Mindfulness-Based Stress Reduction, Cognitive Behavioral Therapy, and Acupuncture in Chronic Low Back Pain: Protocol for Two Linked Randomized Controlled Trials.

BACKGROUND: Nonpharmacologic mind-body therapies have demonstrated efficacy in low back pain. However, the mechanisms underlying these therapies remain to be fully elucidated. OBJECTIVE: In response to these knowledge gaps, the Stanford Center for Low Back Pain-a collaborative, National Institutes of Health P01-funded, multidisciplinary research center-was established to investigate the common and distinct biobehavioral mechanisms of three mind-body therapies for chronic low back pain: cognitive behavioral therapy (CBT) that is used to treat pain, mindfulness-based stress reduction (MBSR), and electroacupuncture. Here, we describe the design and implementation of the center structure and the associated randomized controlled trials for characterizing the mechanisms of chronic low back pain treatments. METHODS: The multidisciplinary center is running two randomized controlled trials that share common resources for recruitment, enrollment, study execution, and data acquisition. We expect to recruit over 300 chronic low back pain participants across two projects and across different treatment arms within each project. The first project will examine pain-CBT compared with MBSR and a wait-list control group. The second project will examine real versus sham electroacupuncture. We will use behavioral, psychophysical, physical measure, and neuroimaging techniques to characterize the central pain modulatory and emotion regulatory systems in chronic low back pain at baseline and longitudinally. We will characterize how these interventions impact these systems, characterize the longitudinal treatment effects, and identify predictors of treatment efficacy. RESULTS: Participant recruitment began on March 17, 2015, and will end in March 2023. Recruitment was halted in March 2020 due to COVID-19 and resumed in December 2021. CONCLUSIONS: This center uses a comprehensive approach to study chronic low back pain. Findings are expected to significantly advance our understanding in (1) the baseline and longitudinal mechanisms of chronic low back pain, (2) the common and distinctive mechanisms of three mind-body therapies, and (3) predictors of treatment response, thereby informing future delivery of nonpharmacologic chronic low back pain treatments. TRIAL REGISTRATION: ClinicalTrials.gov NCT02503475; https://clinicaltrials.gov/ct2/show/NCT02503475. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/37823.

Signature for Pain Recovery IN Teens (SPRINT): protocol for a multisite prospective signature study in chronic musculoskeletal pain.

INTRODUCTION: Current treatments for chronic musculoskeletal (MSK) pain are suboptimal. Discovery of robust prognostic markers separating patients who recover from patients with persistent pain and disability is critical for developing patient-specific treatment strategies and conceiving novel approaches that benefit all patients. Given that chronic pain is a biopsychosocial process, this study aims to discover and validate a robust prognostic signature that measures across multiple dimensions in the same adolescent patient cohort with a computational analysis pipeline. This will facilitate risk stratification in adolescent patients with chronic MSK pain and more resourceful allocation of patients to costly and potentially burdensome multidisciplinary pain treatment approaches. METHODS AND ANALYSIS: Here we describe a multi-institutional effort to collect, curate and analyse a high dimensional data set including epidemiological, psychometric, quantitative sensory, brain imaging and biological information collected over the course of 12 months. The aim of this effort is to derive a multivariate model with strong prognostic power regarding the clinical course of adolescent MSK pain and function. ETHICS AND DISSEMINATION: The study complies with the National Institutes of Health policy on the use of a single internal review board (sIRB) for multisite research, with Cincinnati Children's Hospital Medical Center Review Board as the reviewing IRB. Stanford's IRB is a relying IRB within the sIRB. As foreign institutions, the University of Toronto and The Hospital for Sick Children (SickKids) are overseen by their respective ethics boards. All participants provide signed informed consent. We are committed to open-access publication, so that patients, clinicians and scientists have access to the study data and the signature(s) derived. After findings are published, we will upload a limited data set for sharing with other investigators on applicable repositories. TRIAL REGISTRATION NUMBER: NCT04285112.

Amygdala functional connectivity mediates the association between catastrophizing and threat-safety learning in youth with chronic pain.

