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Patients with rheumatic diseases often have mixed pain states, with varying degrees of nociceptive, neuropathic, and nociplastic mechanisms, which exist on a continuum. When individuals with any chronic pain have a nociplastic component to their symptoms, they are less likely to respond to treatments (eg, injections, surgery, biologics, and opioids) that work better for acute or purely nociceptive pain.

Summary Nociplastic pain is the semantic term suggested by the international community of pain researchers to describe a third category of pain that is mechanistically distinct from nociceptive pain, which is caused by ongoing inflammation and damage of tissues, and neuropathic pain, which is caused by nerve damage. The mechanisms that underlie this type of pain are not entirely understood, but it is thought that augmented CNS pain and sensory processing and altered pain modulation play prominent roles. The symptoms observed in nociplastic pain include multifocal pain that is more widespread or intense, or both, than would be expected given the amount of identifiable tissue or nerve damage, as well as other CNS-derived symptoms, such as fatigue, sleep, memory, and mood problems. This type of pain can occur in isolation, as often occurs in conditions such as fibromyalgia or tension-type headache, or as part of a mixed-pain state in combination with ongoing nociceptive or neuropathic pain, as might occur in chronic low back pain. It is important to recognise this type of pain, since it will respond to different therapies than nociceptive pain, with a decreased responsiveness to peripherally directed therapies such as anti-inflammatory drugs and opioids, surgery, or injections.

Objective To determine the validity of self-reported physician diagnosis of rheumatoid arthritis (RA) using multiple gold-standard measures based on Medicare claims in a nationally representative sample of older adults and to verify whether additional questions about taking medication and having seen a physician in the past two years for arthritis can improve the positive predictive value (PPV) and other measures of the validity of self-reported RA. Methods A total of 3768 Medicare-eligible respondents with and without incident self-reported RA were identified from the 2004, 2008, and 2012 waves of the United States Health and Retirement Study. Self-reported RA was validated using the following three claims-based algorithms: 1) a single International Classification of Diseases, ninth edition, Clinical Modification claim for RA, 2) two or more claims no greater than 2 years apart, and 3) two or more claims with at least one diagnosis by a rheumatologist. Additional self-report questions of medication use and having seen a doctor for arthritis in the past two years were validated against the same criteria. Results A total of 345 respondents self-reported a physician diagnosis of RA. Across all three RA algorithms, the PPV of self-report ranged from 0.05 to 0.16., the sensitivity ranged from 0.23 to 0.55., and the κ statistic ranged from 0.07 to 0.15. Additional self-report data regarding arthritis care improved the PPV and other validity measures of self-report; however, the values remained low. Conclusion Most older adults who self-report RA do not have a Medicare claims history consistent with that diagnosis. Revisions to current self-reported RA questions may yield more valid identification of RA in national health surveys.

Background Mounting evidence suggests that central nervous system amplification, similar to that seen in fibromyalgia (FM), contributes to the pain experience in a subset of patients with temporomandibular disorders (TMD). Methods In this prospective observational study, patients with TMD completed the 2011 FM survey questionnaire, a surrogate measure of “centralized” pain. The influence of centralized pain on TMD pain, dysfunction, and disability was assessed dichotomously by determining the incidence of FM-positive cases in the sample and by using FM survey scores as a continuous measure of “fibromyalgia-ness” (“FM-ness”). Results The patients meeting criteria for FM diagnosis (17 of 89) had significantly more disease burden on numerous measures. FM-ness was positively associated with pain at rest, negative mood, tenderness to palpation, perceived jaw functional limitation, and pain-related disability, and it was negatively associated with comfortable pain-free jaw opening. The impact of FM-ness on perceived jaw functional limitation and disability was mediated by levels of spontaneous, ongoing pain in the orofacial region. Importantly, this pattern of findings was still present even in those not meeting the criteria for FM diagnosis. Conclusion Together, these results imply that higher FM-ness increases TMD patient burden by amplifying spontaneous pain and further hampering painless jaw function, even in patients who do not meet criteria for FM diagnosis. These results are highly relevant for the clinical management of TMD, as they imply that targeting the central nervous system in the treatment of patients with TMD with evidence of pain centralization may help ameliorate both pain and jaw dysfunction.

Multimodal hypersensitivity (MMH)—greater sensitivity across multiple sensory modalities (e.g., light, sound, temperature, pressure)—is hypothesized to be responsible for the development of chronic pain and pelvic pain. However, previous studies of MMH are restricted given their reliance on biased self-report questionnaires, limited use of multimodal quantitative sensory testing (QST), or limited follow-up. Therefore, we conducted multimodal QST on a cohort of 200 reproductive age women at elevated risk for developing or maintaining chronic pelvic pain conditions and pain-free controls. Pelvic pain self-report was examined over a four-year follow-up period. Multimodal QST was comprised of visual, auditory, bodily pressure, pelvic pressure, thermal, and bladder testing. A principal component analysis of QST measures resulted in three orthogonal factors that explained 43% of the variance: MMH, pressure stimulus-response, and bladder hypersensitivity. MMH and bladder hypersensitivity factors correlated with baseline self-reported menstrual pain, genitourinary symptoms, depression, anxiety, and health. Baseline self-report pain ratings were significant predictors of pelvic pain up to three years after assessment but decreased in their predictive ability of pelvic pain outcome over time. In contrast, MMH increased its predictive ability of pelvic pain outcome over time and was the only factor to predict outcome up to four years later. These results suggest that a “centralized” component of MMH is an important long-term risk factor for pelvic pain. Further research on the modifiability of MMH could provide options for future treatment avenues for chronic pain.

