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Sean P McDermott, Ajay D Wasan Division of Pain Medicine, Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USACorrespondence: Sean P McDermott, UPMC Pain Medicine, 5750 Centre Ave, Suite 400, Pittsburgh, PA, 15232, USA, Tel +1 412-665-8030, Fax +1 412-647-2993, Email seanmcd@umich.eduPurpose: This study evaluates the utility of machine learning (ML) and natural language processing (NLP) in the processing and initial analysis of data within the electronic health record (EHR). We present and evaluate a method to classify medication names as either opioids or non-opioids using ML and NLP.Patients and Methods: A total of 4216 distinct medication entries were obtained from the EHR and were initially labeled by human reviewers as opioid or non-opioid medications. An approach incorporating bag-of-words NLP and supervised ML classification was implemented in MATLAB and used to automatically classify medications. The automated method was trained on 60% of the input data, evaluated on the remaining 40%, and compared to manual classification results.Results: A total of 3991 medication strings were classified as non-opioid medications (94.7%), and 225 were classified as opioid medications by the human reviewers (5.3%). The algorithm achieved a 99.6% accuracy, 97.8% sensitivity, 94.6% positive predictive value, F1 value of 0.96, and a receiver operating characteristic (ROC) curve with 0.998 area under the curve (AUC). A secondary analysis indicated that approximately 15– 20 opioids (and 80– 100 non-opioids) were needed to achieve accuracy, sensitivity, and AUC values of above 90– 95%.Conclusion: The automated approach achieved excellent performance in classifying opioids or non-opioids, even with a practical number of human reviewed training examples. This will allow a significant reduction in manual chart review and improve data structuring for retrospective analyses in pain studies. The approach may also be adapted to further analysis and predictive analytics of EHR and other “big data” studies.Keywords: retrospective, classification, machine learning, natural language processing, translational, opioids

Background:Rheumatoid arthritis (RA) is an inflammatory condition that mostly affects synovial joints. It produces severe swelling and ongoing inflammation, and as it worsens, the cartilage and bone begin to erode, resulting in deformed joints and bone erosion. Objectives:The purpose of this study is to evaluate the levels of anti-cyclic citrullinated peptide (anti-CCP) antibodies and determine the role of interleukin-1 beta (IL-1β), interleukin-18 (IL-18), interleukin-38 (IL-38), and transforming growth factor-beta2 (TGF-β2) in studied groups (RA patients and apparently healthy control). Materials and Methods:The study included collecting blood samples from a group of patients infected with RA involving 60 patients (21 male and 39 female), and the healthy group included 50 individuals as control group (21 males and 29 females). Results:The outcomes showed of anti-CCP a highly significant difference for RA patients compared to the control group by 0.603 ± 0.02 and 0.274 ± 0.01, respectively, and some immunological parameters that involve inflammation-promoting interleukins (IL-1β and IL-18), the results showed the significant differences at the level (P < 0.01) of patients was 126.79 ± 4.18 and 194.37 ± 12.71 compared with control 91.85 ± 2.11 and 92.27 ± 2.08, respectively. The identical results to measure anti-inflammatory interleukins (IL-38, TGF-β2) represented of patients were 190.43 ± 9.82 and 403.23 ± 21.20 compared with control group was 88.39 ± 1.56 and 115.59 ± 5.63, respectively. Conclusion:The immunological parameters represented high expression of pro-inflammatory interleukins (IL-1β and IL-18), so, elevation levels of anti-inflammatory interleukins (IL-38 and TGF-β2) of RA patients.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that primarily affects the synovial joints and produces recurring inflammation of the synovial membrane, which ultimately causes joint degeneration, deformity, and disability. The current study included 110 blood samples collected from patients infected with rheumatoid arthritis (60) and 50 blood samples from controls. The results showed that investigation of some hematological tests revealed a high significant erythrocyte sedimentation rate (ESR) for the patient group compared to the control group (28.25 ± 2.72, 16.24 ± 1.83), respectively. But it is non-significant for patients for (WBC, RBC, and PLT) was (7.34 ± 0.25, 4.71 ± 0.08, and 248.26 ± 9.18), while the control group was (6.73 ±0.19, 4.96 ±0.10, and 263.64 ±8.26), respectively. As well as the result of the rheumatoid arthritis factor (Rh) level, there was a significant increase in patients with positive RF 45 (75.00%) and negative RF 15 (25.00%). while the result for the C-reactive protein (CRP) test for patients was positive 26 (43.33%) and negative 34 (56.67%).

