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In this Review, the phenotypic and genetic markers for common musculoskeletal pain conditions are discussed. Furthermore, the authors propose a heuristic approach to evaluation of the different kinds of markers associated with these conditions, which could enable greater understanding of the underlying pathophysiological processes. Musculoskeletal pain conditions, such as fibromyalgia and low back pain, tend to coexist in affected individuals and are characterized by a report of pain greater than expected based on the results of a standard physical evaluation. The pathophysiology of these conditions is largely unknown, we lack biological markers for accurate diagnosis, and conventional therapeutics have limited effectiveness. Growing evidence suggests that chronic pain conditions are associated with both physical and psychological triggers, which initiate pain amplification and psychological distress; thus, susceptibility is dictated by complex interactions between genetic and environmental factors. Herein, we review phenotypic and genetic markers of common musculoskeletal pain conditions, selected based on their association with musculoskeletal pain in previous research. The phenotypic markers of greatest interest include measures of pain amplification and 'psychological' measures (such as emotional distress, somatic awareness, psychosocial stress and catastrophizing). Genetic polymorphisms reproducibly linked with musculoskeletal pain are found in genes contributing to serotonergic and adrenergic pathways. Elucidation of the biological mechanisms by which these markers contribute to the perception of pain in these patients will enable the development of novel effective drugs and methodologies that permit better diagnoses and approaches to personalized medicine. Key Points Musculoskeletal pain conditions such as low back pain, chronic widespread pain, fibromyalgia and temporomandibular joint disorders are highly prevalent These conditions have measurable phenotypic signatures, which are heterogeneous in nature Musculoskeletal pain conditions have a genetic basis, with both common and rare genetic variants contributing to the conditions and associated endophenotypes Physical and psychological environmental exposures can produce epigenetic effects that alter gene expression, biological pathway activity, and thus the manifestation of clinical phenotypes of musculoskeletal pain conditions Genetic association studies combined with in vitro and in vivo follow-up studies can identify effective therapeutic agents for the treatment of large subpopulations of patients with musculoskeletal pain conditions

Methadone and buprenorphine, effective treatments for opioid use disorder (OUD), also provide analgesia for managing pain, which is commonly experienced by patients with OUD. Limited population-based evidence exists comparing pain-related and treatment outcomes for methadone versus buprenorphine among patients with OUD and comorbid pain. The study aims to examine pain-related and treatment outcomes among Medicare patients with comorbid pain and OUD who initiated methadone or buprenorphine. We conducted a retrospective cohort study with target trial emulation using the 100% Medicare data from 2020 to 2023. Participants included patients with comorbid chronic pain and OUD who initiated methadone or buprenorphine. The key dependent variables were pain-related outcomes that included hospitalization and emergency department (ED) visit due to pain, and treatment outcomes that included opioid overdose and all-cause mortality. Outcomes were assessed 1 year following treatment initiation. Intention-to-treat and per-protocol analyses were conducted to estimate incidence rate ratios (IRRs) for pain-related outcomes and opioid overdose and hazard ratios (HRs) for all-cause mortality. For each outcome, we also calculated the adjusted risk difference (aRD) between the methadone and buprenorphine groups. We identified 49,727 eligible Medicare patients (mean [SD] age, 59.0 [11.6] years; 24,538 [49.3%] female and 25,189 [50.7%] male). Of the identified patients, 16,174 (32.5%) initiated methadone solely administered at opioid treatment programs, and 33,553 (67.5%) initiated buprenorphine primarily prescribed at office-based clinics. Compared with buprenorphine, initiation of methadone was associated with lower adjusted incidence rates of pain-related hospitalization (IRR, 0.64 (95% CI [0.58, 0.70]; P < .001); aRD, -7.2 (95% CI [-8.8 to -5.7]) per 1,000 person-years) and ED visit (IRR, 0.87 (95% CI [0.82, 0.92]; P < .001); aRD, -10.2 (95% CI [-14.4, -5.9]) per 1,000 person-years) in per-protocol analyses, with no difference in opioid overdose (IRR, 1.02 (95% CI [0.93,1.10]; P = .72); aRD, 0.33 (95% CI [-1.5, 2.1]) per 1,000 person-years) and all-cause mortality (HR, 1.06 (95% CI, [0.81-1.39]; P = .66); aRD, 1.1 (95% CI [-1.3, 1.0]) per 1,000 person-years) rates. Similar results were observed in intention-to-treat analyses. Main study limitations included unmeasured confounders and limited generalizability. This population-based cohort study of Medicare patients with comorbid chronic pain and OUD found that methadone administered at opioid treatment programs is associated with reduced hospitalizations and ED visits for pain-related visits while offering treatment outcomes similar to buprenorphine primarily prescribed at office-based clinics. The favorable pain-related outcomes in patients with methadone should be interpreted with caution, as the finding may reflect differences in the underlying patient population, treatment dosing practices, pharmacological properties, and treatment practice settings, which cannot be measured in Medicare data and merit further investigations.

