Florida-California Cancer Research, Education and Engagement (CaRE2) Health Equity Center: Structure, Innovations, and Initial Outcomes.

INTRODUCTION: The Florida-California Cancer Research, Education, and Engagement (CaRE2) Health Equity Center is a triad partnership committed to increasing institutional capacity for cancer disparity research, the diversity of the cancer workforce, and community empowerment. This article provides an overview of the structure, process innovations, and initial outcomes from the first 4 years of the CaRE2 triad partnership. METHODS: CaRE2 serves diverse populations in Florida and California using a "molecule to the community and back" model. We prioritize research on the complex intersection of biological, environmental, and social determinants health, working together with scientific and health disparities communities, sharing expertise across institutions, bidirectional training, and community outreach. Partnership progress and outcomes were assessed using mixed methods and four Program Steering Committee meetings. RESULTS: Research capacity was increased through development of a Living Repository of 81 cancer model systems from minority patients for novel cancer drug development. CaRE2 funded 15 scientific projects resulting in 38 publications. Workforce diversity entailed supporting 94 cancer trainees (92 URM) and 34 ESIs (32 URM) who coauthored 313 CaRE2-related publications and received 48 grants. Community empowerment was promoted via outreaching to more than 3000 individuals, training 145 community cancer advocates (including 28 Community Scientist Advocates), and publishing 10 community reports. CaRE2 members and trainees together have published 639 articles, received 61 grants, and 57 awards. CONCLUSION: The CaRE2 partnership has achieved its initial aims. Infrastructure for translational cancer research was expanded at one partner institution, and cancer disparities research was expanded at the two cancer centers.

CYP2D6-guided opioid therapy for adults with cancer pain: A randomized implementation clinical trial.

INTRODUCTION: The CYP2D6 enzyme metabolizes opioids commonly prescribed for cancer-related pain, and CYP2D6 polymorphisms may contribute to variability in opioid response. We evaluated the feasibility of implementing CYP2D6-guided opioid prescribing for patients with cancer and reported pilot outcome data. METHODS: Adult patients from two cancer centers were prospectively enrolled into a hybrid implementation-effectiveness clinical trial and randomized to CYP2D6-genotype-guided opioid selection, with clinical recommendations, or usual care. Implementation metrics, including provider response, medication changes consistent with recommendations, and patient-reported pain and symptom scores at baseline and up to 8 weeks, were assessed. RESULTS: Most (87/114, 76%) patients approached for the study agreed to participate. Of 85 patients randomized, 71% were prescribed oxycodone at baseline. The median (range) time to receive CYP2D6 test results was 10 (3-37) days; 24% of patients had physicians acknowledge genotype results in a clinic note. Among patients with CYP2D6-genotype-guided recommendations to change therapy (n = 11), 18% had a change congruent with recommendations. Among patients who completed baseline and follow-up questionnaires (n = 48), there was no difference in change in mean composite pain score (-1.01 ± 2.1 vs. -0.41 ± 2.5; p = 0.19) or symptom severity at last follow-up (3.96 ± 2.18 vs. 3.47 ± 1.78; p = 0.63) between the usual care arm (n = 26) and genotype-guided arm (n = 22), respectively. CONCLUSION: Our study revealed high acceptance of pharmacogenetic testing as part of a clinical trial among patients with cancer pain. However, provider response to genotype-guided recommendations was low, impacting assessment of pain-related outcomes. Addressing barriers to utility of pharmacogenetics results and clinical recommendations will be critical for implementation success.

Circulating Inflammatory Biomarkers Predict Pain Change Following Exercise-Induced Shoulder Injury: Findings From the Biopsychosocial Influence on Shoulder Pain Preclinical Trial.