Background: Performance indicators are used to assess patient safety, efficacy, equity, patient-centeredness, punctuality, and efficiency. The benchmark values for each Key Performance Indicator are aspirational values, and the minimum performance level values are the number of fertilized oocytes on Day 1 and the Normal Fertilization Rate, respectively (presence of 2Pro Nucleus and 2Polar Body measured at 17 h post-injection) as a Failed fertilization rate is calculated as the proportion of IVF cycles (excluding cycles with intracytoplasmic injection) on Day 1 (17 hours after insemination) with no signs of pregnancy. During fertilization (i.e., 0 oocytes with 2Pro Nucleus). The percentage of zygotes on Day 2 (44 hours after insemination) is known as the cleavage rate, and it can suggest an issue with sperm quality (sperm function, oocyte activation, and gamete receptors), sperm processing, or the quantity of spermatozoa used for insemination. which cleaves to create embryos. The percentage of cleaved embryos per successfully fertilized egg that are at the 4-cell stage on Day 2 (44 hours post-insemination) or at the 8-cell stage on Day 3 (68 hours post-insemination) is known as the embryo development rate. This evaluates the viability and quality of the embryos as well as the capacity of the culture system to promote cleavage at the necessary stages. The critical factor is the proportion of blastocysts observed at 116 hours after insemination as a function of the number of correctly fertilized oocytes. Measures of performance blastocyst development rate. The viability of the embryo as well as the culture system's capacity to support blastocyst formation from fertilized oocytes (i.e., the formation of an intracellular mass and a blastocoele cavity) are both determined by this factor. It should be noted that this phrase only considers blastocyst formation and not blastocyst stage or quality. The damage rate is the proportion of oocytes that are injured or have deteriorated by the time of fertilization assessment on Day 1 as a result of the intracytoplasmic injection. The percentage of biopsied and tubed/fixed samples where DNA is found represents the success rate of the biopsy. It serves as a gauge of the embryologists' ability to transfer biopsied samples to test tubes, as shown by successful DNA amplification. The number of gestational sacs divided by the total number of transplanted embryos is how one calculates the implantation rate, which is dependent on the cleavage stage. By dividing the number of gestational sacs by the total number of transplanted blastocysts, the implantation KPI (blastocyst stage) is calculated.

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., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Background: There is potential for adverse events from corticosteroid injections, including increase in blood glucose, decrease in bone mineral density and suppression of the hypothalamic-pituitary axis. Published studies note that doses lower than those commonly injected provide similar benefit., Methods: Development of the practice guideline was approved by the Board of Directors of American Society of Regional Anesthesia and Pain Medicine with several other societies agreeing to participate. The scope of guidelines was agreed on to include safety of the injection technique (landmark-guided, ultrasound or radiology-aided injections); effect of the addition of the corticosteroid on the efficacy of the injectate (local anesthetic or saline); and adverse events related to the injection. Based on preliminary discussions, it was decided to structure the topics into three separate guidelines as follows: (1) sympathetic, peripheral nerve blocks and trigger point injections; (2) joints; and (3) neuraxial, facet, sacroiliac joints and related topics (vaccine and anticoagulants). Experts were assigned topics to perform a comprehensive review of the literature and to draft statements and recommendations, which were refined and voted for consensus (≥75% agreement) using a modified Delphi process. The United States Preventive Services Task Force grading of evidence and strength of recommendation was followed., Results: This guideline deals with the use and safety of corticosteroid injections for sympathetic, peripheral nerve blocks and trigger point injections for adult chronic pain conditions. All the statements and recommendations were approved by all participants after four rounds of discussion. The Practice Guidelines Committees and Board of Directors of the participating societies also approved all the statements and recommendations. The safety of some procedures, including stellate blocks, lower extremity peripheral nerve blocks and some sites of trigger point injections, is improved by imaging guidance. The addition of non-particulate corticosteroid to the local anesthetic is beneficial in cluster headaches but not in other types of headaches. Corticosteroid may provide additional benefit in transverse abdominal plane blocks and ilioinguinal/iliohypogastric nerve blocks in postherniorrhaphy pain but there is no evidence for pudendal nerve blocks. There is minimal benefit for the use of corticosteroids in trigger point injections., Conclusions: In this practice guideline, we provided recommendations on the use of corticosteroids in sympathetic blocks, peripheral nerve blocks, and trigger point injections to assist clinicians in making informed decisions., Competing Interests: Competing interests: HTB, MD: NIH NIAMS P30AR072579. AC, MD: Research Funding: RM1NS128956-01A1; Consultant: Swing Therapeutics, Scilex Pharmaceuticals. SS, MD: Consultant: SPR Therapeutics, Allergan, Inc. DS, MD: Advisory Board, Funded research: Scilex; Speaker: AbbVie. AN, MD: Speaker: Averitas Pharmaceuticals; Research: Saol Therapeutics. AA-E, MD: Consultant: Curonix. TD, MD: Research support: Biohaven, NIH; Consultant: Guidepoint Global; Speaker honorarium: Remedy Health Media. MSE, MD: Funded research: SPR Therapeutics; Consultant: Avanos, Abbott. TH, MD: Acella: Advisory board, speaker: Acella. CH, MD: Research grant: Nevro, Inc. CP, MD: Consulting: Mainstay Medical; Royalties, UpToDate. BS, MD: Consultant: State Farm, Carelon. AS, MD: NIH R34AR080279. MM, MD: Consultant: Juris Medicus. JAH, MD: Grants: Neiman Health Policy Institute (there is no number associated with this foundation grant; Consulting (last 12 months): Medtronic, Relievant, Persica; DMC Chair: Balt, Rapid Medical, Arsenal. AW, MD: Investigator-initiated grant, Goodblends, PA. DAP, MD: Consulting: Avanos, Boston Scientific, Medtronic, Nevro, and SI Bone. Research support: Avanos, Boston Scientific, Medtronic, Nevro, Stimgenics, Abbott. SPC, MD: Consulting (past 2 years): Avanos, Scilex, SPR, SWORD, Releviate (ended), Clearing (ended), Persica (inactive); Research funds paid to institution: Scilex, Avanos. TM, MD: Consultant, Interventional AnalgesiX. The remaining authors declare no competing interests., (© American Society of Regional Anesthesia & Pain Medicine 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Fewer than 30% of all medical schools have programs that encourage medical design innovation or entrepreneurship at the trainee level. This is particularly evident in the fields of anesthesiology and pain medicine, where utilizing medical devices constitutes a significant part of a clinician's daily practice. To fix this gap, our institution has developed an incubator club where trainees can learn about medical devices and entrepreneurship. Our goal is to present how this can be incorporated at other institutions because these clubs are a low resource utilization investment that can teach trainees valuable skills in innovation and entrepreneurship., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 International Anesthesia Research Society.)