Objective Perceived cognitive dysfunction in fibromyalgia (FM), "fibrofog," is common. Prior laboratory-based studies have limited our understanding of cognitive function in FM in daily life. The objective of this study was to explore levels of subjective and objective cognitive functioning and the association between subjective and objective aspects of cognition in people with and without FM in the lived environment. Methods Participants (n = 50 adults with FM; n = 50 adults without FM, matched for age, sex, and education) completed baseline measures of subjective and objective cognitive functioning (NIH Toolbox). They also completed ecological momentary assessments of cognitive clarity and speed and tests of processing speed and working memory, via a smart phone app, 5×/day for 8 days. Results On baseline objective measures, the FM group demonstrated poorer cognitive functioning across 3 NIH Toolbox tests. There were no strong correlations between subjective and objective cognitive functioning in both the FM and control groups. In the lived environment, the FM group demonstrated poorer subjective cognition and objective working memory; groups did not differ on processing speed. Momentary ratings of subjective cognitive dysfunction were significantly related to changes in objective processing speed but not working memory, with no group differences. Conclusion Findings indicate worse laboratory-based and ambulatory subjective and objective cognitive function for those individuals with FM compared to those without FM. Similar associations between measures of subjective and objective cognitive functioning for the groups suggest that people with FM are not overstating cognitive difficulties. Future research examining contributors to ambulatory fibrofog is warranted.

Objective To determine the association between dysregulated central pain processing and treatment response in rheumatoid arthritis (RA). Methods One hundred eighty-two participants with active RA were followed up for 12 weeks after starting a disease-modifying antirheumatic drug (DMARD). To assess central pain processing, participants underwent quantitative sensory testing (QST), including assessment of pressure pain thresholds (PPTs) at the trapezius muscles, temporal summation, and conditioned pain modulation (CPM). QST measures were categorized as high central dysregulation versus low central dysregulation. The association between baseline central dysregulation and treatment response, as defined by the European League Against Rheumatism (EULAR) response criteria, was assessed using multiple logistic regression adjusted for demographic characteristics, RA-related variables, and psychosocial variables. Results A good EULAR response was achieved in fewer participants with high CPM dysregulation than participants with low CPM dysregulation (22.5% versus 40.3%; P = 0.01). A similar trend, though not significant, was noted when central dysregulation was assessed with PPT and temporal summation. The adjusted odds ratios (ORs) for the association between high central dysregulation and good EULAR response were 0.59 for PPTs (95% confidence interval [95% CI] 0.28-1.23), 0.60 for temporal summation (95% CI 0.27-1.34), and 0.40 for CPM (95% CI 0.19-0.83). In a model examining the combined effects of dysregulated temporal summation and CPM, dysregulation of both measures was associated with lower odds of achieving a good EULAR response (OR 0.23 [95% CI 0.07-0.73]). Conclusion Low CPM was significantly associated with lower odds of achieving a good EULAR response, suggesting that inefficient descending inhibitory mechanisms may be a potential treatment target for further study.

Objective Pain is a significant burden for patients with rheumatoid arthritis (RA) despite advancements in treatment. We undertook this study to examine the independent contribution of pain centralization to the pain experience of patients with active RA. Methods A total of 263 RA patients with active disease underwent quantitative sensory testing (QST), including assessment of extraarticular pressure pain thresholds (PPTs), temporal summation (TS), and conditioned pain modulation (CPM). The pain experience was assessed by a pain intensity numeric rating scale and the Patient-Reported Outcomes Measurement Information System pain interference computerized adaptive test. We examined associations between QST measures and pain intensity and pain interference. Multiple linear regression models were adjusted for demographic and clinical variables, including swollen joint count and C-reactive protein level. Results Patients with the lowest PPTs (most central dysregulation) reported higher pain intensity than patients with the highest PPTs (adjusted mean difference 1.02 [95% confidence interval (95% CI) 0.37, 1.67]). Patients with the highest TS (most central dysregulation) had higher pain intensity than those with the lowest TS (adjusted mean difference 1.19 [95% CI 0.54, 1.84]). CPM was not associated with differences in pain intensity. PPT and TS were not associated with pain interference. Patients with the lowest CPM (most centrally dysregulated) had lower pain interference than patients with the highest CPM (adjusted mean difference -2.35 [95% CI -4.25, -0.44]). Conclusion Pain centralization, manifested by low PPTs and high TS, was associated with more intense pain. Clinicians should consider pain centralization as a contributor to pain intensity, independent of inflammation.

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.

Background and aims The ACR1990 criteria of fibromyalgia (FM) have been criticized due to poor reliability of tender points counting (TPC), inconsistent definitions of the widespread pain, and by not considering other symptoms than pain in the FM phenotype. Therefore, several newer self-report measures for FM criteria have emerged. The aim of this study was to translate the fibromyalgia survey questionnaire (FSQ) to Norwegian and validate both the 2011 and the 2016 fibromyalgia survey diagnostic criteria (FSDC) against the ACR1990 criteria. Methods One hundred and twenty chronic pain patients formerly diagnosed with fibromyalgia according to the ACR1990 criteria, and 62 controls not diagnosed or where fibromyalgia was not suspected, were enrolled in this study. All responded to a Norwegian version of the FSQ. Also, they had a clinical examination according to ACR1990 fibromyalgia criteria including a counting of significant tender points with an algometer (TPC). The FSQ with the Widespread Pain Index (WPI) and Symptom Severity scale (SSS) subscales, Fibromyalgia Severity (FS) sum score, was examined for correlations with the fibromyalgia impact questionnaire (FIQ) and TPCs. Face-validity, internal consistence, test-retest reliability and construct validity with convergent and divergent approaches were examined and a Receiver Operating Characteristics (ROC) analysis was performed. Results The internal consistency of FS measured by Cronbach’s alfa was good (=0.904). The test-retest reliability measures using intra class correlation were respectable for the FS, including WPI and SSS subscales (0.86, 0.84 and 0.87). FS, WPI and SSS correlated significantly with FIQ (0.74, 0.59 and 0.85) and TPC indicating an adequate construct, convergent validity. The medians of FS, WPI and SSS in the fibromyalgia-group were significantly different from the non-fibromyalgia-group indicating good construct, divergent validity. Using the 2011 and 2016 FSDC vs. ACR 1990 as a reference, sensitivity, specificity, positive likelihood ratio (LR +) and negative likelihood ratio (LR−) were identified. The accuracy rate for both 2011 and 2016 FSDC were respectable (84%). ROC analysis using FS revealed a very good Area Under the Curve (AUC) = 0.860. Conclusion The current study revealed that the Norwegian versions of FSQ is a valid tool for assessment of fibromyalgia according to the 2011 and 2016 (FSDC).

