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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

Nathan Anderson,1 Andrea G Gillman,1 Ajay D Wasan1,2 1Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 2UPMC Pain Medicine, Pittsburgh, PA, USACorrespondence: Ajay D Wasan Tel +1 412 665 8048Fax +1 412 665 8033Email wasanad@upmc.eduPurpose: Xtampza ER® (XER) is a long-acting oxycodone formulation which was designed to be abuse-deterrent and to overcome capsule-swallowing issues. This pilot study evaluated the effectiveness of XER at reducing swallowing difficulty while providing effective analgesia in the setting of chronic pain.Subjects and Methods: Eleven subjects with chronic pain who reported pill-swallowing difficulty were enrolled in a 6-week uncontrolled open-label pilot study in which their prescribed daily opioid medication was converted to XER. Swallowing difficulty, pain intensity, opioid satisfaction, and secondary indicators of pain response were recorded for subjects throughout the study.Results: Both swallowing difficulty and opioid satisfaction (XER vs baseline opioid) improved significantly over the 6-week study period (p < 0.05), while pain intensity ratings demonstrated no significant change. No significant change was noted in any of the secondary pain, mental health, or physical function measures after conversion to XER compared to baseline.Conclusion: Subjects experienced improvement in both swallowing and opioid medication satisfaction after conversion to XER with no significant change in pain intensity and related measures.Keywords: opioid medication, swallowing difficulty, chronic pain, abuse deterrent formulation

Alex M Dressler,1,2,* Andrea G Gillman,1,2,* Ajay D Wasan1,2 1Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 2UPMC Pain Medicine, Pittsburgh, PA, USA *These authors contributed equally to this work Abstract: Chronic pain is a widespread and complex set of conditions that are often difficult and expensive to treat. Comparative effectiveness research (CER) is an evolving research method that is useful in determining which treatments are most effective for medical conditions such as chronic pain. An underutilized mechanism for conducting CER in pain medicine involves combining patient-reported outcomes (PROs) with electronic health records (EHRs). Patient-reported pain and mental and physical health outcomes are increasingly collected during clinic visits, and these data can be linked to EHR data that are relevant to the treatment of a patient’s pain, such as diagnoses, medications ordered, and medical comorbidities. When aggregated, this information forms a data repository that can be used for high-quality CER. This review provides a blueprint for conducting CER using PROs combined with EHRs. As an example, the University of Pittsburgh’s patient outcomes repository for treatment is described. This system includes PROs collected via the Collaborative Health Outcomes Information Registry software and cross-linked data from the University of Pittsburgh Medical Center EHR. The requirements, best practice guidelines, statistical considerations, and caveats for performing CER with this type of data repository are also discussed. Keywords: chronic pain, patient-reported outcomes, comparative effectiveness, computerized adaptive testing, CAT

Hayden E Hundley,1 Mark E Hudson,2,3 Ajay D Wasan,3,4 Trent D Emerick3,4 1Department of Anesthesiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 2Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 3University of Pittsburgh Physicians, Pittsburgh, PA, USA; 4Division of Chronic Pain, Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Objective: The aim of this study is to identify scheduling inefficiencies and to develop a personalized schedule based on diagnosis, service time (face-to-face time between the patient and the provider), and patient wait time using a Gantt diagram in a chronic pain clinic.Design: This is an observational prospective cohort quality improvement (QI) study.Setting: This study was carried out at a single outpatient multidisciplinary pain management clinic in a university teaching hospital.Subjects: New and established chronic pain patients at the University of Pittsburgh Medical Center (UPMC) Montefiore Chronic Pain Clinic were recruited for this study.Methods: Time tracking data for each phase of clinic visit and pain-related diagnoses were collected from 81 patients on 5 clinic days in March 2016 for patient flow analysis.Results: A Gantt diagram was created using Microsoft Excel® software. Areas of overbooking and underbooking were identified. Median service times (minutes) differed dramatically based on the diagnosis and were highest for facial pain (23 [IQR, 15–31]) and chronic abdominal and/or pelvic pain (21.5 [IQR, 16–27]) and lowest for myalgia. Abdominal and/or pelvic pain and facial pain median service times consistently exceeded the 15-minute allocation for return visits.Conclusion: Schedule efficiency analysis using the Gantt diagram identified trends of overbooking and underbooking and inefficiencies in examination room utilization. A 15-minute appointment for all return patients is unrealistic due to variation of service times for some diagnoses. Scheduling appointments based on the diagnosis is an innovative approach that may reduce scheduling inefficiencies and improve patient satisfaction and the overall quality of care. To the best of our knowledge, this type of scheduling diagram has not been used in a chronic pain clinic. Keywords: quality of health care, chronic pain, outcome assessment, pain management, physician performance, referral and consultation, satisfaction, strategic planning

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.

تعد قابلية الإصغاء من المهارات الأساسية لتعلم اللغة الأجنبية. وقد لاحظ الباحثان أن البحوث في هذا المجال قد أثبتت أن مهارة الإصغاء تستخدم كثيراً من قبل الطلبة. لذلك تعد استراتيجيات الإصغاء و القابلية على استخدامها بشكل فعال ضرورية في تعلم اللغة الأجنبية. تبحث هذه الدراسة في الإستراتيجيات التي يستخدمها طلبة قسم اللغة الانكليزية في كلية التربية / جامعة الموصل. تكون مجتمع البحث من طلبة قسم اللغة الانكليزية / السنوات الأربع للعام الدراسي ( 2017/ 2018 ) . و تكونت عينة البحث من 239 طالب و طالبة.تم استخدام استبياناً مكوناً من 30 فقرة ضمت استراتيجيات ما وراء المعرفة, الاستراتيجيات المعرفية , و الاستراتيجيات الاجتماعية. و اظهرت النتائج ان معظم الطلبة لا يزالون غير قادرين على استخدام الإستراتيجية المناسبة لاستيعاب اللغة الأجنبية و هم بحاجة الى توجيه من قبل مدرسيهم.. إن نتائج هذه الدراسة قدمت جهدا متواضعاً للمدرسين و المتعلمين الذين يدرسون التمارين الاستيعابية في حجرة الصف