Shoulder pain is a highly prevalent musculoskeletal condition that frequently leads to suboptimal clinical outcomes. This study tested the extent to which circulating inflammatory biomarkers are associated with reports of shoulder pain and upper-extremity disability for a high-risk genetic by psychological subgroup (catechol-O-methyltransferase [COMT] variation by pain catastrophizing [PCS]). Pain-free adults meeting high-risk COMT × PCS subgroup criteria completed an exercise-induced muscle injury protocol. Thirteen biomarkers were collected and analyzed from plasma 48 hours after muscle injury. Shoulder pain intensity and disability (Quick-DASH) were reported at 48 and 96 hours to calculate change scores. Using an extreme sampling technique, 88 participants were included in this analysis. After controlling for age, sex, and BMI, there were moderate positive associations between higher c-reactive protein (CRP; ߈ = .62; 95% confidence interval [CI] = -.03, 1.26), interleukin-6 (IL-6; ߈ = 3.13; CI = -.11, 6.38), and interleukin-10 (IL-10; ߈ = 2.51; CI = -.30, 5.32); and greater pain reduction from 48 to 96 hours post exercise muscle injury. Using an exploratory multivariable model to predict pain changes from 48 to 96 hours, we found participants with higher IL-10 were less likely to experience a high increase in pain (߈ = -10.77; CI = -21.25, -2.69). Study findings suggest CRP, IL-6, and IL-10 are related to shoulder pain change for a preclinical high-risk COMT × PCS subgroup. Future studies will translate to clinical shoulder pain and decipher the complex and seemingly pleiotropic interplay between inflammatory biomarkers and shoulder pain change. PERSPECTIVE: In a preclinical high-risk COMT × PCS subgroup, 3 circulating inflammatory biomarkers (CRP, IL-6, and IL-10) were moderately associated with pain improvement following exercise-induced muscle injury.

Efficiency of pain inhibition and facilitation of fibromyalgia patients is not different from healthy controls: Relevance of sensitivity-adjusted test stimuli.

Background: Pain is a dynamic phenomenon dependent on the balance of endogenous excitatory and inhibitory systems, which can be characterized by quantitative sensory testing. Many previous studies of pain modulatory capacity of patients with fibromyalgia syndrome (FM) have reported decreased pain inhibition or increased pain facilitation. This is the first study to assess pain modulation, including conditioned pain modulation (CPM) and temporal pain summation, in the same healthy control (HC) and FM participants. Methods: Only sensitivity-adjusted stimuli were utilized for testing of conditioned pain modulation (CPM) and temporal pain summation in 23 FM patients and 28 HC. All subjects received sensitivity-adjusted ramp-hold (sRH) during testing of pain facilitation (temporal summation) and pain inhibition (CPM). CPM efficacy was evaluated with test stimuli applied either concurrently or after application of the conditioning stimulus. Finally, the effects of CPM on pressure pain thresholds were tested. Results: FM subjects required significantly less intense test and conditioning stimuli than HC participants to achieve standardized pain ratings of 50 ± 10 numerical rating scale (NRS) (p = 0.03). Using such stimuli, FM subjects' temporal pain summation and CPM efficacy was not significantly different from HC (all p > 0.05), suggesting similar pain facilitation and inhibition. Furthermore, the CPM efficacy of FM and HC participants was similar regardless of whether the test stimuli were applied during or after the conditioning stimulus (p > 0.05). Conclusion: Similar to previous studies, FM participants demonstrated hyperalgesia to heat, cold, and mechanical stimuli. However, using only sensitivity-adjusted stimuli during CPM and temporal summation testing, FM patients demonstrated similarly effective pain inhibition and facilitation than HC, suggesting that their pain modulation is not abnormal.

Enrichment of genomic pathways based on differential DNA methylation profiles associated with knee osteoarthritis pain.

Our study aimed to identify differentially methylated regions (i.e., genomic region where multiple adjacent CpG sites show differential methylation) and their enriched genomic pathways associated with knee osteoarthritis pain (KOA). We recruited cognitively healthy middle to older aged (age 45-85) adults with (n = 182) and without (n = 31) self-reported KOA pain. We also extracted DNA from peripheral blood that was analyzed using MethylationEPIC arrays. The R package minfi (Aryee et al., 2014) was used to perform methylation data preprocessing and quality control. To investigate biological pathways impacted by differential methylation, we performed pathway enrichment analysis using Ingenuity Pathway Analysis (IPA) to identify canonical pathways and upstream regulators. Annotated genes within ± 5 kb of the putative differentially methylated regions (DMRs, p < 0.05) were subjected to the IPA analysis. There was no significant difference in age, sex, study site between no pain and pain group (p > 0.05). Non-Hispanic black individuals were overrepresented in the pain group (p = 0.003). At raw p < 0.05 cutoff, we identified a total of 19,710 CpG probes, including 13,951 hypermethylated CpG probes, for which DNA methylation level was higher in the groups with highest pain grades. We also identified 5,759 hypomethylated CpG probes for which DNA methylation level was lower in the pain groups with higher pain grades. IPA revealed that pain-related DMRs were enriched across multiple pathways and upstream regulators. The top 10 canonical pathways were linked to cellular signaling processes related to immune responses (i.e., antigen presentation, PD-1, PD-L1 cancer immunotherapy, B cell development, IL-4 signaling, Th1 and Th2 activation pathway, and phagosome maturation). Moreover, in terms of upstream regulators, NDUFAF3 was the most significant (p = 8.6E-04) upstream regulator. Our findings support previous preliminary work suggesting the importance of epigenetic regulation of the immune system in knee pain and the need for future work to understand the epigenetic contributions to chronic pain.