ABSTRACT: There is a need to identify brain connectivity alterations predictive of transdiagnostic processes that may confer vulnerability for affective symptomology. Here, we tested whether amygdala resting-state functional connectivity (rsFC) mediated the relationship between catastrophizing (negative threat appraisals and predicting poorer functioning) and altered threat-safety discrimination learning (critical to flexibly adapt to new and changing environments) in adolescents with persistent pain. We examined amygdala rsFC in 46 youth with chronic pain and 29 healthy peers (age M = 15.8, SD = 2.9; 64 females) and its relationship with catastrophizing and threat-safety learning. We used a developmentally appropriate threat-safety learning paradigm and performed amygdala seed-based rsFC and whole-brain mediation analyses. Patients exhibited enhanced connectivity between the left amygdala and right supramarginal gyrus (SMG) (cluster-level P-FDR < 0.05), whereas right amygdala rsFC showed no group differences. Only in patients, elevated catastrophizing was associated with facilitated threat-safety learning (CS+>CS-; rp = 0.49, P = 0.001). Furthermore, in patients, elevated catastrophizing was associated with reduced left amygdala connectivity with SMG / parietal operculum, and increased left amygdala connectivity with hippocampus, dorsal striatum, paracingulate, and motor regions (P < 0.001). In addition, blunted left amygdala rsFC with right SMG/parietal operculum mediated the association between catastrophizing and threat-safety learning (P < 0.001). To conclude, rsFC between the left amygdala (a core emotion hub) and inferior parietal lobe (involved in appraisal and integration of bodily signals and attentional reorienting) explains associations between daily-life relevant catastrophizing and threat-safety learning. Findings provide a putative model for understanding pathophysiology involved in core psychological processes that cut across diagnoses, including disabling pain, and are relevant for their etiology.

Virtual Reality in Pain Rehabilitation for Youth With Chronic Pain: Pilot Feasibility Study.

BACKGROUND: In the field of pain, virtual reality (VR) technology has been increasingly common in the context of procedural pain management. As an interactive technology tool, VR has the potential to be extended beyond acute pain management to chronic pain rehabilitation with a focus on increasing engagement with painful or avoided movements. OBJECTIVE: We outline the development and initial implementation of a VR program in pain rehabilitation intervention to enhance function in youth with chronic pain. METHODS: We present the development, acceptability, feasibility, and utility of an innovative VR program (Fruity Feet) for pediatric pain rehabilitation to facilitate increased upper and lower extremity engagement. The development team was an interdisciplinary group of pediatric experts, including physical therapists, occupational therapists, pain psychologists, anesthesiologists, pain researchers, and a VR software developer. We used a 4-phase iterative development process that engaged clinicians, parents, and patients via interviews and standardized questionnaires. RESULTS: This study included 17 pediatric patients (13 female, 4 male) enrolled in an intensive interdisciplinary pain treatment (IIPT) program, with mean age of 13.24 (range 7-17) years, completing a total of 63 VR sessions. Overall reports of presence were high (mean 28.98; max 40; SD 4.02), suggestive of a high level of immersion. Among those with multisession data (n=8), reports of pain (P<.001), fear (P=.003), avoidance (P=.004), and functional limitations (P=.01) significantly decreased. Qualitative analysis revealed (1) a positive experience with VR (eg, enjoyed VR, would like to utilize the VR program again, felt VR was a helpful tool); (2) feeling distracted from pain while engaged in VR; (3) greater perceived mobility; and (4) fewer clinician-observed pain behaviors during VR. Movement data support the targeted impact of the Fruity Feet compared to other available VR programs. CONCLUSIONS: The iterative development process yielded a highly engaging and feasible VR program based on qualitative feedback, questionnaires, and movement data. We discuss next steps for the refinement, implementation, and assessment of impact of VR on chronic pain rehabilitation. VR holds great promise as a tool to facilitate therapeutic gains in chronic pain rehabilitation in a manner that is highly reinforcing and fun.

Something Else Going On? Diagnostic Uncertainty in Children with Chronic Pain and Their Parents.

Diagnostic uncertainty, the perceived lack of an accurate explanation of the patient's health problem, remains relatively unstudied in children. This study examined the prevalence, familial concordance, and correlates of diagnostic uncertainty in children and their parents presenting to a multidisciplinary pain clinic in the United States. One hundred and twenty-six parents and 91 of their children (Mage = 13.93 years, range = 8-18 years) completed a brief three-item measure of diagnostic uncertainty, as well as measures of pain-related distress and functioning. Forty-eight percent of children and 37% of parents believed something else was going on with the child's pain that doctors had not found out about yet. Across the three items, 66%-77% of children and their parents agreed in their endorsement of diagnostic uncertainty. Parents who believed that something else was going on with their child's pain had children with higher avoidance of pain-related activities (F = 5.601, p = 0.020) and lower pain willingness (F = 4.782, p = 0.032). Neither parent nor child diagnostic uncertainty was significantly related to the child's pain-related functioning. Diagnostic uncertainty, particularly in parents, is relevant in the experience of pediatric chronic pain and warrants further investigation as both a risk factor and therapeutic target.