The troubled life and death of William Thomas Green Morton has been described in several texts. His first public demonstration of ether anesthesia was the highpoint of a life that was less than successful in many of his endeavors. Close examination of this life reveals a pattern of behavior that progresses from narcissistic traits to narcissistic personality pathology. This retrospective psychiatric analysis of Morton's life was undertaken to theorize as to why Morton, after having successfully demonstrated ether anesthesia, did not continue to develop anesthesia as a clinical specialty. Biographies about Morton were used to explore details of his life. The Diagnostic and Statistical Manual of Mental Disorders classification of narcissistic personality disorder was used to analyze his life. We conclude that Morton progressed from displaying narcissistic personality trait to disorder over his lifetime. [ABSTRACT FROM AUTHOR]

Background: The varying nature of chronic pain (CP) is difficult to correlate to neural activity using typical functional magnetic resonance imaging methods. Arterial spin labeling is a perfusion-based imaging technique allowing the absolute quantification of regional cerebral blood flow, which is a surrogate measure of neuronal activity.Methods: Subjects with chronic low back and radicular pain and matched healthy normal subjects, undergoing identical procedures, participated in three sessions: a characterization and training session and two arterial spin labeling sessions. In the first imaging session, CP (if any) was exacerbated using clinical maneuvers; in the second session, noxious heat was applied to the affected leg dermatome, the intensity of which was matched to the pain intensity level of the CP exacerbations for each back pain subject.Results: The clinically significant worsening of ongoing CP (≤ 30%, n = 16) was associated with significant regional blood flow increases (6-10 mm/100 g of tissue/min, P less than 0.01) within brain regions known to activate with experimental pain (somatosensory, prefrontal, and insular cortices) and in other structures observed less frequently in experimental pain studies, such as the superior parietal lobule (part of the dorsal attention network). This effect is specific to changes in ongoing CP as it is observed during worsening CP, but it is not observed after thermal pain application, or in matched, pain-free healthy controls.Conclusions: Study findings demonstrate the use of arterial spin labeling to investigate the neural processing of CP, and these findings are a step forward in the quest for objective biomarkers of the chronic pain experience. [ABSTRACT FROM AUTHOR]

Chronic periodontitis is an inflammatory disease that extends into the tissues supporting the teeth. Recent studies have demonstrated that various human herpes viruses especially human cytomegalovirus (HCMV) may play a part in the pathogenesis of human chronic periodontitis. The aim of this study is to detect HCMV DNA in saliva of chronic periodontitis patients by real time polymerase chain reaction (PCR) test, measure its copy number and find its relation with severity of the disease. The study sample consisted of fifty – three chronic periodontitis patients of both genders (27 males and 26 females) with ages ranged from 25 to 45 years and all the selected patients have not any systemic diseases. Periodontal parameters used in this study were [plaque index (PLI), gingival index (GI), bleeding on probing (BOP), probing pocket depth (PPD) and clinical attachment level (CAL)]. Unstimulated saliva samples were collected from all subjects and examined by real time PCR test for HCMV DNA detection. The results of this study observed that the percentage of study group who were positive for HCMV DNA was (22.6%). The present study observed that there was no relation between PLI and GI with HCMV DNA salivary level. Concerning BOP and PPD there was no relation found between BOP and PPD with HCMV DNA level. For CAL there was a significant relation found between CAL and HCMV DNA level.

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.

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).)

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: 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.)

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.

Background: In clinical practice, the bodily distribution of chronic pain is often used in conjunction with other signs and symptoms to support a diagnosis or treatment plan. For example, the diagnosis of fibromyalgia involves tallying the areas of pain that a patient reports using a drawn body map. It remains unclear whether patterns of pain distribution independently inform aspects of the pain experience and influence patient outcomes. The objective of the current study was to evaluate the clinical relevance of patterns of pain distribution using an algorithmic approach agnostic to diagnosis or patient-reported facets of the pain experience., Methods and Findings: A large cohort of patients (N = 21,658) completed pain body maps and a multi-dimensional pain assessment. Using hierarchical clustering of patients by body map selection alone, nine distinct subgroups emerged with different patterns of body region selection. Clinician review of cluster body maps recapitulated some clinically-relevant patterns of pain distribution, such as low back pain with radiation below the knee and widespread pain, as well as some unique patterns. Demographic and medical characteristics, pain intensity, pain impact, and neuropathic pain quality all varied significantly across cluster subgroups. Multivariate modeling demonstrated that cluster membership independently predicted pain intensity and neuropathic pain quality. In a subset of patients who completed 3-month follow-up questionnaires (N = 7,138), cluster membership independently predicted the likelihood of improvement in pain, physical function, and a positive overall impression of change related to multidisciplinary pain care., Conclusions: This study reports a novel method of grouping patients by pain distribution using an algorithmic approach. Pain distribution subgroup was significantly associated with differences in pain intensity, impact, and clinically relevant outcomes. In the future, algorithmic clustering by pain distribution may be an important facet in chronic pain biosignatures developed for the personalization of pain management., Competing Interests: The authors have declared that no competing interests exist.