Association of injury after prescription opioid initiation with risk for opioid-related adverse events among older Medicare beneficiaries in the United States: A nested case-control study.

BACKGROUND: Injury, prevalent and potentially associated with prescription opioid use among older adults, has been implicated as a warning sign of serious opioid-related adverse events (ORAEs) including opioid misuse, dependence, and poisoning, but this association has not been empirically tested. The study aims to examine the association between incident injury after prescription opioid initiation and subsequent risk of ORAEs and to assess whether the association differs by recency of injury among older patients. METHODS AND FINDINGS: This nested case-control study was conducted within a cohort of 126,752 individuals aged 65 years or older selected from a 5% sample of Medicare beneficiaries in the United States between 2011 and 2018. Cohort participants were newly prescribed opioid users with chronic noncancer pain who had no injury or ORAEs in the year before opioid initiation, had 30 days or more of observation, and had at least 1 additional opioid prescription dispensed during follow-up. We identified ORAE cases as patients who had an inpatient or outpatient encounter with diagnosis codes for opioid misuse, dependence, or poisoning. During a mean follow-up of 1.8 years, we identified 2,734 patients who were newly diagnosed with ORAEs and 10,936 controls matched on the year of cohort entry date and a disease risk score (DRS), a summary score derived from the probability of an ORAE outcome based on covariates measured prior to cohort entry and in the absence of injury. Multivariate conditional logistic regression was used to estimate ORAE risk associated with any and recency of injury, defined based on the primary diagnosis code of inpatient and outpatient encounters. Among the cases and controls, 68.0% (n = 1,859 for cases and n = 7,436 for controls) were women and the mean (SD) age was 74.5 (6.9) years. Overall, 54.0% (n = 1,475) of cases and 46.0% (n = 1,259) of controls experienced incident injury after opioid initiation. Patients with (versus without) injury after opioid therapy had higher risk of ORAEs after adjustment for time-varying confounders, including diagnosis of tobacco or alcohol use disorder, drug use disorder, chronic pain diagnosis, mental health disorder, pain-related comorbidities, frailty index, emergency department visit, skilled nursing facility stay, anticonvulsant use, and patterns of prescription opioid use (adjusted odds ratio [aOR] = 1.4; 95% confidence interval (CI) 1.2 to 1.5; P < 0.001). Increased risk of ORAEs was associated with current (≤30 days) injury (aOR = 2.8; 95% CI 2.3 to 3.4; P < 0.001), whereas risk of ORAEs was not significantly associated with recent (31 to 90 days; aOR = 0.93; 95% CI 0.73 to 1.17; P = 0.48), past (91 to 180 days; aOR = 1.08; 95% CI 0.88 to 1.33; P = 0.51), and remote (181 to 365 days; aOR = 0.88; 95% CI 0.73 to 1.1; P = 0.18) injury preceding the incident diagnosis of ORAE or matched date. Patients with injury and prescription opioid use versus those with neither in the month before the ORAE or matched date were at greater risk of ORAEs (aOR = 5.0; 95% CI 4.1 to 6.1; P < 0.001). Major limitations are that the study findings can only be generalized to older Medicare fee-for-service beneficiaries and that unknown or unmeasured confounders have the potential to bias the observed association toward or away from the null. CONCLUSIONS: In this study, we observed that incident diagnosis of injury following opioid initiation was associated with subsequent increased risk of ORAEs, and the risk was only significant among patients with injury in the month before the index date. Regular monitoring for injury may help identify older opioid users at high risk for ORAEs.

Circulating polyunsaturated fatty acids, pressure pain thresholds, and nociplastic pain conditions.