Aims The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network initiated a second observational cohort study-the Symptom Patterns Study (SPS)-to further investigate the underlying pathophysiology of Urologic Chronic Pelvic Pain Syndrome (UCPPS) and to discover factors associated with longitudinal symptom changes and responses to treatments. Methods This multisite cohort study of males and females with UCPPS features a run-in period of four weekly web-based symptom assessments before a baseline visit, followed by quarterly assessments up to 36 months. Controls were also recruited and assessed at baseline and 6 months. Extensive clinical data assessing urological symptoms, nonurological pain, chronic overlapping pain syndromes, and psychosocial factors were collected. Diverse biospecimens for biomarker and microbiome studies, quantitative sensory testing (QST) data under multiple stimuli, and structural and functional neuroimaging scans were obtained under a standardized protocol. Results Recruitment was initiated (July 2015) and completed (February 2019) at six discovery sites. A total of 620 males and females with UCPPS and 73 Controls were enrolled, including 83 UCPPS participants who re-enrolled from the first MAPP Network cohort study (2009-2012). Baseline neuroimaging scans, QST measures, and biospecimens were obtained on 578 UCPPS participants. The longitudinal follow-up of the cohort is ongoing. Conclusions This comprehensive characterization of a large UCPPS cohort with extended follow-up greatly expands upon earlier MAPP Network studies and provides unprecedented opportunities to increase our understanding of UCPPS pathophysiology, factors associated with symptom change, clinically relevant patient phenotypes, and novel targets for future interventions.

As many as one third of patients undergoing minimally invasive thoracic surgery and one half undergoing thoracotomy will have chronic pain, defined as pain lasting 2 to 3 months. There is limited information regarding predictors of chronic pain and even less is known about its impact on health-related quality of life, known as pain interference. Currently, there is a focus on decreased opioid prescribing after surgery. Interestingly, thoracic surgical patients are the least likely to be receiving opioids before surgery and have the highest rate of new persistent opioid use after surgery compared with other surgical cohorts. These studies of opioid use have identified important predictors of new persistent opioid use, but their findings are limited by failing to correlate opioid use with pain. The objectives of this invited review are to present the findings of pertinent studies of chronic pain and opioid use after thoracic surgery, "where we are," and to discuss gaps in our knowledge of these topics and opportunities for research to fill those gaps, "where we need to go."

Cannabis is widely used for chronic pain. However, there is some evidence of an inverse dose–response relationship between cannabis effects and pain relief that may negatively affect analgesic outcomes. In this cross-sectional survey, we examined whether daily cannabis use frequency was associated with pain severity and interference, quality of life measures relevant to pain (eg, anxiety and depressive symptoms), and cannabis use preferences (administration routes and cannabinoid ratio). Our analysis included 989 adults who used cannabis every day for chronic pain. Participant use was designated as light, moderate, and heavy (1–2, 3–4, and 5 or more cannabis uses per day, respectively). The sample was also subgrouped by self-reported medical-only use (designated MED, n = 531, 54%) versus medical use concomitant with a past-year history of recreational use (designated MEDREC, n = 458, 46%). In the whole sample, increased frequency of use was significantly associated with worse pain intensity and interference, and worse negative affect, although high-frequency users also reported improved positive affect. Subgroup analyses showed that these effects were driven by MED participants. Heavy MED participant consumption patterns showed greater preference for smoking, vaporizing, and high tetrahydrocannabinol products. In contrast, light MED participants had greater preference for tinctures and high cannabidiol products. Selection bias, our focus on chronic pain, and our cross-sectional design likely limit the generalizability of our results. Our findings suggest that lower daily cannabis use frequency is associated with better clinical profile as well as lower risk cannabis use behaviors among MED participants. Future longitudinal studies are needed to examine how high frequency of cannabis use interacts with potential therapeutic benefits. Perspective Our findings suggest that lower daily cannabis use frequency is associated with better clinical profile as well as safer use behaviors (eg, preference for cannabidiol and noninhalation administration routes). These trends highlight the need for developing cannabis use guidelines for clinicians to better protect patients using cannabis.

Objectives Quantitative sensory testing may help predict treatment responses in individuals with chronic pain. Our objective was to determine whether evoked pain sensitivity at baseline predicted preferential treatment responses to either emotional awareness and expression therapy (EAET) or cognitive behavioral therapy (CBT) in individuals with fibromyalgia (FM). Methods This was a secondary analysis of a previous randomized clinical trial, in which individuals with FM were randomized to EAET, CBT, or Education as a control intervention. Only females who completed baseline and post-treatment assessments were analyzed (n=196). The primary outcome was change in overall clinical pain severity from pretreatment to posttreatment, and the primary predictor of interest was pressure pain tolerance at baseline. Results Among patients with low pain tolerance at baseline (n=154), both EAET and CBT led to small but significant improvements in clinical pain severity (CBT mean=0.66, 95% confidence interval [0.24-1.07]; EAET mean=0.76 [0.34-1.17]). Conversely, in patients with normal pain tolerance (n=42), there was no significant improvement in clinical pain after CBT (0.13 [-0.88 to 1.14]), a small improvement after FM Education (0.81 [0.14-1.48]), but a much larger and statistically significant improvement after EAET (2.14 [1.23-3.04]). Discussion Normal levels of pressure pain tolerance at baseline predicted greater improvement in clinical pain severity after EAET than CBT. Quantitative sensory testing may provide insights about individual responses to psychologically based therapies for individuals with chronic pain.