Background: Many patients with acute low back pain (LBP) first seek care from primary care physicians. Evidence is lacking for interventions to prevent transition to chronic LBP in this setting. We aimed to test if implementation of a risk-stratified approach to care would result in lower rates of chronic LBP and improved self-reported disability., Methods: We conducted a pragmatic, cluster randomized trial using 77 primary care clinics in four health care systems across the United States. Practices were randomly assigned to a stratified approach to care (intervention) or usual care (control). Using the STarTBack screening tool, adults with acute LBP were screened low, medium, and high-risk. Patients screened as high-risk were eligible. The intervention included electronic best practice alerts triggering referrals for psychologically informed physical therapy (PIPT). PIPT education was targeted to community clinics geographically close to intervention primary care clinics. Primary outcomes were transition to chronic LBP and self-reported disability at six months. Trial Registry: ClinicalTrials.gov NCT02647658., Findings: Between May 2016 and June 2018, 1207 patients from 38 intervention and 1093 from 37 control practices were followed. In the intervention arm, around 50% of patients were referred for physical therapy (36% for PIPT) compared to 30% in the control. At 6 months, 47% of patients reported transition to chronic LBP in the intervention arm (38 practices, n  = 658) versus 51% of patients in the control arm (35 practices, n  = 635; OR=0.83 95% CI 0.64, 1.09; p  = 0.18). No differences in disability were detected (difference -2·1, 95% CI -4.9-0.6; p  = 0.12). Opioids and imaging were prescribed in 22%-25% and 23%-26% of initial visits, for intervention and control, respectively. Twelve-month LBP utilization was similar in the two groups., Interpretation: There were no differences detected in transition to chronic LBP among patients presenting with acute LBP using a stratified approach to care. Opioid and imaging prescribing rates were non-concordant with clinical guidelines., Funding: Patient-Centered Outcomes Research Institute (PCORI) contract # PCS-1402-10867., Competing Interests: Dr. Delitto reports grants from PCORI, grants from NIH, grants from DOD, outside the submitted work; Dr. Patterson reports grants from Patient Centered Outcomes Research Institute, during the conduct of the study; Dr. Stevans reports grants from PCORI, during the conduct of the study; Dr. Khoja reports grants from PCORI, during the conduct of the study; Dr. Freel has nothing to disclose; Dr. Schneider reports grants from Patient Centered Outcomes Research Institute, during the conduct of the study; Dr. Greco reports grants from Patient-Centered Outcomes Research Institute, during the conduct of the study; Dr. Sowa reports grants from PCORI, during the conduct of the study; grants from NIH, USAMRMC, VA, The Pittsburgh Foundation, outside the submitted work; Dr. Brennan reports other institutional support from Patient Centered Outcomes Research Institute (PCORI), during the conduct of the study; other institutional support from Patient Centered Outcomes Research Institute (PCORI), outside the submitted work; Stephen J. Hunter has nothing to disclose; Dr. Minick has nothing to disclose; Dr. Wasan has nothing to disclose; Dr. Wegener reports grants from PCORI, during the conduct of the study; Ms. Ephraim has nothing to disclose; Dr. Freburger reports other from American Physical Therapy Association, outside the submitted work; Dr. Beneciuk reports grants from Patient-Centered Outcomes Research Institute, during the conduct of the study; Dr. George reports personal fees from Rehab Essentials, Inc, personal fees from Med Risk, LLC, grants from NIH, other from Duke University, all outside the submitted work; Dr. Saper has nothing to disclose., (© 2021 The Authors.)

Importance: Acute low back pain (LBP) is highly prevalent, with a presumed favorable prognosis; however, once chronic, LBP becomes a disabling and expensive condition. Acute to chronic LBP transition rates vary widely owing to absence of standardized operational definitions, and it is unknown whether a standardized prognostic tool (ie, Subgroups for Targeted Treatment Back tool [SBT]) can estimate this transition or whether early non-guideline concordant treatment is associated with the transition to chronic LBP., Objective: To assess the associations between the transition from acute to chronic LBP with SBT risk strata; demographic, clinical, and practice characteristics; and guideline nonconcordant processes of care., Design, Setting, and Participants: This inception cohort study was conducted alongside a multisite, pragmatic cluster randomized trial. Adult patients with acute LBP stratified by SBT risk were enrolled in 77 primary care practices in 4 regions across the United States between May 2016 and June 2018 and followed up for 6 months, with final follow-up completed by March 2019. Data analysis was conducted from January to March 2020., Exposures: SBT risk strata and early LBP guideline nonconcordant processes of care (eg, receipt of opioids, imaging, and subspecialty referral)., Main Outcomes and Measures: Transition from acute to chronic LBP at 6 months using the National Institutes of Health Task Force on Research Standards consensus definition of chronic LBP. Patient demographic characteristics, clinical factors, and LBP process of care were obtained via electronic medical records., Results: Overall, 5233 patients with acute LBP (3029 [58%] women; 4353 [83%] White individuals; mean [SD] age 50.6 [16.9] years; 1788 [34%] low risk; 2152 [41%] medium risk; and 1293 [25%] high risk) were included. Overall transition rate to chronic LBP at six months was 32% (1666 patients). In a multivariable model, SBT risk stratum was positively associated with transition to chronic LBP (eg, high-risk vs low-risk groups: adjusted odds ratio [aOR], 2.45; 95% CI, 2.00-2.98; P < .001). Patient and clinical characteristics associated with transition to chronic LBP included obesity (aOR, 1.52; 95% CI, 1.28-1.80; P < .001); smoking (aOR, 1.56; 95% CI, 1.29-1.89; P < .001); severe and very severe baseline disability (aOR, 1.82; 95% CI, 1.48-2.24; P < .001 and aOR, 2.08; 95% CI, 1.60-2.68; P < .001, respectively) and diagnosed depression/anxiety (aOR, 1.66; 95% CI, 1.28-2.15; P < .001). After controlling for all other variables, patients exposed to 1, 2, or 3 nonconcordant processes of care within the first 21 days were 1.39 (95% CI, 1.21-2.32), 1.88 (95% CI, 1.53-2.32), and 2.16 (95% CI, 1.10-4.25) times more likely to develop chronic LBP compared with those with no exposure (P < .001)., Conclusions and Relevance: In this cohort study, the transition rate to chronic LBP was substantial and increased correspondingly with SBT stratum and early exposure to guideline nonconcordant care.

The estimated probability of progressing from phase 3 analgesic clinical trials to regulatory approval is approximately 57%, suggesting that a considerable number of treatments with phase 2 trial results deemed sufficiently successful to progress to phase 3 do not yield positive phase 3 results. Deficiencies in the quality of clinical trial conduct could account for some of this failure. An Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting was convened to identify potential areas for improvement in trial conduct in order to improve assay sensitivity (ie, ability of trials to detect a true treatment effect). We present recommendations based on presentations and discussions at the meeting, literature reviews, and iterative revisions of this article. The recommendations relate to the following areas: 1) study design (ie, to promote feasibility), 2) site selection and staff training, 3) participant selection and training, 4) treatment adherence, 5) data collection, and 6) data and study monitoring. Implementation of these recommendations may improve the quality of clinical trial data and thus the validity and assay sensitivity of clinical trials. Future research regarding the effects of these strategies will help identify the most efficient use of resources for conducting high quality clinical trials. PERSPECTIVE: Every effort should be made to optimize the quality of clinical trial data. This manuscript discusses considerations to improve conduct of pain clinical trials based on research in multiple medical fields and the expert consensus of pain researchers and stakeholders from academia, regulatory agencies, and industry., (Copyright © 2020. Published by Elsevier Inc.)

