIH approaches is associated with pain care quality (PCQ) in the Veterans Health Administration (VHA) primary care setting. Methods: We followed a cohort of 62,721 Veterans with newly diagnosed musculoskeletal disorders between October 2016 and September 2017 over 1-year. PCQ scores were derived from primary care progress notes using natural language processing. CIH exposure was defined as documentation of acupuncture, chiropractic or massage therapies by providers. Propensity scores (PSs) were used to match one control for each Veteran with CIH exposure. Generalized estimating equations were used to examine associations between CIH exposure and PCQ scores, accounting for potential selection and confounding bias. Results: CIH was documented for 14,114 (22.5%) Veterans over 16,015 primary care clinic visits during the follow-up period. The CIH exposure group and the 1:1 PS-matched control group achieved superior balance on all measured baseline covariates, with standardized differences ranging from 0.000 to 0.045. CIH exposure was associated with an adjusted rate ratio (aRR) of 1.147 (95% confidence interval [CI]: 1.142, 1.151) on PCQ total score (mean: 8.36). Sensitivity analyses using an alternative PCQ scoring algorithm (aRR: 1.155; 95% CI: 1.150-1.160) and redefining CIH exposure by chiropractic alone (aRR: 1.118; 95% CI: 1.110-1.126) derived consistent results. Discussion: Our data suggest that incorporating CIH approaches may reflect higher overall quality of care for patients with musculoskeletal pain seen in primary care settings, supporting VHA initiatives and the Declaration of Astana to build comprehensive, sustainable primary care capacity for pain management. Future investigation is warranted to better understand whether and to what degree the observed association may reflect the therapeutic benefits patients actually received or other factors such as empowering provider-patient education and communication about these approaches.

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.

Intervention Fidelity in Pain Pragmatic Trials for Nonpharmacologic Pain Management: Nuanced Considerations for Determining PRECIS-2 Flexibility in Delivery and Adherence.

Nonpharmacological treatments are considered first-line pain management strategies, but they remain clinically underused. For years, pain-focused pragmatic clinical trials (PCTs) have generated evidence for the enhanced use of nonpharmacological interventions in routine clinical settings to help overcome implementation barriers. The Pragmatic Explanatory Continuum Indicator Summary (PRECIS-2) framework describes the degree of pragmatism across 9 key domains. Among these, "flexibility in delivery" and "flexibility in adherence," address a key goal of pragmatic research by tailoring approaches to settings in which people receive routine care. However, to maintain scientific and ethical rigor, PCTs must ensure that flexibility features do not compromise delivery of interventions as designed, such that the results are ethically and scientifically sound. Key principles of achieving this balance include clear definitions of intervention core components, intervention monitoring and documentation that is sufficient but not overly burdensome, provider training that meets the demands of delivering an intervention in real-world settings, and use of an ethical lens to recognize and avoid potential trial futility when necessary and appropriate. PERSPECTIVE: This article presents nuances to be considered when applying the PRECIS-2 framework to describe pragmatic clinical trials. Trials must ensure that patient-centered treatment flexibility does not compromise delivery of interventions as designed, such that measurement and analysis of treatment effects is reliable.

An Analysis of the Role of Mental Health in a Randomized Trial of a Walking Intervention for Black Veterans With Chronic Pain.