In healthy individuals slow temporal summation of pain or wind-up (WU) can be evoked by repetitive heat-pulses at frequencies of ≥.33 Hz. Previous WU studies have used various stimulus frequencies and intensities to characterize central sensitization of human subjects including fibromyalgia (FM) patients. However, many trials demonstrated considerable WU-variability including zero WU or even wind-down (WD) at stimulus intensities sufficient for activating C-nociceptors. Additionally, few WU-protocols have controlled for contributions of individual pain sensitivity to WU-magnitude, which is critical for WU-comparisons. We hypothesized that integration of 3 different WU-trains into a single WU-response function (WU-RF) would not only control for individuals' pain sensitivity but also better characterize their central pain responding including WU and WD. 33 normal controls (NC) and 38 FM patients participated in a study of heat-WU. We systematically varied stimulus intensities of.4 Hz heat-pulse trains applied to the hands. Pain summation was calculated as difference scores of 1st and 5th heat-pulse ratings. WU-difference (WU-Δ) scores related to 3 heat-pulse trains (44°C, 46°C, 48°C) were integrated into WU-response functions whose slopes were used to assess group differences in central pain sensitivity. WU-aftersensations (WU-AS) at 15 s and 30 s were used to predict clinical FM pain intensity. WU-Δ scores linearly accelerated with increasing stimulus intensity (p<.001) in both groups of subjects (FM>NC) from WD to WU. Slope of WU-RF, which is representative of central pain sensitivity, was significantly steeper in FM patients than NC (p<.003). WU-AS predicted clinical FM pain intensity (Pearson's r = .4; p<.04). Compared to single WU series, WU-RFs integrate individuals' pain sensitivity as well as WU and WD. Slope of WU-RFs was significantly different between FM patients and NC. Therefore WU-RF may be useful for assessing central sensitization of chronic pain patients in research and clinical practice.

Musculoskeletal pain conditions incur high costs and produce significant personal and public health consequences, including disability and opioid-related mortality. Persistence of high-cost health care utilization for musculoskeletal pain may help identify system inefficiencies that could limit value of care. The objective of this study was to identify factors associated with persistent high-cost utilization among individuals seeking health care for musculoskeletal pain. This was a retrospective cohort study of Medical Expenditure Panel Survey data (2008-2013) that included a non-institutionalized, population-based sample of individuals seeking health care for a musculoskeletal pain condition (n = 12,985). Expenditures associated with musculoskeletal pain conditions over two consecutive years were analyzed from prescribed medicine, office-based medical provider visits, outpatient department visits, emergency room visits, inpatient hospital stays, and home health visits. Persistent high-cost utilization was defined as being in the top 15th percentile for annual musculoskeletal pain-related expenditures over 2 consecutive years. We used multinomial regression to determine which modifiable and non-modifiable sociodemographic, health, and pain-related variables were associated with persistent high-cost utilization. Approximately 35% of direct costs for musculoskeletal pain were concentrated among the 4% defined as persistent high-cost utilizers. Non-modifiable variables associated with expenditure group classification included age, race, poverty level, geographic region, insurance status, diagnosis type and total number of musculoskeletal pain diagnoses. Modifiable variables associated with increased risk of high expenditure classification were higher number of missed work days, greater pain interference, and higher use of prescription medication for pain, while higher self-reported physical and mental health were associated with lower risk of high expenditure classification. Health care delivery models that prospectively identify these potentially modifiable factors may improve the costs and value of care for individuals with musculoskeletal pain prone to risk for high-cost care episodes.