Chronic low back pain (cLBP) is a prevalent disorder. A growing body of evidence linking the pathology of the reward network to chronic pain suggests that pain sensitization may contribute to cLBP chronification via disruptions of mesocortical and mesolimbic circuits in the reward system. Resting-state (RS) functional magnetic resonance imaging (fMRI) data was acquired from 90 patients with cLBP and 74 matched pain-free controls (HCs) at baseline and after a manipulation for back pain intensification. The ventral tegmental area (VTA) was chosen as a seed region to perform RS functional connectivity (FC) analysis. Baseline rsFC of both the mesocortical (between the VTA and bilateral rostral anterior cingulate cortex (rACC)/and medial prefrontal cortex (mPFC)) and mesolimbic (between the VTA and bilateral hippocampus/parahippocampus) pathways was reduced in patients with cLBP (vs. HCs). In addition, patients exhibiting higher back pain intensity (compared to the relatively lower back pain intensity condition) also showed increases in both mesocortical and mesolimbic connectivity, implicating these pathways in pain downregulation in cLBP. Mediation analysis further isolated the mesolimbic (VTA-hippocampus/parahippocampus) dysconnectivity as a neural mechanism mediating the association between mechanical pain sensitivity (indexed by P40 pressure) and cLBP severity. In sum, the current study demonstrates deficient mesocorticolimbic connectivity in cLBP, with mesolimbic dysconnectivity potentially mediating the contribution of pain sensitization to pain chronification. These reward network dysfunctions and purportedly, dopaminergic dysregulations, may help us to identify key brain targets of neuromodulation in the treatment of cLBP., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Prior studies have shown that patients suffering from chronic Low Back Pain (cLBP) have impaired somatosensory processing including reduced tactile acuity, i.e. reduced ability to resolve fine spatial details with the perception of touch. The central mechanism(s) underlying reduced tactile acuity are unknown but may include changes in specific brain circuitries (e.g. neuroplasticity in the primary somatosensory cortex, S1). Furthermore, little is known about the linkage between changes in tactile acuity and the amelioration of cLBP by somatically-directed therapeutic interventions, such as acupuncture. In this longitudinal neuroimaging study, we evaluated healthy control adults (HC, N ​= ​50) and a large sample of cLBP patients (N ​= ​102) with structural brain imaging (T1-weighted MRI for Voxel-Based Morphometry, VBM; Diffusion Tensor Imaging, DTI) and tactile acuity testing using two-point discrimination threshold (2PDT) over the lower back (site of pain) and finger (control) locations. Patients were evaluated at baseline and following a 4-week course of acupuncture, with patients randomized to either verum acupuncture, two different forms of sham acupuncture (designed with or without somatosensory afference), or no-intervention usual care control. At baseline, cLBP patients demonstrated reduced acuity (greater 2PDT, P ​= ​0.01) over the low back, but not finger (P ​= ​0.29) locations compared to HC, suggesting that chronic pain affects tactile acuity specifically at body regions encoding the experience of clinical pain. At baseline, Gray Matter Volume (GMV) was elevated and Fractional Anisotropy (FA) was reduced, respectively, in the S1-back region of cLBP patients compared to controls (P ​< ​0.05). GMV in cLBP correlated with greater 2PDT-back scores (ρ ​= ​0.27, P ​= ​0.02). Following verum acupuncture, tactile acuity over the back was improved (reduced 2PDT) and greater improvements were associated with reduced S1-back GMV (ρ ​= ​0.52, P ​= ​0.03) and increased S1-back adjacent white matter FA (ρ ​= ​-0.56, P ​= ​0.01). These associations were not seen for non-verum control interventions. Thus, S1 neuroplasticity in cLBP is linked with deficits in tactile acuity and, following acupuncture therapy, may represent early mechanistic changes in somatosensory processing that track with improved tactile acuity., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

In health and disease, the somatosensory system has been interrogated with standardized research techniques, collectively referred to as quantitative sensory testing (QST). In neuropathic pain, QST has been used to characterize multiple sensory derangements. However, the use of QST outside the lab has been limited by several factors, including a lack of standardization, variability in procedural technique, and duration of testing that would be unacceptable for clinic. To address these shortcomings, the Neuropathic Pain Research Consortium designed an easy and low-cost "bedside" QST procedure. To test the hypothesis that this procedure would be clinically reliable over time and across different examiners, a multisite, blinded study was performed in subjects with postherpetic neuralgia. Generally, agreement between 2 examiners and over 2 study visits with 1 examiner was high. Additionally, intraclass correlation coefficients and Kappa statistics calculated showed that the battery of QST tests included were highly reliable. Interestingly, mechanical modalities (light brush, pinprick, pressure, and vibration) showed the highest reliability. The least reliable modalities were cool (room temperature) and warmth (38°C). These data demonstrate that the Neuropathic Pain Research Consortium beside QST protocol is reliable across examiner and over time, providing a validated QST tool for use in clinical practice and clinical trials. PERSPECTIVE: This blinded, multicenter trial in 32 patients with postherpetic neuralgia demonstrates bedside QST is reliable and suitable as a clinical trial outcome. The novel bedside battery could be used in clinical trials or in clinical practice over time given the reliability data presented in this article., (Copyright © 2019 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Pain medication plays an important role in the treatment of acute and chronic pain conditions, but some drugs, opioids in particular, have been overprescribed or prescribed without adequate safeguards, leading to an alarming rise in medication-related overdose deaths. The NIH Helping to End Addiction Long-term (HEAL) Initiative is a trans-agency effort to provide scientific solutions to stem the opioid crisis. One component of the initiative is to support biomarker discovery and rigorous validation in collaboration with industry leaders to accelerate high-quality clinical research into neurotherapeutics and pain. The use of objective biomarkers and clinical trial end points throughout the drug discovery and development process is crucial to help define pathophysiological subsets of pain, evaluate target engagement of new drugs and predict the analgesic efficacy of new drugs. In 2018, the NIH-led Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened scientific leaders from academia, industry, government and patient advocacy groups to discuss progress, challenges, gaps and ideas to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement.