Objective Many studies suggest a strong familial component to fibromyalgia (FM). However, those studies have nearly all been confined to individuals with primary FM, i.e., FM without any other accompanying disorder. The current 2011 and 2016 criteria for diagnosing FM construct a score using a combination of the number of painful body sites and the severity of somatic symptoms (FM score). This study was undertaken to estimate the genetic heritability of the FM score across sex and age groups to identify subgroups of individuals with greater heritability, which may help in the design of future genetic studies. Methods We collected data on 26,749 individuals of European ancestry undergoing elective surgery at the University of Michigan (Michigan Genomics Initiative study). We estimated the single-nucleotide polymorphism-based heritability of FM score by age and sex categories using genome-wide association study data and a linear mixed-effects model. Results Overall, the FM score had an estimated heritability of 13.9% (SE 2.9%) (P = 1.6 × 10-7 ). Estimated FM score heritability was highest in individuals ≤50 years of age (23.5%; SE 7.9%) (P = 3.0 ×10-4 ) and lowest in individuals >60 years of age (7.5%; SE 8.1%) (P = 0.41). These patterns remained the same when we analyzed FM as a case-control phenotype. Even though women had an ~30% higher average FM score than men across age categories, FM score heritability did not differ significantly by sex. Conclusion Younger individuals appear to have a much stronger genetic component to the FM score than older individuals. Older individuals may be more likely to have what was previously called "secondary FM." Regardless of the cause, these results have implications for future genetic studies of FM and associated conditions.

Background: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating condition carrying substantial psychosocial burden. Psychological treatment for IC/BPS is little studied, and there are barriers to its use in clinical management. Whether psychological treatments benefit patients with IC/BPS is unclear and we do not know whether such treatments would meet patient needs. Aims: Incorporating patient-reported needs and acknowledging diversity in pain experiences can inform patient-centered interventions for IC/BPS. This project characterized the experience of living with IC/BPS and patient perceptions of needs in its treatment, with the goal of informing patient-centered treatment for IC/BPS. Methods: Using both quantitative and qualitative methods, 27 females with IC/BPS participated in a focus group and completed validated self-report assessments evaluating urinary symptoms, pain, and emotional functioning. Focus groups were audio recorded and transcribed and then coded and analyzed using an iterative inductive/deductive approach. Linear regression models evaluated the relationship between psychological functioning and symptom severity. Results: We conducted six focus groups between August and December 2017. Five major themes emerged from qualitative analysis: managing physical symptoms, emotional symptoms, impact on daily life and socio-contextual factors, responding to illness, and addressing needs in treatment. The physiological and emotional consequences of IC/BPS were reported, highlighting their impact on interpersonal relationships and challenges in obtaining appropriate treatment for IC/BPS. Quantitative analysis showed that depression levels were significantly associated with worsened IC/BPS symptomology, after controlling for known confounding factors. Conclusion: Individuals with IC/BPS could benefit from tailored psychological interventions focusing on pain management, emotion regulation, communications skills, along with sexual dysfunction and intimacy fears.

Pain, fatigue, and depression frequently co-occur as a symptom cluster. While commonly occurring in those with cancer and autoimmune disease, the cluster is also found in the absence of systemic illness or inflammation. Loneliness is a common psychosocial stressor associated with the cluster cross-sectionally. We investigated whether loneliness predicted the development of pain, fatigue, depression, and the symptom cluster over time.Data from the Health and Retirement Study were used. We included self-respondents ≥50 year-old who had at least two measurements of loneliness and the symptom cluster from 2006-2016 (n = 5974). Time-varying loneliness was used to predict pain, fatigue, depression, and the symptom cluster in the subsequent wave(s) using generalized estimating equations (GEE) and adjusting for sociodemographic covariates, living arrangement, and the presence of the symptom(s) at baseline.Loneliness increased the odds of subsequently reporting pain (aOR 1.22, 95% CI 1.08, 1.37), fatigue (aOR 1.47, 95% CI 1.32, 1.65), depression (aOR 2.33, 95% CI 2.02, 2.68), as well as the symptom cluster (aOR 2.15, 95% CI 1.74, 2.67). The median time between the baseline and final follow-up measurement was 7.6 years (IQR 4.1, 8.2).Loneliness strongly predicts the development of pain, fatigue, and depression as well as the cluster of all three symptoms several years later in a large, nonclinical sample of older American adults. Future studies should examine the multiple pathways through which loneliness may produce this cluster, as well as examine whether other psychosocial stressors also increase risk. It is possible that interventions which address loneliness in older adults may prevent or mitigate the cluster of pain, fatigue, and depression.

Pediatric chronic pain represents heterogeneous diagnoses; often, primary pain location informs research classifications and treatment. In contrast, recent research has highlighted the role of widespread pain and this perspective has been adopted in assessments in specialty pediatric pain clinics. The lack of direct comparison between these 2 methods of categorizing pediatric chronic pain may hinder the adoption of evidence-based practices across the spectrum of care. Therefore, this study aimed to compare whether primary pain location or pain widespreadedness is more informative for pain-related symptoms in pediatric chronic pain.Youth (n=223) between the ages of 8 to 23 years (M=15.93, SD=2.11, 83% female) completed surveys upon intake at the pediatric chronic pain clinic. Free-text entries of primary pain location were coded into categories: headache, abdominal pain, and musculoskeletal pain. Additional domains assessed included widespread pain, pain interference, kinesiophobia, catastrophizing, anxiety, depression, sleep, and fatigue.Differences based on primary pain location only emerged for kinesiophobia, F(2150)=8.20, P0.001, with the highest scores among those with musculoskeletal pain. In contrast, controlling for sex, age, and pain intensity, pain widespreadedness was associated with pain interference, pain catastrophizing, fatigue, anxiety, and depression (P0.05).Pain widespreadedness was more consistently associated with pain-related outcomes among pediatric chronic pain patients than primary pain location, and body maps may be useful in determining a nociplastic pain mechanism to inform treatment. Improved assessment of pediatric pain mechanisms may help advance more precise treatment delivery.