OBJECTIVE: Polyunsaturated fatty acids (PUFAs) play a role in pain regulation. This study sought to determine whether free PUFAs found in red blood cells also play a role in nociceptive processing. We examined associations between circulating PUFAs and nociceptive thresholds to noxious mechanical stimuli. We also determined whether nociceptive thresholds were associated with nociplastic pain conditions. METHODS: This cross-sectional study used stored red bloods cells and data from 605 adult participants in the OPPERA-2 study of chronic overlapping pain conditions. In OPPERA-2 adults completed quantitative sensory testing in which pressure algometry measured deep muscular tissue sensitivity at six anatomical sites. Standardized protocols classified adults for presence or absence of five nociplastic pain conditions: temporomandibular disorder, headache, low back pain, irritable bowel syndrome and fibromyalgia. Liquid chromatography tandem mass spectroscopy quantified erythrocyte PUFAs. We conducted three sets of analyses. First, a multivariable linear regression model assessed the association between n-6/n-3 PUFA ratio and the number of overlapping nociplastic pain conditions. Second, a series of 36 multivariable linear regression models assessed covariate-adjusted associations between PUFAs and nociceptive thresholds at each of six anatomical sites. Third, a series of 30 multivariable linear regression models assessed covariate-adjusted associations between nociceptive thresholds at six anatomical sites and each of five pain conditions. RESULTS: In multiple linear regression, each unit increase in n-6/n-3 PUFA ratio was associated with more pain conditions (ß = 0.30, 95% confidence limits: 0.07, 0.53, p = 0.012). Omega-6 linoleic acid and arachidonic acid were negatively associated with lower nociceptive thresholds at three and at five, respectively, anatomical sites. In contrast, omega-3 alpha-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid and the n-6/n-3 PUFA ratio were not associated with nociceptive thresholds at any site. Pain cases had significantly lower nociceptive thresholds than non-case controls at all anatomical sites. CONCLUSION: A higher n-6/n-3 PUFA ratio was associated with more pain conditions. Omega-6 PUFAs may promote a generalized upregulation of nociceptive processing.

Implementing a pragmatic clinical trial to tailor opioids for acute pain on behalf of the IGNITE ADOPT PGx investigators.

Opioid prescribing for postoperative pain management is challenging because of inter-patient variability in opioid response and concern about opioid addiction. Tramadol, hydrocodone, and codeine depend on the cytochrome P450 2D6 (CYP2D6) enzyme for formation of highly potent metabolites. Individuals with reduced or absent CYP2D6 activity (i.e., intermediate metabolizers [IMs] or poor metabolizers [PMs], respectively) have lower concentrations of potent opioid metabolites and potentially inadequate pain control. The primary objective of this prospective, multicenter, randomized pragmatic trial is to determine the effect of postoperative CYP2D6-guided opioid prescribing on pain control and opioid usage. Up to 2020 participants, age ≥8 years, scheduled to undergo a surgical procedure will be enrolled and randomized to immediate pharmacogenetic testing with clinical decision support (CDS) for CYP2D6 phenotype-guided postoperative pain management (intervention arm) or delayed testing without CDS (control arm). CDS is provided through medical record alerts and/or a pharmacist consult note. For IMs and PM in the intervention arm, CDS includes recommendations to avoid hydrocodone, tramadol, and codeine. Patient-reported pain-related outcomes are collected 10 days and 1, 3, and 6 months after surgery. The primary outcome, a composite of pain intensity and opioid usage at 10 days postsurgery, will be compared in the subgroup of IMs and PMs in the intervention (n = 152) versus the control (n = 152) arm. Secondary end points include prescription pain medication misuse scores and opioid persistence at 6 months. This trial will provide data on the clinical utility of CYP2D6 phenotype-guided opioid selection for improving postoperative pain control and reducing opioid-related risks.

Sociodemographic and Clinical Characteristics Associated With Worst Pain Intensity Among Cancer Patients.

AIMS: Patients with cancer have pain due to their cancer, the cancer treatment and other causes, and the pain intensity varies considerably between individuals. Additional research is needed to understand the factors associated with worst pain intensity. Our study aim was to determine the association between worst pain intensity and sociodemographics and cancerspecific factors among patients with cancer. DESIGN: A total of 1,280 patients with cancer recruited from multiple cancer centers over 25 years in the United States were asked to complete a questionnaire that collected respondents' demographic, chronic pain, and cancer-specific information. SETTINGS: Worst, least, and current pain intensities were captured using a modified McGill Pain Questionnaire (pain intensity measured on 0-10 scale). A generalized linear regression analysis was utilized to assess the associations between significant bivariate predictors and worst pain intensity scores.Our study sample was non-Hispanic White (64.5%), non-Hispanic Black (28.3%), and Hispanic (7.2%). On average, participants were 59.4 (standard deviation = 14.4) years old. The average worst pain intensity score was 6.6 (standard deviation = 2.50). After controlling for selected covariates, being Hispanic (ß = 0.6859), previous toothache pain (ß = 0.0960), headache pain (ß = 0.0549), and stomachache pain (ß = 0.0577) were positively associated with worse cancer pain. Notably, year of enrollment was not statistically associated with pain. CONCLUSIONS: Our study sample was non-Hispanic White (64.5%), non-Hispanic Black (28.3%), and Hispanic (7.2%). On average, participants were 59.4 (standard deviation = 14.4) years old. The average worst pain intensity score was 6.6 (standard deviation = 2.50). After controlling for selected covariates, being Hispanic (ß = 0.6859), previous toothache pain (ß = 0.0960), headache pain (ß = 0.0549), and stomachache pain (ß = 0.0577) were positively associated with worse cancer pain. Notably, year of enrollment was not statistically associated with pain. Findings identified being Hispanic and having previous severe toothache, stomachache, and headache pain as significant predictors of worst pain intensity among patients with cancer. After controlling for selected covariates, we did not note statistical differences in worst pain during a 25-year period. Therefore,studies focused on improving the management of pain among patients with cancer should target interventions for those with Hispanic heritage and those with past history of severe common pain.