Black patients and those with co-occurring mental health disorders are disproportionately affected by chronic pain, but few interventions target these populations. This is a secondary analysis of a randomized trial of a walking-focused proactive counseling intervention for Black Veterans with chronic musculoskeletal pain (ACTION). The primary aim was to examine intervention effectiveness among Veterans with an electronic health record-documented mental health diagnosis [depressive disorder, anxiety disorder, substance use disorder, post-traumatic stress disorder or serious mental illness (n = 205)] and those without a diagnosis (n = 175). About 380 Black Veterans receiving care at the Atlanta VA Health Care System were enrolled from 2016 to 2019 and randomized to the intervention or usual care (UC) (1:1). The intervention featured 6 telephone coaching sessions over 8-14 weeks to encourage walking. Participants with a mental health disorder were more likely to complete all counseling sessions (56% vs 38%) and reported improvements in global perceptions of pain and pain intensity/interference (secondary outcomes) at 3-months vs UC. Among participants without a mental health disorder, the intervention was associated with an improvement in pain-related disability at 6-months (primary outcome). Black chronic pain patients with co-occurring mental health disorders may require more intensive treatment to affect improvement in pain-related disability. PERSPECTIVE: This study examines the effectiveness of a walking intervention for chronic pain among Black Veterans with a mental health disorder. These patients were more engaged with the intervention than those without a mental health disorder. However, they did not experience reductions in pain-related disability, suggesting more intensive treatment is needed.

Perspectives on Participation in Clinical Trials Among Individuals With Pain, Depression, and/or Anxiety: An ACTTION Scoping Review.

For individuals experiencing pain, the decision to engage in clinical trials may be influenced by a number of factors including current and past care, illness severity, physical functioning, financial stress, and caregiver support. Co-occurring depression and anxiety may add to these challenges. The aim of this scoping review was to describe perspectives about clinical trial participation, including recruitment and retention among individuals with pain and pain comorbidities, including depression and/or anxiety. We searched PubMed, CINAHL, PsycINFO, and Cochrane CENTRAL databases. Study features, sample demographics, perspectives, barriers and/or motivations were collected and described. A total of 35 assessments were included in this scoping review with 24 focused on individuals with pain (24/35, 68.6%), 9 on individuals with depression and/or anxiety (9/35, 25.7%), and 2 on individuals with pain and co-occurring depression/anxiety (2/35, 5.7%). Barriers among participants with pain and those with depression included: research team's communication of information, fear of interventional risks, distrust (only among respondents with pain), too many procedures, fear of inadequate treatment, disease-life stressors, and embarrassment with study procedures (more commonly reported in participants with depression). Facilitators in both groups included: altruism and supportive staff, better access to care, and the ability to have outcome feedback (more commonly among individuals with depression). Individuals with pain and depression experience challenges that affect trial recruitment and retention. Engaging individuals with pain within research planning may assist in addressing these barriers and the needs of individuals affected by pain and/or depression. PERSPECTIVE: This review highlights the need to address barriers and facilitators to participation in clinical trials, including the need for an assessment of perspectives from underserved or marginalized populations.

Optimizing and Accelerating the Development of Precision Pain Treatments for Chronic Pain: IMMPACT Review and Recommendations.

Large variability in the individual response to even the most-efficacious pain treatments is observed clinically, which has led to calls for a more personalized, tailored approach to treating patients with pain (ie, "precision pain medicine"). Precision pain medicine, currently an aspirational goal, would consist of empirically based algorithms that determine the optimal treatments, or treatment combinations, for specific patients (ie, targeting the right treatment, in the right dose, to the right patient, at the right time). Answering this question of "what works for whom" will certainly improve the clinical care of patients with pain. It may also support the success of novel drug development in pain, making it easier to identify novel treatments that work for certain patients and more accurately identify the magnitude of the treatment effect for those subgroups. Significant preliminary work has been done in this area, and analgesic trials are beginning to utilize precision pain medicine approaches such as stratified allocation on the basis of prespecified patient phenotypes using assessment methodologies such as quantitative sensory testing. Current major challenges within the field include: 1) identifying optimal measurement approaches to assessing patient characteristics that are most robustly and consistently predictive of inter-patient variation in specific analgesic treatment outcomes, 2) designing clinical trials that can identify treatment-by-phenotype interactions, and 3) selecting the most promising therapeutics to be tested in this way. This review surveys the current state of precision pain medicine, with a focus on drug treatments (which have been most-studied in a precision pain medicine context). It further presents a set of evidence-based recommendations for accelerating the application of precision pain methods in chronic pain research. PERSPECTIVE: Given the considerable variability in treatment outcomes for chronic pain, progress in precision pain treatment is critical for the field. An array of phenotypes and mechanisms contribute to chronic pain; this review summarizes current knowledge regarding which treatments are most effective for patients with specific biopsychosocial characteristics.