The safety of pharmacokinetic opioid-antidepressant interactions may be affected by the sequence in which the drug is initiated. Previous literature showed that initiation of cytochrome P450 (CYP) 2D6-inhibiting versus CYP2D6-neutral antidepressants concomitantly with existing CYP2D6-metabolized opioids (i.e., antidepressant-triggered interaction) was associated with heightened risks of adverse outcomes (e.g., worsening pain). However, little is known about whether and to what extent the risks exist when CYP2D6-metabolized opioids are initiated on existing antidepressants (i.e., opioid-triggered interaction), a more common pattern of concomitant use of these two drugs. The study aims to examine the association of initiation of CYP2D6-metabolized opioids with risks of adverse outcomes among older nursing home residents who already received antidepressants. We conducted a retrospective cohort study using a 100% Medicare nursing home sample linked to Medicare claims and Minimum Data Set (MDS) assessments from January 1, 2010, to December 31, 2021. Participants included long-term care residents 65 years of age or older who initiated CYP2D6-metabolized opioids while already receiving antidepressants for at least 30 days. The key exposure was the use of CYP2D6-inhibiting (versus CYP2D6-neutral) antidepressants concomitantly with CYP2D6-metabolized opioids, with day 1 of antidepressant-opioid concomitant use designated as cohort entry. Patients were followed from cohort entry until the end of 1 year, nursing home discharge, death, or study end (12/31/2021). Seven adverse outcomes included worsening pain, physical function, and depression, and counts of pain-related hospitalizations and emergency department (ED) visits, opioid use disorder (OUD), and opioid overdose (OD). We identified 127,200 older nursing home long-term residents who initiated CYP2D6-metabolized opioids while already receiving antidepressants (mean [SD] age, 84.4 [8.7] years). After covariate adjustment via inverse probability of treatment weighting, use of CYP2D6-inhibiting (versus CYP2D6-neutral) antidepressants concomitantly with CYP2D6-metabolized opioids was associated with a higher risk of worsening pain (relative risk:1.04 [95% CI, 1.02, 1.06]; P < 0.001; risk difference (RD): 1.1% [95% CI, 0.6%, 1.6%]) and a higher incidence rate of pain-related hospitalizations (incidence rate ratio [IRR]:1.13 [95% CI, 1.04, 1.22]; P = 0.003; RD: 1.21 [95% CI, 0.39, 1.89] per 1,000 patient-years) and pain-related ED visits (IRR = 1.17 [95% CI, 1.07, 1.29]; P = 0.003; RD: 0.85 [95% CI, 0.29, 1.41] per 1,000 patient-years), with no difference in physical function, depression, OUD, and OD. Main study limitations included unmeasured confounding and limited generalizability. This cohort study of older nursing home residents showed that initiation of CYP2D6-metabolized opioids on existing CYP2D6-inhibiting (versus CYP2D6-neutral) antidepressants was associated with increased risk of worsening pain, pain-related hospitalizations, and pain-related ED visits, although the relative and absolute risks are small to moderate. Clinicians should be aware of potential worsening pain and hospital and ED visits due to pain among patients who used CYP2D6-metabolizing opioids concomitantly with antidepressants, particularly those with CYP2D6-inhibiting antidepressants.

This study evaluated the contributions of psychological status and cardiovascular responsiveness to racial/ethnic differences in experimental pain sensitivity. The baseline measures of 3,159 healthy individuals-non-Hispanic white (NHW): 1,637, African-American (AA): 1,012, Asian: 299, and Hispanic: 211-from the OPPERA prospective cohort study were used. Cardiovascular responsiveness measures and psychological status were included in structural equation modeling based mediation analyses. Pain catastrophizing was a significant mediator for the associations between race/ethnicity and heat pain tolerance, heat pain ratings, heat pain aftersensations, mechanical cutaneous pain ratings and aftersensations, and mechanical cutaneous pain temporal summation for both Asians and AAs compared to NHWs. HR/MAP index showed a significant inconsistent (mitigating) mediating effect on the association between race/ethnicity (AAs vs. NHWs) and heat pain tolerance. Similarly, coping inconsistently mediated the association between race/ethnicity and mechanical cutaneous pain temporal summation in both AAs and Asians, compared to NHWs. The factor encompassing depression, anxiety, and stress was a significant mediator for the associations between race/ethnicity (Asians vs. NHWs) and heat pain aftersensations. Thus, while pain catastrophizing mediated racial/ethnic differences in many of the QST measures, the psychological and cardiovascular mediators were distinctly restrictive, signifying multiple independent mechanisms in racial/ethnic differences in pain.