Associations between pain catastrophizing and resting-state functional brain connectivity: Ethnic/race group differences in persons with chronic knee pain.

Chronic pain is a significant public health problem, and the prevalence and societal impact continues to worsen annually. Multiple cognitive and emotional factors are known to modulate pain, including pain catastrophizing, which contributes to pain facilitation and is associated with altered resting-state functional connectivity in pain-related cortical and subcortical circuitry. Pain and catastrophizing levels are reported to be higher in non-Hispanic black (NHB) compared with non-Hispanic White (NHW) individuals. The current study, a substudy of a larger ongoing observational cohort investigation, investigated the pathways by which ethnicity/race influences the relationship between pain catastrophizing, clinical pain, and resting-state functional connectivity between anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (dlPFC), insula, and primary somatosensory cortex (S1). Participants included 136 (66 NHBs and 70 NHWs) community-dwelling adults with knee osteoarthritis. Participants completed the Coping Strategies Questionnaire-Revised Pain Catastrophizing subscale and Western Ontario and McMaster Universities Osteoarthritis Index. Magnetic resonance imaging data were obtained, and resting-state functional connectivity was analyzed. Relative to NHW, the NHB participants were younger, reported lower income, were less likely to be married, and self-reported greater clinical pain and pain catastrophizing (ps < 0.05). Ethnicity/race moderated the mediation effects of catastrophizing on the relationship between clinical pain and resting-state functional connectivity between the ACC, dlPFC, insula, and S1. These results indicate the NHB and NHW groups demonstrated different relationships between pain, catastrophizing, and functional connectivity. These results provide evidence for a potentially important role of ethnicity/race in the interrelationships among pain, catastrophizing, and resting-state functional connectivity.

The prevalence of comorbid chronic pain conditions among patients with temporomandibular disorders: A systematic review.

BACKGROUND: This systematic review was designed to evaluate the presence of comorbid conditions among patients with temporomandibular disorders (TMDs). TYPES OF STUDIES REVIEWED: The authors reviewed studies that reported the prevalence or incidence of chronic pain conditions or psychiatric disorders (anxiety, mood, personality disorders) among patients with any type of TMD. The authors calculated sample size-weighted prevalence estimates when data were reported in 2 or more studies for the same comorbid condition. RESULTS: A total of 9 prevalence studies and no incidence studies were eligible for review; 8 of the studies examined chronic pain comorbidities. Weighted estimates showed high prevalence of pain comorbidities across studies, including current chronic back pain (66%), myofascial syndrome (50%), chronic stomach pain (50%), chronic migraine headache (40%), irritable bowel syndrome (19%), and fibromyalgia (14%). A single study examined psychiatric disorders and found that current depression was the most prevalent disorder identified (17.5%). CONCLUSIONS AND PRACTICAL IMPLICATIONS: There is a high prevalence of comorbid chronic pain conditions among patients with TMDs, with more than 50% of patients reporting chronic back pain, myofascial syndrome, and chronic stomach pain. Psychiatric disorders among patients with different types of TMDs were studied less commonly in this pain population. Knowledge of the distribution of these and other comorbid disease conditions among patients with different types of TMDs can help dentists and other health care providers to identify personalized treatment strategies, including the coordination of care across medical specialties.

Effects of Patient and Surgery Characteristics on Persistent Postoperative Pain: A Mediation Analysis.