Sleep problems are common in individuals with chronic low back pain (CLBP). Central sensitization (CS) is present in a subgroup of individuals with CLBP. However, our knowledge about whether sleep quality varies between the subgroups of CLBP is limited. Therefore, we sought to examine whether the subgroup of CLBP with CS has poorer sleep quality than the subgroup without CS.2011 Fibromyalgia Survey (2011 FM survey) was used as a surrogate measure of CS to divide the CLBP participants into two subgroups: CLBP with CS and CLBP without CS. We also created a CS index comprising a set of quantitative sensory testing measures (i.e., pressure pain thresholds, conditioned pain modulation) to evaluate pain sensitivity. Sleep quality was assessed with Pittsburgh Sleep Quality Index (PSQI). Group differences about PSQI and CS index and associations between sleep quality and CS across the groups were analyzed.We included 60 participants with CLBP and 23 healthy controls (HCs). Overall, 80% of the participants with CLBP presented with poor sleep quality. Participants with CLBP with CS showed significantly higher PSQI scores (poorer sleep) than participants with CLBP without CS and HCs (p 0.05). Both the 2011 FM survey and CS index were significantly correlated with sleep quality (r = 0.5870, p 0.001 and r = -0.264, p = 0.04). Logistic regression models revealed that the FM status (odds ratio (OR) = 6.00, p = 0.02 [95% confidence interval: 1.31-42.1]), but not the CS index (OR = 1.11, p = 0.79 [95% CI: 0.48-2.71]) was associated with PSQI. After adjusting covariates, the results remained similar but became non-significant for the FM status.We found that sleep problems were more common and severe in those who exhibited signs of CS. Thus, clinicians may consider using 2011 FM survey to identify those with CS and co-existing sleep problems.

Persistent fatigue is common among military servicemembers returning from deployment, especially those with a history of mild traumatic brain injury (mTBI). The purpose of this study was to characterize fatigue following deployment using the Multidimensional Fatigue Inventory (MFI), a multidimensional self-report instrument. The study was developed to test the hypothesis that if fatigue involves disrupted effort/reward processing, this should manifest as altered basal ganglia functional connectivity as observed in other amotivational states.Twenty-eight current and former servicemembers were recruited and completed the MFI. All 28 participants had a history of at least one mTBI during deployment. Twenty-six participants underwent resting-state functional MRI. To test the hypothesis that fatigue was associated with basal ganglia functional connectivity, the investigators measured correlations between MFI subscale scores and the functional connectivity of the left and right caudate, the putamen, and the globus pallidus with the rest of the brain, adjusting for the presence of depression.The investigators found a significant correlation between functional connectivity of the left putamen and bilateral superior frontal gyri and mental fatigue scores. No correlations with the other MFI subscales survived multiple comparisons correction.This exploratory study suggests that mental fatigue in military servicemembers with a history of deployment with at least one mTBI may be related to increased striatal-prefrontal functional connectivity, independent of depression. A finding of effort/reward mismatch may guide future treatment approaches.

BackgroundPatients with rheumatoid arthritis (RA) commonly demonstrate disordered pain processing, termed pain centralization. Heightened pain sensitivity and pain pathways associated with pain centralization are often assessed using quantitative sensory testing (QST), which is not routinely available and burdensome to patients. The self-administered fibromyalgia survey questionnaire (FSQ) has been proposed as a low-burden, surrogate measure of pain centralization. We examined the correlation between FSQ and QST as measures of pain centralization in a cohort of patients with active RA. MethodsParticipants in the multicenter Central Pain in Rheumatoid Arthritis (CPIRA) cohort underwent FSQ and QST evaluation at enrollment. QST measures included pressure pain threshold (PPT) at the thumb, trapezius, wrist and knee; temporal summation (TS) at the wrist and arm; and conditioned pain modulation (CPM). Partial Spearman correlation was assessed between FSQ and each QST measure, adjusted for age, sex, race, body mass index, serologic status, swollen joint count, C-reactive protein, pain catastrophizing, and study site. We performed sensitivity analyses including a) stratified analysis by sex and b) correlations between the two sub-components of the FSQ (widespread pain index [WPI], and symptom severity scale [SSS]) and QST measures.ResultsAmong 285 participants with high RA disease activity (mean baseline Clinical Disease Activity Index score 24.56), FSQ was weakly but statistically significantly correlated with PPT ( r = -0.21 to -0.31) and TS ( r = 0.13 to 0.15) at all sites in unadjusted analyses. After adjustment, statistically significant correlations persisted for PPT at all sites except the thumb, and for TS at the wrist Sensitivity analyses did not identify differences in association based on sex or with the components of the FSQ (WPI or SSS).ConclusionsFSQ and QST were correlated among participants with active RA, but the strength of association was modest. This may be due to the high level of RA disease activity of the cohort studied. Both QST and the FSQ are likely imperfect singular measures of pain centralization.

Objective:\ud \ud Rheumatoid arthritis (RA) patients with concomitant fibromyalgia (FM) exhibit alterations in brain connectivity synonymous with central sensitization. This study was undertaken to investigate how peripheral inflammation, the principal nociceptive stimulus in RA, interacts with brain connectivity in RA patients with FM.\ud Methods:\ud \ud RA patients with concomitant FM and those without FM (FM+ and FM−, respectively; n = 27 per group) underwent functional connectivity magnetic resonance imaging. Seed‐to–whole‐brain functional connectivity analyses were conducted using seeds from the left mid/posterior insula and left inferior parietal lobule (IPL), which are regions that have been previously linked to FM symptoms and inflammation, respectively. The association between functional connectivity and erythrocyte sedimentation rate (ESR) was assessed in each group separately, followed by post hoc analyses to test for interaction effects. Cluster‐level, family‐wise error (FWE) rates were considered significant if the P value was less than 0.05.\ud Results:\ud \ud The group of RA patients with FM and those without FM did not differ by age, sex, or ESR (P > 0.2). In FM+ RA patients, increased functional connectivity of the insula–left IPL, left IPL–dorsal anterior cingulate, and left IPL–medial prefrontal cortex regions correlated with higher levels of ESR (all FWE‐corrected P < 0.05). Post hoc interaction analyses largely confirmed the relationship between ESR and connectivity changes as FM scores increased.\ud Conclusion:\ud \ud We report the first neurobiologic evidence that FM in RA may be linked to peripheral inflammation via pronociceptive patterns of brain connectivity. In patients with such “bottom‐up” pain centralization, concomitant symptoms may partially respond to antiinflammatory treatments.

