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192 Background: Sleep disturbance negatively impacts quality of life and recovery. Our objective was to evaluate the relationship between individual patient factors (demographic, surgical, pain, opioid use, and psychosocial factors) and greater sleep disturbance. Methods: In this prospective longitudinal study, patients completed validated measures regarding their sleep disturbance, pain, opioid use, and psychological symptoms preoperatively and then 2 weeks, 6 and 12 months postoperatively. Objective pain sensitivity measures were evaluated at baseline using quantitative sensory testing. Univariable and multivariable generalized estimating equations (GEE) evaluated demographic, surgical, pain, and psychological predictors of sleep disturbance during the first year after surgery for breast cancer. Results: Female patients (n = 259) reported varying degrees of sleep disturbance, which were longitudinally associated with pain, psychosocial factors such as anxiety, depression, and affect. While the mean degree of sleep disturbance did not change substantially over time, the link to pain severity appeared to strengthen over the first postoperative year. Independent preoperative predictors of worse sleep disturbance on multivariable longitudinal GEE included younger age (B = -.09, p =.006), opioid use (B = 3.09, p =.02), higher pain (B =.19, p =

Persistent postmastectomy pain after breast surgery is variable in duration and severity across patients, due in part to interindividual variability in pain processing. The Rapid OPPERA Algorithm (ROPA) empirically identified 3 clusters of patients with different risk of chronic pain based on 4 key psychophysical and psychosocial characteristics. We aimed to test this type of group-based clustering within in a perioperative cohort undergoing breast surgery to investigate differences in postsurgical pain outcomes. Women (N = 228) scheduled for breast cancer surgery were prospectively enrolled in a longitudinal observational study. Pressure pain threshold (PPT), anxiety, depression, and somatization were assessed preoperatively. At 2-weeks, 3, 6, and 12-months after surgery, patients reported surgical area pain severity, impact of pain on cognitive/emotional and physical functioning, and pain catastrophizing. The ROPA clustering, which used patients' preoperative anxiety, depression, somatization, and PPT scores, assigned patients to 3 groups: Adaptive (low psychosocial scores, high PPT), Pain Sensitive (moderate psychosocial scores, low PPT), and Global Symptoms (high psychosocial scores, moderate PPT). The Global Symptoms cluster, compared to other clusters, reported significantly worse persistent pain outcomes following surgery. Findings suggest that patient characteristic-based clustering algorithms, like ROPA, may generalize across diverse diagnoses and clinical settings, indicating the importance of "person type" in understanding pain variability. PERSPECTIVE: This article presents the practical translation of a previously developed patient clustering solution, based within a chronic pain cohort, to a perioperative cohort of women undergoing breast cancer surgery. Such preoperative characterization could potentially help clinicians apply personalized interventions based on predictions concerning postsurgical pain.

Objectives This study investigated the efficacy of a transcutaneous electrical nerve stimulation (TENS) device (Quell®) for persons with symptoms due to fibromyalgia (FM). Materials and methods One hundred nineteen (N = 119) subjects were randomly assigned to use an active (N = 62) or sham (N = 57) TENS for three months. All subjects completed baseline questionnaires and were administered quantitative sensory testing (QST). Subjects completed the Patients' Global Impression of Change (PGIC, primary outcome measure) and other mailed questionnaires (secondary outcome measures) at six weeks and three months. Results The subjects averaged 50.4 ± 13.5 years of age, 93.3% were female, and 79.8% were Caucasian. Most showed benefit from using the TENS, but no differences between groups were found on the primary outcome measure after three months (active 3.87 ± 1.85, sham 3.73 ± 1.80, 95% confidence interval [CI] [-0.60, 0.88], p = 0.707). Those with more hypersensitivity showed most improvement on the PGIC at six weeks (0.22, 95% CI [0.01, 0.43], p = 0.042) and three months (0.20, 95% CI [0.00, 0.41], p = 0.049) and among those with higher sensitivity based on QST, the active TENS group showed the most benefit with TENS compared with the sham treatment (1.20, 95% CI [0.22, 2.18], p = 0.017). No TENS-related serious adverse events were reported. Subjects in the sham group correctly identified their treatment 87.5% of the time, while, surprisingly, subjects in the active group correctly identified their treatment only 17.4% of the time. Conclusion This study found no differences between those who were exposed to maximal-frequency active stimulation or minimal-frequency sham stimulation from a wearable TENS in reducing FM-related symptoms. However, those with greater hypersensitivity showed most benefit from TENS. Additional studies to help determine the role individual differences play in the use of TENS in managing FM-related symptoms are needed.

Aromatase inhibitors (AIs), which potently inhibit estrogen biosynthesis, are a standard treatment for hormone sensitive early-stage breast cancer. AIs have been associated with substantial joint pain and muscle stiffness (aromatase inhibitor-associated musculoskeletal syndrome). However, the link between AIs and number of clinical pain locations and pain sensitivity are less well understood. The aim of this study was to compare longitudinal changes in clinical pain and quantitative pain sensitivity between women who did or did not receive AI therapy.Women with early-stage breast cancer were prospectively enrolled and assessed for clinical pain in surgical and nonsurgical body areas using the Brief Pain Inventory and Breast Cancer Pain Questionnaire, and for pain sensitivity using quantitative sensory testing preoperatively and at 1 year postoperatively. Pain outcomes between participants who did and did not begin adjuvant AI therapy were compared using Wilcoxon Signed-Ranks and generalized estimating equation linear regression analyses.Clinical pain and pain sensitivity were comparable between AI (n=49) and no-AI (n=106) groups preoperatively. After adjusting for body mass index, AI therapy was associated with a greater increase in the number of painful nonsurgical body sites (significant time by treatment interaction, P =0.024). Pain location was most frequent in knees (28%), lower back (26%), and ankles/feet (17%). Quantitative sensory testing revealed a significant decrease in pain sensitivity (increased pressure pain threshold) in the no-AI group over time, but not in the AI group.AI therapy was associated with increased diffuse joint-related pain and greater post-treatment pain sensitivity, potentially implicating central sensitization as a contributing pain mechanism of aromatase inhibitor-associated musculoskeletal syndrome worthy of future investigation.

