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.

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.

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.

Expectations for Improvement: A Neglected but Potentially Important Covariate or Moderator for Chronic Pain Clinical Trials.

Variability in pain-related outcomes can hamper assay sensitivity of chronic pain clinical trials. Expectations of outcome in such trials may account for some of this variability, and thereby impede development of novel pain treatments. Measurement of participants' expectations prior to initiating study treatment (active or placebo) is infrequent, variable, and often unvalidated. Efforts to optimize and standardize measurement, analysis, and management of expectations are needed. In this Focus Article, we provide an overview of research findings on the relationship between baseline expectations and pain-related outcomes in clinical trials of pharmacological and nonpharmacological pain treatments. We highlight the potential benefit of adjusting for participants' expectations in clinical trial analyses and draw on findings from patient interviews to discuss critical issues related to measurement of expectations. We conclude with suggestions regarding future studies focused on better understanding the utility of incorporating these measures into clinical trial analyses. PERSPECTIVE: This focus article provides an overview of the relationship between participants' baseline expectations and pain-related outcomes in the setting of clinical trials of chronic pain treatments. Systematic research focused on the measurement of expectations and the impact of adjusting for expectations in clinical trial analyses may improve assay sensitivity.

Initial Content Validation and Roadmap for a New Patient-Reported Outcome Measure of Pain Intensity.

Measures of pain intensity (eg, numeric rating scales [NRS]) are widely used in clinical research and practice. While these measures have evidence for validity and reliability, poor standardization of instructions, and response options limits precision of pain assessment, allows for inconsistency in interpretation, and presents a challenge for comparison and aggregation of study results. Despite these pitfalls, the 0 to 10 NRS remains the most commonly used primary outcome measure in clinical trials of pain treatments and is the core measure recommended by regulatory agencies. The purpose of this study was to describe the first phase in the development of a pain intensity measure that is easily interpretable, psychometrically sound, and that adheres to FDA qualification processes. The Analgesic, Anesthetic, and Addiction Clinical Trial, Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership conducted concept elicitation interviews (N = 44; 22 with acute pain; 22 with chronic pain) to understand the patient perspective on rating pain intensity and to identify actionable suggestions for improved clarity and meaningfulness of instructions, recall periods, and response options. This article summarizes interview findings, describes how patient input and FDA feedback informed preliminary candidate measures, and provides an overview of the FDA qualification process. PERSPECTIVE: Concept elicitation interviews informed the development of content-valid candidate measures of acute and chronic pain intensity for planned use in clinical trials of pain treatments, and comprise the initial stage in FDA clinical outcome assessment qualification. Measures will subsequently be evaluated through cognitive interviews and a series of psychometric studies.

A high stress profile is associated with severe pain in oncology patients receiving chemotherapy.

PURPOSE: Oncology patients receiving chemotherapy can experience both cancer and non-cancer pain. In addition, oncology patients face numerous stressors and their responses are highly variable. Stress and pain are intricately linked. The purpose of this study was to evaluate for differences in pain characteristics and mood disturbance among oncology patients with distinct stress profiles. METHODS: From a sample of 957 patients with and without pain, latent profile analysis identified three groups of patients with distinct stress profiles (i.e., Stressed, Normative, Resilient). In the subset of 671 patients with pain, receiving chemotherapy for breast, lung, gastrointestinal, or gynecologic cancer, we evaluated for differences among the stress profiles in terms of pain characteristics (e.g., intensity, qualities, interference) and mood disturbance (anxiety, depressive symptoms). RESULTS: Compared to Normative patients (n = 333; 49.6%), Stressed patients (n = 305; 45.5%) reported higher levels of pain intensity, pain interference, anxiety, and depressive symptoms and more commonly described pain as throbbing, shooting, burning, exhausting, tiring, penetrating, nagging, miserable, and unbearable. Compared to Resilient patients (n = 33; 4.9%), Stressed patients reported significantly higher mood-related pain interference scores and more severe anxiety and depressive symptoms. CONCLUSIONS: A high stress profile is common (45.5%) and is associated with more severe pain and associated symptoms. Efforts to identify and target this group for interventions may improve patient outcomes.