Cannabis is commonly used to manage chronic pain, but cannabis use patterns among individuals with chronic pain, has not been well-characterized. We report cannabinoid, administration route, and product selection preferences among medical cannabis users with chronic pain from an ongoing, online survey. We also examined whether these preferences are affected by differences in sex, intentions behind use (medical only [MED] vs medical + recreational [MEDREC]), and experience with cannabis (novice:1 year vs experienced: ≥1 year). The survey was completed by 1,321 participants (59% female) 76.5% of whom used cannabis every day. 93.4% used 2 or more administration routes and 72.5% used 3 or more. Female, MED, and novice users were less likely to smoke or vaporize (all P.0001), but more likely to rank edibles, tinctures, and topicals as a first-choice administration route than their counterparts. Female and MED users also preferred low THC: high cannabidiol ratios significantly more than their counterparts. Overall, only 2.6% of participants selected cannabis products with input from a medical professional, although 54.9% relied on advice from dispensary employees. More male, MEDREC, and experienced users selected products based on factors that reflected greater comfort with cannabis (eg, smell, visual properties, cannabis variety). The wide variability in cannabis use among these different groups indicates the need for further research to investigate how specific use routines relate to clinical outcomes. PERSPECTIVE: Medical cannabis users with chronic pain show distinct differences in cannabinoid preferences and administration associated with user sex, intentions behind use, and experience with cannabis. This article highlights the wide variability in cannabis preferences among medical cannabis users with chronic pain, which may be relevant for clinical outcomes.

OBJECTIVES: Limited research suggests commonalities between urologic chronic pelvic pain syndromes (UCPPS) and other non-urologic chronic overlapping pain conditions (COPCs) including fibromyalgia, chronic fatigue syndrome, and irritable bowel syndrome. The goal of this case-control study was to examine similarities and differences between UCPPS and these other COPCs. METHODS: As part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network, we examined 1,039 individuals with UCPPS (n = 424), non-urologic COPCs (n = 200), and healthy controls (n = 415). Validated standardized measures were used to assess urological symptoms, non-urological pain symptoms, and psychosocial symptoms and traits. RESULTS: Participants with UCPPS had more urologic symptoms than non-urologic COPCs or healthy controls (p < 0.001); non-urological COPC group also had significantly worse urological symptoms than healthy controls (p < 0.001). Participants with non-urological COPCs reported more widespread pain than those with UCPPS (p < 0.001), yet both groups had similarly increased symptoms of anxiety, depression, negative affect, perceived stress, neuroticism, and lower levels of extraversion than healthy controls (p < 0.001). Participants with UCPPS with and without COPCs reported more catastrophizing than those with non-urological COPCs (p < 0.001). DISCUSSION: Findings are consistent with the hypothesis of common underlying biopsychosocial mechanisms and can guide the comprehensive assessment and treatment of these conditions regardless of the primary site of pain or diagnosis. Heightened catastrophizing in UCPPS should be examined to inform psychosocial interventions and improve patient care.

OBJECTIVE To evaluate the effects of shared decision making using a simple decision aid for opioid prescribing after hysterectomy. METHODS We conducted a prospective quality initiative study including all patients undergoing hysterectomy for benign, nonobstetric indications between March 1, 2018, and July 31, 2018, at our academic institution. Using a visual decision aid, patients received uniform education regarding postoperative pain management. They were then educated on the department's guidelines regarding the maximum number of tablets recommended per prescription and the mean number of opioid tablets used by a similar cohort of patients in a previously published study at our institution. Patients were then asked to choose their desired number of tablets to receive on discharge. Structured telephone interviews were conducted 14 days after surgery. The primary outcome was total opioids prescribed before compared with after implementation of the decision aid. Secondary outcomes included opioid consumption, patient satisfaction, and refill requests after intervention implementation. RESULTS Of 170 eligible patients, 159 (93.5%) used the decision aid (one patient who used the decision aid was subsequently excluded from the analysis owing to significant perioperative complications), including 110 (69.6%) laparoscopic, 40 (25.3%) vaginal, and eight (5.3%) abdominal hysterectomies. Telephone surveys were completed for 89.2% (n=141) of participants. Student's t-test showed that patients who participated in the decision aid (post-decision aid cohort) were discharged with significantly fewer oral morphine equivalents than patients who underwent hysterectomy before implementation of the decision aid (pre-decision aid cohort) (92±35 vs 160±81, P

OBJECTIVE: Determine preoperative patient characteristics associated with postoperative outpatient opioid use and assess the frequency of postoperative opioid overprescribing. SUMMARY BACKGROUND DATA: Although characteristics associated with inpatient opioid use have been described, the patient factors associated with opioid use after discharge are unknown but could inform the development of individualized approaches to postoperative prescribing. METHODS: We included opioid-naïve patients undergoing hysterectomy, thoracic surgery, and total knee and hip arthroplasty in a single-center prospective observational cohort study. Preoperative phenotyping included self-report measures to assess pain severity, fibromyalgia survey criteria score, pain catastrophizing, depression, anxiety, functional status, fatigue, and sleep disturbance. Our primary outcome measure was self-reported total opioid use in oral morphine equivalents (OMEs). We constructed multivariable linear regression models predicting opioids consumed in the first postoperative month. RESULTS: We enrolled 1,181 patients; 1,001 had complete primary outcome data and 913 had complete phenotype data. Younger age, non-Caucasian race, lack of a college degree, higher anxiety, greater sleep disturbance, heavy alcohol use, current tobacco use, and larger initial opioid prescription size were associated with increased opioid consumption. Median total OMEs prescribed was 600 (equivalent to 120 5-mg hydrocodone pills), while median opioid consumption was 188 OMEs (38 pills). CONCLUSIONS: In this prospective cohort of opioid-naïve patients undergoing major surgery, we found a number of characteristics associated with greater opioid use in the first month after surgery. Future studies should address the use of non-opioid medications and behavioral therapies in the perioperative period for these higher risk patients.