Chronic low back pain (cLBP) is a common disorder with unsatisfactory treatment options. Acupuncture has emerged as a promising method for treating cLBP. However, the mechanism underlying acupuncture remains unclear. In this study, we investigated the modulation effects of acupuncture on resting state functional connectivity (rsFC) of the periaqueductal gray (PAG) and ventral tegmental area (VTA) in patients with cLBP. Seventy-nine cLBP patients were recruited and assigned to four weeks of real or sham acupuncture. Resting state functional magnetic resonance imaging data were collected before the first and after the last treatment. Fifty patients completed the study. We found remission of pain bothersomeness in all treatment groups after four weeks, with greater pain relief after real acupuncture compared to sham acupuncture. We also found that real acupuncture can increase VTA/PAG rsFC with the amygdala, and the increased rsFC was associated with decreased pain bothersomeness scores. Baseline PAG-amygdala rsFC could predict four-week treatment response. Our results suggest that acupuncture may simultaneously modulate the rsFC of key regions in the descending pain modulation (PAG) and reward systems (VTA), and the amygdala may be a key node linking the two systems to produce antinociceptive effects. Our findings highlight the potential of acupuncture for chronic low back pain management.

Background: Data linking labor pain and postpartum depression are emerging. Robust, prospective evaluations of this relationship while factoring other important variables are lacking. We assessed perinatal pain and other factors predicting postpartum depression (PPD) symptoms., Methods: Third trimester women, stratified by a priori plan to receive or avoid labor epidural analgesia, were longitudinally followed from the prenatal period through labor and delivery, until 6 weeks and 3 months postpartum. Electronic pain data was collected hourly during labor in real time, capturing pain unpleasantness, intensity, pain management satisfaction, and expectations. Prenatal and postpartum data included anxiety, depression, the Brief Pain Inventory (BPI), pain catastrophizing, resiliency, and perceived social support and stress. The primary outcome was Edinburgh Postnatal Depression Score (EPDS) as a marker of PPD symptoms. The primary pain variable of interest was labor pain emotional valence (unpleasantness burden, area under the curve for entire labor duration). Single and multivariable linear regressions examined perinatal pain variables in relation to EPDS., Results: Of 72 subjects included, 55 planned/received labor epidural analgesia and 17 planned avoidance/avoided it. In the planned epidural group, the emotional valence of labor pain independently predicted six-week EPDS (labor pain unpleasantness burden, R 2  = 0.42, P = 0.002). In addition to labor pain, prenatal and postpartum pain variables from the BPI independently predicted six-week EPDS. Three-month depression scores were linked to labor and acute pain (6 weeks postpartum), but not to chronic (3 months postpartum) pain variables. Intrapartum pain management satisfaction and expectations were largely met or exceeded and did not differ between analgesia groups., Conclusion: For susceptible women, pain at all perinatal time points-prenatal, labor, and postpartum-appear to be independently linked to depression scores at 6 weeks postpartum. The relationships are true, even though satisfaction and expectations regarding labor pain management were met or exceeded. These data support the concept that labor and acute postpartum pain influences both acute and long-term PPD symptoms, although additional data are needed to assess how analgesia preference interacts with these relationships.

Chronic low back pain (cLBP) is associated with widespread functional and structural changes in the brain. This study aims to investigate the resting state functional connectivity (rsFC) changes of visual networks in cLBP patients and the feasibility of distinguishing cLBP patients from healthy controls using machine learning methods. cLBP (n = 90) and control individuals (n = 74) were enrolled and underwent resting-state BOLD fMRI scans. Primary, dorsal, and ventral visual networks derived from independent component analysis were used as regions of interest to compare resting state functional connectivity changes between the cLBP patients and healthy controls. We then applied a support vector machine classifier to distinguish the cLBP patients and control individuals. These results were further verified in a new cohort of subjects. We found that the functional connectivity between the primary visual network and the somatosensory/motor areas were significantly enhanced in cLBP patients. The rsFC between the primary visual network and S1 was negatively associated with duration of cLBP. In addition, we found that the rsFC of the visual network could achieve a classification accuracy of 79.3% in distinguishing cLBP patients from HCs, and these results were further validated in an independent cohort of subjects (accuracy = 66.7%). Our results demonstrate significant changes in the rsFC of the visual networks in cLBP patients. We speculate these alterations may represent an adaptation/self-adjustment mechanism and cross-model interaction between the visual, somatosensory, motor, attention, and salient networks in response to cLBP. Elucidating the role of the visual networks in cLBP may shed light on the pathophysiology and development of the disorder., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Despite the high prevalence and socioeconomic impact of chronic low back pain (cLBP), treatments for cLBP are often unsatisfactory, and effectiveness varies widely across patients. Recent neuroimaging studies have demonstrated abnormal resting-state functional connectivity (rsFC) of the default mode, salience, central executive, and sensorimotor networks in chronic pain patients, but their role as predictors of treatment responsiveness has not yet been explored. In this study, we used machine learning approaches to test if pre-treatment rsFC can predict responses to both real and sham acupuncture treatments in cLBP patients. Fifty cLBP patients participated in 4 weeks of either real (N = 24, age = 39.0 ± 12.6, 16 females) or sham acupuncture (N = 26, age = 40.0 ± 13.7, 15 females) treatment in a single-blinded trial, and a resting-state fMRI scan prior to treatment was used in data analysis. Both real and sham acupuncture can produce significant pain reduction, with those receiving real treatment experiencing greater pain relief than those receiving sham treatment. We found that pre-treatment rsFC could predict symptom changes with up to 34% and 29% variances for real and sham treatment, respectively, and the rsFC characteristics that were significantly predictive for real and sham treatment differed. These results suggest a potential way to predict treatment responses and may facilitate the development of treatment plans that optimize time, cost, and available resources., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Pain catastrophizing is a common feature of chronic pain, including fibromyalgia (FM), and is strongly associated with amplified pain severity and disability. While previous neuroimaging studies have focused on evoked pain response modulation by catastrophizing, the brain mechanisms supporting pain catastrophizing itself are unknown. We designed a functional magnetic resonance imaging (fMRI)-based pain catastrophizing task whereby patients with chronic pain engaged in catastrophizing-related cognitions. We undertook this study to test our hypothesis that catastrophizing about clinical pain would be associated with amplified activation in nodes of the default mode network (DMN), which encode self-referential cognition and show altered functioning in chronic pain., Methods: During fMRI, 31 FM patients reflected on how catastrophizing (CAT) statements (drawn from the Pain Catastrophizing Scale) impact their typical FM pain experience. Response to CAT statements was compared to response to matched neutral (NEU) statements., Results: During statement reflection, higher fMRI signal during CAT statements than during NEU statements was found in several DMN brain areas, including the ventral (posterior) and dorsal (anterior) posterior cingulate cortex (vPCC and dPCC, respectively). Patients' ratings of CAT statement applicability were correlated solely with activity in the vPCC, a main DMN hub supporting self-referential cognition (r = 0.38, P < 0.05). Clinical pain severity was correlated solely with activity in the dPCC, a PCC subregion associated with cognitive control and sensorimotor processing (r = 0.38, P < 0.05)., Conclusion: These findings provide evidence that the PCC encodes pain catastrophizing in FM and suggest distinct roles for different PCC subregions. Understanding the brain circuitry encoding pain catastrophizing in FM will prove to be important in identifying and evaluating the success of interventions targeting negative affect in chronic pain management., (© 2018, American College of Rheumatology.)