Comparison of PACU length of stay and opioid requirements of patients maintained on buprenorphine or methadone for opioid use disorder.

OBJECTIVES: Literature supporting best practice of perioperative buprenorphine management for opioid use disorder is evolving with more recent studies trending toward maintenance of home dose. To guide treatment protocols at our institution, we evaluated patients taking medication for opioid use disorder (MOUD) undergoing similar surgeries. Patients were maintained on either their outpatient buprenorphine or methadone. PATIENTS AND PARTICIPANTS: Data were collected on 46 patients maintained on buprenorphine MOUD who underwent surgery. A subset of these patients (n = 24) was compared with 24 patients maintained on methadone MOUD, matched on surgical procedure, admission date, age, and sex. DESIGN: This is a retrospective matched control study. SETTING: An academic, tertiary, Level 1 trauma center. MAIN OUTCOME MEASURES: Primary outcomes were post-operative opioid use and post-anesthesia care unit (PACU) length of stay. RESULTS: No significant differences in demographic characteristics, physical status, comorbid psychiatric diagnoses, or illicit substance use history were observed between patient groups. A higher proportion of patients taking methadone was admitted due to infection (41.7 percent vs 16.7 percent, p = 0.031) and underwent nonelective surgery (75.0 percent vs 45.8 percent, p = 0.039). No significant differences were observed between patients taking buprenorphine versus methadone with respect to PACU length of stay, post-operative opioid consumption, time-to-transition to oral opioids, or discharge opioid prescriptions. Patients taking buprenorphine were more likely to receive intravenous lidocaine (25.0 percent vs 0.0 percent, p = 0.031) and ketamine (83.3 percent vs 54.2 percent, p = 0.039). CONCLUSION: Findings from this study support accumulating evidence that patients should be maintained on buprenorphine MOUD throughout the perioperative period.

Partnering with patients in clinical trials of pain treatments: a narrative review.

ABSTRACT: The interest and the rationale for meaningful engagement of patients as partners in clinical trials of pain treatments has been increasing. No specific guidance on patient engagement for pain research studies currently exists; thus, the goal of this narrative review was to provide a historical perspective and a current evaluation of the literature on engaging patients as partners in clinical studies in general and in pain-related studies more specifically. We described how regulatory and funding agencies have developed approaches to incorporate input from patients and patient partners in their decision-making processes. We provided an overview on key practices of patient recruitment and engagement as partners in clinical research and highlighted the perceived benefits and challenges of such partnerships. We summarized factors that can facilitate or hinder meaningful patient engagement in clinical trials of pain treatments and outlined gaps that future research should address to optimize patient-centered clinical research.

Chronic Breast Pain Prior to Breast Cancer Surgery Is Associated with Worse Acute Postoperative Pain Outcomes.

Acute postoperative pain is associated with adverse short and long-term outcomes among women undergoing surgery for breast cancer. Previous studies identified preexisting pain as a predictor of postoperative pain, but rarely accounted for pain location or chronicity. This study leveraged a multinational pain registry, PAIN OUT, to: (1) characterize patient subgroups based on preexisting chronic breast pain status and (2) determine the association of preexisting chronic pain with acute postoperative pain-related patient-reported outcomes and opioid consumption following breast cancer surgery. The primary outcome was a composite score comprising the mean of pain intensity and pain interference items from the International Pain Outcomes Questionnaire. The secondary outcome was opioid consumption in the recovery room and ward. Among 1889 patients, we characterized three subgroups: no preexisting chronic pain (n = 1600); chronic preexisting pain elsewhere (n = 128) and; chronic preexisting pain in the breast with/without pain elsewhere (n = 161). Controlling for covariates, women with preexisting chronic breast pain experienced more severe acute postoperative pain and pain interference (ß = 1.0, 95% CI = 0.7-1.3, p < 0.001), and required higher doses of opioids postoperatively (ß = 2.7, 95% CI = 0.6-4.8, p = 0.013). Preexisting chronic breast pain may be an important risk factor for poor pain-related postoperative outcomes. Targeted intervention of this subgroup may improve recovery.