OBJECTIVE: Little is known about how changes in psychosocial factors impact changes in pain outcomes among patients with cancer and chronic pain. This longitudinal cohort study of cancer patients investigated the relationships between changes in psychosocial factors and changes in pain severity and interference over time. METHODS: Data from patients with cancer and chronic pain (n = 316) treated at a tertiary pain clinic were prospectively collected. At their baseline visit (Time 1), patients provided demographic and clinical information, and completed validated psychosocial and pain assessments. Psychosocial and pain assessments were repeated at a follow-up visit (Time 2), on average 4.9 months later. Change scores (Time 2-Time 1) were computed for psychosocial and pain variables. Multivariable hierarchical linear regressions assessed the associations between changes in psychosocial factors with changes in pain outcomes over time. RESULTS: Participants were an average age of 59 years, were 61% female, and 69% White. Overall, a decrease in pain severity (p ≤ 0.001), but not pain interference, was observed among the group over time. In multivariable analyses, increased pain catastrophizing was significantly associated with increased pain severity over time (β = 0.24, p ≤ 0.001). Similarly, increased pain catastrophizing (β = 0.21, p ≤ 0.001) and increased depression (β = 0.20, p ≤ 0.003) were significantly associated with increased pain interference over time. Demographic and clinical characteristics were not significantly related to changes in pain outcomes. CONCLUSIONS: Increased pain catastrophizing was uniquely associated with increased chronic pain severity and interference. Our findings indicate that cancer patients with chronic pain would likely benefit from the incorporation of nonpharmacological interventions, simultaneously addressing pain and psychological symptoms.

Endogenous pain modulatory processes appear to play an important role in shaping pain-related outcomes, but we know relatively little about the influence of psychosocial factors on those pain modulatory processes. The primary objective of this study was to explore associations between endogenous pain modulation (ie, conditioned pain modulation, CPM; temporal summation, TS), chronic pain, and negative affective factors (ie, depression, anxiety symptoms) in a sample of participants with chronic low back pain (CLBP) treated with long-term daily opioids.Adults with opioid-treated CLBP (N=107) completed questionnaires assessing pain, pain symptoms, and psychological measures. CPM and TS were evaluated as predictors of pain intensity ratings (Brief Pain Inventory), with depression scores (Hospital Anxiety and Depression Scale, depression subscale) examined as potential moderators of those associations.Moderation analyses demonstrated associations between CPM and back pain intensity ratings, moderated by depression symptom scores (B=-0.002, SE=0.0008, P0.01) when controlling for daily opioid dose, with participants with higher depression scores showing a relatively stronger link between lower CPM and increased pain intensity ratings. Significant associations were observed between depression, pain intensity, and CPM-derived outcomes.Our findings suggest that reduced pain-inhibitory capacity is associated with elevated self-reported pain intensity in adults with opioid-treated CLBP, particularly among those with higher severity of depression symptoms.

Although an inverse relation between social support and psychological distress among chronic pain patients has been previously reported, little is known about what mediates this association. We examined mindfulness as a mediator of the relationship between social support and psychological distress. In this cross-sectional study, chronic pain patients (N=94) completed assessments of social support, mindfulness, and psychological distress. Greater social support was associated with less psychological distress. Greater mindfulness was associated with greater social support and less psychological distress. Mediation analyses demonstrated that mindfulness partially mediated the relationship between social support and psychological distress. Findings support and extend prior research by demonstrating a potentially important mediating effect of mindfulness within chronic pain patients. This suggests an important link between social support and mindfulness, and that their integration in the pursuit of mental health should be considered in future behavioral interventions.

There is an urgent need for safe and effective nonpharmacologic approaches to treat chronic knee pain in older adults. Although virtual reality (VR) has shown some effectiveness for acute pain, there is limited evidence on the effects of VR on chronic pain particularly with older adult populations. This single application, within-subject pilot study evaluated the feasibility and effectiveness of VR as a clinical treatment for older adults with chronic osteoarthritis knee pain. Nineteen participants aged 60+ years old participated in a 10-min VR meditation program. Data on pain and affect were collected immediately prior to, post, and 24-48 h after the VR. Results suggest that VR meditation had significant moderate to large analgesic effects on knee pain intensity, primarily during VR (d = 1.10) and post VR (d = 0.99), with some lasting effects into next day (d = 0.58). The findings also suggest VR meditation intervention had a positive effect on affect, with a significant large decrease in negative affect scores pre- to post-VR (d = 1.14). The significant moderate to large decreases in pain interference for normal work (d = 0.71), mood (d = 0.53), sleep (d = 0.67), and enjoyment of life (d = 0.72) suggest that older adults may have a higher ability to participate in meaningful daily activities up to 24-48 h after VR meditation. VR appears to be a feasible and effective nonpharmacological tool for older adults to treat chronic overall and knee-specific pain.

Insomnia is highly prevalent among persons with chronic pain. Although cognitive behavioral therapy for insomnia is recommended as first-line treatment for insomnia, it is underutilized. We tested the feasibility of a potentially scalable alternative - Brief Behavioral Therapy for Insomnia (BBTI) for former National Football League (NFL) players, a group with a high prevalence of chronic pain. We assessed changes in sleep, pain, and psychological health.Single-arm clinical trial of an adapted telephone-delivered BBTI intervention in 40 former NFL players with insomnia. We collected data on changes in sleep, pain, and psychological health outcomes.Among former players (30% racial/ethnic minorities), BBTI was both acceptable and feasible. BBTI was associated with improvements in sleep disturbance (primary exploratory sleep outcome, mean T-score change -6.2, 95% CI: -7.6, -4.8), sleep-related impairment (mean T-score change -5.7, 95% CI: -7.9, -3.5) and insomnia severity (mean change -5.3, 95% CI: -6.8, -3.5) post-intervention. Improvements were maintained at 2-months. BBTI was also associated with improvements in pain interference and intensity, but not psychological health.An adapted telephone-delivered BBTI is acceptable and feasible among retired players with a range of insomnia symptoms and shows promise for improving sleep and pain. These data support the need for future trials assessing BBTI's effect on both sleep and pain outcomes.