Currently-used assessments for fibromyalgia require clinicians to suspect a fibromyalgia diagnosis, a process susceptible to unintentional bias. Automated assessments of standard patient-reported outcomes (PROs) could be used to prompt formal assessments, potentially reducing bias. We sought to determine whether hierarchical clustering of patient-reported pain distribution on digital body map drawings predicted fibromyalgia diagnosis. Using an observational cohort from the University of Pittsburgh's Patient Outcomes Repository for Treatment registry, which contains PROs and electronic medical record data from 21,423 patients (March 17, 2016-June 25, 2019) presenting to pain management clinics, we tested the hypothesis that hierarchical clustering subgroup was associated with fibromyalgia diagnosis, as determined by ICD-10 code. Logistic regression revealed a significant relationship between the body map cluster subgroup and fibromyalgia diagnosis. The cluster subgroup with the most body areas selected was the most likely to receive a diagnosis of fibromyalgia when controlling for age, gender, anxiety, and depression. Despite this, more than two-thirds of patients in this cluster lacked a clinical fibromyalgia diagnosis. In an exploratory analysis to better understand this apparent underdiagnosis, we developed and applied proxies of fibromyalgia diagnostic criteria. We found that proxy diagnoses were more common than ICD-10 diagnoses, which may be due to less frequent clinical fibromyalgia diagnosis in men. Overall, we find evidence of fibromyalgia underdiagnosis, likely due to gender bias. Coupling PROs that take seconds to complete, such as a digital pain body map, with machine learning is a promising strategy to reduce bias in fibromyalgia diagnosis and improve patient outcomes. PERSPECTIVE: This investigation applies hierarchical clustering to patient-reported, digital pain body maps, finding an association between body map responses and clinical fibromyalgia diagnosis. Rapid, computer-assisted interpretation of pain body maps would be clinically useful in prompting more detailed assessments for fibromyalgia, potentially reducing gender bias., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Gordon reported grants from the National Institutes of Health, Veterans Affairs, and US Department of Health and Health Services during the conduct of the study as well as personal fees from UpToDate and board service with the American Society of Addiction Medicine, Association for Multidisciplinary Education and Research in Substance use and Addiction, and International Society of Addiction Journal Editors outside the submitted work. Dr. Wright reported grants from the Patient-Centered Outcomes Research Institute (PCORI) during the conduct of the study and grants from Pfizer and grants from the National Institute on Drug Abuse outside the submitted work. Drs. Cochran and Hardy reported grants from PCORI during the conduct of the study. Dr. Wasan reported consulting fees from Greenwich Biosciences and grants from Parallel outside the submitted work. No other disclosures were reported.