OBJECTIVE: Acute postoperative pain intensity is associated with persistent postsurgical pain (PPP) risk. However, it remains unclear whether acute postoperative pain intensity mediates the relationship between clinical factors and persistent pain. MATERIALS AND METHODS: Participants from a mixed surgical population completed the Brief Pain Inventory and Pain Catastrophizing Scale before surgery, and the Brief Pain Inventory daily after surgery for 7 days and at 30 and 90 days after surgery. We considered mediation models using the mean of the worst pain intensities collected daily on each of postoperative days (PODs) 1 to 7 against outcomes of worst pain intensity at the surgical site endpoints reflecting PPP (POD 90) and subacute pain (POD 30). RESULTS: The analyzed cohort included 284 participants for the POD 90 outcome. For every unit increase of maximum acute postoperative pain intensity through PODs 1 to 7, there was a statistically significant increase of mean POD 90 pain intensity by 0.287 after controlling for confounding effects. The effects of female versus male sex (m=0.212, P=0.034), pancreatic/biliary versus colorectal surgery (m=0.459, P=0.012), thoracic cardiovascular versus colorectal surgery (m=0.31, P=0.038), every minute increase of anesthesia time (m=0.001, P=0.038), every unit increase of preoperative average pain score (m=0.012, P=0.015), and every unit increase of catastrophizing (m=0.044, P=0.042) on POD 90 pain intensity were mediated through acute PODs 1 to 7 postoperative pain intensity. DISCUSSION: Our results suggest the mediating relationship of acute postoperative pain on PPP may be predicated on select patient and surgical factors.

Research design considerations for chronic pain prevention clinical trials: IMMPACT recommendations.

Although certain risk factors can identify individuals who are most likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of preventive interventions, an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses. We provide a detailed examination of 4 models of chronic pain prevention (ie, chronic postsurgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, in many instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (ie, surgery, viral infection, injury, and toxic or noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials.

Quality of opioid prescribing in older adults with or without Alzheimer disease and related dementia.

BACKGROUND: Pain is common among individuals with Alzheimer's disease and related dementias (ADRD), and use of opioids has been increasing over the last decade. Yet, it is unclear to what extent opioids are appropriately prescribed for patients with ADRD and whether the appropriateness of opioid prescribing differs by ADRD status. The objective of this study is to compare the quality of opioid prescribing among patients with or without ADRD who have chronic noncancer pain. METHODS: A nationally representative cohort study of Medicare beneficiaries aged 50 years or older who had chronic pain but who had no cancer, hospice, or palliative care from 2011 to 2015. Four indicators of potentially inappropriate opioid prescribing were measured in patients residing in communities (75,258 patients with and 435,870 patients without ADRD); five indicators were assessed in patients in nursing homes (NHs) (37,117 patients with and 5128 patients without ADRD). Each indicator was calculated as the proportion of eligible patients with inappropriate opioid prescribing in the year after a chronic pain diagnosis. Differences in proportions between ADRD and non-ADRD groups were estimated using a generalized linear model adjusting for covariates through inverse probability weighting. RESULTS: Patients with ADRD versus those without had higher concurrent use of opioids and central nervous system-active drugs (community 44.1% vs 33.3%; NH 58.8% vs 54.1%, both P < 0.001) and no opioids or scheduled pain medications for moderate or severe pain (NH 60.1% vs 52.5%, P < 0.001). The ADRD versus non-ADRD group had higher use of long-term opioids for treating neuropathic pain in communities (21.7% vs 19.5%, P = 0.003) but lower use in NHs (26.9% vs 36.0%, P < 0.001). Use of strong or high-dose opioids when naive to opioids (community 1.5% vs 2.8%; NH 2.5% vs 3.5%) and use of contraindicated opioids (community 0.08% vs 0.12%; NH 0.05% vs 0.21%) were rare for either group. CONCLUSION: Potential inappropriate opioid prescribing in 2 areas of pain care was more common among patients with ADRD than among patients without ADRD in community or NH settings. Further studies aimed at understanding the factors and effects associated with opioid prescribing patterns that deviate from guidelines are warranted.

Slow Dynamics of Acute Postoperative Pain Intensity Time Series Determined via Wavelet Analysis Are Associated With the Risk of Severe Postoperative Day 30 Pain.