Neuroimaging is a powerful tool to investigate potential associations between chronic pain and brain structure. However, the proliferation of studies across diverse chronic pain syndromes and heterogeneous results challenges data integration and interpretation. We conducted a preregistered anatomical likelihood estimate meta-analysis on structural magnetic imaging studies comparing patients with chronic pain and healthy controls. Specifically, we investigated a broad range of measures of brain structure as well as specific alterations in gray matter and cortical thickness. A total of 7849 abstracts of experiments published between January 1, 1990, and April 26, 2021, were identified from 8 databases and evaluated by 2 independent reviewers. Overall, 103 experiments with a total of 5075 participants met the preregistered inclusion criteria. After correction for multiple comparisons using the gold-standard family-wise error correction ( P < 0.05), no significant differences associated with chronic pain were found. However, exploratory analyses using threshold-free cluster enhancement revealed several spatially distributed clusters showing structural alterations in chronic pain. Most of the clusters coincided with regions implicated in nociceptive processing including the amygdala, thalamus, hippocampus, insula, anterior cingulate cortex, and inferior frontal gyrus. Taken together, these results suggest that chronic pain is associated with subtle, spatially distributed alterations of brain structure.

Objective Expectancies have a well-documented influence on the experience of pain, responses to treatment, and postsurgical outcomes. In individuals with osteoarthritis, several studies have shown that expectations predict increased pain and disability after total knee replacement surgery. Despite the growing recognition of the importance of expectancies in clinical settings, few studies have examined the influence of expectancies throughout postsurgical recovery trajectories. The objective of the present study was to examine the role of presurgical expectancies on pain and function at 6-week, 6-month, and 1-year follow-ups after total knee arthroplasty. Design and Participants Data were collected from patients scheduled for total knee arthroplasty 1 week before surgery and then at 6 weeks, 6 months, and 1 year after surgery. Correlational and multivariable regression analyses examined the influence of expectancies on patients’ perceptions of pain reduction and functional improvement at each time point. Analyses controlled for age, sex, body mass index, presurgical pain intensity and function, pain catastrophizing, anxiety, and depression. Results Results revealed that expectancies significantly predicted pain reduction and functional improvement at 1-year follow-up. However, expectancies did not predict outcomes at the 6-week and 6-month follow-ups. Catastrophizing and depressive symptoms emerged as short-term predictors of postsurgical functional limitations at 6-week and 6-month follow-ups, respectively. Conclusions The results suggest that targeting high levels of catastrophizing and depressive symptoms could optimize short-term recovery after total knee arthroplasty. However, the results demonstrate that targeting presurgical negative expectancies could prevent prolonged recovery trajectories, characterized by pain and loss of function up to 1 year after total knee arthroplasty.

Duloxetine is a treatment approved by the US Food and Drug Administration for both osteoarthritis (OA) pain and depression, though uptake of duloxetine in knee OA management varies. We examined the cost-effectiveness of adding duloxetine to knee OA care in the absence or presence of depression screening.We used the Osteoarthritis Policy Model, a validated computer microsimulation of knee OA, to examine the value of duloxetine for patients with knee OA who have moderate pain by comparing 3 strategies: 1) usual care, 2) usual care plus duloxetine for patients who screen positive for depression on the Patient Health Questionnaire 9 (PHQ-9), and 3) usual care plus universal duloxetine. Outcome measures included quality-adjusted life years (QALYs), lifetime direct medical costs, and incremental cost-effectiveness ratios (ICERs), discounted at 3% annually. Model inputs, drawn from the published literature and national databases, included annual cost of duloxetine ($721-937); average pain reduction for duloxetine (17.5 points on the Western Ontario and McMaster Universities Osteoarthritis Index pain scale [0-100]), and likelihood of depression remission with duloxetine (27.4%). We considered 2 willingness-to-pay (WTP) thresholds of $50,000/QALY and $100,000/QALY. We varied parameters related to the PHQ-9 and the cost of duloxetine, efficacy, and toxicities to address uncertainty in model inputs.The screening strategy led to an additional 17 QALYs per 1,000 subjects and increased costs by $289/subject (ICER = $17,000/QALY). Universal duloxetine led to an additional 31 QALYs per 1,000 subjects and $1,205 per subject (ICER = $39,300/QALY). Under the majority of sensitivity analyses, universal duloxetine was cost-effective at the $100,000/QALY threshold.The addition of duloxetine to usual care for knee OA patients with moderate pain, regardless of depressive symptoms, is cost-effective at frequently used WTP thresholds.

Abnormal central pain processing is a leading cause of pain in fibromyalgia (FM) and is perceptually characterized with the psychophysical measure of temporal summation of pain (TSP). TSP is the perception of increasingly greater pain in response to repetitive or tonic noxious stimuli. Previous neuroimaging studies have used static (i.e., summary) measures to examine the functional magnetic resonance imaging (fMRI) correlates of TSP in FM. However, functional brain activity rapidly and dynamically reorganizes over time, and, similarly, TSP is a temporally evolving process. This study was undertaken to demonstrate how a complete understanding of the neural circuitry supporting TSP in FM thus requires a dynamic measure that evolves over time.We utilized novel methods for analyzing dynamic functional brain connectivity in patients with FM in order to examine how TSP-associated fluctuations are linked to the dynamic functional reconfiguration of the brain. In 84 FM patients and age- and sex-matched healthy controls, we collected high-temporal-resolution fMRI data during a resting state and during a state in which sustained cuff pressure pain was applied to the leg.FM patients experienced greater TSP than healthy controls (mean ± SD TSP score 17.93 ± 19.24 in FM patients versus 9.47 ± 14.06 in healthy controls; P = 0.028), but TSP scores varied substantially between patients. In the brain, the presence versus absence of TSP in patients with FM was marked by more sustained enmeshment between sensorimotor and salience networks during the pain period. Furthermore, dynamic enmeshment was noted solely in FM patients with high TSP, as interactions with all other brain networks were dampened during the pain period.This study elucidates the dynamic brain processes underlying facilitated central pain processing in FM. Our findings will enable future investigation of dynamic symptoms in FM.