Relationship Between Post-Traumatic Stress Disorder Symptoms and Chronic Pain-Related Symptom Domains Among Military Active Duty Service Members.

OBJECTIVE: This study examined the relationships between symptom domains relevant to post-traumatic stress disorder (PTSD) diagnosis, PTSD screening, and chronic pain-related symptoms (pain intensity, pain interference, physical function, fatigue, depression, anxiety, anger, satisfaction with social roles) experienced by active duty military service members with chronic pain. DESIGN: ross-sectional study. SETTING: This study was conducted at the Interdisciplinary Pain Management Center (IPMC) at Madigan Army Medical Center between 2014 and 2018. SUBJECTS: Active duty service members receiving care at IPMC (n = 2745) were included in this study. METHODS: Independent sample t test was conducted to compare pain intensity and pain-related measures of physical, emotional, and social functioning among patients with and without a PTSD diagnosis or PTSD positive screen (≥3 symptoms). Relative weight analysis was used to identify the relative importance of each PTSD symptom cluster (e.g., intrusion, avoidance, hyperarousal, emotional numbness) to pain and related domains. RESULTS: Approximately 27.9% of the patients had a positive screen for PTSD, and 30.5% of the patients had a PTSD diagnosis. Patients with PTSD diagnosis and positive screening had higher pain interference and lower physical function and social satisfaction scores (P < 0.001) and had increased anger, anxiety, fatigue, and depression scores (P < 0.001). Emotional numbness accounted for the largest proportion of variance in average pain intensity, pain interference, and psychological functioning, and avoidance accounted for the largest proportion of variance in physical function. CONCLUSION: To improve treatment effectiveness and overall functioning for active duty military patients, integrated treatment and therapies targeted to reducing chronic pain and PTSD symptoms (focus on emotional numbness and avoidance) are recommended.

Association of personality profiles with coping and adjustment to cancer among patients undergoing chemotherapy.

OBJECTIVE: Specific personality traits are associated with differential use of various coping strategies. Few studies have examined the relationship between personality and coping in oncology patients undergoing chemotherapy. We, therefore, examined the relationship between previously identified personality profiles (ie, Distressed [14.3% of total sample], Normative [53.8%], Resilient [31.9%]) and measures of coping and adjustment. METHODS: Patients (n = 1248) undergoing chemotherapy for breast, gastrointestinal, gynecological, or lung cancer completed measures of personality (NEO-Five Factor Inventory), coping (Brief COPE), and psychological adjustment to cancer (Mental Adjustment to Cancer [MAC] scale). Differences in coping and adjustment among the three personality profiles were evaluated using analysis of variance. RESULTS: On the Brief COPE, the Distressed class endorsed lower use of Active Coping, Positive Reframing, Acceptance, Emotional Support (ie, "engagement" coping); and greater use of Denial, Venting, Behavioral Disengagement, Self-Blame (ie, "disengagement" coping) compared to the Normative and Resilient classes. On the MAC scale, the Distressed class scored higher on Anxious Preoccupation, Helplessness/Hopelessness, Fatalism, and Avoidance, and lower on Fighting Spirit, compared to the other two classes. CONCLUSIONS: In this sample of oncology patients receiving chemotherapy, patients in the Distressed personality class showed a reduced repertoire of adaptive coping strategies, while those in the Resilient class reported greater use of adaptive or engagement coping strategies. Further work should examine the potential mediating or moderating role of coping and adjustment in the relationships between personality and patient outcomes. Interventions to enhance beneficial and reduce harmful coping strategies in cancer patients should be evaluated.

Cognitive bias: how understanding its impact on antibiotic prescribing decisions can help advance antimicrobial stewardship.