Mental Health Diagnoses are Not Associated With Indicators of Lower Quality Pain Care in Electronic Health Records of a National Sample of Veterans Treated in Veterans Health Administration Primary Care Settings.

Prior research has demonstrated disparities in general medical care for patients with mental health conditions, but little is known about disparities in pain care. The objective of this retrospective cohort study was to determine whether mental health conditions are associated with indicators of pain care quality (PCQ) as documented by primary care clinicians in the Veterans Health Administration (VHA). We used natural language processing to analyze electronic health record data from a national sample of Veterans with moderate to severe musculoskeletal pain during primary care visits in the Fiscal Year 2017. Twelve PCQ indicators were annotated from clinician progress notes as present or absent; PCQ score was defined as the sum of these indicators. Generalized estimating equation Poisson models examined associations among mental health diagnosis categories and PCQ scores. The overall mean PCQ score across 135,408 person-visits was 8.4 (SD = 2.3). In the final adjusted model, post-traumatic stress disorder was associated with higher PCQ scores (RR = 1.006, 95%CI 1.002-1.010, P = .007). Depression, alcohol use disorder, other substance use disorder, schizophrenia, and bipolar disorder diagnoses were not associated with PCQ scores. Overall, results suggest that in this patient population, presence of a mental health condition is not associated with lower quality pain care. PERSPECTIVE: This study used a natural language processing approach to analyze medical records to determine whether mental health conditions are associated with indicators of pain care quality as documented by primary care clinicians. Findings suggest that presence of a diagnosed mental health condition is not associated with lower quality pain care.

Long-term opioid therapy trajectories and overdose in patients with and without cancer.

Objective: Pain is experienced by most patients with cancer and opioids are a cornerstone of management. Our objectives were (1) to identify patterns or trajectories of long-term opioid therapy (LTOT) and their correlates among patients with and without cancer and (2) to assess the association between trajectories and risk for opioid overdose, considering the potential moderating role of cancer. Methods and Analysis: We conducted a retrospective cohort study among individuals in the US Veterans Health Administration (VHA) database with incident LTOT with and without cancer (N=44,351; N=285,772, respectively) between 2010-2017. We investigated the relationship between LTOT trajectory and all International Classification of Diseases-9 and 10-defined accidental and intentional opioid-related overdoses. Results: Trajectories of opioid receipt observed in patients without cancer and replicated in patients with cancer were: low-dose/stable trend, low-dose/de-escalating trend, moderate-dose/stable trend, moderate-dose/escalating with quadratic downturn trend, and high-dose/escalating with quadratic downturn trend. Time to first overdose was significantly predicted by higher-dose and escalating trajectories; the two low-dose trajectories conferred similar, lower risk. Conditional hazard ratios (99% CI) for the moderate-dose, moderate-dose/escalating with quadratic downturn and high-dose/escalating with quadratic downturn trends were 1·84 (1·18, 2·85), 2·56 (1·54, 4·25), and 2·41 (1·37, 4·26), respectively. Effects of trajectories on time to overdose did not differ by presence of cancer; inferences were replicated when restricting to patients with stage 3/4 cancer. Conclusion: Patients with cancer face opioid overdose risks like patients without cancer. Future studies should seek to expand and address our knowledge about opioid risk in cancer patients. Trial registration: None.

Patient-Centered Pain Care Using Artificial Intelligence and Mobile Health Tools: A Randomized Comparative Effectiveness Trial.