Objective Respiratory-gated Auricular Vagal Afferent Nerve stimulation (RAVANS) is a safe nonpharmacological approach to managing chronic pain. The purpose of the current study was to examine (1) the feasibility and acceptability of RAVANS, combined with mindful meditation (MM) for chronic low back pain (CLBP), (2) the potential synergy of MM+RAVANS on improving pain, and (3) possible moderators of the influence of MM+RAVANS on pain. Design Pilot feasibility and acceptability study. Setting Pain management center at large academic medical center. Subjects Nineteen adults with CLBP and previous MM training. Methods Participants attended two sessions during which they completed quantitative sensory testing (QST), rated pain severity, and completed a MM+stimulation session. Participants received RAVANS during one visit and sham stimulation during the other, randomized in order. Following intervention, participants repeated QST. Results MM+RAVANS was well tolerated, acceptable, and feasible to provide relief for CLBP. Both MM+stimulation sessions resulted in improved back pain severity, punctate pain ratings, and pressure pain threshold. Individuals with greater negative affect showed greater back pain improvement from MM+RAVANS while those with greater mindfulness showed greater back pain improvement from MM+sham. Conclusions Results suggest that for CLBP patients with prior MM training, the analgesic effects of MM may have overshadowed effects of RAVANS given the brief single session MM+RAVANS intervention. However, those with greater negative affect may benefit from combined MM+RAVANS.

John Lydgate is the major poet of his era. He is the most successful and recognized claimant to Chaucer’s literary heritage in the national tradition that emerges in the fifteenth and sixteenth centuries. As a poet and author, he depends on a selective appropriation of Chaucer’s materials and style, balanced by the critical distance of a clerical historian-moralist, the self-described ‘Monk of Bury’. The range of Lydgate’s writing is decisively shaped by commissions, specific occasions, patrons, and audiences. His earliest dated poem, Troy Book (1412), begins an epic project that encompasses the heroic and aristocratic narratives of antiquity and medieval modernity in the Siege of Thebes (1422), the prose Serpent of Division (1422), and Fall of Princes (1431–9). Alongside these dynastic and public works, Lydgate composes courtly dream visions, fables, hagiography, didactic and religious verse, and paradramatic works that rewrite their sources and shift them to a distinctive stylistic register.

Class III obesity (BMI40kg/mUsing the Osteoarthritis Policy Model (OAPol) and data from published literature to derive model inputs for RYGB, LSG, LNSWL, and TKR, we assessed the long-term clinical benefits, costs, and cost-effectiveness of weight loss interventions for patients with Class III obesity considering TKR. We assessed the following strategies with a healthcare sector perspective: 1)no weight loss/no TKR, 2)immediate TKR, 3)LNSWL, 4)LSG, and 5)RYGB. Each weight loss strategy was followed by annual TKR reevaluation. Primary outcomes were cost, quality-adjusted life-expectancy (QALE), and incremental cost-effectiveness ratios (ICERs), discounted 3%/year. We conducted deterministic and probabilistic sensitivity analyses to examine the robustness of conclusions to input uncertainty.LSG increased QALE by 1.64 quality-adjusted life-years (QALYs) and lifetime medical costs by $17,347 compared to no intervention, leading to an ICER of $10,600/QALY. RYGB increased QALE by 0.22 and costs by $4,607 beyond LSG, resulting in an ICER of $20,500/QALY. Relative to immediate TKR, LSG and RYGB delayed and decreased TKR utilization. In the probabilistic sensitivity analysis, RYGB was cost-effective in 67% of iterations at a willingness-to-pay (WTP) threshold of $50,000/QALY.For patients with Class III obesity considering TKR, RYGB provides good value while immediate TKR without weight loss is not economically efficient.

Pragmatic clinical trials (PCTs) are well-suited to address unmet healthcare needs, such as those arising from the dual public health crises of chronic pain and opioid misuse, recently exacerbated by the COVID-19 pandemic. These overlapping epidemics have complex, multifactorial etiologies, and PCTs can be used to investigate the effectiveness of integrated therapies that are currently available but underused. Yet individual pragmatic studies can be limited in their reach because of existing structural and cultural barriers to dissemination and implementation. The National Institutes of Health, Department of Defense, and Department of Veterans Affairs formed an interagency research partnership, the Pain Management Collaboratory. The partnership combines pragmatic trial design with collaborative tools and relationship building within a large network to advance the science and impact of nonpharmacological approaches and integrated models of care for the management of pain and common co-occurring conditions. The Pain Management Collaboratory team supports 11 large-scale, multisite PCTs in veteran and military health systems with a focus on team science with the shared aim that the “whole is greater than the sum of the parts.” Herein, we describe this integrated approach and lessons learned, including incentivizing all parties; proactively offering frequent opportunities for problem-solving; engaging stakeholders during all stages of research; and navigating competing research priorities. We also articulate several specific strategies and their practical implications for advancing pain management in active clinical, “real-world,” settings.

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

Objective To assess whether brief mindfulness-based cognitive behavioral therapy (MBCBT) could enhance the benefits of total knee arthroplasty (TKA) in improving pain and pain-related disability. Specifically, to determine 1) whether patients who received MBCBT differed from matched controls who received treatment-as-usual with regard to postsurgical pain outcomes and 2) whether changes in pain catastrophizing, depression, or anxiety explained the potential effects of MBCBT on pain outcomes. Design Pilot clinical trial. Setting An academic teaching hospital serving a large urban and suburban catchment area surrounding the Boston, Massachusetts metropolitan region. Subjects Sample of 44 patients undergoing TKA. Patients who completed a brief MBCBT intervention (n = 22) were compared with age-, race-, and sex-matched controls who received treatment-as-usual (n = 22). Methods The MBCBT intervention included four 60-minute sessions delivered by a pain psychologist in person and via telephone during the perioperative period. Participants were assessed at baseline and at 6 weeks, 3 months, and 6 months after surgery. Results Compared with matched controls, patients who received MBCBT had lower pain severity and pain interference at 6 weeks after surgery. Group differences in outcomes were mediated by changes in pain catastrophizing but not by changes in depression or anxiety. The MBCBT group had similar reductions in pain severity and interference as the control group did at 3 and 6 months after surgery. Conclusions This work offers evidence for a safe and flexibly delivered nonpharmacological treatment (MBCBT) to promote faster recovery from TKA and identifies change in pain catastrophizing as a mechanism by which this intervention could lead to enhanced pain-related outcomes.