Introduction: Chronic low back pain (cLBP) is highly prevalent in the United States and globally, resulting in functional impairment and lowered quality of life. While many treatments are available for cLBP, clinicians have little information about which specific treatment(s) will work best for individual patients or subgroups of patients. The Back Pain Research Consortium, part of the National Institutes of Health Helping to End Addiction Long-term SM (HEAL) Initiative, will conduct a collaborative clinical trial, which seeks to develop a personalized medicine algorithm to optimize patient and provider treatment selection for patients with cLBP., Objective: The primary objective of this article is to provide an update on evidence-based cLBP interventions and describe the process of reviewing and selecting interventions for inclusion in the clinical trial., Methods: A working group of cLBP experts reviewed and selected interventions for inclusion in the clinical trial. The primary evaluation measures were strength of evidence and magnitude of treatment effect. When available in the literature, duration of effect, onset time, carryover effect, multimodal efficacy, responder subgroups, and evidence for the mechanism of treatment effect or biomarkers were considered., Conclusion: The working group selected 4 leading, evidence-based treatments for cLBP to be tested in the clinical trial and for use in routine clinical treatment. These treatments include (1) duloxetine, (2) acceptance and commitment therapy, (3) a classification-based exercise and manual therapy intervention, and (4) a self-management approach. These interventions each had a moderate to high level of evidence to support a therapeutic effect and were from different therapeutic classes., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Objective: Fibromyalgia (FM) is characterized by pervasive pain-related symptomatology and high levels of negative affect. Mind-body treatments such as cognitive behavioral therapy (CBT) appear to foster improvement in FM via reductions in pain-related catastrophizing, a set of negative, pain-amplifying cognitive and emotional processes. However, the neural underpinnings of CBT's catastrophizing-reducing effects remain uncertain. This randomized controlled mechanistic trial was designed to assess CBT's effects on pain catastrophizing and its underlying brain circuitry., Methods: Of 114 enrolled participants, 98 underwent a baseline neuroimaging assessment and were randomized to 8 weeks of individual CBT or a matched FM education control (EDU) condition., Results: Compared with EDU, CBT produced larger decreases in pain catastrophizing post treatment (P < 0.05) and larger reductions in pain interference and symptom impact. Decreases in pain catastrophizing played a significant role in mediating those functional improvements in the CBT group. At baseline, brain functional connectivity between the ventral posterior cingulate cortex (vPCC), a key node of the default mode network (DMN), and somatomotor and salience network regions was increased during catastrophizing thoughts. Following CBT, vPCC connectivity to somatomotor and salience network areas was reduced., Conclusion: Our results suggest clinically important and CBT-specific associations between somatosensory/motor- and salience-processing brain regions and the DMN in chronic pain. These patterns of connectivity may contribute to individual differences (and treatment-related changes) in somatic self-awareness. CBT appears to provide clinical benefits at least partially by reducing pain-related catastrophizing and producing adaptive alterations in DMN functional connectivity., (© 2023 American College of Rheumatology.)

Background: Mood disorders (anxiety, depression), sleep disorders, and catastrophizing lead to increased post-operative pain perception, increase in postoperative opioid consumption, decreased engagement with physical activity, and increased resource utilization in surgical patients. Psychosocial disorders significantly affect postoperative outcome. Unfortunately, studies focused on perioperative psychological assessment and treatment are scarce. We propose to test whether digital cognitive behavioral intervention (dCBI) can help surgical patients. dCBI such as RxWell™ is a proven treatment for mood disorders in medical patients such as reducing depression in patients with inflammatory bowel disease. We hypothesize that RxWell™ will also be effective in surgical patients. This study aims to test whether RxWell™ can improve preoperative mood disorders and subsequently reduce postoperative pain and opioid requirement in patients scheduled for primary total hip and knee arthroplasty (THA, TKA). We named the trial as the SuRxgWell trial., Methods: This is a randomized, controlled trial that will enroll primary and unilateral THA or TKA patients with anxiety and/or depression symptoms before surgery to receive the SuRxgWell dCBI program and investigate its impact on postoperative outcomes including postoperative pain, anxiety, depression, sleep disorder, and catastrophizing. After signing an informed consent, subjects will be screened using the PROMIS questionnaires, and subjects with a T-score of ≥ 60 on the short Patient-Reported Outcomes Measurement Information System (PROMIS) 4a Anxiety and/or short PROMIS 4a Depression questionnaires will be randomized to either usual care (control group) or the cognitive behavioral intervention, RxWell™, plus usual care (intervention group). The control group will receive information on how to locate tools to address anxiety and depression, whereas the intervention group will have access to SuRxgWell 1 month prior to surgery and up to 3 months after surgery. The allocation will be 3:1 (intervention to control). Investigators will be blinded, but research coordinators approaching patients and research subjects will not. The primary outcome will be day of surgery anxiety or depression symptoms measured with the PROMIS Short Form v1.0 -Anxiety 4a/Depression and Generalized Anxiety Disorder Measure (GAD-7) and Patient Health Questionnaire (PHQ-8). Secondary end points include measuring other health-related quality of life outcomes including sleep disturbance, fatigue, ability to participate in social roles, pain interference, cognitive function, pain catastrophizing, and physical function. Other secondary outcomes include collecting data about preoperative and postoperative pain scores, and pain medication usage, and orthopedic functional recovery at baseline, day of surgery, and 1, 2, and 3 months after the surgery with the Pain Catastrophizing Scale, the Knee injury and Osteoarthritis Outcome Score (KOOS), and Hip injury and Osteoarthritis Outcome Score (HOOS). In addition, subjects will be asked to complete a GAD-7 and PHQ-8 questionnaires bi-weekly (via the RxWell™ app for the interventional group or REDCAP for the control group). Data about postsurgical complications, and resource utilization will also be recorded. We will also receive monthly reports measuring the usage and engagement of RxWell use for each participant randomized to that arm. The primary hypotheses will be assessed with intention-to-treat estimates, and differences in primary outcome will be tested using independent two sample t-tests. This trial is registered to the ClinicalTrials.gov database (NCT05658796) and supported by the DAPM, UPMC Health Plan, and the NIH., Discussion: Our trial will evaluate the feasibility of digital cognitive behavioral intervention as a perioperative tool to improve anxiety and depression before and after major orthopedic surgery in comparison to education. If digital cognitive behavioral intervention proves to be effective, this might have important clinical implications, reducing the incidence of chronic postsurgical pain and improving outcomes., (© 2023. The Author(s).)