Graded exposure treatment for adolescents with chronic pain (GET Living): Protocol for a randomized controlled trial enhanced with single case experimental design.

Chronic musculoskeletal pain in adolescence is a significant public health concern with 3-5% of adolescents suffering from significant pain-related disability. Pain-related fear and avoidance of activities has been found to have a significant influence on pain outcomes in children and adolescents and is a risk factor for less favorable response to treatment. To address this need, we developed graded exposure treatment for youth with chronic pain (GET Living). We describe the rationale, design, and implementation of a two-group randomized controlled trial (RCT) enhanced with single-case experimental design (SCED) methodology with a sample of 74 adolescents with chronic musculosketal pain and their parent caregivers. GET Living includes education, behavioral exposures, and parent intervention jointly delivered by pain psychology and physical therapy providers. The multidisciplinary pain management control group includes pain psychology delivered education and pain self-management skills training (e.g., relaxation, cognitive skills) and separate physical therapy. Assessments include brief daily diaries (baseline to discharge, 7-days at 3-month and 6-month follow-up), comprehensive in-person evaluations at baseline and discharge, and questionnaire across all time points (baseline, discharge, 3-month and 6-month follow-up). Primary outcome is pain-related fear avoidance. Secondary outcome is functional disability. We also outline all additional outcomes, exploratory outcomes, covariates, and implementation measures. The objective is to offer a mechanism-based, targeted intervention to youth with musculoskeletal pain to enhance likelihood of return to function.

Use of Immersive Learning and Simulation Techniques to Teach and Research Opioid Prescribing Practices.

INTRODUCTION: Unsafe opioid prescribing practices to treat acute and chronic pain continue to contribute to the opioid overdose crisis in the United States, a growing public health emergency that harms patients and their communities. Poor opioid prescribing practices stem in part from a lack of education and skills training surrounding pain and opioid management. METHODS: As part of the Clinical Pain Medicine Fellowship at Stanford University, physicians were given the opportunity to participate in a pilot program to practice opioid management in a live, simulated interaction. Twenty-seven physician trainees participated in the simulation with a live, standardized patient actor. Before beginning the simulation, participants were given a detailed patient history that included the patient's risk for opioid abuse. They were also provided with relevant risk evaluation and mitigation (REM) tools. All simulation interactions were video-recorded and coded by two independent reviewers. A detailed coding scheme was developed before video analysis, and an inter-rater reliability score showed substantial agreement between reviewers. RESULTS: Contrary to expectations, many of the observed performances by trainees contained aspects of unsafe opioid prescribing, given the patient history. Many trainees did not discuss their patient's aberrant behaviors related to opioids or the patient's risk for opioid abuse. Marked disparities were also observed between the trainees' active patient interactions and their written progress notes. DISCUSSION: This simulation addresses a pressing need to further educate, train, and provide point-of-care tools for providers prescribing opioids. We present our experience and preliminary findings.

Rapid reduction in breast cancer mortality with inorganic arsenic in drinking water.

BACKGROUND: Arsenic trioxide is effective in treating promyelocytic leukemia, and laboratory studies demonstrate that arsenic trioxide causes apoptosis of human breast cancer cells. Region II in northern Chile experienced very high concentrations of inorganic arsenic in drinking water, especially in the main city Antofagasta from 1958 until an arsenic removal plant was installed in 1970. METHODS: We investigated breast cancer mortality from 1950 to 2010 among women in Region II compared to Region V, which had low arsenic water concentrations. We conducted studies on human breast cancer cell lines and compared arsenic exposure in Antofagasta with concentrations inducing apoptosis in laboratory studies. FINDINGS: Before 1958, breast cancer mortality rates were similar, but in 1958-1970 the rates in Region II were half those in Region V (rate ratio RR = 0·51, 95% CI 0·40-0·66; p<0·0001). Women under the age of 60 experienced a 70% reduction in breast cancer mortality during 1965-1970 (RR=0·30, 0·17-0·54; p<0·0001). Breast cancer cell culture studies showed apoptosis at arsenic concentrations close to those estimated to have occurred in people in Region II. INTERPRETATION: We found biologically plausible major reductions in breast cancer mortality during high exposure to inorganic arsenic in drinking water which could not be attributed to bias or confounding. We recommend clinical trial assessment of inorganic arsenic in the treatment of advanced breast cancer.