Placebo treatments and healing rituals share much in common, such as the effects of expectancy, and have been used since the beginning of human history to treat pain. Previous mechanistic neuroimaging studies investigating the effects of expectancy on placebo analgesia have used young, healthy volunteers. Using functional magnetic resonance imaging (fMRI), we aimed to investigate the neural mechanisms by which expectancy evokes analgesia in older adults living with a chronic pain disorder and determine whether there are interactions with active treatment. In this fMRI study, we investigated the brain networks underlying expectancy in participants with chronic pain due to knee osteoarthritis (OA) after verum (genuine) and sham electroacupuncture treatment before and after experiencing calibrated experimental heat pain using a well tested expectancy manipulation model. We found that expectancy significantly and similarly modulates the pain experience in knee OA patients in both verum (n = 21, 11 female; mean ± SD age 57 ± 7 years) and sham (n = 22, 15 female; mean ± SD age 59 ± 7 years) acupuncture treatment groups. However, there were different patterns of changes in fMRI indices of brain activity associated with verum and sham treatment modalities specifically in the lateral prefrontal cortex. We also found that continuous electroacupuncture in knee OA patients can evoke significant regional coherence decreases in pain associated brain regions. Our results suggest that expectancy modulates the experience of pain in knee OA patients but may work through different pathways depending on the treatment modality and, we speculate, on pathophysiological states of the participants., Perspective: To investigate the neural mechanisms underlying pain modulation, we used an expectancy manipulation model and fMRI to study response to heat pain stimuli before and after verum or sham acupuncture treatment in chronic pain patients. Both relieve pain and each is each associated with a distinct pattern of brain activation., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Using labor, epidural analgesia has been linked to a reduced risk of postpartum depression, but the role of labor pain relief in this association remains unclear. The goal of this study was to test the hypothesis that effective epidural analgesia during labor is associated with reduced postpartum depression symptomatology., Methods: A single, institutional, retrospective, observational cohort design was chosen. The primary outcome was Edinburgh postnatal depression scale (EPDS) score, measured at the 6-week postpartum visit. Subjects included in the final analysis had (1) received labor epidural analgesia; (2) pain assessed during labor both before and during initiation of labor epidural analgesia by 0-10 numeric rating scores; and (3) depression risk assessed by the EPDS and documented at their 6-week postpartum visit. Simple and multiple linear regression was used to identify the best model for assessing the association between pain improvement, defined as percent improvement in pain (PIP), and depression, after adjusting for a history of anxiety or depression, other psychiatric history, abuse, trauma, mode of delivery, and other maternal or fetal comorbid diseases., Results: Two hundred one patients were included in the final analysis. Women with higher improvements in pain were associated with lower EPDS scores (r = 0.025; P = .002). Variables known to be associated with depression (body mass index, anxiety and/or depression, third- and fourth-degree perineal lacerations, and anemia) were significantly correlated with EPDS score and included in the final model. After we adjusted for these covariates, PIP remained a significant predictor of EPDS score (r = 0.49; P = .008), accounting for 6.6% of the variability in postpartum depression scores. The full model including pain, body mass index, anxiety and/or depression, perineal lacerations, and anemia explained 24% of the variability in postpartum depression scores., Conclusions: Although the extent of labor pain relief by epidural analgesia predicts lower postpartum depression scores, the relative contribution of PIP to risk for postpartum depression symptoms may be less than other established risk factors for depression. These data support that the clinical significance of labor analgesia in the development of postpartum depression needs to be more clearly defined.

Objectives: Expectation can significantly modulate pain and treatment effects. This study aims to investigate if boosting patients' expectancy can enhance the treatment of knee osteoarthritis (KOA), and its underlying brain mechanism., Methods: Seventy-four KOA patients were recruited and randomized to three groups: boosted acupuncture (with a manipulation to enhance expectation), standard acupuncture, or treatment as usual (TAU). Each patient underwent six treatments before being debriefed, and four additional treatments after being debriefed. The fMRI scans were applied during the first and sixth treatment sessions., Results: We found significantly decreased knee pain in the boosted acupuncture group compared to the standard acupuncture or TAU groups after both six and ten treatments. Resting state functional connectivity (rsFC) analyses using the nucleus accumbens (NAc) as the seed showed rsFC increases between the NAc and the medial prefrontal cortex (MPFC)/rostral anterior cingulate cortex (rACC) and dorsolateral prefrontal cortex in the boosted group as compared to the standard acupuncture group after multiple treatments. Expectancy scores after the first treatment were significantly associated with increased NAc-rACC/MPFC rsFC and decreased knee pain following treatment., Conclusions: Our study provides a novel method and mechanism for boosting the treatment of pain in patients with KOA. Our findings may shed light on enhancing outcomes of pharmacological and integrative medicines in clinical settings.