In 2019, the National Health Interview survey found that nearly 59% of adults reported pain some, most, or every day in the past 3 months, with 39% reporting back pain, making back pain the most prevalent source of pain, and a significant issue among adults. Often, identifying a direct, treatable cause for back pain is challenging, especially as it is often attributed to complex, multifaceted issues involving biological, psychological, and social components. Due to the difficulty in treating the true cause of chronic low back pain (cLBP), an over-reliance on opioid pain medications among cLBP patients has developed, which is associated with increased prevalence of opioid use disorder and increased risk of death. To combat the rise of opioid-related deaths, the National Institutes of Health (NIH) initiated the Helping to End Addiction Long-TermSM (HEAL) initiative, whose goal is to address the causes and treatment of opioid use disorder while also seeking to better understand, diagnose, and treat chronic pain. The NIH Back Pain Consortium (BACPAC) Research Program, a network of 14 funded entities, was launched as a part of the HEAL initiative to help address limitations surrounding the diagnosis and treatment of cLBP. This paper provides an overview of the BACPAC research program's goals and overall structure, and describes the harmonization efforts across the consortium, define its research agenda, and develop a collaborative project which utilizes the strengths of the network. The purpose of this paper is to serve as a blueprint for other consortia tasked with the advancement of pain related science., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Academy of Pain Medicine.)

The Biobehavioral Working Group of BACPAC was charged to evaluate a range of psychosocial, psychophysical, and behavioral domains relevant to chronic low back pain, and recommend specific assessment tools and procedures to harmonize biobehavioral data collection across the consortium. Primary references and sources for measure selection were the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials, the Minimum Data Set from the National Institutes of Health (NIH) Research Task Force on Standards for Chronic Low Back Pain, the Patient-Reported Outcomes Measurement Information System, and NeuroQOL. The questionnaire's recommendations supplemented the NIH HEAL Common Data Elements and BACPAC Minimum Data Set. Five domains were identified for inclusion: Pain Characteristics and Qualities; Pain-Related Psychosocial/Behavioral Factors; General Psychosocial Factors; Lifestyle Choices; and Social Determinants of Health/Social Factors. The Working Group identified best practices for required and optional Quantitative Sensory Testing of psychophysical pain processing for use in BACPAC projects., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Academy of Pain Medicine.)

Objective: Patients with chronic low back pain (CLBP) and comorbid depression or anxiety disorders are highly prevalent. Negative affect (NA) refers to a combination of negative thoughts, emotions, and behaviors. Patients with CLBP with high NA have greater pain, worse treatment outcomes, and greater prescription opioid misuse. We present the protocol for SYNNAPTIC (SYNergizing Negative Affect & Pain Treatment In Chronic pain)., Design: A randomized comparative-effectiveness study of antidepressants, fear-avoidance rehabilitation, or their combination in 300 patients with CLBP with high NA. In the antidepressant- or rehabilitation-only arms, SYNNAPTIC includes an adaptive design of re-randomization after 4 months for nonresponders., Setting: A multisite trial conducted in routine pain clinical treatment settings: pain clinics and physical and occupational therapy treatment centers., Methods: Inclusion criteria include CLBP with elevated depression and anxiety symptoms. Antidepressant and rehabilitation treatments follow validated and effective protocols for musculoskeletal pain in patients with high NA. Power and sample size are based on superior outcomes of combination therapy with these same treatments in a 71-subject 4-arm pilot randomized controlled trial., Conclusions: SYNNAPTIC addresses the lack of evidence-based protocols for the treatment of the vulnerable subgroup of patients with CLBP and high NA. We hypothesize that combination therapy of antidepressants plus fear-avoidance rehabilitation will be more effective than each treatment alone., Trial Registration: ClinicalTrials.gov ID: NCT04747314., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Academy of Pain Medicine.)

Objective: One aim of the Back Pain Consortium (BACPAC) Research Program is to develop an integrated model of chronic low back pain that is informed by combined data from translational research and clinical trials. We describe efforts to maximize data harmonization and accessibility to facilitate Consortium-wide analyses., Methods: Consortium-wide working groups established harmonized data elements to be collected in all studies and developed standards for tabular and nontabular data (eg, imaging and omics). The BACPAC Data Portal was developed to facilitate research collaboration across the Consortium., Results: Clinical experts developed the BACPAC Minimum Dataset with required domains and outcome measures to be collected by use of questionnaires across projects. Other nonrequired domain-specific measures are collected by multiple studies. To optimize cross-study analyses, a modified data standard was developed on the basis of the Clinical Data Interchange Standards Consortium Study Data Tabulation Model to harmonize data structures and facilitate integration of baseline characteristics, participant-reported outcomes, chronic low back pain treatments, clinical exam, functional performance, psychosocial characteristics, quantitative sensory testing, imaging, and biomechanical data. Standards to accommodate the unique features of chronic low back pain data were adopted. Research units submit standardized study data to the BACPAC Data Portal, developed as a secure cloud-based central data repository and computing infrastructure for researchers to access and conduct analyses on data collected by or acquired for BACPAC., Conclusions: BACPAC harmonization efforts and data standards serve as an innovative model for data integration that could be used as a framework for other consortia with multiple, decentralized research programs., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Academy of Pain Medicine.)