BACKGROUND: Evidence suggests that increased early postoperative pain (POP) intensities are associated with increased pain in the weeks following surgery. However, it remains unclear which temporal aspects of this early POP relate to later pain experience. In this prospective cohort study, we used wavelet analysis of clinically captured POP intensity data on postoperative days 1 and 2 to characterize slow/fast dynamics of POP intensities and predict pain outcomes on postoperative day 30. METHODS: The study used clinical POP time series from the first 48 hours following surgery from 218 patients to predict their mean POP on postoperative day 30. We first used wavelet analysis to approximate the POP series and to represent the series at different time scales to characterize the early temporal profile of acute POP in the first 2 postoperative days. We then used the wavelet coefficients alongside demographic parameters as inputs to a neural network to predict the risk of severe pain 30 days after surgery. RESULTS: Slow dynamic approximation components, but not fast dynamic detailed components, were linked to pain intensity on postoperative day 30. Despite imbalanced outcome rates, using wavelet decomposition along with a neural network for classification, the model achieved an F score of 0.79 and area under the receiver operating characteristic curve of 0.74 on test-set data for classifying pain intensities on postoperative day 30. The wavelet-based approach outperformed logistic regression (F score of 0.31) and neural network (F score of 0.22) classifiers that were restricted to sociodemographic variables and linear trajectories of pain intensities. CONCLUSIONS: These findings identify latent mechanistic information within the temporal domain of clinically documented acute POP intensity ratings, which are accessible via wavelet analysis, and demonstrate that such temporal patterns inform pain outcomes at postoperative day 30.

Patient and Procedural Determinants of Postoperative Pain Trajectories.

BACKGROUND: The primary goal of this study was to evaluate patterns in acute postoperative pain in a mixed surgical patient cohort with the hypothesis that there would be heterogeneity in these patterns. METHODS: This study included 360 patients from a mixed surgical cohort whose pain was measured across postoperative days 1 through 7. Pain was characterized using the Brief Pain Inventory. Primary analysis used group-based trajectory modeling to estimate trajectories/patterns of postoperative pain. Secondary analysis examined associations between sociodemographic, clinical, and behavioral patient factors and pain trajectories. RESULTS: Five distinct postoperative pain trajectories were identified. Many patients (167 of 360, 46%) were in the moderate-to-high pain group, followed by the moderate-to-low (88 of 360, 24%), high (58 of 360, 17%), low (25 of 360, 7%), and decreasing (21 of 360, 6%) pain groups. Lower age (odds ratio, 0.94; 95% CI, 0.91 to 0.99), female sex (odds ratio, 6.5; 95% CI, 1.49 to 15.6), higher anxiety (odds ratio, 1.08; 95% CI, 1.01 to 1.14), and more pain behaviors (odds ratio, 1.10; 95% CI, 1.02 to 1.18) were related to increased likelihood of being in the high pain trajectory in multivariable analysis. Preoperative and intraoperative opioids were not associated with postoperative pain trajectories. Pain trajectory group was, however, associated with postoperative opioid use (P < 0.001), with the high pain group (249.5 oral morphine milligram equivalents) requiring four times more opioids than the low pain group (60.0 oral morphine milligram equivalents). CONCLUSIONS: There are multiple distinct acute postoperative pain intensity trajectories, with 63% of patients reporting stable and sustained high or moderate-to-high pain over the first 7 days after surgery. These postoperative pain trajectories were predominantly defined by patient factors and not surgical factors.

Predicting long-term postsurgical pain by examining the evolution of acute pain.

BACKGROUND: Increased acute postoperative pain intensity has been associated with the development of persistent postsurgical pain (PPP) in mechanistic and clinical investigations, but it remains unclear which aspects of acute pain explain this linkage. METHODS: We analysed clinical postoperative pain intensity assessments using symbolic aggregate approximations (SAX), a graphical way of representing changes between pain states from one patient evaluation to the next, to visualize and understand how pain intensity changes across sequential assessments are associated with the intensity of postoperative pain at 1 (M1) and 6 (M6) months after surgery. SAX-based acute pain transition patterns were compared using cosine similarity, which indicates the degree to which patterns mirror each other. RESULTS: This single-centre prospective cohort study included 364 subjects. Patterns of acute postoperative pain sequential transitions differed between the 'None' and 'Severe' outcomes at M1 (cosine similarity 0.44) and M6 (cosine similarity 0.49). Stratifications of M6 outcomes by preoperative pain intensity, sex, age group, surgery type and catastrophising showed significant heterogeneity of pain transition patterns within and across strata. Severe-to-severe acute pain transitions were common, but not exclusive, in patients with moderate or severe pain intensity at M6. CONCLUSIONS: Clinically, these results suggest that individual pain-state transitions, even within patient or procedural strata associated with PPP, may not alone offer good predictive information regarding PPP. Longitudinal observation in the immediate postoperative period and consideration of patient- and surgery-specific factors may help indicate which patients are at increased risk of PPP. SIGNIFICANCE: Symbolic aggregate approximations of clinically obtained, acute postoperative pain intraday time series identify different motifs in patients suffering moderate to severe pain 6 months after surgery.