Fibromyalgia (FM) is a common chronic pain disorder that presents diagnostic challenges for clinicians. Several classification, diagnostic and screening criteria have been developed over the years, but there continues to be a need to develop criteria that reflect the current understanding of FM and are practical for use by clinicians and researchers. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) public-private partnership with the U.S. Food and Drug Administration (FDA) and the American Pain Society (APS) initiated the ACTTION-APS Pain Taxonomy (AAPT) to develop a diagnostic system that would be clinically useful and consistent across chronic pain disorders. The AAPT established an international FM working group consisting of clinicians and researchers with expertise in FM to generate core diagnostic criteria for FM and apply the multidimensional diagnostic framework adopted by AAPT to FM. The process for developing the AAPT criteria and dimensions included literature reviews and synthesis, consensus discussions, and analyses of data from large population-based studies conducted in the United Kingdom. The FM working group established a revised diagnosis of FM and identified risk factors, course, prognosis, and pathophysiology of FM. Future studies will assess the criteria for feasibility, reliability, and validity. Revisions of the dimensions will also be required as research advances our understanding of FM. PERSPECTIVE: The ACTTION-APS FM taxonomy provides an evidence-based diagnostic system for FM. The taxonomy includes diagnostic criteria, common features, comorbidities, consequences, and putative mechanisms. This approach might improve the recognition of FM in clinical practice.

Chronic pain is a common public health problem that has a detrimental impact on patient health, quality of life (QoL), and function, and poses a substantial socioeconomic burden. Evidence supports the redefinition of chronic pain as a distinct disease entity, not simply a symptom of injury or illness. Chronic pain conditions are characterized by three types of pain pathophysiology (i.e. nociceptive, neuropathic, and centralized pain/central sensitization) influenced by a cluster of coexisting psychosocial factors. Negative risk/vulnerability factors (e.g. mood or sleep disturbances) and positive resilience/protective factors (e.g. social/interpersonal relationships and active coping) interact with pain neurobiology to determine patients' unique pain experience. Viewing chronic pain through a biopsychosocial lens, instead of a purely biomedical one, clinicians need to adopt a practical integrated management approach. Thorough assessment focuses on the whole patient (not just the pain), including comorbidities, cognitive/emotional/behavioral characteristics, social environment, and QoL/functional impairment. As for other complex chronic illnesses, the treatment plan for chronic pain can be developed based on pain subtype and psychosocial profile, incorporating pharmacotherapy and self-management modalities. Preferred pharmacologic treatment of conditions primarily associated with nociception (e.g. osteoarthritis) includes acetaminophen and non-steroidal anti-inflammatory drugs, whereas preferred pharmacologic treatment of conditions primarily associated with neuropathy or central sensitization (e.g. fibromyalgia) includes tricyclic compounds, serotonin-norepinephrine reuptake inhibitors, and α2δ ligands. Education, exercise, cognitive behavioral therapy, and many other non-pharmacological approaches, alone or combined with pharmacotherapy, have been shown to be effective for any type of pain, although they remain underutilized due to lack of awareness of their benefits and reimbursement obstacles.

Experimental pain sensitivity was assessed in individuals with urologic chronic pelvic pain syndrome (UCPPS) as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. A series of computer-controlled pressure stimuli were delivered to the thumbnail bed, an asymptomatic site distant from the area of UCPPS pain that is considered to be indicative of overall body pain threshold. Stimuli were rated according to a standardized magnitude estimation protocol. Pain sensitivity in participants with UCPPS was compared with healthy controls and a mixed pain group composed of individuals with other chronic overlapping pain conditions, including fibromyalgia, chronic fatigue, and irritable bowel syndromes. Data from 6 participating MAPP testing sites were pooled for analysis. Participants with UCPPS (n = 153) exhibited an intermediate pain sensitivity phenotype: they were less sensitive relative to the mixed pain group (n = 35) but significantly more sensitive than healthy controls (n = 100). Increased pain sensitivity in patients with UCPPS was associated with both higher levels of clinical pain severity and more painful body areas outside the pelvic region. Exploratory analyses in participants with UCPPS revealed that pain sensitivity increased during periods of urologic symptom flare and that less pressure pain sensitivity at baseline was associated with a greater likelihood of subsequent genitourinary pain improvement 1 year later. The finding that individuals with UCPPS demonstrate nonpelvic pain hypersensitivity that is related to clinical symptoms suggests that central nervous system mechanisms of pain amplification contribute to UCPPS.

Altered brain structure and function is evident in adults with multisite chronic pain. Although many such adults trace their pain back to childhood, it has been difficult to disentangle whether central nervous system alterations precede or are consequences of chronic pain. If the former is true, aberrant brain activity may identify children vulnerable to developing chronic pain later in life. We examined structural and functional brain magnetic resonance imaging metrics in a subset of children from the first two assessments of the Adolescent Brain and Cognitive Development (ABCD) Study. Children (ages 9-10) who were pain-free at baseline and then developed multisite pain one year later (n=115) were matched to control children who were pain-free at both timepoints (n=230). We analyzed brain structure (cortical thickness and gray matter volume) and function (spontaneous neural activity and functional connectivity). Results were deemed significant at the cluster level p < 0.05 false discovery rate corrected for multiple comparisons. At baseline, children who subsequently developed multisite pain had increased neural activity in superior parietal/primary somatosensory and motor cortices and decreased activity in the medial prefrontal cortex. They also exhibited stronger functional connectivity between the salience network, somatosensory and default mode network regions. No significant differences in brain structure were observed. Increased neural activity and functional connectivity between brain regions, consistent to that seen in adults with chronic pain, exist in children prior to developing multisite pain. These findings may represent a neural vulnerability to developing future chronic pain.