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., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Objective: Clinical trials of cannabinoids for chronic pain have mixed and often inconclusive results. In contrast, many prospective observational studies show the analgesic effects of cannabinoids. This survey study aimed to examine the experiences/attitudes of individuals with chronic pain who are currently taking, have previously taken, or never taken cannabinoids for chronic pain to inform future research., Methods: This study is based on a cross-sectional, web-based survey of individuals with self-reported chronic pain. Participants were invited to participate through an email that was distributed to the listservs of patient advocacy groups and foundations that engage individuals with chronic pain., Results: Of the 969 respondents, 444 (46%) respondents reported currently taking, 213 (22%) previously taken, and 312 (32%) never taken cannabinoids for pain. Participants reported using cannabinoids to treat a wide variety of chronic pain conditions. Those currently taking cannabinoids (vs previously) more frequently reported: (1) large improvements from cannabinoids in all pain types, including particularly difficult-to-treat chronic overlapping pain conditions (eg, pelvic pain), (2) improvements in comorbid symptoms (eg, sleep), and (3) lower interference from side effects. Those currently taking cannabinoids reported more frequent and satisfactory communication with clinicians regarding cannabinoid use. Those never taken cannabinoids reported a lack of suggestion/approval of a clinician (40%), illegality (25%), and lack of FDA regulation (19%) as reasons for never trying cannabinoids., Conclusion: These findings underscore the importance of conducting high-quality clinical trials that include diverse pain populations and clinically relevant outcomes that if successful, could support FDA approval of cannabinoid products. Clinicians could then prescribe and monitor these treatments similarly to other chronic pain medications., Competing Interests: GW Pharmaceuticals (Cambridgeshire, UK) provided funds to support the conduct of the survey, including consulting fees too. The analyses and writing of this manuscript were supported by NIH (Bethesda, MD) grant K24NS126861. R.F., J.S.G., K.P.H., R.R.E., and A.D.W. received consulting fees from GW to design the survey. B.L.F. has obtained funding from Pfizer Inc. (GRAND Awards, including salary support) for investigator-initiated projects; Indivior for a clinical trial sponsored by Indivior. B.L.F. has in-kind donations of cannabis products from Aurora Cannabis Enterprises Inc. and study medication donations from Pfizer Inc. (varenicline for smoking cessation) and Bioprojet Pharma. He was also provided a coil for a Transcranial magnetic stimulation (TMS) study from Brainsway. B.L.F. has obtained industry funding from Canopy Growth Corporation (through research grants handled by the Centre for Addiction and Mental Health and the University of Toronto), Bioprojet Pharma, Alcohol Countermeasure Systems (ACS), Alkermes and Universal Ibogaine. He has participated in a session of a National Advisory Board Meeting (Emerging Trends BUP-XR) for Indivior Canada and has been consultant for Shinogi. He is supported by CAMH, Waypoint Centre for Mental Health Care, a clinician-scientist award from the department of Family and Community Medicine of the University of Toronto, and a Chair in Addiction Psychiatry from the department of Psychiatry of University of Toronto. The remaining authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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., (Copyright © 2023 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors have no conflicts of interest to declare.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

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., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Preoperative anxiety and depression have been shown to increase postoperative pain and opioid consumption by up to 50% in patients undergoing primary unilateral Total Knee Arthroplasty (TKA). We hypothesized that the use of a telemedicine-based digital Cognitive Behavioral Intervention program (RxWell ® ) started one month prior to surgery would control anxiety and depression prior to surgery., Materials and Methods: This was a randomized, controlled trial that enrolled patients undergoing primary unilateral TKA. At least a month prior to surgery, patients who gave consent to participate were asked to complete PROMIS ® (Patient-Reported Outcomes Measurement Information System) emotional anxiety short form 8a and PROMIS ® emotional depression short form-8a questionnaires. Patients with T-scores of ≥ 57 were randomized to either a no intervention (control group) or a RxWell ® program (treatment group) for a month prior to surgery. The primary outcome of this proof-of-concept study was the ability of the RxWell ® to normalize patients' PROMIS anxiety T scores., Results: T scores for anxiety and depression among patients randomized to the RxWell ® group significantly decreased from 64.3 ± 3.0 at the time of randomization to 58.5 ± 2.6 prior to surgery (n=5, p=0.006), whereas no changes in T scores were recorded in the control group (59.4 ± 4.2 at the time of randomization vs . 57.7 ± 6.2; n=6, p=0.559)., Conclusion: These preliminary data suggest that the use of a RxWell ® program represents an effective approach to control anxiety and depression prior to surgery. In contrast, it seems that in the absence of treatment, anxiety level remains similar over a month prior to surgery.