Background There exists limited data on the association between unhealthy body weight and chronic pain, and whether this association is explained by frailty status of older adults. Methods We included older adults aged ≥65 years from the 1999–2004 National Health and Nutrition Examination Survey (NHANES). Chronic pain was defined by self-reported pain lasting for ≥3 months in the past year. Body mass index (BMI) was categorized as underweight, normal, overweight, and obese. Participants were dichotomized as frail or non-frail based on a validated frailty index calculated as the proportion of the number of deficits present to a total of 45 possible deficits ascertained in NHANES. We used modified Poisson regression models to estimate prevalence ratios (PRs) and their 95% confidence intervals (CIs). Results Of 3693 older participants, one in six (15.9%) experienced chronic pain, with higher prevalence among the underweight (24.6%) and obese (20.2%) group. Frailty versus non-frailty was independently associated with BMI (PR = 1.25, 95% CI = 1.16–1.36 for underweight; and PR = 1.15, 95% CI = 1.07–1.22 for obese), and chronic pain (PR = 2.84, 95% CI = 2.18–3.69). After adjustment for frailty, the association between BMI and chronic pain decreased from PR = 1.82 to 1.64 for the underweight and 1.41 to 1.33 for the obese group. We did not observe an interaction effect between frailty and BMI. Conclusions Unhealthy body weight was associated with increased chronic pain and the associations were partially explained by frailty status of older adults. Our findings generate hypotheses for further investigations of the interplay of these chronic conditions in older adults.

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. 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. 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.

Chronic musculoskeletal pain including knee osteoarthritis (OA) is a leading cause of disability worldwide. Previous research indicates ethnic-race groups differ in the pain and functional limitations experienced with knee OA. However, when socioenvironmental factors are included in analyses, group differences in pain and function wane. Pain-related brain structures are another area where ethnic-race group differences have been observed. Environmental and sociocultural factors e.g., income, education, experiences of discrimination, and social support influence brain structures. We investigate if environmental and sociocultural factors reduce previously observed ethnic-race group differences in pain-related brain structures. Data were analyzed from 147 self-identified non-Hispanic black (NHB) and non-Hispanic white (NHW), middle and older aged adults with knee pain in the past month. Information collected included health and pain history, environmental and sociocultural resources, and brain imaging. The NHB adults were younger and reported lower income and education compared to their NHW peers. In hierarchical multiple regression models, sociocultural and environmental factors explained 6–37% of the variance in pain-related brain regions. Self-identified ethnicity-race provided an additional 4–13% of explanatory value in the amygdala, hippocampus, insula, bilateral primary somatosensory cortex, and thalamus. In the rostral/caudal anterior cingulate and dorsolateral prefrontal cortex, self-identified ethnicity-race was not a predictor after accounting for environmental, sociocultural, and demographic factors. Findings help to disentangle and identify some of the factors contributing to ethnic-race group disparities in pain-related brain structures. Numerous arrays of environmental and sociocultural factors remain to be investigated. Further, the differing sociodemographic representation of our NHB and NHW participants highlights the role for intersectional considerations in future research.

Objective Lower socioeconomic status (SES) is a risk factor for poorer pain-related outcomes. Further, the neighborhood environments of disadvantaged communities can create a milieu of increased stress and deprivation that adversely affects pain-related and other health outcomes. Socioenvironmental variables such as the Area Deprivation Index, which ranks neighborhoods based on socioeconomic factors could be used to capture environmental aspects associated with poor pain outcomes. However, it is unclear whether the ADI could be used as a risk assessment tool in addition to individual-level SES. Methods The current study investigated whether neighborhood-level disadvantage impacts knee pain-related outcomes above sociodemographic measures. Participants were 188 community-dwelling adults who self-identified as non-Hispanic Black or non-Hispanic White and reported knee pain. Area Deprivation Index (ADI; measure of neighborhood-level disadvantage) state deciles were derived for each participant. Participants reported educational attainment and annual household income as measures of SES, and completed several measures of pain and function: Short-form McGill Pain Questionnaire, Western Ontario and McMaster Universities Osteoarthritis Index, and Graded Chronic Pain Scale were completed, and movement-evoked pain was assessed following the Short Physical Performance Battery. Hierarchical linear regression analyses were used to assess whether environmental and sociodemographic measures (i.e., ADI 80/20 [80% least disadvantaged and 20% most disadvantaged]; education/income, race) were associated with pain-related clinical outcomes. Results Living in the most deprived neighborhood was associated with poorer clinical knee pain-related outcomes compared to living in less deprived neighborhoods ( p s < 0.05). Study site, age, BMI, education, and income explained 11.3–28.5% of the variance across all of the individual pain-related outcomes. However, the ADI accounted for 2.5–4.2% additional variance across multiple pain-related outcomes. Conclusion The ADI accounted for a significant amount of variance in pain-related outcomes beyond the control variables including education and income. Further, the effect of ADI was similar to or higher than the effect of age and BMI. While the effect of neighborhood environment was modest, a neighborhood-level socioenvironmental variable like ADI might be used by clinicians and researchers to improve the characterization of patients’ risk profile for chronic pain outcomes.