We recently showed that patients with different chronic pain conditions (such as chronic low back pain, fibromyalgia, migraine and Gulf War illness) demonstrated elevated brain and/or spinal cord levels of the glial marker 18-kDa translocator protein (TSPO), which suggests that neuroinflammation might be a pervasive phenomenon observable across multiple aetiologically heterogeneous pain disorders. Interestingly, the spatial distribution of this neuroinflammatory signal appears to exhibit a degree of disease specificity (e.g. with respect to the involvement of the primary somatosensory cortex), suggesting that different pain conditions may exhibit distinct ‘neuroinflammatory signatures’. To explore this hypothesis further, we tested whether neuroinflammatory signal can characterize putative aetiological subtypes of chronic low back pain patients based on clinical presentation. Specifically, we explored neuroinflammation in patients whose chronic low back pain either did or did not radiate to the leg (i.e. ‘radicular’ versus ‘axial’ back pain). Fifty-four patients with chronic low back pain, 26 with axial back pain [43.7 ± 16.6 years old (mean ± SD)] and 28 with radicular back pain (48.3 ± 13.2 years old), underwent PET/MRI with 11C-PBR28, a second-generation radioligand for TSPO. 11C-PBR28 signal was quantified using standardized uptake values ratio (validated against volume of distribution ratio; n = 23). Functional MRI data were collected simultaneously to the 11C-PBR28 data (i) to functionally localize the primary somatosensory cortex back and leg subregions; and (ii) to perform functional connectivity analyses (in order to investigate possible neurophysiological correlations of the neuroinflammatory signal). PET and functional MRI measures were compared across groups, cross-correlated with one another and with the severity of ‘fibromyalgianess’ (i.e. the degree of pain centralization, or ‘nociplastic pain’). Furthermore, statistical mediation models were used to explore possible causal relationships between these three variables. For the primary somatosensory cortex representation of back/leg, 11C-PBR28 PET signal and functional connectivity to the thalamus were: (i) higher in radicular compared to axial back pain patients; (ii) positively correlated with each other; (iii) positively correlated with fibromyalgianess scores, across groups; and finally (iv) fibromyalgianess mediated the association between 11C-PBR28 PET signal and primary somatosensory cortex–thalamus connectivity across groups. Our findings support the existence of ‘neuroinflammatory signatures’ that are accompanied by neurophysiological changes and correlate with clinical presentation (in particular, with the degree of nociplastic pain) in chronic pain patients. These signatures may contribute to the subtyping of distinct pain syndromes and also provide information about interindividual variability in neuroimmune brain signals, within diagnostic groups, that could eventually serve as targets for mechanism-based precision medicine approaches.

Background The cortisol awakening response (CAR) is a core biomarker of hypothalamic-pituitary-adrenal (HPA) axis regulation. To date, however, studies of HPA-axis function among patients with chronic pain are scarce and show equivocal results. The objectives of this study were to investigate the association between CAR and pain-related outcomes and to investigate potential sex differences in patients with knee osteoarthritis (KOA). Methods In this cross-sectional study, KOA patients (N = 96) completed self-report questionnaires assessing pain and psychosocial factors and underwent Quantitative Sensory Testing (QST) to assess pressure pain threshold (PPT). Additionally, salivary cortisol samples (N = 60) were collected to assess HPA-axis function at 6 time points (awakening, 15- and 30-minute post-awakening, 4 PM, 9 PM and bedtime). The CAR was calculated by examining increases in salivary cortisol from awakening to 30 min post awakening and the total post-awakening cortisol concentration by calculating the lower areas under the curve of cortisol with respect to ground (AUCG). Results Patients with a relatively blunted CAR had significantly higher anxiety levels and lower PPT than patients with relatively normal CAR. Similarly, patients with a relatively reduced AUCG had significantly higher pain interference and anxiety levels compared to patients with relatively normal AUCG. PPT was positively correlated with CAR and AUCG and negatively correlated with pain severity and anxiety. Men with KOA had significantly lower anxiety, higher PPT and higher CAR and AUCG than women with KOA. Mediation analysis results revealed a significant indirect effect of PPT on the relationship between sex and AUCG. Conclusions The findings of this study suggest that neuroendocrine factors such as CAR and AUCG may contribute to individual differences in pain-related outcomes in patients with KOA. Additionally, our results show sex differences in the magnitude of morning HPA activation and pain-related outcomes. Finally, our findings are suggestive of a sex-dependent relationship between post-awakening cortisol concentrations and pain perception. Future research should examine these associations across various pain populations.

COVID-19 social distancing mandates increased social isolation, resulting in changes in pain severity and interference among individuals with chronic pain. Differences in personality (e.g., introversion/extraversion) may modulate responses to social isolation. We examined the influence of introversion on reported social distancing-related increases in pain interference and assessed for mediators of this relationship. Individuals with chronic pain (n = 150) completed validated questionnaires 4-8 weeks after implementation of social distancing mandates. Introversion/extraversion was measured using a subscale of the Myers-Briggs Type Indicator and changes in pain and psychosocial variables were calculated by comparing participants' recalled and current scores. Association between introversion/extraversion and other variables were assessed using linear regression. A parallel mediation was used to examine mediators of the association between introversion and change in pain interference. Higher introversion was associated with a decrease in pain interference after social distancing (Rho = - .194, p = .017). Parallel mediation analysis revealed that the relationship between introversion/extraversion and change in pain interference was mediated by changes in sleep disturbance and depression, such that higher introversion was associated with less isolation-induced sleep disruption and depression, and thereby less worsening of pain interference. These findings suggest that personality factors such as introversion/extraversion should be considered when personalizing treatment of chronic pain.

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.

BACKGROUND Fibromyalgia is a centralized multidimensional chronic pain syndrome, but its pathophysiology is not fully understood. METHODS We applied 3D magnetic resonance spectroscopic imaging (MRSI), covering multiple cortical and subcortical brain regions, to investigate the association between neuro-metabolite (e.g. combined glutamate and glutamine, Glx; myo-inositol, mIno; and combined (total) N-acetylaspartate and N-acetylaspartylglutamate, tNAA) levels and multidimensional clinical/behavioural variables (e.g. pain catastrophizing, clinical pain severity and evoked pain sensitivity) in women with fibromyalgia (N = 87). RESULTS Pain catastrophizing scores were positively correlated with Glx and tNAA levels in insular cortex, and negatively correlated with mIno levels in posterior cingulate cortex (PCC). Clinical pain severity was positively correlated with Glx levels in insula and PCC, and with tNAA levels in anterior midcingulate cortex (aMCC), but negatively correlated with mIno levels in aMCC and thalamus. Evoked pain sensitivity was negatively correlated with levels of tNAA in insular cortex, MCC, PCC and thalamus. CONCLUSIONS These findings support single voxel placement targeting nociceptive processing areas in prior 1 H-MRS studies, but also highlight other areas not as commonly targeted, such as PCC, as important for chronic pain pathophysiology. Identifying target brain regions linked to multidimensional symptoms of fibromyalgia (e.g. negative cognitive/affective response to pain, clinical pain, evoked pain sensitivity) may aid the development of neuromodulatory and individualized therapies. Furthermore, efficient multi-region sampling with 3D MRSI could reduce the burden of lengthy scan time for clinical research applications of molecular brain-based mechanisms supporting multidimensional aspects of fibromyalgia. SIGNIFICANCE This large N study linked brain metabolites and pain features in fibromyalgia patients, with a better spatial resolution and brain coverage, to understand a molecular mechanism underlying pain catastrophizing and other aspects of pain transmission. Metabolite levels in self-referential cognitive processing area as well as pain-processing regions were associated with pain outcomes. These results could help the understanding of its pathophysiology and treatment strategies for clinicians.