Introduction: Chronic low back pain (cLBP) is highly prevalent in the United States and globally, resulting in functional impairment and lowered quality of life. While many treatments are available for cLBP, clinicians have little information about which specific treatment(s) will work best for individual patients or subgroups of patients. The Back Pain Research Consortium, part of the National Institutes of Health Helping to End Addiction Long-term SM (HEAL) Initiative, will conduct a collaborative clinical trial, which seeks to develop a personalized medicine algorithm to optimize patient and provider treatment selection for patients with cLBP., Objective: The primary objective of this article is to provide an update on evidence-based cLBP interventions and describe the process of reviewing and selecting interventions for inclusion in the clinical trial., Methods: A working group of cLBP experts reviewed and selected interventions for inclusion in the clinical trial. The primary evaluation measures were strength of evidence and magnitude of treatment effect. When available in the literature, duration of effect, onset time, carryover effect, multimodal efficacy, responder subgroups, and evidence for the mechanism of treatment effect or biomarkers were considered., Conclusion: The working group selected 4 leading, evidence-based treatments for cLBP to be tested in the clinical trial and for use in routine clinical treatment. These treatments include (1) duloxetine, (2) acceptance and commitment therapy, (3) a classification-based exercise and manual therapy intervention, and (4) a self-management approach. These interventions each had a moderate to high level of evidence to support a therapeutic effect and were from different therapeutic classes., Competing Interests: D. Williams is a consultant to Swing Therapeutics Inc. and to Community Health Focus Inc. Afton Hassett is a consultant to Happify, Inc. The remaining authors have no conflicts of interest to declare. This research was supported by NIH HEAL Initiative of the National Institutes of Health under award number U24AR076730. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or its NIH HEAL Initiative., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

Importance: Prescription opioids can treat acute pain in primary care but have potential for unsafe use and progression to prolonged opioid prescribing., Objective: To compare clinician-facing interventions to prevent unsafe opioid prescribing in opioid-naive primary care patients with acute noncancer pain., Design Setting and Participants: We conducted a multisite, cluster-randomized, 2 × 2 factorial, clinical trial in 3 health care systems that comprised 48 primary care practices and 525 participating clinicians from September 2018 through January 2021. Patient participants were opioid-naive outpatients, 18 years or older, who presented for a qualifying clinic visit with acute noncancer musculoskeletal pain or nonmigraine headache., Interventions: Practices randomized to: (1) control; (2) opioid justification; (3) monthly clinician comparison emails; or (4) opioid justification and clinician comparison. All groups received opioid prescribing guidelines via the electronic health record at the time of a new opioid prescription., Main Outcomes and Measures: Primary outcome measures were receipt of an initial opioid prescription at the qualifying clinic visit. Other outcomes were opioid prescribing for more than 3 months and a concurrent opioid/benzodiazepine prescription over 12-month follow-up., Results: Among 22 616 enrolled patient participants (9740 women [43.1%]; 64 American Indian/Alaska Native [0.3%]; 590 Asian [2.6%], 1120 Black/African American [5.0%], 1777 Hispanic [7.9%], 225 Native Hawaiian/Pacific Islander [1.0%], and 18 981 White [83.9%] individuals), the initial opioid prescribing rates at the qualifying clinic visit were 3.1% in the total sample, 4.2% in control, 3.6% in opioid justification, 2.6% in clinician comparison, and 1.9% in opioid justification and clinician comparison. Compared with control, the adjusted odds ratio (aOR) for a new opioid prescription was 0.74 (95% CI, 0.46-1.18; P  = .20) for opioid justification and 0.60 (95% CI, 0.38-0.96; P  = .03) for clinician comparison. Compared with control, clinician comparison was associated with decreased odds of opioid therapy of more than 3 months (aOR, 0.79; 95% CI, 0.69-0.91; P  = .001) and concurrent opioid/benzodiazepine prescription (aOR, 0.85; 95% CI, 0.72-1.00; P  = .04), whereas opioid justification did not have a significant effect., Conclusions and Relevance: In this cluster randomized clinical trial, comparison emails decreased the proportion of opioid-naive patients with acute noncancer pain who received an opioid prescription, progressed to treatment with long-term opioid therapy, or were exposed to concurrent opioid and benzodiazepine therapy. Health care systems can consider adding clinician-targeted nudges to other initiatives as an efficient, scalable approach to further decrease potentially unsafe opioid prescribing., Trial Registration: ClinicalTrials.gov Identifier: NCT03537573., Competing Interests: Conflict of Interest Disclosures: Dr Gordon reported grants from the National Institutes of Health, Veterans Affairs, and US Department of Health and Health Services during the conduct of the study as well as personal fees from UpToDate and board service with the American Society of Addiction Medicine, Association for Multidisciplinary Education and Research in Substance use and Addiction, and International Society of Addiction Journal Editors outside the submitted work. Dr Wright reported grants from the Patient-Centered Outcomes Research Institute (PCORI) during the conduct of the study and grants from Pfizer and grants from the National Institute on Drug Abuse outside the submitted work. Drs Cochran, Fischer, Gellad, and Hamm reported grants from PCORI during the conduct of the study. Dr Wasan reported consulting fees from Greenwich Biosciences and grants from Parallel outside the submitted work. No other disclosures were reported., (Copyright 2022 Kraemer KL et al. JAMA Health Forum.)