The way clinicians think about decision-making is evolving. Human decision-making shifts between two modes of thinking, either fast/intuitive (Type 1) or slow/deliberate (Type 2). In the healthcare setting where thousands of decisions are made daily, Type 1 thinking can reduce cognitive load and help ensure decision making is efficient and timely, but it can come at the expense of accuracy, leading to systematic errors, also called cognitive biases. This review provides an introduction to cognitive bias and provides explanation through patient vignettes of how cognitive biases contribute to suboptimal antibiotic prescribing. We describe common cognitive biases in antibiotic prescribing both from the clinician and the patient perspective, including hyperbolic discounting (the tendency to favour small immediate benefits over larger more distant benefits) and commission bias (the tendency towards action over inaction). Management of cognitive bias includes encouraging more mindful decision making (e.g., time-outs, checklists), improving awareness of one's own biases (i.e., meta-cognition), and designing an environment that facilitates safe and accurate decision making (e.g., decision support tools, nudges). A basic understanding of cognitive biases can help explain why certain stewardship interventions are more effective than others and may inspire more creative strategies to ensure antibiotics are used more safely and more effectively in our patients.

Evaluation of the Impact of an Online Opioid Education Program for Acute Pain Management.

OBJECTIVE: The University of Washington instituted a policy requiring all credentialed clinicians who prescribe opioids to complete a one-time education activity about safe and responsible opioid prescribing. A scenario-based, interactive online learning module was developed for opioid management of acute pain in hospitalized adults. This study examined the impact of the education module on learners' knowledge, perceived competence, and use of guideline-adherent practices. METHODS: Clinicians who completed the education module participated in a voluntary de-identified online survey approximately six months after the learning activity. Survey questions were related to 1) the perception of improved knowledge; 2) impact on learner's use of three guideline-adherent practices; and 3) perceived competence in managing opioids for acute pain. Descriptive statistics were generated, and multiple linear regression models were used for analysis. RESULTS: Clinicians (N = 167) reported improvement in knowledge and perceived competence. Controlling for other aspects of knowledge evaluated, learning to construct a safe opioid taper plan for acute pain, distinguishing between short- and long-acting opioids, and safely initiating opioids for acute pain were significantly associated with increased self-reported likelihood of incorporating the Washington state Prescription Monitoring Program (P = 0.003), using multimodal analgesia (P = 0.022), and reducing the duration of opioids prescribed (P = 0.016). Only improvement in knowledge of how to construct a safe opioid taper plan was significantly associated with increased perceived competence (P = 0.002). CONCLUSIONS: Our findings suggest that this online education module about safe opioid prescribing for acute pain management was effective at improving knowledge, increasing the likelihood of using guideline-adherent clinical practices, and increasing perceived competence.

Telementoring for improving primary care provider knowledge and competence in managing chronic pain: A randomised controlled trial.

Introduction: Primary care providers are frequently unprepared to manage chronic pain adequately due in part to insufficient professional training. This study evaluated the effect of a telementoring intervention on knowledge and perceived competence related to chronic pain management. Methods: The study design was a cluster randomised controlled trial. Primary care clinics that were part of the University of Washington Medicine Telehealth network were the unit of randomization. Primary care providers comprised the intervention group (n = 23) and the control group (n = 18). Providers in the intervention group attended telementoring sessions through the TelePain programme and presented patient cases at the beginning and end of their enrolled patients' 12-week study period. TelePain sessions included a didactic presentation and telementoring for specific patient cases by a panel of pain specialists from the disciplines of pain medicine, internal medicine, anaesthesiology, rehabilitation medicine, psychiatry, addiction medicine, nursing and complementary and integrative pain management. Providers' baseline and end-of-study knowledge and perceived competence in managing chronic pain were assessed by three questionnaires: Knowledge and Attitudes Survey Regarding Pain, the KnowPain-12 and the Perceived Competence Scale. Results: Knowledge (Z = ­0.34, p = 0.97 (Knowledge and Attitudes Survey Regarding Pain) and Z = 0.49, p = 0.62 (KnowPain-12)) and perceived competence (Z = ­0.74, p = 0.46) did not increase for providers in the intervention group compared with providers in the control group. These providers attended on average 12.5 sessions (range 0­31) while participating in the study. Discussion: Further research is recommended to establish the effectiveness of this telementoring intervention.