An urgent need exists to better understand the transition from short-term opioid use to unintended prolonged opioid use (UPOU). The purpose of this work is to propose a conceptual framework for understanding UPOU that posits the influence of 3 principal domains that include the characteristics of (1) individual patients, (2) the practice environment, and (3) opioid prescribers. Although no standardized method exists for developing a conceptual framework, the process often involves identifying corroborative evidence, leveraging expert opinion to identify factors for inclusion in the framework, and developing a graphic depiction of the relationships between the various factors and the clinical problem of interest. Key patient characteristics potentially associated with UPOU include (1) medical and mental health conditions; (2) pain etiology; (3) individual affective, behavioral, and neurophysiologic reactions to pain and opioids; and (4) sociodemographic factors. Also, UPOU could be influenced by structural and health care policy factors: (1) the practice environment, including the roles of prescribing clinicians, adoption of relevant practice guidelines, and clinician incentives or disincentives, and (2) the regulatory environment. Finally, characteristics inherent to clinicians that could influence prescribing practices include (1) training in pain management and opioid use; (2) personal attitudes, knowledge, and beliefs regarding the risks and benefits of opioids; and (3) professionalism. As the gatekeeper to opioid access, the behavior of prescribing clinicians directly mediates UPOU, with the 3 domains interacting to determine this behavior. This proposed conceptual framework could guide future research on the topic and allow plausible hypothesis-based interventions to reduce UPOU., (Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Accurate assessment of inappropriate medication use events (ie, misuse, abuse, and related events) occurring in clinical trials is an important component in evaluating a medication's abuse potential. A meeting was convened to review all instruments measuring such events in clinical trials according to previously published standardized terminology and definitions. Only 2 approaches have been reported that are specifically designed to identify and classify misuse, abuse, and related events occurring in clinical trials, rather than to measure an individual's risk of using a medication inappropriately: the Self-Reported Misuse, Abuse, and Diversion (SR-MAD) instrument and the Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS). The conceptual basis, strengths, and limitations of these methods are discussed. To our knowledge, MADDERS is the only system available to comprehensively evaluate inappropriate medication use events prospectively to determine the underlying intent. MADDERS can also be applied retrospectively to completed trial data. SR-MAD can be used prospectively; additional development may be required to standardize its implementation and fully appraise the intent of inappropriate use events. Additional research is needed to further demonstrate the validity and utility of MADDERS as well as SR-MAD., Perspective: Identifying a medication's abuse potential requires assessing inappropriate medication use events in clinical trials on the basis of a standardized event classification system. The strengths and limitations of the 2 published methods designed to evaluate inappropriate medication use events are reviewed, with recommended considerations for further development and current implementation., (Copyright © 2017 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Valid and reliable biomarkers can play an important role in clinical trials as indicators of biological or pathogenic processes or as a signal of treatment response. Currently, there are no biomarkers for pain qualified by the U.S. Food and Drug Administration or the European Medicines Agency for use in clinical trials. This article summarizes an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting in which 3 potential biomarkers were discussed for use in the development of analgesic treatments: 1) sensory testing, 2) skin punch biopsy, and 3) brain imaging. The empirical evidence supporting the use of these tests is described within the context of the 4 categories of biomarkers: 1) diagnostic, 2) prognostic, 3) predictive, and 4) pharmacodynamic. Although sensory testing, skin punch biopsy, and brain imaging are promising tools for pain in clinical trials, additional evidence is needed to further support and standardize these tests for use as biomarkers in pain clinical trials., Perspective: The applicability of sensory testing, skin biopsy, and brain imaging as diagnostic, prognostic, predictive, and pharmacodynamic biomarkers for use in analgesic treatment trials is considered. Evidence in support of their use and outlining problems is presented, as well as a call for further standardization and demonstrations of validity and reliability., (Copyright © 2017 American Pain Society. All rights reserved.)

Unlabelled: The recently proposed Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION)-American Pain Society (APS) Pain Taxonomy (AAPT) provides an evidence-based, multidimensional, chronic pain classification system. Psychosocial factors play a crucial role within several dimensions of the taxonomy. In this article, we discuss the evaluation of psychosocial factors that influence the diagnosis and trajectory of chronic pain disorders. We review studies in individuals with a variety of persistent pain conditions, and describe evidence that psychosocial variables play key roles in conferring risk for the development of pain, in shaping long-term pain-related adjustment, and in modulating pain treatment outcomes. We consider "general" psychosocial variables such as negative affect, childhood trauma, and social support, as well as "pain-specific" psychosocial variables that include pain-related catastrophizing, self-efficacy for managing pain, and pain-related coping. Collectively, the complexity and profound variability in chronic pain highlights the need to better understand the multidimensional array of interacting forces that determine the trajectory of chronic pain conditions., Perspective: The AAPT is an evidence-based chronic pain classification system in which psychosocial concepts and processes are essential in understanding the development of chronic pain and its effects. In this article we review psychosocial processes that influence the onset, exacerbation, and maintenance of chronic pain disorders., (Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Background: Patients with painful knee osteoarthritis (OA) demonstrate hyperalgesia and altered pain-modulatory responses. While some prior work has demonstrated cross-sectional associations between laboratory and clinical pain measures, it is unknown whether individual variability in quantitative sensory testing (QST) responses at baseline can prospectively predict analgesic treatment responses., Method: Patients with knee OA (n = 35) were compared on QST responses to a demographically-matched pain-free control group (n = 39), after which patients completed a month-long treatment study of diclofenac sodium topical gel (1 %), applied up to 4 times daily., Results: OA patients demonstrated reduced pain thresholds at multiple anatomic sites, as well as reduced conditioned pain modulation (CPM) and enhanced temporal summation of pain. The most pain-sensitive patients tended to report the most intense and neuropathic OA pain. Following diclofenac treatment, the knee OA cohort showed a roughly 30 % improvement in pain, regardless of the presence or absence of neuropathic symptoms. Baseline CPM scores, an index of endogenous pain-inhibitory capacity, were prospectively associated with treatment-related changes in clinical pain. Specifically, participants with higher CPM at baseline (i.e., better functioning endogenous pain-inhibitory systems) showed more reduction in pain at the end of treatment (p < .05)., Conclusions: These results support prior findings of amplified pain sensitivity and reduced pain-inhibition in OA patients. Moreover, the moderate to strong associations between laboratory-based measures of pain sensitivity and indices of clinical pain highlight the clinical relevance of QST in this sample. Finally, the prospective association between CPM and diclofenac response suggests that QST-based phenotyping may have utility in explaining inter-patient variability in long-term analgesic treatment outcomes., Trial Registration: ClinicalTrials.Gov Identifier: NCT01383954 . Registered June 22, 2011.