Abstract: Chronic pain clinical trials have historically assessed benefit and risk outcomes separately. However, a growing body of research suggests that a composite metric that accounts for benefit and risk in relation to each other can provide valuable insights into the effects of different treatments. Researchers and regulators have developed a variety of benefit-risk composite metrics, although the extent to which these methods apply to randomized clinical trials (RCTs) of chronic pain has not been evaluated in the published literature. This article was motivated by an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting and is based on the expert opinion of those who attended. In addition, a review of the benefit-risk assessment tools used in published chronic pain RCTs or highlighted by key professional organizations (ie, Cochrane, European Medicines Agency, Outcome Measures in Rheumatology, and U.S. Food and Drug Administration) was completed. Overall, the review found that benefit-risk metrics are not commonly used in RCTs of chronic pain despite the availability of published methods. A primary recommendation is that composite metrics of benefit-risk should be combined at the level of the individual patient, when possible, in addition to the benefit-risk assessment at the treatment group level. Both levels of analysis (individual and group) can provide valuable insights into the relationship between benefits and risks associated with specific treatments across different patient subpopulations. The systematic assessment of benefit-risk in clinical trials has the potential to enhance the clinical meaningfulness of RCT results., (Copyright © 2021 International Association for the Study of Pain.)

Background: The establishment of test-retest reliability and reproducibility (TRR) is an important part of validating any research tool, including functional magnetic resonance imaging (fMRI). The primary objective of this study is to investigate the reliability of pseudo-Continuous Arterial Spin Labeling (pCASL) and Blood Oxygen Level Dependent (BOLD) fMRI data acquired across two different scanners in a sample of healthy adults. While single site/single scanner studies have shown acceptable repeatability, TRR of both in a practical multisite study occurring in two facilities spread out across the country with weeks to months between scans is critically needed., Methods: Ten subjects were imaged with similar 3 T MRI scanners at the University of Pittsburgh and Massachusetts General Hospital. Finger-tapping and Resting-state data were acquired for both techniques. Analysis of the resting state data for functional connectivity was performed with the Functional Connectivity Toolbox, while analysis of the finger tapping data was accomplished with FSL. pCASL Blood flow data was generated using AST Toolbox. Activated areas and networks were identified via pre-defined atlases and dual-regression techniques. Analysis for TRR was conducted by comparing pCASL and BOLD images in terms of Intraclass correlation coefficients, Dice Similarity Coefficients, and repeated measures ANOVA., Results: Both BOLD and pCASL scans showed strong activation and correlation between the two locations for the finger tapping tasks. Functional connectivity analyses identified elements of the default mode network in all resting scans at both locations. Multivariate repeated measures ANOVA showed significant variability between subjects, but no significant variability for location. Global CBF was very similar between the two scanning locations, and repeated measures ANOVA showed no significant differences between the two scanning locations., Conclusions: The results of this study show that when similar scanner hardware and software is coupled with identical data analysis protocols, consistent and reproducible functional brain images can be acquired across sites. The variability seen in the activation maps is greater for pCASL versus BOLD images, as expected, however groups maps are remarkably similar despite the low number of subjects. This demonstrates that multi-site fMRI studies of task-based and resting state brain activity is feasible., (© 2022. The Author(s).)

Offset analgesia is defined by a dramatic drop in perceived pain intensity with a relatively small decrease in noxious input. Although functional magnetic resonance imaging studies implicate subcortical descending inhibitory circuits during offset analgesia, the role of cortical areas remains unclear. The current study identifies cortical correlates of offset analgesia using functional near infrared spectroscopy (fNIRS). Twenty-four healthy volunteers underwent fNIRS scanning during offset (OS) and control (Con) heat stimuli applied to the forearm. After controlling for non-neural hemodynamic responses in superficial tissues, widespread increases in cortical oxygenated hemoglobin concentration were observed, reflecting cortical activation during heat pain. OS-Con contrasts revealed deactivations in bilateral medial prefrontal cortex (mPFC) and bilateral somatosensory cortex (SSC) associated with offset analgesia. Right dorsolateral prefrontal cortex (dlPFC) showed activation only during OS. These data demonstrate opposing cortical activation patterns during offset analgesia and support a model in which right dlPFC underlies ongoing evaluation of pain intensity change. With predictions of decreasing pain intensity, right dlPFC activation likely inhibits ascending noxious input via subcortical pathways resulting in SSC and mPFC deactivation. This study identifies cortical circuitry underlying offset analgesia and introduces the use of fNIRS to study pain modulation in an outpatient clinical environment.