Importance: Cognitive behavioral therapy for chronic pain (CBT-CP) is a safe and effective alternative to opioid analgesics. Because CBT-CP requires multiple sessions and therapists are scarce, many patients have limited access or fail to complete treatment. Objectives: To determine if a CBT-CP program that personalizes patient treatment using reinforcement learning, a field of artificial intelligence (AI), and interactive voice response (IVR) calls is noninferior to standard telephone CBT-CP and saves therapist time. Design, Setting, and Participants: This was a randomized noninferiority, comparative effectiveness trial including 278 patients with chronic back pain from the Department of Veterans Affairs health system (recruitment and data collection from July 11, 2017-April 9, 2020). More patients were randomized to the AI-CBT-CP group than to the control (1.4:1) to maximize the system's ability to learn from patient interactions. Interventions: All patients received 10 weeks of CBT-CP. For the AI-CBT-CP group, patient feedback via daily IVR calls was used by the AI engine to make weekly recommendations for either a 45-minute or 15-minute therapist-delivered telephone session or an individualized IVR-delivered therapist message. Patients in the comparison group were offered 10 therapist-delivered telephone CBT-CP sessions (45 minutes/session). Main Outcomes and Measures: The primary outcome was the Roland Morris Disability Questionnaire (RMDQ; range 0-24), measured at 3 months (primary end point) and 6 months. Secondary outcomes included pain intensity and pain interference. Consensus guidelines were used to identify clinically meaningful improvements for responder analyses (eg, a 30% improvement in RMDQ scores and pain intensity). Data analyses were performed from April 2021 to May 2022. Results: The study population included 278 patients (mean [SD] age, 63.9 [12.2] years; 248 [89.2%] men; 225 [81.8%] White individuals). The 3-month mean RMDQ score difference between AI-CBT-CP and standard CBT-CP was -0.72 points (95% CI, -2.06 to 0.62) and the 6-month difference was -1.24 (95% CI, -2.48 to 0); noninferiority criterion were met at both the 3- and 6-month end points (P < .001 for both). A greater proportion of patients receiving AI-CBT-CP had clinically meaningful improvements at 6 months as indicated by RMDQ (37% vs 19%; P = .01) and pain intensity scores (29% vs 17%; P = .03). There were no significant differences in secondary outcomes. Pain therapy using AI-CBT-CP required less than half of the therapist time as standard CBT-CP. Conclusions and Relevance: The findings of this randomized comparative effectiveness trial indicated that AI-CBT-CP was noninferior to therapist-delivered telephone CBT-CP and required substantially less therapist time. Interventions like AI-CBT-CP could allow many more patients to be served effectively by CBT-CP programs using the same number of therapists. Trial Registration: ClinicalTrials.gov Identifier: NCT02464449.

TIDieR-telehealth: precision in reporting of telehealth interventions used in clinical trials - unique considerations for the Template for the Intervention Description and Replication (TIDieR) checklist.

BACKGROUND: Recent international health events have led to an increased proliferation of remotely delivered health interventions. Even with the pandemic seemingly coming under control, the experiences of the past year have fueled a growth in ideas and technology for increasing the scope of remote care delivery. Unfortunately, clinicians and health systems will have difficulty with the adoption and implementation of these interventions if ongoing and future clinical trials fail to report necessary details about execution, platforms, and infrastructure related to these interventions. The purpose was to develop guidance for reporting of telehealth interventions. METHODS: A working group from the US Pain Management Collaboratory developed guidance for complete reporting of telehealth interventions. The process went through 5-step process from conception to final checklist development with input for many stakeholders, to include all 11 primary investigators with trials in the Collaboratory. RESULTS: An extension focused on unique considerations relevant to telehealth interventions was developed for the Template for the Intervention Description and Replication (TIDieR) checklist. CONCLUSION: The Telehealth Intervention guideline encourages use of the Template for the Intervention Description and Replication (TIDieR) checklist as a valuable tool (TIDieR-Telehealth) to improve the quality of research through a reporting guide of relevant interventions that will help maximize reproducibility and implementation.