Unlabelled: Recent advances in brain imaging have contributed to our understanding of the neural activity associated with acupuncture treatment. In this study, we investigated functional connectivity across longitudinal acupuncture treatments in older patients with knee osteoarthritis (OA). Over a period of 4 weeks (six treatments), we collected resting state functional magnetic resonance imaging (fMRI) scans from 30 patients before and after their first, third and sixth treatments. Clinical outcome showed a significantly greater pain subscore on the Knee Injury and Osteoarthritis Outcome Score (KOOS) (indicative of improvement) with verum acupuncture than with sham acupuncture. Independent component analysis (ICA) of the resting state fMRI data showed that the right frontoparietal network (rFPN) and the executive control network (ECN) showed enhanced functional connectivity (FC) with the rostral anterior cingulate cortex/medial prefrontal cortex, a key region in the descending pain modulatory system, in the verum groups as compared to the sham group after treatments. We also found that the rFPN connectivity with the left insula is (1) significantly associated with changes in KOOS pain score after treatments, and (2) significantly enhanced after verum acupuncture treatments as compared to sham treatment. Analysis of the acupuncture needle stimulation scan showed that compared with sham treatment, verum acupuncture activated the left operculum/insula, which also overlaps with findings observed in resting state analysis. Our results suggest that acupuncture may achieve its therapeutic effect on knee OA pain by modulating functional connectivity between the rFPN, ECN and the descending pain modulatory pathway., Clinical Trial Number: NCT01079390.

Background: Opioids are frequently prescribed for chronic low back pain (CLBP), but there are little prospective data on which patient subgroups may benefit. Psychiatric comorbidity, such as high levels of depression and anxiety symptoms (termed comorbid negative affect [NA]), is a common presentation and may predict diminished opioid analgesia and/or increased opioid misuse., Methods: The authors conducted a 6½-month prospective cohort study of oral opioid therapy, with an active drug/placebo run-in period, in 81 CLBP patients with low, moderate, and high levels of NA. Treatment included an opioid titration phase with a prescribing physician blinded to NA group assignment and a 4-month continuation phase, during which subjects recorded daily pain levels using an electronic diary. The primary outcome was the percent improvement in average daily pain, summarized weekly., Results: There was an overall 25% dropout rate. Despite the high NA group being prescribed a higher average daily dose of morphine equivalents, linear mixed model analysis revealed that the 24 study completers in each of the high NA and low NA groups had an average 21 versus 39% improvement in pain, respectively (P < 0.01). The high NA group also had a significantly greater rate of opioid misuse (39 vs. 8%, P < 0.05) and significantly more and intense opioid side effects (P < 0.01)., Conclusions: These results indicate that the benefit and risk considerations in CLBP patients with high NA versus low NA are distinctly different. Thus, NA is an important phenotypic variable to characterize at baseline, before deciding whether to prescribe opioids for CLBP.

Unlabelled: Although high levels of negative affect and cognitions have been associated with greater pain sensitivity in chronic pain conditions, the neural mechanisms mediating the hyperalgesic effect of psychological factors in patients with pain disorders are largely unknown. In this cross-sectional study, we hypothesized that 1) catastrophizing modulates brain responses to pain anticipation and 2) anticipatory brain activity mediates the hyperalgesic effect of different levels of catastrophizing in fibromyalgia (FM) patients. Using functional magnetic resonance imaging, we scanned the brains of 31 FM patients exposed to visual cues anticipating the onset of moderately intense deep-tissue pain stimuli. Our results indicated the existence of a negative association between catastrophizing and pain-anticipatory brain activity, including in the right lateral prefrontal cortex. A bootstrapped mediation analysis revealed that pain-anticipatory activity in the lateral prefrontal cortex mediates the association between catastrophizing and pain sensitivity. These findings highlight the role of the lateral prefrontal cortex in the pathophysiology of FM-related hyperalgesia and suggest that deficits in the recruitment of pain-inhibitory brain circuitry during pain-anticipatory periods may play an important contributory role in the association between various degrees of widespread hyperalgesia in FM and levels of catastrophizing, a well-validated measure of negative cognitions and psychological distress., Perspective: This article highlights the presence of alterations in pain-anticipatory brain activity in FM. These findings provide the rationale for the development of psychological or neurofeedback-based techniques aimed at modifying patients' negative affect and cognitions toward pain., (Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Objective: Fibromyalgia (FM) is a chronic functional pain syndrome characterized by widespread pain, significant pain catastrophizing, sympathovagal dysfunction, and amplified temporal summation for evoked pain. While several studies have demonstrated altered resting brain connectivity in FM, studies have not specifically probed the somatosensory system and its role in both somatic and nonsomatic FM symptoms. Our objective was to evaluate resting primary somatosensory cortex (S1) connectivity and to explore how sustained, evoked deep tissue pain modulates this connectivity., Methods: We acquired functional magnetic resonance imaging and electrocardiography data on FM patients and healthy controls during rest (the rest phase) and during sustained mechanical pressure-induced pain over the lower leg (the pain phase). Functional connectivity associated with different S1 subregions was calculated, while S1(leg) connectivity (representation of the leg in the primary somatosensory cortex) was contrasted between the rest phase and the pain phase and was correlated with clinically relevant measures in FM., Results: During the rest phase, FM patients showed decreased connectivity between multiple ipsilateral and cross-hemispheric S1 subregions, which was correlated with clinical pain severity. Compared to the rest phase, the pain phase produced increased S1(leg) connectivity to the bilateral anterior insula in FM patients, but not in healthy controls. Moreover, in FM patients, sustained pain-altered S1(leg) connectivity to the anterior insula was correlated with clinical/behavioral pain measures and autonomic responses., Conclusion: Our study demonstrates that both somatic and nonsomatic dysfunction in FM, including clinical pain, pain catastrophizing, autonomic dysfunction, and amplified temporal summation, are closely linked with the degree to which evoked deep tissue pain alters S1 connectivity to salience/affective pain-processing regions. Additionally, diminished connectivity between S1 subregions during the rest phase in FM may result from ongoing widespread clinical pain., (© 2015 American College of Rheumatology.)