Objective Immune-mediated inflammatory diseases (IMID) are characterized by systemic inflammation affecting the joints and bodily organs. Studies examining the association between individual IMIDs and the risk of Alzheimer’s disease (AD) have yielded inconsistent findings. This study examines AD risk across a group of IMIDs in a large population-based sample of older adults. Methods Data on a national sample of US adults over age 50 was drawn from the Health and Retirement Study (HRS) and linked Medicare claims from 2006 to 2014. IMIDs include rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and related conditions. We identified IMIDs from 2006 to 2009 Medicare claims using International Classification of Diseases (ICD9-CM) codes. The date of incident AD was derived from Chronic Conditions Warehouse (CCW) identifiers. We examined the risk of AD from 2009 to 2014 using Cox proportional hazards models, both unadjusted and adjusted for age, gender, education, race, and the genetic risk factor APOE-e4. Results One hundred seventy-one (6.02%) of the 2842 total HRS respondents with Medicare coverage and genetic data were classified with IMIDs. Over the subsequent 6 years, 9.36% of IMID patients developed AD compared to 8.57% of controls (unadjusted hazard ratio (HR): 1.09, 95% CI .66–1.81, p = 0.74). Adjusted HR 1.27 (95% CI 0.76–2.12, p = 0.35). Age (HR for 10-year increment 3.56, p p = .007), and APOE-e4 (HR 2.61, p Conclusion HRS respondents with common IMIDs do not have increased risk of Alzheimer’s disease over a 6-year period.

Objective To examine the impact of educational materials for chronic overlapping pain conditions (COPCs), the feasibility of delivering materials online, and to explore its impact on self-reported self-management applications at 3-month follow-up. Design Prospective cohort study Setting Online Subjects Individuals from a university-wide active research repository with ≥1 coded diagnostic COPC by ICD-9/10 in the medical record. Methods We determined the number of COPCs per participant as indicated by diagnostic codes in the medical record. Consenting participants completed self-report questionnaires and read educational materials. We assessed content awareness and knowledge pre- and post-exposure to education. Comprehension was assessed via embedded questions in reading materials in real time. Participants then completed assessments regarding concept retention, self-management engagement, and pain-related symptoms at 3-months. Results N = 216 individuals enrolled, with 181 (84%) completing both timepoints. Results indicated that participants understood materials. Knowledge and understanding of COPCs increased significantly after education and was retained at 3-months. Patient characteristics suggested the number of diagnosed COPCs was inversely related to age. Symptoms or self-management application did not change significantly over the 3-month period. Conclusions The educational materials facilitated teaching of key pain concepts in self-management programs, which translated easily into an electronic format. Education alone may not elicit self-management engagement or symptom reduction in this population; however, conclusions are limited by the study’s uncontrolled design. Education is likely an important and meaningful first step in comprehensive COPC self-management.

Central sensitization was first described in the 1980s as a spinal mechanism of augmenting painful stimuli, causing hyperalgesia and allodynia. During the years to follow it was discovered that parts of the brain are also involved in this inadequate amplification of sensory inputs.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic debilitating disease characterized by severe and disabling fatigue that fails to improve with rest; it is commonly accompanied by multifocal pain, as well as sleep disruption, and cognitive dysfunction. Even mild exertion can exacerbate symptoms. The prevalence of ME/CFS in the U.S. is estimated to be 0.5-1.5 % and is higher among females. Viral infection is an established trigger for the onset of ME/CFS symptoms, raising the possibility of an increase in ME/CFS prevalence resulting from the ongoing COVID-19 pandemic. Current treatments are largely palliative and limited to alleviating symptoms and addressing the psychological sequelae associated with long-term disability. While ME/CFS is characterized by broad heterogeneity, common features include immune dysregulation and mitochondrial dysfunction. However, the underlying mechanistic basis of the disease remains poorly understood. Herein, we review the current understanding, diagnosis and treatment of ME/CFS and summarize past clinical studies aimed at identifying effective therapies. We describe the current status of mechanistic studies, including the identification of multiple targets for potential pharmacological intervention, and ongoing efforts towards the discovery of new medicines for ME/CFS treatment.

Neural circuitry regulating urine storage in humans has been largely inferred from fMRI during urodynamic studies driven by catheter infusion of fluid into the bladder. However, urodynamic testing may be confounded by artificially filling the bladder repeatedly at a high rate and examining associated time-locked changes in fMRI signals. Here we describe and test a more ecologically-valid paradigm to study the brain response to bladder filling by (1) filling the bladder naturally with oral water ingestion, (2) examining resting state fMRI (rs-fMRI) which is more natural since it is not linked with a specific stimulus, and (3) relating rs-fMRI measures to self-report (urinary urge) and physiologic measures (voided volume). To establish appropriate controls and analyses for future clinical studies, here we analyze data collected from healthy individuals (N = 62) as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. Participants orally ingested approximately 350 mL of water, and had a 10 min “fuller bladder” rs-fMRI scan approximately 1 h later. A second 10 min “empty bladder” rs-fMRI scan was conducted immediately following micturition. We examined multiple spatial scales of brain function, including local activity, circuits, and networks. We found changes in brain function distributed across micturition loci (e.g., subregions of the salience, sensorimotor, and default networks) that were significantly related to the stimulus (volume) and response (urinary urge). Based on our results, this paradigm can be applied in the future to study the neurobiological underpinnings of urologic conditions.

BACKGROUND/OBJECTIVES The physiological mechanisms underlying the pain-modulatory effects of clinical neurostimulation therapies, such as spinal cord stimulation (SCS) and dorsal root ganglion stimulation (DRGS), are only partially understood. In this pilot prospective study, we used patient-reported outcomes (PROs) and quantitative sensory testing (QST) to investigate the physiological effects and possible mechanisms of action of SCS and DRGS therapies. MATERIALS AND METHODS We tested 16 chronic pain patients selected for SCS and DRGS therapy, before and after treatment. PROs included pain intensity, pain-related symptoms (e.g., pain interference, pain coping, sleep interference) and disability, and general health status. QST included assessments of vibration detection theshold (VDT), pressure pain threshold (PPT) and tolerance (PPToL), temporal summation (TS), and conditioned pain modulation (CPM), at the most painful site. RESULTS Following treatment, all participants reported significant improvements in PROs (e.g., reduced pain intensity [p