Chronic low back pain (cLBP) has been associated with changes in brain plasticity. Nonpharmacological therapies such as Manual Therapy (MT) have shown promise for relieving cLBP. However, translational neuroimaging research is needed to understand potential central mechanisms supporting MT. We investigated the effect of MT on resting-state salience network (SLN) connectivity, and whether this was associated with changes in clinical pain. Fifteen cLBP patients, and 16 matched healthy controls (HC) were scanned with resting functional Magnetic Resonance Imaging (fMRI), before and immediately after a MT intervention (cross-over design with two separate visits, pseudorandomized, grades V 'Manipulation' and III 'Mobilization' of the Maitland Joint Mobilization Grading Scale). Patients rated clinical pain (0-100) pre- and post-therapy. SLN connectivity was assessed using dual regression probabilistic independent component analysis. Both manipulation (Pre: 39.43 ± 16.5, Post: 28.43 ± 16.5) and mobilization (Pre: 38.83 ± 17.7, Post: 31.76 ± 19.4) reduced clinical back pain (P.05). Manipulation (but not mobilization) significantly increased SLN connectivity to thalamus and primary motor cortex. Additionally, a voxelwise regression indicated that greater MT-induced increase in SLN connectivity to the lateral prefrontal cortex was associated with greater clinical back pain reduction immediately after intervention, for both manipulation (r = -0.8) and mobilization (r = -0.54). Our results suggest that MT is successful in reducing clinical low back pain by both spinal manipulation and spinal mobilization. Furthermore, this reduction post-manipulation occurs via modulation of SLN connectivity to sensorimotor, affective, and cognitive processing regions. PERSPECTIVE: MT both reduces clinical low back pain and modulates brain activity important for the processing of pain. This modulation was shown by increased functional brain connectivity between the salience network and brain regions involved in cognitive, affective, and sensorimotor processing of pain.

The COVID-19 pandemic has had a tremendous impact, including on individuals with chronic pain. The social distancing policies necessary to slow the spread of SARS-CoV-2 have involved increased levels of social isolation. This cross-sectional survey study examined pain severity and interference among individuals with chronic pain during an early phase of social distancing mandates and identified characteristics of individuals who were most impacted. Approximately 4 to 8 weeks after social distancing mandates commenced in the state ofMassachusetts, 150 patients with fibromyalgia, chronic spine, and postsurgical pain completed demographic, pain, social distancing, and validated psychosocial questionnaires. Patients self-reported an overall significant increase in pain severity and pain interference, compared with before social distancing, although both pain severity and interference were quite variable among individuals under conditions of social distancing. Several demographic, socioeconomic, and psychosocial factors were associated with greater pain severity and interference during social distancing. Multivariable linear regression demonstrated that female sex, nonwhite race, lower education, disability, fibromyalgia, and higher pain catastrophizing were independently associated with greater pain severity, while female sex and pain catastrophizing were independently associated greater pain interference. The findings suggest that individual differences among patients with chronic pain should be considered in the planning, development, and prioritization of interventions to improve pain care and to prevent worsening of symptoms during the continuing COVID-19 pandemic.

Jenna M Wilson, Carin A Colebaugh, Samantha M Meints, K Mikayla Flowers, Robert R Edwards, Kristin L Schreiber Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, USACorrespondence: Jenna M Wilson, Brigham and Women’s Hospital, Harvard Medical School, 45 Francis St, Boston, MA, 02115, USA, Tel +1 7813673972, Email jwilson47@bwh.harvard.eduPurpose: Loneliness increased during the COVID-19 pandemic and social distancing guidelines, potentially exacerbating negative cognitions about pain. The present study investigated the longitudinal relationship between loneliness, assessed during the early weeks of the pandemic, and pain catastrophizing, assessed after living in the pandemic for approximately 1 year, among chronic pain patients. We also examined whether severity of depressive symptoms mediated this association.Methods: This prospective longitudinal study recruited individuals with chronic pain (N=93) from Massachusetts using an online convenience sampling method via the platform Rally. Participants completed an initial survey early after the onset of social distancing (4/28/20– 6/17/20; Time 1) and a follow-up survey 1 year later (5/21/21– 6/7/21; Time 2). Participants completed validated assessments of loneliness (T1), pain catastrophizing (T2), and depression (T2). Spearman correlations and Mann–Whitney U-tests were used to explore associations among psychosocial, pain, and participant characteristics. A mediation analysis was conducted to test whether the association between loneliness and pain catastrophizing was mediated by depression.Results: Participants had a mean age of 40.6 years and were majority female (80%) and White (82%). Greater loneliness was associated with subsequent higher pain catastrophizing (b=1.23, 95% CI [0.03, 2.44]). Mediation analysis showed a significant indirect effect (b=0.57, 95% CI [0.10, 1.18) of loneliness (T1) on catastrophizing (T2) through depression (T2) while accounting for several important covariates. The direct effect of loneliness on catastrophizing was no longer significant when depression was included in the model (b=0.66, 95% CI [− 0.54, 1.87]).Conclusion: Findings suggest that greater loneliness during the pandemic was associated with higher pain catastrophizing 1 year later, and severity of depression after living in the pandemic mediated this association. As loneliness, depression, and catastrophizing can all be modified with behavioral interventions, understanding the temporal associations among these variables is important for the employment of future empirically supported treatments.Keywords: loneliness, pain catastrophizing, depression, chronic pain, COVID-19