The Prevalence of Psychiatric and Chronic Pain Comorbidities in Fibromyalgia: an ACTTION systematic review.

Fibromyalgia (FM) is a chronic widespread pain condition that overlaps with multiple comorbid health conditions and contributes to considerable patient distress. The aim of this review was to provide a systematic overview of psychiatric and chronic pain comorbidities among patients diagnosed with FM and to inform the development of recommendations for the design of clinical trials. Thirty-one, cross-sectional, clinical epidemiology studies that evaluated patients diagnosed with FM were included for review. None of the reviewed studies reported on the incidence of these comorbidities. Sample size-weighted prevalence estimates were calculated when prevalence data were reported in 2 or more studies for the same comorbid condition. The most prevalent comorbidity across all studies reviewed was depression/major depressive disorder (MDD) with over half of the patients included having this diagnosis in their lifetime (weighted prevalence up to 63%). In addition, nearly one-third of FM patients examined had current or lifetime bipolar disorder, panic disorder, or post-traumatic stress disorder. Less common psychiatric disorders reported included generalized anxiety disorder, obsessive compulsive disorder, and specific phobias (agoraphobia, social phobia). There were fewer studies that examined chronic pain comorbidities among FM patients, but when evaluated, prevalence was also high ranging from 39% to 76% (i.e., chronic tension-type or migraine headache, irritable bowel syndrome, myofascial pain syndrome, and temporomandibular disorders). The results of the review suggest that depression and chronic pain conditions involving head/jaw pain and IBS were elevated among FM patients compared to other conditions in the clinic-based studies. In contrast, anxiety-related disorders were much less common. Addressing the presence of these comorbid health conditions in clinical trials of treatments for FM would increase the generalizability and real-world applicability of FM research.

Overlap of Five Chronic Pain Conditions: Temporomandibular Disorders, Headache, Back Pain, Irritable Bowel Syndrome, and Fibromyalgia.

AIMS: To assess cohort retention in the OPPERA project and to compare the degree of overlap between pairs of chronic overlapping pain conditions (COPCs) using a cross-sectional analysis of data from 655 adults who completed follow-up in the OPPERA study. METHODS: Subjects were classified for the absence or presence of each of the five COPCs. The extent of overlap beyond chance was quantified using odds ratios, which were calculated using binary logistic regression models. RESULTS: While overlap was the norm, its magnitude varied according to COPC: 51% of people with headache had one or more overlapping COPCs, and this proportion increased to 90% for people with fibromyalgia. The degree of overlap between pairs of COPCs also varied considerably, with odds ratios being greatest for associations between musculoskeletal conditions (fibromyalgia, temporomandibular disorders, and low back pain) and less pronounced for overlap involving headache or IBS. Furthermore, univariate associations between some pairs of COPCs were nullified after adjusting for other COPCs. CONCLUSION: There was greater overlap between fibromyalgia and either temporomandibular disorders or low back pain than between other pairs of COPCs. While musculoskeletal conditions exhibited some features that could be explained by a single functional syndrome, headache and irritable bowel syndrome did not.

Clinical Characteristics of Pain Among Five Chronic Overlapping Pain Conditions.

AIMS: To describe the pain characteristics of five index chronic overlapping pain conditions (COPCs) and to assess each COPC separately in order to determine whether the presence of comorbid COPCs is associated with bodily pain distribution, pain intensity, pain interference, and high-impact pain of the index COPC. METHODS: Data were from a convenience sample of 655 US adults, of whom 388 had one or more of the five COPCs: painful temporomandibular disorders, headache, low back pain, irritable bowel syndrome, and/or fibromyalgia. Data were collected using pain location checklists and self-report questions regarding pain attributes. The contributions of the COPCs to reported pain intensity and interference were assessed using multivariable regression models. RESULTS/CONCLUSION: Heat maps from a pain body manikin illustrated that very little of the body was pain free within these COPCs. All pain attributes were the most severe for fibromyalgia and the least severe for irritable bowel syndrome. Within each index COPC, pain intensity, pain interference, and the proportion of participants with high-impact pain increased with each additional comorbid COPC up to four or more COPCs (including the index COPC) (P < .01). High-impact pain associated with an index COPC was influenced by type and number of comorbid COPCs, largely in a gradient-specific manner.