Younger age is a risk factor for worse pain outcomes following breast cancer surgery, yet little is known about how younger women's psychological state may contribute to their pain experience. Using prospectively collected longitudinal data from a surgical cohort, we examined whether early postoperative psychological distress at 2 weeks mediated the association between younger age and subsequent worse pain-related functioning 3 months after surgery.Patients (N = 159) were recruited before breast cancer surgery into this longitudinal cohort study. Age at time of surgery, psychological distress (anxiety, depression, and sleep disturbance) assessed 2 weeks postoperatively, and impact of surgical pain on cognitive/emotional functioning and physical functioning assessed 3 months postoperatively were used for analysis.Younger age was associated with greater depression, anxiety, and sleep disturbance 2 weeks postoperatively. Younger age was also associated with greater ratings of pain impacting cognitive/emotional functioning and physical functioning 3 months postoperatively. The association between younger age and worse cognitive/emotional impact of pain was mediated by greater anxiety and sleep disturbance. Similarly, the association between younger age and worse physical impact of pain was mediated by greater sleep disturbance.The degree of anxiety and sleep disturbance that occur early after breast surgery may contribute to greater chronic pain-related functional disability among younger patients. Anxiety and sleep disturbance are modifiable with behavioral interventions, making them potential perioperative targets to improve long-term outcomes in young breast cancer survivors.

Chronic pain affects about 100 million U.S. adults, with chronic low back pain (CLBP) cited as the most prevalent type. Although there is evidence that non-pharmacological therapies seem to be effective for treating low back pain, there is limited evidence of the effectiveness of EMG biofeedback with non-specific chronic low back pain (NCLBP). The purpose of this study is, therefore, to determine the efficacy of a portable EMG biofeedback device on pain in individuals with CLBP.This study is a prospective, single-center, assessor-blind, two-arm, parallel randomized controlled trial to be conducted at Brigham and Women's Hospital, Boston, MA. Eighty patients with CLBP will be randomized in a 2:1 ratio to receive sEMG-BF (surface EMG biofeedback) or continued care (no intervention). All participants will receive treatment virtually weekly for 8 weeks. The primary outcome will be pain intensity (Brief Pain Inventory). The secondary outcomes will include pain interference (Brief Pain Inventory), disability (The Oswestry Disability Index (ODI)), anxiety and depression (Hospital Anxiety and Depression Scale). All outcomes will be assessed at baseline, immediately post-intervention, and 3 months follow-up.To our knowledge, this study will be the first powered randomized controlled trial to compare the effectiveness of a virtual sEMG-BF protocol specifically designed for CLBP. The outcome of the study may provide evidence for the effectiveness of biofeedback using digital therapeutics to relieve pain in individuals with CLBP.Clinical Trials Registry (http://ClinicalTrials.gov Identifier: NCT04607460). Registered on October 29, 2020.

Objectives Approximately 20% of knee osteoarthritis patients undergoing total knee arthroplasty (TKA) report chronic postoperative pain. Studies suggest that preoperative variables such as impaired descending pain control, catastrophizing, function, and neuropathic pain–like symptoms may predict postoperative pain 12 months after TKA, but the combined prediction value of these factors has not been tested. The current prospective cohort study aimed to combine preoperative risk factors to investigate the predictive value for postoperative pain 12 months after TKA. Design Prospective cohort with follow-up 12 months after surgery. Patients A consecutive sample of 131 knee osteoarthritis patients undergoing TKA. Methods Pain intensity, Pain Catastrophizing Scale (PCS) scores, PainDETECT Questionnaire scores, conditioned pain modulation (CPM), and Oxford Knee Score (OKS) were obtained before and 12 months after TKA. Results TKA improved pain (P < 0.001), PCS scores (P < 0.001), PainDETECT Questionnaire scores (P < 0.001), and OKSs (P < 0.001). Preoperative pain correlated with preoperative PCS scores (r = 0.38, P < 0.001), PainDETECT scores (r = 0.53, P < 0.001), and OKSs (r = –0.25, P = 0.001). Preoperative PainDETECT scores were associated with preoperative PCS scores (r = 0.53, P < 0.001) and OKSs (r = –0.25, P = 0.002). Higher postoperative pain was correlated with high preoperative pain (r = 0.424, P < 0.001), PCS scores (r = 0.33, P < 0.001), PainDETECT scores (r = 0.298, P = 0.001), and lower CPM (r = –0.18, P = 0.04). The combination of preoperative pain, PCS score, and CPM explained 20.5% of variance in follow-up pain. PCS scores had a significant effect on pain trajectory when accounting for patient variance (t = 14.41, P < 0.0005). Conclusion The combination of high preoperative clinical pain intensity, high levels of pain catastrophizing thoughts, and impaired CPM may predict long-term postoperative pain 12 months after surgery.

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.

There is a pressing need to better understand the factors contributing to prescription opioid misuse among patients with chronic pain. Cross-sectional studies have been conducted in this area, but longitudinal studies examining the determinants of prescription opioid misuse repeatedly over the course of opioid therapy have yet to be conducted. The main objective of this study was to examine the relative contribution of pain and psychological factors to the occurrence of opioid misuse among patients with chronic pain prescribed opioids. Of particular interest was to examine whether pain intensity and psychological factors were more strongly associated with certain types of opioid misuse behaviors. Patients with chronic pain (n = 194) prescribed long-term opioid therapy enrolled in this longitudinal observational cohort study. Patients completed baseline measures and were then followed for 6 months. Opioid misuse was assessed once a month using self-report measures, and urine toxicology screens complemented patients' reports of opioid misuse. Heightened pain intensity levels were associated with a greater likelihood of opioid misuse (p = .014). However, pain intensity was no longer significantly associated with opioid misuse when controlling for psychological factors (i.e., negative affect, catastrophizing). Subsequent analyses revealed that higher levels of catastrophizing were associated with a greater likelihood of running out of opioid medication early, even after controlling for patients' levels of pain intensity and negative affect (p = .016). Our findings provide new insights into the determinants of prescription opioid misuse and have implications for the nature of interventions that may be used to reduce specific types of opioid misuse behaviors. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Objective Self-compassion meditation, which involves compassion toward the self in moments of suffering, shows promise for improving pain-related functioning, but its underlying mechanisms are unknown. This longitudinal, exploratory pilot study investigated the effects of a brief (eight contact hours, two weeks of home practice) self-compassion training on pain-related brain processing in chronic low back pain (cLBP). Methods We evaluated functional magnetic resonance imaging (fMRI) response to evoked pressure pain and its anticipation during a self-compassionate state and compared altered brain responses following training with changes on self-reported measures of self-compassion (Self-Compassion Scale [SCS]), interoceptive awareness (Multidimensional Assessment of Interoceptive Awareness [MAIA]), and clinical pain intensity. Results In a sample of participants with cLBP (N = 20 total, N = 14 with complete longitudinal data) who underwent self-compassion training, we observed reduced clinical pain intensity and disability (P Discussion These findings, though exploratory and lacking comparison with a control condition, suggest that self-compassion training supports regulation of pain through the involvement of self-referential (vPCC), salience-processing (TPJ), and emotion regulatory (dlPFC) brain areas. The results also suggest that self-compassion could be an important target in the psychotherapeutic treatment of cLBP, although further studies using controlled experimental designs are needed to determine the specificity of these effects.

Gulf War Illness (GWI) is a chronic disorder affecting approximately 30% of the veterans who served in the 1991 Gulf War. It is characterised by a constellation of symptoms including musculoskeletal pain, cognitive problems and fatigue. The cause of GWI is not definitively known but exposure to neurotoxicants, the prophylactic use of pyridostigmine bromide (PB) pills, and/or stressors during deployment have all been suspected to play some pathogenic role. Recent animal models of GWI have suggested that neuroinflammatory mechanisms may be implicated, including a dysregulated activation of microglia and astrocytes. However, neuroinflammation has not previously been directly observed in veterans with GWI. To measure GWI-related neuroinflammation in GW veterans, we conducted a Positron Emission Tomography (PET) study using [11C]PBR28, which binds to the 18 kDa translocator protein (TSPO), a protein upregulated in activated microglia/macrophages and astrocytes. Veterans with GWI (n = 15) and healthy controls (HC, n = 33, including a subgroup of healthy GW veterans, HCVET, n = 8), were examined using integrated [11C]PBR28 PET/MRI. Standardized uptake values normalized by occipital cortex signal (SUVR) were compared across groups and against clinical variables and circulating inflammatory cytokines (TNF-α, IL-6 and IL-1β). SUVR were validated against volume of distribution ratio (n = 13). Whether compared to the whole HC group, or only the HCVET subgroup, veterans with GWI demonstrated widespread cortical elevations in [11C]PBR28 PET signal, in areas including precuneus, prefrontal, primary motor and somatosensory cortices. There were no significant group differences in the plasma levels of the inflammatory cytokines evaluated. There were also no significant correlations between [11C]PBR28 PET signal and clinical variables or circulating inflammatory cytokines. Our study provides the first direct evidence of brain upregulation of the neuroinflammatory marker TSPO in veterans with GWI and supports the exploration of neuroinflammation as a therapeutic target for this disorder.

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., In 2018, the Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened to discuss strategies to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement.

ObjectiveA growing body of literature shows that justice-related appraisals are significant determinants of pain-related outcomes and prolonged trajectories of recovery. We conducted a systematic review of the literature assessing the relationship between perceived injustice and pain-related outcomes in individuals with musculoskeletal pain.Design and ParticipantsA search of published studies in English in PubMed, PsychInfo, Embase, and Cochrane Database of Systematic Reviews from database inception through May 2019 was performed. Search terms included “perceived injustice,” “injustice appraisals,” “perceptions of injustice,” and “pain” or “injury.”ResultsThirty-one studies met inclusion criteria. Data for a total of 5,969 patients with musculoskeletal pain were extracted. Twenty-three studies (71.9%) reported on individuals with persistent pain lasting over three months, and 17 studies (53.1%) reported on individuals with injury-related musculoskeletal pain. Significant associations were found between perceived injustice and pain intensity, disability and physical function, symptoms of depression and anxiety, post-traumatic stress disorder, quality of life and well-being, and quality of life and social functioning.ConclusionsThis systematic review summarizes the current evidence for the association between perceived injustice and pain-related outcomes. There is strong evidence that perceived injustice is associated with pain intensity, disability-related variables, and mental health outcomes. Implications and directions for future research are discussed.

Objective. Music has been shown to modulate pain, although the impact of music on specific aspects of nociceptive processing is less well understood. Using quantitative sensory testing (QST), we assessed the impact of a novel music app on specific aspects of nociceptive processing. Design. Within-subjects paired comparison of pain processing in control vs music condition. Setting. Human psychophysical laboratory. Subjects. Sixty healthy adult volunteers. Methods. Subjects were assessed for baseline anxiety, depression, and catastrophizing using validated questionnaires. QSTs measured included 1) pain threshold and tolerance to deep muscle pressure, 2) pain with mechanical pinprick, 3) temporal summation of pain (TSP) with a repeated pain stimulus, and 4) conditioned pain modulation (CPM) with a second painful stimulus. QSTs were performed in the absence and presence of music delivered through a music app. Results. We found an increase in pressure pain thresholds in both the forearm (P = 0.007) and trapezius (P = 0.002) with music, as well as a decrease in the amount of pinprick pain (P

Introduction: Migraine is the second leading cause of disability worldwide, yet many patients are unable to tolerate, benefit from, or afford pharmacological treatment options. Non-pharmacological migraine therapies exist, especially to reduce opioid use, which represents a significant unmet need. Mindfulness-based interventions (MBI) have potential as a non-pharmacological treatment for migraine, primarily through the development of flexible attentional capacity across sensory, cognitive, and emotional experiences.Areas covered: The authors review efficacy and potential mechanisms of MBIs for migraine, including mindfulness-based stress reduction (MBSR) and mindfulness-based cognitive therapy (MBCT).Expert opinion: While most mindfulness research studies for migraine to date have been pilot trials, which are small and/or lacked rigor, initial evidence suggests there may be improvements in overall headache-related disability and psychological well-being. Many research questions remain to help target the treatment to patients most likely to benefit, including the ideal dosage, duration, delivery method, responder characteristics, and potential mechanisms and biomarkers. A realistic understanding of these factors is important for patients, providers, and the media. Mindfulness will not 'cure' migraine; however, mindfulness may be an important tool as part of a comprehensive treatment approach to help patients 'mindfully' engage in valued life activities.